OncoTrials - мониторинг клинических исследований

Описание

A Clinical Study on the Safety and Effectiveness of donor derived CD19 CAR-T Cells in the treatment of R/R B-cell acute lymphoblastic leukemia

Критерии включения

• * 1. Age ≥18 years old, gender unlimited;
• * 2. Abnormal B cell immunotyping was CD19 positive;
• * 3. Patients diagnosed with B-cell acute lymphoblastic leukemia by histological or immunotyping;
• * 4. Meets the diagnosis of relapsed or refractory B-cell acute lymphoblastic leukemia (R/R B-ALL) and includes any of the following conditions:
• 1. No CR was obtained after standard chemotherapy;
• 2. CR was induced for the first time, but the duration of CR was less than 12 months;
• 3. R/R B-ALL that does not work after the first or more remedial treatments;
• 4. Two or more relapses;
• * 5. The researchers believed that the patient had been adequately treated, such as auto-HSCT, auto-CART could not be prepared or preparation failed. Autologous CAR-T preparation failure was defined as including too few autologous lymphocytes (/<1×109) or insufficient expansion during preparation or failure to meet the release criteria;
• * 6. Total bilirubin ≤51 ( μmol/L), alanine aminotransferase (ALT)/aspartate aminotransferase (AST) ≤ 3 times the upper limit of normal, creatinine ≤176.8 (μmol/L);
• * 7. Absolute neutrophil count: ≥ 0.5×109/L; Platelet: ≥ 30×109/L; Hemoglobin ≧60g/L;
• * 8. Echocardiography showed left ventricular ejection fraction (LVEF) ≥40%;
• * 9. The estimated survival is more than 3 months;
• * 10. ECOG score 0-2;
• * 11. Women and men who are fertile must consent to the use of appropriate contraception before entering the study, during study participation, and for 6 months after transfusion (the safety of this therapy for the unborn child is not known, with unknown risks);
• * 12. Subjects who are willing to participate in the study are able to understand and have the ability to sign informed consent.

Критерии исключения

• * 1. Known allergies to research preconditioning measures, etc;
• * 2. People with a history of epilepsy or other central nervous system disorders;
• * 3. People with a history of prolonged QT or severe heart disease;
• * 4. Less than 100 days after receiving allogeneic hematopoietic stem cell transplantation;
• * 5. Hiv-infected person;
• * 6. Persons with active hepatitis B or C virus; Those who are not cured have active infections;
• * 7. Insufficient amplification ability (/< 5x) in response to CD3 / CD28 costimulatory signals;
• * 8. Combined use of systemic steroids (e.g., prednisone ≥20mg) within 3 days prior to screening, except for ongoing or intermittent use of topical, inhaled or intranasal steroids within 2 weeks or at present; Or have systemic diseases that require long-term use of immunological agents;
• * 9. Patients who received anti-cancer chemotherapy or other drugs within 2 weeks prior to screening;
• * 10. Any situation that the investigator believes may increase the risk of the subjects or interfere with the study results.

Описание

This study seeks to determine if diagnosing cardiac autonomic dysfunction (AD) can be done remotely with the same accuracy as in-person testing. If so, the identification of AD could happen sooner, facilitating remote studies of the condition and potentially reducing the risk of illness. Childhood cancer survivors, particularly survivors of acute lymphoblastic leukemia (ALL) and Hodgkins`s lymphoma (HL), appear to be at increased risk for AD.

Primary Objectives:

* To determine the sensitivity and specificity of heart rate variability (HRV), measured remotely with biosensor technology (Actigraph LEAP), compared to in-person assessment using the Ewing battery as the reference standard to identify cardiac autonomic dysfunction (AD) among survivors of leukemia and lymphoma.
* To determine the sensitivity and specificity of the Composite Autonomic Symptom Scale 31 (COMPASS31) compared to the Ewing battery to identify AD among leukemia and lymphoma survivors.

Критерии включения

• * Participants enrolled in St. Jude Lifetime Cohort (SJLIFE) />18 years of age.
• * Primary diagnosis of acute lymphoblastic leukemia (ALL), Hodgkin`s Lymphoma (HL), or Non-Hodgkin`s Lymphoma (Non-HL).
• * Not currently taking beta-blocker medication.

Критерии исключения

• * Individuals who cannot speak, read, and/or understand English.
• * Individuals who are unable to follow directions/instructions in order to complete the Ewing battery.
• * Individuals with acute heart failure (new or worsening signs and symptoms of heart failure, including a combination of the following: dyspnea, orthopnea, lower limb swelling, elevated jugular venous pressure, and pulmonary congestion).
• * Women who are currently pregnant.

Описание

This is a clinical trial testing whether the addition of one of two chemotherapy agents, dasatinib or venetoclax, can improve outcomes for children and young adults with newly diagnosed T-cell acute lymphoblastic leukemia and lymphoma or mixed phenotype acute leukemia.

Primary Objective

* To evaluate if the end of induction MRD-negative rate is higher in patients with T-ALL treated with dasatinib compared to similar patients treated with 4-drug induction on AALL1231.
* To evaluate if the end of induction MRD-negative rate is higher in patients with ETP or near-ETP ALL treated with venetoclax compared to similar patients treated with 4-drug induction on AALL1231.

Secondary Objectives

* To assess the event free and overall survival of patients treated with this therapy.
* To compare grade 4 toxicities, event-free survival (EFS) and overall survival (OS) of patients treated with this therapy in induction and reinduction to toxicities of similar patients treated on TOT17.

Критерии включения

• * Enrollment on INITIALL.
• * Age 1-18.99 years at the time of enrollment on INITIALL.
• * T-Acute lymphoblastic leukemia or lymphoblastic lymphoma or mixed phenotype acute leukemia/ lymphoma
• * No prior chemotherapy excluding therapy given on or allowed by INITIALL.
• * Patient has completed no more than 3 days of chemotherapy on INITIALL.
• * Direct bilirubin ≤ 1.5x the upper limit of normal for age
• * Alanine aminotransferase (ALT) ≤ 5x the upper limit of normal for age
• * Calculated glomerular filtration rate (GFR) ≥ 50 mL/min/1.73m/^2 using the Bedside Schwartz equation OR creatinine below or equal to the maximum defined below:
• * Age: 1 to /< 2 years - Maximum serum creatinine (mg/dL): 0.6 (Male), 0.6 (Female)
• * Age: 2 to /< 6 years - Maximum serum creatinine (mg/dL): 0.8 (Male), 0.8 (Female)
• * Age: 6 to /< 10 years - Maximum serum creatinine (mg/dL): 1 (Male), 1 (Female)
• * Age: 10 to /< 13 years - Maximum serum creatinine (mg/dL): 1.2 (Male), 1.2 (Female)
• * Age: 13 to /< 16 years - - Maximum serum creatinine (mg/dL): 1.5 (Male), 1.4 (Female)
• * Age: ≥ 16 years - Maximum serum creatinine (mg/dL): 1.7 (Male), 1.4 (Female)

Критерии исключения

• * Inability or unwillingness to give informed consent/ assent as applicable.
• * Patients with /> Grade 2 neuropathy at the time of enrollment (participant with T-LLy only).
• * Documented malabsorption syndrome or any other condition that precludes receipt of oral medications.
• * Known HIV infection or active hepatitis B (defined as hepatitis B surface antigen-positive) or C (defined as hepatitis C antibody-positive).
• * Pregnant or lactating.
• * For patients of reproductive potential, unwillingness to use highly effective contraception for the duration of protocol therapy and for 90 days afterwards.
• * Receipt of a strong or moderate CYP3A4 inducer such as rifampin, carbamazepine, phenytoin, and St. John`s wort within 7 days of the start of protocol treatment.
• * Consumption of grapefruit, grapefruit products, Seville oranges, or starfruit within 3 days of the start of protocol therapy.

Описание

The goal of this study is to provide sufficient therapy during the time a patients` B-cell Acute Lymphoblastic Leukemia (ALL) or Lymphoblastic Leukemia (LLy) risk category is being determined. The term "risk" refers to the chance of the ALL or LLy coming back after treatment.

Primary Objectives

* To provide sufficient therapy to enable testing of newly diagnosed acute lymphoblastic leukemia/lymphoma and mixed phenotype acute leukemia/lymphoma tumor samples to determine eligibility and appropriate risk stratification for SJALL therapeutic studies.
* To develop a central database of genomic and clinical findings.

Secondary Objectives

* To assess event free and overall survival data of patients enrolled on this study.

Критерии включения

• * Age 1-18.99 years
• * Diagnosis of acute leukemia / lymphoma as below:
• * Acute lymphoblastic leukemia (ALL) with at least 25% bone marrow blasts or definitive evidence of ALL in peripheral blood (in those without an available bone marrow sample).
• * Lymphoblastic lymphoma (LLy) with immunophenotypic evidence of a lymphoblastic population and /<25% bone marrow blasts and less than 1,000 circulating blasts/ microL.
• * Mixed phenotype acute leukemia (MPAL) with or without 25% bone marrow involvement (i.e. patients with either leukemia or lymphoma are eligible).

Критерии исключения

• * Pregnant or breastfeeding
• * Receipt of prior cancer directed therapy with the exclusion of up to 1 dose of intrathecal chemotherapy, 1 dose of vincristine, or emergency radiotherapy due to organ compromising malignant mass. There is no exclusion for prior steroid therapy.
• * Known to be currently ineligible for available SJALL therapeutic studies (e.g. receipt of prohibited therapy, no appropriate SJALL therapeutic study available, enrolled on competing trial, etc.).
• Note: the intention of this exclusion criterion is to only enroll participants who may subsequently enroll on an SJALL therapeutic trial. If participant is screened as a potential participant for subsequent SJALL and later found to be ineligible due to information obtained during INITIALL, this will not make the participant ineligible for INITIALL.
• * Inability or unwillingness of research participant or legal guardian/representative to give written informed consent.
• * Major pre-existing abnormalities such as ataxia telangiectasia, Fanconi anemia, Charcot Marie Tooth, etc.

Описание

This is a Phase II clinical trial testing the use of two antigen-directed therapies, inotuzumab and blinatumomab, as part of induction therapy for children and young adults with newly diagnosed B-cell precursor acute lymphoblastic leukemia and lymphoma.

Primary Objective

* To assess if the flow-cytometry assessed MRD-negative remission rate following an immunotherapy-based Induction in NCI-high risk patients without favorable genetic features is higher than the results of similar patients treated on AALL1131.

Secondary Objectives

* To compare flow-cytometry assessed MRD-negative rates at the end of Induction for patients treated with this therapy compared to similar patients treated on TOT17.
* To compare the rate of significant toxicities in patients treated with this therapy to those treated with standard-risk therapy on TOT17.
* To assess the event free and overall survival of patients treated with this therapy.

Критерии включения

• * Enrollment on INITIALL.
• * Age 1-18.99 years at the time of enrollment on INITIALL.
• * B-Acute lymphoblastic leukemia or lymphoblastic lymphoma.
• * No prior chemotherapy excluding therapy given on or allowed by INITIALL.
• * NCI high-risk (age 10 years or greater or presenting WBC count ≥50,000 cells/microL) or NCI standard-risk and a HR clinical feature as listed below:
• * CNS3 disease (≥5 WBC/microL CSF with blasts present)
• * Testicular involvement of leukemia
• * Steroid pretreatment defined as />24 hours of therapy in the 14 days prior to enrollment on INITIALL if a preceding WBC to define NCI risk is unavailable
• * For lymphoblastic lymphoma, Stage 3-4 disease OR Stage 1-2 disease in patient ages ≥10 years OR HR clinical feature as defined above.
• * Adequate liver function defined as:
• * Direct bilirubin ≤ 1.5x the upper limit of normal for age and alanine transaminase (ALT) ≤ 5x the upper limit of normal for age.
• * Patients with ALT or aspartate transferase (AST) 2.5-5x the upper limit of normal for age are ineligible unless the increase is attributable to hemolysis.
• * Adequate renal function defined as:
• * Calculated glomerular filtration rate (GFR) ≥ 50 mL/min/1.73m/^2 using the Bedside Schwartz equation OR creatinine below or equal to the maximum defined below:
• * Age: 1 to /<2 years; maximum serum creatinine (mg/dL): 0.6 (male and female)
• * Age: 2 to /<6 years; maximum serum creatinine (mg/dL): 0.8 (male and female)
• * Age: 6 to /<10 years; maximum serum creatinine (mg/dL): 1.0 (male and female)
• * Age: 10 to /<13 years; maximum serum creatinine (mg/dL): 1.2 (male and female)
• * Age: 13 to /<16 years; maximum serum creatinine (mg/dL): 1.5 (male); 1.4 (female)
• * Age: ≥16 years; maximum serum creatinine (mg/dL): 1.7 (male); 1.4 (female)
• * Eligibility for inclusion post-induction requires meeting the first 4 Inclusion criteria above AND:
• * Treatment on SJALL23H for Induction OR
• * Lymphoblastic lymphoma, initially treated on an SJALL protocol OR standard (non-protocol) therapy, without a complete response at the end of induction OR
• * NCI-SR ALL at diagnosis and treated with an SJALL protocol OR standard (non-protocol) therapy who have
• * Slow response to therapy (≥0.1% MRD at end of induction for patients with hyperdiploid ALL or ≥0.01% MRD at end of induction for others with ALL) OR
• * HR genetics as defined in the protocol.

Критерии исключения

• * Presence of ETV6::RUNX1 fusion unless also having a HR clinical feature OR slow response to induction therapy.
• * History or presence of clinically relevant central nervous system (CNS) pathology or event such as epilepsy, childhood or adult non-febrile seizure, paresis, aphasia, stroke, severe brain injuries, dementia, Parkinson`s disease, cerebellar disease, organic brain syndrome, or psychosis. History of simple febrile seizure during childhood and presence of CNS leukemia at diagnosis are not exclusions to participation.
• * Active uncontrolled infection.
• * Current active autoimmune disease or history of autoimmune disease with the potential for CNS involvement.
• * History of venoocclusive disease/ sinusoidal obstructive syndrome.
• * Unstable cardiac disease including QTc />500msec.
• * Inability or unwillingness to give informed consent/ assent as applicable.
• * Pregnant or lactating.
• * For patients of reproductive potential, unwillingness to use effective contraception for the duration of protocol therapy.

Описание

Adult patients with refractory or relapsed CD123+ hematologic malignancies, including acute myeloid leukemia, myelodysplastic syndrome, acute lymphoblastic leukemia, or blastic plasmocytoid dentritic cell neoplasm will be recruited in the trial. CART123 cells will be manufatured from blood of each patient. During the production of CAR123 cells, patients may receive appropriate bridging therapy. After cells are produced, participants will undergo a single course of lymphodepleting chemotherapy and receive a single dose of CAR123 T cells. The trial will establish the recommended dose for further studies, either the Maximum Tolerated Dose (MTD) or Maximum Feasible Dose (MFD). Patients must be eligible for hematopoietic stem cell transplantation in order to participate in the trial.

Критерии включения

• 1. Patients with AML, MDS-IB2, BPDCN or ALL positive for CD123 antigen, who meet one of disease specific criteria below:
• a) Patients with AML will be eligible if they meet one of the following criteria:
• i) Patient with refractory AML defined as failure to achieve CR or CRi after at least 2 cycles of induction chemotherapy or 1 cycle of high dose salvage regimen or 4 cycles of venetoclax with azacytidine OR
• ii) Second or subsequent relapse of AML OR
• iii) Relapse after allogeneic HSCT.
• b) Patients with ALL will be eligible if they meet one of following criteria:
• i) disease refractory to or relapsed after CAR-19 cell therapy OR
• ii) CD19 negative relapse ineligible for treatment with TKI inhibitors and inotuzumab ozogamicin.
• c) Patients with BPDCN will be eligible if they meet following criteria:
• i) Refractory or relapsing after chemotherapy with or without allogeneic stem cell transplantation.
• d) Patients with MDS-IB2 will be eligible if they meet one of following criteria:
• i) Disease refractory to at least four cycles of azacytidine or progression on azacytidine-based therapy OR
• ii) Disease refractory to induction chemotherapy OR
• iii) Relapse after haematopoietic stem cell transplantation.
• 2. CD123 expression on malignant cells confirmed by flow cytometry or by immunohistochemistry.
• 3. Age between 18 and 70 years.
• 4. Patient has a suitable donor for allogeneic hematopoietic stem cell transplantation. Workup and clearance of the donor must be completed before IMP administration.
• 5. Patient able to understand and sign informed consent.
• 6. Women of child-bearing potential: negative pregnancy test at enrolment (PSV) and at Visit 1.
• 7. Patient for whom there are no standard-of-care treatments available or such treatment options have been exhausted.

Критерии исключения

• 1. Known hypersensitivity to any component of the IMP.
• 2. Allogeneic HSCT within 3 months prior to IMP administration.
• 3. Severe, uncontrolled active infection.
• 4. Life expectancy /< 8 weeks.
• 5. Respiratory insufficiency (need for oxygen therapy).
• 6. Significant liver impairment: bilirubin /> 50 µmol/L, AST or ALT /> 4 times normal upper limit.
• 7. Acute kidney injury with serum creatinine /> 180 µmol/L, oliguria or need for acute dialysis.
• 8. Heart failure with LVEF /< 50% by echocardiography.
• 9. Presence of active grade 3 - 4 acute GvHD or severe chronic GvHD.
• 10. Serious uncontrolled neurological comorbidity.
• 11. Vaccination with live virus vaccines in the 4 weeks before IMP administration and within 90 days after the IMP dose.
• 12. Women: pregnancy or breast-feeding.
• 13. Subjects of fertile age, unless permanent sexual abstinence is their lifestyle choice:
• 1. female patients of childbearing potential not willing to use a highly effective method of contraception during the study,
• 2. male patients whose sexual partner(s) are women of childbearing potential who are not willing to use a highly effective method of contraception during the study.

Описание

This is a phase I dose-finding trial of an autologous CD22 targeting chimeric antigen receptor (CAR)-T cell product, called CLIC-2201, for participants with relapsed/refractory B cell malignancies. In the proposed trial, eligible enrolled participants will undergo leukapheresis for autologous T cell collection to enable CLIC-2201 manufacturing, followed by lymphodepletion with cyclophosphamide and fludarabine, then intravenous infusion of the autologous CLIC-2201 product. The trial will use the 3+3 design to escalate or de-escalate the dose level of CLIC-2201 administered. Participants will be monitored for safety and tolerability up to day 365 following CLIC-2201 infusion.

The primary objective is to evaluate the safety and tolerability of CLIC-2201 and estimate the maximum tolerated dose (MTD) of CLIC-2201 in B-cell malignancies.

The secondary objectives are to evaluate the (i) feasibility; (ii) anti-tumour activity of CLIC-2201; (iii) and characterize the pharmacokinetic (PK) profile of CLIC-2201.

Exploratory objectives will include: i) characterizing the cellular and humoral immune responses against CLIC-2201 up to 1 year following infusion of CLIC-2201; (ii) characterizing the phenotype and gene expression profile of CLIC-2201 cells; (iii) evaluating immune and tumour cells at baseline and relapse for biomarkers of response or toxicity; (iv) evaluating serum cytokines, circulating tumour DNA (ctDNA) and B cell aplasia as biomarkers of clinical outcomes; and (v) assessing the quality of life.

Критерии включения

• in Cohort A:
• Participants must meet the following criteria to be enrolled on the trial:
• 1. Participants in the cohort A must be 18 years of age or older of age at time of informed consent.
• 2. Participants must provide written informed consent. The investigator is responsible for obtaining written informed assent/consent for the subject after adequate explanation of the study design, anticipated benefits and the potential risks. Subjects should sign the most current REB approved assent/consent prior to any study specific activity or procedure is performed. (Sites will follow their REB board requirements for consenting).
• 3. Participants must have a relapsed or refractory B cell lymphoma, including one of the following:
• 1. diffuse large B-cell lymphoma (DLBCL) not otherwise specified (NOS),
• 2. high grade B cell lymphoma NOS,
• 3. high grade B cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements,
• 4. primary mediastinal large B-cell lymphoma (PMBCL),
• 5. aggressive B cell lymphoma transformed from an indolent lymphoma,
• 6. mantle cell lymphoma (MCL),
• 4. Participants must have refractory or relapsed disease, defined as one of the following:
• 1. Relapse or refractory disease after at least 2 lines of therapy, OR
• 2. Any relapse after autologous or allogeneic hematopoietic cell transplantation (HCT), OR
• 3. Any relapse after CAR-T cell therapy.
• 5. Participants must have adequate organ function at enrolment, defined as:
• 1. Left ventricular ejection fraction (LVEF) ≥40%,
• 2. Creatinine clearance using Cockcroft-Gault of /> 30 mL/min, AND
• 3. ALP/ALT /< 5X upper limit of normal (ULN), conjugated bilirubin /< 2X ULN, and no evidence or history of liver cirrhosis.
• 6. Participants must have Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2 or Karnofsky Score ≥50%.
• 7. Females of child-bearing potential and sexually active males must agree to use a highly effective contraception method (see section 5.4) through to at least one year following administration of the CLIC-2201 product.
• 8. Participants with accessible disease, willingness to undergo a tumour biopsy at enrolment. For participants with a recent (within 3 months) tumor biopsy, access to the archival biopsy is acceptable.
• Inclusion Criteria in Cohort B:
• 1. Participants in the cohort B must be between 1-21 years of age at the time of consent.
• 2. Parent or legal guardian of the participant signed the informed consent and the participant`s assent/consent is obtained (if applicable). The investigator is responsible for obtaining written informed assent/consent for the subject or legally acceptable representative (e.g. parent, legal guardian) after adequate explanation of the study design, anticipated benefits and the potential risks. Subjects should sign the most current REB approved assent/consent prior to any study specific activity or procedure is performed. (Sites will follow their REB board requirements for consenting).
• 3. Participants must have a relapsed or refractory B cell acute lymphoblastic leukemia (B-ALL).
• 4. Participants must have refractory or relapsed disease, defined as one of the following:
• 1. Relapse or refractory disease after at least 2 lines of therapy, OR
• 2. Any relapse after autologous or allogeneic hematopoietic cell transplantation (HCT), OR
• 3. Any relapse after CAR-T cell therapy.
• 5. Participants in cohort B and/or those who have received CD22 targeted therapy must have documentation of CD22 tumour expression within the 6 months prior to study screening, and after any prior CD22 directed therapy (if applicable).
• 6. Participants must have adequate organ function at enrolment, defined as:
• 1. Left ventricular ejection fraction (LVEF) ≥45%,
• 2. Creatinine clearance using Cockcroft-Gault or Schwartz equation of /> 30 mL/min, AND
• 3. ALP/ALT /< 5X upper limit of normal (ULN), conjugated bilirubin /< 2X ULN, and no evidence or history of liver cirrhosis.
• 7. Participants must have a Karnofsky or Lansky Score ≥50%.
• 8. Participants in reproductive age must agree to use a highly effective contraception method (see section 5.4) through to at least one year following administration of the CLIC-2201 product.
• 9. Participants willingness to undergo a bone marrow biopsy at enrolment.

Критерии исключения

• 1. Any uncontrolled or serious active infection at the time of enrolment.
• 2. Active autoimmune disease requiring immunosuppressive therapy within 4 weeks of enrolment.
• 3. Live vaccine ≤6 weeks prior to enrolment
• 4. Active Graft Versus Host Disease (GVHD) requiring systemic immunosuppressive therapy within 4 weeks of enrolment.
• 5. Treatment with any of the following in the specified time period before leukapheresis:
• 1. Allogeneic HCT within 3 months,
• 2. Autologous HCT within 3 months,
• 3. CD19 CAR-T cell infusion within 3 months,
• 4. Donor lymphocyte infusion (DLI) within 3 months,
• 5. Bendamustine within the last 6 months,
• 6. Any investigational agent within 30 days or 5 half-lives (whichever is shorter),
• 7. Systemic administration of therapeutic dose corticosteroids (/>20 mg/day prednisone or equivalent for adults and ≥ 12 mg/m2/day for paediatric participants) within 7 days prior to leukapheresis.
• 8. Immunosuppressive therapies (i.e., calcineurin inhibitors, methotrexate, mycophenolate, rapamycin) within 4 weeks.
• 9. Oral chemotherapy agents (i.e., venetoclax) within 5 half-lives. An exception to this is that bruton tyrosine kinase (BTK) inhibitors like ibrutinib can be continued in participants with mantle cell lymphoma throughout the trial period.
• 6. Other concurrent malignancy or a prior malignancy treated within the past 2 years, except carcinoma in situ of the skin or cervix treated with curative intent and with no evidence of active disease.
• 7. Concomitant genetic syndrome associated with bone marrow failure such as Fanconi anemia, Kostmann syndrome, Shwachman syndrome or any other known bone marrow failure or immunodeficiency syndrome.
• 8. Active (confirmed by PCR) hepatitis B or hepatitis C at time of screening confirmed by PCR.
• 9. Any Human Immunodeficiency Virus (HIV) infection at time of screening.
• 10. Hypersensitivity to fludarabine or cyclophosphamide.
• 11. Any allergy to gentamycin or its derivatives
• 12. Pregnant or nursing participants.

Описание

In this study, CD19/CD22 dual-target CAR-T therapy will be carried out among children patients who are still positive after induction remission, and subsequent chemotherapy will continue after CAR-T cells exert their functions. This study intends to use retroviral vector-based tandem CAR-T cells targeting CD19/CD22 to treat MRD-positive ALL. The CAR-T cells were provided by Shenzhen Cell Valley. The results of the research team from Stanford University School of Medicine in the United States have already demonstrated the feasibility and safety of producing bispecific CD19/CD22.BB.z-CAR T cells in a closed system as well as the high clinical activity shown in the treatment of CAR19-resistant B-ALL (B-lineage acute lymphoblastic leukemia) and LBCL (Large B-cell lymphoma). The investigators look forward to expanding the application of CAR-T cells in MRD positive B-ALL through this clinical study on safety and efficacy and greatly improving the prognosis of children patients with this type of B-ALL.

Критерии включения

• 1. Parents or legal guardians fully understand, are informed of this study and sign the informed consent form (ICF); are willing to follow and can complete all test procedures.
• 2. Chinese children aged 1-18 years old at the time of screening, regardless of gender, with a body weight ≥ 10 kg.
• 3. Bone marrow examination confirms that MRD is still positive on the 46th day after induction remission.
• 4. Tumor cells in the bone marrow (BM) or peripheral blood (PB) express CD19/CD22 within 3 months before screening.
• 5. Good organ function, which needs to meet the following criteria: (1)ALT ≤ 5 times the upper limit of normal value (ULN); (2)total bilirubin ≤ 2 times ULN (Gilbert`s syndrome ≤ 3 times ULN); (3)without /> grade 1 dyspnea when not inhaling oxygen, and oxygen saturation /> 95%; (4)left ventricular ejection fraction (LVEF) ≥ 50%; (5)serum creatinine ≤ 1.5 times ULN.
• 6. Karnofsky score (≥ 16 years old) ≥ 70 or Lansky (/< 16 years old) score ≥ 50.
• 7. Expected survival period of at least 12 weeks.
• 8. Have sufficient venous access (for apheresis or venous blood sampling), and have no other contraindications for blood cell separation.

Критерии исключения

• 1. Have genetic diseases, except Down syndrome.
• 2. Have a history of other malignancies or have other malignancies simultaneously.
• 3. Meet any of the following conditions: (1)hepatitis B surface antigen (HBsAg) positive or HBV DNA quantification higher than the upper limit of normal value; (2)hepatitis C antibody (HCV Ab) positive and HCV RNA quantification higher than the upper limit of normal value; (3)human immunodeficiency virus antibody (HIV-Ab) positive; (4)Treponema pallidum antibody (TP-Ab) positive; (5)EBV DNA higher than the upper limit of normal value; (6)cytomegalovirus DNA higher than the upper limit of normal value.
• 4. Have or are suspected to have uncontrolled or require intravenous drug treatment for fungal, bacterial, viral or other infections.
• 5. Long-acting G-CSF is prohibited within 21 days before screening, and short-acting G-CSF is prohibited within 7 days before screening.
• 6. Have active central nervous system leukemia.
• 7. Are allergic to albumin and aminoglycoside antibiotics.
• 8. Have undergone organ transplantation (except hematopoietic stem cell transplantation).
• 9. Have participated in other interventional clinical studies within 3 months before screening (received active test drug treatment), or intend to participate in another clinical trial or receive anti-tumor treatment other than that specified in the protocol during the entire study period.
• 10. Cannot tolerate chemotherapy and cytokine storm due to impaired function of important organs.
• 11. Other situations that the investigator deems not suitable for participating in this clinical trial.

Описание

Precursor B cell acute lymphoblastic leukemia (B-ALL) is an aggressive type of leukemia, with high relapse rate and poor long term survival in adults. Philadelphia chromosome positive (Ph+) ALL is defined as ALL with translocation between chromosomes 9 and 22. And t(9;22)(q34;q11) is the most common chromosomal abnormality in ALL. Before the emergence of TKI, the prognosis of Ph+ ALL was extremely poor, and the long-term survival rate was only 10%-35%. Ph+ ALL accounts for about 30% of adult ALL. In this study, the investigators propose a treatment approach that combines Venetoclax with Olverembatinib and Predinisone in Ph+ B-ALL adults. The study aims to answer the safety and efficacy of this treatment regimen, and further improve the survival for those participants.

Критерии включения

• 1. Before enrollment, the patient must be diagnosed with de novo precursor B-cell acute lymphoblastic leukemia and positive for Philadelphia chromosome (presence of t(9;22) and/or BCR::ABL1 positive and/or FISH positive). The diagnostic criteria refer to the 2022 WHO classification;
• 2. Age ≥ 18 years;
• 3. Eastern Cooperative Oncology Group (ECOG) performance status score of 0-2;
• 4. Expected survival time ≥ 3 months;
• 5. No organ dysfunction that would restrict the use of this protocol during the screening period;
• 6. Understand the study and sign the informed consent form.
• 7. Men, women of childbearing age (only postmenopausal women who have been menopausal for at least 12 months can be considered infertile), and their partners voluntarily take effective contraceptive measures deemed effective by the investigator during the treatment period and for at least 12 months after the last dose of the study drug.

Критерии исключения

• 1. Accelerated phase or blast crisis of chronic myeloid leukemia;
• 2. Subjects with involvement of the central nervous system (CNS) or accompanied by extramedullary lesions;
• 3. Subjects who have received systemic anti-leukemia treatment (including but not limited to TKI, radiotherapy or chemotherapy, except for the allowed pretreatment);
• 4. Subjects with a history of myocardial infarction within 12 months, or have clinical manifestations of heart disease (including but not limited to unstable angina pectoris, congestive heart failure, uncontrolled hypertension and uncontrolled arrhythmia, etc.); left ventricular ejection fraction (LVEF) on echocardiography /<50%;
• 5. Diseases with abnormal functions of organs such as lung, liver, and kidney that may limit the patient`s participation in this trial (including but not limited to severe infection, uncontrolled diabetes, active tuberculosis, asthma, COPD, bronchiectasis, etc.);
• 6. History of other malignancies within the past 5 years, excluding localized thyroid cancer and in situ skin cancer;
• 7. Serum total bilirubin /> 1.5 ULN (upper limit of normal); ALT or AST /> 2.5 ULN; serum creatinine /> 1.5 ULN;
• 8. Known HIV infection;
• 9. Conditions affecting the use of the study drug as assessed by the investigator;
• 10. Unable to understand or comply with the study protocol.

Описание

This is a prospective, multicenter, real-world study of 500 participants with childhood acute lymphoblastic leukemia who are scheduled to receive dolasetron mesylate injection for prophylaxis against chemotherapy-induced nausea and vomiting.

This study did not make any decision or process intervention for clinical antitumor therapy. The study plans to observe the control of nausea and vomiting within 120 h (D1-D5) after receiving induction chemotherapy and the safety within 7 days (or until this discharge, whichever occurs first).

During the whole study, demographic data, history of motion sickness, ECOG score, complications, name and dosage of anti-tumor therapy drugs, this antiemetic regimen, nausea and vomiting, rescue therapy drugs, combined drugs and adverse events were recorded.

Критерии включения

• 1. Age 2/~17 years old
• 2. The diagnosis of acute lymphoblastic leukemia was analyzed by comprehensive examination of bone marrow cell morphology, immune typing, cytogenetics and molecular biology.
• 3. The subjects plan to receive induced remission therapy such as VDLP/VDLD+CAM, multicenter CCCG ALL 2015 protocol, SCCCG-ALL-2023 protocol, etc. according to Guidelines for Diagnosis and Treatment of Childhood acute lymphoblastic Leukemia (2018 Edition) for the first time
• 4. Eastern Cooperative Oncology Group (ECOG) performance status (PS) score 0-2
• 5. Expected to survive for more than 3 months
• 6. Subject or guardian can read, understand and complete subject diary.

Критерии исключения

• 1. Allergic to Dolasetron mesylate injection and its excipients
• 2. Patients with prolonged QTc interval (QT interval ≥460 ms)
• 3. Other conditions considered by the researchers not to be included in the group.

Описание

This phase I trial tests the safety, side effects, best dose and effectiveness of revumenib in treating patients with acute leukemia after allogeneic stem cell transplant. Revumenib is in a class of medications called menin inhibitors. Revumenib targets and binds to the protein menin, thereby preventing the interaction between menin and the mixed lineage leukemia protein. Disrupting this interaction prevents the activation of specific genes that fuel the development of leukemia cells and inhibits the survival, growth, and production of certain kinds of leukemia cells. Giving revumenib may be safe, tolerable, and/or effective in treating patients with acute leukemia after allogeneic stem cell transplant.

Критерии включения

• * PATIENTS WHO ARE SCHEDULED TO UNDERGO HEMATOPOIETIC CELL TRANSPLANTATION (HCT) OR THOSE WHO HAVE UNDERGONE HCT: Documented informed consent of the participant and/or legally authorized representative
• * PATIENTS WHO ARE SCHEDULED TO UNDERGO HCT OR THOSE WHO HAVE UNDERGONE HCT: Agreement to allow the use of archival tissue from diagnostic tumor biopsies; if unavailable, exceptions may be granted with study principal investigator (PI) approval
• * PATIENTS WHO ARE SCHEDULED TO UNDERGO HCT OR THOSE WHO HAVE UNDERGONE HCT: Participant is willing and able to adhere to the study visit schedule and other protocol requirements
• * PATIENTS WHO ARE SCHEDULED TO UNDERGO HCT OR THOSE WHO HAVE UNDERGONE HCT: Age: />= 2 years
• * PATIENTS WHO ARE SCHEDULED TO UNDERGO HCT OR THOSE WHO HAVE UNDERGONE HCT: Have a date for transplant within the next 4 weeks or have received transplant within the last 4 months
• * PATIENTS WHO ARE SCHEDULED TO UNDERGO HCT OR THOSE WHO HAVE UNDERGONE HCT: Participant was diagnosed with an acute leukemia as defined by the World Health Organization (WHO) 5th edition criteria for acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), or acute leukemia with ambiguous lineage
• * PATIENTS WHO ARE SCHEDULED TO UNDERGO HCT OR THOSE WHO HAVE UNDERGONE HCT: Participant must meet one of the following disease characteristics:
• * Confirmed NPM1m AML with at least one of the following additional characteristics
• * FLT3-ITD co-mutation
• * Pre-transplant MRD+ disease by flow cytometry or real time polymerase chain reaction (qPCR)
• * Requires more than one AML induction regimen to acquire complete response (CR)1
• * In second or later complete remission
• * Confirmed KMT2Ar acute leukemia obtained by fluorescence in situ hybridization (11q23 MLL-break apart fluorescence in situ hybridization /[FISH/]) or next-generation sequencing (NGS)
• * PATIENTS WHO ARE SCHEDULED TO UNDERGO HCT OR THOSE WHO HAVE UNDERGONE HCT: Any donor (sibling, unrelated, mismatched related/unrelated, cord and haploidentical) or graft source (peripheral blood /[PB/] stem cell or bone marrow /[BM/]) will be included
• * PATIENTS WHO ARE SCHEDULED TO UNDERGO HCT OR THOSE WHO HAVE UNDERGONE HCT: Conditioning regimen: investigator`s choice based on center guidelines
• * PATIENTS WHO ARE SCHEDULED TO UNDERGO HCT OR THOSE WHO HAVE UNDERGONE HCT: GVHD prophylaxis: investigator`s choice based on center guidelines
• * PATIENTS WHO ARE SCHEDULED TO UNDERGO HCT OR THOSE WHO HAVE UNDERGONE HCT: Patients receiving menin inhibitors prior to alloHCT are eligible
• * PATIENTS WHO ARE SCHEDULED TO UNDERGO HCT OR THOSE WHO HAVE UNDERGONE HCT: Negative serum pregnancy test for female patients of childbearing potential who have already undergone alloHCT
• * PATIENTS WHO ARE SCHEDULED TO UNDERGO HCT OR THOSE WHO HAVE UNDERGONE HCT: If a female of childbearing potential, must be willing to use a highly effective method of contraception or double barrier method from the time of enrollment through 120 days following the last study drug dose
• * PATIENTS WHO ARE SCHEDULED TO UNDERGO HCT OR THOSE WHO HAVE UNDERGONE HCT: If male of childbearing potential, must agree to use barrier contraception from the time of enrollment through 120 days following the last study drug dose
• * Childbearing potential defined as not being surgically sterilized (men and women) or have not been free from menses for /> 1 year (women only)
• * PATIENTS WHO HAVE NOT YET UNDERGONE HCT: Participant has an Eastern Cooperative Oncology Group (ECOG) =/< 2 or Karnofsky Performance Status (KPS) />= 70, or a Lansky Performance Score of />= 70 (if aged /< 18 years)
• * PATIENTS WHO HAVE NOT YET UNDERGONE HCT: Participant must be eligible for alloHCT by City of Hope (COH) standard operating procedure (SOP) guidelines
• * CRITERIA TO PROCEED TO MAINTENANCE THERAPY WITH REVUMENIB: Patients should be in complete remission (CR) by day + 30 (± 7 days) post-HCT BM biopsy
• * CRITERIA TO PROCEED TO MAINTENANCE THERAPY WITH REVUMENIB: No evidence of active or uncontrolled infection at the time of start of revumenib therapy
• * CRITERIA TO PROCEED TO MAINTENANCE THERAPY WITH REVUMENIB: Participant has an ECOG =/< 2 or KPS />= 70, or Lansky Performance Score of />= 70 if aged /< 18 years
• * CRITERIA TO PROCEED TO MAINTENANCE THERAPY WITH REVUMENIB: No active grade 2-4 acute GVHD (prednisone dose of =/< 0.5 mg/kg daily is allowed)
• * CRITERIA TO PROCEED TO MAINTENANCE THERAPY WITH REVUMENIB: Hemoglobin (Hgb) />= 9. Transfusion or growth factors are not allowed to achieve these levels
• * CRITERIA TO PROCEED TO MAINTENANCE THERAPY WITH REVUMENIB: Platelets />= 75 thousand (k). Transfusion or growth factors are not allowed to achieve these levels
• * CRITERIA TO PROCEED TO MAINTENANCE THERAPY WITH REVUMENIB: Patients must be fully engrafted after HCT, defined as absolute neutrophil count (ANC) />= 500 for 3 days. Patients may NOT be given granulocyte colony-stimulating factor (GCSF) to meet eligibility criteria; however, they may receive GCSF after start of treatment
• * CRITERIA TO PROCEED TO MAINTENANCE THERAPY WITH REVUMENIB: No morphologic evidence of relapse post-HCT (pre-HCT MRD+ is)
• * CRITERIA TO PROCEED TO MAINTENANCE THERAPY WITH REVUMENIB: Participant is between day + 50 and + 150 after first alloHCT with no morphologic evidence of relapse post-HCT
• * CRITERIA TO PROCEED TO MAINTENANCE THERAPY WITH REVUMENIB: Total bilirubin =/< 1.5 x upper limit of normal (ULN) (unless considered to be due to Gilbert`s syndrome)
• * Note: Participants who are /< 75 years of age may have a bilirubin of =/< 3.0 x ULN. Patients with abnormal liver function tests (LFTs) in the context of active GVHD will not be included
• * CRITERIA TO PROCEED TO MAINTENANCE THERAPY WITH REVUMENIB: Aspartate aminotransferase (AST) =/< 2.5 x ULN
• * CRITERIA TO PROCEED TO MAINTENANCE THERAPY WITH REVUMENIB: Alanine aminotransferase (ALT) =/< 2.5 x ULN
• * CRITERIA TO PROCEED TO MAINTENANCE THERAPY WITH REVUMENIB: QTc using Fridericia`s correction (QTcF) =/< 450 msec (males) or =/< 470 msec (females)
• * CRITERIA TO PROCEED TO MAINTENANCE THERAPY WITH REVUMENIB: Ejection fraction (EF) of />= 50% by echocardiogram or multigated acquisition (MUGA) scan
• * CRITERIA TO PROCEED TO MAINTENANCE THERAPY WITH REVUMENIB: Creatinine clearance of />= 60 mL/min per 24 hour urine test or the Cockcroft-Gault formula

Критерии исключения

• * PATIENTS WHO ARE SCHEDULED TO UNDERGO HCT OR THOSE WHO HAVE UNDERGONE HCT: Prior diagnosis of acute promyelocytic leukemia
• * PATIENTS WHO ARE SCHEDULED TO UNDERGO HCT OR THOSE WHO HAVE UNDERGONE HCT: Participants who are unable to take a strong CYP3A4 inhibitor such as voriconazole or posaconazole. Note: Patients must be taking a strong CYP3A4 inhibiting antifungal at least 7 days prior to starting revumenib cycle 1
• * PATIENTS WHO ARE SCHEDULED TO UNDERGO HCT OR THOSE WHO HAVE UNDERGONE HCT: Patients requiring the concurrent use of medications known or suspected to prolong the QT/corrected QT (QTc) interval, with the exception of drugs with low risk of QT/QTc prolongation that are used as standard supportive therapies (e.g., diphenhydramine, famotidine, ondansetron, bactrim, tacrolimus, azoles)
• * PATIENTS WHO ARE SCHEDULED TO UNDERGO HCT OR THOSE WHO HAVE UNDERGONE HCT: History of or any concurrent condition, therapy, laboratory abnormality, or allergy to excipients that in the investigator`s opinion might confound the results of the study, interfere with the patient`s participation for the full duration of the study, or is not in the best interest of the patient to participate
• * PATIENTS WHO ARE SCHEDULED TO UNDERGO HCT OR THOSE WHO HAVE UNDERGONE HCT: Prospective participants who, in the opinion of the investigator, may not be able to comply with all study procedures (including compliance issues related to feasibility/logistics)
• * PATIENTS WHO HAVE NOT YET UNDERGONE HCT: Participant has detectable human immunodeficiency virus (HIV) viral load within the previous 6 months (must have viral load testing prior to study enrollment if participant has a known history of HIV 1/2 antibodies)
• * PATIENTS WHO HAVE NOT YET UNDERGONE HCT: Active uncontrolled hepatitis B or C, defined as hepatitis B or C virus (HBV/HCV) surface antigen positive and HBV/HCV core antibody positive, with positive HBV/HCV deoxyribonucleic acid (DNA), or HBV/HCV positive core antibody alone with positive HBV/HCV DNA
• * PATIENTS WHO HAVE NOT YET UNDERGONE HCT: Hepatitis C, defined as positive HCV antibody with reflex to positive HCV ribonucleic acid (RNA)
• * PATIENTS WHO HAVE NOT YET UNDERGONE HCT: Other active malignancy; patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial
• * CRITERIA TO PROCEED TO MAINTENANCE THERAPY WITH REVUMENIB: Active grade II-IV acute GVHD, chronic GVHD (moderate or severe) and/or requiring systemic steroids with prednisone dose equivalent of />= 0.25mg/kg within 4 weeks of revumenib administration
• * CRITERIA TO PROCEED TO MAINTENANCE THERAPY WITH REVUMENIB: Participant has active uncontrolled systemic fungal, bacterial, or viral infection (defined as ongoing signs/symptoms related to the infection without improvement despite appropriate antibiotics, antiviral therapy, and/or other treatment)
• * CRITERIA TO PROCEED TO MAINTENANCE THERAPY WITH REVUMENIB: Participants who are unable to take a strong CYP3A4 inhibitor such as voriconazole or posaconazole. Note: Patients must be taking a strong CYP3A4 inhibiting antifungal at least 7 days prior to starting revumenib in cycle 1
• * CRITERIA TO PROCEED TO MAINTENANCE THERAPY WITH REVUMENIB: Patients requiring the concurrent use of medications known or suspected to prolong the QT/QTc interval, with the exception of drugs with low risk of QT/QTc prolongation that are used as standard supportive therapies (e.g., diphenhydramine, famotidine, ondansetron, bactrim, tacrolimus, and azoles)
• * CRITERIA TO PROCEED TO MAINTENANCE THERAPY WITH REVUMENIB: Female participant who is pregnant or lactating
• * CRITERIA TO PROCEED TO MAINTENANCE THERAPY WITH REVUMENIB: Participant has a malabsorption syndrome or other condition that precludes enteral route of administration
• * CRITERIA TO PROCEED TO MAINTENANCE THERAPY WITH REVUMENIB: Participant has chronic respiratory disease that requires continuous oxygen, or significant renal, neurologic, psychiatric, endocrinologic, metabolic, immunologic, hepatic, cardiovascular disease, or any other medical condition that in the opinion of the investigator would adversely affect participation in this study
• * CRITERIA TO PROCEED TO MAINTENANCE THERAPY WITH REVUMENIB: Cardiac disease: any of the following within the 6 months prior to study entry:
• * Myocardial infarction
• * Uncontrolled/unstable angina
• * Congestive heart failure (New York Heart Association Classification class />= II)
• * Life-threatening or uncontrolled arrhythmia
• * Cerebrovascular accident
• * Transient ischemic attack
• * CRITERIA TO PROCEED TO MAINTENANCE THERAPY WITH REVUMENIB: Gastrointestinal disease:
• * Any gastrointestinal issue of the upper gastrointestinal (GI) tract likely to affect oral drug absorption or ingestion (e.g., gastric bypass, gastroparesis, etc.)
• * Cirrhosis with a Child-Pugh score of B or C
• * CRITERIA TO PROCEED TO MAINTENANCE THERAPY WITH REVUMENIB: GVHD: Signs or symptoms of acute or cGVHD /> grade 0 within 4 weeks of enrollment. Patients may be on physiological doses of steroids

Описание

This investigator-initiated, prospective, single-arm, open-label, single-center clinical study aims to evaluate the efficacy and safety of Inaticabtagene autoleucel (Inati-cel;CNCT19)CD19 CAR-T theraphy in adults B-ALL that are in first complete remission(CR1) with minimal residual disease (MRD) positivity. This trial will enroll 20 participants for leukapheresis and treatment with lymphodepleting chemotherapy followed by Inati-cel CAR T cell infusion. Patients will be assessed for MRD negativity rate(at months 1, 2, 3, and 6 after CAR-T transfusion), duration of MRD negativity, overall survival(OS), relapse-free survival(RFS), pharmacokinetics(PK) characteristics, incidence of adverse events(AEs), exploratory biomarker research at 1,2,3,6,9,12,15,18,21 and 24- months post Inati-cel infusion.

Критерии включения

• * Age between ≥16 and ≤70 years at screening, no gender restrictions
• * ECOG score of 0-1 at screening
• * Newly diagnosed Ph-negative B-ALL, MRD positive(bone marrow MRD ≥0.01% by flow cytometry) in CR1 (with /<5% blasts in bone marrow, no blasts in peripheral blood, no extramedullary disease)after induction chemotherapy or consolidation chemotherapy.
• * Newly diagnosed Ph-positive B-ALL, MRD positive(bone marrow MRD ≥0.01% by flow cytometry or BCR-ABL1 />0.01% detected by qPCR) in CR1 (with /<5% blasts in bone marrow, no blasts in peripheral blood, no extramedullary disease) .
• * At diagnosis of B-ALL,CD19 expression of leukemic cells is positive by flow cytometry in bone marrow or peripheral blood.
• * Appropirate organ function, meeting the following criteria:
• 1. Aspartate aminotransferase (AST) ≤3 times the upper limit of normal (ULN);
• 2. Alanine aminotransferase (ALT) ≤3 times ULN;
• 3. Total bilirubin ≤2 times ULN (for patients with Gilbert`s syndrome, total bilirubin ≤3.0 times ULN and direct bilirubin ≤1.5 times ULN);
• 4. Serum creatinine ≤1.5 times ULN, or creatinine clearance ≥60 mL/min (using the Cockcroft-Gault formula);
• 5. International Normalized Ratio (INR) ≤1.5 times ULN and activated partial thromboplastin time (APTT) ≤1.5 times ULN;
• 6. Left ventricular ejection fraction (LVEF) ≥50%;
• 7. Minimum pulmonary reserve, with oxygen saturation />91% on room air;
• * Meets leukapheresis standard of the study center, with no contraindications for blood cell separation;
• * Voluntarily agrees to participate in this study and signs on the informed consent form(ICF).

Критерии исключения

• * Received CAR-T cell therapy before screening;
• * Inherited bone marrow failure syndrome(IBMFS) or any other known bone marrow failure syndromes;
• * Active systemic autoimmune diseases requiring treatment;
• * Any of the following conditions:
• 1. HBsAg and/or HBeAg positive;
• 2. HBe-Ab and/or HBc-Ab positive with HBV-DNA levels above the lower limit of quantification;
• 3. HCV-Ab positive;
• 4. TP-Ab positive;
• 5. HIV antibody positive;
• 6. EBV-DNA or CMV-DNA levels above the lower limit of quantification;
• * Active infection at screening.
• * Any other malignancy within the past five years before screening, excluding cases where the patient has been disease-free for more than 5 years after curative treatment or has a low risk of relapse as assessed by the investigator;
• * Any of the following cardiac conditions:
• 1. NYHA Class III or IV congestive heart failure;
• 2. Severe arrhythmia requiring treatment;
• 3. Uncontrolled hypertension or pulmonary hypertension despite standard therapy;
• 4. Unstable angina;
• 5. Myocardial infarction, bypass surgery, or stent placement within six months before cell retransfusion;
• 6. Clinically significant valvular disease;
• 7. Other cardiac conditions deemed unsuitable by the investigator;
• * History of epilepsy, cerebellar disease, or other active central nervous system disorders;
• * Uncontrolled diabetes;
• * History of symptomatic deep vein thrombosis or pulmonary embolism within six months before screening that is not well controlled;
• * History of hypersensitivity to any component of the investigational product.
• * Received a live vaccine within six weeks before screening;
• * Life expectancy of less than three months;
• * Participation in another interventional clinical trial and receiving investigational drugs within three months (for unapproved drugs) or within five half-lives (for approved drugs) before cell infusion, or plans to participate in another clinical trial or receive anti-cancer therapy outside the study protocol during the study period;
• * Other conditions deemed unsuitable for participation in this clinical trial by the investigator.

Описание

Precursor B cell acute lymphoblastic leukemia (B-ALL) is an aggressive type of leukemia, with high relapse rate and poor long term survival in adults. Traditional treatment regimens mainly include chemotherapy and hematopoietic stem cell transplantation. In the past decade, with the application of molecular targeted drugs and immunotherapy, the survival of B-ALL patients has significantly improved. In this study，we propose a treatment approach that combines Blinatumomab and Reduced-dose Chemotherapy in B-ALL adults. Our study aims to answer the safety and efficacy of this treatment regimen, and further improve the survival for those participants.

Критерии включения

• * 1. Before enrollment, patients must be diagnosed with de novo precursor B-cell acute lymphoblastic leukemia and be negative for Philadelphia chromosome. The diagnostic criteria refer to the 2022 WHO classification; 2. Age≥15 years， ≤59 years; 3. Eastern Cooperative Oncology Group (ECOG) performance status score of 0-2; 4. Expected survival time ≥ 2 months; 5. No organ dysfunction that would restrict the use of this protocol during the screening period; 6. Understand the study and sign the informed consent form. 7. Men, women of childbearing age (only postmenopausal women who have been menopausal for at least 12 months can be considered infertile), and their partners voluntarily take effective contraceptive measures deemed effective by the investigator during the treatment period and for at least 12 months after the last dose of the study drug.

Критерии исключения

• * 1. Patients with known central nervous system (CNS) involvement of ALL; 2. Diseases with abnormal heart, lung, liver, kidney, or other organ functions that may limit the patient`s participation in this trial (including but not limited to severe infections, uncontrolled diabetes, severe heart failure or angina, active pulmonary tuberculosis, asthma, COPD, bronchiectasis, etc.); 3. Cardiac ultrasound LVEF /< 45%; 4. History of other malignancies within the past 5 years, excluding localized thyroid cancer and in situ skin cancer; 5. Serum total bilirubin /> 1.5 ULN (upper limit of normal); ALT or AST /> 2.5 ULN; serum creatinine /> 1.5 ULN; 6. Known HIV infection; 7. Conditions affecting the use of the study drug as assessed by the investigator; 8. Unable to understand or comply with the study protocol.

Описание

This clinical trial identifies and addresses barriers to pediatric medication adherence among families of children with acute lymphoblastic leukemia. Pediatric nonadherence (noncompliance) to medication is a significant public health problem, and rigorous research repeatedly documents that nonadherence increases risk for hospitalization, healthcare cost, disease progression, and death. Pediatric acute lymphoblastic leukemia (ALL) patients who miss 5% of 6-mercaptopurine (6-MP) doses within the 2-year 6-MP regimen have a 2.7-fold risk of cancer that comes back after a period of improvement (relapse). To address these families` needs, researchers have developed MedSupport, a theory-based multilevel intervention with targets at the organizational, healthcare team, and caregiver levels that is designed to address root barriers to medication adherence. This study is being done to better understand families` experiences giving their child oral chemotherapy at home and to help families cope with the day-to-day challenges of giving their child medication.

Критерии включения

• * Parent of a child who is diagnosed and receiving first line therapy for acute lymphoblastic leukemia (ALL) at a study site.
• * Parent`s child patient is age 365 days to /< 19 years at time of study entry.
• * Parent`s child patient`s therapy must include 6-mercaptopurine (6-MP) administered orally or by nasogastric (NG) tube.
• * Parent has verbal English, French, or Spanish fluency.
• * Parent has a smartphone or access to a computer with an Internet connection.
• * Participant must understand the investigational nature of this study and sign an Independent Ethics Committee/Institutional Review Board approved written informed consent form prior to receiving any study related procedure.

Критерии исключения

• * Parent is unwilling or unable to follow protocol requirements.

Описание

Acute T cell lymphoblastic leukemia/lymphoma (T-ALL/LBL) is an aggressive type of leukemia that results from the malignant evolution of T-lineage progenitor cells at different differentiation stages. After induction chemotherapy and consolidation chemotherapy, there are still about 30% of patients who cannot achieve complete remission of clinical symptoms or negative MRD. This is also an important factor for the recurrence of ALL patients. In addition, most relapsed T-ALL/LBL patients relapse during first-line treatment. Once the disease relapses, it is difficult to cure for most young and adult patients, and the overall survival rate of patients is less than 10%.

Критерии включения

• * 1. Before enrollment, a diagnosis of newly diagnosed T-cell acute leukemia/lymphoma.The diagnostic criteria refer to the 2022 WHO classification; 2. Age ≥ 14 years,/<75 years; 3. Clincally diagnosed as relapsed or refractory T-ALL/LBL; 4. Eastern Cooperative Oncology Group (ECOG) performance status score of 0-2; 5. Expected survival time ≥ 2 months; 6. No organ dysfunction that would restrict the use of this protocol during the screening period; 7. Understand the study and sign the informed consent form.

Критерии исключения

• * 1. Patients with known central nervous system (CNS) involvement of T-ALL/LBL; 2. Diseases with abnormal heart, lung, liver, kidney, or other organ functions that may limit the patient`s participation in this trial (including but not limited to severe infections, uncontrolled diabetes, severe heart failure or angina, active pulmonary tuberculosis, asthma, COPD, bronchiectasis, etc.) 3. Cardiac ultrasound LVEF /< 45%; 4. History of other malignancies within the past 5 years, excluding localized thyroid cancer and in situ skin cancer; 5. Serum total bilirubin /> 1.5 ULN (upper limit of normal); ALT or AST /> 2.5 ULN; serum creatinine /> 1.5 ULN; 6. Known HIV infection; 7. Conditions affecting the use of the study drug as assessed by the investigator; 8. Inability to understand or comply with the study protocol.

Описание

This clinical trial tests different programs to help patients with acute lymphoblastic leukemia (ALL) remember to take their medications during maintenance therapy at home. One problem with ALL maintenance treatment is remembering to take medicines at home like patients are supposed to. In maintenance, a medicine called 6-mercaptopurine or "6MP" is taken by mouth every day at home. In this study, 6MP prescriptions are filled into a special medication bottle called MEMS® which is fitted with a special cap called TrackCap™ that electronically records when the medication bottle is opened. Researchers are trying a new program to help patients be better at taking their 6MP like they`re supposed to. MEMS® TrackCap™ may help patients to remember to take their 6MP medication.

Критерии включения

• * Age: />= 10 years and =/< 25 years
• * Previously enrolled onto AALL1732
• * Consented to the AALL1732 mercaptopurine adherence correlative study
• * Maintenance therapy has not yet begun
• * English or Spanish-speaking (patient and parent/other adult)
• * Planning to receive 6MP (as tablets) during maintenance phase of therapy
• * Able and willing to use the MEMS® TrackCap™ (e.g., not using a pillbox or prescribed liquid 6MP)
• * Has a designated parent/other adult who is willing to enter into a mutual agreement with the patient to participate in a daily supervised medication administration routine
• * Patient/parent/other adult must be willing to use a smartphone to receive medication reminders
• * Receiving treatment at a Children`s Oncology Group (COG) institution in the United States

Критерии исключения

• * Patients who have previously participated in or are currently participating in another intervention clinical trial designed to improve adherence
• * Regulatory requirements
• * All patients and/or their parents or legal guardians must sign a written informed consent
• * All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met

Описание

This study is a multi-center, open, prospective single-arm clinical study of patients with relapsed / refractory B cell hematological tumors to evaluate the safety and efficacy of CD19 /& CD22 bispecific CAR-T cells in relapsed / refractory B cell hematological tumors while collecting pharmacokinetics and pharmacodynamics indicators of CAR-T cells.

Критерии включения

• 1.CD 19 + / CD 22 + B cell hematological tumor was confirmed by pathological and histological examination, and the patient met the following criteria for relapsed or refractory B cell hematological tumor:
• 1. Refractory / relapsed B lymphocytic leukemia (1 of the following 4 items can be met):
• i . Recurrence within 6 months of first remission; ii. Primary refractory without complete remission after 2 cycles of standard chemotherapy regimen; iii. No complete remission or recurrence after first-line or multiline salvage chemotherapy; iv. Not eligible for HSCT conditions, abandonment of HSCT, or relapse after HSCT due to conditional limitations.
• 2. Refractory / relapsed B-cell lymphoma (meet the following item 1 of the first 4 items plus item 5):
• i . After four courses of chemotherapy with a standard regimen, tumor shrinkage was less than 50% or disease progression; ii . CR after standard regimen chemotherapy, but relapsed within 6 months; iii.2 or more recurrences after CR; iv . Not suitable for hematopoietic stem cell transplantation, or abandoning HSCT due to conditional restrictions or relapse after hematopoietic stem cell transplantation; v . Subject must have received prior adequate treatment, including at least: a monoclonal antibody against CD 20 and combination chemotherapy containing an anthracycline drug agent.
• 2.The results of FCM or immunohistochemical detection of tumor antigen (CD 19 / CD 22) were positive.
• 3.The estimated survival period is more than 3 months starting from the signing of the informed consent form.
• 4.Good organ function,Meet the following requirements：
• 1. HGB≥70g/L(transfusible)
• 2. Liver and kidney function: creatinine ≤1.5XULN: total bilirubin ≤1.5XULN:ALT and AST≤2.5X ULN
• 3. Cardiopulmonary function: left ventricular ejection fraction />50%; Blood oxygen saturation />90%;
• 5.Subjects with the Eastern Cooperative Oncology Group (ECOG) fitness scores of 0 to 2.

Критерии исключения

• ：(If meet any of the following criteria, patients will not be included)
• 1. Serious heart insufficiency,LVEF /<50%
• 2. History of severe pulmonary function impairment disease.
• 3. Other malignant tumors in the advanced stage.
• 4. Severe infection or persistent infection that cannot be effectively controlled.
• 5. Combined with severe autoimmune disease or innate immune deficiency.
• 6. Active hepatitis (hepatitis B virus deoxyribonucleic acid /[HBV-DNA 500 IU / ml and abnormal liver function/] or hepatitis C antibody /[HCV-Ab/] positive, HCV-RNA above the lower limit of detection of the analytical method and abnormal liver function).
• 7. Human immunodeficiency virus (HIV) infection or syphilis infection.
• 8. History of severe allergies to biological products (including antibiotics).
• 9. Acute graft-versus-host response (GVHD) allogeneic hematopoietic stem remained one month after immunosuppressant discontinuation.
• 10. Patients who have other serious physical or mental illnesses or abnormalities in laboratory tests that may increase the risk of participating in the clinical trial or interfere with the study results, and who are deemed unsuitable for participation in the clinical trial by the investigator

Описание

This is a prospective, descriptive study designed to assess the feasibility of administering CAR T therapy among patients with moderate to severe renal impairment using dose adjusted lymphodepleting chemotherapy.

Критерии включения

• * Receiving lymphodepleting chemotherapy prior to commercial CAR-T administration for multiple myeloma, leukemia, or lymphoma
• * Adequate bone marrow function to receive lymphodepleting chemotherapy
• * Renal function /</= 60mL/min/1.73m2
• * ECOG 0-2

Критерии исключения

• * Relative CNS disorders
• * Active uncontrolled infection or any other concurrent disease or medical condition that was deemed to interfere with the conduct of the study as judged by the investigator
• * Use of therapeutic dose systemic corticosteroids (defined as />20mg/day prednisone or equivalent) within 72 hours of CAR-T administration

Описание

Over 90% of children and adolescents diagnosed with acute lymphoblastic leukemia (ALL) will survive long term. Part of the successful treatment that patients receive is the delivery of chemotherapy directly into their spinal fluid via a spinal tap. This takes place approximately 20 times over the course of treatment. Most children and adolescents receive general anesthesia during this procedure to manage pain and anxiety. It is now understood that general anesthesia contributes to impairments in brain functioning in the long term. Therefore, it is important to identify ways to manage pain and anxiety during these procedures that does not include general anesthesia. The investigators propose to test whether virtual reality (VR: a technology that provides immersive experiences utilizing content uploaded on a headset), used with local anesthesia and the option for an anti-anxiety medication will be an adequate replacement for general anesthesia for participants 7 years of age and over, with ALL in the maintenance phase of treatment.

Критерии включения

• * Initial diagnosis of ALL or Lymphoma (as they receive the same therapy)
• * In maintenance phase of treatment
• * Still have 2 maintenance cycles planned
• * Aged 7 and over
• * Patient able to speak English
• * Caregiver able to complete consent and study questionnaires in English or Spanish

Критерии исключения

• * Relapsed or refractory disease
• * Previously required ultrasound guided LP procedure
• * Already does LPs without anesthesia

Описание

The planned trial offers treatment cohorts for patients with full cytologic relapse (R/R ALL - Cohort 1), as well as for patients with molecular failure/relapse (MRD+ ALL - Cohort 2). Basically, the study aims to develop data for optimization of first-line therapy of T-ALL, either by modification of standard induction with Isatuximab or by establishing a post-induction therapy for eradication of MRD and thereby evaluates in parallel two different strategies.

Критерии включения

• - Patients with CD38 positive T-ALL fitting either to the definitions for cohort 1 or cohort 2:
• Cohort 1: In relapse or with primary refractory disease defined as ≥5% blasts in bone marrow after at least three chemotherapy cycles (induction I-II, consolidation I) with the following additional specifications:
• * early relapse within 12 months from first achievement of CR or
• * late relapse later than 12 months from first achievement of CR or
• * primary refractory disease without any CR or
• * any relapse after stem cell transplantation or
• * any refractory relapse, defined as no response to at least one salvage therapy or
• * any second or later relapse and
• * Availability of patient material with blast cells (bone marrow or peripheral blood) for central MRD assessment or availability of respective predefined marker.
• Cohort 2: In complete hematological remission (defined as less than 5% blasts in bone marrow and no evidence of extramedullary disease) after at least three chemotherapy cycles (induction I-II, consolidation I)
• * Detection of quantifiable MRD at a level of ≥10-4, either as molecular failure without prior achievement of molecular remission or molecular relapse after prior achievement of molecular remission
• * MRD assay at the central reference lab with at least one marker a minimum sensitivity of 10-4
• * MRD detection for study inclusion after an interval of at least 2 weeks from last systemic chemotherapy including antibody therapy
• * (in patients without clonal molecular MRD marker, MRD testing can be based on flow-cytometry established in reference laboratory)
• ECOG status:
• * Cohort 1: 0-2
• * Cohort 2: 0-1
• Age ≥ 18 years Evidence of a personally signed and dated informed consent indicating that the patient has been informed of all pertinent aspects of the study Patient must be willing and able to comply with scheduled visits, treatment plan, laboratory tests and other study procedures
• Regeneration from last chemotherapy defined as follows:
• Cohort 1:
• * Platelets ≥10.000/uL (platelet transfusion allowed)
• * Hemoglobin ≥ 7.5 g/dl (red blood cell transfusion allowed)
• Cohort 2:
• * Neutrophils ≥1.000/uL
• * Platelets ≥50.000/uL
• * Hemoglobin ≥9 g/dl
• Adequate liver function defined as follows:
• * Bilirubin ≤ 1.5 ULN (unless Gilbert Meulengracht disease or classified as result of liver infiltration by investigator)
• * AST and ALT ≤ 2.5 x ULN (unless classified as result of liver infiltration by investigator)
• Adequate renal function defined as follows:
• * Serum creatinine ≤ 2 x ULN
• * Any serum creatinine level associated with a calculated creatinine clearance ≤ 40 mL/min
• * Negative pregnancy test in women of childbearing potential (WOCBP)
• * WOCBP must commit to either abstain continuously from heterosexual sexual intercourse or to use 2 methods of reliable birth control simultaneously.
• * Men who are sexually active with a WOCBP must agree to use a barrier method of contraception
• * Participation in the registry of the German Multicenter Study Group for Adult ALL (GMALL)

Критерии исключения

• * Extramedullary involvement except for non-bulky (/<7.5 cm) lymph node involvement, splenomegaly, or hepatomegaly
• * Patients who have received prior antileukemic immunotherapy within 2 weeks prior to start of Isatuximab treatment
• * Patients who have received treatment for leukemia with chemotherapy as follows:
• Cohort 1:
• * Patients who have received treatment for leukemia with chemotherapy within 2 weeks prior to start of Isatuximab treatment (exception: pre-phase therapy with 5-7 days of Dexamethasone, 3 days of Cyclophosphamide; intrathecal prophylaxis)
• * Patients who are candidates for a treatment with Nelarabine
• Cohort 2:
• * Any chemotherapy or antibody therapy after the MRD assay leading to study inclusion (exception: intrathecal prophylaxis)
• * Patients must have recovered from acute non-hematologic toxicity from previous therapies to ≤ grade I unless signs or symptoms are correlated to leukemia involvement
• * Prior SCT ≤ 3 months from start of study treatment
• * Acute GvHD ≥ grade II or active chronic GvHD requiring systemic treatment
• * Any systemic GvHD prophylaxis or treatment within 2 weeks from start of study treatment
• * Known HIV positivity, known hepatitis B surface antigen positivity or known history of hepatitis C
• * Unstable or severe uncontrolled medical condition e.g. unstable cardiac function or unstable pulmonary condition
• * Treatment with an investigational agent within 4 weeks from start of study treatment (safety follow-up period of respective study)
• * Concurrent active malignancy other than non-melanoma skin cancer, carcinoma in situ of the cervix, or localized prostate cancer that has been treated with radiation or surgery; patients with previous malignancies are eligible if they have been disease free for ≥ 2 years and do not require any antitumor therapy.
• * Evidence of uncontrolled current serious active infection or recent history (within 4 months) of deep tissue infections such as fasciitis or osteomyelitis
• * Known allergies, hypersensitivity, or intolerance to boron or Mannitol, corticosteroids, mAb (including Isatuximab) or human proteins, or their excipients (refer to respective Summary of Product Characteristics), or known sensitivity to mammalian-derived products.
• * Active infection, any other concurrent disease or medical condition that are deemed to interfere with the conduct of the study as judged by the investigator
• * Pregnant or breastfeeding females
• * Vaccination with live attenuated vaccines within 4 weeks of first study agent administration.
• * Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgement of the investigator, would make the patient inappropriate for entry into this study

Описание

This study is testing a new type of treatment called anti-CD19 CAR-T cell therapy for adults with certain blood cancers that have returned or did not respond to previous treatments. CAR-T cells are a type of immune cell that is specially designed in a lab to target and destroy cancer cells with a marker called CD19. The main goals of this study are to find out if this treatment is safe, how well patients tolerate it, and how effective it is at controlling cancer.

The study will include 60 adults, ages 18-70, who meet specific criteria for participation. Patients will first receive a short course of chemotherapy to prepare their bodies for the CAR-T cells. The CAR-T cells will then be given in two doses through an IV. Patients will be monitored closely in the hospital for about a month to check for any side effects and see how their cancer responds. The researchers will also follow up with patients over time to learn more about how long the CAR-T cells stay active, how well they fight cancer, and the overall health of the patients after treatment.

Критерии включения

• 1. Patients with B-cell lymphoproliferative disorders:
• 1a. In cases of B-cell lymphoproliferative disorders developed from lymphocyte precursors (ALL/LBL), the disease status satisfies one of the following criteria:
• * Failure of induction (primary-refractory course or MOB persistence), absence of clinical and hematologic remission after first-line therapy,
• * MOB persistence with achieved second and subsequent clinical and morphologic remissions,
• * Early medullary or combined relapse if the duration of the first remission is not more than 12 months, provided the disease is stabilized,
• * Confirmed MOB relapse,
• * Second and subsequent relapses, including neurorelapse,
• * Refractory disease course after two or more lines of chemotherapy,
• * Relapsed or refractory disease after allo-HSCT with transplantation performed more than 100 days ago and more than 4 weeks after withdrawal of immunosuppressive therapy before inclusion.
• 1. b. In the case of Ph-positive ALL/LBL:
• * Molecular relapse, advanced relapse, isolated neurorelapse, or refractory disease after the use of more than 2 lines of ITC.
• 1c. In cases of aggressive B-cell non-Hodgkin`s lymphoma, disease status satisfies one of the following criteria:
• * Absence of remission after 1-2 courses of intensive chemotherapy or in the presence of factors of unfavorable prognosis (TP53 mutation, co-expression of c-MYC and BCL2, abnormalities of c-MYC, BCL2, BCL6, and other genes),
• * Disease progression on chemotherapy in the form of the appearance of a new lesion focus or increase of the initial focus by at least 50% during therapy,
• * Relapse within 12-18 months after the end of chemotherapy, regardless of the presence or absence of factors of unfavorable prognosis,
• * Resistance to 2 or more prior lines of therapy.
• 1d. In cases of indolent B-cell non-Hodgkin`s lymphoma, disease status satisfies one of the following criteria:
• * early relapse (POD 24) in patients with contraindications to auto-HSCT,
• * absence of clinical and hematologic remission after 1 line of therapy in the presence of TR53 mutation,
• * relapse in the presence of signs of transformation into aggressive lymphoma,
• * resistance to the previously performed 2 or more lines of therapy. 2. Male or Female subjects aged 18-70 years (at the time of signing the informed consent form).
• 3. CD19 antigen expression of ≥20% (for B-ALL) or presence of CD19 expressing tumor cell population (for lymphoma).
• 4. ECOG 0-2 points. 5. Life expectancy of at least 12 weeks. 6. Absolute CD3+ lymphocyte count in peripheral blood greater than 0.1/*10/^9 cells/L.
• 7. Preserved organ function, defined as:
• * Lung function: absence of hypoxemia according to pulse oximetry (SrO2 />91%) when breathing atmospheric air;
• * Renal function: creatinine /<130 µmol/L or ICF />60 ml/min per 1.73m2;
• * Liver function: total bilirubin concentration less than 34 μmol/L, ALT concentration not exceeding more than 5 times the upper limit of reference values (except for Gilbert`s syndrome);
• * Cardiac function: stable hemodynamics and ejection fraction not less than 45%, absence of ejection in the pericardial cavity.
• 8. Male or female patients with a very low probability of conception characterized by meeting at least one of the following criteria:
• * Patient is not of reproductive potential. A female patient of no reproductive potential characterized by one of two criteria: (1) attainment of natural menopause (defined as 12 months of spontaneous amenorrhea in women />45 years of age or 6 months of spontaneous amenorrhea with a serum FSH concentration characteristic of the postmenopausal range as determined by the laboratory) or (2) bilateral ovariectomy and/or hysterectomy or bilateral fallopian tube ligation at least 6 weeks before screening.
• * The patient is of reproductive potential and agrees to abstain from sexual activity or to use (including partner use) an acceptable method of contraception for the planned duration of the study. Acceptable contraceptive methods are hormonal contraception, intrauterine contraceptive device (IUD), diaphragm with spermicide, contraceptive sponge, condom, and vasectomy (performed at least 6 weeks prior to screening).
• 9. Consent for continued follow-up for 15 years from study inclusion. 10. Adequate central or peripheral vascular access for the apheresis procedure. 11. The patient understands the study procedures, available alternative therapies, and study risks and voluntarily agrees to participate by providing written informed consent.

Критерии исключения

• 1. Tumor cell surface CD19 expression level /<20% for B-ALL by flow cytometry or no CD19 expression for lymphoma by immunohistochemical analysis.
• 2. Acute/active hepatitis B, C, or acute HIV infection, COVID-19.
• 3. Uncontrolled life-threatening infection (positive blood culture within 72 h prior to CAR-T product transfusion). Urinary tract infection is allowed. Patients receiving intravenous antibiotics prior to transfusion or in whom intravenous antibiotics have not been discontinued 7 days before inclusion in the study are not included. Prophylactic use of antibiotics, antiviral, and antifungal agents is allowed.
• 4. CD3+ T-lymphocyte content in peripheral blood is less than 0.1/*10/^9 cells/L.
• 5. Previous treatment with gene therapy products.
• 6. Clinically significant CNS pathology (epilepsy, generalized convulsive disorder, paresis, aphasia, stroke, severe brain damage, dementia, Parkinson`s disease, cerebellar disease, organic cerebral syndrome, psychosis) at present or in the anamnesis.
• 7. NYHA class III or IV heart failure, coronary angioplasty or stenting, myocardial infarction, unstable angina, or any other significant cardiac pathology within the previous 6 months.
• 8. Associated genetic syndromes (such as Nijmegen syndrome, Kostman syndrome, Schwachman syndrome, or any other known bone marrow failure syndrome).
• 9. Pregnancy, planning pregnancy during the study, or lactation period.
• 10. Use of drugs or therapeutic interventions prohibited by the protocol (glucocorticosteroids, allogeneic cell therapy, GvHD therapy, chemotherapy, alemtuzumab, clofarabine, cladribine, mouse-derived biologics).
• 11. Participation in a clinical trial taking any investigational drug within 30 days prior to screening with the exception of investigational antimicrobials (antibiotics, antimycotics, and antivirals).
• 12. Any clinically relevant data that, in the opinion of the investigator, affects the patient`s ability to enter the study and puts the patient at risk if they participate in the study.
• 13. Uncontrolled medical, psychological, familial, sociological, or geographical conditions and conditions that, in the investigator`s opinion, make it impossible to achieve acceptable adherence to the study protocol and the subjects` unwillingness or inability to follow the protocol procedures.

Описание

This phase I trial tests the safety, side effects, best dose, and effectiveness of 225Ac-DOTA-Anti-CD38 daratumumab monoclonal antibody in combination with fludarabine, melphalan and total marrow and lymphoid irradiation (TMLI) as conditioning treatment for donor stem cell transplant in patients with high-risk acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL) and myelodysplastic syndrome (MDS). Daratumumab is in a class of medications called monoclonal antibodies. It binds to a protein called CD38, which is found on some types of immune cells and cancer cells. Daratumumab may block CD38 and help the immune system kill cancer cells. Radioimmunotherapy is treatment with a radioactive substance that is linked to a monoclonal antibody, such as daratumumab, that will find and attach to cancer cells. Radiation given off by the radioisotope my help kill the cancer cells. Chemotherapy drugs, such as fludarabine and melphalan, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Radiation therapy uses high energy x-rays, particles, or radioactive seeds to kill cancer cells and shrink tumors. TMLI is a targeted form of body radiation that targets marrow, lymph node chains, and the spleen. It is designed to reduce radiation-associated side effects and maximize therapy effect. Actinium Ac 225-DOTA-daratumumab combined with fludarabine, melphalan and TMLI may be safe, tolerable, and/or effective as conditioning treatment for donor stem cell transplant in patients with high-risk AML, ALL, and MDS.

Критерии включения

• * Documented informed consent of the participant and/or legally authorized representative
• * Assent, when appropriate, will be obtained per institutional guidelines
• * ≥ 60 years. Note: Patients ≥ 18 years and /< 60 years with HCT-comorbidity index (CI) ≥ 2 are also included
• * Karnofsky performance status ≥ 70
• * Eligible patients will have a histopathological confirmed diagnosis of hematologic malignancy in one of the following categories :
• * Acute myelogenous leukemia:
• * Patients with de novo or secondary disease in unfavorable risk group including poor risk cytogenetics according to National Comprehensive Cancer Network (NCCN) guidelines for AML i.e., monosomal karyotype, -5,5q-,-7,7q-,11q23-non t(9;11), inv (3), t(3;3), t(6;9), t(9;22) and complex karyotypes (≥ 3 unrelated abnormalities), or all patient in intermediate risk groups accept patients with FLT3-NPM1+ disease, OR
• * Patients with a complete morphological remission (CR) with minimal residual disease (MRD)-positive status by flow cytometry (≥ 0.1% by flow cytometry) or cytogenetic after at least 2 prior induction therapies, OR
• * Patients with chemosensitive active disease defined as at least 50% reduction in their blast count after last treatment
• * Myelodysplastic syndrome in high-intermediate (int-2) and high-risk categories per Revised International Prognostic Scoring System- (IPSS-R)
• * Acute lymphocytic leukemia
• * Patients with de novo or secondary disease according to NCCN guidelines for ALL hypoploidy (/< 44 chromosomes); t(v;11q23): MLL rearranged; t(9;22) (q34;q11.2); complex cytogenetics (5 or more chromosomal abnormalities); high white blood cell (WBC) at diagnosis (≥ 30,000 for B lineage or ≥ 50,000 for T lineage); iAMP21loss of 13q, and abnormal 17p, OR
• * Patients with a complete response (CR) with MRD-positive status by flow cytometry (≥ 0.1% by flow cytometry) or cytogenetics after at least 2 prior induction therapies, OR
• * Patients with chemosensitive active disease defined as at least 50% reduction in their blast count after last treatment
• * A pretreatment measured creatinine clearance (absolute value) of ≥ 60 ml/minute (To be performed within 30 days prior to day 1 of protocol therapy unless otherwise stated)
• * Patients must have a serum bilirubin ≤ 2.0 mg/dl (To be performed within 30 days prior to day 1 of protocol therapy unless otherwise stated)
• * Patients must have a serum glutamic oxaloacetic transaminase (SGOT) ≤ 2.5 times the institutional upper limits of normal (To be performed within 30 days prior to day 1 of protocol therapy unless otherwise stated)
• * Patients must have a serum glutamic pyruvic transaminase (SGPT) ≤ 2.5 times the institutional upper limits of normal (To be performed within 30 days prior to day 1 of protocol therapy unless otherwise stated)
• * Ejection fraction measured by echocardiogram or multigated acquisition scan (MUGA) ≥ 50% (To be performed within 30 days prior to day 1 of protocol therapy unless otherwise stated)
• * Diffusion capacity of the lung for carbon monoxide (DLCO) /> 50% predicted (To be performed within 30 days prior to day 1 of protocol therapy unless otherwise stated)
• * Forced expiratory volume in 1 second (FEV1) /> 50% predicted (To be performed within 30 days prior to day 1 of protocol therapy unless otherwise stated)
• * Agreement by females and males of childbearing potential to use an effective method of birth control or abstain from heterosexual activity for the course of the study through at least 6 months after the last dose of protocol therapy
• * Childbearing potential defined as not being surgically sterilized (men and women) or have not been free from menses for /> 1 year (women only)
• * DONOR SPECIFIC CRITERIA: All candidates for this study must have an human leukocyte antigen (HLA) (A, B, C, and DR) identical sibling who is willing to donate mobilized peripheral blood stem cells (preferred) or bone marrow, or have a 10/10 (A, B, C, DR and DQ) allele matched unrelated donor. DQ or DP mismatch is allowed per discretion of the principal investigator. City of Hope (COH) standards of practice (SOP) (B.001.11) will be used for allogeneic donor evaluation, selection, and consent. Donor screening will be in compliance with all requirements of Food and Drug Administration (FDA) regulation 21 CFR Part 1271 including donor screening for COVID-19 exposure or infection

Критерии исключения

• * Patients who had a prior allogeneic transplant
• * All patients with prior radiation treatment to the lung, liver, and kidney
• * Patients who have received prior radiopharmaceutical therapy
• * Inclusion of other patients with previous radiation exposure will be determined based on the radiation oncologist medical doctor (MD) principal investigator (PI) evaluation and judgement
• * For patients with leukemia or MDS: Patients may not have received more than 3 prior regimens, where the regimen intent was to induce remission
• * Receiving any other investigational agents or concurrent biological, intensive chemotherapy or radiation therapy for the previous 2 weeks from conditioning
• * Patients should have discontinued all previous intensive therapy, chemotherapy, or radiotherapy for 2 weeks prior to commencing therapy on this study. Note: Low dose chemotherapy or maintenance chemotherapy given within 7 days of planned study enrollment is permitted. These include hydroxyurea, 6-meraptopurine, oral methotrexate, vincristine, oral etoposide, and tyrosine kinase inhibitors (TKIs). FLT-3 inhibitors can also be given up to 3 days before conditioning regimen
• * History of allergic reactions attributed to compounds of similar chemical or biologic composition to study agent
• * Patients with other active malignancies are ineligible for this study, other than non-melanoma skin cancers
• * Patients should not have any uncontrolled illness including ongoing or active bacterial, viral or fungal infection
• * The recipient has a medical problem or neurologic/psychiatric dysfunction which would impair his/her ability to be compliant with the medical regimen and to tolerate transplantation or would prolong hematologic recovery which in the opinion of the investigator (treating physician) would place the recipient at unacceptable risk
• * Females only: Pregnant or breastfeeding
• * Any other condition that would, in the Investigator`s judgment, contraindicate the patient`s participation in the clinical study due to safety concerns with clinical study procedures
• * Prospective participants who, in the opinion of the investigator, may not be able to comply with all study procedures (including compliance issues related to feasibility/logistics)

Описание

This clinical trial aims to investigate the safety, optimal dosage, and effectiveness of allogeneic CD19-targeted CAR-γδT Cell in treating CD19-positive relapsed/refractory B-ALL

Критерии включения

• 1. Age ≥14 years, gender not specified;
• 2. Diagnosed with B-ALL according to the World Health Organization (WHO) classification of hematopoietic and lymphoid tissue tumors (2022 version);
• 3. Meet the diagnosis of relapsed/refractory leukemia, excluding isolated extramedullary relapse; For relapsed or refractory B-ALL, including any of the following situations: a) Relapse: Peripheral blood or bone marrow recurrence of primitive cells />5% or extramedullary lesions appear again after complete remission; b) Refractory: Primary refractory patients who fail to achieve complete remission after standard induction chemotherapy；those with positive measurable residual disease can also be included；
• 4. Flow cytometry confirms positive CD19 expression in leukemia cells；
• 5. Estimated survival />3 months;
• 6. Eastern Cooperative Oncology Group (ECOG) performance status score ≤2;
• 7. The vital organs function in accordance with the following requirements:
• 7.1Left ventricular ejection fraction (LVEF) ≥50%; 7.2Pulmonary function：normal oxygen saturation without oxygen supplementation; 7.3Total bilirubin (TBil) ≤3×upper limit of normal (ULN), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤3×ULN； 7.4Creatinine ≤1.5×ULN;
• 8. Pregnancy test must be negative, and fertile non-abstinent female patients must agree to use effective contraception from the start of self-screening to 1 year after cell infusion. Fertile male patients with fertile partners must agree to use effective contraception from the start of self-screening to 1 year after cell infusion, and should not donate semen or sperm throughout the study period；
• 9. No obvious hereditary diseases；
• 10. The subject and their legal guardian voluntarily participate in this study, understand the trial information and objectives, and provide informed consent with a signed and dated signature.

Критерии исключения

• 1. Patients with severe autoimmune diseases or immunodeficiency diseases;
• 2. Patients with a history of severe central nervous system diseases, such as uncontrolled seizures, stroke, severe brain injury resulting in aphasia, paralysis, dementia, Parkinson`s disease, psychiatric disorders, etc.;
• 3. Any unstable diseases occurring within screening period (including but not limited to): unstable angina, ischemic or cerebrovascular accidents, myocardial infarction, severe arrhythmias requiring drug treatment (such as rapid atrial fibrillation, high-degree atrioventricular block, ventricular tachycardia, ventricular fibrillation, or torsades de pointes), cardiac catheterization or coronary artery stenting, or coronary artery bypass surgery, thrombotic or embolic events.
• 4. Active graft-versus-host disease requiring continued systemic therapy;
• 5. The presence of anti-FMC63 and a positive DSA reaction;
• 6. Patients who have previously received CAR-T cell therapy within 6 months or donor lymphocyte infusion within 6 weeks before screening;
• 7. History of or concomitant active malignant tumors, excluding cured non-invasive basal cell or squamous cell skin cancer, uterine cervical carcinoma in situ or localized prostate cancer or breast ductal carcinoma in situ without recurrence for at least 2 years;
• 8. Presence of other severe medical conditions as determined by the investigator, such as uncontrolled hypertension or diabetes, severe renal insufficiency, severe pulmonary dysfunction, etc.;
• 9. Other severe or persistent active infections;
• 10. Other conditions deemed by the investigator to potentially increase subject risk or interfere with trial results.

Описание

This study is a prospective, phase II clinical trial with the primary objective of assessing the effectiveness of demethylating agents combined with venetoclax in the prevention of recurrence after allogeneic hematopoietic stem cell transplantation (allo-HSCT) of high risk T-lymphoblastic lymphoma/leukemia (T-LBL/ALL) patients.

Критерии включения

• * 1.14-55 years old, male,or female.
• * 2.Patients with allo-HSCT due to T-LBL/ALL, the donor type is not limited.
• * 3.ECOG score is 0-2 points.
• * 4.Blood routine: ANC ≥ 1.0 × 109/L, PLT ≥ 50 × 109/L.
• * 5.One of the following high-risk factors:
• * a. Age of initial diagnosis ≥ 35 years old.
• * b. Initial diagnosis of WBC ≥ 100 × 109/L.
• * c. Initial diagnosis of LDH exceeding the upper limit of normal values.
• * d. Initial diagnosis of bone marrow involvement (blast cells ≥ 5%).
• * e. Initial diagnosis of a bulky in the mediastinum (longest diameter ≥ 10cm).
• * f. ETP immunophenotype.
• * g. During the induction chemotherapy process, 2 courses did not achieve partial remission and/or 4 courses did not achieve complete remission.
• * h. Residual lesions before transplantation: Flow cytometry analysis showed that the proportion of abnormal lymphoid cells in the bone marrow was greater than 0.01%; Positive detection of minimal residual lesions in molecular biology; PET-CT scan shows that residual lesions are still active.
• * i. Based on the ELN recommendation based on adult T-ALL: gene mutations involving myeloid related genes, RAS/PI3K/AKT, JAK/STAT signaling pathway, and epigenetics, such as FLT3, NRAS/KRAS, PTEN, IL7R, JAK1, JAK3, DNMT3A, IDH1, IDH2; TP53, BCL2 mutations; t (8; 14) (q24; q11)/MYC rearrangement; t (7; 19) (q34; p13)/TCR-LYL1，TCR-MEF2C; del(5q) (q14).
• * j. High risk subgroups based on NGS definition: PI3K signaling pathway/NRAS, KRAS/TP53/IKZF1/DNTM3A/IDH1, IDH2 gene mutation with or without NOTCH1, FBXW7/PHF6/EP300 gene mutation.

Критерии исключения

• ：
• * 1.Central involvement during any course of the disease.
• * 2.Patients who have not achieved complete remission before transplantation.
• * 3.Identify those with available targeted drugs.
• * 4.For those who are resistant to BCL-2 inhibitors before transplantation, if the disease progresses during the application process, or if 3-4 courses of induction therapy containing BCL2 inhibitors do not improve.
• * 5.Individuals who are known to be allergic to demethylating drugs or venetoclax.
• * 6.Individuals with grade 2 or more degrees of active acute GVHD.
• * 7.Individuals with moderate to severe chronic GVHD.
• * 8.T-LBL/ALL relapse (flow cytometry abnormal lymphocyte cell proportion/>0.01%, WT1 positive, fusion gene positive, or extramedullary recurrence), or transplant rejection, bone marrow donor cell chimerism/<95%.
• * 9.Blood routine: ANC/<1.0 × 109/L or PLT/<50 × 109/L.
• * 10.Combined with severe organ dysfunction; The ratio of aspartate aminotransferase (AST)/alanine aminotransferase (ALT) is more than 3 times the normal value or the normal value of direct bilirubin is more than 3 times; The endogenous creatinine clearance rate (Ccr) is less than 50mL/min or 1.5 times the normal value of blood creatinine, regardless of whether hemodialysis treatment is used.
• * 11.Merge severe active infections.
• * 12.Pregnant or lactating women.
• * 13. Accepting other investigational drugs.
• * 14.According to the researchers` assessment, the patient may have complications that could lead to other dangers.

Описание

Leukaemia is a major disease that seriously endangers human health, the long-term survival rate of acute myeloid leukaemia receiving conventional chemotherapy is only 10% to 45%, haematological relapse is the main cause of treatment failure in acute myeloid leukaemia, reducing the relapse rate is the key to improving the efficacy of acute leukaemia, biomarker-guided preemptive therapy is an effective way to reduce the recurrence of leukaemia, existing markers to predict the recurrence has a high false Existing markers have high false-negative and false-positive rates for predicting relapse, and improving the accuracy of leukaemia relapse prediction is a major clinical problem that needs to be solved urgently. The group has found that circulating leukaemia stem cells remaining after chemotherapy are the key to relapse, therefore, we propose to conduct a multicentre prospective clinical study on the prediction of acute leukaemia relapse by circulating leukaemia stem cells.

Критерии включения

• * Newly diagnoses candidates with acute myeloid leukemia.
• * Lower than or equal to 18 years-old;
• * Subjects are able to provide written informed consent.

Критерии исключения

• * Subjects who cannot comply with the study;
• * Subjects with severe cardiac disease (ejection fraction/<50% ), liver disease (total bilirubin />34umol/L, ALT and AST/>1.5×upper limit normal) or kidney disease (Serum creatinine/>130umol/L).
• * Subjects with severe infection.
• * Subjects with other conditions that cannot receive chemotherapy or transplantation.

Описание

Traditional salvage chemotherapy has low efficacy and poor long-term prognosis for relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL). Targeted CD19 CAR-T cell immunotherapy is an effective means of treating R/R B-ALL. Several clinical studies have shown that its remission rate for R/R B-ALL can reach 68-93%. However, long-term follow-up found that the remission time after CD19 CAR-T treatment is short and the relapse rate is high. Therefore, how to ensure the long-term survival of R/R B-ALL patients after remission by CAR-T therapy is an urgent problem to be solved. Some studies have shown that timely bridging allo-HSCT after CAR-T treatment can overcome the risk of relapse and further improve the long-term survival of patients. However, there is currently no randomized controlled study on whether to bridge transplantation after CAR-T. The purpose of this study is to evaluate the efficacy and safety of S1904 in the treatment of relapsed or refractory CD19-positive B-cell acute lymphoblastic leukemia with or without bridging to allogeneic hematopoietic stem cell transplantation after remission.

Критерии включения

• 1. The subject or guardian understands and voluntarily signs the Informed Consent Form (ICF);
• 2. Male or female, aged 12-65 years (including the cutoff value) when signing the informed consent form;
• 3. Expected survival period is not less than 12 weeks;
• 4. ECOG physical performance score is 0-1 when signing the ICF;
• 5. The subject must be diagnosed with relapsed/refractory B-cell acute lymphoblastic leukemia when signing the ICF, and at least one of the following must be met:
• 1. Relapse: including relapse within 12 months after the first remission, 2 or more relapses;
• 2. Refractory: including primary refractory, failure to achieve remission after at least 2 courses of induction therapy, or failure to achieve remission after at least 1 course of salvage therapy after the first relapse.
• 6. For patients with Philadelphia chromosome-positive ALL (Ph+ ALL), in addition to meeting the above relapse or refractory criteria, they should have failed at least two tyrosine kinase inhibitor (TKI) treatments (except for those with T315I mutations), or be unable to tolerate TKI treatment, or have contraindications to TKI treatment;
• 7. Bone marrow morphology examination at screening showed that the proportion of primitive immature lymphocytes in the bone marrow was />5%;
• 8. Tumor cells in the bone marrow or peripheral blood were CD19 positive by flow cytometry at screening;
• 9. Major organ functions must meet the following requirements:
• 1. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5×upper limit of normal (ULN);
• 2. Total bilirubin ≤2×ULN;
• 3. Serum creatinine clearance of adult subjects ≥60 mL/min (Cockcroft-Gault formula) or creatinine ≤1.5×upper limit of normal (ULN);
• 4. Serum creatinine for children: no more than 1.2 mg/dL for 10 to 13 years old, no more than 1.5 mg/dL for males aged 13 to 16 years old, no more than 1.4 mg/dL for females aged 13 years and above, and no more than 1.7 mg/dL for males aged 16 years and above.
• 10. Blood oxygen saturation/>92%;
• 11. Males and females of childbearing age with fertility must agree to use effective contraceptive measures from the signing of the informed consent form until 2 years after the use of the study drug. Females of childbearing age include premenopausal women and women within 2 years after menopause. The blood pregnancy test of females of childbearing age must be negative at the time of screening.

Критерии исключения

• 1. Isolated extramedullary relapse;
• 2. Burkitt`s lymphoma/leukemia;
• 3. Previous history of CNS disease, including but not limited to epilepsy, paralysis, aphasia, stroke, severe brain injury, dementia, Parkinson`s disease, neuropathy (except inactive CNS leukemia);
• 4. Previous hematopoietic stem cell transplantation;
• 5. History of autoimmune disease requiring systemic immunosuppressive drug treatment within 2 years before signing the ICF (including but not limited to Crohn`s disease, rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, inflammatory bowel disease, vasculitis, psoriasis);
• 6. Any uncontrolled active infection at the time of signing the ICF or within 4 weeks before apheresis, requiring antibiotic, antiviral or antifungal treatment;
• 7. Previous anti-tumor therapy targeting CD19, including but not limited to belintoquinone, targeted CD19 cell therapy (autologous or allogeneic);
• 8. Received CAR-T therapy or other cell/gene therapy before screening;
• 9. Those who tested positive for hepatitis B surface antigen (HBsAg) during screening need to be excluded; if HBsAg is negative but hepatitis B core antibody (HBcAb) is positive, those with peripheral blood hepatitis B virus (HBV) DNA above the detection limit need to be excluded; those who tested positive for hepatitis C virus (HCV) antibody and HCV RNA need to be excluded; those who tested positive for human immunodeficiency virus (HIV) antibody; those who tested positive for cytomegalovirus (CMV) DNA; those who tested positive for human lymphotropic herpes virus (EBV) DNA; those who tested positive for both Treponema pallidum-specific and non-specific antibodies;
• 10. Clinically significant cardiovascular disease, including any of the following:
• 1. QTc interval ≥470 ms after heart rate correction (QTc interval calculated by Fridericia formula);
• 2. New York Heart Association (NYHA) grade II or above heart failure;
• 3. Unstable angina or acute myocardial infarction within 6 months before signing the ICF;
• 4. Left ventricular ejection fraction (LVEF) /< 50%;
• 5. Poorly controlled hypertension (systolic blood pressure ≥ 150 mm Hg and/or diastolic blood pressure ≥ 95 mm Hg);
• 6. Arrhythmias with clinical significance or requiring antiarrhythmic treatment (such as sustained ventricular tachycardia, ventricular fibrillation, torsade de pointes tachycardia and complete left bundle branch block, etc.);
• 11. Allergic to any drug component to be used in this study, including but not limited to S1904, clearing drugs (cyclophosphamide, fludarabine), etc.;
• 12. Received any study drug treatment or other systemic anti-tumor treatment within 4 weeks before apheresis (or 5 half-lives of the drug, whichever is more appropriate as determined by the researcher);
• 13. Received extensive radiotherapy within 4 weeks before signing the ICF, except for local radiotherapy of non-target lesions for symptom relief within 2 weeks before signing the ICF or expected during the study period;
• 14. At the time of signing the ICF, except for alopecia and pigmentation, the toxicity caused by previous anti-tumor treatment has not recovered to grade 1 or baseline level (according to NCI-CTCAE version 5.0);
• 15. Patients who need to receive systemic corticosteroids (dose equivalent to or higher than 10 mg/day of prednisone) or other immunosuppressive drugs within 2 weeks before signing the ICF or within 2 weeks before apheresis or during the study, except for the following:
• 1. Intranasal, inhaled, local steroids or local steroid injections (such as intra-articular injections), or
• 2. Systemic corticosteroid treatment not exceeding 10 mg/day of prednisone or its equivalent physiological dose, or
• 3. Steroids as a preventive medication for allergic reactions (such as pretreatment before computed tomography /[CT/]), or
• 4. Used for symptomatic treatment of adverse reactions after reinfusion;
• 16. Subjects who have undergone major surgery (except routine biopsy) within 4 weeks before signing the ICF, or are expected to undergo major surgery during the study;
• 17. Subjects with a history of active tuberculosis infection within 1 year before signing the ICF (except for subjects with a history of active tuberculosis infection more than 1 year ago who are judged by the investigator to have no evidence of active tuberculosis);
• 18. Subjects with clinically significant thyroid dysfunction as judged by the investigator;
• 19. Subjects with or with a history of interstitial lung disease or interstitial pneumonia;
• 20. Subjects with a history of other primary malignant tumors within 5 years before signing the ICF, except for the following:
• 1. Cervical carcinoma in situ that has been fully treated and cured;
• 2. Localized basal cell carcinoma or squamous cell carcinoma of the skin;
• 21. Subjects who have received attenuated/inactivated vaccines within 4 weeks before signing the ICF, or subjects who are planned to receive attenuated/inactivated vaccines during the screening period;
• 22. The researcher believes that the subject`s complications or other conditions may affect compliance with the protocol or may be unsuitable for participation in this study;
• 23. Pregnancy or lactation.

Описание

The goal of this clinical trial is to test daratumumab in adult very high risk T-lineage lymphoblastic leukemia.

The main question it aims to answer is wether the addition of daratumumab daratumumab to the national standard of care is able to increase the rate of MRD-negative patients after induction therapy.

Participants will be treated with:

• daratumumab in combination with a pediatric-inspired treatment scheme - as in the previous GIMEMA LAL1913 protocol.

Критерии включения

• 1. Age 18-65 years.
• 2. A diagnosis of T-ALL according to the 2022 International Consensus Classification (ICC) is required, either de novo or secondary to chemo-radiotherapy for another cancer. Pre-treatment with low-dose corticosteroids +/- cyclophosphamide in patients presenting with hyperleukocytosis is allowed.
• 3. Availability of fresh bone marrow (BM) (or peripheral blood (PB) in patients with hyperleukocytosis) samples to perform diagnostic procedures. ).
• 4. Bone marrow blast percentage at diagnosis ≥20%.
• 5. CD38 positivity on ALL blasts (any level of positivity).
• 6. ETP and near ETP at diagnosis according to internationally accepted criteria (appendix G) at diagnosis or other VHR T-ALL subtypes (WBC count />100 x109/L; complex karyotype with ≥5 unrelated anomalies; other CD1a-negative immunophenotypes). T-Myeloid MPAL according to the 2022 ICC of Acute Leukemias of Ambiguous Lineage (appendix H) can also be eligible and considered as VHR.
• 7. Availability of full cytological, cytochemical, immunophenotypic, cytogenetic and molecular disease characterization according to the EGIL and WHO classifications.
• 8. An ECOG performance status 0-2, unless a performance of 3 is unequivocally caused by the disease itself, (and not by pre-existing comorbidities,) and is considered and/or documented to be reversible following the application of anti-leukemic therapy and appropriate supportive measures.
• 9. For females of childbearing potential, a negative pregnancy test must be documented. Female and male patients who are fertile must agree to use an effective form of contraception with their sexual partners from enrollment through 12 months after the end of treatment.
• 10. Signed written informed consent according to ICH/E U/GCP and national local laws.

Критерии исключения

• 1. Diagnosis of B-lineage ALL, and Ph+ ALL.
• 2. Down`s syndrome.
• 3. Prior systemic chemotherapy for ALL (excluding cyclophosphamide during pre-phase).
• 4. Pre-existing, uncontrolled pathology such as heart failure (congestive/ischemic, acute myocardial infarction within the past 3 months, untreatable arrhythmias, NYHA classes III and IV), severe liver disease with serum direct bilirubin />3 mg/dL (unless attributable to Gilbert` syndrome or ALL) and/or ALT />5x upper normal limit (unless attributable to ALL), kidney function impairment with serum creatinine />2 mg/dL (unless attributable to ALL), and severe neuropsychiatric disorder that impairs the patient`s ability to understand and sign the informed consent, or to cope with the intended treatment plan. N.B. For altered liver and kidney function tests, eligibility criteria can be reassessed at 24-96 hours, following the institution of adequate supportive measures.
• 5. Presence of serious, active, uncontrolled infections.
• 6. A history of cancer that is not in a remission phase following surgery and/or radiotherapy and/or chemotherapy, with a life expectancy /<2 years.
• 7. Patients who have undergone major surgery ≤ 2 weeks prior to starting study drug or who have not recovered from side effects of such therapy.

Описание

This is a Phase 1/2, first-in-human, open-label, dose-escalating trial designed to assess the safety and efficacy of VNX-101 in patients with relapsed or refractory CD19+ B-cell acute lymphoblastic leukemia (ALL).

Критерии включения

• * Age: Part 1: 18-90 years of age, Part 2: 13-90 years of age
• * Relapsed B-cell ALL with bone marrow blasts />= 5%
• * Refractory B-cell ALL as defined in the protocol
• * Bone marrow blasts requirement (flow cytometry): Part 1: />0.01% to /<5% prior to VNX-101 dosing, Part 2: />0.01% to /<50% prior to VNX-101 dosing.
• * Ineligible or declined CAR-T therapy or failed to respond or relapsed after such therapy
• * If prior blinatumomab treatment, cells remain CD19+ and not refractory to blinatumomab
• * AAV specified capsid total antibody /<1:400
• * Protocol-specified ranges for renal, liver, cardiac and pulmonary function
• * Protocol-specified ranges for hematology parameters

Критерии исключения

• * Hepatoxicity (AST or ALT /> 2x upper limit of normal)
• * History of thrombotic microangiopathy or cardiomyopathy, or evidence of sensory neuropathy
• * Pregnant or nursing (lactating) women
• * Acute Graft versus Host Disease (GvHD): Grade 2-4 or chronic GvHD of any grade
• * History of hypersensitivity to corticosteroids or history of corticosteroid-related toxicity
• * Chemotherapy given within the protocol-specified discontinuation timelines
• Other Inclusion/Exclusion criteria to be applied per protocol.

Описание

The safety and efficacy of the chimeric antigen receptor (CAR)-T, a CD19-targeting, TRAC and Power3 double gene deleted allogeneic CAR-T cell product, are undergoing rigorous evaluation in NHL subjects from the ATHENA trial (NCT06014073). Unexpectedly, expansion of the initial residual CD3-positive CAR T from products were measured in patients` peripheral blood (PB) without exception. Accompanying with host immune reconstitution and appearance of the detectable B cells, the CD3-positive allogenic CAR T cells exhibited a compelling amplification advantage over CD3-negative CAR T cells. The amplification of CD3-positive CAR T cell population dynamically suppressed host B cell recovery, and presumably surveilled the recurrence or progression of tumors, but did not induce typical Graft-versus-host-disease (GvHD). Additionally, a series of in vitro experiments illustrated that the HLA-mismatched fratricide between host T cells and TCR-reserved Power3-deleted allogenic CAR T cells was markedly slashed, which in combination with investigators` observed clinical safety date supported the notion that only genomic deletion of Power3 gene in allo-CAR T cells is sufficient to overcome GvHD and host T cell-mediated rejection response.

In this study, investigators will disable the Power3 gene of T cells from healthy donors to prepare CAR T cells. This approach harnesses the tonic signaling of CAR T cells, resulting in enhanced persistence and improved response to treatment. The purpose of this study is to evaluate the safety and efficacy of allogeneic Power3 knock-out CD19 CAR-T in B-cell acute lymphoblastic leukaemia (B-ALL).

Критерии включения

• 1. Age 16-70 (inclusive).
• 2. Patient with r/r CD19+ B-ALL, as per guidelines (NCCN, 2019)
• * morphologically confirmed with ≥ 5% leukaemic blasts in the bonemarrow;
• * or presenting a quantifiable MRD load of 1x10/^-3 , assessed by multiparameter flow cytometry and/or quantitative polymerase chain reaction, at the end of the last induction treatment.
• Relapsed disease is defined as:
• * second or subsequent bone marrow relapse or,
• * any bone marrow relapse after allo-HSCT.
• Refractory disease is defined by not achieving an initial CR after 2 cycles of a standard chemotherapy regimen (primary refractory). Subjects who were refractory to subsequent chemotherapy regimens after an initial remission were considered chemorefractory.
• 3. Toxicities due to prior therapy must be stable and recovered to ≤ Grade 1 (except for hematological toxicities and clinically non-significant toxicities such as alopecia).
• 4. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.
• 5. Adequate renal, hepatic, pulmonary and cardiac function defined as:
• * Serum creatinine≤1.5 upper limit of normal (ULN) or creatinine clearance (as estimated by Cockcroft Gault) ≥ 60 mL/min.
• * Serum alanine aminotransferase / aspartate aminotransferase (ALT/AST) ≤ 3 upper limit of normal (ULN); Total bilirubin ≤ 1.5 ULN, except in subjects with 3) Gilbert`s syndrome.
• * Cardiac ejection fraction ≥ 50%, no evidence of pericardial effusion as determined by an echocardiogram (ECHO), and no clinically significant electrocardiogram (ECG) findings.
• * Coagulation Function: International Normalized Ratio (INR) ≤ 1.5 times the upper limit of normal (ULN), and Activated Partial Thromboplastin Time (APTT) ≤ 1.5 times ULN.
• * Baseline oxygen saturation />91% on room air.
• 6. Subjects of both genders who are willing to practice birth control from the time of consent through 6 months after the completion of conditioning chemotherapy. Females of childbearing potential must have a negative serum or urine pregnancy test (females who have undergone surgical sterilization or who have been postmenopausal for at least 2 years are not considered to be of childbearing potential).
• 7. Voluntarily participate in this clinical trial and sign an informed consent form.

Критерии исключения

• 1. Expected survival time /< 3 months per Principal Investigator`s opinion.
• 2. History of malignancy other than nonmelanoma skin cancer or carcinoma in situ (e.g. cervix, bladder, breast) unless disease free for at least 3 years.
• 3. History of allogeneic stem cell transplantation.
• 4. Patients who received any immunocellular therapy within 3 months before enrollment.
• 5. Active central nervous system (CNS) leukaemia (CNS-3).
• 6. Burkitt cell (L3 ALL) or mixed lineage acute leukaemia.
• 7. Clinically active significant CNS dysfunction.
• 8. Known history of irreversible severe neurological toxicity related to previous antileukaemic treatment leading to organic central nervous system lesions.
• 9. B-ALL with clinically suspected extra-medullary involvement.
• 10. Use of previous anti-leukemic therapy within 5 half-lives prior to allogeneic Power3 knock-out CD19 CAR-T administration; participation in non-interventional registries or epidemiological studies is allowed.
• 11. Radioimmunotherapy, radiotherapy, within 8 weeks (except prophylaxis of CNS involvement) before Inclusion.
• 12. History of severe, immediate hypersensitivity reaction attributed to lymphodepletion drugs or any component of allogeneic Power3 knock-out CD19 CAR-T.
• 13. Presence or suspicion of fungal, bacterial, viral, or other infection that is uncontrolled or requiring intravenous (IV) antimicrobials for management.
• 14. Uncontrolled or active infectious diseases, such as human immunodeficiency virus (HIV) infection, acute or chronic active hepatitis B or C, epstein-barr virus (EBV), and cytomegalovirus (CMV) infection.
• 15. History or presence of CNS disorder such as seizure disorder, cerebrovascular ischemia/hemorrhage, dementia, cerebellar disease, or any autoimmune disease with CNS involvement.
• 16. Subjects with cardiac atrial or cardiac ventricular lymphoma involvement.
• 17. History of myocardial infarction, cardiac angioplasty or stenting, unstable angina, or other clinically significant cardiac disease within 12 months of enrollment.
• 18. Expected or possible requirement for urgent therapy within 6 weeks due to ongoing or impending oncologic emergency (eg, tumor mass effect, tumor lysis syndrome).
• 19. Primary immunodeficiency.
• 20. History of autoimmune disease (e.g. Crohn`s, rheumatoid arthritis, systemic lupus) resulting in end organ injury or requiring systemic immunosuppression/systemic disease modifying agents within the last 2 years.
• 21. History of symptomatic deep vein thrombosis or pulmonary embolism requiring systemic anticoagulation within 6 months of enrollment.
• 22. Any medical condition likely to interfere with assessment of safety or efficacy of study treatment.
• 23. History of severe immediate hypersensitivity reaction to any of the agents used in this study.
• 24. Vaccine ≤ 6 weeks prior to planned start of conditioning regimen.
• 25. In the investigator`s judgment, the subject is unlikely to complete all protocol-required study visits or procedures, including follow-up visits, or comply with the study requirements for participation.

Описание

* Clinical and genetic factors consistent with High risk : Induction → Consolidation

1. BM MRD /< 0.01% : IM #1 → DI #1 → IM #2 → Maintenance
2. BM MRD ≥ 0.01% : IM #1 → DI #1 → IM #2 → DI #2 → Maintenance
3. BM MRD ≥ 0.01% after Consolidation

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1. T cell ALL : Change to very high risk regimen
2. Pre-B ALL : IM #1 → Intensification

1. BM MRD /< 0.01% after IM #1 : DI #1 → IM #2 → DI #2 → Maintenance
2. BM MRD ≥ 0.01% after IM #1 : Change to Very high risk regimen

* Difference in the number of /'interim maintenance(IM)/' and /'delayed intensification(DI)/' is important for chemotherapies based on MRD.

Критерии включения

• * Age: 1year/~19years of age at diagnosis
• * Patients who are newly diagnosed Pre-B ALL and meet one of the following criteria
• * High-risk group according to the National Cancer Institute (NCI)/Rome: Age greater than or equal to 10 years and less than 19 years at diagnosis, or white blood cell count greater than or equal to 50 x 109/L at diagnosis
• * If extra-bone marrow lesions are identified at the time of diagnosis, Central nervous system involvement (CNS3) or testicular involvement
• * High-risk gene variants:
• KMT2A rearrangement intrachromosomal amplification of chromosome 21 (iAMP21)
• * If subjects are classified as a standard risk group but have an NGS MRD ≥ 0.01% after remission induction, these subjects will be reclassified and treated as a high-risk group after consolidation.
• * If subjects are under the age of 10 at the time of diagnosis and took steroids for more than 24 hours within two weeks before the diagnosis, the risk group will be determined by the presence of a whole blood test within three days before starting steroids. If a whole blood test is performed within three days before beginning steroids, the risk group will be assessed based on the white blood cell count in the test. If there is no whole blood test before starting steroids, subjects are classified as a high-risk group. If subjects are ten or older at diagnosis, pre-diagnosis steroid treatment will not affect the risk classification.
• * Newly diagnosed T cell ALL

Критерии исключения

• * Patients with Burkitt leukemia/lymphoma or mature B-cell leukemia
• * Patients with Down syndrome
• * potential of pregnancy or during pregnancy (patients of childbearing age need adequate contraception for the duration of the trial)
• * Patients who have already received steroid treatment for newly diagnosed ALL specified in the above selection criteria or chemotherapies more than one intrathecal cytarabine treatment
• * Participating in an interventional clinical trial other than this research

Описание

The purpose of this study is to learn more about LP-118 (an experimental drug) and its side effects and decide on acceptable doses. The purpose of this study is to determine if LP-118 can be given safely with another medicine called ponatinib, that is FDA-approved for the treatment of acute lymphoblastic leukemia.

Критерии включения

• 1. Relapsed or refractory patients with T-lineage acute lymphoblastic leukemia or T-lymphoblastic lymphoma
• 2. 18 years old or older
• 3. Bone marrow or peripheral blood involvement with ≥5% lymphoblasts or measurable residual disease with />10-4 level detected by multiparameter flow cytometry or next-generation sequencing (NGS)-based measurable residual disease (ClonoSEQ, Adaptive Technologies). Patients with isolated extramedullary disease that is measurable by computed tomography (CT) scan are also eligible.
• 4. Eastern Cooperative Oncology Group performance status 0-2.
• 5. Adequate organ function as defined by all of the following:
• 1. Creatinine clearance ≥50 mL/min, determined by the Cockroft-Gault formula, or measured by a 24-hour urine collection.
• 2. Aspartate transaminase (AST) and alanine transaminase (ALT) ≤2.5 x upper limit of normal (ULN) and bilirubin ≤1.5 x ULN (unless considered due to Gilbert`s syndrome or of non-hepatic origin i.e,, leukemic involvement). For patients with Gilbert`s syndrome, bilirubin ≤1.5 x of their baseline bilirubin level will be required.
• 6. Participants must be at least 2 weeks from major surgery or radiation therapy. A wash-out period of 4 half-lives is required for patients who participated in other investigational trials. These patients must have recovered from clinically significant toxicities related to these prior treatments.
• 7. Participants must voluntarily sign and date an informed consent, approved by an Independent Ethics Committee (IEC)/Institutional Review Board (IRB), prior to the initiation of any screening or study-specific procedures.
• 8. Females of childbearing potential will use effective contraception during protocol treatment and for at least 8 months after the last dose. Males with female partners of reproductive potential will use effective contraception during protocol treatment and for at least 5 months after the last dose. A patient is of childbearing potential if, in the opinion of the treating investigator, he/she is biologically capable of having children and is sexually active. Female patients who are not of childbearing potential (ie, meet at least one of the following criteria):
• a. Have undergone hysterectomy or bilateral oophorectomy; or have medically confirmed ovarian failure; or are medically confirmed to be post-menopausal (cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause).
• 9. Participants who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.

Критерии исключения

• 1. Active central nervous system (CNS) leukemia
• 2. Active or chronic hepatitis B or C infection as evidenced by hepatitis B surface antigen and anti-hepatitis C antibody positivity, respectively, or known seropositivity for human immunodeficiency virus (HIV). Patients with HIV but an undetectable viral load are eligible for enrollment.
• 3. Major surgery within /<2 weeks before randomization.
• 4. Unstable or severe uncontrolled medical condition (eg, unstable cardiac function or unstable pulmonary condition.
• 5. Concurrent active malignancy other than non-melanoma skin cancer, carcinoma in situ of the cervix, or localized prostate cancer that has been definitely treated with radiation or surgery. Patients with previous malignancies are eligible provided that they have been disease free for ≥2 years or are not currently requiring treatment.
• 6. Uncontrolled cardiac disease.
• 7. Pregnant females; breastfeeding females; males with female partners of reproductive potential and females of childbearing potential not using highly effective contraception or not agreeing to continue highly effective contraception for a minimum of 5 months after the last dose of investigational product if male and 8 months after the last dose of investigational product if female.
• 8. Participation in other investigational studies during active treatment phase.
• 9. Other severe acute, chronic medical, psychiatric condition, or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the treating physician, would make the patient inappropriate for entry into this study.

Описание

To learn if the combination of blinatumomab and asciminib can help to control Ph+ ALL.

Критерии включения

• 1. Diagnosis of one of the following:
• a) Participants ≥18 years of age with previously untreated or minimally pretreated Ph-positive ALL who are not suitable candidates for intensive chemotherapy. Participants who have received no more than one or two courses of chemotherapy with or without other TKIs are considered minimally pretreated and still eligible if they have persistently detectable MRD.
• i. If they are in morphologic remission at enrollment, they are evaluable only MRD responses, RFS and OS b) Participants ≥ 18 years of age with relapsed/refractory Ph-positive ALL or with previously treated lymphoid blast phase CML
• 2. Performance status ≤2 (ECOG Scale)
• 3. Adequate liver function as defined by the following criteria (unless the increased values are judged to be leukemia disease related):
• 1. Total serum bilirubin ≤ 2 x upper limit of normal (ULN), unless due to Gilbert`s syndrome
• 2. Alanine aminotransferase (ALT) ≤ 3 x ULN, OR
• 3. Aspartate aminotransferase (AST) ≤ 3 x ULN
• 4. Adequate renal function defined as:
• a) Creatinine clearance ≥30 mL/min
• 5. Adequate pancreatic function as defined by the following criteria:
• a) Serum lipase and amylase /< 1.5 x ULN
• 6. Adequate cardiac function as assessed clinically by history and physical examination.
• 7. For females of childbearing potential, a negative urine pregnancy test must be documented
• 8. Willingness to use adequate contraception prior to study entry, for the duration of study participation, and for 4 months after completion of study participation. For women of child-bearing potential, adequate methods of contraception include: complete abstinence, hormonal contraception (i.e. birth control pills, injection, implant, transdermal patch, vaginal ring), intrauterine device (IUD), tubal Ligation or hysterectomy, subject/partner post vasectomy, implantable or injectable contraceptives, and condoms plus spermicide
• 9. Ability to understand and the willingness to sign a written informed consent document.
• 10. Signed informed consent

Критерии исключения

• 1. Active serious infection not controlled by oral or intravenous antibiotics.
• 2. Active secondary malignancy other than skin cancer (e.g., basal cell carcinoma or squamous cell carcinoma) that in the investigator`s opinion will shorten survival to less than 1 year.
• 3. Active Grade III-V cardiac failure as defined by the New York Heart Association Criteria.
• 4. Prolonged QTc interval on pre-entry electrocardiogram (/> 470 msec) unless corrected after electrolyte replacement or approved by cardiologist
• 5. History or presence of clinically relevant CNS pathology such as epilepsy, childhood or adult seizure, paresis, aphasia, stroke, severe brain injuries, dementia, Parkinson`s disease, cerebellar disease, organic brain syndrome, or psychosis. (Participants with active CNS leukemia will NOT be excluded)
• 6. Treatment with any investigational antileukemic agents or chemotherapy agents in the last 7 days before study entry, unless full recovery from side effects has occurred or patient has rapidly progressive disease judged to be life-threatening by the investigator. Cytarabine 2 g/m2 (or alternative) for cytoreduction is permitted.
• 7. Pregnant and lactating women will not be eligible; women of childbearing potential should have a negative pregnancy test prior to entering on the study and be willing to practice methods of contraception. Women do not have childbearing potential if they have had a hysterectomy or are postmenopausal without menses for 12 months. In addition, men enrolled on this study should understand the risks to any sexual partner of childbearing potential and should practice an effective method of birth control.

Описание

Substudy 01A is part of a platform study. The purpose of this study is to assess the efficacy and safety of zilovertamab vedotin in pediatric participants with relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL), diffuse large B-cell lymphoma (DLBCL)/Burkitt lymphoma, or neuroblastoma and in pediatric and young adult participants with Ewing sarcoma.

Критерии включения

• The main inclusion and exclusion criteria include but are not limited to the following:
• Inclusion Criteria:
• * For hematological malignancies: Confirmed diagnosis of B-precursor B-ALL or DLBCL/Burkitt lymphoma according to World Health Organization (WHO) classification of neoplasms of the lymphoid tissues.
• * For solid tumor malignancies: Histologically confirmed diagnosis of neuroblastoma or Ewing sarcoma.

Критерии исключения

• * History of solid organ transplant.
• * Clinically significant (ie, active) cardiovascular disease.
• * Known history of liver cirrhosis.
• * Ongoing Grade />1 peripheral neuropathy.
• * Demyelinating form of Charcot-Marie-Tooth disease.
• * Diagnosed with Down syndrome.
• * Ongoing graft-versus-host disease (GVHD) of any grade or receiving systemic GVHD treatment or prophylaxis.
• * History of human immunodeficiency virus (HIV) infection.
• * Contraindication or hypersensitivity to any of the study intervention components.
• * Received prior radiotherapy within 4 weeks of start of study intervention. Participants must have recovered from all radiation-related toxicities.
• * Ongoing, chronic corticosteroid therapy (exceeding 10 mg daily of prednisone equivalent). Prednisone equivalent dosing must have been stable for at least 4 weeks before Cycle 1 Day 1 (C1D1).
• * Received a strong cytochrome P450 3A4 (CYP3A4) inhibitor within 7 days or a strong CYP3A4 inducer within 14 days before the start of study intervention or expected requirement for chronic use of a strong CYP3A4 inhibitor or inducer during the study intervention period and for 30 days after the last dose of study intervention
• * Received prior systemic anticancer therapy including investigational agents within 4 weeks before the first dose of study intervention (except for prophylactic intrathecal chemotherapy and/or cytoreductive therapy with steroids/hydroxyurea.
• * Received a live or live-attenuated vaccine within 30 days before the first dose of study intervention. Administration of killed vaccines is allowed.
• * Has received an investigational agent or has used an investigational device within 4 weeks prior to study intervention administration.
• * Known additional malignancy that is progressing or has required active treatment within the past 1 year.
• * Active infection requiring systemic therapy.
• * Known history of Hepatitis B or known active Hepatitis C virus infection.
• * Participants who have not adequately recovered from major surgery or have ongoing surgical complications.

Описание

This research is being done to investigate the safety and effectiveness of Darzalex Faspro (daratumumab and hyaluronidase-fihj) (a monoclonal antibody that targets plasma cells that make antibodies) and whether it can lower donor specific antibodies (DSA) levels to low enough levels to permit patients to proceed with allogeneic peripheral blood transplant (alloBMT). Those being asked to participate have high DSA levels that puts those being asked to participate at high risk of rejecting the available donor`s blood stem cells and making those being asked to participate ineligible to receive a stem cell transplant.

Критерии включения

• 1. Participates must meet all other institutional criteria for the planned reduced intensity conditioning allogeneic peripheral blood stem cell transplant (RIC alloHSCT) as defined in Johns Hopkins BMT Policy; all potential non-cord blood donor sources are included: matched related, haploidentical, matched unrelated, mismatched unrelated.
• 2. Participants must be ≥18 years of age.
• 3. Participants must have adequate organ function for undergoing RIC allogeneic peripheral blood stem cell transplant, and for undergoing a clinical trial.
• a. Hematologic. i. White blood cell (WBC). ANC ≥ 500/mm3 (growth factor support allowed). ii. Hemoglobin. No specific cut-off. (PRBC transfusion allowed). iii. Platelets. Platelets ≥ 10,000/mm3 (platelet transfusion allowed). b. Liver. Bilirubin ≤ 3.0 mg/dL (unless due to Gilbert`s syndrome or hemolysis), and Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) /< 5x Upper limit of normal (ULN) c. Renal. Serum creatinine ≤ 2.0 mg/dL. d. Cardiac. Left ventricular ejection fraction ≥ 35%. e. Pulmonary. FEV1 ≥ 50%.
• 4. Subjects are eligible if there are high levels of Donor Specific Antibody levels based on protocol specific scoring system regardless of prior attempts at standard desensitization.
• 5. Participants must have a no other readily available suitable alternative donor.
• 6. All potential Participants must be pre-approved by BMT faculty consensus.
• 7. Participants must have adequate willingness to participate in a clinical trial.

Критерии исключения

• 1. Previous exposure to Daratumumab-SC or other anti-CD38 therapy
• 1. Exposure to Daratumumab-SC or other anti-CD38 therapies (unless a re-treatment study)
• 2. Exposure to an investigational drug (including investigational vaccine) or invasive investigational medical device for any indication within 4 weeks or 5 pharmacokinetic half-lives, whichever is longer.
• 3. Focal radiation therapy within 14 days prior to beginning of planned RIC allogeneic peripheral blood stem cell transplant regimen with the exception of palliative radiotherapy for symptomatic management but not on measurable extramedullary plasmacytoma
• 2. Chronic obstructive pulmonary disease (COPD) with a forced expiratory volume in 1 second (FEV1) /< 50% of predicted normal. Note that FEV1 testing is required for participants suspected of having COPD and participants must be excluded if FEV1 is /< 50% of predicted normal.
• 3. Moderate or severe persistent asthma within the past 2 years, or uncontrolled asthma of any classification. Note that participants who currently have controlled intermittent asthma or controlled mild persistent asthma are allowed to participate.
• 4. Known hypersensitivity or intolerance to boron or mannitol, sorbitol, corticosteroids, monoclonal antibodies or human proteins, or the excipients
• 5. Diagnosis of multiple myeloma or Amyloid light-chain (AL) amyloidosis
• 6. A planned myeloablative alloBMT or the planned use of bone marrow or cord blood as a stem cell source
• 7. History of HIV infection at any time in past.
• 8. Seropositive for hepatitis B (HBV) (defined by a positive test for hepatitis B surface antigen /[HBsAg/] positive, or antibodies to hepatitis B surface and/or core antigens /[antiHBs or antiHBc, respectively/] with hepatitis B virus /[HBV/]- DNA quantitation positive). Patients who are positive for antiHBs and/or antiHBc must have a negative polymerase chain reaction (PCR) for HBV-DNA quantitation result during screening. Patients with serologic findings suggestive of HBV vaccination (antiHBs positivity as the only serologic marker) AND a known history of prior HBV vaccination do not need to be tested for HBV DNA by PCR. Those who are PCR positive will be excluded.
• 9. Seropositive for hepatitis C (except in the setting of a sustained virologic response (SVR), defined as aviremia at least 12 weeks after completion of antiviral therapy)
• 10. Clinically significant cardiac disease, including:
• 1. Myocardial infarction within 6 months before RIC alloHSCT or unstable or uncontrolled disease/condition related to or affection cardiac function (e.g., unstable angina, congestive heart failure, New York Heart Association Class III-IV)
• 2. Uncontrolled cardiac arrhythmia

Описание

A Clinical Study on the Safety and Effectiveness of targeting CD5 CAR-T Cells in the treatment of r/r CD5+ T-ALL

Критерии включения

• * 1. According to the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines for Acute Lymphocytic Leukemia (2020. v1), patients diagnosed as CD5+T-ALL;
• * 2. Consistent with r/r CD5+T-ALL diagnosis, including any of the following conditions:
• 1. No CR after standard chemotherapy;
• 2. The first induction reaches CR, but CR ≤ 12 months;
• 3. Patients with r/r CD5+T-ALL have not responded to the first or multiple remedial treatments;
• c.Multiple recurrences.
• * 3. CD5 expression rate was />90%;
• * 4. Number of blasts in the bone marrow (protolychic + larvae) />5% (morphology) and/or />1% (flow cytometry);
• * 5. Total bilirubin ≤51 (mol/L), Alanine aminotransferase (ALT)/Aspartate aminotransferase (AST) ≤ 3 times the upper limit of the normal range, creatinine ≤176.8 (mol/L);
• * 6. Echocardiography showed left ventricular ejection fraction (LVEF) ≥50%;
• * 7.Refers to the pulse oxygen saturation 92% or higher oxygen (state);
• * 8.Estimated life expectancy of minimum of 12 weeks;
• * 9.ECOG 0-2;
• * 10.Pregnant/lactating women, or male or female patients who have fertility and are willing to take effective contraceptive measures at least 6 months after the last cell infusion during the study period;
• * 11. Those who voluntarily participated in this trial and provided informed consent

Критерии исключения

• * 1.Patients with the history of epilepsy or other CNS disease;
• * 2. Patients with prolonged QT interval time or severe heart disease;
• * 3. Active infection of hepatitis B virus, C virus or hepatitis E virus;
• * 4. Active infection with no cure;
• * 5. Before using any gene therapy products;
• * 6. Received anti-tumor therapy before infusion, should meet the following any one should be ruled out:
• 1. treated with systemic corticosteroids therapy within 72 hours (except glucocorticoid physiological replacement therapy, such as prednisone /< 10 mg/d or an equivalent dose of the drug);
• 2. received within 72 hours of small molecule targeted therapy;
• 3. 2 weeks received systemic chemotherapy except (pretreatment);
• 4. four weeks received radiotherapy;
• * 7. The proiferation rate is less than 5 times response to CD3/CD28 co-stimulation signal;
• * 8. Any unsuitable to participate in this trial judged by the investigator;
• * 9. Any situation that researchers believe may increase the risk to the subjects or interfere with the trial results.

Описание

A Clinical Study on the Safety and Effectiveness of targeting CD5 CAR-T Cells in the treatment of r/r CD5+ T-lymphoma

Критерии включения

• * 1. According to the 2016 WHO classification of lymphocyte tumors, histologically confirmed CD5-positive T-cell non-Hodgkin lymphoma (T-NHL),
• R/R T-NHL(meets one of the following conditions) :
• 1. Subjects did not go into remission or relapse after receiving second-line or more chemotherapy regiments;
• 2. Primary drug resistance;
• 3. Relapse after autologous hematopoietic stem cell transplantation;
• * 2.CD5 expression rate was />90%;
• * 3. According to Lugano 2014, there should be at least one evaluable tumor lesion;
• * 4. Total bilirubin ≤51 (mol/L), Alanine aminotransferase (ALT)/Aspartate aminotransferase (AST) ≤ 3 times the upper limit of the normal range, creatinine ≤176.8 (mol/L);
• * 5. Echocardiography showed left ventricular ejection fraction (LVEF) ≥50%;
• * 6. Refers to the pulse oxygen saturation 92% or higher oxygen (state);
• * 7. Estimated life expectancy of minimum of 12 weeks;
• * 8. ECOG 0-2;
• * 9. Pregnant/lactating women, or male or female patients who have fertility and are willing to take effective contraceptive measures at least 6 months after the last cell infusion during the study period;
• * 10. Those who voluntarily participated in this trial and provided informed consent

Критерии исключения

• * 1. History of epilepsy or other central nervous system disorders;
• * 2. Electrocardiogram shows prolonged QT interval, severe heart diseases such as severe arrhythmia in the past;
• * 3. Active infection of hepatitis B virus, C virus or hepatitis E virus;
• * 4. Active infected persons who are not cured;
• * 5. Before using any gene therapy products;
• * 6. Received anti-tumor therapy before infusion, should meet the following any one should be ruled out:
• 1. treated with systemic corticosteroids therapy within 72 hours (except glucocorticoid physiological replacement therapy, such as prednisone /< 10 mg/d or an equivalent dose of the drug);
• 2. received within 72 hours of small molecule targeted therapy;
• 3. 2 weeks received systemic chemotherapy except (pretreatment);
• 4. four weeks received radiotherapy;
• * 7. The proiferation rate is less than 5 times response to CD3/CD28 co-stimulation signal;
• * 8. Any unsuitable to participate in this trial judged by the investigator;
• * 9. Any situation that researchers believe may increase the risk to the subjects or interfere with the trial results.

Описание

Evaluate the safety and efficacy of Inaticabtagene autoleucel combined with autologous hematopoietic stem cell transplantation in adolescents or adults with MRD-positive initial complete remission in B-cell acute lymphoblastic leukemia.

Критерии включения

• * ECOG score of 0 to 1
• * Newly diagnosed Ph-negative B-ALL within 6 months, achieving CR1 after standard induction chemotherapy, undergoing at least one consolidation therapy, and patients with bone marrow MRD ≥ 0.01% detected by routine flow cytometry.
• * Or newly diagnosed Ph-positive B-ALL within 6 months, achieving CR1 after guideline-recommended induction chemotherapy (or use of TKI), undergoing at least one consolidation therapy, and patients with BCR-ABL1 /> 0% detected by routine q-PCR technology.
• * No significant organ dysfunction
• * Willing and meet the conditions for autologous hematopoietic stem cell transplantation

Критерии исключения

• * Burkitt lymphoma/leukemia, heterozygous or double-expressor leukemia, or chronic myeloid leukemia in blast phase.
• * Before screening or pre-treatment, bone marrow or peripheral blood with blasts ≥ 5%; or extramedullary leukemia.
• * Individuals who have received CAR-T cell therapy before screening or pre-treatment; or patients who have undergone hematopoietic stem cell transplantation.
• * Patients with associated genetic syndromes related to bone marrow failure, such as Fanconi anemia, Kostmann syndrome, Shwachman syndrome, or any other known bone marrow failure syndromes.

Описание

The experimental group included patients diagnosed with T-ALL/LBL (T-lymphoblastic leukemia/ lymphoma) at initial diagnosis, who received treatment with BCL-2 inhibitors combined with the Hyper CVAD regimen. The control group consisted of patients diagnosed with T-ALL/LBL from multiple centers, for whom basic information, disease information, treatment details, and efficacy data were collected. Propensity score matching was conducted with historical data (matching factors included age, gender, initial LDH levels, and the presence or absence of a large mediastinal mass at diagnosis) to compare the advantages and disadvantages of the experimental regimen with previous induction treatment protocols. The primary endpoint was the complete remission (CR) rate after induction chemotherapy, while secondary endpoints included duration of remission (DOR), progression-free survival (PFS), overall survival (OS), and the occurrence of adverse events. This study aims to provide a more effective and safer treatment option for patients with T-LBL.

Критерии включения

• Age 18-60 years, regardless of gender; Expected survival time greater than 12 weeks; ECOG score 0-2; Pathologically or flow cytometrically confirmed as T-cell lymphoblastic lymphoma, with less than 25% tumor cell proportion in bone marrow smears;
• Liver and kidney function, as well as cardiopulmonary function, meet the following requirements:
• Creatinine clearance (calculated using the Cockcroft-Gault formula) ≥60 mL/min; Left ventricular ejection fraction greater than 50%, with no clinically significant ECG changes; Baseline oxygen saturation greater than 92% Total bilirubin ≤1.5×ULN; ALT and AST ≤3×ULN Able to understand the trial and has signed the informed consent form Exclusion Criteria A history of acute T-cell leukemia, T-cell lymphoma, or T-cell lymphoblastic lymphoma within the past 5 years, except for adequately treated carcinoma in situ of the cervix, basal cell carcinoma or squamous cell carcinoma of the skin, localized prostate cancer after radical surgery, ductal carcinoma in situ after radical surgery, or thyroid cancer after radical surgery Active bacterial, viral, or fungal infections that require treatment and are not controlled; those who are HBsAg or HBcAb positive, with peripheral blood HBV DNA ≥ the lower limit of detection; individuals who are positive for hepatitis C virus antibodies and have positive peripheral blood HCV RNA; individuals who test positive for syphilis (TRUST test); individuals who are positive for human immunodeficiency virus (HIV) antibodies Dysfunction of important organs (cardiovascular, pulmonary) or a history of active gastrointestinal bleeding within the past 3 months; individuals with uncontrolled hypertension, hypertensive crisis, or a history of hypertensive encephalopathy, and a history or evidence of significant cardiovascular risk, including any of the following: congestive heart failure, unstable angina, clinically significant arrhythmias (e.g., ventricular fibrillation, ventricular tachycardia); a history of arterial thrombosis within the past 3 months (e.g., stroke, transient ischemic attack); a history of symptomatic deep vein thrombosis, pulmonary embolism within the past 6 months, or a history of coronary angioplasty, defibrillation, or any clinical complications or diseases that may pose a risk to the participant/'s safety or interfere with the evaluation, procedures, or completion of the study Any uncontrolled active disease that may interfere with participation in the trial; Active, uncontrolled central nervous system diseases or a history of central nervous system disease requiring treatment (e.g., epilepsy) Pregnant or breastfeeding women; and individuals planning to become pregnant within 1 year after infusion, during treatment, or after treatment ends Presence of uncontrolled active infections (except for simple urinary tract infections or upper respiratory infections Known allergies to any components of cyclophosphamide, doxorubicin, vincristine, cytarabine, methotrexate, etc.
• Any situation that the investigator believes would compromise participant safety or interfere with the study objectives, or any individual deemed inappropriate for participation by the investigator Individuals with diseases affecting their ability to sign the written informed consent form or comply with study procedures; those unwilling or unable to adhere to study requirements

Критерии исключения

Описание

The purpose of this study is to assess the safety, tolerability, pharmacokinetics and preliminary anti-tumor activity of YK012 administered as monotherapy in participants with B-cell acute lymphoblastic leukemia (B-ALL).

Критерии включения

• 1. Participants or their legally acceptable representative must sign an ICF indicating that the participants understand the purpose of, and procedures required for the study and are willing to participate in the study.
• 2. Eastern Cooperative Oncology Group Performance Status (ECOG) of 0-2.
• 3. An estimated survival time of more than 12 weeks.
• 4. A definitive diagnosis of CD19-positive B-cell acute lymphoblastic leukemia with any of the following conditions:
• 1. Ph-negative B-ALL with any of the following: i. Failure to achieve complete remission after initial induction therapy. ii. Failure to achieve complete remission after salvage treatment. iii. Relapse with first remission duration ≤12 months. iv. Second or later relapse. v. Relapse after hematopoietic stem cell transplantation (HSCT).
• 2. Ph-positive B-ALL: failure to 1 or more tyrosine kinase inhibitors (TKIs), or intolerance to treatment with TKIs, or with the T315I mutation.
• 5. ≥ 5% blasts in the bone marrow by morphologic assessment.
• 6. Recovery to Grade 0-1 (Graded by National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI CTCAE) Version (v) 5.0) from adverse events related to prior therapy except alopecia.
• 7. Adequate hematological and organ function.
• 8. Female participants of childbearing potential must have a negative serum pregnancy test at screening. Female patients who are sexually active must use highly effective methods of contraception throughout the study and for 3 months following the last dose of study treatment.
• 9. Male participants must agree to use reliable methods of contraception (barrier methods or sexual abstinence) and avoid sperm donation throughout the study period and until 3 months after the last dose.

Критерии исключения

• 1. Burkitt´s Leukemia according to World Health Organization (WHO) classification.
• 2. History of antitumor therapy as follows, before the first dose of study drug:
• 1. Targeted therapy with small molecule drug within 2 weeks or 5 half-lives, whichever is longer
• 2. Targeted therapy with macromolecular drug or Immunomodulatory agent therapy within 3 weeks
• 3. Radiotherapy or chemotherapy (except for intrathecal chemotherapy and dexamethasone), or treatment with Chinese traditional/patent medicine that has definite antitumor effect within 2 weeks
• 4. Treatment with an investigational drug within 4 weeks or 5 half-lives, whichever is shorter
• 5. Receipt of any live attenuated vaccines or live virus vaccine within 4 weeks
• 6. Autologous stem cell transplantation within 6 weeks
• 7. History of organ transplant, or allogeneic stem cell transplantation within 12 weeks.
• 3. Any active acute graft-versus-host disease (GvHD), grade 2-4 (according to Glucksberg criteria) or active chronic GvHD requiring systemic treatment.
• 4. Other malignancy within 5 years, except localized malignancies that have been adequately treated or free of the disease for ≥ 5 years, e.g., basal cell carcinoma of the skin, squamous cell carcinoma of the skin, non-muscle invasive bladder cancer, localized prostate cancer, carcinoma in situ of the cervix, carcinoma in situ of the breast.
• 5. Active central nervous system (CNS) involvement or meningeal involvement with clinical signs, or other evidence of uncontrolled metastases to the CNS or meninges, judged by the investigator.
• 6. a. History of or current relevant CNS pathology as epilepsy, seizure, paresis, aphasia, apoplexia, severe brain injuries, cerebellar disease, organic brain syndrome, psychosis. b. Evidence for presence of inflammatory lesions and/or vasculitis on cerebral MRI.
• 7. History or evidence of cardiovascular disease, including:
• 1. Acute coronary syndromes (e.g., myocardial infarction, unstable angina)
• 2. Coronary angioplasty or stenting within 6 months prior to enrollment
• 3. Clinically significant unstable arrhythmias (e.g., atrial fibrillation), however, atrial fibrillation has been controlled for over 30 days prior to the first dose of YK012 were allowed
• 4. New York Heart Association (NYHA) stage III or higher congestive heart failure
• 5. Left ventricular ejection fraction (LVEF) below lower limit of the study center, or LVEF/<50% if there is no lower limit at the study center
• 6. The Fridericia-corrected QT interval (QTcF, mean of triplicate measurements) ≥ 470 msec (female) or ≥ 450 msec (male)
• 7. Implantable defibrillator
• 8. Clinically uncontrollable hypertension (i.e., SBP≥160 mm Hg and/or DBP≥100 mm Hg).
• 8. Known allergy to monoclonal antibody drugs or exogenous immunoglobulin.
• 9. History of CD19 targeted therapy and positive test result for immunogenicity of YK012 at screening.
• 10. Any major organ surgery or significant trauma within 4 weeks prior to the first dose of YK012, or those requiring elective surgeries during the study, and all AEs associated with surgery or significant trauma have not recovered to Grade ≤1 or baseline graded by CTCAE v5.0 before the first dose of the YK012.
• 11. Regular dose of systemic corticosteroids during 4 weeks prior to initiation of study drug, or anticipated need of corticosteroids exceeding prednisone 20 mg/day or equivalent during the trial, or any other immunosuppressive therapy within 4 weeks prior to study entry.
• 12. Virological tests: Hepatitis B virus surface antigen (HBsAg) positive and/or hepatitis B core antibody (HBcAb) positive, and hepatitis B virus (HBV) deoxyribonucleic acid (DNA)/>ULN of the testing agency; Hepatitis C antibody (HCV-Ab) positive and hepatitis C virus-RNA (HCV-RNA)/>ULN of the testing agency; Anti-human immunodeficiency virus (Anti-HIV) positive. Participants will be excluded from the study if any of the above criteria is met.
• 13. Uncontrolled active infections requiring oral or intravenous systemic therapy, except for local treatment.
• 14. Uncontrolled pleural effusion, pericardial effusion, or ascites requiring repeated drainage (once a month or more frequently).
• 15. Pregnant or lactating women.
• 16. Known mental disorder that may affect study compliance or poor compliance.
• 17. Other serious systemic diseases or laboratory abnormalities or other reasons that the investigator believes are not appropriate for participating in the study.

Описание

This study will evaluate the safety and tolerability of administering a novel bispecific CD19/CD22-directed CAR T cell product (CD19x22) for the treatment of relapsed or refractory pediatric B-ALL.

Критерии включения

• 1. Subjects must have a history of B precursor ALL with any of the following conditions:
• 1. Relapsed two or more times.
• 2. Relapsed at any time after allogeneic bone marrow transplant (BMT).
• 3. Relapse or refractory after single antigen targeting CAR T cell therapy.
• i. 90 days must have elapsed post previous CAR infusion prior to apheresis. d. Refractory to standard therapy as determined by the treating physician. e. Patient and/or parents declining BMT options and would prefer CAR T Therapy.
• 2. CD19 and/or CD22 present on last relapsed/refractory disease evaluation.
• 3. Performance score (Lansky or Karnofsky ≥ 50%; or Eastern Cooperative Oncology Group (ECOG) must be ≤2).
• 4. Meets criteria for potential leukapheresis collection or has leukapheresis product previously collected and stored per recommended guidelines.
• 5. Males OR non-pregnant, non-lactating females.
• 6. Aged 3 months to 30 years (inclusive) at time of consent and enrollment.
• 7. Provision of a signed and dated consent form from parent or guardian (patients /< 18), the patient themselves (/> 18), or legally authorized representative (patient /> 18 who lack decision-making capacity) after standard of care (SOC) screening assessments are performed.
• 8. Stated willingness to comply with all study procedures and be available for the duration of the study.
• 9. Willingness to participate in long-term follow-up protocol.

Критерии исключения

• 1. Active, uncontrolled central nervous system (CNS) leukemia as determined by the treating physician at eligibility, prior to lymphodepleting chemotherapy (LD chemo), and pre- CD19x22 CAR T cell infusion.
• 2. History of allogeneic stem cell transplantation prior to apheresis that meet the following criteria:
• 1. Less than 100 days post-transplant;
• 2. Evidence of active Graft-versus-Host Disease (GvHD) requiring systemic therapy;
• 3. Less than 6 weeks post donor lymphocyte infusion (DLI).
• 3. Active, uncontrolled, life-threatening infection that at the determination of the treating physician would preclude safe apheresis or tolerance of lymphodepleting chemotherapy, cell infusion, or increased risk of cytokine release syndrome.
• 4. Evidence of severe organ dysfunction defined by:
• 1. Baseline oxygen saturation of /< 90% on room air
• 2. Myocardial dysfunction (based on age standards): Ejection fraction ≤/< 40% or shortening fraction ≤ 28%,, evidence of physiologically significant pericardial effusion as determined by an echocardiogram (ECHO), and clinically significant electrocardiogram (ECG) findings
• 3. Transaminases /> 10x upper limit of normal (ULN) or bilirubin /> 5x the ULN, unless thought to be related to primary disease
• 4. Estimated Creatinine (Cr) clearance /< 60 mL/min/1.73 m2 (if nuclear medicine GFR or other more specific testing exceeds this level than it can supersede the estimated clearance)
• 5. Post-pubertal females that are pregnant, planning to become pregnant, or unwilling to use birth control (includes abstinence) for the study duration.
• 6. Known HIV infection or active Hepatitis B or Hepatitis C infection.

Описание

Precursor B cell acute lymphoblastic leukemia (B-ALL) is an aggressive type of leukemia, with high relapse rate and poor long term survival in adults. Traditional treatment regimens mainly include chemotherapy and hematopoietic stem cell transplantation. In the past decade, with the application of molecular targeted drugs and immunotherapy, the survival of B-ALL patients has significantly improved. In this study，we propose a treatment approach that combines Blinatumomab and Venetoclax sequenced with Inotuzumab Ozogamicin in B-ALL adults. Our study aims to answer the safety and efficacy of this treatment regimen, and further improve the survival for those participants.

Критерии включения

• 1. Before enrollment, a diagnosis of newly diagnosed precursor B-cell acute lymphoblastic leukemia with Philadelphia chromosome-negative must be confirmed. The diagnostic criteria refer to the 2022 WHO classification.
• 2. Age ≥ 40 years;
• 3. Eastern Cooperative Oncology Group (ECOG) performance status score of 0-2;
• 4. Expected survival time ≥ 3 months;
• 5. No organ dysfunction that would restrict the use of this protocol during the screening period;
• 6. Understand the study and sign the informed consent form.
• 7. Men, women of childbearing age (only postmenopausal women who have been menopausal for at least 12 months can be considered infertile), and their partners voluntarily take effective contraceptive measures deemed effective by the investigator during the treatment period and for at least 12 months after the last dose of the study drug.

Критерии исключения

• 1. Patients with known central nervous system (CNS) involvement of ALL;
• 2. Diseases with abnormal heart, lung, liver, kidney, or other organ functions that may limit the patient`s participation in this trial (including but not limited to severe infections, uncontrolled diabetes, severe heart failure or angina, active pulmonary tuberculosis, asthma, COPD, bronchiectasis, etc.);
• 3. Cardiac ultrasound LVEF /< 45%;
• 4. History of other malignancies within the past 5 years, excluding localized thyroid cancer and in situ skin cancer;
• 5. Serum total bilirubin /> 1.5 ULN (upper limit of normal); ALT or AST /> 2.5 ULN; serum creatinine /> 1.5 ULN;
• 6. Known HIV infection;
• 7. Conditions affecting the use of the study drug as assessed by the investigator;
• 8. Inability to understand or comply with the study protocol.

Описание

The purpose of this first-in-human study is to evaluate the safety of INT2104 when administered to humans in a broad population of participants with refractory/relapsing B-cell malignancies. Preliminary efficacy information may also be obtained.

INT2104 is a gene therapy delivering a transgene for a chimeric antigen receptor (CAR) specific for CD20 (CAR20). The lentiviral vector is designed to generate CAR T and CAR Natural Killer (NK) cells inside the body following intravenous (IV) administration.

Study details include the following:

* The study duration will be 5 years
* The treatment duration will be a one-time intravenous (IV) infusion of INT2104

Критерии включения

• * Age 18 or older and capable of giving signed informed consent
• * Diagnosed with relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma (B-NHL) (Burkitt`s lymphoma are eligible for Part B only) confirmed by histology or flow cytometry Note: Bone Marrow involvement is allowed
• * B-NHL must have CD20 antigen positive tumour confirmed from a tumour biopsy taken at screening
• * Measurable disease at the time of enrolment
• * Progression after at least 2 lines of systemic therapy
• * Has not received more than one prior marketed CAR-T cell therapy (including tandem or bispecific CAR-T) or other genetically modified T-cell therapy.
• * Sex and Contraceptive/Barrier Requirements consistent with local regulations for clinical trials Females: must have negative serum pregnancy test at screening and on Day -1 prior to INT2104 infusion Both sexes: must agree to use highly effective methods, including a barrier methodafter INT2104 infusion
• * Haematological criteria:
• Absolute lymphocyte count (ALC) ≥300/µL Platelet count ≥50,000/mL Absolute neutrophil count (ANC) ≥500/µL
• * Eastern Cooperative Oncology Group (ECOG) score of 0 or 1
• * Adequate renal, cardiac, hepatic, and lung function
• Key Inclusion Part B only
• * Diagnosed with relapsed/refractory B-cell acute lymphoblastic leukaemia (B-ALL), and with exceptions as detailed in exclusion criteria. Participants with Philadelphia chromosome (Ph+) B-ALL disease are eligible
• * B-ALL participants must have CD20 antigen positive leukaemia
• * Measurable disease at the time of enrolment
• * Participants with Burkitt`s lymphoma are eligible for Part B only

Критерии исключения

• * Central Nervous System (CNS)-only B-cell malignancy, or B-cell malignancy with R/R secondary CNS involvement.
• * Diagnosis of chronic lymphocytic leukaemia (CLL) (including large cell /[Richter/] transformation of CLL) or small lymphocytic lymphoma (SLL)
• * Diagnosis of cutaneous lymphoma
• * History of another primary malignancy that has not been in remission for at least 3 years before signing informed consent (except for: non-melanoma skin cancer, non-melanoma skin cancer or carcinoma in situ (e.g., cervix, bladder, breast))
• * Acute or chronic graft-versus-host disease
• * Participant has received donor lymphocyte infusion within 6 weeks prior to INT2104 infusion
• * History of autoimmune disease requiring systemic immunosuppression/ systemic disease modifying agents within 2 years before enrolment
• * History or presence of CNS disorder
• * History of myocardial infarction, cardiac angioplasty or stenting, unstable angina, or other clinically significant cardiac disease within 12 months before signing informed consent
• * Participants has active syphilis, cytomegalovirus (CMV), acute or chronic active hepatitis B, or untreated hepatitis C.
• * Participant is Human immunodeficiency virus (HIV) positive.
• * Any medical condition likely to interfere with assessment of safety or efficacy of the study treatment
• * A vaccine within 4 weeks prior to INT2104 infusion
• * Intolerance or severe hypersensitivity reaction to any excipients of the INT2104 product.
• * An active fungal, bacterial, viral, or other infection that is uncontrolled or requires antimicrobials at the time of INT2104 infusion.
• * Participant is pregnant or nursing.
• * In the investigator`s judgment, the participant is unlikely to complete all protocol-required study visits or procedures, including follow-up visits, or comply with the study requirements for participation

Описание

Patients with leukemia and concomitant neutropenia are at high risk of developing invasive fungal infections (IFI) that are associated with high morbidity and mortality. As these patients typically have severe thrombocytopenia, direct diagnostic sampling with invasive procedures is often not possible due to the high peri-interventional risk. Therefore, the presumptive diagnosis of IFI is primarily based on compatible lung findings on computed tomography and serologic detection of fungal cell wall components, which, however, have limited sensitivity and specificity.

With the present study, the investigators aim to determine a set of specific volatile biomarkers in leukemia patients with proven or probable IFI using secondary electrospray ionization high-resolution mass spectrometry (SESI-HRMS).

Критерии включения

• * Diagnosis of acute leukemia
• * Planned chemotherapy with a duration of hospitalisation of 2 weeks or longer
• * Neutropenia (/<500/µl) present at inclusion or planned chemotherapy with expected neutropenia (/<500/µl) for more than 7 days

Критерии исключения

• * Unable to follow instructions for breath analysis
• * Anatomic abnormalities precluding the use of a mouthpiece for breath analysis

Описание

The study participant has one of the following blood cancers: acute myelogenous leukemia (AML)/myelodysplastic syndrome (MDS), acute lymphoblastic leukemia (B-ALL, T-ALL) or Lymphoma. Your cancer has been difficult to treat (refractory) or has come back after treatment (relapse).

Primary Objective

To determine the safety and maximum tolerated dose of intravenous infusions of escalating doses of CD70-CAR T cells in patients (≤21 years) with recurrent/refractory CD70+ hematological malignancies after lymphodepleting chemotherapy.

Secondary Objectives

To evaluate the antileukemic activity of CD70-CAR T cells. We will determine the anti- leukemic activity of the CD70-CAR T cells in the bone marrow and in the treatment of extramedullary disease.

Критерии включения

• Age ≤21 years old
• Relapsed/refractory CD70+ hematological malignancy
• Relapsed disease: Patients developing recurrent disease after a prior complete remission (CR)
• Refractory disease: Patients with persistent disease despite 3 cycles of induction chemotherapy.
• * Relapsed/refractory CD70+ AML or MDS:
• * Relapsed disease that is CD70 positive
• * Refractory disease that is persistent despite 3 cycles of chemotherapy
• * Relapsed/refractory CD70+ B-cell ALL:
• * Relapsed disease that is CD70 positive and CD19 negative/dim or patients otherwise ineligible for CD19-directed therapies including:
• * Patients in 2nd or greater relapse
• * Patients with relapse after allogeneic HSCT
• * Relapsed/refractory CD70+ T-cell ALL:
• * Relapsed /refractory disease that is CD70 positive
• * Mixed Phenotype Acute Leukemia (MPAL):
• * Relapsed/refractory that is CD70 positive
• * Relapsed/refractory CD70+ lymphoma:
• * Relapsed disease that is CD70 positive and CD19 negative/dim or patients otherwise ineligible for CD19-directed therapies including:
• * Patients in 2nd or greater relapse
• * Patients with relapse after allogeneic HSCT
• Estimated life expectancy of />12 weeks
• Karnofsky or Lansky (age- dependent) performance score ≥50
• Patients with a history of prior allogeneic HCT must be clinically recovered from prior HCT therapy, have no evidence of active GVHD and have not received a donor lymphocyte infusion (DLI) within the 28 days prior to apheresis
• Patient must have an identified HCT donor
• For females of childbearing age:
• i. Not lactating with intent to breastfeed
• ii. Not pregnant with negative serum or urine pregnancy test within 7 days prior to enrollment

Критерии исключения

• * Known primary immunodeficiency
• * Known history of HIV positivity
• * Severe intercurrent bacterial, viral or fungal infection
• * History of hypersensitivity to cornstarch or hydroxyethyl starch
• * Patients with acute promyelocytic leukemia (APL)
• * Known contraindication to protocol defined lymphodepleting
• * chemotherapy regimen of Fludarabine/cyclophosphamide

Описание

This phase Ib trial tests the safety, side effects, and effectiveness of humanized (hu)CD19-chimeric antigen receptor (CAR) T cell therapy in treating patients with CD19 positive B-cell acute lymphoblastic leukemia (ALL) that has come back after a period of improvement (relapsed) or that has not responded to previous treatment (refractory). CAR T-cell therapy is a treatment in which a patient`s T cells (a type of immune system cell) are changed in the laboratory so they will attack cancer cells. T cells are taken from a patient`s blood. Then the gene for a special receptor that binds to a certain protein, such as CD19, on the patient`s cancer cells is added to the T cells in the laboratory. The special receptor is called a chimeric antigen receptor (CAR). Large numbers of the huCD19 positive CAR T cells are grown in the laboratory and given to the patient by infusion for treatment of certain cancers. Chemotherapy drugs, such as fludarabine and cyclophosphamide, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. huCD19-CAR T cell therapy may be safe, tolerable and effective in treating patients with relapsed or refractory CD19 positive ALL.

Критерии включения

• * Documented informed consent of the participant
• * Agreement to allow the use of archival tissue from diagnostic tumor biopsies.
• * If unavailable, exceptions may be granted with study principal investigator (PI) approval
• * Note: For research participants who do not speak English, a short form consent may be used with a City of Hope (COH) certified interpreter/translator to proceed with screening and leukapheresis, while the request for a translated full consent is processed. However, the research participant is allowed to proceed with lymphodepletion and T cell infusion only after the translated full consent form is signed
• * Age: ≥ 18 years
• * Eastern Cooperative Oncology Group (ECOG) 0-2 / Karnofsky performance status (KPS) ≥ 70
• * Histologically confirmed CD19+ relapsed/refractory ALL with at least 2 prior lines of therapy
• * Prior alloHCT /> 100 days prior to enrollment may be considered a prior line of therapy
• * Research participants with confirmed 1st or higher relapse of disease by morphology, cytogenetics or molecular, or research participants with refractory or residual disease
• * Participants with central nervous system (CNS) involvement by leukemia (CNS2 and CNS3) may be considered eligible after discussions with the study team
• * Patients with only MRD+ disease may be eligible
• * Patients with isolated extramedullary disease may also be eligible
• * Total bilirubin ≤ 2.0 X upper limit of normal (ULN) (unless has Gilbert`s disease or related to leukemia involving the liver)
• * Aspartate aminotransferase (AST) ≤ 2.5 x ULN (unless related to leukemia involving the liver)
• * Alanine aminotransferase (ALT) ≤ 2.5 x ULN (unless related to leukemia involving the liver)
• * Creatinine clearance of ≥ 50 mL/min per 24-hour urine test or the Cockcroft-Gault formula
• * Left ventricular ejection fraction (LVEF) ≥ 45%
• * Note: To be performed within 28 days prior to start of protocol therapy
• * Cardiac function (12 lead-electrocardiogram /[ECG/]): Corrected QT interval (QTc) must be ≤ 480 msec
• * Oxygen (O2) saturation /> 92% on room air
• * Note To be performed within 28 days prior to start of protocol therapy
• * Seronegative for HIV quantitative polymerase chain reaction (qPCR), hepatitis C virus (HCV), active hepatitis B virus (HBV) (surface antigen negative), and syphilis (rapid plasma reagin /[RPR/])
• * If positive, hepatitis C ribonucleic acid (RNA) quantitation must be performed. OR
• * If seropositive for HIV, HCV or HBV, nucleic acid quantitation must be performed. The viral load must be undetectable
• * Meets other institutional and federal requirements for infectious disease titer requirements
• * Note Infectious disease testing to be performed within 28 days prior to start of protocol therapy
• * Women of childbearing potential (WOCBP): negative urine or serum pregnancy test. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
• * Agreement by females and males of childbearing potential to use an effective method of birth control or abstain from heterosexual activity for the course of the study through at least 6 months after the last dose of protocol therapy
• * Childbearing potential defined as not being surgically sterilized (men and women) or have not been free from menses for /> 1 year (women only)
• * ELIGIBILITY TO PROCEED WITH PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMC) COLLECTION FOR CAR T CELL MANUFACTURING
• * Research participant has signed the `screening and leukapheresis` informed consent
• * Research participant must have appropriate venous access, have a central line or be willing to undergo central or temporary line placement
• * The last dose of systemic chemotherapy must be at least 2 weeks before the leukapheresis procedure with the following exceptions:
• * Steroids and vincristine are allowed up to 7 days prior to leukapheresis.
• * Intrathecal chemotherapy is allowed up to 3 days prior to leukapheresis.
• * Tyrosine kinase inhibitors are allowed up to 48 hours prior to leukapheresis.
• * Hydrea is allowed up to 48 hours prior to leukapheresis.
• * The research participant cannot be on ≥ 7.5 mg prednisone or equivalent doses of other corticosteroids at the time of leukapheresis. Note: Topical and inhaled corticosteroids in standard doses and physiologic replacement for subjects with adrenal insufficiency are allowed
• * The last dose of prior targeted agents, immunotherapy or radiation must be at least 2 weeks before the leukapheresis procedure
• * If the research participant has undergone prior alloHCT, 100 days must have elapsed since allogeneic stem cell transplant to undergo PBMC collection for CAR T cell manufacturing
• * ELIGIBILITY TO UNDERGO LYMPHODEPLETION
• * Research participant`s absolute leukemic blast count does not exceed 10,000 cells/uL
• * The last dose of chemotherapy, maintenance therapy, radiation therapy, biological therapy, and/or immunotherapy must have been 7 days prior to start of lymphodepletion
• * The following washout periods must be met:
• * Corticosteroids 3 days
• * Biologic agents 3 half lives
• * Oral chemotherapeutic agents 3 half lives
• * Intrathecal chemotherapy 3 days
• * Chemo and/or immunotherapy 2 weeks
• * Local radiation to sites 7 days
• * Non myeloablative agents 7 days
• * Investigational agents 2 weeks, or at least 3 half lives
• * Hydroxyurea no washout period
• * Research participant has a released cryopreserved CAR T cell product for CAR T cell infusion on approximately day 0 (performed no more than 7 days prior to start of lymphodepletion)
• * ECOG /< 2 / KPS ≥ 70 (performed no more than 7 days prior to start of lymphodepletion)
• * No ongoing post treatment ≥ grade 3 non-heme toxicities (with exception of grade 3 glucose intolerance, cholesterol, triglyceride, peripheral neuropathy, and hyperglycemia) (performed no more than 7 days prior to start of lymphodepletion)
• * Research participant does not require supplemental oxygen to keep saturation greater than or equal to 92% and/or does not have any radiographic abnormalities on chest x-ray that are progressive (performed no more than 7 days prior to start of lymphodepletion)
• * Research participant does not require pressor support and/or does not have symptomatic cardiac arrhythmias (performed no more than 7 days prior to start of lymphodepletion)
• * Research participant does not have a fever exceeding 38.5 degree Celsius (C); there is an absence of positive blood cultures for bacteria, fungus, or virus within 48-hours prior to lymphodepletion and/or there aren`t any indications of meningitis (performed no more than 7 days prior to start of lymphodepletion)
• * Research participant serum total bilirubin does not exceed 2.5X normal limit or transaminases do not exceed 3X normal limit unless related to underlying leukemia (to be discussed at the discretion of the PI/study team) (performed no more than 7 days prior to start of lymphodepletion)
• * Note: in the event a participant has elevated levels of liver enzymes possibly related to underlying disease/disease progression, the participant will still be considered eligible
• * Research participant serum creatinine ≤ 2 mg/dL (performed no more than 7 days prior to start of lymphodepletion)
• * Research participant does not have uncontrolled seizure activity (performed no more than 7 days prior to start of lymphodepletion)
• * ELIGIBILITY TO PROCEED WITH CAR T CELL INFUSION
• * No ongoing post treatment ≥ grade 3 non-heme toxicities (with exception of grade 3 glucose intolerance, cholesterol, triglyceride, peripheral neuropathy, and hyperglycemia)
• * Prednisone (or prednisone equivalent) dose of ≤ 7.5 mg/kg/day is allowed
• * Prohibited medications have not been administered
• * KPS ≥ 70
• * No untreated or active systemic infection
• * No Class III/IV cardiovascular disability according to the NYHA Classification
• * Research participant does not require supplemental oxygen to keep saturation greater than or equal to 92% and/or does not have any radiographic abnormalities on chest x-ray that are progressive
• * Research participant does not require pressor support and/or does not have symptomatic cardiac arrhythmias
• * Research participant does not have a fever exceeding 38.5 degree C; there is an absence of positive blood cultures for bacteria, fungus, or virus within 48-hours prior to T cell infusion and/or there aren`t any indications of meningitis
• * Research participant serum total bilirubin does not exceed 2.5X normal limit or transaminases do not exceed 3X normal limit unless related to underlying leukemia (to be discussed at the discretion of the PI/study team)
• * Research participant serum creatinine ≤ 2 mg/dL
• * Research participant does not have uncontrolled seizure activity
• * ELIGIBILITY TO PROCEED WITH OPTIONAL CAR T CELL ABLATION
• * Research participant has /> 1% CAR T cells in the peripheral blood
• * No known hypersensitivity to cetuximab
• * Not requiring supplemental oxygen or mechanical ventilation, oxygen saturation 92% or higher on room air
• * Not requiring pressor support, no symptomatic cardiac arrhythmias, no acute coronary syndrome, or uncontrolled hypertension
• * Serum creatinine did NOT increase by more than 2.5 fold from base line (at time of screening )
• * Adequate liver function defined as total bilirubin /< 3.0 mg/dl, AST /< 5 x ULN; ALT /< 5 x ULN
• * Research participant without clinically significant encephalopathy/new focal deficits
• * No clinical evidence of uncontrolled active infectious process

Критерии исключения

• * Allogeneic stem cell transplant within 100 days at the time of enrollment
• * Received prior CAR T therapy within 90 days of enrollment
• * EXCEPTION: Participants who have previously received B-cell-activating factor receptor (BAFFR)-CAR T cells will be excluded from this study
• * Failure of research participant to understand the basic elements of the protocol and/or the risks/benefits of participating in this phase I study
• * History of allergic reactions attributed to compounds of similar chemical or biologic composition to study agent(s)
• * History or presence of clinically relevant CNS pathology such as uncontrolled seizure disorder, recent stroke, severe brain injuries, dementia, cerebellar disease or psychosis
• * Autoimmune disease or active graft versus host disease (GVHD) requiring systemic immunosuppressant therapy
• * Class III/IV cardiovascular disability according to the New York Heart Association (NYHA) Classification
• * History of other malignancies, except for malignancy surgically resected (or treated with other modalities) with curative intent, basal cell carcinoma of the skin or localized squamous cell carcinoma of the skin; non-muscle invasive bladder cancer; malignancy treated with curative intent with no known active disease present for ≥ 2 years
• * Clinically significant uncontrolled illness
• * Active systemic uncontrolled infection requiring antibiotics
• * Known history of immunodeficiency virus (HIV) or hepatitis B or hepatitis C infection
• * Subjects who are hepatitis B core antibody (anti-HBc) positive and who are surface antigen negative will need to have a negative polymerase chain reaction (PCR) result. Those who are hepatitis B surface antigen (HbsAg) positive or hepatitis B PCR positive will be excluded
• * Subjects who are hepatitis B core antibody positive (or have a known history of HBV infection) should be monitored quarterly with a quantitative PCR test for HBV deoxyribonucleic acid (DNA). HBV monitoring should last until 12 months after the last dose of study drug. Any subject with a rising viral load (above lower limit of detection) should discontinue study drug and have antiviral therapy instituted and a consultation with a physician with expertise in managing hepatitis B. Subjects who are core antibody (Ab) positive at study enrollment are strongly recommended to start Entecavir before start and until completion of study treatment
• * Subjects who are hepatitis C antibody positive will need to have a negative PCR result. Those who are hepatitis C PCR positive will be excluded
• * Females only: Pregnant or breastfeeding
• * Concurrent use of systemic steroids or chronic use of immunosuppressant medications. Recent or current use of topical or inhaled steroids is not exclusionary. Physiologic replacement of steroids (prednisone ≤ 7.5 mg /day or equivalent) is allowed
• * Any other condition that would, in the investigator`s judgment, contraindicate the patient`s participation in the clinical study due to safety concerns with clinical study procedures
• * Prospective participants who, in the opinion of the investigator, may not be able to comply with all study procedures (including compliance issues related to feasibility/logistics)

Описание

Background:

Chimeric antigen receptor T-cell (CART) therapy is a form of immunotherapy which can be used to treat people with relapsed B-ALL. For those who achieve remission after CART alone, it may cure up to 50% of people who receive this therapy. However, for people who relapse after CART, it can be hard to achieve remission again. In patients where CART fails, stem cell transplant (HCT) can be used to prevent relapse and achieve cure. But HCT can cause serious side effects. Better testing is needed to distinguish people who can be cured with CART alone from people who may also need to have HCT.

Objective:

To see if the use of a series of blood and bone marrow tests at regular intervals can help monitor for B-ALL relapse after CART therapy.

Eligibility:

People aged 1 to 25 years with B-ALL who have had CART therapy within the past 42 days. They must never have had a blood stem cell transplant; they must also have no measurable blood cancer cells.

Design:

Participants will visit the clinic every 2 weeks starting 42 days after they receive CART therapy. Each visit will be about the same amount of time as a regular clinic visit. about 8 hours.

Participants will have blood drawn for testing on each visit.

Bone marrow biopsy/aspirate will be done during 4 of the visits at routine timepoints after CART. A needle will be inserted to draw a sample of tissue from inside the bone in the hip.

A small amount of blood and tissue will be tested with ClonoSEQ and to evaluate for normal B-cells side by side with the standard tests.

The combined testing may help determine whether participants are eligible for HCT and/or at risk of relapse after CART.

Participants will be in the study for 1 year

Критерии включения

• * INCLUSION CRITERIA:
• * Age />=1 year and /<= 25 years old at the time of CD19 CART infusion
• * Confirmed diagnosis of CD19+ B-ALL with an informative NGS clonality sample
• --Have an informative NGS clonality sample for MRD assessment based on immunoglobulin rearrangement in bone marrow or blood at any time of active disease between diagnosis and CD19 CART infusion and any time prior to the first on-study intervention confirmed by NGS MRD testing.
• * Post-CD19 CART infusion disease status:
• * Are in bone marrow morphologic complete remission and are flow cytometry measurable residual disease (MRD) negative within 42 days post CD19 CART infusion and within 14 days prior to the first on-study intervention.
• * Are NGS MRD negative by tracking sample in the bone marrow within 42 days post CD19 CART infusion and within 14 days prior to the first on-study intervention confirmed by NGS MRD testing.
• * Have an absolute neutrophil count (ANC) /> 500 cell/mm/^3 without needing growth factor support by 42 days post CD19 CART infusion and within 4 days prior to the first on-study intervention.
• * Received first CD19 (4-1BB) CART within 42 days prior to the first on-study intervention. Note: Eligible CART including FDA approved Kymriah (tisagenlecleucel) infused on a treatment plan, research study, or other comparable 4-1BB based constructs.
• Study chairs will determine whether other 4-1BB CART are considered comparable.
• * All participants must have an allogeneic HCT donor identified for potential HCT. Note: Donor identification and selection will be according to institutional practice.
• * Have B-cell aplasia (BCA) post CD19 CART persisting within 14 days prior to the first on-study intervention. Note: BCA persisting is defined as /<1% B cells lymphocytes or /<50 B cells/microliter in the peripheral blood
• * Performance of all screening tests prior to day 42 post CD19 CART.
• * The ability of participant or parent/guardian to understand and the willingness to sign a written consent document or participants unable to consent if they are represented by a Legally Authorized Representative (LAR).

Критерии исключения

• * Prior hematopoietic stem cell transplantation (HCT)
• * Recent history of the extramedullary disease (EMD) that requires ongoing radiographic surveillance (e.g., participants with active EMD at CD19 CART infusion that requires monitoring by imaging without the ability to more precisely assess disease status will be ineligible). A remote history of EMD does not exclude the participant.
• * Active and/or residual central nervous system (CNS) disease that requires ongoing therapy or monitoring.
• * Co-morbidities precluding myeloablative HCT. Note: Determination of co-morbidities precluding myeloablative HCT will be made by the treating transplant (HCT) physician and documented in the research record. This does not require that the participant is immediately fully eligible for HCT, only that there are no long-term comorbidities that would preclude a myeloablative approach (e.g., renal failure, severe cardiac failure, long-term oxygen requirement).
• * Uncontrolled, symptomatic, intercurrent illness or social situations that would limit compliance with study requirements. Note: Determination of uncontrolled, symptomatic illness or social situation that would limit compliance with the study requirements will be made by the site-PI and documented in the research record.

Описание

The current study will assess the acceptability and feasibility of the CareMeds intervention with a larger sample (N = 100) across multiple sites in Buffalo, NY, and Atlanta, GA.

Критерии включения

• * Parent of a child who is diagnosed and being treated for any type of acute lymphoblastic leukemia (ALL) at a study site.
• * Parent has primary medication responsibility.
• * Pediatric patient aged 3-9 years
• * Child on therapy that includes home-based oral anti-cancer medication taken at home, such as 6-MP.
• * Parent has verbal English or Spanish fluency.
• * Participant must understand the investigational nature of this study and sign an Independent Ethics Committee/Institutional Review Board approved written informed consent form prior to receiving any study related procedure

Критерии исключения

• * Parent of a child who is not diagnosed nor being treated for any type of acute lymphoblastic leukemia (ALL) at a study site.
• * Parent does not have primary medication responsibility.
• * Pediatric patient aged 3-9 years
• * Pediatric patient is not on therapy that includes oral anti-cancer medication (e.g., 6-MP).
• * Parent does not have verbal English or Spanish fluency.
• * Parent is unwilling or unable to follow protocol requirements