OncoTrials - мониторинг клинических исследований

Описание

This phase III trial compares the effect of the combination of blinatumomab with dasatinib or imatinib and standard chemotherapy versus dasatinib or imatinib and standard chemotherapy for treating patients with Philadelphia chromosome positive (PH+) or ABL-class Philadelphia chromosome-like (Ph-Like) B-Cell acute lymphoblastic leukemia (B-ALL). Blinatumomab is a bispecific antibody that binds to two different proteins-one on the surface of cancer cells and one on the surface of cells in the immune system. An antibody is a protein made by the immune system to help fight infections and other harmful processes/cells/molecules. Blinatumomab may bind to the cancer cell and a T cell (which plays a key role in the immune system`s fighting response) at the same time. Blinatumomab may strengthen the immune system`s ability to fight cancer cells by activating the body`s own immune cells to destroy the tumor. Dasatinib and imatinib are in a class of medications called tyrosine kinase inhibitors. They work by blocking the action of an abnormal protein that signals cancer cells to multiply, which may help keep cancer cells from growing. Giving blinatumomab and dasatinib or imatinib in combination with standard chemotherapy may work better in treating patients with PH+ or Ph-Like ABL-class B-ALL compared to dasatinib or imatinib and chemotherapy alone.

Критерии включения

• * Patients must be /> 365 days and /< 18 years (for AIEOP-BFM), /> 365 days and /< 22 years (for Children`s Oncology Group /[COG/]) and /> 365 days and /< 46 years (for ALLTogether sites) at the time of enrollment
• * Newly-diagnosed Ph+ or Ph-like ABL-class B-ALL. Leukemic blasts must express CD19. ABL-class fusions are defined as rearrangements involving the following genes predicted to be sensitive to imatinib and/or dasatinib: ABL1, ABL2, CSF1R, and PDGFRB
• * Evidence of BCR::ABL1 should be documented by a clinically-validated assay prior to study entry on day 15 from the first dose of vinCRIStine during Induction therapy. ABL-class Ph-like B-ALL gene rearrangements should be documented by a clinically-validated assay and enrolled on study by day 1 of Blinatumomab Block 1. Accepted methods of detection include fluorescence in situ hybridization (FISH) using break-apart of colocalization signal probes, singleplex or multiplex reverse-transcription polymerase chain reaction (RT-PCR), whole-transcriptome or panel-based ribonucleic acid (RNA) sequencing (e.g., Hematologic Cancer Fusion Analysis, TruSight RNA Pan-Cancer Panel or equivalent). Confirmation of 5` fusion partner genes is not required for study enrollment
• * Patients with Ph+ B-ALL must have previously started Induction therapy, which includes vinCRIStine, a corticosteroid, pegaspargase or calaspargase pegol, with or without anthracycline, and/or other standard cytotoxic chemotherapy
• * Patients with Ph+ B-ALL have not received more than 14 days of systemic Induction therapy beginning with the first Induction dose of vinCRIStine
• * Patients with ABL-class Ph-like B-ALL must have previously completed 4 or 5 weeks of multiagent Induction chemotherapy (Induction 1A)
• * Patients may have started either imatinib or dasatinib prior to study entry but should have received no more than 14 days of TKI for Ph+ B-ALL or no more than 35 days of TKI for ABL-class Ph-like B-ALL
• * Patients must have a performance status corresponding to Eastern Cooperative Oncology Group (ECOG) scores of ≤ 2 or Karnofsky and Lansky performance scores ≥ 50%. Use Karnofsky for patients /> 16 years of age and Lansky for patients ≤ 16 years of age
• * For pediatric patients (age 1-17 years): a glomerular filtration rate (GFR) ≥ 50 mL/min/1.73 m/^2, as determined by one of the following methods (must be performed within 7 days prior to enrollment unless otherwise indicated):
• * Estimated GFR (eGFR) ≥ 50 mL/min/1.73 m2
• * Measured GFR ≥ 50 mL/min/1.73 m/^2 (any age). If measured GFR is used, it must be performed using direct measurement with a nuclear blood sampling method or small molecule clearance method (iothalamate or other molecule per institutional standard
• * For adult patients (age 18 years or older): Creatinine clearance ≥ 30 mL/min, as estimated by the Cockcroft and Gault formula. The creatinine value used in the calculation must have been obtained within 28 days prior to registration. Estimated creatinine clearance is based on body weight
• * Direct bilirubin /< 2.0 mg/dL (34.2 micromoles/L) (must be performed within 7 days prior to enrollment unless otherwise indicated)
• * Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 10 x upper limit of normal (ULN) (must be performed within 7 days prior to enrollment unless otherwise indicated)
• * /* Shortening fraction of ≥ 27% by echocardiogram (must be obtained within 21 days prior to enrollment and start of protocol therapy /[repeat if necessary/]) OR
• * Left Ventricular Ejection fraction of ≥ 50% by radionuclide angiogram or echocardiogram (must be obtained within 21 days prior to enrollment and start of protocol therapy /[repeat if necessary/]) AND
• * Corrected QT Interval, QTc /< 480mSec (must be obtained within 21 days prior to enrollment and start of protocol therapy /[repeat if necessary/])
• * Note: Repeat echocardiogram and electrocardiogram are not required if they were performed at or after initial ALL diagnosis before study enrollment

Критерии исключения

• * Known history of chronic myeloid leukemia (CML)
• * ABL-class Ph-like B-ALL who are CNS2 or CNS3 at end of Induction phase
• * ALL developing after a previous cancer treated with cytotoxic chemotherapy
• * Active, uncontrolled infection or active systemic illness that requires ongoing vasopressor support or mechanical ventilation
• * Down syndrome (trisomy 21)
• * Pregnancy and breast feeding
• * Female patients who are pregnant since fetal toxicities and teratogenic effects have been noted for several of the study drugs. A negative pregnancy test is required for female patients of childbearing potential within 7 days prior to enrollment
• * Lactating females who plan to breastfeed their infants
• * Sexually active male and female patients of reproductive potential who have not agreed to use an effective contraception method for the duration of treatment according to protocol
• * NOTE: Patients who could become pregnant or could father a child must use effective contraception during protocol treatment and for 30 days after the last dose of dasatinib or 14 days after the last dose of imatinib dose or per institutional standard of care for multiagent chemotherapy, whichever is longer
• * Prior treatment with TKIs before study entry with the exception of imatinib or dasatinib
• * Patients with congenital long QT syndrome, history of ventricular arrhythmias, or heart block
• * Patients with known Charcot-Marie-Tooth disease
• * Patients with significant central nervous system pathology that would preclude treatment with blinatumomab, including history of severe neurologic disorder or autoimmune disease with central nervous system (CNS) involvement
• * Note: Patients with a history of seizures that are well controlled on stable doses of anti-epileptic drugs are eligible. Patients with a history of cerebrovascular ischemia/hemorrhage with residual deficits are not eligible. Patients with a history of cerebrovascular ischemia/hemorrhage remain eligible provided all neurologic deficits have resolved
• * HIV-infected patients are eligible if on effective anti-retroviral therapy that does not interact with planned study agents and with undetectable viral load within 6 months of treatment
• * 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 is a prospective, multicenter, randomized controlled trial designed to evaluate whether short-term blinatumomab intensification before allogeneic hematopoietic stem cell transplantation (allo-HSCT) can improve survival outcomes in adults with high-risk BCR::ABL1-negative B-cell acute lymphoblastic leukemia (B-ALL) who have achieved measurable residual disease (MRD) negativity. Blinatumomab, a CD19/CD3 bispecific T-cell engager, has shown promising efficacy in eradicating MRD and prolonging survival in B-ALL patients. In this study, eligible participants will be randomly assigned to receive either short-term blinatumomab consolidation prior to allo-HSCT or proceed directly to allo-HSCT. The primary endpoint is relapse-free survival (RFS). This study aims to optimize treatment strategies and improve long-term outcomes for patients with high-risk BCR::ABL1-negative B-ALL.

Критерии включения

• 1. Diagnosed with B-cell acute lymphoblastic leukemia (B-ALL) according to the 2022 WHO classification.
• 2. Age between 18 and 65 years. 3. Meets the National Comprehensive Cancer Network (NCCN) criteria for high-risk B-ALL, based on clinical or cytogenetic/molecular features:
• 1. Clinical high-risk features (any of the following):
• 1. Age /> 35 years
• 2. Peripheral WBC count /> 30 × 10⁹/L
• 3. Cytogenetic/molecular high-risk features (any of the following):
• 2. Cytogenetic and molecular high-risk features (at least one of the following):
• 1. Hypodiploidy (/<44 chromosomes)
• 2. TP53 mutation
• 3. KMT2A rearrangement
• 4. MLL rearrangement
• 5. HLF rearrangement
• 6. ZNF384 rearrangement
• 7. MEF2D rearrangement
• 8. MYC rearrangement
• 9. BCR-ABL1-like (Ph-like) ALL, including:
• 10. JAK pathway rearrangements (CRLF2r, EPORr, JAK1/2/3r, TYK2r, SH2B3 mutation, IL7R mutation, JAK1/2/3 mutations)
• 11. ABL-class rearrangements (ABL1, ABL2, PDGFRA, PDGFRB, FGFR1)
• 12. Other kinase fusions (e.g., NTRK3r, FLT3r, LYNr, PTK2Br)
• 13. PAX5alt
• 14. t(9;22)(q34.1;q11.2); BCR-ABL1 with IKZF1 mutation and/or prior chronic myeloid leukemia (CML)
• 15. Intrachromosomal amplification of chromosome 21 (iAMP21)
• 16. IKZF1 alteration
• 17. Complex karyotype (≥5 chromosomal abnormalities) 4. CD19-positive by immunophenotyping. 5. BCR::ABL1-negative. 6. Achieved complete remission (CR) after induction therapy. 7. Measurable residual disease (MRD)-negative by flow cytometry (FCM). 8. Availability of a matched sibling donor, haploidentical related donor, or matched/unmatched unrelated donor.
• 9. ECOG performance status score of 0-2. 10. Creatinine clearance ≥ 60 mL/min (by Cockcroft-Gault formula). 11. AST and ALT ≤ 3 × upper limit of normal (ULN); total bilirubin ≤ 2 × ULN. 12. Left ventricular ejection fraction (LVEF) ≥ 50% by echocardiography. 13. Expected survival /> 8 weeks. 14. Signed written informed consent, with ability to understand and comply with the study protocol.
• Exclusion Criteria:
• 1. Prior exposure to blinatumomab, chimeric antigen receptor (CAR) T-cell therapy, or anti-CD22 immunotoxins.
• 2. Clinically significant cardiovascular disease, including uncontrolled arrhythmia, uncontrolled hypertension, congestive heart failure, NYHA class III or IV heart disease, or myocardial infarction within 3 months prior to screening.
• 3. Other severe comorbidities that may limit participation in the trial (e.g., severe infection, renal failure).
• 4. Known HIV infection or uncontrolled severe viral hepatitis.
• 5. Pregnant or breastfeeding women.

Критерии исключения

Описание

The goal of this clinical trial is to see if adding abatacept to tacrolimus and MMF prevents or reduces the chances of acute graft versus host disease which is a complication that can occur after transplant in participants with blood cancer. The usual therapy for graft versus host disease prevention after a cord blood transplant includes tacrolimus and MMF. The main question this clinical trial aims to answer is whether or not abatacept will be safe and effective in reducing aGVHD rates in dCBT.

Participants will:

* Partake in exams, tests, and procedures as part of usual cancer care.
* Partake in conditioning, which is the treatment that is given before a transplant.
* Have a cord blood transplant.
* Partake in radiation following the transplant.

Критерии включения

• * Patients with the following hematologic malignancies:
• * Acute myelogenous leukemia (AML): High-risk and intermediate-risk AML including:
• * Antecedent hematological disease (e.g., myelodysplasia (MDS))
• * Treatment-related leukemia
• * Complete Remission (CR1) with poor or intermediate-risk cytogenetics or molecular markers (e.g. Flt 3 mutation, 11q23, del 5, del 7, complex cytogenetics)
• * CR2 or CR3
• * Induction failure or 1st relapse with /< 10% blasts in the marrow
• * Acute lymphoblastic leukemia (ALL):
• * High-risk CR1 including:
• * Poor-risk cytogenetics (e.g., Philadelphia chromosome t(9;22)or 11q23 rearrangements)
• * Philadelphia chromosome-like ALL
• * Presence of minimal disease by flow cytometry after 2 or more cycles of chemotherapy
• * No CR within 4 weeks of initial treatment
• * Induction failure with /< 10% blasts in the marrow
• * CR2 or CR3
• * Myelodysplastic syndromes (MDS), Intermediate, High or Very High Risk by the revised international prognostic scoring system or treatment related MDS.
• * Bi-phenotypic or mixed-phenotypic acute leukemia in:
• * CR.
• * Induction failure or 1st relapse with /< 10% blasts in the marrow.
• * Chronic Myelogenous Leukemia (CML) in second chronic phase after accelerated or blast crisis.
• * Chronic Myelomonocytic Leukemia (CMML)
• * Hodgkin`s Lymphoma that is relapsed or refractory
• * Age /> or equal to 18 years, /< or equal to 70yrs
• * KPS /> or equal to 80 for Flu/Cy/Thio/TBI; KPS /> 60 for Flu/Treo/TBI
• * Patients without a suitable HLA-matched related or unrelated donor
• * Patient with the following CB units:
• * At least two 4-8/8 HLA high resolution matched CB units. Both must have a cell dose of 1.5x107 TNC/kg each and 1.5x105 CD34+/kg
• * A minimum of 1 CB unit as back up.
• * Concurrent Therapy for Extramedullary Leukemia or CNS Lymphoma: Concurrent therapy or prophylaxis for testicular leukemia, CNS leukemia, and CNS lymphoma including standard intrathecal chemotherapy and/or radiation therapy will be allowed as clinically indicated. Such treatment may continue until the planned course is completed. Subjects must be in CNS remission at the time of protocol enrollment if there is a history of CNS involvement. Maintenance therapy after transplant is allowed.
• * Subjects must have the ability to understand and the willingness to sign a written informed consent document.
• * For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use a contraceptive method with a failure rate of /< 1% per year during the treatment period and for 12 months after the last dose of abatacept.
• * A woman is considered to be of childbearing potential if she is /< 60 years old, postmenarcheal, has not reached a postmenopausal state (/< 12 continuous months of amenorrhea with no identified cause other than menopause), and has not undergone surgical sterilization (removal of ovaries and/or uterus).
• * Examples of contraceptive methods with a failure rate of /< 1% per year include bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices.
• The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception.
• * For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures with female partners of reproductive potential, and agreement to refrain from donating sperm, as defined below:
• * With female partners of childbearing potential, men must remain abstinent or use a condom plus an additional contraceptive method that together result in a failure rate of /< 1% per year during the treatment period and for 12 months after the last dose of abatacept. Men must refrain from donating sperm during this same period. With pregnant female partners, men must remain abstinent or use a condom during the treatment period and for at least 12 months after the last dose of abatacept.
• * The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception.

Критерии исключения

• * Patients with inadequate Organ Function as defined by:
• * Creatinine clearance /< 50ml/min
• * Bilirubin /> 2X institutional upper limit of normal unless Gilbert syndrome
• * AST (SGOT) /> 3X institutional upper limit of normal
• * ALT (SGPT) /> 3X institutional upper limit of normal
• * Pulmonary function: DLCOc /< 60% normal
• * Cardiac: left ventricular ejection fraction /< 50
• * Patients with uncontrolled inter-current illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
• * Pregnant or breastfeeding women are excluded from this study because chemotherapy involved with RIC have the significant potential for teratogenic or abortifacient effects.
• * Any condition that would, in the investigator`s judgment, interfere with full participation in the study, including administration of study drug and attending required study visits; pose a significant risk to the subject; or interfere with interpretation of study data.
• * Known allergies, hypersensitivity, or intolerance to any of the study medications, excipients, or similar compounds.
• * Presence of donor-specific antibodies against chosen graft source.
• * Hematopoietic Cell Transplantation Comorbidity index (HCT-CI) /> 5.
• * Prior autologous or allogenic stem cell transplant within the preceding 12 months.

Описание

CAR19PK is a research study evaluating the use of lymphodepleting chemotherapy and chimeric antigen receptor (CAR) T cell therapy, a type of cellular therapy, for the treatment of refractory and/or relapsed leukemia. For this type of therapy, peripheral (circulating) immune cells are collected and then modified so that they can recognize an antigen, which is a particle present on the surface of a cancer cell. The CD19-CAR T cell product will be manufactured at the St. Jude Children`s Research Hospital`s Good Manufacturing Practice (GMP) facility.

The main purpose of this study is to determine:

* Evaluate different doses of fludarabine prior CAR T cell infusion
* How your body processes fludarabine and cyclophosphamide,
* How long the CAR T cells last in the body,
* Whether or not treatment with this therapy is effective in treating people with refractory or relapsed leukemia, and
* The side effects of this therapy.

Критерии включения

• Autologous Apheresis and Manufacturing
• Inclusion Criteria:
• * CD19+ leukemia/*/* with any of the following:
• * Refractory disease (primary or in relapse)
• * 2nd or greater relapse
• * Any relapse after allogeneic hematopoietic cell transplantation
• * 1st relapse if patient requires an allogeneic HCT as part of standard of care relapse therapy, but is found to be ineligible and/or unsuitable for HCT
• * must be confirmed to be CD19+ within 3 months prior to enrollment for treatment
• * Age: ≤ 21 years of age
• * Karnofsky or Lansky (age-dependent) performance score ≥ 50 (Appendix A)
• * Estimated life expectancy of /> 12 weeks. Patients with a history of prior allogeneic hematopoietic cell transplantation /[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
• * For females of child bearing age:
• * Not lactating with intent to breastfeed
• * Not pregnant with negative serum pregnancy test within 7 days prior to enrollment

Критерии исключения

• * Known primary immunodeficiency
• * History of HIV infection
• * Severe intercurrent bacterial, viral or fungal infection
• * History of hypersensitivity reactions to murine protein-containing products
• * Known contraindication to receiving protocol defined lymphodepleting chemotherapy regimen
• Treatment
• Inclusion Criteria:
• * Age: ≤ 21 years of age
• * Estimated life expectancy of /> 8 weeks
• * Detectable disease
• * Prior to planned CAR T cell infusion, patients with a history of prior allogeneic HCT must:
• * be at least 3 months from HCT
• * have no evidence of active GVHD
• * have not received a donor lymphocyte infusion (DLI) within the 28 days prior to planned infusion
• * Adequate cardiac function defined as left ventricular ejection fraction /> 40%, or shortening fraction ≥ 25%
• * EKG without evidence of clinically significant arrhythmia
• * Adequate renal function defined as creatinine clearance or radioisotope GFR ³ 50 ml/min/1.73m2 (GFR ³ 40 ml/min/1.73m2 if /< 2 years of age)
• * Adequate pulmonary function defined as forced vital capacity (FVC) ≥ 50% of predicted value; or pulse oximetry ≥ 92% on room air if patient is unable to perform pulmonary function testing
• * Karnofsky or Lansky (age-dependent) performance score ≥ 50 (Appendix A)
• * Total Bilirubin ≤ 3 times the upper limit of normal for age, except in subjects with Gilbert`s syndrome
• * Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≤ 5 times the upper limit of normal for age
• * Has recovered from all NCI CTAE grade III-IV, non-hematologic acute toxicities from prior therapy
• * For patients of child bearing age:
• * Not lactating with intent to breastfeed
• * Not pregnant with negative serum pregnancy test within 7 days prior to enrollment
• * If sexually active, agreement to use birth control until 6 months after T cell infusion.
• Exclusion Criteria:
• * Active CNS-3 disease
• * Known primary immunodeficiency
• * History of HIV infection
• * Evidence of active, uncontrolled neurologic disease
• * Severe, uncontrolled bacterial, viral or fungal infection
• * History of hypersensitivity reactions to murine protein-containing products
• * Known contraindication to receiving protocol defined lymphodepleting chemotherapy regimen

Описание

This study is an investigator-initiated single center, single arm clinical study with a target population of patients with relapsed or refractory B cell lymphoma /leukemia. It is an early exploratory clinical study of the safety, tolerability and initial efficacy of JY231 injection in the treatment of relapsed or refractory B cell lymphoma / leukemia.

Критерии включения

• 1. Subject voluntarily sign informed consent and are willing and able to comply with all trial requirements;
• 2. Age is 18-75 years old and gender is not limited;
• 3. Malignancy cells in bone marrow or peripheral blood are Cluster of Differentiation 19 - positive(CD19+) detected by flow cytometric analysis;
• 4. Meet the clinical criteria for relapsed or refractory B-cell lymphoma, including: indolent lymphoma (iNHL), such as follicular lymphoma (FL) and marginal zone lymphoma (MZL); aggressive B-cell lymphoma, like diffuse large B-cell lymphoma (DLBCL), primary mediastinal large B-cell lymphoma (PMBCL), transformed follicular lymphoma (TFL), and T-rich lymphocyte-bearing large B-cell lymphoma (TCRBCL), or have a diagnosis of acute B-lymphocytic leukemia (B-ALL) and meet one of the following conditions:
• * Refractory B-ALL: those who did not achieve complete remission after 2 courses of standard induction regimen chemotherapy, or those who did not achieve complete remission after first-line or multi-line salvage chemotherapy;
• * Relapsed B-ALL: relapse within 12 months after first remission, or relapse after first-line / multi-line salvage chemotherapy;
• * Relapse after autologous or allogeneic hematopoietic stem cell transplantation; In addition, patients with Philadelphia chromosome positive (Ph +) should be relapsed after at least two tyrosine kinase inhibitors (TKI) treatment, or they could not tolerate TKI therapy, or have a t315i mutation, resistant to TKI drugs.
• 5. Morphological examination of bone marrow cells showed the proportion of primitive and naive lymphocytes was/> 5%;
• 6. No Hematopoietic Stem Cell Transplantation(HSCT) within 6 months before enrollment;
• 7. At least one measurable lesion was imaging for relapsed or refractory B cell lymphoma, long diameter of/> 15mm, or extranodal lesion of/> 10mm, along with a positive Positron Emission Tomography - Computed Tomography(PET-CT) examination.
• 8. More than 12 weeks of expected survival period
• 9. Baseline Eastern Cooperative Oncology Group(ECOG) score was 0-1;
• 10. Adequate organ function (criteria regarding liver and kidney function can be moderately relaxed):
• * Glutamic aminotransferase (ALT) ≤3 times upper limit of normal (ULN);
• * Grass aminotransferase (AST) ≤3 times ULN;
• * Total bilirubin ≤1.5 times ULN;
• * Serum creatinine ≤ 1.5 times ULN, or creatinine clearance ≥ 60 mL/min;
• * Indoor oxygen saturation ≥ 92%;
• * Left ventricular ejection fraction (LVEF)≥55%, echocardiography confirmed no pericardial effusion and no clinically significant ECG findings;
• * There is no clinically significant pleural effusion;
• 11. Adequate bone marrow reserve without transfusion, defined as:
• * Absolute neutrophil count (ANC)/>1.000 / mm3;
• * Absolute lymphocyte count (ALC)≥ 300 / mm3;
• * Platelet≥50.000/mm3;
• * Hemoglobin/>8.0 g/dl;
• 12. Subjects using the following drugs need to meet the following conditions:
• * Steroids: The therapeutic dose of steroids must be stopped 72 hours before JY231 infusion. However, physiological alternative doses of steroids are allowed;
• * Immunosuppression: Any immunosuppressive drug must be stopped at ≥4 weeks prior to enrollment;
• * Antiproliferative therapy other than lymphodepletion chemotherapy within two weeks of infusion;
• * Cluster of Differentiation 20(CD20) antibody-related therapy must be stopped within 4 weeks before infusion or 5 half-lives after the CD20 antibody;
• * CNS disease prophylaxis must be stopped 1 week before JY231 infusion (e. g. intrathecal methotrexate).
• 13. Reproductive men, sexual partners ensure effective contraception; fertile women, adopted effective contraception and agreed to use contraception throughout the study period.

Критерии исключения

• 1. Subjects with active cerebrospinal fluid malignant cells or brain metastases, or subjects with active central nervous system (CNS) lymphoma, or CNS leukaemia;
• 2. Subjects with a history of active CNS disease, such as seizures, cerebrovascular ischemia / hemorrhage, dementia, cerebellar disease, or any autoimmune disease associated with CNS involvement;
• 3. Subjects who have received other study drugs within 30 days before screening, or are still in the washout period;
• 4. Patients who have previously received any anti-CD19 / anti-Cluster of Differentiation 3(CD3) therapy or any other anti-CD19 therapy (except for those with normal T cell numbers and function and with CD19-positive tumors);
• 5. Patients who have been previously treated with any gene therapy product, including Chimeric Antigen Receptor T(CAR-T) therapy (except patients who do not have CAR-T cells in vivo and have normal T cell number and function and are with CD19 positive tumors);
• 6. Subjects with radiation therapy within 2 weeks prior to the infusion;
• 7. Subjects with active hepatitis B (defined as Hepatitis B Virus(HBV) DNA test value/> 500 IU / mL) or hepatitis C (HCV RNA positive); subjects with HIV positive or treponema pallidum positive;
• 8. Subjects with uncontrolled acute life-threatening bacterial, viral, or fungal infection (e. g. positive blood culture 72 hours before infusion);
• 9. Subjects with unstable angina pectoris and / or myocardial infarction within the 6 months prior to screening;
• 10. Subjects with concurrent or previously diagnosed with other malignancies, except for the patients under following conditions:
• * Well treated basal cells, papillary thyroid carcinoma, squamous cell carcinoma (adequate wound healing is required before enrollment into this study);
• * Carcinoma in situ of cervical cancer or breast cancer, after curative treatment, showed no signs of recurrence for at least 3 years before the study;
• * The primary malignancy has been completely removed and is in complete remission for 5 years.
• 11. Arrhythmic subjects without medical management control;
• 12. Subjects receiving oral anticoagulation within 1 week before JY231 injection infusion;
• 13. Having active neurological autoimmune or inflammatory conditions (such as Guillain-Barre syndrome, amyotrophic lateral sclerosis);
• 14. Female subjects in pregnant or lactating, or women with planned pregnancy within 2 years after JY231 infusion or male partner with planned pregnancy within 2 years after JY231 infusion;
• 15. Subjects with taboo study procedures or other medical conditions that may put them at unacceptable risk according to the investigator`s judgment and / or clinical criteria.
• 16）Other conditions that the investigator believes that the subjects should not be enrolled in this clinical trial, such as poor compliance.

Описание

This is a single-arm pilot clinical trial evaluating dalbavancin-based prophylaxis in children and adolescents with acute myeloid leukemia or relapsed lymphoblastic leukemia receiving myelosuppressive chemotherapy.

Primary objective:

- To estimate the rate of bacterial bloodstream infection in pediatric patients with AML or relapsed ALL undergoing chemotherapy receiving dalbavancin-based prophylaxis

Secondary objectives:

* To describe the population pharmacokinetics of every 28 days dalbavancin up to 12 weeks in pediatric patients with AML or relapsed ALL undergoing chemotherapy
* To describe the tolerability of every 28 days dalbavancin prophylaxis in pediatric patients with AML or relapsed ALL undergoing chemotherapy
* To describe the acceptability of every 28 days dalbavancin prophylaxis in pediatric patients with AML or relapsed ALL undergoing chemotherapy
* To estimate the rates of likely bacterial infections, Clostridioides difficile infection, and febrile neutropenia in pediatric patients receiving dalbavancin-based prophylaxis

Критерии включения

• * Aged less than or equal to 25 years at enrollment
• * Receiving treatment for AML or relapsed ALL at St. Jude and treatment is expected to cause prolonged (/> 7 days) severe neutropenia (ANC /< 500/ml)
• * Expected to receive care at St. Jude for at least 56 days following enrollment on the protocol
• * Female participant, greater than or equal to 9 years old, has a documented negative pregnancy test prior to receipt of study drug.

Критерии исключения

• * Allergy to vancomycin, dalbavancin, teicoplanin, levofloxacin or ciprofloxacin (Not including non-anaphylactic vancomycin infusion reaction)
• * Documented past or current infection or colonization with pathogenic bacteria resistant to vancomycin plus either ciprofloxacin or levofloxacin
• * Diagnosed with long QT syndrome
• * Any condition judged by the investigator to put the participant at high risk from participation
• * Suspected or proven active bacterial infection
• * Inability to complete requirements of participation in the study (in the opinion of the investigator)
• * Expected survival /<28 days
• * Alkaline phosphatase, alanine transferase or total bilirubin ≥ 3x upper limit of normal for age
• * Estimated glomerular filtration rate (EGFR) /<30 mL/minute/1.73 m2
• * Other absolute contraindication to administration of fluoroquinolone antibiotics or dalbavancin
• * Participant is pregnant or breastfeeding a child

Описание

This is an open label, single-site, dose-escalation study in up to 18 participants with Relapsed or Refractory Multiple Myeloma, Acute B-Cell Leukemia, and B-Cell Lymphoma. This study aims to evaluate the safety and efficacy of the treatment with Anti-BCMA and CD19 CART

Критерии включения

• 1. The patient or his/her guardian is fully informed and agrees to participate in this clinical study and signs the informed consent form;
• 2. At the time of signing the informed consent form, be over 3 years of age, regardless of gender;
• 3. Patients with a confirmed diagnosis of acute B-cell leukemia/B-cell lymphoma/multiple myeloma who meet one of the following criteria:
• 1. B diffuse large B-cell lymphoma (DLBCL), germinal center, or activated B-cell type; Primary cutaneous DLBCL; Primary mediastinal (thymic) large B-cell lymphoma; ALK anaplastic large B-cell lymphoma; High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangement (i.e., "double or triple hit"); High-grade B-cell lymphoma; T-cell-rich B-cell lymphoma; transformed follicular lymphoma; or any aggressive B-cell lymphoma caused by indolent lymphoma; follicular lymphoma; mantle cell lymphoma; Patients with large cell transformation (Richter`s Transformation) with CLL who have not achieved remission or have progressed after achieving remission after at least 1 prior line of therapy.
• 2. Patients diagnosed with acute B-cell leukemia: Patients who have achieved relapse after achieving remission after prior chemotherapy; or patients who have failed to achieve remission (/<5% bone marrow blasts or persistent extramedullary or central nervous system disease) after 2 prior cycles of induction chemotherapy, or who still maintain MRD.
• 3. Multiple Myeloma: Patients with confirmed diagnosis of multiple myeloma and patients with relapsed or refractory multiple myeloma according to IMWG 2016 diagnostic criteria.
• 4. For patients with B-cell lymphoma, according to the recommendations for initial evaluation, staging, and response evaluation of Hodgkin and non-Hodgkin lymphoma (2014 edition), at least one measurable lesion in the baseline period, i.e., lymph node lesions with a length diameter of /> 15 mm, or an extranodal lesion with a length diameter of /> 10 mm according to PETCT or CT imaging;
• 5. For patients with B-ALL, the proportion of bone marrow primitive and naïve lymphocytes in the screening period ≥5%;
• 6. CD19 expression of tumor cells confirmed by flow cytometry or immunohistochemistry: the proportion of CD19 cells detected by peripheral blood flow cytometry in patients with B-ALL was ≥30%, and the proportion of CD19 cells in patients with B-cell lymphoma was positive by immunohistochemistry;
• 7. Adequate function of vital organs: liver function satisfies ALT≤3×ULN, AST≤3×ULN; serum creatinine≤140μmol/L; Total bilirubin ≤ 2× ULN, and total bilirubin ≤ 3.0× ULN for patients with Gilbert syndrome; Haemodynamically stable and left ventricular ejection fraction (LVEF) ≥45% as determined by echocardiography or multichannel radionuclide angiography (MUGA); No active pulmonary infection, transcutaneous arterial oxygen saturation ≥92% in non-oxygen-based state;
• 8. ECOG score: 0/~2 points;
• 9. As judged by the investigator, the patient has an expected survival of more than 3 months;
• 10. Subjects of childbearing potential agree to use a reliable and effective method of contraception (excluding contraception during the safe period) for 2 years from the time of signing the informed consent form until receiving ECAR01 cell infusion.

Критерии исключения

• 1. Episodes of central nervous system disease or presence of pathological changes within 6 months prior to screening, including but not limited to: stroke, stroke, aneurysm, epilepsy, convulsions, aphasia, severe head injury, dementia, Parkinson`s disease, cerebellar disease, organic brain syndrome, or mental disorder;
• 2. patients with B-ALL with confirmed diagnosis of isolated extramedullary recurrence;
• 3. presence of malignancies other than acute B-cell leukemia/B-cell lymphoma;
• 4. Received the following anti-tumor therapies before cell collection: chemotherapy, targeted therapy, and other drug therapy within 14 days or at least 5 half-lives; Radiotherapy within 14 days;
• 5. Vaccination, B-cell targeted therapy within 4 weeks prior to screening;
• 6. Patient has systemic autoimmune disease or immunodeficiency;
• 7. Grade 2/~4 acute graft-versus-host disease (GVHD) or moderate to severe chronic GVHD within 4 weeks prior to screening;
• 8. Patients with relatively serious heart disease, such as angina, myocardial infarction, heart failure and arrhythmia;
• 9. History of severe allergy to drugs used in clinical studies or raw and excipient materials of experimental drugs, such as cyclophosphamide, fludarabine, DMSO, etc.;
• 10. Patient has active hepatitis B, or positive HCV antibody, or HIV antibody, or syphilis;
• 11. Presence of active infection requiring intravenous antibiotics or hospitalization;
• 12. Pregnant or lactating women;
• 13. Other investigators believe that the subject is not suitable to participate in this clinical study because it will affect the safety and efficacy judgment of the subject, or for other reasons

Описание

This phase II trial tests the addition of venetoclax and/or blinatumomab to usual chemotherapy for treating infants with newly diagnosed acute lymphoblastic leukemia (ALL) with a KMT2A gene rearrangement (KMT2A-rearranged /[R/]) or without a KMT2A gene rearrangement (KMT2A-germline /[G/]). Venetoclax is in a class of medications called B-cell lymphoma-2 (Bcl-2) inhibitors. It may stop the growth of cancer cells by blocking Bcl-2, a protein needed for cancer cell survival. Blinatumomab is a monoclonal antibody that may interfere with the ability of cancer cells to grow and spread. Chemotherapy drugs 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. Adding venetoclax and/or blinatumomab to standard chemotherapy may be more effective at treating patients with ALL than standard chemotherapy alone, but it may also cause more side effects. This clinical trial evaluates the safety and effectiveness of adding venetoclax and/or blinatumomab to chemotherapy for the treatment of infants with KMT2A-R or KMT2A-G ALL.

Критерии включения

• * All patients must be enrolled on APEC14B1 and consented to eligibility screening (part A) prior to treatment and enrollment on AALL2321
• * Infants (aged 365 days or less) on the date of diagnosis are eligible; infants must be /> 36 weeks gestational age at the time of enrollment
• * Patients must have newly diagnosed B-acute lymphoblastic leukemia (B-ALL, 2017 World Health Organization /[WHO/] classification), also termed B-precursor ALL, or acute leukemia of ambiguous lineage (ALAL), which includes mixed phenotype acute leukemia. For patients with ALAL, the immunophenotype of the leukemia must comprise at least 50% B lineage
• * Diagnostic immunophenotype: Leukemia cells must express CD19

Критерии исключения

• * Patients with Down Syndrome
• * Patients with secondary B-ALL that developed after treatment of a prior malignancy with cytotoxic chemotherapy
• * Patients must not have received any cytotoxic chemotherapy for either the current diagnosis of infant ALL or for any cancer diagnosis prior to the initiation of protocol therapy, with the exception of:
• * Steroid pretreatment:
• * PredniSONE, prednisoLONE, or methylPREDNISolone for ≤ 72 hours (3 days) in the 7 days prior to enrollment. The dose of predniSONE, prednisoLONE or methylPREDNISolone does not affect eligibility
• * Inhaled and topical steroids are not considered pretreatment
• * Note: Pretreatment with dexamethasone in the 28 days prior to initiation of protocol therapy is not allowed with the exception of a single dose of dexamethasone used during or within 6 hours prior to or after sedation to prevent or treat airway edema. However, prior exposure to ANY steroids that occurred /> 28 days before enrollment does not affect eligibility
• * Intrathecal cytarabine or methotrexate:
• * An intrathecal dose of cytarabine or methotrexate in the 7 days prior to enrollment does not affect eligibility
• * Note: The preference is to defer the diagnostic lumbar puncture with intrathecal chemotherapy to day 1 of induction to allow for cytoreduction of circulating blasts and decrease the potential for central nervous system (CNS) contamination due to a traumatic tap. If done prior to day 1 of induction, these results will be used to determine CNS status
• * Hydroxyurea:
• * Pretreatment with ≤ 72 hours (3 days) of hydroxyurea in the 7 days prior to enrollment does not affect eligibility
• * 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 will be a Phase 1, open-label study to evaluate the safety and efficacy of BEAM-201 in patients with R/R T-ALL or T-LLy. BEAM-201 is an allogeneic anti-CD7 CART therapy.

Критерии включения

• 1. Ages 0 to 29 years.
• 2. T-ALL/T-LLy in second or greater relapse, first relapse post-transplant, or chemotherapy-refractory disease. Specifically:
• * Second or greater relapse or post-transplant relapse, defined as:
• * BM with ≥ 5% lymphoblasts by morphologic assessment or evidence of extramedullary disease after second documented CR; OR
• * Flow cytometric confirmation of relapsed T-ALL of at least 0.1% after second CR documented to have been MRD negative /< 0.1%; OR
• * Any detectable relapsed disease post-allogeneic HSCT with flow cytometric confirmation of T-ALL of at least 0.1%; OR
• * Biopsy confirmed evidence of relapsed T-LLy after second CR; OR
• * Any detectable disease post-allogeneic transplant with biopsy confirmed evidence of T-LLy
• * Refractory disease, defined as:
• * Primary refractory T-ALL or T-LLy, defined as failure to achieve CR after induction chemotherapy, per investigator assessment and based on biopsy- or MRD-confirmed evidence of residual T-ALL or T-LLy; OR
• * Relapsed, refractory disease, defined as /> 0.1 % MRD or morphologic evidence of disease or evidence of residual T-LLy after 1 course of re-induction chemotherapy for patients who have relapsed after previously achieving a CR
• NOTE: Patients with mixed phenotype acute leukemia with T cell dominant phenotype may be enrolled if the aforementioned criteria are met.
• 3. Documentation of CD7 expression on leukemic blasts (defined as at least 20% of blasts positive for CD7 by flow cytometry or immunohistochemistry).
• 4. Patients with prior or current history of CNS3 disease will be eligible if CNS disease is responsive to therapy
• 5. Eligible for myeloablative conditioning for and allogeneic HSCT based on the investigator`s assessment with an available donor identified by a FACT accredited transplant center.
• 6. Lansky Performance Status (ages /< 16 years at time of consent) or Karnofsky Performance Status (KPS) (ages ≥ 16 years at time of consent) score of ≥ 50.
• 7. Patients of childbearing potential must have a negative urine or serum pregnancy test at screening.
• 8. Patients who are sexually active and of reproductive potential must agree to use an acceptable form of highly effective contraception from consent to 12 months after BEAM 201 infusion.
• 9. Patients (ages ≥ 18 years) or parent/legal guardians (for patients ages /< 18 years) must provide signed, written informed consent according to local IRB and institutional requirements.

Критерии исключения

• 1. CNS disease that is progressive on therapy, or with CNS parenchymal lesions that might increase the risk of CNS toxicity.
• 2. Clinically active CNS dysfunction or known history of irreversible central neurological toxicity related to prior antileukemic therapy.
• 3. Receipt of prior CD7 targeted therapy.
• 4. Systemic antileukemic therapy intended to induce remission within 14 days prior to completion of screening.
• 5. Radiation therapy within 2 weeks prior to completion of screening, other than prophylaxis for CNS disease.
• 6. Acute GVHD that is grade ≥ 2 and requiring systemic immunosuppression (corticosteroids), or chronic GVHD that is mild, moderate, or severe and requiring systemic immunosuppression (corticosteroids). Grade 1 acute GVHD not requiring immunosuppression is allowable.
• 7. Undergone HSCT within 90 days prior to completion of screening (or donor leukocyte infusion, if received within 30 days prior to completion of screening).
• 8. Evidence of organ dysfunction including:
• * Serum ALT ≥ 5 × ULN for age
• * Total bilirubin ≥ 3 × ULN for age
• * Serum creatinine that exceeds the maximum values listed in the protocol.
• * Any of the following cardiac criteria:
• i. Atrial fibrillation/flutter (not including isolated episodes that responded to medical management) ii. Myocardial infarction within the last 12 months iii. QT interval corrected for heart rate using Fridericia`s method (QTcF) /> 480 msec iv. Cardiac echocardiography (ECHO) with left ventricular shortening fraction (LVSF) /< 30% or left ventricular ejection fraction (LVEF) /< 50% or clinically significant pericardial effusion v. Cardiac dysfunction NYHA (New York Heart Association) III or IV
• * A minimum level of pulmonary reserve defined as />Grade 1 dyspnea and />Grade 3 hypoxia; DLCO 40% (corrected for anemia) if PFTs are clinically appropriate as determined by the investigator
• 9. Positive serology for:
• * Human immunodeficiency virus (HIV) (HIV-1 or HIV2)
• * Human T-cell lymphotropic virus (HTLV) (HTLV-1 or HTLV-2)
• * Hepatitis B (positive surface Ag or positive core Ab unless Hep B DNA negative by polymerase chain reaction /[PCR/])
• * Hepatitis C (if hepatitis C virus /[HCV/] antibody positive) must be HCV RNA PCR negative. Patients with sustained viral response /> 12 weeks following antiviral therapy are eligible as long as no history of hepatic cirrhosis is present.
• 10. Uncontrolled, active bacterial, viral, or fungal infection.
• 11. Any other condition that would make the patient ineligible for HSCT as determined by the investigator.
• 12. Patients with an autoimmune disorder requiring systemic immunosuppressive therapy that cannot be safely withheld for 3 months.
• 13. Concurrent use of systemic corticosteroids for diagnoses unrelated to T-ALL/T-LLy is prohibited, with exception of physiologic corticosteroid replacement therapy treatment for adrenal insufficiency.
• 14. Known primary immunodeficiency or BM failure syndrome.
• 15. Pregnant or breastfeeding.

Описание

This pilot study aims to gather preliminary evidence on how different hemoglobin levels impact blood biomarkers related to bleeding. The feasibility of conducting a future larger clinical trial will also be assessed. Red blood cell transfusions are part of the standard of care for patients with leukemia. This study evaluates two transfusion strategies: one that maintains hemoglobin levels above the standard-of-care threshold, reflecting current routine practice; and another that maintains hemoglobin levels above 110 g/L, which is closer to the normal hemoglobin range. The normal hemoglobin range is 120-160 g/L for females and 140-180 g/L for males. Raising hemoglobin levels closer to normal values may reduce bleeding risk.

Критерии включения

• 1. ≥18 years old.
• 2. Inpatient
• 3. Diagnosis of acute myeloid leukemia or acute lymphocytic leukemia.
• 4. Less than 5 days have elapsed since the start of induction chemotherapy treatment.
• 5. Hemoglobin at enrolment is under 130 g/L.

Критерии исключения

• 1. Failure to provide informed consent.
• 2. Unwilling to receive blood transfusions.
• 3. Life expectancy /<72 hours.
• 4. Undergoing palliative chemotherapy.
• 5. Requires specialized blood products (e.g., antigen-matched, irradiation, etc.).
• 6. Diagnosis of acute promyelocytic leukemia.
• 7. Diagnosis of hyperleukocytosis (a white blood cell count exceeding 100 × 10/^9/L).
• 8. Diagnosed with coagulopathies or ongoing treatment with therapeutic anticoagulants, aspirin or nonsteroidal anti-inflammatory drugs (history of inherited or acquired coagulation disorder, known hemolytic disease, INR /> 1.5)
• 9. Evidence of iron overload (ferritin />800 ng/mL, transferrin saturation />80%) .

Описание

This multicenter phase 1 trial with "3 + 3" dose escalation design seeks to examine the feasibility and safety of the administration of autologous T cells that have been modified through the introduction of chimeric antigen receptors targeting the B cell surface antigens CD19/20/22 following administration of a chemotherapy lymphodepletion regimen in adults with relapsed/refractory B-cell acute lymphoblastic leukemia (ALL) or Non-Hodgkin`s lymphoma (NHL). The overall goals of this study are to estimate maximum tolerated dose (MTD) level, establish the overall safety profile and evaluate initial efficacy of administering duo-CAR-T cell treatment in this patient population.

Критерии включения

• 1. Ability of participant to understand this study, and participant willingness to sign a written informed consent
• 2. Women of childbearing potential must have a negative serum pregnancy test 48 hours prior to the start of preparatory regimen
• 3. Patients must have histologically confirmed aggressive B-Cell NHL or ALL as stated below:
• A. Patients with relapsed or refractory B-Cell ALL i. Demonstration of one or more antigens of interest (CD19, CD20, CD22) in most recent disease evaluation prior to study entry and within 30 days of study entry.
• ii. Patients with relapsed/refractory disease in blood, marrow, and extramedullary sites including CSF will be eligible when there is immunophenotypic evidence of CD19 and/or CD20 and/or CD22 expression
• iii. Primary refractory disease at study entry defined as: A morphologic complete response has never been achieved prior to study entry.
• iv. Early first relapse at study entry defined as: Disease recurrence by morphologic assessment after duration of first remission at ≤ 18 months
• v. Relapsed Refractory disease (first or later relapse) at study entry defined as: Morphologic complete response was not achieved after initiation of a second-line (or later) systemic therapy
• vi. Second or greater relapse at study entry defined as: Any disease recurrence following a second or later complete response (with treatment history including two or more lines of systemic therapy)
• vii. Additional considerations beyond above criteria:
• * Patients with relapsed or refractory disease after allogeneic stem cell transplantation must be />100 days from HSCT to be eligible for study participation. Furthermore, post-HSCT immunosuppressive medications must be discontinued for at least 4 weeks prior to study entry
• * Prior CAR-T therapy is permissible if ≥ 3 months from therapy completion
• * Morphological disease in the bone marrow Note: Morphologic disease is defined as blasts being at least 5% in the bone marrow.
• B. Histologically confirmed aggressive B cell NHL, including the following types defined by WHO 2008 after 2 or more lines of prior therapy:
• i. DLBCL not otherwise specified; T cell/histiocyte rich large B cell lymphoma; DLBCL associated with chronic inflammation; Epstein-Barr virus (EBV)+ DLBCL of the elderly; Primary cutaneous DLBCL, leg type; OR ii. Primary mediastinal (thymic) large B cell lymphoma iii. Follicular lymphoma 3b and transformation of follicular lymphoma to DLBCL will also be included iv. High-grade B cell lymphoma v. Chemotherapy-refractory disease, defined as one or more of the following:
• * Refractory disease is defined as progressive or stable disease as the best response to the most recent prior therapy or relapse within 12 months of autologous stem cell transplantation. Two prior lines of therapy are required for LBCL eligibility. The second line therapy may be chemotherapy based, autologous stem cell transplantation, or CAR-T.
• * Relapsed or refractory disease after allogeneic transplant provided patient is at least 100 days from stem cell transplant at the time of enrollment and off of immunosuppressive medications for at least 4 weeks prior to enrollment
• * Patients must have received 2 or more lines of adequate prior therapy including at a minimum:
• * anti-CD20 monoclonal antibody unless investigator determines that tumor is CD20- negative and
• * an anthracycline containing chemotherapy regimen
• * for patients with transformed FL must have received prior chemotherapy for follicular lymphoma and subsequently have chemorefractory disease after transformation to DLBCL vi. Prior CAR T therapy permissible if ≥ 3 months from the therapy vii. At least 1 measurable lesion according to the revised IWG Response Criteria for Malignant Lymphoma (Cheson 2007). Lesions that have been previously irradiated will be considered measurable only if progression has been documented following completion of radiation therapy C. Relapsed or refractory indolent non-Hodgkin lymphoma i. Histologically confirmed indolent non-Hodgkin lymphoma, including grade 1-3b follicular lymphoma or nodal or extranodal marginal zone lymphoma (both per WHO 2016 classification criteria) ii. Relapsed or refractory disease (per Lugano criteria) after two or more previous lines of therapy, iii. Previous lines of therapy to include an anti-CD20 monoclonal antibody combined with an alkylating agent iv. Prior CAR T therapy permissible if ≥ 3 months from the therapy v. At least 1 measurable lesion according to the revised IWG Response Criteria for Malignant Lymphoma (Cheson 2007). Lesions that have been previously irradiated will be considered measurable only if progression has been documented following completion of radiation therapy vi. Relapsed or refractory disease after allogeneic transplant provided patient is at least 100 days from stem cell transplant at the time of enrollment and off of immunosuppressive medications for at least 4 weeks prior to enrollment D. Relapsed or Refractory Mantle-Cell Lymphoma i. Histologically confirmed mantle-cell lymphoma with either cyclin D1 overexpression or presence of the translocation (T11:14) ii. Disease that is either relapsed or refractory to at least 2 prior lines of previous regimens for mantle-cell lymphoma iii. Previous therapy must have included anthracycline- or bendamustine-containing chemotherapy, an anti-CD20 monoclonal antibody, and BTK inhibitor therapy
• 4. Prior CAR T therapy permissible if ≥ 3 months from the therapy
• 5. At least 1 measurable lesion according to the revised IWG Response Criteria for Malignant Lymphoma (Cheson 2007). Lesions that have been previously irradiated will be considered measurable only if progression has been documented following completion of radiation therapy
• 6. Relapsed or refractory disease after allogeneic transplant provided patient is ≥ 3 months from stem cell transplant at the time of enrollment and off of immunosuppressive medications for at least 4 weeks prior to enrollment
• 7. Meet institutional criteria for leukapheresis procedure or have availability of previously- collected and stored leukapheresis product that satisfies minimum requirements
• 8. Eastern cooperative oncology group (ECOG) performance status of 0 to 2.
• 9. Adequate hematologic and organ function NOTE: Patients with established diagnosis of benign neutropenia are eligible to participate with ANC between 1000-1500 if in the opinion of treating physician the trial treatment does not pose excessive risk of infection to the patient.
• 10. Adults ≥ 18 years of age, with no upper limit of age
• 11. Life expectancy />2 months
• 12. ≥ 3 months from prior CAR
• 13. Women of child-bearing potential and men with partners of child-bearing potential must agree to practice sexual abstinence or to use the forms of contraception listed in Child-Bearing Potential/Pregnancy section from the time of signing informed consent to at least 12 months following DuoCAR20.19.22-D95 infusion and until CAR positive viable T cells are no longer present by quantitative polymerase chain reaction (qPCR) on two consecutive tests. Men must agree not to donate sperm for the same time period.

Критерии исключения

• 1. Patients with CLL, Richter`s transformation, and Burkitt lymphoma
• 2. Active CNS involvement by malignancy - CNS3 disease, i.e., patients with WBC count in CSF ≥5 and having blasts in the CSF in patients with ALL or detection of NHL on CSF by flow cytometry or active CNS involvement on imaging)
• 3. Chemotherapy other than lymphodepleting chemotherapy within 2 weeks of infusion
• 4. Investigational medicinal product within the last 30 days prior to screening Note: Investigational therapies must not be used at any time while on study until the first progression following DuoCAR20.19.22-D95 CAR T infusion.
• 5. The following medications are excluded:
• 1. Steroids: Therapeutic doses of steroids must be stopped /> 72 hours prior to leukapheresis and /> 72 hours prior to DuoCAR20.19.22-D95 infusion. However, the following physiological replacement doses of steroids are allowed: /<12 mg/m2/day hydrocortisone or equivalent
• 2. Immunosuppression: Any other immunosuppressive medication must be stopped ≥ 2 weeks prior to leukapheresis and ≥ 2 weeks prior to DuoCAR20.19.22-D95 infusion. This could include check point inhibitors (monoclonal antibodies and small molecule modulators).
• 3. Antiproliferative therapies other than lymphodepleting chemotherapy within 2 weeks prior to infusion
• 4. Short acting drugs used to treat leukemia or lymphoma (e.g., tyrosine kinase inhibitors, and hydroxyurea) must be stopped /> 72 hour prior to leukapheresis and /> 72 hours prior to DuoCAR20.19.22-D95 infusion
• 5. Other cytotoxic drugs, including low dose daily or weekly maintenance chemotherapy, must not be given within 2 weeks prior to leukapheresis and within 2 weeks prior to DuoCAR20.19.22-D95 infusion.
• 6. Antibody use including anti-CD20 therapy within 4 weeks prior to infusion or 5 half-lives of the respective antibody, whichever is longer. Note: Rituximab is excluded within 4 weeks prior to infusion.
• 7. CNS disease prophylaxis or treatment must be stopped /> 1 week prior to DuoCAR20.19.22-D95 infusion (e.g., intrathecal methotrexate)
• 6. Prior radiation therapy within 2 weeks of infusion
• 7. Active replication of or prior infection with hepatitis B or active hepatitis C (HCV RNA positive)
• 8. HIV positive patients (excluding false positive HIV test resulting from the viral vector used in prior CAR T)
• 9. Uncontrolled acute life threatening bacterial, viral or fungal infection (e.g., blood culture positive ≤ 72 hours prior to infusion)
• 10. Unstable angina and/or myocardial infarction within 6 months prior to screening
• 11. Previous or concurrent malignancy with the following exceptions:
• 1. Adequately treated basal cell or squamous cell carcinoma (adequate wound healing is required prior to study entry)
• 2. In situ carcinoma of the cervix or breast, treated curatively and without evidence of recurrence for at least 3 years prior to the study
• 3. A primary malignancy which has been completely resected and in complete remission for ≥ 5 years
• 12. Simultaneously enrolled in any therapeutic clinical trial (except for long-term follow up studies)
• 13. Current or anticipating use of other anti-neoplastic or investigational agents while participating in this study
• 14. Either diagnosed with a psychiatric illness or under the impact of a social situation that would limit compliance with study requirements in the opinion of the investigator
• 15. Is pregnant or breastfeeding
• 16. Intolerance to the excipients of the cell product
• 17. Cardiac arrhythmia not controlled with medical management
• 18. Active COVID-19 (follow ASTCT guidelines)
• 19. Presence of active grade 2 to 4 acute, extensive chronic graft-versus-host disease (GVHD) or that require systemic steroids
• 20. Patients with active neurological auto immune or inflammatory disorders (e.g., Guillain-Barré Syndrome, Amyotrophic Lateral Sclerosis)

Описание

This is a randomized phase II trial of standard-of-care reduced-intensity conditioning (RIC) with 200 versus 400 cGy of total body irradiation (TBI) in patients with acute leukemia undergoing first allogeneic blood or marrow Transplantation (BMT). The primary objective is to compare the rates of graft-versus-host disease-free and relapse-free survival (GRFS) between patients in the two cohorts.

Критерии включения

• 1. Age ≥ 0 years
• 2. Patients with a diagnosis of acute myeloid leukemia (AML), acute lymphoblastic leukemia or lymphoma (ALL), or acute leukemia of mixed or ambiguous lineage per the 2022 World Health Organization classifications,75,76 with /< 5% blasts on bone marrow morphologic analysis performed within 30 days of planned conditioning initiation
• 1. AML is generally defined as ≥ 20% myeloid blasts identified in the peripheral blood and/or bone marrow. Myeloid sarcoma is also recognized as an AML-defining entity. Situations in which AML can be diagnosed without a specific blast threshold met nor myeloid sarcoma present are when fusions involving RUNX1::RUNX1T1, CBFB::MYH11, DEK:NUP214, or RBM15::MRTFA are present; rearrangements involving KMT2A, MECOM, or NUP98 exist; or there is a mutation in NPM1.
• 2. B- or T-ALL is defined as the presence of lymphoid blasts identified in the peripheral blood and/or bone marrow with no specific blast threshold needed (acute lymphoblastic leukemia) or the presence of a lymphatic-based collection of lymphoblasts (acute lymphoblastic lymphoma).
• 3. Acute leukemia of mixed or ambiguous lineage is defined as mixed or ambiguous lineage blasts identified in the peripheral blood and/or bone marrow or the presence of a lymphatic-based collection (lymphoma) of mixed or ambiguous lineage blasts. A specific blast threshold does not need to be met.
• 4. Patients with a documented diagnosis of myeloproliferative neoplasm (MPN), myelodysplastic syndrome or neoplasm (MDS), and/or MDS/MPN-overlap prior to diagnosis of acute leukemia may be included for randomization in this clinical trial so long as the patient has received at least 4 cycles of DNA methyltransferase inhibitor (e.g., azacitidine, decitabine, decitabine/cedazuradine (Inqovi), and/or any other agent that works via this mechanism) or at least one cycle of induction chemotherapy. A list of antecedent diagnoses per the World Health Organization 2022 classification of hematolymphoid tumors that pertain to this inclusion criterion are listed below 75
• * i. MPN includes myelofibrosis, essential thrombocythemia, polycythemia vera, chronic neutrophilic leukemia, chronic eosinophilic leukemia, juvenile myelomonocytic leukemia, chronic myeloid leukemia (CML), or myeloproliferative neoplasm, not otherwise specified
• * ii. Myelodysplastic syndrome or neoplasm (MDS)
• * iii. MDS/MPN-overlap includes chronic myelomonocytic leukemia (CMML), myelodysplastic/myeloproliferative neoplasm with neutrophilia, myelodysplastic/myeloproliferative neoplasm with SF3B1 mutation and thrombocytosis, or myelodysplastic/myeloproliferative neoplasm, not otherwise specified
• * iv. Of note, patients without a documented history of one of these conditions prior to diagnosis of acute myeloid leukemia with myelodysplastic features would not be restricted to this specific criterion for study inclusion.
• 3. No active extramedullary leukemia or known active Central Nervous System (CNS) involvement by malignancy. Such disease treated into remission is permitted.
• 4. Patients must have a related or unrelated bone marrow or peripheral blood donor
• 1. Human leukocyte antigen (HLA)-matched (10/10) sibling donor (MSD)
• 2. HLA-matched (10/10) unrelated donor (MUD)
• 3. HLA-haploidentical (5/10) related donor (Haplo)
• 4. HLA-mismatched (6-9/10) unrelated donor (mMUD)
• 5. Planned allogeneic BMT using post-transplantation cyclophosphamide (PTCy) as a component of GVHD prophylaxis
• 6. Adequate end-organ function as measured by:
• 1. Left ventricular ejection fraction greater than or equal to 35% or shortening fraction /> 25%
• 2. Bilirubin ≤ 3.0 mg/dL (unless due to Gilbert`s syndrome or hemolysis), and aspartate aminotransferase (AST) and alanine aminotransferase (ALT) /< 5 x Upper Limit of Normal (ULN)
• 3. Forced Expiratory Volume in one second (FEV1) and Forced Vital Capacity (FVC) /> 40% of predicted
• 7. Patients may enroll in other transplant-related trials (e.g., those testing post-transplant maintenance strategies or peri-transplant strategies for the management of donor specific antibodies) as long as other eligibility criteria are met and the requirements do not conflict with the treatment plan as outlined herein. Patients may also receive standard of care post-transplant maintenance therapies.

Критерии исключения

• 1. Acute leukemia with promyelocytic leukemia (PML)/retinoic acid receptor α (RARA) fusion
• 2. Prior allogeneic BMT
• 3. Eastern Cooperative Oncology Group (ECOG) Performance Status /> 2 or Karnofsky/Lansky score /< 60
• 4. Patients with an additional active malignancy with a life expectancy /< 2 years due to that disease
• 5. Symptomatic coronary artery disease
• 6. Uncontrolled infection
• 7. Patients who are pregnant or breastfeeding

Описание

The major morbidities of allogeneic hematopoietic stem cell transplant (HSCT) using donors that are not human leukocyte antigen (HLA) matched siblings are graft vs host disease (GVHD) and life- threatening infections. T cell receptor alpha beta (TCRαβ) T lymphocyte depletion and CD19+ B lymphocyte depletion of alternative donor hematopoietic stem cell (HSC) grafts is effective in preventing GVHD, but immune reconstitution may be delayed, increasing the risk of infections. The central hypothesis of this study is that an addback of CD45RO memory T lymphocytes, derived from a fraction of the original donor peripheral stem cell product depleted of CD45RA naïve T lymphocytes, will accelerate immune reconstitution and help decrease the risk of infections in TCRab/CD19 depleted PSCT.

Критерии включения

• 1. Disease for which allogeneic HSCT may be curative.
• 2. Remission status of hematologic malignancies and additional disease-specific eligibility determinations will be according to standards of practice within the CHOP Cellular Immunotherapy and Transplant Program (CTTS).
• 3. Patients must be 25 years of age and less
• 4. Evaluation for organ and infectious status as per our CTTS standard operating procedure.
• 5. Signed consent by parent/guardian or able to give consent if 18 years of age and older.
• 6. Participants of childbearing potential must have a negative pregnancy test as per institutional SOP.

Критерии исключения

• 1. Patients who have performance score less than 60.
• 2. No suitable donor available for mobilized peripheral stem cells.
• 3. Patients with Hodgkin lymphoma or non-Burkitt, non-lymphoblastic lymphoma.
• 4. Planned receipt of alemtuzumab during conditioning.
• 5. Patients with an available 10/10 HLA matched sibling donor.
• 6. Patients who do not meet institutional disease, organ or infectious criteria.
• Donor selection and eligibility:
• 1. Unrelated donor meets National Marrow Donor Program criteria for donation.
• 2. Related donor (at least haploidentical) willing and able to donate mobilized peripheral stem cells.
• 3. HLA testing/matching
• * HLA testing to be done by molecular methods for A, B, C, DRB1, DQB1
• * Related donor: Must be ≥ 5/10 match
• * Unrelated donor: 10/10 or 9/10 match
• * KIR typing for haploidentical donor for hematologic malignancies
• * Donor specific HLA antibodies (DSA) should be assessed for all subjects receiving an HLA mismatched graft (≤ 9/10).
• 4. Donor must be willing to undergo granulocyte colony stimulating factor (GCSF) mobilization and peripheral blood stem cell collection
• 5. Donors must be willing to sign consent to participate in this study.

Описание

This study aims to determine the impact of massage therapy for pediatric patients receiving intensive chemotherapy or stem cell transplant (SCT).

Критерии включения

• 1. Diagnosis of cancer, such as acute myeloid leukemia (AML) or relapsed acute lymphoblastic leukemia (rALL) OR admitted to receive autologous or allogeneic HSCT for any indication
• 2. Expected to be an inpatient for at least 21 days
• 3. Aged 12 to 21 years at enrollment.
• 4. Inpatient at Children`s National or Children`s Hospital of Philadelphia (CHOP).

Критерии исключения

• 1. Cognitive impairment sufficient to preclude completing questionnaires appropriately
• 2. Insufficient knowledge of English or Spanish that would prohibit completing the study instruments
• 3. Previous enrollment

Описание

The goal of this clinical trial is to learn if BiTE-EV works to treat relapsed/refractory acute B-cell leukemia in adults. It will also learn about the safety of BiTE-EV. The main questions it aims to answer are:

Can BiTE-EV effectively treat relapsed/refractory acute B-cell lymphoblastic leukemia? What medical problems do participants have when taking BiTE-EV?

Participants will:

Take BiTE-EV every other day for 1 or 2 months Keep a diary of their symptoms during the medication period During the follow-up period, visit the clinic once every 4 weeks for checkups and tests

Критерии включения

• Patients can be enrolled in the group only if they meet all of the following conditions:
• * Patients with acute B lymphocytic leukemia who are clinically diagnosed as relapsed (relapsed after CAR-T treatment or relapsed after transplantation), refractory, or whose T cells cannot be used for the production of CAR-T cells.
• * Tumor cells show positive expression of CD19 detected by flow cytometry or immunohistochemistry.
• * The age is between 18 and 70 years old (inclusive).
• * The expected survival period from the date of signing the informed consent form is greater than 3 months.
• * The Eastern Cooperative Oncology Group (ECOG) performance status score is ≤ 2.
• * The functions of vital organs should meet the following requirements:
• * The ejection fraction (EF) is /> 50%, and there is no significant abnormality in the electrocardiogram.
• * The peripheral oxygen saturation (SpO2) is ≥ 92%.
• * The serum creatinine (Cr) is ≤ 1.5 times the upper limit of normal (ULN).
• * Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are ≤ 5 times the upper limit of normal (ULN), and total bilirubin (TBil) is ≤ 3 times the upper limit of normal (ULN).
• * Subjects with pregnancy plans must agree to take contraceptive measures before enrolling in the study and six months after the study. If the subject is pregnant or suspected to be pregnant, they should immediately notify the investigator.
• * The subject or the guardian understands and signs the informed consent form.

Критерии исключения

• If any one of the following conditions is met, the subject cannot be enrolled in the group:
• * Complicated with other diseases that are not effectively controlled, including but not limited to persistent or poorly controlled infections, symptomatic congestive heart failure, unstable angina pectoris, arrhythmia, poorly controlled pulmonary diseases or mental disorders.
• * Having other active malignant tumors.
• * Complicated with severe infections that cannot be effectively controlled.
• * Those who are positive for hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb), and those with peripheral blood hepatitis B virus (HBV) DNA higher than the detection limit need to be excluded; those who are positive for hepatitis C virus (HCV) antibody and positive for peripheral blood HCV RNA need to be excluded; those with positive cytomegalovirus (CMV) DNA detection; those with positive peripheral blood Epstein-Barr virus (EBV) DNA detection.
• * Those who are positive for human immunodeficiency virus (HIV) antibody test or positive for syphilis test.
• * Having a history of severe allergy to biological products (including antibiotics).
• Patients with relapsed after allogeneic hematopoietic stem cell transplantation who have experienced grade 3 - 4 acute graft-versus-host disease (GvHD).
• * Female subjects who are pregnant or in the lactation period.
• * Active autoimmune diseases that require systemic immunosuppressive treatment.
• * Situations that the investigator believes may increase the risk of the subject or interfere with the test results.

Описание

Detectable measurable residual disease (MRD) is the most important prognostic factor for B-cell acute lymphoblastic leukemia (B-ALL) for overall survival (OS) and disease-free survival (DFS). Patients who are MRD positive and have no access to novel immunotherapies should receive an allogeneic hematopoietic stem cell transplantation (HSCT). Blinatumomab is considered a standard of care (SOC) for this group of patients, however, the ideal treatment dose for MRD is unknown as doses were adjusted from the relapsed/refractory setting. Preliminary data suggest short cycles of blinatumomab can also be effective in states of lower disease burden prior to transplant. Thus, the investigators are performing a phase 2 trial assessing 7 days of blinatumomab as a bridge to HSCT

Primary endpoint is assessing the MRD response following a short-course blinatumomab infusion in patients with B-ALL with complete response (CR) and have detectable MRD disease who are candidates for HSCT. Secondary endpoints include incidence of adverse events, OS, DFS, percentage of patients who receive HSCT, incidence of cytokine release syndrome (CRS) and immune effector cell associated neurotoxicity syndrome (ICANS)

Критерии включения

• * Philadelphia chromosome-negative B-cell acute lymphoblastic leukemia
• * MRD detectable in complete response (above the limit of quantification according to FCM)
• * Performance status 0-2 on the ECOG scale
• * No prior organ damage
• * Having a potential related or unrelated donor

Критерии исключения

• * Performance status on the ECOG scale />2
• * HCT-CI />3 points
• * Patients who do not wish to participate in clinical study.
• * Active central nervous system infiltration (CNS3)
• * Active extramedullary disease
• * Having previously received blinatumomab
• * Absence of related or unrelated donors

Описание

To observe the safety and efficacy of Nanobody-Based CD5-targeted chimeric antigen receptor T cells in the treatment of refractory or relapsed T-ALL/LBL.

Критерии включения

• 1. The subject or guardian understands and voluntarily signs the informed consent form (ICF).
• 2. Male or female, aged 3-70 years at the time of signing the ICF (inclusive).
• 3. Expected survival of at least 12 weeks.
• 4. ECOG performance status of 0-2 at the time of ICF signing.
• 5. Diagnosis of relapsed/refractory T-cell lymphoblastic leukemia/lymphoma (R/R T-ALL/LBL) confirmed at screening and meeting at least one of the following criteria:
• 1. Bone marrow involvement: Morphologic examination shows ≥5% lymphoblasts, and/or
• 2. Cerebrospinal fluid (CSF) involvement: Tumor cells detected in CSF, and/or
• 3. Extramedullary disease: Presence of measurable lesions (lymph node/mass ≥1.5 cm in axial diameter or extranodal lesion ≥1 cm in axial diameter).
• 4. CD5 expression: Tumor cells in bone marrow, peripheral blood, or CSF are CD5-positive by flow cytometry, and/or lymph node/mass or extranodal lesions are CD5-positive by pathology.
• 6. Adequate major organ function, defined as:
• 1. AST and ALT ≤5× upper limit of normal (ULN).
• 2. Total bilirubin ≤2× ULN.
• 3. Renal function: Serum creatinine clearance ≥60 mL/min (Cockcroft-Gault formula) or creatinine ≤1.5× ULN.
• 7. Blood oxygen saturation />92%.
• 8. Reproductive health requirements:
• * Fertile men and women of childbearing potential must agree to use effective contraception from ICF signing until 2 years after study drug administration.
• * Women of childbearing potential (pre-menopausal or within 2 years post-menopause) must have a negative blood pregnancy test at screening.

Критерии исключения

• 1. History of central nervous system (CNS) diseases, including but not limited to:
• * Epilepsy
• * Paralysis
• * Aphasia
• * Stroke
• * Severe brain injury
• * Dementia
• * Parkinson`s disease
• * Neuropathy
• 2. History of autoimmune diseases requiring systemic immunosuppressive therapy within 2 years prior to signing the ICF, including but not limited to:
• * Crohn`s disease
• * Rheumatoid arthritis
• * Systemic lupus erythematosus (SLE)
• * Systemic sclerosis
• * Inflammatory bowel disease (IBD)
• * Vasculitis
• * Psoriasis
• 3. Presence of any uncontrolled active infection at the time of signing the ICF or within 4 weeks prior to apheresis that requires antibiotic, antiviral, or antifungal treatment.
• 4. Positive virological or infectious disease markers, including:
• * Hepatitis B virus (HBV): Subjects with positive HBsAg or HBcAb-positive at screening must have undetectable HBV DNA in peripheral blood to be eligible; otherwise, they should be excluded.
• * Hepatitis C virus (HCV): Subjects with positive HCV antibodies and detectable HCV RNA should be excluded.
• * Human immunodeficiency virus (HIV) antibody-positive subjects should be excluded.
• * Cytomegalovirus (CMV) DNA test-positive subjects should be excluded.
• * Epstein-Barr virus (EBV) DNA test-positive subjects should be excluded.
• * Positive serological or non-specific antibodies for Treponema pallidum (syphilis).
• 5. Clinically significant cardiovascular diseases, including any of the following:
• 1. QTc interval ≥480 ms (Fridericia correction formula)
• 2. New York Heart Association (NYHA) Class II or higher heart failure
• 3. Unstable angina or acute myocardial infarction within 6 months prior to signing the ICF
• 4. Left ventricular ejection fraction (LVEF) /<50%
• 5. Poorly controlled hypertension (as determined by the investigator)
• 6. Clinically significant arrhythmias or those requiring antiarrhythmic treatment, including:
• * Persistent ventricular tachycardia
• * Ventricular fibrillation
• * Torsades de pointes
• * Complete left bundle branch block
• 6. History of severe hypersensitivity or allergy to any components of the study drug.
• 7. Receipt of any investigational drug therapy or other systemic antitumor therapy within 4 weeks before apheresis (or 5 half-lives of the drug, whichever is longer, as determined by the investigator).
• 8. Receipt of extensive radiotherapy within 4 weeks prior to signing the ICF, except for palliative radiotherapy for non-target lesions within 2 weeks before signing the ICF or as expected during the study.
• 9. Unresolved toxicity from prior antitumor therapy that has not returned to Grade 1 or baseline levels at the time of signing the ICF, except for hair loss and pigmentation (per NCI-CTCAE v5.0).
• 10. Requirement for systemic corticosteroids or other immunosuppressive therapy (≥10 mg/day prednisone or equivalent) within 3 days prior to apheresis or during the study period, except for:
• 1. Intranasal, inhaled, or topical steroids, or localized steroid injections (e.g., intra-articular injections)
• 2. Systemic corticosteroids ≤10 mg/day prednisone (or equivalent physiological dose)
• 3. Steroids as prophylaxis for allergic reactions (e.g., pre-medication before contrast-enhanced CT)
• 4. Steroids used for symptomatic treatment of transfusion-related reactions
• 11. Major surgery within 4 weeks prior to signing the ICF (excluding routine biopsy procedures) or planned major surgery during the study period.
• 12. History of active tuberculosis infection within 1 year prior to signing the ICF, except for subjects with a history of tuberculosis more than 1 year ago, provided that the investigator determines there is no evidence of active tuberculosis.
• 13. History of other primary malignancies within 5 years prior to signing the ICF, except for:
• 1. Adequately treated carcinoma in situ of the cervix
• 2. Localized basal cell carcinoma or squamous cell carcinoma of the skin
• 14. Receipt of live-attenuated or inactivated vaccines within 4 weeks before signing the ICF or planned vaccination during the screening period.
• 15. Any other condition or complication that, in the investigator`s judgment, may affect adherence to the study protocol or make the subject unsuitable for participation.
• 16. Pregnancy or lactation.

Описание

This early phase I trial tests the safety and side effects of allogeneic CMV-specific CD19-CAR T cells plus CMV-MVA vaccine and how well it works in treating patients with high-risk acute lymphoblastic leukemia after a matched related donor (allogeneic) hematopoietic stem cell transplant (alloHSCT). Chimeric antigen receptor (CAR) T-cell therapy is a type of treatment in which 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, in this study, the T cells are cytomegalovirus (CMV) specific. Then the gene for a special receptor that binds to a certain protein, CD19, on the patient`s cancer cells is added to the CMV-specific T cells in the laboratory. The special receptor is called a CAR. Large numbers of the CAR T cells are grown in the laboratory and given to the patient by infusion for treatment of certain cancers. Vaccines made from three CMV tumor associated antigens, may help the body build an effective immune response to kill cancer cells. Giving allogeneic CMV-specific CD19-CAR T cells plus CMV-MVA vaccine after matched related alloHSCT may be safe, tolerable, and/or effective in treating patients with high-risk acute lymphoblastic leukemia.

Критерии включения

• * Documented informed consent of the participant and/or legally authorized representative
• * Assent, when appropriate, will be obtained per institutional guidelines
• * Agreement to allow the use of archival tissue from diagnostic tumor biopsies
• * If unavailable, exceptions may be granted with study 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
• * Age: ≥ 18 years
• * Karnofsky performance status (KPS) ≥ 70
• * Participants with high-risk ALL defined as:
• * Any complete remission (CR) with minimal residual disease (MRD)+ (by flow cytometry, polymerase chain reaction /[PCR/] or clonoSEQ) at the time of HSCT; or
• * Blasts ≥ 5% at the time of transplant; or
• * Complete response (CR)2 or higher irrespective of MRD status; or
• * Requiring /> 1 regimen to achieve CR1
• * Pathology confirmed CD19+ ALL after the last targeted therapy if the patient has active disease or before the last therapy if the patient is in CR
• * Note: CD19 positivity must be documented in a pathology report; however, it is not a requirement that the CD19 testing be performed by a COH pathologist
• * Planned allogeneic HSCT (myeloablative or reduced intensity conditioning) according to institutional eligibility requirements with an available 8/8 (HLA A, B, C, DR) allele-matched related is allowed per discretion of the principal investigator. for allogeneic HSCT will be unmanipulated mobilized peripheral blood stem cell (PBSC) or bone marrow
• * Participants who received other prior forms of CAR T therapy are eligible
• * No known contraindications to HSCT, leukapheresis, steroids or tocilizum,ab, smallpox vaccine and any other modified vaccinia ankara virus (MVA)-based vaccines
• * Total serum bilirubin ≤ 2.0 mg/dL (to be performed no more than 45-days prior to hematopoeitic stem cell /[HSC/] infusion unless otherwise stated)
• * Participants with Gilbert syndrome may be included if their total bilirubin is ≤ 3.0 (to be performed no more than 45-days prior to HSC infusion unless otherwise stated)
• * Aspartate aminotransferase (AST) /< 2.5 x upper limit of normal (ULN) (to be performed no more than 45-days prior to HSC infusion unless otherwise stated)
• * Alanine aminotransferase /< 2.5 x ULN (to be performed no more than 45-days prior to HSC infusion unless otherwise stated)
• * Serum creatinine ≤ 2.5 x ULN or estimated creatinine clearance of ≥ 40 mL/min per the Cockcroft-Gault formula, and the participant is not on hemodialysis (to be performed no more than 45-days prior to HSC infusion unless otherwise stated)
• * Cardiac function (12 lead-electrocardiogram /[ECG/]): Corrected QT interval (QTc) must be ≤ 480 msec (to be performed no more than 45-days prior to HSC infusion unless otherwise stated)
• * Left ventricular ejection fraction ≥ 45% within 8 weeks before protocol therapy (to be performed no more than 45-days prior to HSC infusion unless otherwise stated)
• * Oxygen (O2) saturation /> 92% without requiring supplemental oxygen (to be performed no more than 45-days prior to HSC infusion unless otherwise stated)
• * Seronegative for HIV quantitative real time polymerase chain reaction (qPCR), hepatitis C virus (HCV), active hepatitis B virus (HBV) (surface antigen negative), and syphilis (RPR) (to be performed no more than 45-days prior to HSC infusion unless otherwise stated)
• * 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. Viral load must be undetectable
• * Negative for COVID-19 within 72 hours of day 0 of protocol therapy (to be performed no more than 45-days prior to HSC infusion unless otherwise stated)
• * Negative for human herpes virus-6 (HHV6) by PCR-based assay (to be performed no more than 45-days prior to HSC infusion unless otherwise stated)
• * Meets other institutional and federal requirements for infectious disease titer requirements (to be performed no more than 45-days prior to HSC infusion unless otherwise stated)
• * Participants must have negative QuantiFERON-TB Gold (QFTG) test (to be performed no more than 45-days prior to HSC infusion unless otherwise stated)
• * Participants with positive QFTG test need clearance from ID before protocol therapy
• * Women of childbearing potential (WOCBP): Negative urine or serum pregnancy test (to be performed no more than 45-days prior to HSC infusion unless otherwise stated)
• * 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)
• * DONOR CRITERIA: The identified donor must be the original donor whose stem cells were used for the research participant`s alloHSCT
• * DONOR CRITERIA: Donor must be CMV seropositive through the following:
• * CMV seropositive AND
• * CMV positive by CMV insight T cell immunity testing through Viracor (Test code 30360)
• * DONOR CRITERIA: The donor`s hepatitis B surface antigen must be negative and the hepatitis C antibody must be nonreactive. In the case of a positive hepatitis C antibody result, the HCV viral PCR will have to be performed and the results should be negative
• * DONOR CRITERIA: The donor must be HIV negative
• * DONOR CRITERIA: KPS ≥ 70
• * DONOR CRITERIA: Documented body weight
• * DONOR CRITERIA: Willingness to sign `donor consent form` and undergo T cell leukapheresis for the collection of PBMCs for cellular manufacture
• * DONOR CRITERIA: COH standard operating procedures (SOP) will be used for allogeneic donor evaluation, selection, and consent.
• * DONOR CRITERIA: The donor is approved and has completed the donor evaluation per institutional guidelines. Additionally, donor will also be screened for the following infectious diseases:
• * Epstein-Barr virus (EBV) by PCR,
• * Human herpes virus 6, 7, and 8 (HHV6, HHV7, HHV8)
• * Parvovirus B19 Note: ID test results for EBV by PCR, HHV6, HHV7, HHV8 and parvovirus B19 are necessary to proceed with the apheresis procedure but do have to be resulted and negative before participant CAR T infusion.
• 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

• * Concurrent use of systemic steroids. Recent or current use of inhaled or topical steroids in standard doses is not exclusionary. Physiologic replacement of steroids (prednisone ≤ 0.5 mg /day, or equivalent doses of other corticosteroids) is allowed
• * Participants with active autoimmune disease requiring systemic immune suppressive therapy are not allowed
• * Any contraindications to standard conditioning transplant regimens per standard of care practices at COH
• * Subjects with clinically significant arrhythmia or arrhythmias not stable on medical management within two weeks of screening
• * History or prior diagnosis of other immunologic or inflammatory disease affecting the central nervous system (CNS), including uncontrolled seizure disorder, any measurable masses of CNS, or any other active CNS disease. Note: Research participants with a history of CNS disease that has been effectively treated to complete remission (/< 5 white blood cells /[WBC/]/mm/^3 and no blasts in CSF) will be eligible
• * Participants should not have any uncontrolled illness including symptomatic congestive heart failure, unstable angina pectoris, poorly controlled pulmonary disease, or psychiatric illness/social situations that would limit compliance with study requirements
• * History of allergic reactions attributed to compounds of similar chemical or biologic composition to study agent
• * History of stroke or intracranial hemorrhage within 3 months prior to screening
• * Known bleeding disorders (e.g., von Willebrand`s disease) or hemophilia
• * Participants with uncontrolled seizures
• * Active viral hepatitis
• * 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 infection not responding to antibiotics
• * 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 study is a phase I study designed to evaluate the safety of CD19-CD22-CAR T cells.

Primary Objective:

To determine the safety profile and propose the recommended phase 2 dose (RP2D) of autologous CD19-CD22-CAR T cells in patients ≤ 21 years of age with recurrent/refractory CD19- and/or CD22-positive leukemia.

Secondary Objective:

To evaluate the anti-leukemic activity of CD19-CD22-CAR T cells.

Критерии включения

• Collection and Manufacturing Eligibility
• Inclusion Criteria:
• * Age /<21 years old
• * Relapsed/refractory CD19- and/or CD22-positive acute leukemia defined as:
• /*CD19 and/or CD22-positivity confirmed within 2 months and after receipt of any CD19 or CD22-directed therapy
• * Second or greater relapse
• * Any relapse after allogeneic HCT
• * Refractory disease (primary or in relapse) despite therapy designed to induce remission
• * Estimated life expectancy of /> 12 weeks
• * Karnofsky or Lansky (age-dependent) performance score ≥50 (Appendix A)
• * For females of childbearing age:
• * Not lactating with intent to breastfeed
• * Not pregnant with negative serum or urine pregnancy test within 7 days prior to enrollment

Критерии исключения

• * Known primary immunodeficiency
• * Known HIV positivity
• * Known contraindication to receiving protocol defined lymphodepleting
• * chemotherapy regimen
• * History of hypersensitivity reaction to murine-containing products
• Treatment Eligibility
• Inclusion Criteria:
• * Age /< 21 years old
• * Detectable CD19- and/or CD22-positive leukemic disease in the bone marrow
• * Estimated life expectancy of /> 8 weeks
• * Karnofsky or Lansky (age-dependent) performance score /> 50 (Appendix A)
• * Adequate cardiac function defined as left ventricular ejection fraction />40%, or shortening fraction /> 25%
• * EKG without evidence of clinically significant arrhythmia
• * Adequate renal function defined as creatinine clearance or radioisotope GFR />50 mL/min/1.73m2 (GFR />40 mL/min/1.73m2 if /<2 years of age)
• * Adequate pulmonary function defined as forced vital capacity (FVC) />50% of predicted value; or pulse oximetry />92% on room air
• * Total bilirubin /< 3 times the upper limit of normal for age, except in subjects with Gilbert`s syndrome
• * Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) /< 5 times the upper limit of normal for age
• * Has recovered from all NCI CTAE grade III-IV, non-hematologic acute toxicities from prior therapy
• * Prior to planned CAR T cell infusion, patients with a history of prior allogeneicHCT must be at least 3 months from HCT, have no evidence of acute GVHD, and have not received a donor lymphocyte infusion (DLI) within the 28 daysprior to planned infusion
• * For females of childbearing age:
• * Not lactating with intent to breastfeed
• * Not pregnant with negative serum or urine pregnancy test within 7 days prior to enrollment
• * If sexually active, agreement to use birth control until 3 months after T cell infusion. Male partners should use a condom.
• Exclusion Criteria:
• * Known primary immunodeficiency
• * Known HIV positivity
• * Known contraindication to receiving protocol defined lymphodepleting
• * chemotherapy regimen
• * History of hypersensitivity reactions to murine protein-containing products
• * Severe, uncontrolled bacterial, viral or fungal infection
• * Active CNS-3 disease
• * Evidence of active, uncontrolled neurologic disease

Описание

B-acute lymphoblastic leukaemia (B-ALL) is the most common cancer in children, with 20% of patients relapsing. CD9, a transmembrane protein, is linked to the migratory and adhesion capacities of leukaemia cells and could be associated with relapses. The aim of this project is to understand how CD9 regulation can be a marker of potential relapses, using bone and blood sampling of newly diagnosed patients at 3 crucial moments of therapy.

Критерии включения

• * Under 18 years
• * With established diagnosis of B-ALL
• * Initial diagnosis made in the investigating centre
• * Having received oral and written information about the protocol, or oral only if the patient is unable to read.
• * Having signed a consent form if the patient is capable of giving informed written consent.
• * Whose legal guardians have received oral and written information about the protocol, and have signed a free, informed and written consent.
• * Beneficiary of a social security scheme

Критерии исключения

• * Isolated extramedullary involvement at inclusion
• * Patient of childbearing age without effective contraception.
• * Adult subject to legal protection (safeguard of justice, curatorship, guardianship), person deprived of liberty.

Описание

The study is a monocentric, interventional study that evaluates the efficacy of allogeneic HLA-matched or haploidentical transplantation consisting of an irradiation-based conditioning regimen coupled with donor Treg/Tcon adoptive immunotherapy for high-risk acute leukemia patients.

Критерии включения

• * AML patients
• * Diagnosis of AML with indication to allogeneic hematopoietic cell transplantation.
• * Diagnosis of adverse genetic risk leukemia or presence of MRD or active disease (bone marrow infiltration 5-30%) at the time of the transplant procedure.
• * Availability of a hematopoietic stem cell donor (family or unrelated HLA-matched or HLA-haploidentical with the patient) suitable to be treated with G-CSF (10 mcg/kg/die) for a maximum of 7 days and able to tolerate 2 or more leukaphereses.
• * Age ≥ 18 and ≤ 65 years
• * ECOG ≤ 2
• * HCT-CI ≤ 4 (51,52)
• * Absence of relevant psychiatric diseases
• * Signature of the informed consent
• ALL patients
• * Diagnosis of ALL, either T or B (Philadelphia negative) or mixed phenotype with indication to allogeneic transplant
• * Presence of MRD or active disease (bone marrow infiltration 5-30%) or patient with ≥ 2nd complete hematologic remission at the time of the transplant procedure.
• * Availability of a hematopoietic stem cell family donor (family or unrelated HLA-matched or HLA-haploidentical with the patient) suitable to be treated with G-CSF (10 mcg/kg/die) for a maximum of 7 days and able to tolerate 2 or more leukaphereses.
• * Age ≥ 18 and ≤ 65 years
• * ECOG ≤ 2
• * HCT-CI ≤ 4
• * Absence of relevant psychiatric diseases
• * Signature of the informed consent

Критерии исключения

• * AML patients
• * AML in CR MRD-
• * AML with /> 5% peripheral blasts or bone marrow infiltration ≥ 30%
• * Age /< 18 years or /> 65 years
• * ECOG /> 2
• * Unacceptable lung, liver, kidney, and/or heart function and presence of relevant psychiatric diseases according to clinical judgment
• * Pregnancy
• * No signature of the informed consent
• * ALL patients
• * ALL with /> 5% peripheral blasts or bone marrow infiltration ≥30%
• * Philadelphia positive ALL
• * Age /< 18 years or /> 65 years
• * ECOG /> 2
• * Unacceptable lung, liver, kidney, and/or heart function and presence of relevant psychiatric diseases according to clinical judgment
• * Pregnancy
• * No signature of the informed consent

Описание

This study aims to compare the effects of two different conditioning regimens on patients with acute lymphoblastic leukemia (ALL) undergoing matched sibling donor hematopoietic stem cell transplantation (MSD-HSCT): Total Body Irradiation (TBI) and Total Marrow, Central Nervous System and Lymphoid Irradiation (TMLI). Both regimens are supported and recommended by literature; however, there is no definitive evidence favoring one over the other. We hypothesize that the TMLI regimen, compared to the TBI regimen, may more effectively eliminate leukemia cells in the bone marrow and lymphoid tissues, thereby reducing the risk of relapse, while also minimizing damage to normal tissues, thus reducing conditioning-related toxicity and transplant-related mortality. This study aims to provide evidence for the optimal conditioning regimen for MSD-HSCT in adult ALL patients, with the goal of improving patient quality of life and survival outcomes.

Критерии включения

• 1. Informed Consent: Participants must voluntarily sign a written informed consent form.
• 2. Age and Gender: Participants should be male or female, aged 18-65 years, inclusive.
• 3. Diagnosis: Participants must be diagnosed with acute lymphoblastic leukemia (ALL) according to World Health Organization (WHO) criteria, and the diagnosis must apply to adults aged 18-65 years.
• 4. Remission Status: The participant`s leukemia must be in hematologic remission (complete remission, CR) prior to transplantation.
• 5. Donor Availability: There must be a suitable mathced sibling donor available, and the participant must consent to undergo MSD hematopoietic stem cell transplantation (MSD-HSCT).
• 6. Karnofsky Performance Status: The participant must have a Karnofsky score of 70 or higher, indicating that they are capable of caring for themselves and carrying out normal activities. Additionally, they must not have significant organ dysfunction, defined by the following:
• * Cardiac Function: New York Heart Association (NYHA) classification of class II or lower.
• * Liver Function: Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels should be no more than 2.5 times the upper limit of normal. Bilirubin levels should be no more than 2 times the upper limit of normal.
• * Renal Function: Serum creatinine levels should be no more than 1.5 times the upper limit of normal, or the creatinine clearance rate should be at least 60 ml/min.
• * Pulmonary Function: Participants should not experience significant dyspnea, should not require oxygen therapy, should not have interstitial lung disease, and should not have any active pulmonary infections.
• 7. Reproductive Health:
• * Women of childbearing potential must test negative for pregnancy with a Human Chorionic Gonadotropin (HCG) test, confirmed by immunofluorescence during both screening and baseline periods. They must also agree to use effective contraception for at least one year following the transplantation.
• * Male participants with female partners of childbearing potential must agree to use effective barrier contraception and refrain from sperm donation for at least one year following the transplantation.

Критерии исключения

• To be eligible for inclusion in the study, participants must not meet any of the following criteria:
• 1. The patient has not achieved hematologic remission before transplantation.
• 2. The patient has chosen a non-MSD donor.
• 3. The patient has severe cardiac, hepatic, renal, or pulmonary diseases that make them unable to tolerate the conditioning regimen.
• 4. The patient has an active or refractory infection, or other life-threatening complications.
• 5. The patient has a history of other malignant tumors, psychiatric disorders, or HIV infection.
• 6. The patient refuses to sign the informed consent form, is unwilling to comply with clinical follow-up required by the study, or does not consent to the use of their data to support future research, project presentations, and clinical practices.
• 7. The investigator deems the patient unsuitable for participation in the study for any other reason.

Описание

This project is a prospective, single-center, randomized controlled clinical study. The subjects were high-risk or relapsed/refractory AML or ALL patients aged ≤ 65 years diagnosed by bone marrow cell morphology, immunology, genetics and therapeutic efficacy evaluation. The TmBU scheme or modified Bu/Cy (mBuCy) scheme was used for pretreatment in allo-HSCT. The primary endpoint of the study was the 2-year cumulative incidence of relapse (CIR) after allo-HSCT, and the secondary endpoints were 2-year overall survival rate (OS), progressing-free survival rate (PFS), non-relapse mortality rate (NRM), graft-versus-host disease (GVHD)-free relapse-free survival (GRFS) rate.

Критерии включения

• * Confirmed diagnosis of AML or ALL according to WHO 2022 guideline criteria, with indications for allo-HSCT list below:
• 1. Relapsed/primary refractory (definitions refer to NCCN 2025) or genetic high-risk group AML at diagnosis (risk stratification refers to ELN 2022)
• 2. High-risk at diagnosis (risk stratification refers to ELN 2022) or MRD positive before transplantation B-ALL
• 3. Confirmed diagnosis of T-ALL
• 4. History of central nervous system leukemia (CNSL) or histopathologically confirmed extramedullary manifestation (EMD) during the course of the AML or ALL
• * Age 15-65 years old (≤ 65 years old)
• * HCT-CI score /< 2 points ECOG 0-2 points
• * Adequate organ function:
• 1. Cardiac NYHA grade ≤ 2, left ventricular ejection fraction ≥55%
• 2. Creatinine clearance ≥ 50ml/min
• 3. ALT and AST ≤ 2.5 times the upper limit of the normal range, and total bilirubin ≤ 1.5 times the upper limit of the normal range
• 4. Oxygen saturation /> 92% without oxygen
• * Expected survival time ≥ 3 months
• * Ability to understand and voluntarily sign the informed consent form

Критерии исключения

• * With other malignant tumors and have received any treatment for this tumor within the past 3 years
• * Previous or current other CNS disease (such as epilepsy, generalized seizure disorder, paresis, aphasia, stroke, severe brain injuries, dementia, Parkinson`s disease, cerebellar disease, organic brain syndrome, or psychosis) or any CNS-related autoimmune disease
• * HIV/Syphilis infection or uncontrolled active other infections (bacteria or fungus or virus is included)
• * With active hepatitis B or hepatitis C infection
• * Patients received cardiac angioplasty or stent implantation within 12 months before signing the informed consent form, or have symptoms requiring medical treatment for coronary heart disease
• * With primary immunodeficiency or active autoimmune disease
• * Previous history of severe immediate hypersensitivity reactions to any of the drugs to be used in this study
• * Received a live vaccine within 6 weeks prior to screening
• * Pregnant, lactating females and patients of childbearing potential who are unwilling to use contraception
• * Inability to cooperate with the requirements of study, treatment and monitoring due to psychiatric illness or other conditions
• * Patients not suitable for the study according to the investigator`s assessment

Описание

This study aims to compare the effects of two different conditioning regimens on patients with acute lymphoblastic leukemia (ALL) undergoing haploidentical allogeneic hematopoietic stem cell transplantation (haplo-HSCT): Total Body Irradiation (TBI) and Total Marrow, Central Nervous System and Lymphoid Irradiation (TMLI). Both regimens are supported and recommended by literature; however, there is no definitive evidence favoring one over the other. We hypothesize that the TMLI regimen, compared to the TBI regimen, may more effectively eliminate leukemia cells in the bone marrow and lymphoid tissues, thereby reducing the risk of relapse, while also minimizing damage to normal tissues, thus reducing conditioning-related toxicity and transplant-related mortality. This study aims to provide evidence for the optimal conditioning regimen for haplo-HSCT in adult ALL patients, with the goal of improving patient quality of life and survival outcomes.

Критерии включения

• 1. Informed Consent: Participants must voluntarily sign a written informed consent form.
• 2. Age and Gender: Participants should be male or female, aged 18-65 years, inclusive.
• 3. Diagnosis: Participants must be diagnosed with acute lymphoblastic leukemia (ALL) according to World Health Organization (WHO) criteria, and the diagnosis must apply to adults aged 18-65 years.
• 4. Remission Status: The participant`s leukemia must be in hematologic remission (complete remission, CR) prior to transplantation.
• 5. Donor Availability: There must be a suitable haploidentical donor available, and the participant must consent to undergo haploidentical hematopoietic stem cell transplantation (haplo-HSCT).
• 6. Karnofsky Performance Status: The participant must have a Karnofsky score of 70 or higher, indicating that they are capable of caring for themselves and carrying out normal activities. Additionally, they must not have significant organ dysfunction, defined by the following:
• * Cardiac Function: New York Heart Association (NYHA) classification of class II or lower.
• * Liver Function: Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels should be no more than 2.5 times the upper limit of normal. Bilirubin levels should be no more than 2 times the upper limit of normal.
• * Renal Function: Serum creatinine levels should be no more than 1.5 times the upper limit of normal, or the creatinine clearance rate should be at least 60 ml/min.
• * Pulmonary Function: Participants should not experience significant dyspnea, should not require oxygen therapy, should not have interstitial lung disease, and should not have any active pulmonary infections.
• 7. Reproductive Health:
• * Women of childbearing potential must test negative for pregnancy with a Human Chorionic Gonadotropin (HCG) test, confirmed by immunofluorescence during both screening and baseline periods. They must also agree to use effective contraception for at least one year following the transplantation.
• * Male participants with female partners of childbearing potential must agree to use effective barrier contraception and refrain from sperm donation for at least one year following the transplantation.

Критерии исключения

• To be eligible for inclusion in the study, participants must not meet any of the following criteria:
• 1. The patient has not achieved hematologic remission before transplantation.
• 2. The patient has chosen a non-haploidentical related donor.
• 3. The patient has severe cardiac, hepatic, renal, or pulmonary diseases that make them unable to tolerate the conditioning regimen.
• 4. The patient has an active or refractory infection, or other life-threatening complications.
• 5. The patient has a history of other malignant tumors, psychiatric disorders, or HIV infection.
• 6. The patient refuses to sign the informed consent form, is unwilling to comply with clinical follow-up required by the study, or does not consent to the use of their data to support future research, project presentations, and clinical practices.
• 7. The investigator deems the patient unsuitable for participation in the study for any other reason.

Описание

This study aims to compare the effects of two different conditioning regimens on patients with acute lymphoblastic leukemia (ALL) undergoing matched sibling donor hematopoietic stem cell transplantation (MSD-HSCT): Total Body Irradiation (TBI) and Total Marrow, Central Nervous System and Lymphoid Irradiation (TMLI). Both regimens are supported and recommended by literature; however, there is no definitive evidence favoring one over the other. We hypothesize that the TMLI regimen, compared to the TBI regimen, may more effectively eliminate leukemia cells in the bone marrow and lymphoid tissues, thereby reducing the risk of relapse, while also minimizing damage to normal tissues, thus reducing conditioning-related toxicity and transplant-related mortality. This study aims to provide evidence for the optimal conditioning regimen for MSD-HSCT in pediatric ALL patients, with the goal of improving patient quality of life and survival outcomes.

Критерии включения

• 1. Informed Consent: Participants or guardians must voluntarily sign a written informed consent form.
• 2. Age and Gender: Participants should be male or female, aged 1-17 years, inclusive.
• 3. Diagnosis: Participants must be diagnosed with acute lymphoblastic leukemia (ALL) according to World Health Organization (WHO) criteria, and the diagnosis must apply to pediatrics aged 1-17 years.
• 4. Remission Status: The participant`s leukemia must be in hematologic remission (complete remission, CR) prior to transplantation.
• 5. Donor Availability: There must be a suitable matched sibling donoravailable, and the participant must consent to undergo MSD hematopoietic stem cell transplantation (MSD-HSCT).
• 6. Karnofsky Performance Status: The participant must have a Karnofsky score of 70 or higher, indicating that they are capable of caring for themselves and carrying out normal activities. Additionally, they must not have significant organ dysfunction, defined by the following:
• * Cardiac Function: New York Heart Association (NYHA) classification of class II or lower.
• * Liver Function: Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels should be no more than 2.5 times the upper limit of normal. Bilirubin levels should be no more than 2 times the upper limit of normal.
• * Renal Function: Serum creatinine levels should be no more than 1.5 times the upper limit of normal, or the creatinine clearance rate should be at least 60 ml/min. o Pulmonary Function: Participants should not experience significant dyspnea, should not require oxygen therapy, should not have interstitial lung disease, and should not have any active pulmonary infections.

Критерии исключения

• To be eligible for inclusion in the study, participants must not meet any of the following criteria:
• 1. The patient has not achieved hematologic remission before transplantation. 2. The patient has chosen a non-MSD donor.
• 3. The patient has severe cardiac, hepatic, renal, or pulmonary diseases that make them unable to tolerate the conditioning regimen.
• 4. The patient has an active or refractory infection, or other life-threatening complications.
• 5. The patient has a history of other malignant tumors, psychiatric disorders, or HIV infection.
• 6. The patients or guardians refuses to sign the informed consent form, is unwilling to comply with clinical follow-up required by the study, or does not consent to the use of their data to support future research, project presentations, and clinical practices.
• 7. The investigator deems the patient unsuitable for participation in the study for any other reason.

Описание

This study aims to compare the effects of two different conditioning regimens on patients with acute lymphoblastic leukemia (ALL) undergoing haploidentical allogeneic hematopoietic stem cell transplantation (haplo-HSCT): Total Body Irradiation (TBI) and Total Marrow, Central Nervous System and Lymphoid Irradiation (TMLI). Both regimens are supported and recommended by literature; however, there is no definitive evidence favoring one over the other. We hypothesize that the TMLI regimen, compared to the TBI regimen, may more effectively eliminate leukemia cells in the bone marrow and lymphoid tissues, thereby reducing the risk of relapse, while also minimizing damage to normal tissues, thus reducing conditioning-related toxicity and transplant-related mortality. This study aims to provide evidence for the optimal conditioning regimen for haplo-HSCT in pediatric ALL patients, with the goal of improving patient quality of life and survival outcomes.

Критерии включения

• 1. Informed Consent: Participants or guardians must voluntarily sign a written informed consent form.
• 2. Age and Gender: Participants should be male or female, aged 1-17 years, inclusive.
• 3. Diagnosis: Participants must be diagnosed with acute lymphoblastic leukemia (ALL) according to World Health Organization (WHO) criteria, and the diagnosis must apply to pediatrics aged 1-17 years.
• 4. Remission Status: The participant`s leukemia must be in hematologic remission (complete remission, CR) prior to transplantation.
• 5. Donor Availability: There must be a suitable haploidentical donor available, and the participant must consent to undergo haploidentical hematopoietic stem cell transplantation (haplo-HSCT).
• 6. Karnofsky Performance Status: The participant must have a Karnofsky score of 70 or higher, indicating that they are capable of caring for themselves and carrying out normal activities. Additionally, they must not have significant organ dysfunction, defined by the following:
• * Cardiac Function: New York Heart Association (NYHA) classification of class II or lower.
• * Liver Function: Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels should be no more than 2.5 times the upper limit of normal. Bilirubin levels should be no more than 2 times the upper limit of normal.
• * Renal Function: Serum creatinine levels should be no more than 1.5 times the upper limit of normal, or the creatinine clearance rate should be at least 60 ml/min.
• * Pulmonary Function: Participants should not experience significant dyspnea, should not require oxygen therapy, should not have interstitial lung disease, and should not have any active pulmonary infections.

Критерии исключения

• To be eligible for inclusion in the study, participants must not meet any of the following criteria:
• 1. The patient has not achieved hematologic remission before transplantation.
• 2. The patient has chosen a non-haploidentical related donor.
• 3. The patient has severe cardiac, hepatic, renal, or pulmonary diseases that make them unable to tolerate the conditioning regimen.
• 4. The patient has an active or refractory infection, or other life-threatening complications.
• 5. The patient has a history of other malignant tumors, psychiatric disorders, or HIV infection.
• 6. The patients or guardians refuses to sign the informed consent form, is unwilling to comply with clinical follow-up required by the study, or does not consent to the use of their data to support future research, project presentations, and clinical practices.
• 7. The investigator deems the patient unsuitable for participation in the study for any other reason.

Описание

The participants are being asked to take part in this trial, because the participant is a survivor of childhood cancer or agreed to be part of a volunteer group to understand the relation between cancer and cancer treatment and muscle weakness in survivors of Acute Lymphoblastic Leukemia (ALL). ALL is cancer of the blood and bone marrow.

Primary Objective

• To compare muscle mtOXPHOS activity and satellite cell content among ALL survivors and controls.

Secondary Objective

* To evaluate the association between muscle mtOXPHOS, muscle satellite cell content and physical performance in ALL survivors.
* To evaluate the association of muscle morphology and epigenetics with muscle mtOXPHOS in ALL survivors.

Критерии включения

• * Survivor- or Control-Participant is age 18 years old or older at time of consent and enrolled in SJLIFE.
• * Survivor- Participant is childhood ALL survivor
• * Survivor- or Control Participant has low muscle mass as defined by relative lean mass z-score of less than or equal to -1 SD (lean mass divided by height in meters squared).
• * Survivor- or Control-Participant is able and willing to give informed consent

Критерии исключения

• * Survivor-Participant has history of cranial radiation.
• * Survivor- or Control-Participant has implanted medical devices or metal that would interfere with MRI or MRS
• * Female Survivor- or Control-Participant is pregnant.
• * Survivor- or Control-Participant is taking anticoagulants (e.g. aspirin, apixaban, coumadin, edoxaban, rivaroxaban)
• * Survivor- or Control-Participant weighs more than 300 pounds.
• * Survivor- or Control-Participant is allergic to local anesthetic (i.e., lidocaine, bupivacaine).
• * Survivor- or Control-Participant cannot lie flat on his/her back for 90 minutes or longer
• * Survivor- or Control-Participant has a current history of peripheral motor neuropathy.

Описание

Building upon the results from the CCCG-ALL-2015, CCCG-ALL-2020 multicenter study cohort, concurrent research findings, and the latest clinical trials, the CCCG-ALL-2025 I/HR-B-ALL is thus developed to further improve the event-free survival (EFS), and overall survival (OS), and quality of life (QoL) of children with intermediate- and high- risk B-cell childhood acute lymphoblastic leukaemia (I/HR-B-ALL), while decreasing adverse reactions and transplantation rates. This trial primarily aims to explore:

1. The efficacy of two randomized Blinatumomab application scheme on I/HR-ALL as determined by MRD negatvitiy rate.
2. The efficacy of modified mini-hyperCVD + Venetoclax in I/HR-ALL cannot afford blinatumomab, in contrast to historical control as determined by MRD negatvitiy rate.

Критерии включения

• 1. Age older than 1 month to younger than 18 years.
• 2. Diagnosis of acute lymphoblastic leukemia by bone marrow morphology.
• 3. Diagnosis of B-ALL by immunophenotyping.

Критерии исключения

• 1. Low-risk ALL
• 2. sIgM+
• 3. Acute leukemias of ambiguous lineage diagnosed according to WHO or EGIL criteria.
• 4. ALL evolved from chronic myeloid leukemia (CML).
• 5. Down`s syndrome, or major congenital or hereditary disease with organ dysfunction
• 6. Secondary leukemia
• 7. Known underlying congenital immunodeficiency or metabolic disease
• 8. Congenital heart disease with cardiac insufficiency.
• 9. Treated with glucocorticoids for ≥14 days, or ABL kinase inhibitors for /> 7 days within one month before enrollment, or any chemotherapy or radiotherapy within 3 months before enrollment (except for emergency radiotherapy to relieve airway compression)

Описание

The main objective of the study is to evaluate safety and tolerability of blinatumomab in adult Japanese participants with newly diagnosed B-ALL.

Критерии включения

• * Japanese adult participants ≥ 18 years and ≤ 70 years at enrollment.
• * Participant should have newly diagnosed B-cell precursor (BCP)
• * Philadelphia-negative ALL in CR/CRh after induction/consolidation therapy with any MRD (+ or -).
• * CR/CRh by the end of induction and 3 blocks of consolidation chemotherapy with ALL MRD2008/2019/2023 protocol regimen or 3 blocks of Hyper-CVAD.
• * Bone marrow function as defined below:
• * Absolute neutrophil count (ANC) (Neutrophils) ≥500/μL
• * Platelets ≥50.000/μL (transfusion permitted)
• * Adequate renal and hepatic function:
• * Total bilirubin (TBL) ≤ 2.0 x upper limit of normal (ULN) (ULN; unless Gilbert`s Disease or if liver involvement with leukemia)
• * Creatinine clearance ≥50 mL/min/1.73 m/^2
• * Eastern Cooperative Oncology Group performance status (ECOG PS) ≤ 2.

Критерии исключения

• Disease Related • Current infiltration of cerebrospinal fluid (CSF) by ALL. If screening CSF demonstrates leukemic blasts, participants must receive intrathecal treatment and demonstrate negative CSF before enrollment and starting blinatumomab infusion.
• Other Medical Conditions
• * History of relevant central nervous system (CNS) pathology or current relevant CNS pathology (e.g., seizure, paresis, aphasia, cerebrovascular ischemia/hemorrhage, severe brain injuries, dementia, Parkinson`s disease, cerebellar disease, organic brain syndrome, psychosis, or coordination or movement disorders).
• * Current autoimmune disease or history of autoimmune disease with potential CNS involvement.
• * Active uncontrolled infection requiring therapy.
• * History of other malignancy within the past 3 years, with the following exceptions:
• * Malignancy treated with curative intent and with no known active disease present for ≥ 3 years before enrollment and felt to be at low risk for recurrence by the treating physician.
• * Adequately treated nonmelanoma skin cancer or lentigo maligna without evidence of disease.
• * Adequately treated cervical carcinoma in situ without evidence of disease.
• * Adequately treated breast ductal carcinoma in situ without evidence of disease.
• * Prostatic intraepithelial neoplasia without evidence of prostate cancer.
• * Adequately treated urothelial papillary noninvasive carcinoma or carcinoma in situ.
• Prior/Concomitant Therapy
• * Systemic cancer chemotherapy within 2 weeks prior to study treatment (except for intrathecal prophylaxis)
• * Known infection with human immunodeficiency virus (HIV) or chronic infection with hepatitis B virus or hepatitis C virus. In Japan, follow the JSH Guidelines for the Management of Hepatitis B Virus Infection version 4 (The Japan Society of Hepatology, 2022) for the screening of Hepatis B virus infection.
• * Radiotherapy within 4 weeks prior to study treatment.
• Prior/Concurrent Clinical Study Experience
• • Currently receiving treatment in another investigational device or drug study, or less than 30 days since ending treatment on another investigational device or drug study(ies). This does not apply to other investigational procedures or participation in observational research studies while participating in this study are excluded.
• Other Exclusions
• * Participants of childbearing potential unwilling to use protocol-specified method of contraception during treatment and for an additional 48 hours after the last dose of blinatumomab.
• * Participants who are breastfeeding or who plan to breastfeed while on study through 48 hours after the last dose of blinatumomab.
• * Participants planning to become pregnant or donate eggs while on study through 48 hours after the last dose of blinatumomab.
• * Participants of childbearing potential with a positive pregnancy test assessed at screening by a highly sensitive urine or serum pregnancy test.
• * Participant has known hypersensitivity to blinatumomab or to any component of the product formulation.
• * Participant likely to not be available to complete all protocol-required study visits or procedures, and/or to comply with all required study procedures (e.g., Clinical Outcome Assessments) to the best of the participant and investigator`s knowledge.
• * History or evidence of any other clinically significant disorder, condition, or disease (except for those outlined above) that, in the opinion of the investigator or Amgen physician, if consulted, would pose a risk to participant safety, or interfere with the study evaluation, procedures, or completion.

Описание

The goal of this clinical trial is to investigate the effects of core stabilization exercises applied in addition to the conventional exercise program on physical function, functional muscle strength, functional exercise capacity, postural control and fatigue in children with acute lymphoblastic leukemia receiving maintenance treatment.

Participants will be divided into two groups; the first group will be given a conventional exercise program, while the second group will be given core stabilization exercises in addition to the conventional exercise program.

Критерии включения

• * Children aged 7-18
• * Diagnosed with ALL
• * In the maintenance phase of chemotherapy
• * Children without acute thrombosis, active ischemia, hemodynamic instability
• * Children without uncontrolled pain
• * Children who can follow verbal instructions.

Критерии исключения

• * Children who have received or are receiving cranial radiotherapy
• * Children with any cardiovascular disease, acute or chronic respiratory disease
• * Children with acute or chronic bone, joint, muscle problems
• * Children diagnosed with neuromotor deficits or genetic disorders
• * Children with vision problems other than refractive errors

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

The goal of this study is to provide sufficient therapy during the time a patients` B-cell Acute Lymphoblastic Leukemia (ALL) or Lymphoblastic Lymphoma (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 enroll all newly diagnosed ALL/ LLy/ MPAL patients. 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 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

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

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

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

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

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 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-positive hematologic malignancies.

Критерии включения

• * Age: Part 1: 18-90 years of age, Part 2: 13-90 years of age
• * Relapsed or refractory CD-19 positive leukemia or lymphoma as defined in the protocol
• * CD19-positive expression
• * 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 (SPPL3) 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 (SPPL3)-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 (SPPL3) 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 (SPPL3) 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 (SPPL3) 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 (SPPL3) 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 (SPPL3) 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

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 2 years.

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.
• * Are NGS MRD negative by tracking sample in the bone marrow within 42 days post CD19 CART infusion confirmed by NGS MRD testing.
• * Received first CD19 (4-1BB) CART within 42 days prior to enrollment. 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 42 days post CD19 CART infusion. 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.