Developing a Patient-Reported Outcome (PRO) Screening Measure for Infections and Measuring Quality of Life in Hematological Patients With Secondary Immunodeficiency (SID) Across the Treatment Trajectory - The PRO SID Project
Developing a Patient-Reported Outcome (PRO) Screening Measure for Infections and Measuring Quality of Life in Hematological Patients With Secondary Immunodeficiency (SID) Across the Treatment Trajectory - The PRO SID Project
Теги: #Plasma cell leukemia
Локации: BKH Kufstein; Kufstein; Austria,Klinikum Garmisch-Partenkirchen; Garmisch-Partenkirchen; Germany,Medizinische Universität Graz; Graz; Austria,Medizinische Universität Innsbruck; Innsbruck; Tyrolia; Austria,Onkologischer Schwerpunkt am Oskar-Helene-Heim; Berlin; Germany
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Описание
The goal of this observational study is to improve the treatment of hematological patients with secondary immunodeficiency (SID) by developing a patient-reported outcome (PRO) instrument to detect clinically diagnosed infections. The study focuses on adults diagnosed with chronic lymphocytic leukemia (CLL) or multiple myeloma (MM) who are at increased risk of infections due to SID.
The main questions it aims to answer are:
1. Can a newly developed PRO screening tool for infection-related symptoms reliably detect infections in patients with SID?
2. How does the health-related quality of life change over the treatment course
Participants will:
* Complete daily electronic PRO questionnaires (ePRO) to monitor infection-related symptoms
* Complete ePRO health-related quality of life questionnaires every 1.5 months
* Participate in study visits every three months to ensure documentation of clinical data
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Критерии включения
* Adult patient (/>=18 years of age)
* Access to an internet device (e.g., personal computer or tablet to use a web-based platform, or smartphone where the study app can be installed - all common iOS and Android systems)
* German-speaking
* Diagnosis of multiple myeloma or chronic lymphocytic leukemia
* Secondary immunodeficiency (defined as: recurrent infections, infections requiring inpatient treatment, hypogammaglobulinemia, neutropenia and/or lymphopenia on differential blood cell counts, deficit in lymphocyte subsets as assessed by flow cytometry)
Epcoritamab in Chronic Lymphocytic Leukemia and Richter Syndrome
Correlative Study of Epcoritamab in Chronic Lymphocytic Leukemia and Richter Syndrome
Локации: National Institutes of Health Clinical Center; Bethesda; Maryland; United States
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Описание
This correlative study aims to understand the pharmacodynamic effects and clonal dynamics in response to epcoritamab by obtaining and analyzing lymph node, bone marrow, and blood samples from subjects enrolled in GCT3013-03 trial sponsored by Genmab at NIH. Samples will be collected before and at multiple time points during treatment with epcoritamab. National Heart, Lung, and Blood Institute (NHLBI) investigators are experienced in testing samples treated with bsAb2,3 including epcoritamab in an ongoing pre-clinical collaboration with Genmab. Addressing the objectives of this correlative study will advance the science and clinical application of epcoritamab specifically as well as T-cell engaging bsAb in general as an emerging class of immunotherapy for cancer.
The study is enrolling by invitation only.
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Критерии включения
* INCLUSION CRITERIA:
In order to be eligible to participate in this study, an individual must meet all of the following criteria:
* Must be undergoing screening for GCT3013-03
* Stated willingness to comply with all study procedures and availability for the duration of the study
* Ability of subject to understand and the willingness to sign a written informed consent document.
A Study to Investigate the Safety of Novel Dose Ramp-up Schedule(s) When Initiating Sonrotoclax in Participants Treated for Blood Cancers.
A Phase 1/2 Open-label Study to Investigate the Safety of Sonrotoclax Ramp-up Schedule(s) in Adult Patients With Hematological Malignancies.
Локации: Blacktown Cancer and Haematology Centre; Blacktown; New South Wales; Australia,Chu Dijon; Dijon; France,Chu Montpellier Hopital Saint Eloi; Montpellier Cedex; France,Dana Farber Cancer Institute; Boston; Massachusetts; United States,Fort Wayne Medical Oncology and Hematology; Fort Wayne; Indiana; United States,Fred Hutchinson Cancer Research Center; Seattle; Washington; United States,Hopital Avicenne, Aphp, Bobigny; Bobigny; France,Hopital Larchet Chu Nice; Nice; France,Iuct Oncopole; Toulouse Cedex; France,Linear Clinical Research; Nedlands; Western Australia; Australia,Moffitt Cancer Center; Tampa; Florida; United States,Queen Elizabeth Hospital; Birmingham; United Kingdom,Rockingham Hospital; Cooloongup; Western Australia; Australia,St Jamess University Hospital; Leeds; United Kingdom,The Alfred Hospital; Melbourne; Victoria; Australia,The Christie Nhs Foundation Trust Manchester; Manchester; United Kingdom,The University of Kansas Cancer Center; Westwood; Kansas; United States,University Hospitals Bristol
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Описание
The purpose of this study is to establish the safety of novel dosing and ramp-up schedules for sonrotoclax in participants with hematological malignancies.
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Критерии включения
1. Stable ECOG Performance Status ≤ 2.
2. Adequate organ function and no very recent transfusion or blood growth factor
3. Participants of childbearing potential must be willing to use a highly effective method of birth control and refrain from egg donation for the duration of the study and for ≥ 90 days after the last dose of sonrotoclax or ≥ 30 days after the last dose of zanubrutinib, whichever is later.
4. Confirmed diagnosis of CLL, based on Hallek et al 2018, and requiring treatment due to certain features of their disease
5. At least 1 measurable lesion based on computed tomography (CT)/magnetic resonance imaging (MRI) and no history of prolymphocytic leukemia or Richter`s transformation.
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Критерии исключения
1. Participants unable to comply with the requirements of the protocol
2. Serologic status reflecting active viral HBV or HCV infection
3. Positive HIV serology (HIVAb) status unless certain conditions are met.
4. Participants with any major surgical procedure ≤ 28 days before first dose of study treatment
5. Prior systemic treatment for the CLL
6. Uncontrolled autoimmune hemolytic anemia or immune thrombocytopenia requiring treatment
NOTE: Other protocol defined Inclusion/Exclusion criteria may apply.
A Study Evaluating the Efficacy and Safety of Pirtobrutinib in Participants With Relapsed or Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
A Phase 2, Open-Label, Randomized Study Evaluating the Efficacy and Safety of 3 Doses of Pirtobrutinib in Participants With Relapsed or Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma Who Previously Received Treatment With a Covalent Bruton Tyrosine Kinase Inhibitor
Теги: #Relapsed|Refractory
Локации: A.O.U.C. Policlinico di Bari; Bari; Puglia; Italy,Aarhus Universitetshospital, Skejby; Aarhus; Midtjylland; Denmark,AIDPORT Sp. z o.o.; Skórzewo; Wielkopolskie; Poland,American Oncology Partners of Maryland, PA; Bethesda; Maryland; United States,Ankara University Health Practice and Research Hospitals; Ankara; Turkey,AO Santa Maria della Misericordia; Perugia; Umbria; Italy,AOU Policlinico Umberto I; Roma; Italy,ASST Grande Ospedale Metropolitano Niguarda; Milan; Lombardia; Italy,Attikon General University Hospital; Chaidari; Attikí; Greece,AZ Delta vzw; Roeselare; West-Vlaanderen; Belgium,AZ Nikolaas; Sint-Niklaas; Oost-Vlaanderen; Belgium,AZ Sint-Jan Brugge-Oostende AV; Brugge; West-Vlaanderen; Belgium,Az. Osp. Ospedali Riuniti VILLA SOFIA-CERVELLO; Palermo; Sicilia; Italy,Azienda Ospedale - Università Padova; Padova; Veneto; Italy,Azienda Ospedaliera Universitaria Careggi; Firenze; Toscana; Italy,Azienda Ospedaliero Universitaria Maggiore della Carità; Novara; Italy,Azienda Ospedaliero Universitaria S.
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Описание
The main purpose of this study is to assess the efficacy and safety of 3 dose levels of Pirtobrutinib in participants with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), who have received 1-3 lines of treatment including a covalent Bruton tyrosine kinase (BTK) inhibitor. The study is expected to last approximately 3 years.
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Критерии включения
* Have confirmed diagnosis of CLL/SLL as defined by these iwCLL 2018 criteria.
* Have received prior CLL/SLL treatment
* Have received at least 1, but not more than 3 lines of prior treatment for CLL/SLL
* Have received a covalent BTK inhibitor
* Have a requirement for therapy consistent with iwCLL 2018 criteria for initiation of therapy
* Capable of swallowing oral study medication.
* Have an Eastern Cooperative Oncology Group Performance Status (ECOG) score of 0 to 2.
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Критерии исключения
* Have received prior treatment with a BTK degrader and a noncovalent BTK inhibitor
* Have a history of greater than or equal to (/>=) Grade 3 bleeding due to treatment with a BTK inhibitor
* Have known or suspected Richter`s transformation
* Have known or suspected history of central nervous system involvement by CLL/SLL
* Previous or concurrent cancer distinct from CLL/SLL within 3 years before randomization. Exceptions may occur with documented sponsor approval. Examples include:
* nonmelanoma skin cancer or lentigo maligna melanoma
* cervical carcinoma in situ
* localized prostate cancer undergoing active surveillance, and
* localized (for example, lymph node negative) breast cancer with no evidence of active disease present for more than 3 years. Individual may be receiving adjuvant hormonal therapy
A Study of AUR104 in Patients with Relapsed/Refractory Lymphoid Malignancies (VIJAY-1)
A Phase 1, Open Label, Dose Escalation, Multicenter Study Evaluating the Safety, Pharmacokinetics, and Pharmacodynamics of Oral AUR104 in Patients with Select Relapsed/Refractory Lymphoid Malignancies (VIJAY-1)
Теги: #Relapsed|Refractory
Локации: Adwaita Cancer Hospital & ICU; Surat; Gujarat; India,Kiran Multi Super Speciality Hospital and Research Centre; Surat; Gujarat; India,Kolhapur Cancer Centre Pvt. Ltd.; Kolhapur; Maharashtra; India,MMFHA Joshi Hospital; Pune; Maharashtra; India,Sunshine Global Hospitals; Surat; Gujarat; India
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Описание
This is a multicenter, open-label, Phase 1 study of AUR104 in adult patients with select Relapsed/Refractory (R/R) Lymphoid Malignancies. The main objective of the study is to evaluate the safety and tolerability of the study drug AUR104.In this study, safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy of AUR104 will be evaluated in dose escalation manner.
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Критерии включения
1. Males and females ≥ 18 years of age.
2. Eastern Cooperative Oncology Group (ECOG) Performance status of 0 or 1.
3. Acceptable bone marrow and organ function at screening as described below:
* Platelet count: For patients with CLL ≥ 50,000/μL, For patients with lymphomas ≥ 75,000/μL without bone marrow involvement and ≥ 50,000/μL with bone marrow involvement. These thresholds should be qualified without current transfusion support.
* Hemoglobin ≥ 9 g/dL (Transfusion is allowed to achieve this Hb).
* Total Bilirubin ≤ 1.5 x ULN (Patients with known Gilbert`s syndrome are allowed with a Total Bilirubin ≤ 2.5 x ULN).
* AST (SGOT) ≤ 3 x ULN (≤ 5 × ULN if known liver metastases).
* ALT (SGPT) ≤ 3 x ULN (≤ 5 × ULN if known liver metastases).
* Creatinine clearance (CrCl) ≥ 60 mL/min (either measured or estimated by the Cockcroft-Gault formula). Cockcroft-Gault formula for estimated creatinine clearance (eCrCl):(140 - Age) × Weight (kg) × (0.85 if Female)/(72 × serum creatinine in mg/dL).
4. Ability to swallow and retain oral medications.
5. Histopathological diagnosis of Non-Hodgkin Lymphoma (NHL) or Chronic Lymphocytic Leukemia (CLL) or Hodgkin disease.
Note:
5a. The lymphoma should be either in Stage III or IV according to Lugano classification at screening.
5b. The lymphomas included in this study must fall within one of the following 2017 World Health Organization categories except lymphoma mentioned in Exclusion criterion #5:
* Mature B-cell neoplasms (excluding plasma cell neoplasms, heavy chain disease, and primary central nervous system /[CNS/] lymphoma).
* Mature T- and NK-cell neoplasms.
* Hodgkin lymphomas. 5c. The CLL should be Binet Stage C/Rai stage III or IV, as per the International Workshop on Chronic Lymphocytic Leukemia (iwCLL) guidelines.
6) In the case of patients who have lymphoid malignancies for which high-dose chemotherapy and autologous stem cell transplantation (HD-ASCT) is considered standard curative therapy, eligibility for this study requires that the disease has relapsed after HD-ASCT, or the subject is not eligible for HD-ASCT, or the subject has refused HD-ASCT.
7) In the case of patients who have lymphoid malignancies for which CAR-T therapy is indicated, eligibility for this study requires that the disease has relapsed after CAR-T, or the patient is not eligible for CAR-T, or the patient has refused CAR-T, or the CAR-T is not available locally.
8) Evidence of measurable disease as per Lugano Criteria for Lymphoma or evidence of measurable disease as per iwCLL Criteria for CLL.
Note: Patients with Small Lymphocytic Lymphoma (SLL) alone or in combination with CLL are allowed.
9) Standard curative measures do not exist, and the patient must have exhausted all effective therapies available locally. At a minimum, the patients must have relapsed or refractory disease to at least 2 prior lines of systemic therapies for NHL or CLL, or Hodgkin`s disease.
Note: Any cancer patient with access to any effective therapy locally must not be enrolled.
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Критерии исключения
1. Systemic anti-cancer therapy, such as chemotherapy, biological therapy, or immunomodulatory drug therapy, received within the past 28 days or 5 half-lives, whichever is longer, from Cycle 1 Day 1 of the study.
Note: Concomitant use of low-dose prednisone (up to 10 mg/day) is allowed.
2. Presence of acute or chronic toxicity resulting from prior anti-cancer treatment, except for alopecia or nail changes that have not resolved to Grade ≤ 1, as determined by NCI CTCAE v 5.0.
3. Definitive Radiotherapy within the last 21 days of Cycle 1 Day 1 (limited field palliative radiation is allowed and no restrictions during the screening period or during the trial).
4. Use of any investigational agent within 28 days or 5 half-lives (whichever is longer) prior to Cycle 1 Day 1.
6. Known symptomatic or untreated or recently treated (≤ 6 months of screening) central nervous system (CNS) lymphoma. Patients with previously treated (more than 6 months of screening) CNS lymphoma and are now stable and asymptomatic, from a CNS perspective, are allowed.
7. Patients with lymphoma requiring immediate cytoreductive therapy.
8. Patients with low-grade or indolent lymphoma not meeting conventional criteria for treatment.
9. Elevated Serum cardiac Troponin I or troponin T more than ULN at screening.
10. Serum magnesium and calcium levels more than 1.2 x ULN or less than 0.8 x LLN.
11. Serum Potassium more than 1.0 x ULN or less than 1.0 x LLN. Note: Patients experiencing hypokalemia are permitted to undergo treatment to attain normal potassium levels during the screening period.
12. Mean Heart Rate less than 60 at screening or Cycle 1 Day 1 (to be recorded at least 3 times at least 5 minutes apart) in ECG.
13. Left ventricular ejection fraction (LVEF) less than 50% as determined by an echocardiogram (ECHO) or Multigated Acquisition (MUGA) scan.
14. QTcF (Fridericia) interval more than 450 ms for patients on ECG at screening and/or at Cycle 1 Day 1.
15. Uncontrolled arterial hypertension defined as supine SBP of ≥ 140 mm Hg AND/OR supine DBP ≥ 90 mmHg on stable doses of three or lesser different classes of antihypertensive drugs.
Notes:
* Patients taking 4 or more classes of antihypertensives are excluded. Diuretics (such as furosemide or spironolactone) are considered as one class of anti-hypertensives.
* The blood pressure has to be recorded 3 times at least 10 minutes apart during Screening and Cycle 1 Day 1 (before dosing) in the supine position. Among these recordings, a single instance of SBP ≥140 mm Hg or DBP ≥ 90 mmHg will exclude the patient. Note: A patient excluded on these criteria can be re-screened after optimal BP management.
16. Current or past history of heart failure (NYHA Class 2 or higher)
17. Having a history of moderate to severe cardiovascular disease including unstable angina, myocardial infarction, cerebrovascular accident, or transient ischemic attack (TIA), within 1 year prior to Cycle 1 Day 1.
18. Ongoing cardiac arrhythmias or conduction blocks.
19. History of any ventricular arrhythmia including supraventricular or ventricular premature contractions.
20. Patients on drugs which are sensitive substrates of CYP3A4 and cannot be discontinued at least one week prior to Cycle 1 Day 1.
21. Use of strong CYP3A4 inhibitors or inducers within 2 weeks prior to Cycle 1 Day 1.
22. Concomitant use of any drug which is known to prolong QTc interval or use of such drugs within one week prior to Cycle 1 Day 1.
23. Major surgery ≤ 28 days from Cycle 1 Day 1 (major surgery is defined as a procedure requiring general anesthesia)
24. Active infection requiring systemic therapy. Note: Prophylactic use of antibiotics is allowed. Any infection detected during the screening period, which is resolved adequately according to the investigator before Cycle 1 Day 1, is allowed.
25. Known to be human immunodeficiency virus (HIV) positive or have an acquired immunodeficiency syndrome-related illness.
26. Known active or chronic hepatitis B (HBsAg +ve) or hepatitis C infection (HCV antibody +ve).
27. Patient expected to require any other form of antineoplastic therapy or targeted therapy while in the study.
28. Uncontrolled intercurrent illness including, but not limited to, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, active peptic ulcer disease or significant gastritis, active bleeding diatheses, presence of any major medical illness (e.g., renal, hepatic, hematologic, gastrointestinal, endocrine, pulmonary, or psychiatric illness/social situations or clinically significant laboratory / ECG abnormalities at screening, any or a combination of illnesses, which, in the opinion of the PI, may either put the patient at risk because of participation in the study or influence the results or the patient`s ability to participate in the study
29. Current swab-positive or suspected (under investigation) Covid-19 infection or fever and other signs or symptoms suggestive of Covid-19 infection with recent contact of the person(s) with confirmed Covid-19 infection, at screening or Cycle 1 Day 1.
30. History of another primary malignancy within 5 years prior to starting the study drug, except for adequately treated basal or squamous cell carcinoma of the skin or cancer of the cervix in situ or cured early-stage (Stage 1 or 2) prostate cancer.
31. Positive pregnancy test for women of childbearing potential (WOCBP) at the screening or enrolment visit
32. Lactating women or WOCBP who are neither surgically sterilized nor willing to use reliable contraceptive methods (hormonal contraceptive, IUD, or any double combination of male or female condom, spermicidal gel, diaphragm, sponge, cervical cap).
CLIC-2201 for the Treatment of Relapsed/Refractory B Cell Malignancies
CLIC-02: A Phase I Trial of CLIC-2201 for the Treatment of Relapsed/Refractory B Cell Malignancies
Теги: #Relapsed|Refractory
Локации: Alberta Children`s Hospital; Calgary; Alberta; Canada,BC Children`s Hospital; Vancouver; British Columbia; Canada,Calgary Cancer Centre; Calgary; Alberta; Canada,Princess Margaret Cancer Centre; Toronto; Ontario; Canada,The Hospital for Sick Children; Toronto; Ontario; Canada,The Ottawa Hospital - General Campus; Ottawa; Ontario; Canada,Vancouver General Hospital; Vancouver; British Columbia; Canada
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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.
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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.
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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.
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.
A Phase 1 Study of UB-VV111 With and Without Rapamycin in Relapsed/Refractory CD19+ B-cell Malignancies
A Phase 1, Multicenter, Open-label Study of UB-VV111 in Combination With Rapamycin in Relapsed/Refractory (R/R) CD19+ B-cell Malignancies
Теги: #Relapsed|Refractory
Локации: City of Hope; Duarte; California; United States,University of Nebraska Medical Center; Omaha; Nebraska; United States,Washington University School of Medicine/Siteman Cancer Center; Saint Louis; Missouri; United States
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Описание
This study is a Phase 1 dose-escalation and dose-confirmation study to evaluate the safety and antitumor activity of UB-VV111. The study will enroll patients with relapsed/refractory large B-cell lymphoma (LBCL) and chronic lymphocytic leukemia (CLL).
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Критерии включения
1. 18 years or older
2. Provides voluntary written informed consent
3. Relapsed or refractory large B-cell lymphoma (LBCL) or chronic lymphocytic leukemia (CLL)
4. Measurable disease according to Lugano 2014 criteria (LBCL) or iwCLL 2018 (CLL).
5. No serious concomitant diseases or active/uncontrolled infections
6. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
7. Adequate organ function
8. Patients who have previously received CD19-directed therapy must have biopsy confirming CD19 expression following completion of prior CD19-directed therapy.
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Критерии исключения
1. Women who are pregnant or breastfeeding
2. Current isolated central nervous system (CNS) involvement
3. Prior allogeneic bone marrow transplant, gene therapy, or adoptive cell transfer (except CAR T-cell therapy in CAR T-exposed subjects)
4. History of or active human immunodeficiency virus (HIV)
5. Active hepatitis B or C
6. Systemic autoimmune or immunodeficiency diseases, except for well-controlled Type I diabetes or thyroid disease
7. Ongoing CNS disease that would preclude neurologic assessment
8. Uncontrolled angina or other acute heart disease
9. Currently receiving treatment in another interventional clinical trial.
A Study to Investigate Sonrotoclax Combined With Zanubrutinib Versus Zanubrutinib Alone in Participants With Previously Untreated Chronic Lymphocytic Leukemia
A Multicenter, Open-Label, Phase 2 Study to Investigate the Efficacy and Safety of Sonrotoclax Combined With Zanubrutinib Compared With Zanubrutinib Monotherapy in Adult Patients With Previously Untreated Chronic Lymphocytic Leukemia
Теги: #Newly diagnosed
Локации: Aoor Villa Sofia Cervello; Palermo; Italy,Aou Careggi, Servizio Sanitario Toscana; Firenze; Italy,Azienda Socio Sanitaria Territoriale Degli Spedali Civili Di Brescia; Brescia; Italy,Centro de Pesquisas Oncologicas Cepon; Florianopolis; Brazil,Cleveland Clinic Florida; Weston; Florida; United States,Clinica Universidad de Navarra Pamplona; Pamplona; Spain,Clinica Universidad de Navarra; Madrid; Spain,Fujian Medical University Union Hospital; Fuzhou; Fujian; China,Henan Cancer Hospital; Zhengzhou; Henan; China,Hospital Clinic de Barcelona; Barcelona; Spain,Hospital de Cabuenes; Gijon; Spain,Hospital de Clínicas de Porto Alegre; Porto Alegre; Brazil,Hospital de Clinicas de Porto Alegre; Porto AlegreRS; Brazil,Illinois Cancer Specialists (Niles) Usor; Niles; Illinois; United States,Instituto Dor de Pesquisa E Ensino Sao Paulo; Sao Paulo; Brazil,Jiangsu Province Hospital; Nanjing; Jiangsu; China,Nebraska Cancer Specialists (Satellite Site); Grand Island; Nebraska; United States,Nebraska Cancer Specialists; Grand
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Описание
The purpose of this study is to support the registration plan of sonrotoclax plus zanubrutinib treatment in participants with previously untreated CLL. This study is designed to assess the contribution of sonrotoclax to the efficacy outcome of the combination of zanubrutinib and sonrotoclax.
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Критерии включения
1. Previously untreated adult patient ≥ 18 years with a confirmed diagnosis of CLL.
2. CLL requiring treatment as per pre-defined criteria.
3. Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0, 1, or 2.
4. Measurable disease by CT/MRI.
5. Adequate marrow function.
6. Adequate liver function as indicated by aspartate aminotransferase (AST) alanine aminotransferase (ALT) and serum total bilirubin.
7. Adequate renal function.
8. Life expectancy /> 6 months.
9. Signed informed consent and able to comply with the study protocol in the investigator`s judgment.
10. Women of childbearing potential must be willing to use a highly effective method of birth control for the duration of the study and for ≥ 90 days after the last dose of study drug.
×
Критерии исключения
1. Known prolymphocytic leukemia or history of, or currently suspected, Richter`s transformation
2. Known central nervous system involvement
3. Received previous systemic treatment for CLL
4. Clinically significant cardiovascular disease
5. Severe or debilitating pulmonary disease
6. History of prior malignancy
7. Active fungal, bacterial, and/or viral infection requiring systemic therapy
8. Positive HIV serology (HIVAb) status or serologic status reflecting active hepatitis B or C infection
9. Uncontrolled autoimmune hemolytic anemia or immune thrombocytopenia requiring treatment
10. History of severe bleeding disorder such as hemophilia A, hemophilia B, von Willebrand disease, or history of spontaneous bleeding requiring blood transfusion or other medical intervention
11. History of stroke or intracranial hemorrhage ≤ 6 months before the first dose of study treatment
12. Unable to swallow capsules or tablets or diseases significantly affecting GI function
13. Hypersensitivity to zanubrutinib, sonrotoclax, or any of its excipients
14. Use of investigational agents within the last 4 weeks before screening
15. Pregnant and lactating females
Note: Other protocol defined Inclusion/Exclusion criteria may apply
Universal CAR-T Cells (REVO-UWD-19) for Refractory and Relapsed B-Cell Tumors
A Clinical Study Evaluating the Safety and Efficacy of Universal CD19-Targeted CAR-T (UWD-CD19) Therapy for Refractory and Relapsed B-Cell Tumors
Теги: #Relapsed|Refractory
Локации: The First Affiliated Hospital of University of Science and Technology of China; Hefei; Anhui; China
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Описание
This study is a single-arm, single-center, investigator-initiated clinical trial. The primary objective is to evaluate the safety and preliminary efficacy of administering universal CD19 CAR-T cells to subjects with refractory and relapsed B-cell tumors. Eligible participants will undergo FC lymphodepleting chemotherapy preconditioning after signing an informed consent form, followed by a one-time injection of universal UWD-19 to assess its safety and efficacy. Subjects will be hospitalized for a period, and after discharge, they will undergo periodic efficacy assessments and long-term survival follow-up for at least five years.
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Критерии включения
* Patients (or their guardians) understand the study and voluntarily sign the informed consent form, with an expected ability to complete follow-up evaluations and treatments as per study protocol.
Age range: 3-70 years, no gender restrictions. Diagnosis of B-cell lymphoma, meeting the 2018 NCCN B-Cell Lymphoma guidelines (Version 5), with CD19 positivity confirmed by flow cytometry or immunohistochemistry.
At least one evaluable or measurable lesion per Lugano 2014 criteria. Evaluable lesions are indicated by FDG uptake above liver levels on FDG/PET or by lymphoma-like characteristics on PET/CT. Measurable lesions require a nodal diameter />15 mm or extranodal lesion />10 mm (with post-radiation evidence of progression if previously irradiated). Cases without measurable lesions but with diffuse liver FDG uptake are excluded.
Refractory and relapsed B-cell lymphoma, meeting at least one of the following: a. Received ≥2 cycles of standardized second-line or higher treatment, and meets Lugano 2014 criteria for best clinical response:
Progressive Disease (PD) on the most recent treatment.
Stable Disease (SD) lasting /<6 months before progressing. b. Recurrence or progression ≤12 months post-autologous stem cell transplant. c. Based on investigator judgment, the potential benefit may outweigh risk in cases such as:
Recent SD with measurable disease progression but not meeting PD criteria. Partial remission (PR) or better lasting /<6 months post-treatment, then progression.
Intolerance to most recent chemotherapy. Relapsed/refractory CD19-positive acute B lymphoblastic leukemia.
Laboratory values indicating adequate organ and marrow function, with no severe cardiac, pulmonary, hepatic, renal, or immune dysfunction:
Serum albumin ≥25 g/L Creatinine clearance ≥30 mL/min/1.73 m² ALT and AST ≤3.0× ULN Total bilirubin ≤2.0× ULN (exceptions for congenital hyperbilirubinemia like Gilbert syndrome with direct bilirubin ≤1.5× ULN) PT and APTT /<2× ULN Oxygen saturation ≥95% Blood transfusions allowed to maintain hemoglobin ≥8.0 g/dL. ECOG performance status 0-1. Expected survival time />90 days. Negative β-hCG test for women of childbearing potential at screening and prior to chemotherapy.
Women of childbearing potential must use a highly effective contraceptive method (annual failure rate /<1%) from the time of consent until 1 year after UWD-CD19 infusion, including:
Non-user-dependent: implantable progestogen, IUD, hormone-releasing system, or partner vasectomy.
User-dependent: combination hormonal contraception, progestogen-only pill, or injection.
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Критерии исключения
* History of aggressive malignancies other than B-cell lymphoma, except:
Cancer in remission />2 years post-curative therapy. Non-melanoma skin cancer successfully treated and inactive.
Prior anti-cancer therapy including:
Targeted, epigenetic, or experimental drug therapy within 14 days or 5 half-lives.
Cytotoxic therapy within 14 days. Immunomodulators within 7 days. Monoclonal antibodies within 21 days. Radiotherapy within 14 days. Active CNS involvement. Conditions like Waldenström`s macroglobulinemia, POEMS syndrome, or primary AL amyloidosis.
Active hepatitis B (HBsAg or HBcAb positive with viral load />1000 copies/ml), hepatitis C (HCV RNA positive), HIV, CMV, or syphilis positivity.
Severe allergy history, or known allergy to trial components, adjuvants, or animal-derived proteins.
Severe cardiac conditions such as arrhythmias, unstable angina, recent MI, heart failure (NYHA III/IV), uncontrolled hypertension.
Unstable systemic disease, including significant liver, kidney, or metabolic disease requiring medication.
Acute/chronic GVHD or requiring immunosuppressants within 6 months. Active autoimmune or inflammatory neurologic diseases. Urgent tumor-related conditions requiring emergency treatment. Uncontrolled bacterial, fungal, or viral infections. Major surgery within 4 weeks or planned major surgery during the study. Live virus vaccination within 4 weeks prior to screening. Severe psychiatric disorders. History of substance abuse. Pregnant or lactating women, or individuals planning conception within 2 years of cell infusion.
Any contraindications per investigator`s judgment due to clinical standards or patient`s condition.
Zanubrutinib With Obinutuzumab in Untreated Patients With Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma
A Multicenter, Phase 2 Randomized, Open Label Study to Evaluate Zanubrutinib in Combination With Obinutuzumab in Previously Untreated Patients With Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL) (GELLC-10-ZANUBIO)
Теги: #Newly diagnosed
Локации: H. Vall d`Hebrón; Barcelona; Spain
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Описание
The goal of this phase II randomized open label study is to compare the rate of complete remission (CR) with undetectable minimal residual disease (uMRD) obtained with zanubrutinib in combination with obinutuzumab with two different schedules of administration of obinutuzumab (starting obinutuzumab at cycle 2 or 12 months) in patients with previously untreated Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL). There is scarce information about which is the most appropriate schedule of combining the BTKi and the anti-CD20 monoclonal antibody, and whether treatment can be safely stopped in those patients attaining deep responses (CR with uMRD) remains to be determined.
Response will be assessed after 20 cycles of treatment for the primary objective of the study. Patients attaining uMRD will stop treatment with zanubrutinib, whereas the rest of patients will continue on treatment with zanubrutinib until progression, unacceptable toxicity, or trial completion, whichever comes first.
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Критерии включения
1. Adult patients with previously untreated CLL defined following IWCLL criteria (Hallek, 2018).
2. Must understand and voluntarily sign an informed consent form.
3. Age ≥ 18 years at the time of signing the informed consent form and must be able to adhere to the study visit schedule and other protocol requirements.
4. Must have a documented diagnosis of CLL or SLL /[IWCLL guidelines for diagnosis and treatment of CLL (Hallek, 2018)/] meeting at least one of the following criteria:
* Evidence of progressive marrow failure as manifested by the development of, or worsening of, anemia and/or thrombocytopenia.
* Massive (i.e. ≥6 cm below the left costal margin) or progressive or symptomatic splenomegaly.
* Massive nodes (i.e. ≥10 cm in longest diameter) or progressive or symptomatic lymphadenopathy.
* Progressive lymphocytosis with an increase of ≥50% over a 2-month period, or lymphocyte doubling time (LDT) of less than 6 months.
* A minimum of any one of the following disease-related symptoms: unintentional weight loss ≥ 10% within the previous 6 months, significant fatigue (i.e., ECOG PS 2 or worse; cannot work or unable to perform usual activities), fevers of greater than 38.0°C for 2 or more weeks without other evidence of infection, or night sweats for more than 1 month without evidence of infection.
* Autoimmune complications including anemia or thrombocytopenia poorly responsive to corticosteroids.
5. Must have an Eastern Cooperative Oncology Group (ECOG) performance status score of ≤2.
6. Female patients of childbearing potential must practice highly effective methods of contraception initiated prior to first dose of study drug, for the duration of the study, and for ≥ 90 days after the last dose of zanubrutinib and 18 months after last dose of obinutuzumab.
Male patients are eligible if vasectomized or if they agree to the use of barrier contraception with other applicable highly effective methods described below during the study treatment period and for ≥ 90 days after the last dose of zanubrutinib and 18 months after last dose of obinutuzumab.
A woman is considered of childbearing potential, ie, fertile, following menarche and until becoming postmenopausal unless permanently sterile. Permanent sterilization methods include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy. Contraception methods include the following:
* Combined (estrogen- and progestogen- containing) hormonal contraception associated with the inhibition of ovulation - Oral, intravaginal, or transdermal.
* Progestogen-only hormonal contraception associated with the inhibition of ovulation - Oral, injectable, implantable.
* An intrauterine device.
* Intrauterine hormone-releasing system.
* Bilateral tubal occlusion.
* Vasectomized partner (provided that the vasectomized partner is the sole sexual partner of the woman of childbearing potential study participant and that the vasectomized partner has received medical assessment of surgical success).
* Sexual abstinence (defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatment, starting the day prior to first dose of study drug, for the duration of the study, and for ≥ 90 days after the last dose of zanubrutinib or ibrutinib. Total sexual abstinence should only be used as a contraceptive method if it is in line with the patients` usual and preferred lifestyle. Periodic abstinence (eg, calendar, ovulation, symptothermal, post-ovulation methods), declaration of abstinence for the duration of exposure to investigational medicinal product, and withdrawal are not acceptable methods of contraception.
Of note, barrier contraception (including male and female condoms with or without spermicide) is not considered a highly effective method of contraception, and, if used, this method must be used in combination with another acceptable method listed above.
If patient is using hormonal contraceptives such as birth control pills or devices, a barrier method of contraception (eg, condoms) must also be used.
A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle-stimulating hormone level in the postmenopausal range may be used to confirm a postmenopausal state in women not using hormonal contraception or hormonal replacement therapy. However, in the absence of 12 months of amenorrhea, a single follicle-stimulating hormone measurement is insufficient.
7. Female subjects of childbearing potential must have a negative pregnancy test at screening. Females of child bearing potential are defined as sexually mature women without prior hysterectomy or who have had any evidence of menses in the past 12 months. However, women who have been amenorrheic for 12 or more months are still considered to be of childbearing potential if the amenorrhea is possibly due to other causes, including prior chemotherapy, anti-estrogens, or ovarian suppression.
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Критерии исключения
1. Prior treatment for CLL.
2. Known Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV) and/or Hepatitis C Virus (HCV) infection. Subjects who are hepatitis B core antibody (anti-HBc) positive and who are surface antigen negative could be eligible if they have an undetectable HBV DNA (negative polymerase chain reaction (PCR) /<20 IU). Those who are hepatitis B surface antigen (HbsAg) positive or hepatitis B PCR positive will be excluded. Subjects who are hepatitis C antibody positive will need to have a negative PCR result. Those who are hepatitis C PCR positive will be excluded.
Per published guidelines (NCCN 2012) or institutional guidelines, patients should be closely monitored for hepatitis B reactivation. Obtaining repeated hepatitis B PCR every 3 months during treatment and for the 12 months after last dose of study drug according to usual clinical practice in order to monitor for reactivation of hepatitis B is recommended.
3. Estimated Glomerular Filtration Rate (Cockcroft-Gault Appendix C) ≤30 mL/min/1.73m2.
4. Absolute neutrophil count (ANC) /< 1.0 X 109/L.
5. Platelet count /< 75 X 109/L, except for patients with bone marrow involvement by CLL in which case the platelet count must be ≥ 30 X 109/L.
6. Serum aspartate aminotransferase (AST)/serum glutamic-oxaloacetic transaminase (SGOT) or alanine transaminase (ALT)/serum glutamate pyruvate transaminase (SGPT) />2.5 x upper limit of normal (ULN).
7. Serum total bilirubin /> 1.5 x ULN, except in cases of Gilbert`s syndrome.
8. Prothrombin time/INR or aPTT (in the absence of Lupus anticoagulant) /> 2x ULN.
9. Active bleeding, history of bleeding diathesis (eg, haemophilia or von Willebrand disease).
10. Unable to swallow capsules, or has disease significantly affecting gastrointestinal function that would limit absorption of oral medication.
11. Currently active, clinically significant cardiovascular disease or a history of myocardial infarction within 3 months prior to enrollment. Exception: Subjects with controlled, asymptomatic atrial fibrillation during screening can enrol on study.
12. Requires or receiving anticoagulation with warfarin or equivalent vitamin K antagonists (eg, phenprocoumon) within 7 days of first dose of study drug.
13. Systemic infection that has not resolved prior to initiating study treatment in spite of adequate anti-infective therapy.
14. Pregnant or lactating females.
15. Participation in any clinical study or having taken any investigational therapy within 28 days prior to initiating study therapy.
16. Central nervous system (CNS) involvement as documented by spinal fluid cytology or imaging.
17. Prior history of malignancies, other than CLL, unless the patient has been free of the disease for ≥ 3 years.
Exceptions include the following:
* Basal cell carcinoma of the skin
* Squamous cell carcinoma of the skin
* Carcinoma in situ of the cervix
* Carcinoma in situ of the breast
* Incidental histologic finding of prostate cancer (TNM stage of T1a or T1b)
18. Presence of autoimmune haemolytic anaemia or autoimmune thrombocytopenia.
19. Major surgery within the last 28 days prior to registration.
20. History of stroke or intracranial haemorrhage within 6 months prior to enrollment.
21. Requires treatment with strong CYP3A4/5 Inhibitors.
22. Known history of drug-specific hypersensitivity or anaphylaxis to study drug (including active product or excipient components).
23. Any life-threatening illness, medical condition, or organ system dysfunction which, in the Investigator`s opinion, could compromise the subject`s safety, interfere with the absorption or metabolism of zanubrutinib, or put the study outcomes at undue risk.
Phase I/II Trial of Anti-CD19 Chimeric Antigen Receptor T-Cell Immunotherapy for Chronic Lymphocytic Leukemia (CLL)
Теги: #Relapsed|Refractory
Локации: National Institutes of Health Clinical Center; Bethesda; Maryland; United States
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Описание
Background:
Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are blood cancers that affect certain white blood cells. Advanced forms of these diseases are difficult to treat. CD19 is a protein often found on the surfaces of these cancer cells. Researchers can modify a person`s own immune cells (T cells) to target CD19. When these modified T cells are returned to the body-a treatment called anti-CD19 chimeric antigen receptor (CAR) T cell therapy-they may help kill cancer cells.
Objective:
To test anti-CD19 CAR T cell therapy in people with CLL or SLL.
Eligibility:
People aged 18 years and older with CLL or SLL that has not been controlled with standard drugs.
Design:
Participants will be screened. They will have imaging scans and tests of their heart function. If a sample of tissue from their tumor is not available, a new one may be taken; the sample will be tested for CD19.
Participants will receive a drug to reduce the leukemia cells in their blood. Then they will undergo apheresis: Blood will be taken from the body through a needle. The blood will pass through a machine that separates out the T cells. The remaining blood will be returned to the body through a different needle. The collected T cells will be gene edited to make them attack cells with CD19.
Participants will take drugs to prepare them for treatment for 3 days. These drugs will start 5 days before the treatment. Then their own modified CAR T cells will be returned to their bloodstream. Participants will stay in the hospital for at least 9 days after the treatment.
Follow-up visits will continue for 5 years.
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Критерии включения
* INCLUSION CRITERIA:
* Malignancy criteria
* Histologically confirmed participants with either CLL or SLL will be eligible.
* Demonstration of CD19 expression on CLL/SLL, as assessed by the NCI Laboratory of Pathology or NIH Department of Laboratory Medicine Hematopathology section.
* CD19 expression must be uniform meaning no populations of clearly CD19-negative CLL/SLL cells are observed.
* Participants must have received prior systemic therapy. The last dosage of systemic therapy (including corticosteroids) must be at least 14 days prior to the first dose of rituximab.
* For participants who have received antibodies targeting CD19, at least sixty days must elapse between therapy with antibodies targeting CD19 and CAR T-cell infusion.
* Participants must have received at least two prior treatment regimens at least one of which must have contained a Bruton s tyrosine kinase (BTK) inhibitor. Participants who took a BTK inhibitor but stopped due to intolerance are potentially eligible.
* All participants must have measurable malignancy as defined by at least one of the criteria below.
* Presence of CLL or SLL masses that are measurable (minimum 1.5 cm in largest diameter) by CT scan is required unless bone marrow or blood involvement with malignancy is detected. All masses must be less than or equal to 10.0 cm in the largest diameter.
* For CLL with only bone marrow and/or blood involvement, no mass is necessary, but if a mass is not present, bone marrow and/or blood malignancy must be detectable by flow cytometry. Any level of CLL detectable by flow cytometry is sufficient for enrollment.
* Other inclusion criteria:
* Age />= 18 years.
* Performance status (ECOG) 0-1.
* Participants must have adequate organ and marrow function as defined below:
* ANC />= 1,000/mcL without the support of filgrastim or other growth factors in the 10 days prior to enrollment
* platelets />= 50,000/mcL without transfusion support
* hemoglobin />= 8 g/dL
* total bilirubin /<= 2.0 mg/dL
* ALT or AST Serum ALT and AST less or equal to 3 times the upper limit of the institutional normal unless liver involvement by malignancy is demonstrated. If liver involvement with malignancy is detected, ALT and AST must be less than or equal to 5 times the upper limit of normal
* Serum Creatinine Serum creatinine levels /< 1.5 X institutional ULN. Participants with serum creatinine />= 1.5 X institutional ULN may participate if serum creatinine eGFR is />=50 mL/min/1.73m/^2 by 2021 CKD-EPI equation.
* ALT (SGPT)=alanine aminotransferase (serum glutamic pyruvic transaminase);
* (A)Creatinine clearance (CrCl) or eGFR should be calculated per institutional standard.
* B cells must make up less than 90% of blood lymphocytes on a lymphocyte phenotyping profile TBNK at the time of enrollment.
* Room air oxygen saturation of 92% or greater
* Participants of child-bearing or child-fathering potential must be willing to practice abstinence or highly effective contraception from the time of enrollment on this study and for 12 months after receiving the protocol treatment, or until CAR T cells are no longer detectable in the blood, whichever is later.
* Participants must agree not to donate eggs for 12 months after receiving the protocol treatment, or until CAR T cells are no longer detectable in the blood, whichever is later.
* Participants who are breastfeeding must be willing to cease breastfeeding from time of enrollment until 6 months after receiving treatment, or until CAR T cells are no longer detectable in the blood, whichever is later.
* Participants must have a negative blood PCR test for hepatitis B DNA. If hepatitis B DNA (PCR) testing is not available, participants must have a negative hepatitis B surface antigen and negative hepatitis B core antibody test.
* Participants must have a negative blood PCR test for hepatitis C RNA. Only if Hepatitis C PCR testing is not available in a timely manner, participants must have a negative Hepatitis C antibody test.
* Cardiac ejection fraction of greater than or equal to 50% by echocardiography and no evidence of hemodynamically significant pericardial effusion as determined by an echocardiogram within 30 days prior to treatment start.
* All participants must have the ability to understand and willingness to sign a written informed consent.
* All participants must be willing to undergo mandatory biopsies during the study. A bone marrow biopsy will be required prior to the chemotherapy and CAR T-cell infusion. Another bone marrow biopsy will be required approximately 14 days after CAR T-cell infusion.
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Критерии исключения
* Participants who are receiving any other investigational agents.
* Participants who have had prior CAR T-cell therapy.
* Participants who have had a live-attenuated or viral vector-based vaccine in the last 60 days prior to pre-leukapheresis rituximab. Participants who plan to receive a live attenuated or viral vector-based vaccine within the first 100 days after CAR T-cell infusion.
* Participants that require urgent therapy due to tumor mass effects or spinal cord compression.
* Participants that have active hemolytic anemia.
* Current/active HIV infection, as measured by seropositivity for HIV antibody.
* Participants with second malignancies in addition to their CLL are not eligible if the second malignancy has required treatment with surgery, radiation or chemotherapy, or other therapies within the past 3 years or is not in complete remission. Exceptions are that, in the last 3 years, participants may have had successful resection of nonmetastatic basal cell or squamous cell carcinoma of the skin, and participants may have received hormonal therapy for fully resected breast cancer.
* Positive beta Human chorionic gonadotropin (Beta-HCG) serum or urine pregnancy test in women of childbearing potential (WOCBP) performed at screening.
* Active uncontrolled systemic infections (defined as infections causing fevers within 48 hours of the date of planned protocol rituximab or chemotherapy start and infections requiring intravenous antibiotics when intravenous antibiotics have been administered for less than 72 hours at the time of protocol rituximab or chemotherapy start). There must be objective evidence of infection, including, but not limited to, a positive blood, urine or sputum culture, positive nasal swab or blood test for viral infection, or the appearance of infiltrates on imaging of the lung.
* Active coagulation disorders or other major uncontrolled medical illnesses of the cardiovascular, respiratory, endocrine, renal, gastrointestinal, genitourinary or immune system, history of myocardial infarction, history of ventricular tachycardia or ventricular fibrillation, active cardiac arrhythmias (Resolved atrial fibrillation that is not treated with anticoagulants is allowed.), active obstructive or restrictive pulmonary disease, active autoimmune diseases such as rheumatoid arthritis.These include uncontrolled intercurrent illness manifesting as electrolyte derangements or as assessed by chemistries.
* Significant neurologic disorders, including a history of a seizure disorder as an adult, that are not completely and permanently resolved and not requiring current treatment.
* Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency Disease).
* Prior allogeneic stem cell transplant
* Systemic corticosteroid steroid therapy of any dose greater than 5 mg/day or more of prednisone or equivalent is not allowed within 14 days prior to the first dose of rituximab. Corticosteroid creams, ointments, and eye drops are allowed.
* Participants on systemic anticoagulant therapy except aspirin.
* History of severe immediate hypersensitivity reaction to any of the agents used in this study, including hypersensitivity to aminoglycoside antibiotics, which may be used in the cell culture media.
* Active central nervous system/brain metastases or cerebrospinal fluid malignancy.
* Checkpoint inhibitor drugs such as pembrolizumab or nivolumab or other antibodies targeting PD-1 or PDL-1 within 180 days of protocol enrollment. This is because of possible effects checkpoint inhibitor therapy could have on the participant`s T cells.
* Known active alcohol or drug abuse.
* History of allergy to study drug components.
* Active tumor lysis syndrome as assessed by serum uric acid, LDH, calcium, and phosphorus.
* Active rhabdomyolysis as assessed by elevated CK and acute change in renal function as reflected by increased creatinine and blood urea nitrogen (BUN).
* Active diabetic ketoacidosis or hyperosmolar hyperglycemic state, as assessed by serum glucose. The urine will be tested for ketones if serum glucose is over 350 mg/dL at screening.
Pirtobrutinib (LOXO-305) and Venetoclax for the Treatment of Patients with CLL or SLL Resistant to Covalent BTKi
Phase 2 Study of Combination Pirtobrutinib (LOXO-305) and Venetoclax in CLL Patients with Resistance to Covalent BTKi
Локации: Ohio State University Comprehensive Cancer Center; Columbus; Ohio; United States
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Описание
This phase II trial tests how well pirtobrutinib (LOXO-305) and venetoclax works in treating patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) that remains despite treatment (resistant) with covalent bruton tyrosine kinase inhibitors (BTKi). Pirtobrutinib is in a class of medications called kinase inhibitors. It works by blocking the action of the a protein that signals cancer cells to multiply. 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. Giving pirtobrutinib and venetoclax may kill more cancer cells in patients with CLL or SLL that is resistant to covalent BTKi.
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Критерии включения
* Diagnosis of CLL or SLL according to the International Workshop on Chronic Lymphocytic Leukemia (iwCLL) 2018 guidelines
* Detectable CLL on flow cytometry of the blood or marrow at time of enrollment
* Age ≥ 18 years old
* Eastern Cooperative Oncology Group (ECOG) performance 0-2
* Currently taking ibrutinib, acalabrutinib, or zanubrutinib at any daily dose and tolerating it for /> 4 weeks
* Evidence of progressive disease by iwCLL 2018 criteria for progressive disease or doubling of absolute lymphocyte count (ALC) in ≤ 6 months while on BTK inhibitor provided ALC is /> 5 k/uL
* Aspartate aminotransferase (AST) / alanine aminotransferase (ALT) ≤ 3 x the upper limit of normal (ULN) or ≤ 5 x ULN with documented liver involvement
* Bilirubin ≤ 1.5 x ULN or ≤ 3 x ULN with documented liver involvement and/or Gilbert`s disease
* Creatinine clearance (CrCl) ≥ 30 according to modified Cockcroft-Gault equation
* Absolute neutrophil count (ANC) ≥ 0.75 k/uL
* Without transfusion or growth factor administration in the 7 days prior to screening
* Any values if cytopenias are due to bone marrow involvement with disease
* Hemoglobin ≥ 8 g/dL
* Without transfusion or growth factor administration in the 7 days prior to screening
* Any values if cytopenias are due to bone marrow involvement with disease
* Platelets ≥ 50 k/uL
* Without transfusion or growth factor administration in the 7 days prior to screening
* Any values if cytopenias are due to bone marrow involvement with disease
* Prothrombin time (PT) and partial thromboplastin time (PTT) ≤ 1.5 x ULN
* No known inherited qualitative platelet defect (e.g. delta granule storage pool deficiency)
* Willing and able to complete study activities and treatment
* Willing and capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in the protocol
* Willingness of men and women of reproductive potential and their partners to observe conventional and highly effective or acceptable birth control methods for the duration of treatment and for 6 months following the last dose of pirtobrutinib or 30 days from the last dose of venetoclax
* ELIGIBILITY FOR RE-TREATMENT WITH PIRTOBRUTINIB: Discontinued initial study treatment ≤ 12 months ago
* ELIGIBILITY FOR RE-TREATMENT WITH PIRTOBRUTINIB: Meets iwCLL 2018 criteria for progressive disease
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Критерии исключения
* Inability to tolerate 2 Liters of oral or intravenous (IV) hydration
* Prior venetoclax exposure /> 13 months or known resistance to venetoclax
* Known hypersensitivity to any of the excipients of pirtobrutinib or venetoclax
* Need for treatment with warfarin or other vitamin K antagonist during study treatment
* History of bleeding diathesis
* Patients who experienced a major bleeding event or grade ≥ 3 arrhythmia on prior treatment with a BTK inhibitor. Major bleeding is defined as bleeding having one or more of the following features: potentially life-threatening bleeding with signs or symptoms of hemodynamic compromise; bleeding associated with a decrease in the hemoglobin level of at least 2g per deciliter; or bleeding in a critical area or organ (e.g., retroperitoneal, intraarticular, pericardial, epidural, or intracranial bleeding or intramuscular bleeding with compartment syndrome)
* History of stroke or intracranial hemorrhage within 6 months
* Inability to take pills or oral medications
* Clinically significant active malabsorption syndrome or other condition likely to affect gastrointestinal (GI) absorption of either pirtobrutinib or venetoclax
* Current known central nervous system involvement with CLL or SLL. Patients with previous treatment for central nervous system (CNS) involvement who are neurologically stable and without evidence of disease may be eligible if a compelling clinical rationale is provided by the investigator and with documented approval by the principal investigator
* Treatment with the following:
* Targeted agents, investigational agents, therapeutic monoclonal antibodies, or cytotoxic chemotherapy within 5 half-lives or 2 weeks, whichever is shorter
* Treatment with immunoconjugated antibody treatment within 10 weeks
* Receipt of broad field radiation ( ≥ 30% of the bone marrow or whole brain radiotherapy) within 14 days or palliative limited field radiation within 7 days prior to study enrollment
* Note: Treatment with ibrutinib, acalabrutinib, or zanubrutinib is allowed. Treatment with topical chemotherapy agents for precancerous skin conditions or skin cancers is allowed
* Unresolved adverse events from prior treatment not resolved to grade ≤ 1 with the exception of alopecia or grade 2 peripheral neuropathy
* History of allogeneic or autologous stem cell transplant (SCT) or chimeric antigen receptor-modified T cell (CAR-T) therapy within 60 days. Patients with a history of allogeneic stem cell transplant must be stable off all immunosuppression for at least 2 months prior to study screening. Presence of any of the following, regardless of prior SCT and/or CAR-T therapy timing will be exclusionary:
* Active graft versus host disease (GVHD)
* Cytopenia from incomplete blood cell count recovery post-transplant
* Need for anti-cytokine therapy for toxicity from CAR-T therapy and/or residual symptoms of neurotoxicity /> grade 1 from CAR-T therapy
* Ongoing immunosuppressive therapy
* Active second malignancy unless in remission and with life expectancy /> 2 years. Adjuvant endocrine therapy for breast or prostate cancer that is expected to be cured is allowed. Non-melanoma skin cancers are permitted if adequately treated
* Psychiatric illness, or social situations that would limit compliance with study requirements
* Active uncontrolled auto-immune cytopenia (e.g., autoimmune hemolytic anemia /[AIHA/], idiopathic thrombocytopenic purpura /[ITP/]) for which new therapy was introduced or existing therapy was escalated within the 4 weeks prior to study enrollment to maintain adequate blood counts
* Evidence of other clinically significant uncontrolled condition(s) including but not limited to, uncontrolled systemic bacterial, viral, fungal or parasitic infection (except for fungal nail infection), or other clinically significant active disease process which in the opinion of the investigator may pose a risk for patient participation. Screening for chronic conditions is not required
* Significant cardiovascular disease defined as:
* Unstable angina or acute coronary syndrome within the past 2 months
* History of myocardial infarction within 3 months
* Documented left ventricular ejection fraction (LVEF) by any method of ≤ 40% in the 12 months
* ≥ grade 3 New York Heart Association (NYHA) functional classification system of heart failure
* Uncontrolled or symptomatic arrhythmias
* Prolongation of the QT interval corrected for heart rate (Fridericia`s formula-corrected QT interval /[QTcF/]) /> 470 msec. QTcF is calculated using Fridericia`s formula
* Correction of suspected drug induced QTcF prolongation can be attempted at the investigator¡¦s discretion and only if clinically safe to do so with either discontinuation of the offending drug or switch to another drug not known to be associated with QTcF prolongation
* Correction for underlying bundle branch block (BBB) allowed
* Note: Patients with pacemakers are eligible if they have no history of fainting or clinically relevant arrhythmias while using the pacemaker
* Known active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection based on criteria below:
* Hepatitis B virus (HBV): Patients with positive hepatitis B surface antigen (HBsAg) are excluded. Patients with positive hepatitis B core antibody (anti-HBc) and negative HBsAg require hepatitis B polymerase chain reaction (PCR) evaluation before inclusion. Patients who are hepatitis B PCR positive will be excluded
* Hepatitis C virus (HCV): positive hepatitis C antibody. If positive hepatitis C antibody result, patient will need to have a negative result for hepatitis C ribonucleic acid (RNA) before inclusion. Patients who are hepatitis C RNA positive will be excluded. Patients previously treated for hepatitis C /> 6 months previously with a negative RNA test are eligible
* Known HIV infection. For patients with unknown HIV status, HIV testing will be performed at screening and result should be negative for enrollment
* Known active cytomegalovirus (CMV) infection. Unknown or negative status are eligible
* Treatment with a strong CYP3A inhibitor or inducer and/or strong P-gp inhibitors within 3 days of starting or during study treatment. Treatment with a moderate or strong CYP3A inhibitor or inducer within 7 days prior to first dose of venetoclax or during cycle 2 or 3 of study treatment. Patients may not plan to consume grapefruit or grapefruit products, Seville oranges or products from Seville oranges, or star fruit
* Pregnancy, lactation, or plan to breastfeed during the study or within 6 months of the last dose of either pirtobrutinib or venetoclax
* Major surgery within 4 weeks prior to screening
* Vaccination with live vaccine within 28 days of screening
* Currently incarcerated
* History of progressive multifocal leukoencephalopathy (PML) or human polyomavirus 2 (JC virus) infection
* History of seizure disorder unless controlled without a seizure in the year prior to screening
* ELIGIBILITY FOR RE-TREATMENT WITH PIRTOBRUTINIB: Has not developed any new medical conditions that would change the safety of treatment with pirtobrutinib
A Study to Evaluate Safety, PK, PD and Efficacy of AZD5492, a T Cell-engaging Antibody Targeting CD20 in Subjects With R/R B-Cell Malignancies.
A Modular Phase I/II Open-label Dose Escalation and Dose Expansion Study to Evaluate the Safety, Pharmacokinetics, Pharmacodynamics, and Efficacy of AZD5492, a T Cell-engaging Antibody Targeting CD20 in Subjects With Relapsed or Refractory B-Cell Malignancies (TITANium)
Теги: #Relapsed|Refractory
Локации: Research Site; Barcelona; Spain,Research Site; Bologna; Italy,Research Site; Boston; Massachusetts; United States,Research Site; Calgary; Alberta; Canada,Research Site; Charlotte; North Carolina; United States,Research Site; Chuo-ku; Japan,Research Site; Concord; North Carolina; United States,Research Site; Hackensack; New Jersey; United States,Research Site; Hangzhou; China,Research Site; Houston; Texas; United States,Research Site; Kashiwa; Japan,Research Site; København Ø; Denmark,Research Site; L`Hospitalet de Llobregat; Spain,Research Site; La Jolla; California; United States,Research Site; Madrid; Spain,Research Site; Melbourne; Australia,Research Site; Milano; Italy,Research Site; Montreal; Quebec; Canada,Research Site; München; Germany,Research Site; Nedlands; Australia,Research Site; New York; New York; United States,Research Site; Pessac; France,Research Site; Seattle; Washington; United States,Research Site; Shanghai; China,Research Site; Toronto; Ontario; Canada,Research Site; Ulm; Germany,Rese
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Описание
This is a Phase I/II study designed to evaluate if experimental T cell engaging antibody targeting CD20 AZD5492 is safe, tolerable and efficacious in participants with Relapsed or Refractory B-Cell Malignancies.
Genetically Engineered Cells (EGFRt/19-28z/IL-12 CAR T Cells) for the Treatment of Relapsed or Refractory CD19+ Hematologic Malignancies
A Phase I Trial of CD19-Targeted Chimeric Antigen Receptor (CAR) Modified T Cells Genetically Engineered to Secrete Interleukin 12 (IL-12) and With a Truncated Human Epidermal Growth Factor Receptor (EGFRt) in Patients With Relapsed or Refractory CD19+ Hematologic Malignancies
Теги: #Relapsed|Refractory
Локации: Roswell Park Cancer Institute, Buffalo, New York, United States,Roswell Park Cancer Institute; Buffalo; New York; United States
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Описание
This phase I trial tests the safety, side effects, and best dose of genetically engineered cells called EGFRt/19-28z/IL-12 CAR T cells, and to see how they work in treating patients with hematologic malignancies that makes a protein called CD19 (CD19-positive) that has come back after a period of improvement (relapsed) or that has not responded to previous treatment (refractory). Chimeric Antigen Receptor (CAR) T-cell Therapy is a type of treatment in which a patient`s T cells (a type of immune system cell) are changed in the laboratory so they will attack cancer cells. T cells are taken from a patient`s blood. Then the gene for a special receptor that binds to a certain protein on the patient`s cancer cells is added to the T cells in the laboratory. The special receptor is called a chimeric antigen receptor (CAR). Large numbers of the CAR T cells are grown in the laboratory and given to the patient by infusion for treatment of certain cancers. To improve the effectiveness of the modified T cells and to help the immune system fight cancer cells better, the modified T cells given in this study will include a gene that makes the T cells produce a cytokine (a molecule involved in signaling within the immune system) called interleukin-12 (IL-12). The researchers think that IL-12 may improve the effectiveness of the modified T cells, and it may also strengthen the immune system to fight cancer. Giving EGFRt/19-28z/IL-12 CAR T cells may be safe and tolerable in treating patients with relapsed or refractory CD19+ hematologic malignancies.
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Критерии включения
* Patients with relapsed refractory B Cell malignancies which commonly express CD-19.
* Eligible disease subtypes include the following:
* Patients with diffuse large B-cell lymphoma (de novo or diffuse large B-cell lymphoma /[DLBCL/] transformed from an indolent lymphoma (follicular lymphoma, chronic lymphocytic leukemia) or high grade B-cell Lymphoma (HGBL):
* Relapsed or refractory DLBCL or high-grade B-cell lymphoma (HGBL) following 2 or more prior chemoimmunotherapy regimens containing an anthracycline and CD20-directed therapy following diagnosis of de novo DLBCL/HGBL or DLBCL arising from indolent lymphoma and requiring further treatment.
* Relapse following a single prior chemoimmunotherapy regimen containing an anthracycline and CD20-directed therapy following diagnosis of de novo DLBCL/HGBL or DLBCL arising from indolent lymphoma and considered ineligible for high dose chemotherapy and autologous stem cell rescue as determined by the investigator.
* Patients must have at least one fludeoxyglucose F-18 (FDG)-avid (PET-avid) measurable lesion.
* Biopsy confirmation of relapsed or refractory DLBCL is required.
* Chronic lymphocytic leukemia after 2 lines of therapy including a BTKi (bruton tyrosine kinase inhibitor).
* Mantle cell lymphoma after 2 lines of therapy. Patients must have previously received chemoimmunotherapy and a prior BTK inhibitor.
* Follicular lymphoma after 2 lines of therapy.
* For cohort 1A specifically, patients must additionally have received a prior CD19-targeted CAR T-cell therapy or not have an indication for a Food and Drug Administration (FDA)-approved commercial CD19-targeted CAR T-cell therapy. This will include patients with relapsed/refractory DLBCL, FL, CLL and MCL.
* For cohorts other than cohort 1A (and if needed, cohort -1), patients with an indication for an FDA approved commercial CD19-targeted CAR T-cell therapy are eligible following an informed consent discussion that reviews the risks and benefits of the FDA-approved commercial CD19-targeted CAR T-cell therapy vs the investigational product.
* Prior CD19-targeted therapies, including CAR T-cell therapy, does not exclude participation; however, CD19 expression by immunohistochemical staining or flow cytometry must be confirmed prior to enrollment for patients who have received such therapies.
* Direct bilirubin ≤ 2.0 mg/dL (unless related to disease).
* Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 x upper limit of normal (ULN) (unless related to disease).
* Adequate pulmonary function as assessed by ≥ 90% oxygen saturation on room air by pulse oximetry.
* Have an Eastern Cooperative Oncology Group (ECOG) performance status 0-1.
* Participants of child-bearing potential must agree to use adequate contraceptive methods (e.g., hormonal or barrier method of birth control; abstinence) prior to study entry. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Patients of childbearing age should use effective contraception while on this study and continue for 1 year after all treatment is finished.
* 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.
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Критерии исключения
* Pregnant or lactating patients.
* Impaired cardiac function (left ventricular ejection fraction /[LVEF/] /< 40%) as assessed by ECHO or MUGA scan during screening.
* Patients with active graft versus host disease following allogeneic hematopoietic cell transplantation requiring systemic T cell suppressive therapy are ineligible.
* Patients with active autoimmune disease requiring systemic T cell suppressive therapy are ineligible.
* Patients with following cardiac conditions will be excluded:
* New York Heart Association (NYHA) stage III or IV congestive heart failure.
* Myocardial infarction ≤ 6 months prior to enrollment.
* Any history of clinically significant ventricular arrhythmia or unexplained syncope, not believed to be vasovagal in nature or due to dehydration.
* Patients with HIV are ineligible.
* Patients with active hepatitis B infection (as manifest by either detectable hepatitis B virus deoxyribonucleic acid /[DNA/] by polymerase chain reaction /[PCR/] and/or positivity for hepatitis B surface antigen) are ineligible.
* Patients with active hepatitis C infection (as manifest by detectable hepatitis C virus ribonucleic acid /[RNA/] by PCR) are ineligible. Patients with detectable antibodies to hepatitis C virus will be screened by PCR for evidence of active infection.
* Patients with uncontrolled systemic fungal, bacterial, viral or other infection are ineligible.
* Patients with any concurrent active malignancies as defined by malignancies requiring any therapy other than expectant observation or hormonal therapy, with the exception of squamous and basal cell carcinoma of skin.
* Patients with history or presence of clinically significant neurological disorders such as epilepsy, generalized seizure disorder, severe brain injuries are ineligible.
* Patients with primary central nervous system (CNS) disease are ineligible.
* Unwilling or unable to follow protocol requirements.
* Any other condition/issue which, in the opinion of the treating physician, would make the patient ineligible for the study.