Study Evaluating the Efficacy and Safety of JCAR015 in Adult B-cell Acute Lymphoblastic Leukemia (B-ALL)

Study Overview
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Brief Summary
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This single-arm, multicenter Phase 2 trial will treat adult patients who have relapsed or refractory B-ALL with an infusion of the patient's own T cells that have been genetically modified to express a chimeric antigen receptor (CAR) that will bind to leukemia cells that express the CD19 protein on the cell surface. The study will determine if these modified T cells (called JCAR015) help the body's immune system eliminate leukemia cells. The trial will also study the safety of treatment with JCAR015, how long JCAR015 cells stay in the patient's body, the extent to which JCAR015 eliminates minimal residual disease, and the impact of this treatment on survival.

Detailed Description
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This is a single-arm, multicenter Phase 2 study to determine the efficacy and safety of JCAR015 in adult patients with relapsed or refractory B-ALL. The study will have the following sequential phases: Part A (screening, leukapheresis, cell product preparation, and cytoreductive chemotherapy) and Part B (treatment and follow-up). The follow-up period for each participant is approximately 12 months after the final JCAR015 infusion. The total duration of the study is expected to be approximately 3 years. Long-term follow-up for survival, toxicity, and viral vector safety will continue under a separate long-term follow-up protocol per health regulatory authority guidelines, currently up to 15 years after the last JCAR015 infusion.

Official Title
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A Phase 2, Single-arm, Multicenter Trial to Determine the Efficacy and Safety of JCAR015 in Adult Subjects With Relapsed or Refractory B-Cell Acute Lymphoblastic Leukemia

Conditions
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Acute Lymphoblastic Leukemia

Intervention / Treatment
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* Biological: JCAR015 (CD19-targeted CAR T cells)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18 years at the time of consent Relapsed or refractory B-ALL, defined as: First or greater bone marrow relapse from CR, or Any bone marrow relapse after allogeneic hematopoietic stem cell transplant (HSCT); subjects must be at least 100 days from HSCT at the time of screening and off immunosuppressant medication for at least 1 month at the time of screening, and have no active graft-vs-host disease (GVHD), or Refractory B-ALL, defined by not having achieved a CR or CRi after two attempts at remission induction using standard regimens, or Ph+ B-ALL if subjects are intolerant to or ineligible for tyrosine kinase inhibitor (TKI) therapy, or have progressed after at least one line of TKI therapy Morphological evidence of disease in bone marrow (at least 5% blasts) Evidence of CD19 expression Eastern Cooperative Oncology Group (ECOG) performance status between 0 and 2 at the time of screening Adequate pulmonary, renal, hepatic, and cardiac function Adequate central or peripheral vascular access for leukapheresis procedure Exclusion Criteria: Isolated extramedullary disease relapse Concomitant genetic syndrome or other known bone marrow failure syndrome Burkitt's lymphoma/leukemia or chronic myelogenous leukemia lymphoid blast crisis (p210 BCR-ABL+) Prior malignancy, unless treated with curative intent and with no evidence of active disease present for > 5 years before screening Prior treatment with any gene therapy product Active hepatitis B, active hepatitis C, or any human immunodeficiency virus (HIV) infection at the time of screening Systemic fungal, bacterial, viral, or other infection that is not controlled, at the time of screening Presence of Grade II-IV (Glucksberg) or B-D (IBMTR) acute or extensive chronic GVHD at the time of screening Active central nervous system (CNS) involvement by malignancy (defined as CNS-3 per National Comprehensive Cancer Network [NCCN] guidelines) History of any one of the following cardiovascular conditions within the past 6 months: Class III or IV heart failure as defined by the New York Heart Association (NYHA), cardiac angioplasty or stenting, myocardial infarction, unstable angina, or other clinically significant cardiac disease History or presence of clinically relevant CNS pathology such as epilepsy, generalized seizure disorder, paresis, aphasia, stroke, severe brain injuries, dementia, Parkinson's disease, cerebellar disease, organic brain syndrome, or psychosis Participation in an investigational research study using an investigational agent within 30 days of screening History of treatment with a murine-derived biological product other than blinatumomab unless subject has been shown to be negative for human-anti-mouse-antibodies (HAMA) prior to or during screening Pregnant or nursing women Use of prohibited medications: Steroids: Therapeutic doses of corticosteroids are prohibited within 7 days prior to leukapheresis. Allogeneic cellular therapy: Donor lymphocyte infusions (DLI) are prohibited within 4 weeks prior to leukapheresis GVHD therapies: Any drug used for GVHD within 4 weeks prior to leukapheresis Chemotherapies: Salvage chemotherapy must be stopped at least 1 week prior to leukapheresis Treatment with alemtuzumab within 6 months prior to leukapheresis, or treatment with clofarabine or cladribine within 3 months prior to leukapheresis

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: JCAR015 (CD19-targeted CAR T cells)<br>JCAR015 was administered as two intravenous (IV) infusions separated by 14 to 28 days. | Biological: JCAR015 (CD19-targeted CAR T cells)<br>* Part A: Following leukapheresis and concurrent with generation of JCAR015, participants received, at the Investigator's discretion, cytoreductive chemotherapy based on the Investigator's choice of regimens and/or supportive care. Part B: Participants who were eligible for treatment in Part B received two IV doses of JCAR015 CAR T cells separated by 14 to 28 days. JCAR015 infusion was preceded by lymphodepleting chemotherapy with cyclophosphamide alone or cyclophosphamide + fludarabine.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Complete Remission (CR) or Complete Remission With Incomplete Hematopoietic Recovery (CRi), as Determined by an Independent Review Committee (IRC) | Overall remission rate (ORR) is defined as the percentage of participants with CR or CRi based on IRC assessment. For CR, all of the following must be met: (1) in bone marrow, trilineage hematopoiesis and < 5% blasts; (2) in peripheral blood, neutrophils > 1,000/µL, platelets > 100,000/µL, and circulating blasts < 1%; (3) no clinical evidence of extramedullary disease by physical examination and no symptoms suggestive of CNS involvement (if additional assessments such as CSF assessment by lumbar puncture or Ommaya reservoir tap, CNS imaging, or biopsy are performed, results must show no evidence of disease); (4) no platelet and/or neutrophil transfusions ≤ 7 days before the date of peripheral blood sampling, and (5) no clinical evidence of recurrence for 4 weeks. For CRi, all criteria for CR are met except that one or more of the following exists in the peripheral blood: neutrophils ≤ 1,000/µL, platelets ≤ 100,000/µL, or platelet transfusions ≤ 7 days before blood sampling. | Day 1 (first JCAR015 infusion) up to 12 months after the last JCAR015 infusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With CR or CRi, as Determined by an IRC | ORR is defined as the percentage of participants with CR or CRi based on IRC assessment (refer to criteria in Outcome Measure #1) | Day 1 (first JCAR015 infusion) up to 12 months after the last JCAR015 infusion | 
| Percentage of Participants Who Achieved a CR or CRi, as Determined by an IRC | Best overall response (BOR) is defined as the best disease response recorded from the time of the last JCAR015 infusion until the start of another anticancer therapy (refer to Outcome Measure #1 for criteria for CR and CRi). | Day 1 (first JCAR015 infusion) up to 12 months after the last JCAR015 infusion | 
| Percentage of Participants Who Achieved a CR or CRi, as Determined by an IRC | BOR is defined as the best disease response recorded from the time of the last JCAR015 infusion until the start of another anticancer therapy (refer to Outcome Measure #1 for criteria for CR and CRi). | Day 1 (first JCAR015 infusion) up to 12 months after the last JCAR015 infusion | 
| Percentage of Participants Who Achieved a Minimal Residual Disease (MRD)-Negative CR or CRi | Percentage of participants who achieved a CR or CRi, as determined by an IRC, with no evidence of MRD in the bone marrow (refer to Outcome Measure #1 for criteria for CR and CRi). MRD-negative is defined as undetectable leukemic cells in the bone marrow as determined by a polymerase chain reaction (PCR)-based assay. | Day 1 (first JCAR015 infusion) up to 12 months after the last JCAR015 infusion | 
| Percentage of Participants Who Achieved a MRD-Negative CR or CRi | Percentage of participants who achieved a CR or CRi, as determined by an IRC, with no evidence of MRD in the bone marrow (refer to Outcome Measure #1 for criteria for CR and CRi). MRD-negative is defined as undetectable leukemic cells in the bone marrow as determined by a PCR-based assay. | Day 1 (first JCAR015 infusion) up to 12 months after the last JCAR015 infusion | 
| Relapse-Free Survival (RFS), as Determined by an IRC | RFS is defined as the interval from the first documentation of CR or CRi (refer to Outcome Measure #1) to the earlier date of relapse or death due to any cause. Participants who proceeded to hematopoietic stem cell transplant (HSCT) after JCAR015 infusion were censored at the time of HSCT. | Day 1 (first JCAR015 infusion) up to 12 months after the last JCAR015 infusion | 
| RFS, as Determined by an IRC | RFS is defined as the interval from the first documentation of CR or CRi (refer to Outcome Measure #1) to the earlier date of relapse or death due to any cause. Participants who proceeded to HSCT after JCAR015 infusion were censored at the time of HSCT. | Day 1 (first JCAR015 infusion) up to 12 months after the last JCAR015 infusion | 
| Event-Free Survival (EFS) | EFS is defined as the time from the date of the first JCAR015 infusion to the earliest of the following events: death from any cause, relapse, or treatment failure (defined as no response and subsequent discontinuation from the study for adverse event, lack of efficacy or progressive disease, or new anticancer therapy). Participants who proceeded to HSCT after JCAR015 infusion were censored at the time of HSCT. | Day 1 (first JCAR015 infusion) up to 12 months after the last JCAR015 infusion | 
| EFS | EFS is defined as the time from the date of the first JCAR015 infusion to the earliest of the following events: death from any cause, relapse, or treatment failure (defined as no response and subsequent discontinuation from the study for adverse event, lack of efficacy or progressive disease, or new anticancer therapy). Participants who proceeded to HSCT after JCAR015 infusion were censored at the time of HSCT. | Day 1 (first JCAR015 infusion) up to 12 months after the last JCAR015 infusion | 
| Overall Survival (OS) | OS is defined as the interval from the date of the first JCAR015 infusion to the date of death due to any reason. | Day 1 (first JCAR015 infusion) up to 12 months after the last JCAR015 infusion | 
| OS | OS is defined as the interval from the date of the first JCAR015 infusion to the date of death due to any reason. | Day 1 (first JCAR015 infusion) up to 12 months after the last JCAR015 infusion | 
| Duration of Remission (DOR) as Determined by an IRC | DOR is defined as the interval from the first documentation of CR or CRi to the earlier date of relapse or death due to ALL. | Day 1 (first JCAR015 infusion) up to 12 months after the last JCAR015 infusion | 
| Percentage of Participants Who Achieved a CR or CRi, as Determined by an IRC, at Month 6 After the Final JCAR015 Infusion | ORR at Month 6 is defined as the percentage of participants who achieved a CR or CRi at Month 6 after the final JCAR015 infusion without HSCT during the time period between the final JCAR015 infusion and the Month 6 response assessment (refer to Outcome Measure #1 for criteria for CR and CRi). | Day 1 (first JCAR015 infusion) up to 6 months after the last JCAR015 infusion | 
| Percentage of Participants Who Achieved a Morphologic Remission Within 6 Months After the Final JCAR015 Infusion and Then Proceeded to HSCT | Percentage of participants who achieved a morphologic remission within 6 months after the final JCAR015 infusion and then proceeded to HSCT prior to 12 months after the final JCAR015 infusion | Day 1 (first JCAR015 infusion) up to 12 months after the last JCAR015 infusion | 
| Maximum Concentration of JCAR015 (Cmax) in the Peripheral Blood by Quantitative Polymerase Chain Reaction (qPCR) | Cmax is defined as the highest measured number of copies of JCAR015 transgene per microgram of genomic DNA in peripheral blood cells as assessed by qPCR. | Pre-dose Day 1 of each JCAR015 infusion; Day 4, Day 7, Day 14, Day 21, and Day 28 after the first JCAR015 infusion until receipt of the second infusion; and Day 4, Day 7, Day 14, Day 21, and Day 28 after the second JCAR015 infusion (if applicable) | 
| Maximum Concentration of JCAR015 (Cmax) in the Peripheral Blood by Flow Cytometry | Cmax is defined as the highest measured concentration of JCAR015 CAR T cells per microliter of peripheral blood as measured by flow cytometry. | Pre-dose Day 1 of each JCAR015 infusion; Day 4, Day 7, Day 14, Day 21, and Day 28 after the first JCAR015 infusion until receipt of the second infusion; and Day 4, Day 7, Day 14, Day 21, and Day 28 after the second JCAR015 infusion (if applicable) | 
| Time to Maximum Concentration of JCAR015 (Tmax) in the Peripheral Blood as Measured by qPCR | Tmax is defined as the time after the JCAR015 infusion at which the maximum concentration (Cmax) as measured by qPCR is observed. If Cmax occurred after the second infusion, Tmax was calculated from the time of the second infusion. | Pre-dose Day 1 of each JCAR015 infusion; Day 4, Day 7, Day 14, Day 21, and Day 28 after the first JCAR015 infusion until receipt of the second infusion; and Day 4, Day 7, Day 14, Day 21, and Day 28 after the second JCAR015 infusion (if applicable) | 
| Tmax in the Peripheral Blood as Measured by Flow Cytometry | Tmax is defined as the time after the JCAR015 infusion at which the Cmax as measured by flow cytometry of the JCAR015 CAR is observed. If Cmax occurred after the second infusion, Tmax was calculated from the time of the second infusion. | Pre-dose Day 1 of each JCAR015 infusion; Day 4, Day 7, Day 14, Day 21, and Day 28 after the first JCAR015 infusion until receipt of the second infusion; and Day 4, Day 7, Day 14, Day 21, and Day 28 after the second JCAR015 infusion (if applicable) | 
| Area Under the Concentration-vs-Time Curve (AUC) for JCAR015 in the Peripheral Blood as Measured by qPCR | AUC is defined as the area under the concentration-vs-time curve from Day 1 to Day 29 after the first JCAR015 infusion as measured by qPCR of the JCAR015 transgene. AUC calculation includes pharmacokinetic (PK) results up to the second JCAR015 infusion for subjects who received the second infusion prior to Day 29 after the first JCAR015 infusion. | Pre-dose Day 1 of the first JCAR015 infusion; Day 4, Day 7, Day 14, Day 21, and Day 28 after the first JCAR015 infusion until receipt of the second infusion | 
| AUC for JCAR015 in the Peripheral Blood as Measured by Flow Cytometry | AUC is defined as the area under the concentration-vs-time curve from Day 1 to Day 29 after the first JCAR015 infusion as measured by flow cytometry of the JCAR015 CAR. AUC calculation includes PK results up to the second JCAR015 infusion for subjects who received the second infusion prior to Day 29 after the first JCAR015 infusion. | Pre-dose Day 1 of the first JCAR015 infusion; Day 4, Day 7, Day 14, Day 21, and Day 28 after the first JCAR015 infusion until receipt of the second infusion | 
| Percentage of Participants Who Developed Anti-Therapeutic Antibodies Against JCAR015 | Percentage of participants who developed anti-therapeutic antibodies against JCAR015 | Part B Screening; Day 14 after the first JCAR015 infusion; Pre-Dose Day 1 of the second JCAR015 infusion; Day 14 after the second JCAR015 infusion; and Day 28, Month 3, Month 6, and Month 12 after the last JCAR015 infusion | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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acute lymphoblastic leukemia, ALL, chimeric antigen receptor, CAR, CAR T cells, JCAR015, autologous T cell therapy, cell therapy