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

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ClinicalTrials.gov Identifier: NCT02535364
Recruitment Status : Terminated (Safety reasons)
First Posted : August 28, 2015
Results First Posted : July 19, 2018
Last Update Posted : July 19, 2018
Sponsor:
Information provided by (Responsible Party):
Juno Therapeutics, Inc.

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Acute Lymphoblastic Leukemia Biological: JCAR015 (CD19-targeted CAR T cells) Phase 2

Detailed Description:
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.

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 82 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : August 21, 2015
Actual Primary Completion Date : April 24, 2017
Actual Study Completion Date : September 1, 2017


Arm Intervention/treatment
Experimental: JCAR015 (CD19-targeted CAR T cells)
JCAR015 was administered as two intravenous (IV) infusions separated by 14 to 28 days.
Biological: JCAR015 (CD19-targeted CAR T cells)

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.





Primary Outcome Measures :
  1. Percentage of Participants With Complete Remission (CR) or Complete Remission With Incomplete Hematopoietic Recovery (CRi), as Determined by an Independent Review Committee (IRC) [ Time Frame: Day 1 (first JCAR015 infusion) up to 12 months after the last JCAR015 infusion ]
    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.


Secondary Outcome Measures :
  1. Percentage of Participants With CR or CRi, as Determined by an IRC [ Time Frame: Day 1 (first JCAR015 infusion) up to 12 months after the last JCAR015 infusion ]
    ORR is defined as the percentage of participants with CR or CRi based on IRC assessment (refer to criteria in Outcome Measure #1)

  2. Percentage of Participants Who Achieved a CR or CRi, as Determined by an IRC [ Time Frame: Day 1 (first JCAR015 infusion) up to 12 months after the last JCAR015 infusion ]
    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).

  3. Percentage of Participants Who Achieved a CR or CRi, as Determined by an IRC [ Time Frame: Day 1 (first JCAR015 infusion) up to 12 months after the last JCAR015 infusion ]
    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).

  4. Percentage of Participants Who Achieved a Minimal Residual Disease (MRD)-Negative CR or CRi [ Time Frame: 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, 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.

  5. Percentage of Participants Who Achieved a MRD-Negative CR or CRi [ Time Frame: 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, 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.

  6. Relapse-Free Survival (RFS), as Determined by an IRC [ Time Frame: Day 1 (first JCAR015 infusion) up to 12 months after the last JCAR015 infusion ]
    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.

  7. RFS, as Determined by an IRC [ Time Frame: Day 1 (first JCAR015 infusion) up to 12 months after the last JCAR015 infusion ]
    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.

  8. Event-Free Survival (EFS) [ Time Frame: Day 1 (first JCAR015 infusion) up to 12 months after the last JCAR015 infusion ]
    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.

  9. EFS [ Time Frame: Day 1 (first JCAR015 infusion) up to 12 months after the last JCAR015 infusion ]
    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.

  10. Overall Survival (OS) [ Time Frame: Day 1 (first JCAR015 infusion) up to 12 months after the last JCAR015 infusion ]
    OS is defined as the interval from the date of the first JCAR015 infusion to the date of death due to any reason.

  11. OS [ Time Frame: Day 1 (first JCAR015 infusion) up to 12 months after the last JCAR015 infusion ]
    OS is defined as the interval from the date of the first JCAR015 infusion to the date of death due to any reason.

  12. Duration of Remission (DOR) as Determined by an IRC [ Time Frame: Day 1 (first JCAR015 infusion) up to 12 months after the last JCAR015 infusion ]
    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.

  13. Percentage of Participants Who Achieved a CR or CRi, as Determined by an IRC, at Month 6 After the Final JCAR015 Infusion [ Time Frame: Day 1 (first JCAR015 infusion) up to 6 months after the last 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).

  14. Percentage of Participants Who Achieved a Morphologic Remission Within 6 Months After the Final JCAR015 Infusion and Then Proceeded to HSCT [ Time Frame: Day 1 (first JCAR015 infusion) up to 12 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 prior to 12 months after the final JCAR015 infusion

  15. Maximum Concentration of JCAR015 (Cmax) in the Peripheral Blood by Quantitative Polymerase Chain Reaction (qPCR) [ Time Frame: 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) ]
    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.

  16. Maximum Concentration of JCAR015 (Cmax) in the Peripheral Blood by Flow Cytometry [ Time Frame: 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) ]
    Cmax is defined as the highest measured concentration of JCAR015 CAR T cells per microliter of peripheral blood as measured by flow cytometry.

  17. Time to Maximum Concentration of JCAR015 (Tmax) in the Peripheral Blood as Measured by qPCR [ Time Frame: 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 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.

  18. Tmax in the Peripheral Blood as Measured by Flow Cytometry [ Time Frame: 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 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.

  19. Area Under the Concentration-vs-Time Curve (AUC) for JCAR015 in the Peripheral Blood as Measured by qPCR [ Time Frame: 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 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.

  20. AUC for JCAR015 in the Peripheral Blood as Measured by Flow Cytometry [ Time Frame: 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 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.

  21. Percentage of Participants Who Developed Anti-Therapeutic Antibodies Against JCAR015 [ Time Frame: 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 ]
    Percentage of participants who developed anti-therapeutic antibodies against JCAR015



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Age ≥ 18 years at the time of consent
  2. 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
  3. Morphological evidence of disease in bone marrow (at least 5% blasts)
  4. Evidence of CD19 expression
  5. Eastern Cooperative Oncology Group (ECOG) performance status between 0 and 2 at the time of screening
  6. Adequate pulmonary, renal, hepatic, and cardiac function
  7. Adequate central or peripheral vascular access for leukapheresis procedure

Exclusion Criteria:

  1. Isolated extramedullary disease relapse
  2. Concomitant genetic syndrome or other known bone marrow failure syndrome
  3. Burkitt's lymphoma/leukemia or chronic myelogenous leukemia lymphoid blast crisis (p210 BCR-ABL+)
  4. Prior malignancy, unless treated with curative intent and with no evidence of active disease present for > 5 years before screening
  5. Prior treatment with any gene therapy product
  6. Active hepatitis B, active hepatitis C, or any human immunodeficiency virus (HIV) infection at the time of screening
  7. Systemic fungal, bacterial, viral, or other infection that is not controlled, at the time of screening
  8. Presence of Grade II-IV (Glucksberg) or B-D (IBMTR) acute or extensive chronic GVHD at the time of screening
  9. Active central nervous system (CNS) involvement by malignancy (defined as CNS-3 per National Comprehensive Cancer Network [NCCN] guidelines)
  10. 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
  11. 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
  12. Participation in an investigational research study using an investigational agent within 30 days of screening
  13. 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
  14. Pregnant or nursing women
  15. Use of prohibited medications:

    1. Steroids: Therapeutic doses of corticosteroids are prohibited within 7 days prior to leukapheresis.
    2. Allogeneic cellular therapy: Donor lymphocyte infusions (DLI) are prohibited within 4 weeks prior to leukapheresis
    3. GVHD therapies: Any drug used for GVHD within 4 weeks prior to leukapheresis
    4. Chemotherapies: Salvage chemotherapy must be stopped at least 1 week prior to leukapheresis
  16. Treatment with alemtuzumab within 6 months prior to leukapheresis, or treatment with clofarabine or cladribine within 3 months prior to leukapheresis

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02535364


Locations
United States, Alabama
University of Alabama Birmingham Comprehensive Cancer Center
Birmingham, Alabama, United States, 35295
United States, California
City of Hope
Duarte, California, United States, 91010
University of California
San Francisco, California, United States, 94143
United States, Colorado
University of Colorado Denver -- Anschutz Medical Campus
Aurora, Colorado, United States, 80045
United States, Florida
Sylvester Comprehensive Cancer Center/UMHC
Miami, Florida, United States, 33136
United States, Georgia
The Blood and Marrow Transplant Program at Northside Hospital
Atlanta, Georgia, United States, 30342
United States, Illinois
Northwestern University Robert H Lurie Comprehensive Cancer Center
Chicago, Illinois, United States, 60611
University of Chicago Medical Center
Chicago, Illinois, United States, 60637
United States, Maryland
Sidney Kimmel Comprehensive Cancer Center @ Johns Hopkins
Baltimore, Maryland, United States, 21287
United States, Massachusetts
Massachusetts General Hospital
Boston, Massachusetts, United States, 02114
Dana-Farber Cancer Institute
Boston, Massachusetts, United States, 02215
United States, Missouri
Washington University School of Medicine
Saint Louis, Missouri, United States, 63110
United States, Nebraska
University of Nebraska Medical Center
Omaha, Nebraska, United States, 68198
United States, New York
Roswell Park Cancer Institute
Buffalo, New York, United States, 14263
Memorial Sloan Kettering Cancer Center
New York, New York, United States, 10065
United States, Ohio
Cleveland Clinic
Cleveland, Ohio, United States, 44195
United States, Tennessee
Vanderbilt University Medical Center
Nashville, Tennessee, United States, 37232
United States, Texas
MD Anderson Cancer Center
Houston, Texas, United States, 77030
Sponsors and Collaborators
Juno Therapeutics, Inc.
Investigators
Study Director: Nikolaus Trede, MD, PhD Juno Therapeutics, Inc.
  Study Documents (Full-Text)

Documents provided by Juno Therapeutics, Inc.:
Study Protocol  [PDF] July 14, 2016
Statistical Analysis Plan  [PDF] November 9, 2016


Publications:

Responsible Party: Juno Therapeutics, Inc.
ClinicalTrials.gov Identifier: NCT02535364     History of Changes
Other Study ID Numbers: 015001
First Posted: August 28, 2015    Key Record Dates
Results First Posted: July 19, 2018
Last Update Posted: July 19, 2018
Last Verified: June 2018

Keywords provided by Juno Therapeutics, Inc.:
acute lymphoblastic leukemia
ALL
chimeric antigen receptor
CAR
CAR T cells
JCAR015
autologous T cell therapy
cell therapy

Additional relevant MeSH terms:
Leukemia
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Leukemia, Lymphoid
Burkitt Lymphoma
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Epstein-Barr Virus Infections
Herpesviridae Infections
DNA Virus Infections
Virus Diseases
Tumor Virus Infections
Lymphoma, B-Cell
Lymphoma, Non-Hodgkin
Lymphoma