Clinical trial NCT02535364: Study Evaluating the Efficacy and Safety of JCAR015 in Adult B-cell Acute Lymphoblastic Leukemia (B-ALL)
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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Acute Lymphoblastic Leukemia
Keywords: acute lymphoblastic leukemia
ALL
chimeric antigen receptor
CAR
CAR T cells
JCAR015
autologous T cell therapy
cell therapy
Lead sponsor: Juno Therapeutics, a Subsidiary of Celgene
Sponsor class: INDUSTRY
First posted: 2015-08-28
Enrollment: 82
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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.

Eligibility 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

Primary outcomes:
measure: Percentage of Participants With Complete Remission (CR) or Complete Remission With Incomplete Hematopoietic Recovery (CRi), as Determined by an Independent Review Committee (IRC)
timeFrame: Day 1 (first JCAR015 infusion) up to 12 months after the last JCAR015 infusion
Secondary outcomes:
measure: Percentage of Participants With CR or CRi, as Determined by an IRC
timeFrame: Day 1 (first JCAR015 infusion) up to 12 months after the last JCAR015 infusion
measure: Percentage of Participants Who Achieved a CR or CRi, as Determined by an IRC
timeFrame: Day 1 (first JCAR015 infusion) up to 12 months after the last JCAR015 infusion
measure: Percentage of Participants Who Achieved a CR or CRi, as Determined by an IRC
timeFrame: Day 1 (first JCAR015 infusion) up to 12 months after the last JCAR015 infusion
measure: Percentage of Participants Who Achieved a Minimal Residual Disease (MRD)-Negative CR or CRi
timeFrame: Day 1 (first JCAR015 infusion) up to 12 months after the last JCAR015 infusion
measure: Percentage of Participants Who Achieved a MRD-Negative CR or CRi
timeFrame: Day 1 (first JCAR015 infusion) up to 12 months after the last JCAR015 infusion
measure: Relapse-Free Survival (RFS), as Determined by an IRC
timeFrame: Day 1 (first JCAR015 infusion) up to 12 months after the last JCAR015 infusion
measure: RFS, as Determined by an IRC
timeFrame: Day 1 (first JCAR015 infusion) up to 12 months after the last JCAR015 infusion
measure: Event-Free Survival (EFS)
timeFrame: Day 1 (first JCAR015 infusion) up to 12 months after the last JCAR015 infusion
measure: EFS
timeFrame: Day 1 (first JCAR015 infusion) up to 12 months after the last JCAR015 infusion
measure: Overall Survival (OS)
timeFrame: Day 1 (first JCAR015 infusion) up to 12 months after the last JCAR015 infusion
measure: OS
timeFrame: Day 1 (first JCAR015 infusion) up to 12 months after the last JCAR015 infusion
measure: Duration of Remission (DOR) as Determined by an IRC
timeFrame: Day 1 (first JCAR015 infusion) up to 12 months after the last JCAR015 infusion
measure: Percentage of Participants Who Achieved a CR or CRi, as Determined by an IRC, at Month 6 After the Final JCAR015 Infusion
timeFrame: Day 1 (first JCAR015 infusion) up to 6 months after the last JCAR015 infusion
measure: Percentage of Participants Who Achieved a Morphologic Remission Within 6 Months After the Final JCAR015 Infusion and Then Proceeded to HSCT
timeFrame: Day 1 (first JCAR015 infusion) up to 12 months after the last JCAR015 infusion
measure: Maximum Concentration of JCAR015 (Cmax) in the Peripheral Blood by Quantitative Polymerase Chain Reaction (qPCR)
timeFrame: 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)
measure: Maximum Concentration of JCAR015 (Cmax) in the Peripheral Blood by Flow Cytometry
timeFrame: 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)
measure: Time to Maximum Concentration of JCAR015 (Tmax) in the Peripheral Blood as Measured by qPCR
timeFrame: 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)
measure: Tmax in the Peripheral Blood as Measured by Flow Cytometry
timeFrame: 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)
measure: Area Under the Concentration-vs-Time Curve (AUC) for JCAR015 in the Peripheral Blood as Measured by qPCR
timeFrame: 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
measure: AUC for JCAR015 in the Peripheral Blood as Measured by Flow Cytometry
timeFrame: 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
measure: Percentage of Participants Who Developed Anti-Therapeutic Antibodies Against JCAR015
timeFrame: 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
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama Birmingham Comprehensive Cancer Center
state: Alabama
city: Duarte
country: United States
facility: City of Hope
state: California
city: San Francisco
country: United States
facility: University of California
state: California
city: Aurora
country: United States
facility: University of Colorado Denver -- Anschutz Medical Campus
state: Colorado
city: Miami
country: United States
facility: Sylvester Comprehensive Cancer Center/UMHC
state: Florida
city: Atlanta
country: United States
facility: The Blood and Marrow Transplant Program at Northside Hospital
state: Georgia
city: Chicago
country: United States
facility: Northwestern University Robert H Lurie Comprehensive Cancer Center
state: Illinois
city: Chicago
country: United States
facility: University of Chicago Medical Center
state: Illinois
city: Baltimore
country: United States
facility: Sidney Kimmel Comprehensive Cancer Center @ Johns Hopkins
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Boston
country: United States
facility: Dana-Farber Cancer Institute
state: Massachusetts
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Omaha
country: United States
facility: University of Nebraska Medical Center
state: Nebraska
city: Buffalo
country: United States
facility: Roswell Park Cancer Institute
state: New York
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
city: Houston
country: United States
facility: MD Anderson Cancer Center
state: Texas
Study officials:
affiliation: Juno Therapeutics, Inc., a Bristol-Myers Squibb Company
name: Nikolaus Trede, MD, PhD
role: STUDY_DIRECTOR
References:
citation: Davila ML, Riviere I, Wang X, Bartido S, Park J, Curran K, Chung SS, Stefanski J, Borquez-Ojeda O, Olszewska M, Qu J, Wasielewska T, He Q, Fink M, Shinglot H, Youssif M, Satter M, Wang Y, Hosey J, Quintanilla H, Halton E, Bernal Y, Bouhassira DC, Arcila ME, Gonen M, Roboz GJ, Maslak P, Douer D, Frattini MG, Giralt S, Sadelain M, Brentjens R. Efficacy and toxicity management of 19-28z CAR T cell therapy in B cell acute lymphoblastic leukemia. Sci Transl Med. 2014 Feb 19;6(224):224ra25. doi: 10.1126/scitranslmed.3008226.
citation: Sadelain M, Brentjens R, Riviere I. The basic principles of chimeric antigen receptor design. Cancer Discov. 2013 Apr;3(4):388-98. doi: 10.1158/2159-8290.CD-12-0548. Epub 2013 Apr 2.
citation: Brentjens RJ, Davila ML, Riviere I, Park J, Wang X, Cowell LG, Bartido S, Stefanski J, Taylor C, Olszewska M, Borquez-Ojeda O, Qu J, Wasielewska T, He Q, Bernal Y, Rijo IV, Hedvat C, Kobos R, Curran K, Steinherz P, Jurcic J, Rosenblat T, Maslak P, Frattini M, Sadelain M. CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia. Sci Transl Med. 2013 Mar 20;5(177):177ra38. doi: 10.1126/scitranslmed.3005930.
citation: Brentjens RJ, Riviere I, Park JH, Davila ML, Wang X, Stefanski J, Taylor C, Yeh R, Bartido S, Borquez-Ojeda O, Olszewska M, Bernal Y, Pegram H, Przybylowski M, Hollyman D, Usachenko Y, Pirraglia D, Hosey J, Santos E, Halton E, Maslak P, Scheinberg D, Jurcic J, Heaney M, Heller G, Frattini M, Sadelain M. Safety and persistence of adoptively transferred autologous CD19-targeted T cells in patients with relapsed or chemotherapy refractory B-cell leukemias. Blood. 2011 Nov 3;118(18):4817-28. doi: 10.1182/blood-2011-04-348540. Epub 2011 Aug 17.