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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

IRB JUNO1915

CC 16-288

Hospital Main Campus

Phase Phase 2

Disease Leukemia - Acute Lymphoblastic (ALL)

Drug JCAR015

Description

Primary Objective

• To evaluate the efficacy of JCAR015 as measured by overall remission rate (ORR) after the final JCAR015 infusion in subjects with morphologic evidence of disease, based on independent review committee (IRC) assessment

Secondary Objectives

1. To evaluate the duration of remission
2. To evaluate the percentage of subjects who achieve a CR or CRi with no evidence of MRD in the bone marrow (i.e., below the level of detection for the IgH gene sequencing)
3. To evaluate the safety and tolerability of JCAR015 therapy
4. To evaluate disease control
5. To characterize the cellular pharmacokinetic (PK) profile of JCAR015, including the quantity and persistence in the peripheral blood and bone marrow
6. To characterize the prevalence and incidence of humoral immune responses to JCAR015
7. To evaluate the ORR at Month 6 following the final JCAR015 infusion
8. To compare the safety and tolerability of the JCAR015 cell product with the MSKCC 1928z CAR T cell product
9. To evaluate the percentage of subjects who achieve a morphologic remission within 6 months after the final JCAR015 infusion and then proceed to HSCT

Exploratory Objectives

1. To describe the change in the number of normal B lymphocytes over time following JCAR015 treatment
2. To describe the relationship between CD19 and CD22 expression on leukemic blasts at baseline, blast percentage, and/or bone marrow cellularity, and JCAR015 safety, PK, and efficacy
3. To describe the genomic and immunophenotypic profile of JCAR015 and resident immune cells following infusion
4. To characterize the incidence of anti-JCAR015 antibodies, and of a JCAR015-directed cytotoxic T lymphocytes (CTL) response (i.e., immunogenicity) after JCAR015 treatment
5. To describe changes in the profile of soluble immune factors or inflammatory markers that may be associated sCRS, and the effect of corticosteroid and/or anti-cytokine therapy on this profile
6. To describe the effect of treatments directed at sCRS on duration and severity of sCRS, JCAR015 PK and pharmacodynamics (PD), JCAR015 cell persistence, and disease response
7. To describe the relationship between JCAR015 clinical characteristics (efficacy, safety, PK, and markers of intermediate efficacy) and JCAR015 product quality attributes and process performance attributes
8. To describe the relationship between tumor burden, tumor response, cellular PK/PD, and sCRS
9. To describe the relationship between clinical outcomes (disease response and safety) and genomic features of the underlying leukemia
10. To describe changes in immunophenotype, gene expression profiling, and/or DNA sequencing data between on-study baseline tumor data and on-study relapsed tumor data
11. To describe changes in the tumor microenvironment components following JCAR015 treatment
12. To characterize changes in quality of life outcome measures and hospital resource utilization for subjects treated with JCAR015

Inclusion Criteria

Part A

1. Age ≥ 18 years at the time of consent
2. Signed written informed consent obtained prior to any Part A study procedures
3. Diagnosis of B-cell ALL by flow cytometry
4. Relapsed or refractory disease, defined as:
   • First or greater bone marrow relapse from CR, OR
   • Any bone marrow relapse after allogeneic HSCT; subjects must be at least 100 days from HSCT (i.e., Day 0, receipt of hematopoietic stem cells) at the time of screening and off immunosuppressant medication for at least 1 month at the time of screening (with the exception of low-dose steroids [≤ 20 mg prednisone or equivalent]), and have no active GVHD, OR
   • Refractory ALL, defined by not having achieved a CR or CRi after two attempts at remission induction using standard regimens, OR
   • Ph+ B-cell ALL if subjects are intolerant to or ineligible for TKI therapy, OR have progressed after at least one line of TKI therapy
5. Bone marrow with morphological evidence of disease (≥ 5% blasts by morphology)
6. Evidence of CD19 expression via flow cytometry (peripheral blood or bone marrow) or immunohistochemistry (bone marrow biopsy) from a sample obtained from the current relapse within 2 months of screening
7. Eastern Cooperative Oncology Group (ECOG) performance status between 0 and 2 at the time of screening
8. Adequate organ function, defined as:
   • Serum creatinine ≤ 1.5 x age-adjusted upper limit of normal (ULN) OR calculated creatinine clearance (Cockcroft and Gault; see Appendix E) > 30 mL/min/1.73 m²
   • Alanine aminotransferase (ALT) ≤ 5 x ULN (or ≤ 8 x ULN for subjects with leukemic infiltration of the liver) and direct bilirubin < 2.0 mg/dL (or < 3.0 mg/dL for subjects with leukemic infiltration of the liver)
   • Adequate pulmonary function, defined as ≤ Grade 1 dyspnea and SaO2 ≥ 92% on room air
   • Adequate cardiac function, defined as left ventricular ejection fraction (LVEF) ≥ 40% as assessed by echocardiogram (ECHO) or multiple uptake gated acquisition (MUGA) performed within 1 month of enrollment
9. Adequate central or peripheral vascular access for leukapheresis procedure. If a subject requires central venous catheter (CVC) placement in order to perform leukapheresis, a consultation indicating subject eligibility for CVC placement is sufficient to allow enrollment on the study while the subject awaits CVC placement.
10. Women of reproductive potential (defined as all women physiologically capable of becoming pregnant) must agree to use highly effective methods of contraception during the entire study period (Part A through 12 months after the final JCAR015 infusion) (see Section 5.3). Women of reproductive potential must have a negative serum beta human chorionic gonadotropin (β-hCG) pregnancy test result within 7 days prior to the first dose of cytoreductive chemotherapy.
11. Males who have partners of childbearing potential must agree to use an effective barrier contraceptive method during the entire study period (Part A through 12 months after the final JCAR015 infusion).

Part B

1. Completion of Part A and successful generation of a JCAR015 cell product
2. Results from bone marrow examination following Part A:
   • Group 1: Morphological evidence of disease (≥ 5% blasts by morphology)
   • Group 2: Morphologic complete remission (bone marrow with < 5% blasts) with or without blood count recovery (CR or CRi) or a hypoplastic, aplastic, or "recovery" marrow at Day 42 of Part A
3. ECOG performance status between 0 and 2
4. Adequate organ function, defined as:
   • Serum creatinine ≤ 1.5 x age-adjusted ULN OR calculated creatinine clearance (Cockcroft and Gault; see Appendix E) > 30 mL/min/1.73 m²
   • ALT ≤ 5 x ULN (or ≤ 8 x ULN for subjects with leukemic infiltration of the liver) and direct bilirubin < 2.0 mg/dL (or < 3.0 mg/dL for subjects with leukemic infiltration of the liver)
   • Adequate pulmonary function, defined as ≤ Grade 1 dyspnea and SaO2 ≥ 92% on room air
5. Women of reproductive potential must have a negative serum or urine pregnancy test

Exclusion Criteria

Part A

1. Isolated extramedullary disease relapse
2. Concomitant genetic syndrome such as Fanconi anemia, Kostmann syndrome, Shwachman syndrome, or any other known bone marrow failure syndrome
3. Burkitt's lymphoma/leukemia or chronic myelogenous leukemia (CML) 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, with the following exceptions:
   • Subjects with Stage I breast cancer that has been completely and successfully treated, requiring no therapy or only anti-hormonal therapy
   • Subjects with T1N0M0 or T2N0M0 colorectal cancer who have been completely and successfully resected and who are disease-free for > 2 years prior to screening
   • Subjects with indolent prostate cancer, defined as clinical stage T1 or T2a, Gleason score ≤ 6, and prostate-specific antigen (PSA) < 10 ng/mL, requiring no therapy or only anti-hormonal therapy
   • Subjects with a history of basal cell or squamous cell carcinoma of the skin, or carcinoma in situ of the cervix, fully resected, and with no evidence of active disease
5. Treatment with any prior 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 (defined as exhibiting ongoing signs/symptoms related to the infection and without improvement, despite appropriate antibiotics or other treatment) 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 CNS involvement by malignancy, defined as CNS-3 per NCCN guidelines. Subjects with a history of CNS disease that has been effectively treated (defined as one documented negative CSF evaluation within 1 month prior to screening) will be eligible.
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, with the exception of investigational anti-infective agents (e.g., antibacterial, antifungal, antiviral)
13. History of treatment with a murine-derived biological product (unless subject has been shown to be negative for human anti-mouse antibodies [HAMA] prior to or during screening). Prior use of blinatumomab is permitted (provided there is evidence of CD19 expression per Inclusion Criterion #6). Chimeric biological products (e.g., rituximab) are not considered murine for the purpose of this protocol.
14. Pregnant or nursing (lactating) women
15. Use of prohibited medications (see Section 6.5 for full details):
    • Steroids: Therapeutic doses of corticosteroids (defined as > 20 mg/day prednisone or equivalent) are prohibited within 7 days prior to leukapheresis. Physiologic replacement dosing of steroids (≤ 12 mg/m²/day hydrocortisone or equivalent [≤ 3 mg/m²/day prednisone or ≤ 0.45 mg/m²/day dexamethasone]) is allowed. Topical steroids and intrathecal steroids for CNS relapse prophylaxis are permitted.
    • 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, e.g., calcineurin inhibitors, methotrexate or other chemotherapeutics, mycophenolate mofetil, rapamycin, thalidomide, immunosuppressive antibodies (such as anti-CD20 [rituximab], anti-TNFα, anti-IL-6, or anti-IL-6R)
    • Chemotherapies: Salvage chemotherapy (e.g., cytosine arabinoside > 100 mg/m²/day, anthracyclines, and cyclophosphamide) 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
17. Uncontrolled medical, psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol, as judged by the Investigator; or subject unwillingness or inability to follow the procedures required in the protocol

Part B

1. Systemic fungal, bacterial, viral, or other infection that is not controlled (defined as exhibiting ongoing signs/symptoms related to the infection and without improvement, despite appropriate antibiotics or other treatment)
2. Presence of Grade II-IV (Glucksberg) or B-D (IBMTR) acute or extensive chronic GVHD
3. Use of prohibited medications (see Section 6.5)