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Study Evaluating Safety and Efficacy of JCAR017 in Subjects With Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL)

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ClinicalTrials.gov Identifier: NCT03331198
Recruitment Status : Recruiting
First Posted : November 6, 2017
Last Update Posted : February 5, 2020
Sponsor:
Collaborator:
Celgene Corporation
Information provided by (Responsible Party):
Juno Therapeutics, Inc.

Tracking Information
First Submitted Date  ICMJE October 29, 2017
First Posted Date  ICMJE November 6, 2017
Last Update Posted Date February 5, 2020
Actual Study Start Date  ICMJE December 26, 2017
Estimated Primary Completion Date December 1, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 28, 2019)
  • Phase 1 monotherapy arm: recommended dose [ Time Frame: 28 days ]
    Recommended dose based on assessment of data from each dose level
  • Phase 1 combination therapy arm: adverse events [ Time Frame: Through post-treatment Month 24 ]
    Proportion of subjects experiencing adverse events
  • Phase 1 combination therapy arm: laboratory abnormalities [ Time Frame: Through post-treatment Month 24 ]
    Proportion of subjects experiencing laboratory abnormalities
  • Phase 2: rate of complete remission (CR) [ Time Frame: Through post-treatment Month 24 ]
    Proportion of subjects who have CR after JCAR017 infusion based on Independent Review Committee (IRC) assessment using International Workshop on Chronic Lymphocytic Leukemia (iwCLL) 2018 guidelines
Original Primary Outcome Measures  ICMJE
 (submitted: November 2, 2017)
  • Phase 1 monotherapy arm: recommended dose [ Time Frame: 28 days ]
    Recommended dose based on assessment of data from each dose level
  • Phase 1 combination therapy arm: adverse events [ Time Frame: 30 days ]
    Proportion of subjects experiencing adverse events
  • Phase 1 combination therapy arm: laboratory abnormalities [ Time Frame: 30 days ]
    Proportion of subjects experiencing laboratory abnormalities
  • Phase 2: antitumor activity [ Time Frame: Through post-randomization Month 24 ]
    Complete response rate based on Independent Review Committee assessment using iwCLL 2008 guidelines
Change History Complete list of historical versions of study NCT03331198 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: February 28, 2019)
  • Phase 2: overall response rate [ Time Frame: Through post-treatment Month 24 ]
    Overall response rate based on IRC assessment using iwCLL 2018 guidelines
  • Phase 2: minimal residual disease (MRD)-negative response rate [ Time Frame: Through post-treatment Month 24 ]
    MRD will be measured via IgHV deep sequencing and flow cytometry of peripheral blood and bone marrow
  • Phase 2: adverse events [ Time Frame: Through post-treatment Month 24 ]
    Proportion of subjects experiencing adverse events
  • Phase 2: laboratory abnormalities [ Time Frame: Through post-treatment Month 24 ]
    Proportion of subjects experiencing laboratory abnormalities
  • Phase 2: overall survival [ Time Frame: Through post-treatment Month 24 ]
    Overall survival
  • Phase 2: progression-free survival (PFS) [ Time Frame: Through post-treatment Month 24 ]
    PFS, defined as the time from JCAR017 infusion to disease progression or death
  • Phase 2: PK [ Time Frame: Through post-treatment Month 24 ]
    AUC of JCAR017 in blood and bone marrow
  • Phase 2: PK [ Time Frame: Through post-treatment Month 24 ]
    Cmax of JCAR017 in blood and bone marrow
  • Phase 2: PK [ Time Frame: Through post-treatment Month 24 ]
    Tmax of JCAR017 in blood and bone marrow
  • Phase 2: health economics and outcomes research [ Time Frame: Through post-treatment Month 24 ]
    EuroQol instrument EQ-5D-5L and numbers of intensive care unit (ICU) inpatient days and non-ICU inpatient days
  • Phase 2: health-related quality of life [ Time Frame: Through post-treatment Month 24 ]
    EORTC QLQ-C30
  • Phase 2: health-related quality of life [ Time Frame: Through post-treatment Month 24 ]
    CLL-specific module QLQ-CLL-17
Original Secondary Outcome Measures  ICMJE
 (submitted: November 2, 2017)
  • Phase 2: adverse events [ Time Frame: 30 days ]
    Proportion of subjects experiencing adverse events
  • Phase 2: laboratory abnormalities [ Time Frame: 30 days ]
    Proportion of subjects experiencing laboratory abnormalities
  • Phase 2: overall response rate [ Time Frame: Through post-randomization Month 24 ]
    Overall response rate based on Independent Review Committee assessment using iwCLL 2008 guidelines
  • Phase 2: minimal residual disease (MRD)-negative response rate [ Time Frame: Through post-randomization Month 24 ]
    MRD will be measured via IgHV deep sequencing and flow cytometry of peripheral blood and bone marrow
  • Phase 2: overall survival [ Time Frame: Through post-randomization Month 24 ]
    Overall survival
  • Phase 2: Progression-free survival [ Time Frame: Through post-randomization Month 24 ]
    Progression-free survival
  • Phase 2: PK [ Time Frame: Through post-randomization Month 24 ]
    AUC of JCAR017 in blood and bone marrow
  • Phase 2: PK [ Time Frame: Through post-randomization Month 24 ]
    Cmax of JCAR017 in blood and bone marrow
  • Phase 2: PK [ Time Frame: Through post-randomization Month 24 ]
    Tmax of JCAR017 in blood and bone marrow
  • Phase 2: health-related quality of life and health economics and outcomes research [ Time Frame: Through post-randomization Month 24 ]
    EuroQol instrument EQ-5D-5L Numbers of intensive care unit (ICU) inpatient days and non-ICU inpatient days
  • Phase 2: health-related quality of life and health economics and outcomes research [ Time Frame: Through post-randomization Month 24 ]
    EORTC QLQ-C30 Numbers of intensive care unit (ICU) inpatient days and non-ICU inpatient days
  • Phase 2: health-related quality of life and health economics and outcomes research [ Time Frame: Through post-randomization Month 24 ]
    CLL-specific module QLQ-CLL Numbers of intensive care unit (ICU) inpatient days and non-ICU inpatient days
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Study Evaluating Safety and Efficacy of JCAR017 in Subjects With Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL)
Official Title  ICMJE An Open-Label, Phase 1/2 Study of JCAR017 in Subjects With Relapsed or Refractory Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma (017004)
Brief Summary This is a Phase 1/2, open-label, multicenter study to determine the efficacy and safety of JCAR017 in adult subjects with relapsed or refractory CLL or SLL. The study will include a Phase 1 part to determine the recommended dose of JCAR017 monotherapy in subjects with relapsed or refractory CLL or SLL, followed by a Phase 2 part to further assess the efficacy and safety of JCAR017 monotherapy treatment at the recommended dose. A separate Phase 1 cohort will assess the combination of JCAR017 and concurrent ibrutinib. In all subjects, the safety, efficacy, and pharmacokinetics (PK) of JCAR017 will be evaluated.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:
Phase 1: subjects will be assigned to receive JCAR017, or JCAR017 + ibrutinib Phase 2: subjects will be assigned to receive JCAR017 at the recommended dose
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Leukemia, Lymphocytic, Chronic, B-Cell
  • Lymphoma, Small Lymphocytic
Intervention  ICMJE
  • Biological: JCAR017 (lisocabtagene maraleucel)
    Participants will undergo leukapheresis to isolate peripheral blood mononuclear cells (PBMCs) for the production of JCAR017. During JCAR017 production, participants may receive bridging chemotherapy for disease control. Upon successful generation of JCAR017 product, participants will receive treatment with JCAR017 therapy. Each cycle will include lymphodepleting chemotherapy followed by one dose of JCAR017 administered by intravenous (IV) injection.
  • Biological: JCAR017 (lisocabtagene maraleucel) + ibrutinib
    Participants eligible for this cohort should be receiving ibrutinib at the time of screening. For participants who previously discontinued ibrutinib, ibrutinib will be started at the time of enrollment. Ibrutinib treatment will continue for up to 90 days after JCAR017 infusion (or longer for participants who are receiving benefit from ibrutinib). Participants will undergo leukapheresis to isolate peripheral blood mononuclear cells (PBMCs) for the production of JCAR017. During JCAR017 production, participants may receive bridging chemotherapy for disease control. Upon successful generation of JCAR017 product, participants will receive treatment with JCAR017 therapy. Each cycle will include lymphodepleting chemotherapy followed by one dose of JCAR017 administered by intravenous (IV) injection.
Study Arms  ICMJE
  • Experimental: Phase 1 JCAR017 monotherapy
    Subjects will be assigned to receive JCAR017 (lisocabtagene maraleucel)
    Intervention: Biological: JCAR017 (lisocabtagene maraleucel)
  • Experimental: Phase 1 JCAR017 + ibrutinib
    Subjects receiving ibrutinib at baseline will be assigned to receive JCAR017 (lisocabtagene maraleucel) at the recommended dose + ibrutinib
    Intervention: Biological: JCAR017 (lisocabtagene maraleucel) + ibrutinib
  • Experimental: Phase 2 JCAR017 monotherapy
    Subjects will receive JCAR017 (lisocabtagene maraleucel) at the recommended dose from the Phase 1 monotherapy arm
    Intervention: Biological: JCAR017 (lisocabtagene maraleucel)
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: February 28, 2019)
200
Original Estimated Enrollment  ICMJE
 (submitted: November 2, 2017)
205
Estimated Study Completion Date  ICMJE March 1, 2022
Estimated Primary Completion Date December 1, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Diagnosis of:

    1. CLL with an indication for treatment based on iwCLL guidelines and clinical measurable disease, or
    2. SLL (lymphadenopathy and/or splenomegaly and < 5×10^9 CD19+ CD5+ clonal B lymphocytes/L [< 5000/µL] in the peripheral blood at diagnosis with measurable disease that is biopsy-proven SLL)
  • Subjects (other than those in the ibrutinib + JCAR017 combination therapy arm) must have received and failed Bruton tyrosine kinase inhibitor (BTKi) treatment or have been deemed ineligible for BTKi therapy.
  • Subjects (other than those in the ibrutinib + JCAR017 combination therapy cohort) must have received previous treatment as follows:

    1. Subjects with CLL or SLL and high-risk features must have failed at least 2 lines of prior therapy.
    2. Subjects with CLL or SLL and standard-risk features must have failed at least 3 lines of prior therapy.
  • Subjects in the ibrutinib + JCAR017 combination therapy cohort must either:

    1. be receiving ibrutinib and progressing at the time of study enrollment
    2. be receiving ibrutinib for at least 6 months with a response less than complete response/remission (CR) and have high-risk features as defined in inclusion criterion 5a
    3. have BTK or PLCgamma2 mutations per local laboratory assessment, with or without progression on ibrutinib
    4. have previously received ibrutinib and have no contraindications to restarting ibrutinib
  • Eastern Cooperative Oncology Group performance status of ≤ 1
  • Assessed by the Investigator to have adequate bone marrow function to receive lymphodepleting chemotherapy
  • Adequate organ function, defined as:

    1. Serum creatinine ≤ 1.5 × age-adjusted upper limit of normal (ULN) OR calculated creatinine clearance > 30 mL/min
    2. Alanine aminotransferase ≤ 5 × ULN and total bilirubin < 2.0 mg/dL (or < 3.0 mg/dL for subjects with Gilbert's syndrome or leukemic infiltration of the liver)
    3. Adequate pulmonary function, defined as ≤ Common Terminology Criteria for Adverse Events (CTCAE) Grade 1 dyspnea and saturated oxygen (SaO2) ≥ 92% on room air
    4. Adequate cardiac function, defined as left ventricular ejection fraction ≥ 40% as assessed by echocardiogram or multiple uptake gated acquisition scan performed within 30 days prior to determination of eligibility
  • Subject either currently has central vascular access or is a candidate to receive central vascular access or peripheral vascular access for leukapheresis procedure.
  • If prior CD19-targeted therapy has been administered, subject must have CD19-positive disease confirmed by immunohistochemistry or flow cytometry since completing the prior CD19-targeted therapy.

Exclusion Criteria:

  • Subjects with known active central nervous system (CNS) involvement by malignancy. Those with prior CNS disease that has been effectively treated will be eligible if treatment was completed at least 3 months prior to enrollment with no evidence of symptomatic disease and stable abnormalities on repeat imaging.
  • History of another primary malignancy that has not been in remission for at least 2 years. (The following are exempt from the 2-year limit: nonmelanoma skin cancer, completely resected stage 1 solid tumor with low risk for recurrence, curatively treated localized prostate cancer, cervical carcinoma in situ on biopsy or a squamous intraepithelial lesion on Pap smear, and in situ breast cancer that has been completely resected.)
  • Subjects with Richter's transformation
  • Prior treatment with any gene therapy product
  • Active hepatitis B, active hepatitis C, or any human immunodeficiency virus (HIV) infection
  • Systemic fungal, bacterial, viral, or other infection that is not controlled
  • Presence of acute or extensive chronic graft versus host disease (GVHD)
  • 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, aphasia, stroke with current neurologic sequelae, severe brain injuries, dementia, Parkinson's disease, cerebellar disease,cerebral edema, or psychosis
  • Pregnant or nursing (lactating) women
  • Use of any of the following medications or treatments within the noted time prior to leukapheresis:

    1. Alemtuzumab within 6 months prior to leukapheresis
    2. Allogeneic hematopoietic stem cell transplant within 100 days prior to leukapheresis
    3. Cladribine within 3 months prior to leukapheresis
    4. Donor lymphocyte infusions (DLI) within 2 months prior to leukapheresis
    5. Radiation including large bone marrow fields such as sternum or pelvis within 6 weeks prior to leukapheresis
    6. Fludarabine within 4 weeks prior to leukapheresis
    7. GVHD therapies such as calcineurin inhibitors, methotrexate or other chemotherapeutics, mycophenolate mofetil, rapamycin, or immunosuppressive antibodies (such as anti-tumor necrosis factor-α [TNFα], anti-interleukin-6 [IL-6], or anti-interleukin-6 receptor [IL 6R]) within 4 weeks prior to leukapheresis
    8. Cyclophosphamide, ifosfamide, bendamustine, chlorambucil, or melphalan within 2 weeks prior to leukapheresis
    9. Therapeutic doses of corticosteroids (defined as > 20 mg/day prednisone or equivalent) within 7 days prior to leukapheresis
    10. Anti-CD20 monoclonal antibodies within 7 days prior to leukapheresis
    11. Venetoclax within 4 days prior to leukapheresis
    12. Idelalisib or duvelisib within 2 days prior to leukapheresis
    13. Lenalidomide within 1 day prior to leukapheresis
    14. Experimental agents, including off-label use of approved drugs (with the exception of acalabrutinib which may be continued up to the day before leukapheresis), within 4 weeks prior to leukapheresis unless progression is documented on the experimental therapy and at least 3 half-lives have elapsed prior to leukapheresis
  • 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
  • Tumor invasion of venous or arterial vessels
  • Deep vein thrombosis or pulmonary embolism within 3 months prior to leukapheresis
  • Deep vein thrombosis or pulmonary embolism requiring ongoing therapeutic anticoagulation
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Juno Medical Information 866-599-JUNO (5866) medicalinformation@junotherapeutics.com
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03331198
Other Study ID Numbers  ICMJE 017004
TRANSCEND-CLL-004 ( Other Identifier: Juno Therapeutics, Inc. )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Undecided
Responsible Party Juno Therapeutics, Inc.
Study Sponsor  ICMJE Juno Therapeutics, Inc.
Collaborators  ICMJE Celgene Corporation
Investigators  ICMJE
Study Director: Heidi Gillenwater, MD Juno Therapeutics, Inc.
PRS Account Juno Therapeutics, Inc.
Verification Date March 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP