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

• ClinicalTrials.gov Identifier: NCT03331198
• Recruitment Status: Recruiting
• First Posted: November 6, 2017
• Last Update Posted: August 28, 2020
• Sponsor: Juno Therapeutics, a Subsidiary of Celgene
• Information provided by (Responsible Party): Juno Therapeutics, a Subsidiary of Celgene

Tracking Information

• First Submitted Date: October 29, 2017
• First Posted Date: November 6, 2017
• Last Update Posted Date: August 28, 2020
• Actual Study Start Date: December 26, 2017
• Estimated Primary Completion Date: October 12, 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (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 (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

Current Secondary Outcome Measures (submitted: March 9, 2020)

• 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
• 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: 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 (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: Study Evaluating Safety and Efficacy of JCAR017 in Subjects With Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL)
• Official Title: 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: Interventional
• Study Phase: Phase 1; Phase 2

Study Design

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

• Leukemia, Lymphocytic, Chronic, B-Cell
• Lymphoma, Small Lymphocytic

Intervention

• 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 as soon as possible after eligibility is confirmed. 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

• 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

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: February 28, 2019): 200
• Original Estimated Enrollment (submitted: November 2, 2017): 205
• Estimated Study Completion Date: July 14, 2022
• Estimated Primary Completion Date: October 12, 2021 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Diagnosis of:

  1. CLL with an indication for treatment based on the Investigator's opinion and 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 cohort) 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 active 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
• Progressive vascular tumor invasion, thrombosis, or embolism
• Deep vein thrombosis or embolism not managed on a stable regimen of anticoagulation

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Associate Director Clinical Trial Disclosure; 1-888-260-1599; clinicaltrialdisclosure@celgene.com

• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT03331198
• Other Study ID Numbers: 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

• Plan to Share IPD: Undecided

• Responsible Party: Juno Therapeutics, a Subsidiary of Celgene
• Study Sponsor: Juno Therapeutics, a Subsidiary of Celgene
• Collaborators: Not Provided

Investigators

• Study Director: Heidi Gillenwater, MD; Juno Therapeutics, Inc.

• PRS Account: Juno Therapeutics, a Subsidiary of Celgene
• Verification Date: August 2020