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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 : November 25, 2021
Sponsor:
Information provided by (Responsible Party):
Juno Therapeutics, a Subsidiary of Celgene

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. Another separate Phase 1 cohort will assess the combination of JCAR017 and concurrent venetoclax. In all subjects, the safety, efficacy, and pharmacokinetics (PK) of JCAR017 will be evaluated.

Condition or disease Intervention/treatment Phase
Leukemia, Lymphocytic, Chronic, B-Cell Lymphoma, Small Lymphocytic Biological: JCAR017 (lisocabtagene maraleucel) Biological: JCAR017 (lisocabtagene maraleucel) + ibrutinib Biological: JCAR017 (lisocabtagene maraleucel) + venetoclax Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 259 participants
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
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)
Actual Study Start Date : November 27, 2017
Estimated Primary Completion Date : December 5, 2025
Estimated Study Completion Date : December 4, 2027

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Leukemia Lymphoma
Drug Information available for: Venetoclax

Arm Intervention/treatment
Experimental: Phase 1 JCAR017 monotherapy
Subjects will be assigned to receive JCAR017 (lisocabtagene maraleucel)
Biological: JCAR017 (lisocabtagene maraleucel)
Participants will undergo leukapheresis to isolate peripheral blood mononuclear cells (PBMCs) for the production of JCAR017. During JCAR017 production, participants will receive venetoclax as bridging anticancer therapy on a weekly ramp up dosing schedule until stopping one day prior to lymphodepletion. Treatment will include lymphodepleting chemotherapy followed by one dose of JCAR017 administered by intravenous (IV) injection, and the day after infusion venetoclax will be re-initiated.

Experimental: Phase 1 JCAR017 + ibrutinib
Subjects receiving ibrutinib at baseline will be assigned to receive JCAR017 (lisocabtagene maraleucel) at the recommended dose + ibrutinib
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.

Experimental: Phase 2 JCAR017 monotherapy
Subjects will receive JCAR017 (lisocabtagene maraleucel) at the recommended dose from the Phase 1 monotherapy arm
Biological: JCAR017 (lisocabtagene maraleucel)
Participants will undergo leukapheresis to isolate peripheral blood mononuclear cells (PBMCs) for the production of JCAR017. During JCAR017 production, participants will receive venetoclax as bridging anticancer therapy on a weekly ramp up dosing schedule until stopping one day prior to lymphodepletion. Treatment will include lymphodepleting chemotherapy followed by one dose of JCAR017 administered by intravenous (IV) injection, and the day after infusion venetoclax will be re-initiated.

Experimental: Phase 1 JCAR017 + venetoclax
Subjects will receive venetoclax as bridging anticancer therapy until lymphodepletion chemotherapy/ JCAR017 (lisocabtagene maraleucel) at the recommended dose from the Phase 1 monotherapy arm. After JCAR017 infusion subjects will receive venetoclax until Day 90.
Biological: JCAR017 (lisocabtagene maraleucel)
Participants will undergo leukapheresis to isolate peripheral blood mononuclear cells (PBMCs) for the production of JCAR017. During JCAR017 production, participants will receive venetoclax as bridging anticancer therapy on a weekly ramp up dosing schedule until stopping one day prior to lymphodepletion. Treatment will include lymphodepleting chemotherapy followed by one dose of JCAR017 administered by intravenous (IV) injection, and the day after infusion venetoclax will be re-initiated.

Biological: JCAR017 (lisocabtagene maraleucel) + venetoclax
Participants will undergo leukapheresis to isolate peripheral blood mononuclear cells (PBMCs) for the production of JCAR017. During JCAR017 production, participants will receive venetoclax as bridging anticancer therapy on a weekly ramp up dosing schedule until stopping one day prior to lymphodepletion. Treatment will include lymphodepleting chemotherapy followed by one dose of JCAR017 administered by intravenous (IV) injection, and the day after infusion venetoclax will be re-initiated.




Primary Outcome Measures :
  1. Phase 1 JCAR017 and ibrutinib combination dose escalation therapy arm: adverse events [ Time Frame: Through post treatment Day 90 ]
    Proportion of subjects experiencing adverse events

  2. Phase 1 JCAR017 and ibrutinib combination dose escalation therapy arm: laboratory abnormalities [ Time Frame: Through post treatment Day 90 ]
    Proportion of subjects experiencing laboratory abnormalities

  3. Phase 1 JCAR017 and ibrutinib combination dose expansion therapy arm [ Time Frame: Through post treatment up to Month 48 ]
    Proportion of subjects who have CR after treatment with JCAR017 + ibrutinib using iwCLL 2018 guidelines

  4. Phase 1 JCAR017 and venetoclax combination dose escalation therapy arm [ Time Frame: Through post treatment Day 90 ]
    Recommended dose of venetoclax in combination with JCAR017 based on assessment of data from each dose level of venetoclax

  5. Phase 1 JCAR017 and venetoclax combination dose escalation therapy arm: adverse events [ Time Frame: Through post treatment Day 90 ]
    Proportion of subjects experiencing adverse events

  6. Phase 1 JCAR017 and venetoclax combination dose escalation therapy arm: laboratory abnormalities [ Time Frame: Through post treatment Day 90 ]
    Proportion of subjects experiencing laboratory abnormalities

  7. Phase 1 JCAR017 and venetoclax combination dose expansion therapy arm [ Time Frame: Through post treatment up to Month 48 ]
    Proportion of subjects who have CR after treatment with JCAR017 + venetoclax using iwCLL 2018 guidelines


Secondary Outcome Measures :
  1. Phase 1 JCAR017 and ibrutinib combination dose expansion therapy arm: ORR [ Time Frame: Up to 48 months post treatment ]
    Defined as the rate of CR (including CRi)

  2. Phase 1 JCAR017 and ibrutinib combination dose expansion therapy arm: adverse events [ Time Frame: Up to 48 months post treatment ]
    Proportion of subjects experiencing adverse events

  3. Phase 1 JCAR017 and ibrutinib combination dose expansion therapy arm: laboratory abnormalities [ Time Frame: Up to 48 months post treatment ]
    Proportion of subjects experiencing laboratory abnormalities

  4. Phase 1 JCAR017 and ibrutinib combination dose expansion therapy arm: MRD negative response rate in peripheral blood [ Time Frame: Up to 48 months post treatment ]
    Proportion of subjects who achieve MRD CR

  5. Phase 1 JCAR017 and ibrutinib combination dose expansion therapy arm: MRD-negative CR rate in peripheral blood [ Time Frame: Up to 48 months post treatment ]
    Proportion of subjects who achieve MRD CR

  6. Phase 1 JCAR017 and ibrutinib combination dose expansion therapy arm: Duration of response (DOR) [ Time Frame: Up to 48 months post treatment ]
    Defined as the time from first response (CR, CRi, nPR, or PR) to the earlier date of PD or death due to any cause

  7. Phase 1 JCAR017 and ibrutinib combination dose expansion therapy arm: Duration of complete response (DoCR) [ Time Frame: Up to 48 months post treatment ]
    Defined as the time from first CR or CRi to the earlier date of PD or death due to any cause

  8. Phase 1 JCAR017 and ibrutinib combination dose expansion therapy arm: Time to response (TTR) [ Time Frame: Up to 48 months post treatment ]
    Defined as the interval from JCAR017 infusion to the first documentation of CR, CRi, nPR, or PR

  9. Phase 1 JCAR017 and ibrutinib combination dose expansion therapy arm: PFS [ Time Frame: Up to 48 months post treatment ]
    Defined as the time from JCAR017 infusion to the earlier date of PD or death due to any cause

  10. Phase 1 JCAR017 and ibrutinib combination dose expansion therapy arm: OS [ Time Frame: Up to 48 months post treatment ]
    Defined as the time from JCAR017 infusion to the date of death due to any cause

  11. Phase 1 JCAR017 and ibrutinib combination dose expansion therapy arm: Time to complete response (TTCR) [ Time Frame: Up to 48 months post treatment ]
    Defined as the interval from JCAR017 infusion to the first documentation of CR

  12. Phase 1 JCAR017 and venetoclax combination dose expansion therapy arm: ORR [ Time Frame: Through post treatment Day 90 ]
    Defined as the rate of CR (including CRi)

  13. Phase 1 JCAR017 and venetoclax combination dose expansion therapy arm: adverse events [ Time Frame: Up to 48 months post treatment ]
    Proportion of subject experiencing adverse events

  14. Phase 1 JCAR017 and venetoclax combination dose expansion therapy arm: lab abnormalities [ Time Frame: Up to 48 months post treatment ]
    Proportion of subjects experiencing laboratory abnormalities

  15. Phase 1 JCAR017 and venetoclax combination dose expansion therapy arm: MRD-negative response rate in peripheral blood [ Time Frame: Up to 48 months post treatment ]
    Proportion of subjects who achieve MRD CR

  16. Phase 1 JCAR017 and venetoclax combination dose escalation therapy arm: MRD-negative CR rate in peripheral blood [ Time Frame: Through post treatment Day 90 ]
    Proportion of subjects who achieve MRD CR

  17. Phase 1 JCAR017 and venetoclax combination dose expansion therapy arm: Duration of response (DOR) [ Time Frame: Up to 48 months post treatment ]
    Defined as the time from first response (CR, CRi, nPR, or PR) to the earlier date of PD or death due to any cause

  18. Phase 1 JCAR017 and venetoclax combination dose expansion therapy arm: Duration of complete response (DoCR) [ Time Frame: Up to 48 months post treatment ]
    Defined as the time from first CR or CRi to the earlier date of PD or death due to any cause

  19. Phase 1 JCAR017 and venetoclax combination dose expansion therapy arm: Time to response (TTR) [ Time Frame: Up to 48 months post treatment ]
    Defined as the interval from JCAR017 infusion to the first documentation of CR, CRi, nPR, or PR

  20. Phase 1 JCAR017 and venetoclax combination dose expansion therapy arm: Time to complete response (TTCR) [ Time Frame: Up to 48 months post treatment ]
    Defined as the interval from JCAR017 infusion to the first documentation of CR

  21. Phase 1 JCAR017 and venetoclax combination dose expansion therapy arm: PFS [ Time Frame: Up to 48 months post treatment ]
    Defined as the time from JCAR017 infusion to the earlier date of PD or death due to any cause

  22. Phase 1 JCAR017 and venetoclax combination dose expansion therapy arm: OS [ Time Frame: Up to 48 months post treatment ]
    Defined as the time from JCAR017 infusion to the date of death due to any cause



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.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.
  • Subjects in ibrutinib + JCAR017 combination cohort must have progressed on a BTKi and have received prior therapy with venetoclax
  • Subjects in venetoclax + JCAR017 combination cohort must:

    1. have failed at least 1 prior line of therapy, including failed BTKi therapy or have been deemed ineligible to receive BTKi
    2. be venetoclax naive (required for dose expansion) or
    3. if prior venetoclax (only for dose escalation)
    4. have no contraindictions to re-initiation of venetoclax based on prior intolerance and have had at least 6 months elapsed since the last dose of venetoclax, if either, best response was stable disease, or subject experienced disease progression on venetoclax, or within 6 months of venetoclax discontinuation
  • subjects in the venetoclax + JCAR017 combination must have hemoglobin >=9 g/dL, absolute neutrophil count >=500mm3 and platelets>= 75,000/mm3, unless cytopenias are judged by investigator to be due to CLL infiltration of the bone marrow
  • must have diagnosis of CLL or SLL with an indication for treatment based on the investigator's opinion and measurable disease (any of the following measurable lymph nodes ≥1.5 cm in the greatest transverse diameter and/or hepatomegaly or splenomegaly) and demonstration of CLL cells in the peripheral blood by flow cytometry

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
  • Use of any of the following medications or treatments within the noted time prior to leukapheresis lenalidomide or acalabrutinib within 1 day prior to leukapheresis experimental agents, including off-label use of approved drugs, within 4 weeks prior to leukapheresis.
  • Venous thrombosis or embolism requiring treatment but not managed on a stable regimen of anticoagulation
  • For subjects in the venetoclax + JCAR017 combination cohorts only, concomitant treatment with CYP3A moderate/strong inducers or moderate/strong inhibitors which cannot be discontinued

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): NCT03331198


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

Locations
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Sponsors and Collaborators
Juno Therapeutics, a Subsidiary of Celgene
Investigators
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Study Director: Heidi Gillenwater, MD Juno Therapeutics, Inc.
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Responsible Party: Juno Therapeutics, a Subsidiary of Celgene
ClinicalTrials.gov Identifier: NCT03331198    
Other Study ID Numbers: 017004
TRANSCEND-CLL-004 ( Other Identifier: Juno Therapeutics, Inc. )
First Posted: November 6, 2017    Key Record Dates
Last Update Posted: November 25, 2021
Last Verified: November 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Juno Therapeutics, a Subsidiary of Celgene:
TRANSCEND_CLL_004
Additional relevant MeSH terms:
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Lymphoma
Leukemia
Leukemia, Lymphoid
Leukemia, Lymphocytic, Chronic, B-Cell
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Leukemia, B-Cell
Venetoclax
Antineoplastic Agents