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

Sponsor

Juno Therapeutics, a Subsidiary of Celgene (Industry)

Overall Status

Active, not recruiting

CT.gov ID

NCT03331198

Collaborator

(none)

259

Enrollment

Locations

Arms

104.5

Anticipated Duration (Months)

7.6

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

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

Study Design

Study Type:

Interventional

Anticipated 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 dosePhase 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 :

Nov 27, 2017

Anticipated Primary Completion Date :

Jul 29, 2026

Anticipated Study Completion Date :

Aug 14, 2026

Arms and Interventions

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.

Outcome Measures

Primary Outcome Measures

Phase 1 JCAR017 and ibrutinib combination dose escalation therapy arm: adverse events [Through post treatment Day 90]
Proportion of subjects experiencing adverse events
Phase 1 JCAR017 and ibrutinib combination dose escalation therapy arm: laboratory abnormalities [Through post treatment Day 90]
Proportion of subjects experiencing laboratory abnormalities
Phase 1 JCAR017 and ibrutinib combination dose expansion therapy arm [Through post treatment up to Month 48]
Proportion of subjects who have CR after treatment with JCAR017 + ibrutinib using iwCLL 2018 guidelines
Phase 1 JCAR017 and venetoclax combination dose escalation therapy arm [Through post treatment Day 90]
Recommended dose of venetoclax in combination with JCAR017 based on assessment of data from each dose level of venetoclax
Phase 1 JCAR017 and venetoclax combination dose escalation therapy arm: adverse events [Through post treatment Day 90]
Proportion of subjects experiencing adverse events
Phase 1 JCAR017 and venetoclax combination dose escalation therapy arm: laboratory abnormalities [Through post treatment Day 90]
Proportion of subjects experiencing laboratory abnormalities
Phase 1 JCAR017 and venetoclax combination dose expansion therapy arm [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

Phase 1 JCAR017 and ibrutinib combination dose expansion therapy arm: ORR [Up to 48 months post treatment]
Defined as the rate of CR (including CRi)
Phase 1 JCAR017 and ibrutinib combination dose expansion therapy arm: adverse events [Up to 48 months post treatment]
Proportion of subjects experiencing adverse events
Phase 1 JCAR017 and ibrutinib combination dose expansion therapy arm: laboratory abnormalities [Up to 48 months post treatment]
Proportion of subjects experiencing laboratory abnormalities
Phase 1 JCAR017 and ibrutinib combination dose expansion therapy arm: MRD negative response rate in peripheral blood [Up to 48 months post treatment]
Proportion of subjects who achieve MRD CR
Phase 1 JCAR017 and ibrutinib combination dose expansion therapy arm: MRD-negative CR rate in peripheral blood [Up to 48 months post treatment]
Proportion of subjects who achieve MRD CR
Phase 1 JCAR017 and ibrutinib combination dose expansion therapy arm: Duration of response (DOR) [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
Phase 1 JCAR017 and ibrutinib combination dose expansion therapy arm: Duration of complete response (DoCR) [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
Phase 1 JCAR017 and ibrutinib combination dose expansion therapy arm: Time to response (TTR) [Up to 48 months post treatment]
Defined as the interval from JCAR017 infusion to the first documentation of CR, CRi, nPR, or PR
Phase 1 JCAR017 and ibrutinib combination dose expansion therapy arm: PFS [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
Phase 1 JCAR017 and ibrutinib combination dose expansion therapy arm: OS [Up to 48 months post treatment]
Defined as the time from JCAR017 infusion to the date of death due to any cause
Phase 1 JCAR017 and ibrutinib combination dose expansion therapy arm: Time to complete response (TTCR) [Up to 48 months post treatment]
Defined as the interval from JCAR017 infusion to the first documentation of CR
Phase 1 JCAR017 and venetoclax combination dose expansion therapy arm: ORR [Through post treatment Day 90]
Defined as the rate of CR (including CRi)
Phase 1 JCAR017 and venetoclax combination dose expansion therapy arm: adverse events [Up to 48 months post treatment]
Proportion of subject experiencing adverse events
Phase 1 JCAR017 and venetoclax combination dose expansion therapy arm: lab abnormalities [Up to 48 months post treatment]
Proportion of subjects experiencing laboratory abnormalities
Phase 1 JCAR017 and venetoclax combination dose expansion therapy arm: MRD-negative response rate in peripheral blood [Up to 48 months post treatment]
Proportion of subjects who achieve MRD CR
Phase 1 JCAR017 and venetoclax combination dose escalation therapy arm: MRD-negative CR rate in peripheral blood [Through post treatment Day 90]
Proportion of subjects who achieve MRD CR
Phase 1 JCAR017 and venetoclax combination dose expansion therapy arm: Duration of response (DOR) [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
Phase 1 JCAR017 and venetoclax combination dose expansion therapy arm: Duration of complete response (DoCR) [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
Phase 1 JCAR017 and venetoclax combination dose expansion therapy arm: Time to response (TTR) [Up to 48 months post treatment]
Defined as the interval from JCAR017 infusion to the first documentation of CR, CRi, nPR, or PR
Phase 1 JCAR017 and venetoclax combination dose expansion therapy arm: Time to complete response (TTCR) [Up to 48 months post treatment]
Defined as the interval from JCAR017 infusion to the first documentation of CR
Phase 1 JCAR017 and venetoclax combination dose expansion therapy arm: PFS [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
Phase 1 JCAR017 and venetoclax combination dose expansion therapy arm: OS [Up to 48 months post treatment]
Defined as the time from JCAR017 infusion to the date of death due to any cause

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Diagnosis of:

CLL with an indication for treatment based on the Investigator's opinion and measurable disease, or
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:

Subjects with CLL or SLL and high-risk features must have failed at least 2 lines of prior therapy.
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:

be receiving ibrutinib and progressing at the time of study enrollment
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
have BTK or PLCgamma2 mutations per local laboratory assessment, with or without progression on ibrutinib
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:

Serum creatinine ≤ 1.5 × age-adjusted upper limit of normal (ULN) OR calculated creatinine clearance > 30 mL/min
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)
Adequate pulmonary function, defined as ≤ Common Terminology Criteria for Adverse Events (CTCAE) Grade 1 dyspnea and saturated oxygen (SaO2) ≥ 92% on room air
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:

have failed at least 1 prior line of therapy, including failed BTKi therapy or have been deemed ineligible to receive BTKi
be venetoclax naive (required for dose expansion) or
if prior venetoclax (only for dose escalation)
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:

Alemtuzumab within 6 months prior to leukapheresis
Allogeneic hematopoietic stem cell transplant within 100 days prior to leukapheresis
Cladribine within 3 months prior to leukapheresis
Donor lymphocyte infusions (DLI) within 2 months prior to leukapheresis
Radiation including large bone marrow fields such as sternum or pelvis within 6 weeks prior to leukapheresis
Fludarabine within 4 weeks prior to leukapheresis
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
Cyclophosphamide, ifosfamide, bendamustine, chlorambucil, or melphalan within 2 weeks prior to leukapheresis
Therapeutic doses of corticosteroids (defined as > 20 mg/day prednisone or equivalent) within 7 days prior to leukapheresis
Anti-CD20 monoclonal antibodies within 7 days prior to leukapheresis
Venetoclax within 4 days prior to leukapheresis
Idelalisib or duvelisib within 2 days prior to leukapheresis
Lenalidomide within 1 day prior to leukapheresis
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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama at Birmingham	Birmingham	Alabama	United States	35294
2	Banner MD Anderson Cancer Center	Gilbert	Arizona	United States	85234
3	City of Hope	Duarte	California	United States	91010
4	UC San Diego Moores Cancer Center	La Jolla	California	United States	92093
5	University of California, Los Angeles	Los Angeles	California	United States	90095
6	University of California, San Francisco	San Francisco	California	United States	94143
7	Georgetown University Medical Center	Washington	District of Columbia	United States	20007
8	Mayo Clinic	Jacksonville	Florida	United States	32224
9	The Blood and Marrow Transplant Group of Georgia (BMTGA)	Atlanta	Georgia	United States	30342
10	Northwestern University	Chicago	Illinois	United States	60611
11	University of Chicago Medical Center	Chicago	Illinois	United States	60637
12	Massachusetts General Hospital	Boston	Massachusetts	United States	02114
13	Beth Israel Deaconess Medical Center	Boston	Massachusetts	United States	02215
14	University of Michigan Comprehensive Cancer Center	Ann Arbor	Michigan	United States	48109-5362
15	Barbara Ann Karmanos Cancer Institute	Detroit	Michigan	United States	48201
16	Mayo Clinic	Rochester	Minnesota	United States	55905
17	University of Nebraska Medical Center	Omaha	Nebraska	United States	68198
18	Hackensack University Medical Center	Hackensack	New Jersey	United States	07601
19	Rutgers Cancer Institute of New Jersey	New Brunswick	New Jersey	United States	08903
20	Weill Cornell Medical College	New York	New York	United States	10065
21	Duke University Medical Center	Durham	North Carolina	United States	27710
22	University Hospitals Seidman Cancer Center (Case Western)	Cleveland	Ohio	United States	44106-5061
23	University of Oklahoma Health Sciences Center (Stephenson Cancer Center)	Oklahoma City	Oklahoma	United States	73104
24	University of Pennsylvania Perelman Center for Advanced Medicine	Philadelphia	Pennsylvania	United States	19104
25	Thomas Jefferson University	Philadelphia	Pennsylvania	United States	19107
26	UPMC Hillman Cancer Center	Pittsburgh	Pennsylvania	United States	15232
27	Baylor University Medical Center	Dallas	Texas	United States	75246
28	University of Texas Southwestern Medical Center	Dallas	Texas	United States	75390
29	The University of Texas MD Anderson Cancer Center	Houston	Texas	United States	77030
30	Huntsman Cancer Institute	Salt Lake City	Utah	United States	84112
31	Fred Hutchinson Cancer Research Center	Seattle	Washington	United States	98109
32	Local Institution - 0018	Seattle	Washington	United States	98109
33	Local Institution - 0055	Milwaukee	Wisconsin	United States	53226-3522
34	Medical College of Wisconsin	Milwaukee	Wisconsin	United States	53226

Sponsors and Collaborators

Juno Therapeutics, a Subsidiary of Celgene

Investigators

Study Director: Bristol-Myers Squibb, Bristol-Myers Squibb

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

Publications

None provided.

Responsible Party:

Juno Therapeutics, a Subsidiary of Celgene

ClinicalTrials.gov Identifier:

NCT03331198

Other Study ID Numbers:

017004
TRANSCEND-CLL-004

First Posted:

Nov 6, 2017

Last Update Posted:

Aug 24, 2022

Last Verified:

Aug 1, 2022

Individual Participant Data (IPD) Sharing Statement:

Undecided

Plan to Share IPD:

Undecided

Studies a U.S. FDA-regulated Drug Product:

Yes

Studies a U.S. FDA-regulated Device Product:

Keywords provided by Juno Therapeutics, a Subsidiary of Celgene

TRANSCEND_CLL_004

Additional relevant MeSH terms:

Lymphoma

Leukemia

Leukemia, Lymphoid

Leukemia, Lymphocytic, Chronic, B-Cell

Venetoclax

Study Results

No Results Posted as of Aug 24, 2022