A Study to Compare the Efficacy and Safety of JCAR017 to Standard of Care in Adult Subjects With High-risk, Transplant-eligible Relapsed or Refractory Aggressive B-cell Non-Hodgkin Lymphomas (TRANSFORM)

• ClinicalTrials.gov Identifier: NCT03575351
• Recruitment Status: Completed
• First Posted: July 2, 2018
• Last Update Posted: November 15, 2023
• Sponsor: Celgene
• Information provided by (Responsible Party): Celgene

Tracking Information

• First Submitted Date: June 14, 2018
• First Posted Date: July 2, 2018
• Last Update Posted Date: November 15, 2023
• Actual Study Start Date: October 23, 2018
• Actual Primary Completion Date: October 23, 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: February 28, 2019)

Event-free survival (EFS) [ Time Frame: Approximately 3 years ]

Time from randomization to death from any cause, progressive disease (PD), failure to achieve complete response (CR) or partial response (PR), or start of new antineoplastic therapy due to efficacy concerns, whichever occurs first

Original Primary Outcome Measures (submitted: June 28, 2018)

Event-free survival (EFS) [ Time Frame: Approximately 3 years ]

Time from randomization to death from any cause, progressive disease (PD), as assessed by the independent review committee (IRC) or start of new antineoplastic therapy, whichever occurs first

Current Secondary Outcome Measures (submitted: January 13, 2020)

• Complete response rate (CRR) [ Time Frame: Approximately 3 years ]
  Percentage of subjects achieving a complete response (CR)
• Progression-free survival (PFS) [ Time Frame: Approximately 3 years ]
  Time from randomization to PD or death from any cause, whichever occurs first
• Overall survival (OS) [ Time Frame: Approximately 4.5 years ]
  Time from randomization to time of death due to any cause
• Overall response rate (ORR) [ Time Frame: Approximately 3 years ]
  Percentage of subjects achieving an objective response of partial response (PR) or better according to the Lugano Classification as assessed by IRC review
• Duration of response (DOR) [ Time Frame: Approximately 3 years ]
  Time from first response to disease progression, start of new antineoplastic therapy due to efficacy concerns or death from any cause
• PFS on next line of treatment (PFS-2) [ Time Frame: Approximately 3 years ]
  Time from randomization to second objective disease progression or death from any cause, whichever is first.
• Adverse Events (AEs) [ Time Frame: Approximately 3 years ]
  Type, frequency and severity of adverse events (AEs), serious adverse events (SAE), and laboratory abnormalities (overall and in clinical, histological and molecular subgroups)
• HRQoL using European Organisation for Research and Treatment of Cancer - Quality of Life C30 questionnaire (EORTC-QLQ-C30) [ Time Frame: Approximately 3 years ]
  European Organisation for Research and Treatment of Cancer - Quality of Life C30 questionnaire: The EORTC QLQ-C30 questionnaire will be used as a measure of health-related quality of life, fatigue, physical and cognitive functions.
• HRQoL parameters assessed by FACT-Lym "Additional concerns" subscale [ Time Frame: Approximately 3 years ]
  Functional Assessment of Cancer Therapy-Lymphoma "Additional concerns" subscale: Only the LYM subscale will be administered in this study. This scale addresses symptoms and functional limitations (15 item) that are important to lymphoma patients.
• Reasons for hospital resource utilization [ Time Frame: Approximately 3 years ]
  Will be assessed based on reasons for hospitalization
• Rate of hematopoietic stem cell transplant (HSCT) [ Time Frame: Approximately 3 years ]
  Rate of completion of HDCT and HSCT
• Frequency of hospital resource utilization [ Time Frame: Approximately 3 years ]
  Will be assessed based on frequency of hospitalizations calculated as, inpatient days, intensive care unit (ICU) days, outpatient visits days
• Hospital resource utilization (HRU) [ Time Frame: Approximately 3 years ]
  Will be assessed based on frequency of hospitalizations calculated as, inpatient days, intensive care unit (ICU) days, outpatient visits days and reasons for hospitalization

Original Secondary Outcome Measures (submitted: June 28, 2018)

• Complete response rate (CRR) [ Time Frame: Approximately 3 years ]
  Percentage of subjects achieving a complete response (CR) according to the Lugano Classification assessed by the IRC
• Progression-free survival (PFS) [ Time Frame: Approximately 3 years ]
  Time from randomization to PD, SD at 1st response assessment as per protocol schedule, as per IRC review or death from any cause, whichever occurs first
• Overall survival (OS) [ Time Frame: Approximately 4.5 years ]
  Time from randomization to time of death due to any cause
• Overall response rate (ORR) [ Time Frame: Approximately 3 years ]
  Percentage of subjects achieving an objective response of partial response (PR) or better according to the Lugano Classification as assessed by IRC review
• Duration of response (DOR) [ Time Frame: Approximately 3 years ]
  Time from first response to disease progression, start of new antineoplastic therapy or death from any cause
• PFS on next line of treatment (PFS-2) [ Time Frame: Approximately 3 years ]
  Time from randomization to second objective disease progression or death from any cause, whichever is first.
• Adverse Events (AEs) [ Time Frame: Approximately 3 years ]
  Type, frequency and severity of adverse events (AEs), serious adverse events (SAE), and laboratory abnormalities (overall and in clinical, histological and molecular subgroups)
• HRQoL parameters assessed by European Organisation for Research and Treatment of Cancer - Quality of Life C30 questionnaire (EORTC-QLQ-C30) [ Time Frame: Approximately 3 years ]
  European Organisation for Research and Treatment of Cancer - Quality of Life C30 questionnaire: The EORTC QLQ-C30 questionnaire will be used as a measure of health-related quality of life.
• HRQoL parameters assessed by EQ-5D-5L [ Time Frame: Approximately 3 years ]
  European Quality of Life-5 Dimensions health state classifier to 5 Levels questionnaire: EQ-5D is a standardized measure of health status developed by the EuroQol Group to provide a simple, generic measure of health for clinical and economic appraisal.
• HRQoL parameters assessed by FACT-Lym "Additional concerns" subscale [ Time Frame: Approximately 3 years ]
  Functional Assessment of Cancer Therapy-Lymphoma "Additional concerns" subscale: Only the LYM subscale will be administered in this study. This scale addresses symptoms and functional limitations (15 item) that are important to lymphoma patients.
• Reasons for hospital resource utilization [ Time Frame: Approximately 3 years ]
  Will be assessed based on reasons for hospitalization
• Rate of hematopoietic stem cell transplant (HSCT) [ Time Frame: Approximately 3 years ]
  Rate of completion of HDCT and HSCT
• Frequency of hospital resource utilization [ Time Frame: Approximately 3 years ]
  Will be assessed based on frequency of hospitalizations calculated as, inpatient days, intensive care unit (ICU) days, outpatient visits days

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Study to Compare the Efficacy and Safety of JCAR017 to Standard of Care in Adult Subjects With High-risk, Transplant-eligible Relapsed or Refractory Aggressive B-cell Non-Hodgkin Lymphomas
• Official Title: A Global Randomized Multicenter Phase 3 Trial of JCAR017 Compared to Standard of Care in Adult Subjects With High-risk, Second-line, Transplant-eligible Relapsed or Refractory Aggressive B-cell Non-Hodgkin Lymphomas (TRANSFORM).

Brief Summary

The study will be conducted in compliance with the International Council for Harmonisation (ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use/Good Clinical Practice (GCP) and applicable regulatory requirements.

This is a randomized, open-label, parallel-group, multi-center trial in adult subjects with Relapsed or refractory (R/R) aggressive Non-Hodgkin lymphoma (NHL) to compare safety and efficacy between the standard of care (SOC) strategy versus JCAR017 (also known as lisocabtagene maraleucel or liso-cel). Subjects will be randomized to either receive SOC (Arm A) or to receive JCAR017 (Arm B).

All subjects randomized to Arm A will receive Standard of care (SOC) salvage therapy (R-DHAP, RICE or R-GDP) as per physician's choice before proceeding to High dose chemotherapy (HDCT) and Hematopoietic stem cell transplant (HSCT).

Subjects from Arm A may be allowed to cross over and receive JCAR017 upon confirmation of an EFS event.

Subjects randomized to Arm B will receive Lymphodepleting (LD) chemotherapy followed by JCAR017 infusion.

• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Lymphoma, Non-Hodgkin

Intervention

• Drug: Standard of Care
  Standard of Care
• Genetic: JCAR017
  JCAR017
  Other Name: lisocabtagene maraleucel or liso-cel

Study Arms

• Active Comparator: Arm A - Standard of Care (SOC)
  Subjects should receive SOC (R-DHAP, R-ICE or R-GDP) followed by HDCT (BEAM) and HSCT. Standard of care regimen will be administered as per investigator decision.
  Intervention: Drug: Standard of Care
• Experimental: Arm B - JCAR017
  Lymphodepleting chemotherapy with intravenous (IV) fludarabine (30 mg/m2/day for 3 days) plus cyclophosphamide IV (300 mg/m2/day for 3 days) (flu/cy) concurrently followed by JCAR017 infusion.
  Intervention: Genetic: JCAR017

Publications *

• Kamdar M, Solomon SR, Arnason J, Johnston PB, Glass B, Bachanova V, Ibrahimi S, Mielke S, Mutsaers P, Hernandez-Ilizaliturri F, Izutsu K, Morschhauser F, Lunning M, Maloney DG, Crotta A, Montheard S, Previtali A, Stepan L, Ogasawara K, Mack T, Abramson JS; TRANSFORM Investigators. Lisocabtagene maraleucel versus standard of care with salvage chemotherapy followed by autologous stem cell transplantation as second-line treatment in patients with relapsed or refractory large B-cell lymphoma (TRANSFORM): results from an interim analysis of an open-label, randomised, phase 3 trial. Lancet. 2022 Jun 18;399(10343):2294-2308. doi: 10.1016/S0140-6736(22)00662-6. Erratum In: Lancet. 2022 Jul 16;400(10347):160.
• Ernst M, Oeser A, Besiroglu B, Caro-Valenzuela J, Abd El Aziz M, Monsef I, Borchmann P, Estcourt LJ, Skoetz N, Goldkuhle M. Chimeric antigen receptor (CAR) T-cell therapy for people with relapsed or refractory diffuse large B-cell lymphoma. Cochrane Database Syst Rev. 2021 Sep 13;9(9):CD013365. doi: 10.1002/14651858.CD013365.pub2.
• Kambhampati S, Hunter B, Varnavski A, Fakhri B, Kaplan L, Ai WZ, Pampaloni M, Huang CY, Martin T 3rd, Damon L, Andreadis CB. Ofatumumab, Etoposide, and Cytarabine Intensive Mobilization Regimen in Patients with High-risk Relapsed/Refractory Diffuse Large B-Cell Lymphoma Undergoing Autologous Stem Cell Transplantation. Clin Lymphoma Myeloma Leuk. 2021 Apr;21(4):246-256.e2. doi: 10.1016/j.clml.2020.11.005. Epub 2020 Nov 11.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: March 12, 2022): 184
• Original Estimated Enrollment (submitted: June 28, 2018): 182
• Actual Study Completion Date: October 23, 2023
• Actual Primary Completion Date: October 23, 2023 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Subject is ≥ 18 years and ≤ 75 years of age at the time of signing the informed consent form (ICF).
2. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1.
3. Histologically proven diffuse large B-cell lymphoma (DLBCL) NOS (de novo or transformed indolent NHL), high grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements with DLBCL histology (double/triple-hit lymphoma [DHL/THL]), primary mediastinal (thymic) large B-cell lymphoma (PMBCL), T cell/histiocyte-rich large B-cell lymphoma (THRBCL) or follicular lymphoma grade 3B. Enough tumor material must be available for confirmation by central pathology.
4. Refractory or relapsed within 12 months from CD20 antibody and anthracycline containing first line therapy.
5. [18F] fluorodeoxyglucose (FDG) positron emission tomography (PET) positive lesion at screening. (Deauville score 4 or 5)
6. Adequate organ function
7. Participants must agree to use effective contraception

Exclusion Criteria:

1. Subjects not eligible for hematopoietic stem cell transplantation (HSCT).
2. Subjects planned to undergo allogeneic stem cell transplantation.
3. Subjects with, primary cutaneous large B-cell lymphoma, EBV (Epstein-Barr virus) positive DLBCL, Burkitt lymphoma or transformation from chronic lymphocytic leukemia/small lymphocytic lymphoma (Richter transformation).

4. Subjects with prior history of malignancies, other than aggressive R/R NHL, unless the subject has been free of the disease for ≥ 2 years with the exception of the following noninvasive malignancies:

   • Basal cell carcinoma of the skin
   • Squamous cell carcinoma of the skin
   • Carcinoma in situ of the cervix
   • Carcinoma in situ of the breast
   • Incidental histologic finding of prostate cancer (T1a or T1b using the TNM [tumor, nodes, metastasis] clinical staging system) or prostate cancer that is curative.
   • Other completely resected stage 1 solid tumor with low risk for recurrence
5. Treatment with any prior gene therapy product.
6. Subjects who have received previous CD19-targeted therapy.
7. Subjects with active hepatitis B, or active hepatitis C are excluded. Subjects with negative polymerase chain reaction (PCR) assay for viral load for hepatitis B or C are permitted. Subjects positive for hepatitis B surface antigen and/or anti-hepatitis B core antibody with negative viral load are eligible and should be considered for prophylactic antiviral therapy. Subjects with a history of or active human immunodeficiency virus (HIV) are excluded.
8. Subjects with uncontrolled systemic fungal, bacterial, viral or other infection (including tuberculosis) despite appropriate antibiotics or other treatment.
9. Active autoimmune disease requiring immunosuppressive therapy.
10. History of any one of the following cardiovascular conditions within the past 6 months prior to signing the ICF: 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 central nervous system (CNS) pathology
12. Pregnant or nursing (lactating) women.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 75 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Belgium, Finland, France, Germany, Italy, Japan, Netherlands, Spain, Sweden, Switzerland, United Kingdom, United States
• Removed Location Countries: Canada

Administrative Information

• NCT Number: NCT03575351
• Other Study ID Numbers: JCAR017-BCM-003; U1111-1213-1944 ( Registry Identifier: WHO ); 2018-000929-32 ( EudraCT Number )
• 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: Not Provided
• Current Responsible Party: Celgene
• Original Responsible Party: Same as current
• Current Study Sponsor: Celgene
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Bristol-Myers Squibb; Bristol-Myers Squibb

• PRS Account: Celgene
• Verification Date: November 2023