Clinical trial NCT03575351: 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).
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Lymphoma, Non-Hodgkin
Keywords: Non-Hodgkin Lymphomas
DLBCL
Efficacy
Safety
JCAR017
Liso-cel
High-Risk
Relapsed
Refractory
B-cell NHL
Lead sponsor: Celgene
Sponsor class: INDUSTRY
First posted: 2018-07-02
Enrollment: 184
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


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.

Primary outcomes:
measure: Event-free survival (EFS)
timeFrame: Approximately 3 years
Secondary outcomes:
measure: Complete response rate (CRR)
timeFrame: Approximately 3 years
measure: Progression-free survival (PFS)
timeFrame: Approximately 3 years
measure: Overall survival (OS)
timeFrame: Approximately 4.5 years
measure: Overall response rate (ORR)
timeFrame: Approximately 3 years
measure: Duration of response (DOR)
timeFrame: Approximately 3 years
measure: PFS on next line of treatment (PFS-2)
timeFrame: Approximately 3 years
measure: Adverse Events (AEs)
timeFrame: Approximately 3 years
measure: HRQoL using European Organisation for Research and Treatment of Cancer - Quality of Life C30 questionnaire (EORTC-QLQ-C30)
timeFrame: Approximately 3 years
measure: HRQoL parameters assessed by FACT-Lym "Additional concerns" subscale
timeFrame: Approximately 3 years
measure: Reasons for hospital resource utilization
timeFrame: Approximately 3 years
measure: Rate of hematopoietic stem cell transplant (HSCT)
timeFrame: Approximately 3 years
measure: Frequency of hospital resource utilization
timeFrame: Approximately 3 years
measure: Hospital resource utilization (HRU)
timeFrame: Approximately 3 years
Other outcomes:
Locations:
city: Scottsdale
country: United States
facility: Local Institution - 129
state: Arizona
city: Scottsdale
country: United States
facility: Local Institution - 116
state: Arizona
city: San Francisco
country: United States
facility: Local Institution - 115
state: California
city: Aurora
country: United States
facility: Local Institution - 106
state: Colorado
city: Jacksonville
country: United States
facility: Mayo Clinic - Jacksonville
state: Florida
city: Tampa
country: United States
facility: Local Institution - 126
state: Florida
city: Atlanta
country: United States
facility: Local Institution - 108
state: Georgia
city: Atlanta
country: United States
facility: Local Institution - 107
state: Georgia
city: Chicago
country: United States
facility: Local Institution - 122
state: Illinois
city: Maywood
country: United States
facility: Loyola University Medical Center Cardinal Bernardin Cancer Center
state: Illinois
city: Boston
country: United States
facility: Local Institution - 102
state: Massachusetts
city: Boston
country: United States
facility: Local Institution - 104
state: Massachusetts
city: Ann Arbor
country: United States
facility: Local Institution - 120
state: Michigan
city: Detroit
country: United States
facility: Local Institution - 119
state: Michigan
city: Minneapolis
country: United States
facility: Local Institution - 112
state: Minnesota
city: Rochester
country: United States
facility: Local Institution - 103
state: Minnesota
city: Omaha
country: United States
facility: Local Institution - 100
state: Nebraska
city: Hackensack
country: United States
facility: Local Institution - 121
state: New Jersey
city: Buffalo
country: United States
facility: Local Institution - 111
state: New York
city: New York
country: United States
facility: Local Institution - 117
state: New York
city: Charlotte
country: United States
facility: Local Institution - 125
state: North Carolina
city: Oklahoma City
country: United States
facility: Local Institution - 127
state: Oklahoma
city: Portland
country: United States
facility: Local Institution - 101
state: Oregon
city: Pittsburgh
country: United States
facility: Local Institution - 123
state: Pennsylvania
city: Dallas
country: United States
facility: Local Institution - 109
state: Texas
city: Houston
country: United States
facility: Local Institution - 124
state: Texas
city: Richmond
country: United States
facility: Local Institution - 114
state: Virginia
city: Seattle
country: United States
facility: Local Institution - 110
state: Washington
city: Gent
country: Belgium
facility: Local Institution - 350
city: Helsinki
country: Finland
facility: Local Institution - UNK 25
city: Lille
country: France
facility: Local Institution - 401
city: Marseille cedex
country: France
facility: Local Institution - 400
city: Pierre Benite
country: France
facility: Local Institution - 403
city: Villejuif CEDEX
country: France
facility: Local Institution - 402
city: Dresden
country: Germany
facility: Local Institution - 455
state: Saxony
city: Berlin
country: Germany
facility: Local Institution - 451
city: Hamburg
country: Germany
facility: Local Institution - 452
city: Köln
country: Germany
facility: Local Institution - 450
city: Muenster
country: Germany
facility: Local Institution - 454
city: München
country: Germany
facility: Local Institution - 453
city: Rome
country: Italy
facility: Local Institution - 500
city: Rozzano (MI)
country: Italy
facility: Local Institution - 501
city: Torino
country: Italy
facility: Local Institution - 502
city: Osaka
country: Japan
facility: Local Institution - 203
state: Osaka-shi
city: Chuo-ku
country: Japan
facility: Local Institution - 200
state: Tokyo
city: Minato-ku
country: Japan
facility: Local Institution - 201
state: Tokyo
city: Bunkyo-ku
country: Japan
facility: Local Institution - 202
city: Rotterdam
country: Netherlands
facility: Local Institution - 550
city: Barcelona
country: Spain
facility: Local Institution - 600
city: Madrid
country: Spain
facility: Local Institution - 601
city: Stockholm
country: Sweden
facility: Local Institution - 650
city: Bern
country: Switzerland
facility: Local Institution - 700
city: Southampton
country: United Kingdom
facility: Local Institution - 751
state: Hampshire
city: London
country: United Kingdom
facility: Local Institution - 750
Study officials:
affiliation: Bristol-Myers Squibb
name: Bristol-Myers Squibb
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.
citation: Thiruvengadam SK, 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.