TRANSFORM: 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

Sponsor

Celgene (Industry)

Overall Status

Active, not recruiting

CT.gov ID

NCT03575351

Collaborator

(none)

184

Enrollment

Locations

Arms

61.5

Anticipated Duration (Months)

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

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

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.

Condition or Disease	Intervention/Treatment	Phase
Lymphoma, Non-Hodgkin	Drug: Standard of Care Genetic: JCAR017	Phase 3

Study Design

Study Type:

Interventional

Actual Enrollment :

184 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

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).

Actual Study Start Date :

Oct 23, 2018

Anticipated Primary Completion Date :

Dec 8, 2023

Anticipated Study Completion Date :

Dec 8, 2023

Arms and Interventions

Arm	Intervention/Treatment
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.	Drug: Standard of Care 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.	Genetic: JCAR017 JCAR017 Other Names: lisocabtagene maraleucel or liso-cel

Arm

Intervention/Treatment

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.

Drug: Standard of Care

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.

Genetic: JCAR017

JCAR017

Other Names:

lisocabtagene maraleucel or liso-cel

Outcome Measures

Primary Outcome Measures

Event-free survival (EFS) [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

Secondary Outcome Measures

Complete response rate (CRR) [Approximately 3 years]
Percentage of subjects achieving a complete response (CR)
Progression-free survival (PFS) [Approximately 3 years]
Time from randomization to PD or death from any cause, whichever occurs first
Overall survival (OS) [Approximately 4.5 years]
Time from randomization to time of death due to any cause
Overall response rate (ORR) [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) [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) [Approximately 3 years]
Time from randomization to second objective disease progression or death from any cause, whichever is first.
Adverse Events (AEs) [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) [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 [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 [Approximately 3 years]
Will be assessed based on reasons for hospitalization
Rate of hematopoietic stem cell transplant (HSCT) [Approximately 3 years]
Rate of completion of HDCT and HSCT
Frequency of hospital resource utilization [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) [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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 75 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Subject is ≥ 18 years and ≤ 75 years of age at the time of signing the informed consent form (ICF).
Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1.
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.
Refractory or relapsed within 12 months from CD20 antibody and anthracycline containing first line therapy.
[18F] fluorodeoxyglucose (FDG) positron emission tomography (PET) positive lesion at screening. (Deauville score 4 or 5)
Adequate organ function
Participants must agree to use effective contraception

Exclusion Criteria:

Subjects not eligible for hematopoietic stem cell transplantation (HSCT).
Subjects planned to undergo allogeneic stem cell transplantation.
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).
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

Treatment with any prior gene therapy product.
Subjects who have received previous CD19-targeted therapy.
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.
Subjects with uncontrolled systemic fungal, bacterial, viral or other infection (including tuberculosis) despite appropriate antibiotics or other treatment.
Active autoimmune disease requiring immunosuppressive therapy.
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.
History or presence of clinically relevant central nervous system (CNS) pathology
Pregnant or nursing (lactating) women.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Mayo Clinic Hospital	Phoenix	Arizona	United States	85054
2	HonorHealth	Scottsdale	Arizona	United States	85258
3	University of California San Francisco	San Francisco	California	United States	94143
4	University of Colorado Cancer Center	Aurora	Colorado	United States	80045
5	Mayo Clinic - Jacksonville	Jacksonville	Florida	United States	32224
6	H. Lee Moffitt Cancer Center and Research Institute	Tampa	Florida	United States	33612
7	Emory University	Atlanta	Georgia	United States	30322
8	Local Institution - 107	Atlanta	Georgia	United States	30342
9	Northside Hospital	Atlanta	Georgia	United States	30342
10	Northwestern University-Feinberg School of Medicine	Chicago	Illinois	United States	60611
11	Loyola University Medical Center Cardinal Bernardin Cancer Center	Maywood	Illinois	United States	60153
12	Local Institution - 102	Boston	Massachusetts	United States	02114
13	Massachusetts General Hospital / Dana-Farber Cancer Institute	Boston	Massachusetts	United States	02114
14	Beth Israel Deaconess Medical Center	Boston	Massachusetts	United States	02215
15	University of Michigan	Ann Arbor	Michigan	United States	48109
16	Barbara Ann Karmanos Cancer Center	Detroit	Michigan	United States	48201
17	University of Minnesota	Minneapolis	Minnesota	United States	55455
18	Local Institution - 103	Rochester	Minnesota	United States	55905-0001
19	Mayo Clinic - Rochester	Rochester	Minnesota	United States	55905
20	University of Nebraska Medical Center	Omaha	Nebraska	United States	68198-6805
21	John Theurer Cancer Center at Hackensack University Medical Center	Hackensack	New Jersey	United States	07601
22	Local Institution - 121	Hackensack	New Jersey	United States	07601
23	Roswell Park Cancer Institute	Buffalo	New York	United States	14263
24	Memorial Sloan Kettering Cancer Center	New York	New York	United States	10065
25	Levine Cancer Institute	Charlotte	North Carolina	United States	28204
26	University of Oklahoma Peggy and Charles Stephenson Cancer Center	Oklahoma City	Oklahoma	United States	73104
27	Oregon Health and Science University	Portland	Oregon	United States	97239
28	Hillman Cancer Institute at UPMC	Pittsburgh	Pennsylvania	United States	15232
29	Baylor University Medical Center	Dallas	Texas	United States	75246
30	The University of Texas - MD Anderson Cancer Center	Houston	Texas	United States	77030
31	Virginia Commonwealth University	Richmond	Virginia	United States	23298
32	Fred Hutchinson Cancer Research Center	Seattle	Washington	United States	98109-4417
33	University Hospital Ghent	Ghent		Belgium	9000
34	CHRU-Hopital Claude Huriez	Lille		France	59037
35	Institut Paoli Calmette Hematologie	Marseille cedex		France	13273
36	Centre Hospitalier Lyon Sud	Pierre Benite		France	69495
37	Gustave Roussy	Villejuif CEDEX		France	94805
38	Local Institution - 455	Dresden	Saxony	Germany	01307
39	Local Institution - 451	Berlin		Germany	13125
40	Robert-Rössle-Klinik im HELIOS Klinikum Berlin-Buch Klinik für Hämatologie, Onkologie u. Tumorimmuno	Berlin		Germany	13125
41	Universitaetsklinikum Carl Gustav Carus	Dresden		Germany	01307
42	Universitaetsklinik Hamburg - Eppendorf	Hamburg		Germany	20246
43	Universitat zu Koln	Köln		Germany	50937
44	Universitatsklinik Muenster	Muenster		Germany	48149
45	LMU Klinikum der Universitat	München		Germany	81377
46	La Sapienza, University of Rome	Rome		Italy	00161
47	Istituto Clinico Humanitas	Rozzano (MI)		Italy	20089
48	Azienda Ospedaliera Citta della Salute e della Scienza di Torino	Torino		Italy	10126
49	Local Institution - 203	Osaka	Osaka-shi	Japan	545-8586
50	Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital	Bunkyo-ku		Japan	113-8677
51	National Cancer Center Hospital	Chuo-ku		Japan	104-0045
52	Toranomon Hospital	Minato-ku		Japan	105-8470
53	Osaka City University Hospital	Osaka		Japan	545-8586
54	Erasmus Medical Center-Daniel den Hoed	Rotterdam		Netherlands	3075 EA
55	Local Institution - 550	Rotterdam		Netherlands	3075 EA
56	Hospital Clinic i Provincial de Barcelona - ICMHO	Barcelona		Spain	08036
57	Hospital Universitario 12 de Octubre	Madrid		Spain	28041
58	Karolinska Universitetssjukhuset - Huddinge	Stockholm		Sweden	SE-141 86
59	Inselspital Bern	Bern		Switzerland	CH-3010
60	University College Hospital Macmillan Cancer Centre	London		United Kingdom	WC1E 6AG
61	Local Institution - 751	Southampton		United Kingdom	SO16 6YD
62	University Hospital Southampton NHS Foundation Trust - Southampton General Hospital	Southampton		United Kingdom	SO16 6YD