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

Celgene184 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

184

Conditions

Lymphoma, Non-Hodgkin

Interventions

Eligibility

Sex: ALLMin age: 18 YearsMax age: 75 Years

Medical Language ↔ Plain English

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.

Locations (54)

Local Institution - 129

Scottsdale, Arizona, United States

Local Institution - 116

Scottsdale, Arizona, United States

Local Institution - 115

San Francisco, California, United States

Local Institution - 106

Aurora, Colorado, United States

Mayo Clinic - Jacksonville

Jacksonville, Florida, United States

Outcomes

Primary Outcomes

Event-free Survival (EFS) Per Independent Review Committee (IRC)

Time from randomization to death, progressive disease (PD), failure to achieve complete response (CR) or partial response (PR) by 9 weeks or start of new antineoplastic therapy, whichever occurs first. CR: Target nodes masses must regress to ≤ 1.5cm in LDi, no extralymphatic sites, no new lesions. PR: ≥ 50% decrease in sum of diameters of up to 6 target nodes and extranodal sites, no new lesions, spleen must have regressed \> 50% in length. PD: LDi \> 1.5cm, increase by ≥ 50% from PPD nadir, an increase in LDi or SDi from nadir, 0.5 cm for lesions ≤ 2cm, 1.0cm for lesions \> 2cm. Complete metabolic response: Lymph nodes score 1, 2, 3 with/without residual mass on 5-point scale, no new lesions, no FDG-avid disease. Partial metabolic response: Lymph nodes score 4 or 5, reduced uptake from baseline, no new lesions, residual uptake higher than normal, reduced from baseline. Progressive metabolic disease: Score 4 or 5 with an increase in uptake intensity from baseline and/or new FDG-avid.

Time frame: From randomization to death from any cause, PD, failure to achieve CR or PR by 9 weeks post randomization, or start of new antineoplastic therapy due to efficacy concerns, whichever occurs first (Up to 36 months)

Secondary Outcomes

Complete Response Rate (CRR)

Complete response rate (CRR) is defined as the percentage of participants achieving a best overall response of complete response (CR). Participants with unknown or missing response will be counted as non-evaluable in the analysis. CR: Target nodes/nodal masses must regress to ≤ 1.5 cm in LDi, no extralymphatic sites, no new lesions. Complete metabolic response: Lymph nodes/extralymphatic sites score 1, 2, 3 with/without residual mass on 5-point scale, no new lesions, no FDG-avid disease.

Time frame: From randomization up to 3 years post randomization (Up to 36 months)

Number of Participants With Complete Response (CR)

The number of participants achieving a best overall response of complete response (CR). Participants with unknown or missing response will be counted as non-evaluable in the analysis. CR: Target nodes/nodal masses must regress to ≤ 1.5 cm in LDi, no extralymphatic sites, no new lesions. Complete metabolic response: Lymph nodes/extralymphatic sites score 1, 2, 3 with/without residual mass on 5-point scale, no new lesions, no FDG-avid disease.

Time frame: From randomization up to 3 years post randomization (Up to 36 months)

Progression-free Survival (PFS)

Progression-free survival is defined as the time from randomization to progressive disease (PD) or death from any cause, whichever occurs first. Estimates of time to event are from Kaplan-Meier product-limit estimates. PD: LDi \> 1.5 cm, increase by ≥ 50% from PPD nadir, an increase in LDi or SDi from nadir, 0.5 cm for lesions ≤ 2 cm, 1.0 cm for lesions \> 2 cm. Progressive metabolic disease: Score 4 or 5 with an increase in the intensity of uptake from baseline and/or new FDG-avid.

Time frame: From randomization to progression, or death from any cause, whichever occurs first (Up to 36 months)

Overall Survival (OS)

Overall Survival (OS) is defined as the time from randomization to death due to any cause. Estimates of time to event are from Kaplan-Meier product-limit estimates.

Time frame: From randomization to time of death due to any cause (Up to 36 months)

Overall Response Rate (ORR)

ORR is defined as the percentage of participants achieving a best overall response of partial response (PR) or complete response (CR). CR: Target nodes masses must regress to ≤ 1.5cm in LDi, no extralymphatic sites, no new lesions. PR: ≥ 50% decrease in sum of diameters of up to 6 target nodes and extranodal sites, no new lesions, spleen must have regressed \> 50% in length. Complete metabolic response: Lymph nodes score 1, 2, 3 with/without residual mass on 5-point scale, no new lesions, no FDG-avid disease. Partial metabolic response: Lymph nodes score 4 or 5, reduced uptake from baseline, no new lesions, residual uptake higher than normal, reduced from baseline.

Time frame: From randomization to PR or CR (Up to 36 months)

Duration of Response (DoR) Per Independent Review Committee (IRC)

DoR is defined as the time from first partial or complete response (CR or PR) to disease progression, start of new antineoplastic therapy due to efficacy concerns or death, whichever occurs first. CR: Target nodes masses must regress to ≤ 1.5cm in LDi, no extralymphatic sites, no new lesions. PR: ≥ 50% decrease in sum of diameters of up to 6 target nodes and extranodal sites, no new lesions, spleen must have regressed \> 50% in length. PD: LDi \> 1.5cm, increase by ≥ 50% from PPD nadir, an increase in LDi or SDi from nadir, 0.5 cm for lesions ≤ 2cm, 1.0cm for lesions \> 2cm. Complete metabolic response: Lymph nodes score 1, 2, 3 with/without residual mass on 5-point scale, no new lesions, no FDG-avid disease. Partial metabolic response: Lymph nodes score 4 or 5, reduced uptake from baseline, no new lesions, residual uptake higher than normal, reduced from baseline. Progressive metabolic disease: Score 4 or 5 with an increase in uptake intensity from baseline and/or new FDG-avid.

Time frame: From randomization to to disease progression, start of new antineoplastic therapy due to efficacy concerns or death, whichever occurs first (Up to 36 months)

Number of Participants With Progression-free Survival on Next Line of Treatment (PFS-2)

Progression-free Survival (PFS)-2 based on investigator's assessment is defined as time from randomization to second objective progressive disease (PD) or death from any cause, whichever occurs first. Estimates of time to event are from Kaplan-Meier product-limit estimates. PD: LDi \> 1.5 cm, increase by ≥ 50% from PPD nadir, an increase in LDi or SDi from nadir, 0.5 cm for lesions ≤ 2 cm, 1.0 cm for lesions \> 2 cm. Progressive metabolic disease: Score 4 or 5 with an increase in the intensity of uptake from baseline and/or new FDG-avid.

Time frame: From randomization to second objective progression, or death from any cause, whichever occurs first (Up to 36 months)

Event-free Survival (EFS) Rate

EFS rate is defined as the percentage of participants free of any EFS event at fixed timepoints. Complete response: Target nodes masses must regress to ≤ 1.5cm in LDi, no extralymphatic sites, no new lesions. Partial response: ≥ 50% decrease in sum of diameters of up to 6 target nodes and extranodal sites, no new lesions, spleen must have regressed \> 50% in length. Progression: LDi \> 1.5cm, increase by ≥ 50% from PPD nadir, an increase in LDi or SDi from nadir, 0.5 cm for lesions ≤ 2cm, 1.0cm for lesions \> 2cm. Complete metabolic response: Lymph nodes score 1, 2, 3 with/without residual mass on 5-point scale, no new lesions, no FDG-avid disease. Partial metabolic response: Lymph nodes score 4 or 5, reduced uptake from baseline, no new lesions, residual uptake higher than normal, reduced from baseline. Metabolic progression: Score 4 or 5 with an increase in uptake intensity from baseline and/or new FDG-avid.

Time frame: Months 6, 12, 18, 24, 36

Progression-free Survival (PFS) Rate

Progression-free Survival (PFS) rate is defined as the percentage of participants free of any PFS event at fixed timepoints. Progression-free survival is defined as the time from randomization to progressive disease (PD) or death from any cause, whichever occurs first. Estimates of time to event are from Kaplan-Meier product-limit estimates. PD: LDi \> 1.5 cm, increase by ≥ 50% from PPD nadir, an increase in LDi or SDi from nadir, 0.5 cm for lesions ≤ 2 cm, 1.0 cm for lesions \> 2 cm. Progressive metabolic disease: Score 4 or 5 with an increase in the intensity of uptake from baseline and/or new FDG-avid.

Time frame: Months 6, 12, 18, 24, 36

Overall Survival (OS) Rate

Overall Survival (OS) rate is defined as the percentage of participants alive at fixed timepoints. OS is defined as the time from randomization to death due to any cause. Participants alive or lost to follow up at the time of analysis will be censored at the last date the participants was known to be alive.

Time frame: Months 6, 12, 18, 24, 36

Number of Participants With Treatment Emergent Adverse Events (TEAEs)

An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a pre-existing medical condition in a clinical investigation participant administered study treatment that does not necessarily have a causal relation with this treatment. TEAEs are adverse events occurring or worsening on or after the date of randomization and within 90 days after last dose of chemotherapy (Arm A), or within 90 days after the infusion of JCAR017 (Arm B) or start of new antineoplastic therapy, whichever occurs first as well as those AEs made known to the investigator at any time thereafter that are suspected of being related to study treatment. Graded using Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.

Time frame: From randomization to 90 days after last dose or start of new antineoplastic therapy, whichever occurs first (Up to 16.5 months)

Number of Participants With Serious Treatment-Emergent Adverse Events (TEAEs)

A serious adverse event is defined as any adverse event occurring at any dose that results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; or constitutes an important medical event. Treatment emergent adverse events are adverse events occurring or worsening on or after the date of randomization and within 90 days after last dose of chemotherapy (Arm A), or within 90 days after the infusion of JCAR017 (Arm B) or start of new antineoplastic therapy, whichever occurs first as well as those AEs made known to the investigator at any time thereafter that are suspected of being related to study treatment. Graded using Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.

Time frame: From randomization to 90 days after last dose or start of new antineoplastic therapy, whichever occurs first (Up to 16.5 months)

Change From Baseline in Hematology Parameters 1: Hemoglobin

Change from baseline in hemoglobin. Baseline value will be defined as the last value on the randomization date (+3 days) or before the date/time of randomization (date if date/time not collected).

Time frame: baseline, months 1, 2, 3, 4, 6, 9, 12, 18, 24, 36

Change From Baseline in Selected Hematology Parameters 2

Change from baseline in selected hematology parameters such as leukocytes, lymphocytes, neutrophils, and platelets. Baseline value will be defined as the last value on the randomization date (+3 days) or before the date/time of randomization (date if date/time not collected).

Time frame: baseline, months 1, 2, 3, 4, 6, 9, 12, 18, 24, 36

Change From Baseline in Selected Chemistry Parameters 1

Change from baseline in selected chemistry parameters such as alanine aminotransferase, aspartate aminotransferase, and lactate dehydrogenase. Baseline value will be defined as the last value on the randomization date (+3 days) or before the date/time of randomization (date if date/time not collected).

Time frame: baseline, months 1, 2, 3, 4, 6, 9, 12, 18, 24, 36

Change From Baseline in Selected Chemistry Parameters 2

Change from baseline in selected chemistry parameters such as magnesium, phosphate, potassium, and sodium. Baseline value will be defined as the last value on the randomization date (+3 days) or before the date/time of randomization (date if date/time not collected).

Time frame: baseline, months 1, 2, 3, 4, 6, 9, 12, 18, 24, 36

Overall Response Rate (ORR) by Subgroups

Time frame: From randomization to PR or CR (Up to 36 months)

Event-free Survival (EFS) by Subgroups

Progression-free Survival (PFS) by Subgroups

Time frame: From randomization to progression, or death from any cause, whichever occurs first (Up to 36 months)

Overall Survival (OS) by Subgroups

Overall Survival (OS) is defined as the time from randomization to death due to any cause. Estimates of time to event are from Kaplan-Meier product-limit estimates.

Time frame: From randomization to time of death due to any cause (Up to 36 months)

Change From Baseline in the European Organization for Research and Treatment of Cancer - Quality of Life C30 Questionnaire (EORTC QLQ-C30)

Change from baseline in EORTC QLQ-C30 specified parameters including global health/quality of life, cognitive functioning, physical functioning, and fatigue. It is composed of both multi-item scales and single item measures. All of the scales and single-item measures range in score from 0 to 100. A 10-point change in the scoring is considered to be a meaningful change in HRQoL. Functional scale and global health status/HRQoL higher scale score represents a higher level of well-being and better ability of daily functioning. Symptom scale/item higher score represents a high level of symptomatic problem. Baseline value will be defined as the last value on the randomization date (+3 days) or before the date/time of randomization (date if date/time not collected).

Time frame: baseline, months 1, 6, 9, 12, 18, 24, 36

Change From Baseline in the Functional Assessment of Cancer Therapy-Lymphoma Subscale (FACT-Lym)

Change from Baseline in the Functional Assessment of Cancer Therapy-Lymphoma 15-item lymphoma-specific "Additional concerns" subscale (FACT-Lym). The LYM items are scored on a 0 ("Not at all") to 4 ("Very much") response scale. Items are aggregated to a single score on a 0-60 scale. Baseline value will be defined as the last value on the randomization date (+3 days) or before the date/time of randomization (date if date/time not collected). A meaningful change from baseline in the FACT-Lym score, often referred to as the minimally important difference (MID), typically ranges between 6.5 and 11.2 points for the total score. This range indicates a clinically significant improvement or deterioration in a patient's health-related quality of life.

Time frame: baseline, months 1, 6, 9, 12, 18, 24, 36

Hospital Resource Utilization (HRU) Results

Hospital resource utilization (HRU) results including hospitalized, reasons for hospitalizations, and admitted to intensive care unit (ICU)

Time frame: Up to 36 months

Percentage of Participants Completing High Dose Chemotherapy (HDCT)

Percentage of Participants Completing High Dose Chemotherapy (HDCT).

Time frame: Up to 5 months after first dose

Percentage of Participants Completing Hematopoietic Stem Cell Transplant (HSCT)

Percentage of Participants Completing Hematopoietic Stem Cell Transplant (HSCT).

Time frame: Up to 5 months after first dose