High Durable CR Rates in Relapsed/Refractory (R/R) Aggressive B-NHL Treated with the CD19-Directed CAR T Cell Product JCAR017 (TRANSCEND NHL 001): Defined Composition Allows for Dose-Finding and Definition of Pivotal Cohort

Background

JCAR017 is a CD19-directed 4-1BB CAR T cell product administered in a defined composition at a precise dose of CD8 and CD4 CAR T cells. TRANSCEND NHL 001 is the first multicenter Ph1 trial of JCAR017 in relapsed/refractory (R/R) B cell NHL (NCT02631044; interim results previously reported [Abramson, 14-ICML 2017]) and was designed to determine a recommended regimen and inform a study population for a planned pivotal cohort.

Methods

Patients with R/R DLBCL NOS (de novo or transformed from indolent lymphoma), PMBCL, FL grade 3B, or MCL and adequate organ function are eligible. No minimum ALC is required for apheresis; patients with failed prior allo-SCT, secondary CNS involvement, and ECOG 2 are eligible. Patients receive lymphodepletion with fludarabine and cyclophosphamide, followed by a single flat dose of JCAR017 at one of two dose levels (DL1, 5 × 10⁷ CAR T cells; DL2, 1 × 10⁸ CAR T cells); a small cohort received a 2-dose schedule at DL1. The FULL dataset includes all patients in the DLBCL cohort (DLBCL, NOS, PMBCL, FL grade 3B) treated with JCAR017; CORE dataset includes only patients meeting planned inclusion into the planned pivotal cohort (DLBCL NOS [de novo or transformed from FL], ECOG 0-1, no prior allo-SCT).

Results

As of July 7, 2017, 74 patients were treated (51 male, 23 female); 69 in the DLBCL cohort, including 67 DLBCL NOS (45 de novo, 14 transformed from FL, 8 transformed from CLL or MZL), 1 FL grade 3B, 1 PMBCL; and 5 in the MCL cohort. In the DLBCL cohort, median age was 61 yrs (range 26, 82), median prior therapies was 3 (range 1, 12), 46 (67%) were chemorefractory, 32 (46%) had any prior transplant, and at least 16 (23%) patients had double/triple hit lymphoma.

In the DLBCL cohort, 69 patients are evaluable for safety, 38 at DL1, 25 at DL2, and 6 at DL1 2-dose schedule. Only 21 patients (30%) had CRS, with a single serious CRS event (1%; Gr 4). Neurotoxicity (NT) at any grade developed in 14 (20%), including 10 (14%) with Gr 3-4 events. There were no Gr 5 CRS or NT events. CRS and NT rates did not differ by dose level or schedule. Median onset of CRS and NT was 5 and 10 days, respectively. Thirteen patients (19%) required intervention for CRS or NT with tocilizumab alone (1/69, 1%), dexamethasone alone (6/69, 9%) or both (6/69, 9%). Detailed safety data and outpatient administration of JCAR017 will be presented separately.

In the DLBCL cohort, 68 patients were evaluable for efficacy (FULL dataset); best overall response, 3-month, and 6-month response rates were 75% (51/68), 49% (27/55), and 40% (14/35), respectively. The best overall, 3-month, 6-month CR rates were 56% (38/68), 40% (22/55), and 37% (13/35), respectively. A trend toward improved response rate at 3 months was observed in patients treated at DL2 compared to DL1: 63% (12/19; 95% CI 38, 84) vs 40% (12/30; 95% CI 23, 59) for ORR with p=0.148, and 58% (11/19; 95% CI 34, 80) vs 27% (8/30; 95% CI: 12, 46) for CR with p=0.0385. Among 16 double/triple hit lymphoma patients, best ORR was 81%, and 3-month CR rate was 60%.

A subset analysis of the planned pivotal population (CORE dataset; n=49) shows similar rates of CRS and NT. Best overall, 3-month, and 6-month response rates were 84% (41/49), 65% (26/40), and 57% (13/23), respectively. The best overall, 3-month, and 6-month CR rates were 61% (30/49), 53% (21/40), and 52% (12/23), respectively. A similar trend in improved durable ORR and CR at 3 months at higher doses was again observed: 80% (12/15; 95% CI 52, 96) and 73% (11/15; 95% CI 45, 92) at DL2 compared to 52% (11/21; 95% CI 30, 74) and 33% (7/21; 95% CI 15, 57) in DL1 with p=0.159 and p=0.0409 respectively.

Median DOR in FULL and CORE for the DLBCL cohort was 5.0 and 9.2 months, respectively (Fig 1A); median duration of CR was 9.2 months in FULL and has not been reached in CORE (Fig 1B). Median OS was 13.7 months in FULL and has not been reached in CORE; 6-month OS was 75% in FULL (Fig 1C) and 88% in CORE (Fig 1D) with median follow up of 5.8 and 5.6 months, respectively.

Conclusions

JCAR017, a defined composition CAR T cell product with precise clinical dosing, resulted in high durable CR rates and an emerging dose:response relationship in heavily pretreated R/R DLBCL. Toxicity was manageable and occurred at a lower rate and later than previously reported for other CAR T cell products. The trial is ongoing; updated enrollment, safety, 3 and 6 month response rates, and OS will be presented.

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