Session: 704. Cellular Immunotherapies: Early Phase and Investigational Therapies: Poster II
Hematology Disease Topics & Pathways:
Research, clinical trials, Biological therapies, Clinical Research, Chimeric Antigen Receptor (CAR)-T Cell Therapies, pediatric, Therapies, Immunotherapy, Study Population, Human
PLAT-02 (NCT02028455) enrolled subjects 1-26 years of age with relapsed, refractory CD19+ B-ALL. The primary efficacy cohort was defined as those who received fludarabine/cyclophosphamide (flu/cy) LD and were infused with CAR19. PLAT-03 (NCT03186118) was a pilot study of CD19t T-APCs (manufactured T cells with CD19 tag) administered at doses of 10x106/kg or flat dosing of 5x108 for subjects >25kg every 4 weeks up to 6 total doses. Cohort A included subjects with low CD19 antigen burden, and cohort B included those with rapid early contraction of CAR19.
88 subjects with B-ALL were enrolled on PLAT-02 with plans for treatment at the recommended phase 2 dose (RP2D) of 1x106 CAR+ T cells/kg. Eighty-six percent had at least one prior relapse and 42% had undergone prior hematopoietic cell transplant (HCT). The feasibility of manufacturing was 98%. 71 subjects were in the primary efficacy cohort with an 89% minimal residual disease negative complete remission (MRDneg CR) rate. EFS and OS probability estimates with 95% CI at 1 year following CAR19 were 0.65 (0.53, 0.75) and 0.76 (0.64, 0.84). LFS at 1 year from entering MRDneg CR was 0.71 (0.58, 0.81). Cytokine release syndrome (CRS) was grade (Gr) 1 (53%), Gr 2 (26%), Gr 3 (10%), and Gr 4 (3%). Neurotoxicity occurred in 53%: Gr 1 (24%), Gr 2 (13%), Gr 3 (15%), and Gr 5 (1%).
25 subjects were treated on PLAT-03, 10 as cohort A (10 received CAR19 on PLAT-03, 9 received T-APCs), and 11 as cohort B (5 received CAR19 on PLAT-02, 6 received CAR19 on PLAT-03, and 9 total received T-APCs). One was cohort C (retreatment) and 3 were cohort D (no T-APCs). A total of 72 infusions of T-APCs were administered, with no occurrence of CRS or neurotoxicity. Two subjects had grade 3 toxicities related to T-APCs, 1 febrile neutropenia and 1 infusion related reaction. EFS and OS probability estimates at 1 year following CAR19 were 0.67 (0.43, 0.83) and 0.95 (0.71, 0.99). Overall LFS at 1 year was 0.63 (0.38, 0.80); by cohort: cohort A, 0.44 (0.13, 0.72) and cohort B, 0.80 (0.41, 0.95).
Median duration of persistence, as determined by cumulative incidence using B cell aplasia (BCA) as a surrogate, among all subjects who received RP2D of CAR19 with flu/cy LD across PLAT-02 and PLAT-03, engrafted and achieved MRDneg CR, was 12.9 months (m). For subjects who did not receive T-APCs, the median persistence was 12.1m. Impact of antigen burden prior to LD was again observed; those with >15% CD19 antigen burden had persistence of >12.1m vs. 3.9m in the low antigen burden group. For subjects treated with T-APCs, the median persistence was 16m; 9.9m in cohort A and >16m in cohort B.
The improvement in LFS after SCRI-CAR19 in phase 2 compared to phase 1 is likely multi-factorial, with contributing factors including earlier treatment, uniform use of LD, enhanced persistence, and better allocation of patients who benefit from consolidative HCT. The use of T-APCs was well tolerated without recurrent CAR T cell mediated toxicity. Although not directly comparable, there did appear to be enhancement of CAR T cell persistence with the use of T-APCs in populations predicted to have inferior persistence, including those with low antigen burden. There was not a clear improvement of LFS in those who received T-APCs. However, subjects were not randomized to receive T-APCs and those enrolled on PLAT-03 were more heavily treated and more likely to have received a prior HCT. Further exploration of T-APCs is warranted to define and evaluate their impact on persistence and durable responses.
Disclosures: Agrawal: Y-mAbs Therapeutics: Membership on an entity's Board of Directors or advisory committees. Pulsipher: Vertex Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; CARGO Therapeutics: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Bluebird Bio: Membership on an entity's Board of Directors or advisory committees; GentiBio: Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Research Funding; Miltenyi Biotec: Research Funding. Jensen: Bristol-Myers Squibb: Patents & Royalties. Gardner: Bristol-Myers Squibb: Patents & Royalties.
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