Randomized, phase II dose optimization study of chimeric antigen receptor (CAR) modified T cells directed against CD19 in patients (pts) with relapsed, refractory (R/R) CLL.

3009 Background: Autologous T cells genetically modified to express a CD19-targeting CAR (CTL019) can mediate potent anti-tumor effects in CLL and other CD19+ malignancies. Since CTL019 are self-replicating, and the optimal dose is unknown, we are performing a randomized phase II study of 2 CTL019 doses in R/R CLL. Methods: Eligible pts had > 2 prior therapies and progressed within 2 yrs of >2nd line therapy. Pts receive lymphodepleting chemotherapy before infusion. Stage 1 pts were randomized to 5x108 (high dose) or 5x107(low dose) CTL019; Stage 2 pts receive the chosen optimal dose. 35 pts median age 62 have been enrolled. 40% had deletion of p53, 23% failed ibrutinib, median prior therapies was 3 and all had active disease. Median follow-up is 9 mo (range 1-34). Results: 28 pts were treated on stage 1 with 24 evaluable for response (11 high dose, 13 low dose). 6/11 responded at the high dose (4 CRs) and 4/13 at the low dose (1 CR) (p=0.11) with similar toxicity. Therefore a dose of 5 x 108CTL019 was chosen as optimal for Stage 2; 21 pts have been treated at this dose with 17 evaluable for response (11 Stage 1, 6 Stage 2). 9 of the 17 responded (6 CR, 3PR). 5 remain in CR with median follow-up 26 mo (range 5-34) and1 progressed with CD19- disease. Response did not correlate with typical prognostic factors including age, prior therapies or mutated P53. In contrast, CAR T expansion correlated with response as robust CTL019 in-vivo expansion was noted in all responding pts with a median peak of 14.7% of CD3+ cells but 0.35% in non-responders. All 35 pts were evaluable for toxicity and 19 had delayed cytokine release syndrome (CRS) (7 gr 3-4) associated with high levels of IL6 and IFN-g. Tocilizumab successfully reversed CRS in 4 pts; 15 did not require intervention. Dose was not associated with CRS development or severity. Conclusions: This study identifies optimal dosing of CTL019 for R/R CLL and confirms that CTL019 undergo robust in vivo expansion with manageable CRS. CTL019 proliferation in vivo is a predictive biomarker of response. Additional biomarker studies to identify pts likely to respond will be presented. CTL019 cells can induce potent and durable responses in R/R CLL. Clinical trial information: NCT01747486.