PS1212 UPDATED RESULTS FROM PHASE I TRIALS ASSESSING A NKG2D CAR T‐CELL APPROACH IN RELAPSED/REFRACTORY ACUTE MYELOID LEUKEMIA AND MYELODYSPLASTIC SYNDROME PATIENTS

Abstract

Background:CYAD‐01 cells are chimeric antigen receptor (CAR) T cells based on the NKG2D receptor fused to the intracellular domain of CD3ζ, and bind ligands (MICA/B, ULBP1–6) expressed by a large variety of malignancies, including acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS).Aims:A comprehensive clinical program was developed with the objective to define the optimal CYAD‐01 treatment in relapsed/refractory (r/r) AML/MDS patients (pts).Methods:The Phase I THINK trial (NCT03018405) assesses the safety and clinical activity of multiple CYAD‐01 infusions without preconditioning chemotherapy in various malignancies, including r/r AML, MDS and multiple myeloma (MM). 3 dose levels (DL) were evaluated in the dose escalation segment (3x108, 1x109 and 3x109 T‐cells/inf.). 1st cycle of treatment consists of 3 CYAD‐01 infusions every 2 weeks and a 2nd cycle of 3 CYAD‐01 infusions with a 2 week‐interval in case of no progressive disease (PD) after the 1st cycle. Additional cohorts aim to provide a dense treatment schedule at the same DL (3x 1 CYAD‐01 every week + 3x 1 CYAD‐01 every 2 weeks). The Phase I/II DEPLETHINK study (NCT03466320) evaluates the safety and preliminary efficacy of 1 CYAD‐01 infusion administered after preconditioning with cyclophosphamide and fludarabine to pts with r/r AML/MDS. A 2nd cycle of 3 CYAD‐01 without preconditioning is administered in case of no PD after 1st treatment. 3 DL (1x108, 3x108 and 1x109 cells/inf.) and 2 intervals between preconditioning and CYAD‐01 infusion are evaluated in the dose escalation segment. Data as of February 20, 2019 are presented.Results:THINK study: 16 pts were enrolled in the dose‐escalation segment of the hematological cohort, now completed. 4 pts were enrolled in cohorts with the dense schedule. In total, 7 pts experienced grade (G) 3/4 treatment‐related adverse events (AEs). Cytokine release syndrome (CRS) occurred in 10 pts with only 2 G3 CRS (at DL2) and 1 G4 CRS (at DL3), which resolved with early tocilizumab treatment. No treatment‐related neurotoxicity AEs have been observed.Out of 12 pts who received at least 3 CYAD‐01 infusions in the dose‐escalation segment, 2 pts with MM did not have evidence of clinical response. For pts with r/r AML/MDS, 4/10 pts had overall response (OR) at D29 with 1 complete remission (CR) with partial hematologic recovery (CRh) for 16 months in a r/r AML pt at DL‐1, 2 CR with incomplete hematologic recovery (CRi) for 1 month in AML pts at DL‐1 and DL‐3, and 1 marrow CR (mCR) for 1 month in an MDS pt at DL‐3. 2 AML pts at DL‐2 had stable disease (SD) with bone marrow (BM) blast percentage decrease upon 1st treatment cycle and further reduction upon 2nd treatment cycle. Two other AML pts in DL‐3 achieved SD for at least 2 months. 2 AML pts did not show evidence of clinical response.DEPLETHINK study: 6 pts were enrolled in the first 2 cohorts which evaluated 1x108 cells/inf. In total, there were 3 G3/4 treatment‐related AE observed in the same pt. Five CRS occurred in 4 pts: 3 G1/2 after the 1st infusion and 2 CRS during 2nd cycle (1 G4 CRS and 1 G1), which resolved with tocilizumab treatment. At the 1st cohort, 2 pts reached a stable disease (SD) at D36, allowing the initiation of the 2nd cycle of 3 CYAD‐01 infusions.Summary/Conclusion:Altogether, results obtained to date in both phase 1 trials demonstrate the safety of CYAD‐01 with or without preconditioning chemotherapy in patients with r/r hematological malignancies. A promising OR rate of 40% at D29 was seen in pts with r/r AML/MDS in the THINK study. The DEPLETHINK study is still accruing.image