Phase 1b Dose Escalation Study of BI 836858 and Azacitidine in Previously Untreated AML: Results from Beat AML S2

▪ Background: The prognosis for acute myeloid leukemia (AML) patients age >60 years is poor. Rapid pre-treatment identification of molecular disease subsets may allow specific targeting with novel agents, presenting an opportunity to improve outcomes. The Leukemia and Lymphoma Society (LLS)-sponsored Beat AML master trial was initiated for previously untreated AML patients ≥60 years, with treatment assignment to a sub-study (S1, S2, etc.) based upon cytogenetics and dominant clone by next generation sequencing; patients with multiple mutations are assigned a sub-study according to variant allele frequency and a predetermined prioritization schema. Methods: Patients within two molecular subsets were selected for a phase 1b/2 dose escalation study (S2) of the Fc engineered (for increased binding to FcyRIIIa) CD33 antibody BI 836858 plus azacitidine (AZA). Group A was comprised of patients with mutations that drive hypermethylation, with potential for enhanced sensitivity to AZA: TET2/WT1 or IDH1/2 (for IDH1/2, if no specific targeting agent available). Group B was comprised of “marker-negative” AML (those not eligible for any available targeted sub-study). Both groups were pooled in the phase 1b portion reported herein. Patient eligibility included ECOG performance status < 3, no prior chemotherapy for AML or myelodysplastic syndrome, and preserved organ function. Patients received AZA (75 mg/m2) IV or SQ days 1-7 of 28 day cycles. BI 836858 was given weekly beginning day 9 (provided WBC < 10 x 109/L) and monthly once complete remission with or without sufficient blood count recovery (CR/CRi) was obtained. A standard 3 + 3 design for toxicity was used to guide dosing decisions, with consideration of dose level expansion based on toxicity and CD33 saturation. Dose-limiting toxicity (DLT) was defined by select grade 3/4 toxicities during cycle 1, or failure to recover counts by day 56 in the setting of no residual AML. Results: At data cut off (April 30, 2018) 39 patients were enrolled; 31 were treated with the combination. Eight were not treated with BI 836858 due to failure to start any therapy (3), withdrawal (1), high white blood cell (WBC) count (2), adverse event (1), and early death (1). Median age of the 31 patients was 71 years (range 62-85); median WBC at study enrollment was 5.3 x 109/L (range 0.5-46.7) and platelets 52 x 109/L (range 10-681). Seventeen (55%) were in Group A (9 TET2, 1 with both TET2 and WT1, 3 IDH1, 4 IDH2). Among 27 with known cyt