Trial in Progress: An Open Label Phase I/II, Multicenter Study Evaluating Safety, Pharmacokinetics and Efficacy of S65487, a BCL-2 Inhibitor Combined with Azacitidine in Adults with Previously Untreated Acute Myeloid Leukemia Ineligible for Intensive Treatment
Authors: Pierola Ana Alfonso , De Botton Stephane , Jang Jun Ho , Campbell Victoria , O'Nions Jenny , Calbacho Maria , Ervin-Haynes Annette L. , Keagle Kristen , Maillard Aline , Beneton Maud , Romagnoli Mathilde , Broniscer Alberto 
Published: December 2023

Preclinical and clinical data support combining Bcl-2 inhibitors (Bcl-2i) with hypomethylating agents (HMAs) in the treatment of acute myeloid leukemia (AML). S65487, a potent intravenous Bcl-2i, has shown promising synergistic activity when combined with azacitidine against in vitro AML models.
Based on those data, we initiated a Phase I/II multicenter study of S65487 combined with azacitidine for newly diagnosed patients aged 18 years or older with de novo or secondary AML ineligible for intensive chemotherapy in 6 countries in Europe and Asia (NCT04742101). Secondary AML was defined as those related to previous leukemogenic therapies or transformed from a myelodysplastic syndrome. Patients with AML originating from myeloproliferative disorders were excluded. Ineligibility to intensive chemotherapy was defined as age of at least 75 years or the presence of significant co-morbidities. Previous use of HMA was allowed in the first six dose levels tested in the Phase I portion of the study, but was excluded afterwards, including during the Phase II part. Other eligibility criteria were standard for this patient population.
Each cycle of therapy lasts for 28 days. Subcutaneous or intravenous azacitidine is administered at a dose of 75mg/m 2 in 7 consecutive administrations per cycle starting on day (D) 1 with a 2-day interval during weekends. Three schedules of S65487 are planned to be tested during the Phase I part to increase its concurrent administration with azacitidine and their synergism. Schedule 1 consists of weekly administrations (doses on D1, 8, 15, and 22). Two more intensified schedules consist of S65487 administration on D1, D3, D5, D8 (schedule 2) or D1 through D5, D8, and D9 (schedule 3) on the same days of azacitidine dosing. S65487 is administered over 30 minutes. When administered on the same day, S65487 is given first followed by azacitidine within 30 to 60 minutes. Treatment should be discontinued due to disease progression, or if other standard withdrawal criteria are met.
The Phase I portion of the study follows a standard design guided by an adaptive Bayesian Logistic Regression Model with overdose control to estimate the maximum tolerated dose (MTD) based on the occurrence of dose-limiting toxicities during cycle 1. Patient accrual for the Phase I portion of this study is ongoing. The planned testing of schedule 1 is limited due to the expected low synergism with azacitidine. Once the recommended Phase II dose (RP2D) or MTD are established for schedules 2 and 3, the Phase II part will start and will be comprised of a maximum of two cohorts, each containing up to 27 patients. A Bayesian optimal design based on complete remission rate will guide the Phase II. Interim futility analyses are planned after enrollment of 10 and 20 evaluable patients. Randomization will not be used to allocate patients to one of the two cohorts planned during the Phase II portion of the study.
The primary objective during the Phase I is to determine the safety, tolerability, and the RP2D or MTD of S65487 in combination with azacitidine. The primary objective of the Phase II is to assess the efficacy of this therapy. Pharmacokinetic analyses are included as secondary objectives in both parts of the study. Measurable residual disease will be assessed as a secondary objective in the Phase II part using a well validated, standard flow-cytometry panel. Pharmacodynamic analyses are conducted as exploratory objectives in both parts of the study. In particular, the disruption of the BCL2/BIM complex is followed in peripheral-blood mononuclear cells to guide the estimation of the RP2D.