A Study to Evaluate S227928 as a Single Agent and in Combination With Venetoclax in Patients With R/R AML, MDS/AML, or CMML
NCT Number: NCT06563804
Status: NOT_YET_RECRUITING
Study Type: INTERVENTIONAL
Phases: PHASE1|PHASE2
Conditions: Relapsed/Refractory (R/R) Acute Myeloid Leukemia (AML)|Myelodysplastic Syndrome (MDS)/AML|Chronic Myelomonocytic Leukemia (CMML)
Interventions: DRUG: S227928|DRUG: Venetoclax
Sponsor: Servier Bio-Innovation LLC
Sex: ALL
Age: ADULT, OLDER_ADULT
Enrollment: 132
Study Design: Allocation: NON_RANDOMIZED|Intervention Model: SEQUENTIAL|Masking: NONE|Primary Purpose: TREATMENT
Start Date: 2024-11-15
Completion Date: 2030-08-21

Summary:
The objective of this study is to determine the safety, tolerability, and anti-leukemic activity of S227928 as single agent and in combination with venetoclax, and to determine the recommended Phase 2 dose (RP2D) of this combination. The study will begin as a Phase 1 Dose Escalation study to determine the RP2D and then will transition to a Phase 2 Dose Expansion study to assess the efficacy of the selected RP2D. During the treatment period participants will have study visits every two weeks, with additional visits occurring during the first and second cycle. Approximately 30 days after treatment has ended, an end-of-treatment visit will occur and then participants will be followed for survival every 12 weeks for the next 6 months. Study visits may include a bone marrow aspirate and/or biopsy, blood and urine tests, ECG, vital signs, physical examination, and administration of study treatment.

Primary Outcome Measures: Dose Escalation: Number and severity of Dose Limiting Toxicities (DLTs), Through Cycle 1 (each cycle is 28 days)|Dose Escalation: Number of Adverse Events (AEs) and Serious Adverse Events (SAEs), Through 30 days after the end of treatment (Approximately 3.5 years)|Dose Escalation: Number of dose reductions, interruptions, delays, or study withdrawal due to AEs, Through 30 days after the end of treatment (Approximately 3.5 years)|Dose Expansion: Complete remission (CR), Through 6 months after the end of treatment (Approximately 4 years)
Secondary Outcome Measures: Dose Escalation: Cmax of S227928, total Monoclonal Antibody (mAb), and unconjugated S64315, Through the end of treatment (Approximately 3.5 years)|Dose Expansion: Cmax of S227928, total mAb, and unconjugated S64315, Through the end of treatment (Approximately 3.5 years)|Dose Escalation: Tmax of S227928, total mAb, and unconjugated S64315, Through the end of treatment (Approximately 3.5 years)|Dose Expansion: Tmax of S227928, total mAb, and unconjugated S64315, Through the end of treatment (Approximately 3.5 years)|Dose Escalation: Area Under the Curve (AUC) of S227928, total mAb, and unconjugated S64315, Through the end of treatment (Approximately 3.5 years)|Dose Expansion: AUC of S227928, total mAb, and unconjugated S64315, Through the end of treatment (Approximately 3.5 years)|Dose Escalation: Plasma concentration vs. time profile of S227928, Through the end of treatment (Approximately 3.5 years)|Dose Expansion: Plasma concentration vs. time profile of S227928, Through the end of treatment (Approximately 3.5 years)|Dose Escalation: Plasma concentration vs. time profile of unconjugated S64315, Through the end of treatment (Approximately 3.5 years)|Dose Expansion: Plasma concentration vs. time profile of unconjugated S64315, Through the end of treatment (Approximately 3.5 years)|Dose Escalation: Plasma concentration vs. time profile of total mAb, Through the end of treatment (Approximately 3.5 years)|Dose Expansion: Plasma concentration vs. time profile of total mAb, Through the end of treatment (Approximately 3.5 years)|Dose Escalation (Arm B ONLY): Plasma concentration vs. time profile of venetoclax, Through the end of treatment (Approximately 3.5 years)|Dose Expansion: Plasma concentration vs. time profile of venetoclax, Through the end of treatment (Approximately 3.5 years)|Dose Escalation: Detection of Anti-Drug Antibodies (ADAs) against S227928, Through the end of treatment (Approximately 3.5 years)|Dose Expansion: Detection of ADAs against S227928, Through the end of treatment (Approximately 3.5 years)|Dose Escalation: Complete remission (CR), For patients with R/R AML or MDS/AML, or R/R CMML, Through 6 months after the end of treatment (Approximately 4 years)|Dose Escalation: Complete remission with incomplete hematologic recovery (CRi), For patients with R/R AML or MDS/AML, Through 6 months after the end of treatment (Approximately 4 years)|Dose Expansion: CRi, Cohort 1 only, Through 6 months after the end of treatment (Approximately 4 years)|Dose Escalation: Morphologic leukemia-free state (MLFS), For patients with R/R AML or MDS/AML, Through 6 months after the end of treatment (Approximately 4 years)|Dose Expansion: MLFS, Cohort 1 only, Through 6 months after the end of treatment (Approximately 4 years)|Dose Escalation: CR with partial hematologic recovery (CRh), For patients with R/R AML or MDS/AML, or R/R CMML, Through 6 months after the end of treatment (Approximately 4 years)|Dose Expansion: CRh, Through 6 months after the end of treatment (Approximately 4 years)|Dose Escalation: Partial remission (PR), For patients with R/R AML or MDS/AML, or R/R CMML, Through 6 months after the end of treatment (Approximately 4 years)|Dose Expansion: PR, Through 6 months after the end of treatment (Approximately 4 years)|Dose Escalation: Overall survival (OS), For patients with R/R AML or MDS/AML, or R/R CMML, Through 6 months after the end of treatment (Approximately 4 years)|Dose Expansion: OS, Through 6 months after the end of treatment (Approximately 4 years)|Dose Escalation: Duration of response (DOR), For patients with R/R AML or MDS/AML, Through 6 months after the end of treatment (Approximately 4 years)|Dose Expansion: DOR, Cohort 1 only, Through 6 months after the end of treatment (Approximately 4 years)|Dose Escalation: Time to first remission (CR or CRh or CRi), For patients with R/R AML or MDS/AML, Through 6 months after the end of treatment (Approximately 4 years)|Dose Expansion: Time to first remission (CR or CRh or CRi), Cohort 1 only, Through 6 months after the end of treatment (Approximately 4 years)|Dose Escalation: Red-blood cell (RBC) and platelet transfusion independence for at least 8 weeks, For patients with R/R AML or MDS/AML, Through 6 months after the end of treatment (Approximately 4 years)|Dose Expansion: RBC and platelet transfusion independence for at least 8 weeks, Cohort 1 only, Through 6 months after the end of treatment (Approximately 4 years)|Dose Escalation: CR with limited count recovery (CRL), For patients with R/R CMML, Through 6 months after the end of treatment (Approximately 4 years)|Dose Expansion: CRL, Cohort 2 only, Through 6 months after the end of treatment (Approximately 4 years)|Dose Escalation: CR equivalent, For patients with R/R CMML, Through 6 months after the end of treatment (Approximately 4 years)|Dose Expansion: CR equivalent, Cohort 2 only, Through 6 months after the end of treatment (Approximately 4 years)|Dose Escalation: Hematologic improvement (HI), For patients with R/R CMML, Through 6 months after the end of treatment (Approximately 4 years)|Dose Expansion: HI, Cohort 2 only, Through 6 months after the end of treatment (Approximately 4 years)|Dose Escalation: Overall response rate (ORR)= CR + CR equivalent + CRh + CRL + PR + HI, For patients with R/R CMML, Through 6 months after the end of treatment (Approximately 4 years)|Dose Expansion: Overall response rate (ORR)= CR + CR equivalent + CRh + CRL + PR + HI, Cohort 2 only, Through 6 months after the end of treatment (Approximately 4 years)|Dose Escalation: Progression-free survival (PFS), For patients with R/R CMML, Through 6 months after the end of treatment (Approximately 4 years)|Dose Expansion: PFS, Cohort 2 only, Through 6 months after the end of treatment (Approximately 4 years)|Dose Escalation: Event-free survival (EFS), For patients with R/R CMML, Through 6 months after the end of treatment (Approximately 4 years)|Dose Expansion: EFS, Through 6 months after the end of treatment (Approximately 4 years)|Dose Expansion: Number and severity of Dose Limiting Toxicities (DLTs) of S227928 in combination with venetoclax, Through Cycle 1 (each cycle is 28 days)|Dose Expansion: AEs and SAEs, Through 30 days after the end of treatment (Approximately 3.5 years)|Dose Expansion: Number of dose reductions, interruptions, delays, or study withdrawal due to AEs, Through 30 days after the end of treatment (Approximately 3.5 years)