A Study to Evaluate S241656 Alone or in Combination in Participants With Selected Myeloid Malignancies

A Phase 1/2, Open Label, Multicenter, Multi-cohort Study of S241656 as Monotherapy or in Combination With Other Antileukemic Agents in Participants With Selected Myeloid Malignancies

The objective of this study is to evaluate the safety, tolerability, and pharmacokinetics (PK) of S241656 and to determine the recommended dose for expansion (RDE) of S241656 in participants with relapsed/refractory (R/R) acute myeloid leukemia (AML), myelodysplastic syndrome/acute myeloid leukemia (MDS/AML), or chronic myelomonocytic leukemia (CMML). Part 1A dose escalation will determine the RDE to be used in a future expansion stage of the trial. An optional Part 1B drug-drug interaction (DDI) substudy will evaluate the effect of posaconazole on the PK of S241656.

The study consists of a screening period of up to 21 days, a treatment period consisting of continuous 28-day cycles of treatment, an end-of-treatment visit, a safety follow-up period, and long-term disease and survival follow-up every 3 months. Participants in the optional DDI substudy may continue treatment in the main study following completion of the DDI assessment period. Participants may undergo bone marrow aspirates and/or biopsies, blood tests, electrocardiograms (ECGs), echocardiograms or multigated acquisition (MUGA) scans, physical examinations, ophthalmologic assessments, and disease response questionnaires.

Study Overview

• Status: Not yet recruiting
• Conditions: Acute Myeloid Leukemia; Chronic Myelomonocytic Leukemia; Myelodysplastic Syndrome Acute Myeloid Leukemia
• Intervention / Treatment: Drug: S241656; Drug: Posaconazole

• Study Type: Interventional
• Enrollment (Estimated): 64
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Institut de Recherches Internationales Servier (I.R.I.S.); Phone Number: +33 1 55 72 60 00; Email: scientificinformation@servier.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2.
• Investigator-assessed life expectancy of ≥ 3 months.
• Able and willing to comply with requirements of the study protocol.
• Documented genetic characterization of the disease as per local practice.
• Clinical and laboratory thresholds:
• Cytoreduction: white blood cell (WBC) < 25 × 10⁹/L (hydroxyurea/cytarabine/leukapheresis allowed).
• Renal: creatinine clearance (CrCl) ≥ 60 mL/min (Cockcroft-Gault).
• Hepatic: aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ≤ 3 × upper limit of normal (ULN) (5 × if leukemic); Total bilirubin ≤ 1.5 × ULN (≤ 3 × ULN for Gilbert's syndrome).
• Part 1 Only: Relapsed/Refractory (R/R), pathologically confirmed AML, MDS/AML, or CMML.
• Part 1 Only: Must have failed ≥ 1 approved standard therapy and have no other approved standard options.

Exclusion Criteria:

• Known hypersensitivity to S241656, or Posaconazole (Part 1B).
• Pregnant or breastfeeding; positive serum pregnancy test for WOCBP.
• Diagnosis of acute promyelocytic leukemia (French-American-British [FAB] M3 classification), MPN, mixed/ambiguous lineage, histiocytic/dendritic cell neoplasms, or AML with isolated extramedullary disease (no marrow/blood involvement).
• Active Central Nervous System (CNS) disease (by cytologic or radiographic evidence).
• Failure to recover to ≤ Grade 1 from previous toxicities (except Grade 2 neuropathy/alopecia).
• Major surgery within 4 weeks.
• Any anticancer therapy within 2 weeks or 5 half-lives (28 days for biologics). Cytoreduction with hydroxyurea or cytarabine is permitted.
• Prior use of experimental KRAS/BRAF/MEK/ERK inhibitors (prior FLT3 inhibitors are permitted).
• Uncontrolled infections (human immunodeficiency virus (HIV)/hepatitis B virus (HBV)/hepatitis C virus (HCV) permitted only if viral load is undetectable/controlled and specific cluster of differentiation 4 (CD4)+ criteria are met).
• Malabsorption, Crohn's, or chronic vomiting that impacts oral drug absorption.
• History/risk of retinal vein occlusion (RVO), glaucoma, or hyper-viscosity syndromes.
• Other active malignancy requiring systemic therapy within 2 years (except non-melanoma skin cancer or localized/cured tumors).
• Stroke, myocardial infarction (MI), unstable angina, or acute coronary syndrome within 6 months.
• Congestive heart failure (CHF), clinically significant cardiac arrhythmias according to the investigator's judgement (e.g., ventricular tachycardia), complete left bundle branch block and high-grade atrioventricular (AV) block (e.g., bifascicular block, Mobitz type II- and third degree AV block).
• Fridericia-corrected QT interval (QTcF) > 470 msec or history of Torsades de pointes.
• Disseminated intravascular coagulation (DIC), significant coagulopathy according to the investigator's judgement, or uncontrolled bleeding.
• Proton Pump Inhibitors (PPIs) and potassium-competitive acid blockers ≥ 7 days prior to Cycle 1 Day 1.
• Breast cancer resistance protein (BCRP) sensitive substrate or with a narrow therapeutic index (NTI)
• All herbal preparations/supplements are prohibited.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Part 1A: Dose Escalation	Drug: S241656; Tablets taken by mouth.
Experimental: Part 1B: Optional Drug-Drug Interaction [DDI] Substudy	Drug: S241656; Tablets taken by mouth.; Drug: Posaconazole; Tablets taken by mouth

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
(Part 1A and 1B) Dose limiting toxicity (DLTs) associated with S241656 during the first cycle of treatment	Through Cycle 1 (28 days)
(Part 1A and 1B) Number of Adverse Events (AEs)	Through 30 days after the last dose of treatment, up to approximately 4 years
(Part 1A and 1B) Number of Serious Adverse Events (SAEs)	Through 30 days after the last dose of treatment, up to approximately 4 years
(Part 1A and 1B) Severity of AEs	Through 30 days after the last dose of treatment, up to approximately 4 years
(Part 1A and 1B) Severity of SAEs	Through 30 days after the last dose of treatment, up to approximately 4 years
(Part 1A and 1B) Duration of AEs	Through 30 days after the last dose of treatment, up to approximately 4 years
(Part 1A and 1B) Duration of SAEs	Through 30 days after the last dose of treatment, up to approximately 4 years
(Part 1A and 1B) Number of changes in safety laboratory results	Through 30 days after the last dose of treatment, up to approximately 4 years
(Part 1A and 1B) Number of changes in physical examination	Through 30 days after the last dose of treatment, up to approximately 4 years
(Part 1A and 1B) Number of dose reductions due to AEs	Through end of treatment, up to approximately 4 years
(Part 1A and 1B) Number of dose interruptions due to AEs	Through end of treatment, up to approximately 4 years
(Part 1A and 1B) Number of dose delays due to AEs	Through end of treatment, up to approximately 4 years
(Part 1A and 1B) Number of study withdrawals due to AEs	Through end of treatment, up to approximately 4 years
(Part 1B only) Maximum concentration (Cmax) of S241656	Through Cycle 1 (28 days)
(Part 1B only) Cmax of metabolite S243796	Through Cycle 1 (28 days)
(Part 1B only) Time corresponding to Cmax (Tmax) of S241656	Through Cycle 1 (28 days)
(Part 1B only) Tmax of metabolite S243796	Through Cycle 1 (28 days)
(Part 1B only) Terminal half-life (t1/2) of S241656	Through Cycle 1 (28 days)
(Part 1B only) t1/2 of metabolite S243796	Through Cycle 1 (28 days)
(Part 1B only) Area under the curve (AUC) of S241656	Through Cycle 1 (28 days)
(Part 1B only) AUC of metabolite S243796	Through Cycle 1 (28 days)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
(Part 1A only) Cmax of S241656		Through end of treatment, up to approximately 4 years
(Part 1A only) Cmax of metabolite S243796		Through end of treatment, up to approximately 4 years
(Part 1A only) Tmax of S241656		Through end of treatment, up to approximately 4 years
(Part 1A only) Tmax of metabolite S243796		Through end of treatment, up to approximately 4 years
(Part 1A only) AUC of S241656		Through end of treatment, up to approximately 4 years
(Part 1A only) AUC of metabolite S243796		Through end of treatment, up to approximately 4 years
(Part 1A only) t1/2 of S241656		Through end of treatment, up to approximately 4 years
(Part 1A only) t1/2 of metabolite S243796		Through end of treatment, up to approximately 4 years
(Part 1A and 1B) Complete remission (CR)		Through study completion, approximately 4 years
(Part 1A and 1B) Complete remission with incomplete hematologic recovery (CRi)	In participants with AML or MDS/AML only	Through study completion, approximately 4 years
(Part 1A and 1B) Morphologic leukemia free state (MLFS)	In participants with AML or MDS/AML only	Through study completion, approximately 4 years
(Part 1A and 1B) Complete remission with partial hematologic recovery (CRh)	In participants with AML or MDS/AML only	Through study completion, approximately 4 years
(Part 1A and 1B) Partial response (PR)		Through study completion, approximately 4 years
(Part 1A and 1B) Objective response (OR)		Through study completion, approximately 4 years
(Part 1A and 1B) Composite complete remission (CRc)	In participants with AML or MDS/AML only	Through study completion, approximately 4 years
(Part 1A and 1B) Red blood cell (RBC) and platelet transfusion independence for at least 8 weeks	In participants with AML or MDS/AML only	Through end of treatment, up to approximately 4 years
(Part 1A and 1B) Duration of response (DOR)		Through study completion, approximately 4 years
(Part 1A and 1B) Time to response (TTR)	In participants with AML or MDS/AML only	Through study completion, approximately 4 years
(Part 1A and 1B) Event free survival (EFS)	In participants with AML or MDS/AML only	Through study completion, approximately 4 years
(Part 1A and 1B) Overall survival (OS)		Through study completion, approximately 4 years
(Part 1A and 1B) Marrow response	In participants with CMML only	Through end of treatment, up to approximately 4 years
(Part 1A and 1B) Number of participants with erythroid-, neutrophil-, platelet or spleen-response	In participants with CMML only	Through end of treatment, up to approximately 4 years

Collaborators and Investigators

• Sponsor: Servier

Study record dates

Study Major Dates

• Study Start (Estimated): September 15, 2026
• Primary Completion (Estimated): November 1, 2027
• Study Completion (Estimated): September 30, 2030

Study Registration Dates

• First Submitted: July 8, 2026
• First Submitted That Met QC Criteria: July 17, 2026
• First Posted (Actual): July 22, 2026

Study Record Updates

• Last Update Posted (Actual): July 22, 2026
• Last Update Submitted That Met QC Criteria: July 17, 2026
• Last Verified: July 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms; Chronic Disease; Disease Attributes; Genetic Diseases, Inborn; Neoplasms by Histologic Type; Hematologic Diseases; Leukemia, Myeloid; Myelodysplastic-Myeloproliferative Diseases; Bone Marrow Diseases; Leukemia; Myelodysplastic Syndromes; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Pathological Conditions, Signs and Symptoms; Hemic and Lymphatic Diseases; GATA2 Deficiency; Leukemia, Myeloid, Acute; Leukemia, Myelomonocytic, Chronic; posaconazole
• Other Study ID Numbers: S241656-292; 2025-525128-88-00 (Ctis)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Qualified scientific and medical researchers can request access to anonymized patient-level and study-level clinical trial data.

Access can be requested for all interventional clinical studies:

• used for Marketing Authorization (MA) of medicines and new indications approved after 1 January 2014 in the European Economic Area (EEA) or the United States (US).
• where Servier is the Marketing Authorization Holder (MAH). The date of the first MA of the new medicine (or the new indication) in one of the EEA Member States will be considered for this scope.

In addition, access can be requested for all interventional clinical studies in patients:

• sponsored by Servier
• with a first patient enrolled as of 1 January 2004 onwards
• for New Chemical Entity or New Biological Entity (new pharmaceutical form excluded) for which development has been terminated before any Marketing authorization (MA) approval.

• IPD Sharing Time Frame: After Marketing Authorization in EEA or US if the study is used for the approval.
• IPD Sharing Access Criteria: Researchers should register on Servier Data Portal and fill in the research proposal form. This form in four parts should be fully documented. The Research Proposal Form will not be reviewed until all mandatory fields are completed.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No