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

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Code de protocole Servier: S241656-292 Sponsor: Servier Identifiant Clinicaltrials.gov: NCT07719348 Numéro de l'essai UE (CTIS): 2025-525128-88-00

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Nom: Institut de Recherches Internationales Servier, Département des études cliniques
Numéro de téléphone: +33 1 55 72 60 00

Description de l'étude

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.
Titre officiel: 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
Indications
Acute Myeloid Leukemia Chronic Myelomonocytic Leukemia Myelodysplastic Syndrome Acute Myeloid Leukemia
Interventions / Traitements
  • S241656
  • Posaconazole
Autres numéros d'identification
  • S241656-292

Critères d'éligibilité

Age éligible pour l’étude

18 ans et plus (Adulte, Adulte plus âgé)

Sexe

Homme/Femme

Accepte les volontaires en bonne santé

Non

  • * 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.

  • * 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.

Comment l'étude est-elle conçue ?

Allocation
Non randomisé
Modèle d'étude interventionnelle
Séquentiel
Groupe de participants / Bras de traitement
Expérimental: Part 1A: Dose Escalation
Intervention / Traitement
Traitement: S241656
Tablets taken by mouth.
Groupe de participants / Bras de traitement
Expérimental: Part 1B: Optional Drug-Drug Interaction [DDI] Substudy
Intervention / Traitement
Traitement: S241656
Tablets taken by mouth.
Traitement: Posaconazole
Tablets taken by mouth

Mots clés

Autres termes
Leukemia, Myeloid, Acute Leukemia, Myelomonocytic, Chronic GATA2 Deficiency