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

Ki vehet részt

• 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

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• 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)
• Malabsorption, Crohn's, or chronic vomiting that impacts oral drug absorption
• Known hypersensitivity to S241656, or Posaconazole (Part 1B)
• 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)
• 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)
• 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)
• Disseminated intravascular coagulation (DIC), significant coagulopathy according to the investigator's judgement, or uncontrolled bleeding
• Breast cancer resistance protein (BCRP) sensitive substrate or with a narrow therapeutic index (NTI)
• Pregnant or breastfeeding; positive serum pregnancy test for WOCBP
• Fridericia-corrected QT interval (QTcF) > 470 msec or history of Torsades de pointes
• Proton Pump Inhibitors (PPIs) and potassium-competitive acid blockers ≥ 7 days prior to Cycle 1 Day 1
• All herbal preparations/supplements are prohibited