Can a new pill take on Hard-to-Treat leukemia?

Copied word for word from the study's registry entry, so the wording is the study team's rather than ours.

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.