Acute Myeloid Leukemia, Chronic Myelomonocytic Leukemia, Myelodysplastic Syndrome Acute Myeloid Leukemia
Conditions
Brief summary
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.
Interventions
DRUGS241656
Tablets taken by mouth.
DRUGPosaconazole
Tablets taken by mouth
Sponsors
Servier
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| 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
| Measure | Time frame | Description |
|---|---|---|
| (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) | Through study completion, approximately 4 years | In participants with AML or MDS/AML only |
| (Part 1A and 1B) Morphologic leukemia free state (MLFS) | Through study completion, approximately 4 years | In participants with AML or MDS/AML only |
| (Part 1A and 1B) Complete remission with partial hematologic recovery (CRh) | Through study completion, approximately 4 years | In participants with AML or MDS/AML only |
| (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) | Through study completion, approximately 4 years | In participants with AML or MDS/AML only |
| (Part 1A and 1B) Red blood cell (RBC) and platelet transfusion independence for at least 8 weeks | Through end of treatment, up to approximately 4 years | In participants with AML or MDS/AML only |
| (Part 1A and 1B) Duration of response (DOR) | Through study completion, approximately 4 years | — |
| (Part 1A and 1B) Time to response (TTR) | Through study completion, approximately 4 years | In participants with AML or MDS/AML only |
| (Part 1A and 1B) Event free survival (EFS) | Through study completion, approximately 4 years | In participants with AML or MDS/AML only |
| (Part 1A and 1B) Overall survival (OS) | Through study completion, approximately 4 years | — |
| (Part 1A and 1B) Marrow response | Through end of treatment, up to approximately 4 years | In participants with CMML only |
| (Part 1A and 1B) Number of participants with erythroid-, neutrophil-, platelet or spleen-response | Through end of treatment, up to approximately 4 years | In participants with CMML only |
Contacts
CONTACTInstitut de Recherches Internationales Servier (I.R.I.S.)
Outcome results
None listed