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
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 入组人数
- 38
- 试验地点
- 27
- 主要终点
- Part 1A: - dose limiting toxicities (DLTs) associated with S241656 during the first cycle of treatment - Incidence, severity and duration of AEs and SAEs, changes in safety laboratory results, changes in the physical examination, and in other clinically relevant safety parameters - Dose reductions/interruptions/delays or study withdrawal due to AEs
研究概览
简要总结
Part 1A: To evaluate the safety and tolerability of S241656 as monotherapy in participants with AML, MDS/AML or CMML Part 1B (optional): To assess the effect of multiple oral doses of posaconazole, a strong CYP3A4 inhibitor, on the plasma PK of S241656 and S243796 at steady state. Part 1B (optional): To assess the safety and tolerability of S241656 during and after co-administration with posaconazole.
研究设计
- 分配方式
- Na
- 主要目的
- Part 1B
- 盲法
- None
入排标准
- 年龄范围
- 18 years 至 65+ years（18-64 Years, 65+ Years）
- 接受健康志愿者
- 否
入选标准
- •Age ≥ 18 years
- •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
- •Women of childbearing potential (WOCBP) must use a highly effective method of birth control as specified within the protocol
- •Male participants with WOCBP partners must use a condom as specified within the protocol
- •Disease-specific inclusion by study part: Parts 1 (Dose Escalation and DDI): Relapsed/Refractory (R/R), pathologically confirmed AML, MDS/AML, or CMML (WHO 2022/ICC classifications). Must have failed ≥ 1 approved standard therapy and have no other approved standard options.
- •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).
排除标准
- •General and excluded diagnoses: - Allergy: Known hypersensitivity to S241656 or posaconazole (Part 1B). - Pregnancy: Pregnant or breastfeeding; positive serum pregnancy test for WOCBP. - Acute promyelocytic leukemia (French-American-British [FAB] M3 classification), MPN, mixed/ambiguous lineage, histiocytic/dendritic cell neoplasms - AML with isolated extramedullary disease (no marrow/blood involvement) (WHO 2022). - Active Central Nervous System (CNS) disease (by cytologic or radiographic evidence)
- •Prior therapy and washout: - 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).
- •Medical conditions and infectious diseases: - 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).
- •Cardiovascular and coagulation: - Stroke, myocardial infarction (MI), unstable angina, or acute coronary syndrome within 6 months. - Congestive heart failure (New York Heart Association (NYHA) ≥ II), 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
- •Prohibited concomitant medications - [CCI]: Must discontinue 7–14 days prior to Cycle 1 Day
- •Gastric pH: Proton Pump Inhibitors (PPIs) and potassium-competitive acid blockers ≥ 7 days prior to Cycle 1 Day
- •Substrates: breast cancer resistance protein (BCRP) sensitive substrate or with a narrow therapeutic index (NTI), [CCI] with a NTI and P-gp sensitive substrates or with a NTI - Supplements: All herbal preparations/supplements are prohibited.
研究组 & 干预措施
S241656 film-coated tablet 25mg, S241656 film-coated tablet 50mg
干预措施: S241656 film-coated tablet 25mg (Drug)
S241656 film-coated tablet 25mg, S241656 film-coated tablet 50mg
干预措施: S241656 film-coated tablet 50mg (Drug)
POSACONAZOLE
干预措施: POSACONAZOLE (Drug)
结局指标
主要结局
Part 1A: - dose limiting toxicities (DLTs) associated with S241656 during the first cycle of treatment - Incidence, severity and duration of AEs and SAEs, changes in safety laboratory results, changes in the physical examination, and in other clinically relevant safety parameters - Dose reductions/interruptions/delays or study withdrawal due to AEs
Part 1A: - dose limiting toxicities (DLTs) associated with S241656 during the first cycle of treatment - Incidence, severity and duration of AEs and SAEs, changes in safety laboratory results, changes in the physical examination, and in other clinically relevant safety parameters - Dose reductions/interruptions/delays or study withdrawal due to AEs
Part 1B: - Plasma PK parameters of S241656 and its metabolite S243796 including Cmax, Tmax, t1/2, AUC with and without posaconazole - DLTs associated with S241656 during the first cycle of treatment
Part 1B: - Plasma PK parameters of S241656 and its metabolite S243796 including Cmax, Tmax, t1/2, AUC with and without posaconazole - DLTs associated with S241656 during the first cycle of treatment
Part 1B: - Incidence, severity and duration of AEs and SAEs, changes in safety laboratory results, changes in the physical examination, and other clinically relevant safety parameters, as well as dose reductions/interruptions/delays or study withdrawal due to AEs
Part 1B: - Incidence, severity and duration of AEs and SAEs, changes in safety laboratory results, changes in the physical examination, and other clinically relevant safety parameters, as well as dose reductions/interruptions/delays or study withdrawal due to AEs
次要结局
- Part 1A: PK parameters of S241656 and its metabolite S243796 including but not limited to maximum concentration (Cmax), time to maximum concentration (Tmax), area under the curve (AUC), and terminal half-life (t½)
- Part 1A: - complete remission (CR) - complete remission with incomplete hematologic recovery (Cri) - morphologic leukemia-free state (MLFS) - complete remission with partial hematologic recovery (CRh) - partial remission (PR) - overall response (OR), composite complete remission (CRc) - RBC and platelet transfusion independence for at least 8 weeks
- Part 1A: - duration of response (DOR) - time to response (TTR) - event-free survival (EFS) - overall survival (OS) - Marrow response - Clinical benefit: erythroid-, neutrophil-, platelet- or spleen-response - Clinical efficacy parameters including but not limited to OR, CR, DOR, and EFS
- Part 1A: - Safety and tolerability parameters as defined in the study protocol. - Pharmacokinetic (PK) parameters as defined in the study protocol
- Part 1B: - CR - Cri - MLFS - CRh - PR - OR - CRc - RBC and platelet transfusion independence for at least 8 weeks - DOR - TTR - EFS - OS - Marrow response - Clinical benefit: erythroid-, neutrophil-, platelet- or spleen-response
研究者
Clinical Studies Department
Scientific
Institut De Recherches Internationales Servier IRIS