2024-514356-33-00招募中2 期
Phase 1/2 Clinical Trial of S227928, an Anti-CD74 Antibody-Drug Conjugate Targeting MCL-1, as a Single Agent and in Combination with Venetoclax in Patients with Relapsed/Refractory (R/R) Acute Myeloid Leukemia (AML), Myelodysplastic Syndrome (MDS)/AML, or Chronic Myelomonocytic Leukemia (CMML)
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 入组人数
- 54
- 试验地点
- 7
- 主要终点
- Phase I: Incidence and severity of dose-limiting toxicities (DLTs) of S227928 as a single agent and combined with venetoclax during the first cycle of treatment.
研究概览
简要总结
Phase I: To assess the safety and tolerability, and to determine the maximum tolerated dose (MTD), if appropriate, of S227928 as a single agent Phase I: To assess the safety and tolerability, and to determine the Recommended Phase II Dose (RP2D) and/or the Maximum Tolerated Dose (MTD) of S227928 in combination with venetoclax. Phase II: To assess the anti-leukemic activity of S227928 in combination with venetoclax in participants with R/R AML or MDS/AML (cohort 1). Phase II: To assess the anti-leukemic activity of S227928 in combination with venetoclax in participants with R/R CMML (cohort 2).
研究设计
- 分配方式
- Not Applicable
- 主要目的
- Phase II: Dose expansion (RP2D of S227928 in combination with venetoclax) and CR evaluation
- 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
- 是
入选标准
- •Adult participant (must be ≥ 18 years of age or according to local requirements).
- •Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.except for European Countries where only ECOG performance status of 0 and 1 will be allowed.
- •Written informed consent must be obtained prior to any study-specific procedures.
- •Patients with pathologically confirmed AML, MDS/AML, or CMML as defined by the WHO 2022 classification or ICC, who have been previously treated with at least one prior standard treatment and have relapsed and/or refractory disease: a. Patients must not be candidates for further standard therapy, b. Treatment with agents for lower risk MDS such as erythropoietin or luspatercept are not considered anticancer therapies. c. Patients with R/R MDS with bone marrow blast count that does not meet ICC criteria for MDS/AML (i.e., bone marrow blast count <10%) will not be eligible for this study.
- •Circulating leukocytes < 10 x 10^9/L (use of hydroxycarbamide before study drug initiation is allowed to achieve this inclusion criterion).
- •Adequate renal and hepatic function within 7 days before study enrollment.
排除标准
- •Failure to recover to ≤ Grade 1 (Common Terminology Criteria for Adverse Events version 5.0 [CTCAE v5.0]) from acute non-hematologic toxicities due to previous therapy, prior to screening.
- •For all participants receiving S227928 in combination with venetoclax (i.e., Arm B dose escalation and dose expansion), those with a malabsorption syndrome or other condition that precludes enteral route of administration.
- •For all participants receiving S227928 (as a single agent and in combination with Venetoclax): Although participants may be treated with strong inhibitors of CYP3A4 or of CYP2C8, they may not be treated with medications that are strong inhibitors of both CYP3A4 and CYP2C8, or with separate medications that when combined would cause strong inhibition of these two enzymes. In addition, participants may not be treated with a strong inhibitor of CYP3A4 and a moderate inhibitor of CYP2C8 and/or a moderate inhibitor of P-gp. These prohibitions begin 7 days prior to the start of IMP and continue for the entire duration of treatment. Triazole antifungal agents may be used, but only if they are in agreement with the criteria described above (i.e., they must not be dual strong inhibitors of both CYP3A4 and CYP2C8 or strong inhibitors of CYP3A4 and moderate inhibitors of either CYP2C8 or P-gp.
- •Participants previously treated with S227928 in Arm A will not be eligible for treatment in Arm B.
- •For all participants receiving S227928 in combination with venetoclax (i.e., Arm B dose escalation and dose expansion): Both moderate and strong CYP3A4 inducers are prohibited, beginning 14 days before the start of IMP and continuing for the entire duration of treatment.
- •For all participants receiving S227928 in combination with venetoclax (i.e., Arm B dose escalation and dose expansion): BCRP inhibitors, and medications which are substrates of P-gP, BCRP, or OATP1B1 with a narrow therapeutic index (NTIs) are prohibited, beginning 7 days prior to the start of IMP and continuing for the entire duration of treatment. If concomitant use of P-gp substrate is unavoidable, its dosing should be done at least 6 hours apart from venetoclax.
- •Diagnosis of myeloproliferative neoplasms (MPNs) or other non-CMML MDS/MPNs as defined by the WHO 2022 classification
- •Diagnosis of acute promyelocytic leukemia (French-American-British [FAB] M3 classification).
- •Diagnosis of acute leukemia of mixed or ambiguous lineage or histiocytic/dendritic cell neoplasms defined by the WHO 2022 classification.
- •Uncontrolled infections requiring systemic antibiotics and/or antifungal agents as per investigator’s judgment. Patients receiving prophylactic antibiotics and/or antifungal agents are eligible for this study.
- •Participants with a known clinically significant cardiovascular disease or condition, including: a. Uncontrolled arterial hypertension per the investigator’s judgment, b. New York Heart Association (NYHA) class III or IV congestive heart failure, c. Congenital or substance-induced long QT defined as heart rate-corrected QT (QTc) interval > 470 ms according to Fridericia’s formula, d. Uncontrolled cardiac arrhythmia (e.g., participants with rate-controlled atrial fibrillation are eligible), e. Severe uncorrected conduction disturbances (e.g., 3rd degree heart block). Patients with severe conduction disturbances corrected by a pacemaker are eligible, f. Acute coronary syndrome (including unstable angina pectoris, acute myocardial infarction),coronary angioplasty or bypass grafting within 6 months prior to the first IMP administration, g. Troponin I > ULN or troponin T > ULN if troponin I cannot be assessed, h. Any factors that could increase the risk of QTc interval prolongation or risk of arrhythmic events such as heart failure, family history of QT syndrome, or family history of unexplained sudden death under 40 years of age.
- •Known active central nervous system involvement by AML, MDS/AML, or CMML
结局指标
主要结局
Phase I: Incidence and severity of dose-limiting toxicities (DLTs) of S227928 as a single agent and combined with venetoclax during the first cycle of treatment.
Phase I: Incidence and severity of dose-limiting toxicities (DLTs) of S227928 as a single agent and combined with venetoclax during the first cycle of treatment.
Phase I: Incidence of adverse events (AEs) and serious adverse events (SAEs), changes in vital signs, physical examination, laboratory tests, including cardiac markers,electrocardiogram (ECG), echocardiogram (ECHO) with or without global longitudinal strain (GLS) or multigated acquisition (MUGA) scan, and cardiac magnetic resonance imaging (MRI).
Phase I: Incidence of adverse events (AEs) and serious adverse events (SAEs), changes in vital signs, physical examination, laboratory tests, including cardiac markers,electrocardiogram (ECG), echocardiogram (ECHO) with or without global longitudinal strain (GLS) or multigated acquisition (MUGA) scan, and cardiac magnetic resonance imaging (MRI).
Phase I: Dose reductions/interruptions/delays or study withdrawal due to AEs.
Phase I: Dose reductions/interruptions/delays or study withdrawal due to AEs.
Phase II: Complete Remission (CR).
Phase II: Complete Remission (CR).
次要结局
- Plasma concentration vs. time profile and derived PK parameters (i.e., Cmax, Tmax, AUC) of S227928, total monoclonal antibody (mAb), and unconjugated S64315 and venetoclax (when applicable)
- Phase I: Detection of anti-drug antibodies (ADAs) against S227928 and their titer, when applicable.
- Phase I: Complete remission (CR), complete remission with incomplete hematologic recovery (CRi), morphologic leukemia-free state (MLFS), CR with partial hematologic recovery (CRh), and partial remission (PR) for patients with AML and MDS/AML.
- Phase I: Overall survival (OS), duration of response (DOR), and time to first remission (CR or CRh or CRi) for patients with AML and MDS/AML.
- Phase I: Red-blood cell (RBC) and platelet transfusion independence for at least 8 weeks for patients with AML and MDS/AML.
- Phase I: CR, CRh, CR with limited count recovery (CRL), CR equivalent, PR, hematologic improvement (HI); overall response rate (ORR)= CR + CR equivalent + CRh + CRL+ PR + HI for patients with CMML.
- Phase I: Progression-free survival (PFS), event-free survival (EFS), and OS for patients with CMML.
- Phase II: CRi, MLFS, CRh, PR; OS, EFS, DOR, time to first remission (CR or CRi or CRh); RBC and platelet transfusion independence for at least 8 weeks for patients with AML and MDS/AML.
- Phase II: CRh, CRL, CR equivalent, PR, HI; ORR= CR + CR equivalent + CRh + CRL + PR + HI; PFS, EFS, and OS for patients with CMML.
- Phase II: Plasma concentrations vs. time profile of S227928, total mAb, unconjugated S64315, and venetoclax and derived PK parameters (i.e., Cmax, Tmax, AUC) of S227928, total mAb and unconjugated S64315.
- Phase II: Detection of ADAs against S22798 and their titer, when applicable.
- Phase II: Incidence and severity of DLTs of S227928 in combination with venetoclax; Incidence of AEs and SAEs
- Phase II: changes in vital signs, physical examination, laboratory tests including cardiac markers, ECG, ECHO with or without GLS or MUGA scan, and cardiac MRI.
- Phase II: Dose reduction/interruptions/delays or study withdrawal due to AEs.
研究者
Clinical Studies Department
Scientific
Institut De Recherches Internationales Servier IRIS
研究点 (7)
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