A Phase Ib/II Open Label Dose Confirmation, Proof of Concept Study of Siremadlin in Combination With Venetoclax Plus Azacitidine in Unfit Adult AML Participants Who Responded Sub-optimally to First-line Venetoclax Plus Azacitidine Treatment and in Participants With Newly Diagnosed Unfit AML Presenting With High-risk Clinical Features
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 14
- 试验地点
- 13
- 主要终点
- Percentage of participants treated at the recommended dose for expansion, achieving a complete remission (CR) as per investigator assessment (Arm 1 only)
研究概览
简要总结
A study of siremadlin in combination with venetoclax plus azacitidine in adult participants with AML who are ineligible for chemotherapy.
The primary purpose of this study was to assess whether siremadlin in combination with venetoclax plus azacitidine can enhance the clinical response in unfit AML participants without unacceptable levels of treatment-emergent toxicities.
详细描述
The recommended dose of siremadlin in combination with venetoclax plus azacitidine was to be determined to be explored further in the expansion phase and the preliminary efficacy in achieving Complete Remission (CR) evaluated in participants who responded sub-optimally to first-line venetoclax plus azacitidine treatment.
The study was planned to be conducted in two parts. The primary purpose of Part 1 (Safety Run- in) was to rule out excessive toxicity of siremadlin when administered in combination with venetoclax plus azacitidine while the primary purpose of Part 2 (Expansion) was to evaluate the preliminary efficacy of siremadlin when combined with venetoclax plus azacitidine in the respective patient population.
The study treatment (siremadlin in combination with venetoclax plus azacitidine) was administered in cycles with a planned duration of 28 days for each cycle and would continue until the participants experienced disease progression/relapse or unacceptable toxicity.
The initial enrollment plan and safety review was as follow:
- In the Safety run-in part, 9-15 participants were planned to be enrolled in each arm. Approximately 3-6 participants were planned to be enrolled at the starting dose level of siremadlin in combination with venetoclax plus azacitidine in both arms independently. Provided the starting dose level was determined to be safe, approximately 6-9 additional participants were planned to be enrolled at dose level +1. Safety review meetings were planned to take place involving participating investigators and the Sponsor Team to make decisions regarding siremadlin dose and determine the recommended dose for expansion.
- Approximately 26 patients were planned to be treated at the recommended dose in the expansion part.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 99 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age at the date of signing the informed consent form (ICF):
- •Arm 1 and Arm 2: ≥ 18 years
- •Participants diagnosed with AML based on WHO 2016 classification (Arber et al 2016) who are ineligible for standard induction chemotherapy and:
- •Arm 1 : have received at least 2 cycles and not more than 4 cycles of first-line venetoclax plus azacitidine treatment and have not achieved a CR, CRi, CRh or MLFS.
- •Arm 2 : newly diagnosed AML with adverse genetic risk stratification (according to ELN 2022) (except TP53 mutation positive participants).
- •Participant (in both arms) must be considered ineligible for standard of care intensive induction chemotherapy defined by the following:
- •75 years of age; OR
- •18 to 74 years of age with at least one of the following co-morbidities: Eastern Cooperative Oncology Group (ECOG) Performance Status of 2 or 3; Cardiac history of congestive heart failure (CHF) requiring treatment or Ejection Fraction ≤ 50% or chronic stable angina; DLCO ≤ 65% or FEV1 ≤ 65%.
- •Participants must have an ECOG performance status:
- •0 to 2 for participants ≥ 75 years of age. OR 0 to 3 for participants ≥ 18 to 74 years of age.
- •WBC < 25x109/L
- •AST and ALT ≤ 3 × ULN
- •Estimated Glomerular Filtration Rate (eGFR)≥ 60 mL/min/1.73 m2
排除标准
- •Prior exposure to MDM2-inhibitor therapy at any time.
- •Participants with TP53 mutation positive.
- •Participants with del17p.
- •Participants with AML-M3 / APL (Acute promyelocytic leukemia) with PML-RARA (Promyelocytic leukemia/retinoic acid receptor alpha) or with AML secondary to Down's syndrome.
- •Participants treated with FLT3 inhibitors for AML indication are not eligible.
- •Participants who require treatment with moderate or strong CYP3A4 inducers within 14 days prior to starting study treatment, or are expected to receive moderate or strong CYP3A4 inducers during the entire study
- •Participants who require treatment with substrates of CYP3A4/5 with a narrow therapeutic index.
结局指标
主要结局
Percentage of participants treated at the recommended dose for expansion, achieving a complete remission (CR) as per investigator assessment (Arm 1 only)
时间窗: At least 7 cycles (196 days)
The objective is to evaluate preliminary efficacy of siremadlin at the determined recommended dose for expansion (RDE) when administered in combination with venetoclax and azacitidine. This endpoint will not be analyzed since the recommended dose was not determined due to early termination.
Percentage of participants with Dose Limiting Toxicities (DLTs) as per investigator assessment reported during the first cycle (separately in Arm 1 & Arm 2)
时间窗: From Cycle 1 Day 1 to Cycle 1 Day 28 (28 days)
A dose-limiting toxicity (DLT) is defined as an adverse event (AE) or abnormal laboratory value considered by the Investigator to be at least possibly related to siremadlin as a single contributor or in combination with other component(s) of study treatment that occurs beginning the first day of siremadlin dosing in the study until end of cycle 1.
次要结局
- Time of the date of the first documented CR to the date of the first documented relapse or death due to any cause, whichever occurs first (Arm 1 and Arm 2 separately)(up to 3 years)
- PK parameter: Cmax of siremadlin, venetoclax and azacitidine (Arm 1 and Arm 2)(up to 3 years)
- Percentage of participants achieving CR or complete remission with partial hematological recovery (CRh) and percentage of participants achieving CR or complete remission with incomplete hematological recovery (CRi) (Arm 1 and Arm 2)(up to 3 years)
- The time from start of treatment to death due to any cause (Arm 1 and Arm 2 separately)(up to 3 years)
- PK parameter: Tmax of siremadlin, venetoclax and azacitidine (Arm 1 and Arm 2)(up to 3 years)
- Percentage of participants treated at the recommended dose for expansion, achieving CR as per investigator assessment (Arm 2 only; for Arm 1 assessment of CR is a primary outcome measure))(up to 3 years)
- Pharmacokinetic (PK) parameters: AUCs of siremadlin, venetoclax and azacitidine (Arm 1 and Arm 2)(up to 3 years)
- Percentage of participants died due to any cause from start of treatment until 30- and 60-day (Arm 1 and Arm 2)(30 days & 60 days from start of study treatment)
- Time from the date of the first documented CR/CRh and CR/CRi to the date of first documented relapse or death due to any cause, whichever occurs first (Arm 1 and Arm 2 separately)(up to 3 years)
- Percentage of CR- Measurable Residual Disease (MRD) negative overall and in participants achieving a CR, CR/CRh, and CR/CRi (Arm 1 and Arm 2)(up to 3 years)