An Open-Label, Multicenter, Phase 1b/2 Study of the Safety and Efficacy of KRT-232 When Administered Alone and in Combination With Low-Dose Cytarabine (LDAC) or Decitabine in Patients With Acute Myeloid Leukemia (AML)
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 70
- 试验地点
- 58
- 主要终点
- Part A: To determine KRT-232 recommended phase 2 dose (RP2D)
研究概览
简要总结
This study evaluates KRT-232, a novel oral small molecule inhibitor of MDM2, when administered alone and in combination with low-dose cytarabine (LDAC) or Decitabine for the treatment of adults with Acute Myeloid Leukemia (AML) and AML secondary to myeloproliferative neoplasms (MPN). Participants must be relapsed/refractory (having failed prior therapy) and will be assigned to receive monotherapy (KRT-232 alone) or combination therapy (KRT-232 with LDAC or KRT-232 with Decitabine).
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Part A: Patients with relapsed or refractory AML, or newly-diagnosed AML secondary to MPN
- •Part B:Patients with relapsed or refractory AML secondary to MPN (myelofibrosis [MF], polycythemia vera [PV], or essential thrombocythemia [ET]); patients may have been treated with ≥1 prior lines of therapy for their AML secondary to MPN.
- •Adequate hepatic and renal function
- •Appropriate prior treatment with an FLT3 or IDH1/2 inhibitor where applicable
排除标准
- •Patients who are TP53 mutation positive
- •Prior treatment with an MDM2 antagonist therapy
- •Patients treated with ≥ 18 g/m2 of cytarabine within the prior 90 days are not eligible to be treated with cytarabine on this study but may be treated with decitabine (for Part A) .
- •Patients previously treated with decitabine are not eligible to receive decitabine on this study but may be treated with cytarabine (for Part A) .
- •Patients who have received an allogeneic HSCT within 90 days of enrollment or who have active graft-versus-host disease requiring active therapy (for Part A)
- •Allogeneic stem cell transplant within 3 months; autologous stem cell transplant within 3 months or active graft-versus-host disease prior to first dose of study treatment (for Part B)
- •Patients who have received immunosuppressive therapy for graft-versus-host disease within 1 month prior to enrollment into this study
- •Patients who are eligible for an allogeneic HSCT per the opinion of the investigator and have a donor. Patients who are HSCT-eligible in the opinion of the investigator, but who refuse a transplant, are eligible for the study.
- •Patients with known CNS involvement with AML, acute promyelocytic leukemia (APL), or a history of bleeding diathesis
- •Patients who have had major surgery within 28 days prior to the first treatment with KRT-232
- •Women who are pregnant or breastfeeding
研究组 & 干预措施
Part A - Arm 1
KRT-232+LDAC:
KRT-232 will be administered orally, once daily (QD), on Days 1-7 in combination with LDAC administered at 20 mg/m2/day subcutaneously on Days 1-10 in a 28-day cycle.
干预措施: KRT-232 (Drug)
Part A - Arm 1
KRT-232+LDAC:
KRT-232 will be administered orally, once daily (QD), on Days 1-7 in combination with LDAC administered at 20 mg/m2/day subcutaneously on Days 1-10 in a 28-day cycle.
干预措施: Cytarabine (Drug)
Part A - Arm 2
KRT-232(7-Day)+Decitabine:
KRT-232 will be administered orally, once daily (QD), on Days 1-7 in combination with Decitabine administered at 20 mg/m2/day intravenously on Days 1-5 in a 28-day cycle.
干预措施: KRT-232 (Drug)
Part A - Arm 2
KRT-232(7-Day)+Decitabine:
KRT-232 will be administered orally, once daily (QD), on Days 1-7 in combination with Decitabine administered at 20 mg/m2/day intravenously on Days 1-5 in a 28-day cycle.
干预措施: Decitabine (Drug)
Part A - Arm 3
KRT-232(14-Day)+Decitabine:
KRT-232 will be administered orally, once daily (QD), on Days 1-7 and Days 15-21 (7 days on/7 days off/7 days on/7 days off) in combination with Decitabine administered at 20 mg/m2/day intravenously on Days 1-5 in a 28-day cycle.
干预措施: KRT-232 (Drug)
Part A - Arm 3
KRT-232(14-Day)+Decitabine:
KRT-232 will be administered orally, once daily (QD), on Days 1-7 and Days 15-21 (7 days on/7 days off/7 days on/7 days off) in combination with Decitabine administered at 20 mg/m2/day intravenously on Days 1-5 in a 28-day cycle.
干预措施: Decitabine (Drug)
Part B - Arm 1
KRT-232 administered at 360 mg orally, once daily (QD) on Days 1-7 with 21 days off on a 28-day treatment cycle
干预措施: KRT-232 (Drug)
Part B - Arm 2
KRT-232 administered at 360 mg orally, once daily (QD) on Days 1-7 with 21 days off on a 28-day treatment cycle in Cycle 1, followed by 240 mg orally, once daily (QD) on Days 1-7 with 21 days off on a 28-day cycle, in the subsequent cycles.
干预措施: KRT-232 (Drug)
Part B - Arm 3
KRT-232 administered at 180 mg orally, once daily (QD) on Days 1-7 with 14 days off on a 21-day treatment cycle.
干预措施: KRT-232 (Drug)
结局指标
主要结局
Part A: To determine KRT-232 recommended phase 2 dose (RP2D)
时间窗: 28 Days
Number of dose-limiting toxicities (DLTs) of KRT-232 in combination with cytarabine or decitabine
Part B: To determine the RP2D of KRT-232
时间窗: 2 years after last patient enrolled
The safety review committee (SRC) will determine the RP2D based on safety and tolerability data obtained from each arm
次要结局
- Part A: To determine the rates of complete remission (CR) and complete remission with partial hematological improvement (CRh)(12 weeks)
- Part B: To determine the rates of complete remission (CR), CR with partial hematological improvement (CRh) and CR with incomplete hematologic recovery (CRi)(12 weeks)