A Phase 1b Study to Evaluate the Safety, Tolerability, and Pharmacokinetics/Pharmacodynamics of MK-0482 in Participants With Relapsed or Refractory Acute Myeloid Leukemia or Chronic Myelomonocytic Leukemia
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 13
- 试验地点
- 5
- 主要终点
- Percentage of Participants Who Experienced a Dose-Limiting Toxicity (DLT)
研究概览
简要总结
The purpose of this study is to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and recommended Phase 2 dose (RP2D) of MK-0482. There are 2 parts of this study. Part 1 is a dose escalation which will follow an accelerated titration design (ATD) for participants with relapsed/refractory (R/R) AML or CMML. Part 2 is a dose expansion for participants with R/R AML.
详细描述
In Part 1, single participants will be enrolled sequentially into escalating dose levels. Progression from one dose level to the next higher dose level will be based on the evaluation of dose-limiting toxicity (DLT). Once a preliminary RP2D is identified in Part 1, approximately 10 to 15 additional participants with R/R AML will be enrolled at the RP2D for Part 2.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 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
- •Has confirmed diagnosis of AML with myelomonocytic or monoblastic/monocytic differentiation per World Health Organization (WHO) 2016 criteria and with confirmed refractory or relapsed disease (i.e., ≥5% blast in bone marrow or in peripheral blood) after treatment with available therapies known to benefit participant's AML subtypes or has a known diagnosis of CMML per WHO criteria [2017] with confirmed refractory or released disease after treatment with available therapies known to be active for CMML.
排除标准
- •Has active central nervous system (CNS) leukemia.
- •Has isolated extramedullary disease, i.e., no leukemic involvement in bone marrow or peripheral blood.
- •Has diagnosis of acute promyelocytic leukemia or participants with known Philadelphia chromosome positive (Ph+) AML.
- •Has received previous allogeneic stem cell transplant or organ transplant within 60 days of the start of study treatment.
- •Has a history of a second malignancy, unless potentially curative treatment has been completed with no evidence of malignancy for 1 year.
- •Has a history of any of the following cardiovascular conditions within 6 months of screening: myocardial infarction, unstable angina, cerebrovascular accident, transient ischemic attack, coronary artery bypass graft, or pulmonary embolism; has New York Heart Association (NYHA) Class III or IV congestive heart failure.
- •Has had a severe hypersensitivity reaction to treatment with a monoclonal antibody (mAB) and or any components of the study intervention, MK-
- •Has an active uncontrolled infection requiring directed therapy.
- •Has immediately life-threatening, severe complications of leukemia such as uncontrolled bleeding, pneumonia with hypoxia or shock, or disseminated intravascular coagulation.
- •Has known human immunodeficiency virus (HIV) and/or hepatitis B or C infections, or is known to be positive for HBsAg/ Hepatitis B virus (HBV) Deoxyribonucleic acid (DNA) or hepatitis C antibody or Ribonucleic acid (RNA).
- •Has known psychiatric or substance abuse disorders (verbally reported) that would interfere with the participant's ability to cooperate with the requirements of the study.
- •Is pregnant or breast feeding or expecting to conceive or father children within the projected duration of the study, starting with the Screening Visit through 120 days after the last dose of study intervention.
- •Has received systemic anticancer therapy, radiotherapy, or surgery within 2 weeks before the start of study treatment.
- •Has received hematopoietic cytokines (Granulocyte Colony Stimulating Factor (G-CSF), Granulocyte Macrophage (GM)-CSF, or erythropoietin) within 2 weeks prior to start of study treatment.
- •Has received a live or live attenuated vaccine within 30 days before the first dose of study medication.
- •Is currently participating and receiving study intervention in a study of an investigational agent or has participated and received study intervention in a study of an investigational agent or has used an investigational device within 14 days of administration of MK-
- •Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior the first dose of study medication.
研究组 & 干预措施
MK-0482 7.5 mg Q3W
Participants will receive 7.5 mg of MK-0482 via intravenous (IV) infusion on Day 1 of each 21-day cycle (every 3 weeks [Q3W]) for up to 35 cycles (approximately 24 months).
干预措施: MK-0482 (Biological)
MK-0482 25 mg Q3W
Participants will receive 25 mg of MK-0482 via IV infusion on Day 1 of each 21-day cycle (Q3W) for up to 35 cycles (approximately 24 months).
干预措施: MK-0482 (Biological)
MK-0482 75 mg Q3W
Participants will receive 75 mg of MK-0482 via IV infusion on Day 1 of each 21-day cycle (Q3W) for up to 35 cycles (approximately 24 months).
干预措施: MK-0482 (Biological)
MK-0482 225 mg Q3W
Participants will receive 225 mg of MK-0482 via IV infusion on Day 1 of each 21-day cycle (Q3W) for up to 35 cycles (approximately 24 months).
干预措施: MK-0482 (Biological)
MK-0482 750 mg Q3W
Participants will receive 750 mg of MK-0482 via IV infusion on Day 1 of each 21-day cycle (Q3W) for up to 35 cycles (approximately 24 months).
干预措施: MK-0482 (Biological)
结局指标
主要结局
Percentage of Participants Who Experienced a Dose-Limiting Toxicity (DLT)
时间窗: Cycle 1 (up to 21 days)
DLTs were defined as any of the following assessed as treatment-related by investigator (with pre-specified exceptions): Grade (Gr) 4 non-hematologic toxicity; Gr 3 non-hematologic toxicity; Gr 3 or Gr 4 non-hematologic laboratory value if: clinically significant medical intervention was required to treat the participant, the abnormality led to hospitalization, the abnormality persisted for \>1 week, electrolyte imbalances that lasted \>48 hours despite optimal therapy, or the abnormality resulted in a drug-induced liver injury; Gr 4 neutropenia and/or thrombocytopenia lasting \>14 days; \>2 week-delay in starting Cycle 2 due to treatment-related toxicity; treatment-related toxicity resulting in treatment discontinuation during DLT evaluation period; missing \>25% of MK-0482 dose during DLT evaluation period resulting from treatment-related adverse event (AE); or Gr 5 toxicity. The percentage of participants that experienced a DLT was reported for each arm.
Number of Participants Who Experience at Least One Adverse Event (AE)
时间窗: Up to approximately 10 months
An AE was defined as any untoward medical occurrence in a participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. The number of participants who experienced at least one AE was reported for each arm.
Number of Participants Who Discontinued Study Treatment Due to an AE
时间窗: Up to approximately 4 months
An AE was defined as any untoward medical occurrence in a participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. The number of participants who discontinued study treatment due to an AE was reported for each arm.
次要结局
- Maximum Concentration (Cmax) of MK-0482(Cycle 1: Pre-dose and Days 1, 2, 4, 8, and 15 post-dose. Cycle=21 days.)
- Minimum Concentration (Cmin) of MK-0482(Cycle 1: Pre-dose and Days 1, 2, 4, 8, and 15 post-dose. Cycle=21 days.)
- Area Under the Plasma Concentration-Time Curve From Time Zero to 21 Days (AUC0-21) of MK-0482(Cycle 1: Pre-dose and Days 1, 2, 4, 8, and 15 post-dose. Cycle=21 days.)
- Time to Maximum Concentration (Tmax) of MK-0482(Cycle 1: Pre-dose and Days 1, 2, 4, 8, and 15 post-dose. Cycle=21 days.)
- Plasma Elimination Terminal Half-life (t½) of MK-0482(Cycle 1: Pre-dose and Days 1, 2, 4, 8, and 15 post-dose. Cycle=21 days.)
- Complete Remission (CR) Rate(Up to approximately 10 months)
- Composite CR Rate(Up to approximately 10 months)
- Objective Response Rate (ORR)(Up to approximately 10 months)