A Multi-Center, Open-Label, First-in-Human, Phase I Dose-Escalation Study to Investigate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of RO6839921, An MDM2 Antagonist, Following Intravenous Administration in Patients With Advanced Malignancies, Including Acute Myeloid Leukemia (AML)
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 68
- 试验地点
- 5
- 主要终点
- Incidence of adverse events
研究概览
简要总结
This open label, Phase I study of RO6839921 is a dose-escalation study with two arms. Prior to investigations in either arm, patients in a single cohort, Cohort 0, will receive non-escalating, intravenous (IV) doses of RO6839921 daily on Days 1-5 of a 28-day cycle. Interim PK and safety data from this cohort will be evaluated before initiating dose-escalation.
In arm A, RO6839921 will be given to patients with advanced solid tumor malignancies. In Arm B, RO6839921 will be given to patients with relapsed/refractory acute myeloid leukemia (AML). The arms will escalate independently. Escalation will begin in solid tumor patients (Arm A) in single patient cohorts, using a new Continual Reassessment Method (n-CRM). Escalation for AML patients will be initiated at or below the dose level that causes >/= Grade 2 hematologic side effects in Arm A. Escalation in AML patients will follow a rolling 6 design.
In both arms, RO6839921 will be administered by IV infusion on Days 1-5 of 28-day cycles.
There will be no intrapatient dose escalation. All patients may be treated until disease progression/relapse or unacceptable toxicity.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non 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
- •Cohort 0 and Arm A
- •Patient must have histologically or cytologically confirmed advanced cancer for which standard cures or relieving measures either do not exist, are ineffective or are not acceptable to the patient.
- •Measureable disease according to RECIST criteria version 1.
- •ECOG performance status of 0 to
- •Adequate bone marrow function.
- •Patients with documented acute myeloid leukemia (AML), except for acute promyelocytic leukemia.
- •Patients with relapsed/refractory AML or patients who have not received prior therapy who are high risk according to European LeukemiaNet (ELN) criteria.
- •ECOG performance status of 0 to
- •For Cohort 0, Arms A and B
- •Life expectancy of >/= 12 weeks.
- •Age >/= 18 years or older.
- •All patients must be willing to use effective methods of contraception until 10 days after the last dose; women must not be pregnant or breast-feeding.
- •Adequate renal and hepatic function.
- •Patients with stable central nervous system (CNS) tumors are eligible.
- •There are no requirements or limitations on the amount or type of prior anti-tumor/anti-leukemia therapy.
排除标准
- •Cohort 0 and Arm A
- •Patients with a history of any form of leukemia except for Stage 0 and 1 chronic lymphocytic leukemia (CLL) not requiring treatment.
- •Patients receiving any cancer treatment within 21 days of start of study medication. Patients must also have recovered from severe side effects due to prior treatment before study start.
- •Patients with known bone marrow disorders that may interfere with bone marrow recovery, or patients with delayed recovery from prior chemoradiotherapy.
- •Patients with known bleeding or clotting disorders or non-drug-induced low platelet count.
- •Patients receiving any cancer treatment within 14 days of start of study medication. Hydroxyurea may be taken until first administration of the study drug. Patients must also have recovered from severe side effects due to prior treatment before study start.
- •For Cohort 0, Arms A and B
- •Patients receiving any other test drugs within 30 days of start of study medication
- •Patients receiving the cytochrome P450 inhibitors, substrates or inducers specified in the protocol.
- •Anticoagulation or antiplatelet treatment must be discontinued 7 days prior to start of study medication.
- •Patients who have received hormonal therapy (except for prostate cancer treatment and hormone replacement therapy) within the 2 weeks prior to start of study medication.
- •Patients with evidence of electrolyte imbalance, which may be treated to meet eligibility.
- •Serum albumin < 2.8 g/dL.
- •HIV-positive patients who are currently receiving combination antiretroviral therapy.
- •Patients who have any severe and/or uncontrolled medical conditions or other conditions that could affect their participation in the study.
研究组 & 干预措施
Acute myeloid leukemia patients
干预措施: RO6839921 (Drug)
Cohort 0
干预措施: RO6839921 (Drug)
Solid tumor patients
干预措施: RO6839921 (Drug)
结局指标
主要结局
Incidence of adverse events
时间窗: Approximately 1 year
Incidence of dose-limiting toxicities
时间窗: Approximately 1 year
次要结局
- Changes in serum macrophage inhibitory cytokine-1 (MIC-1) expression measured by enzyme-linked immunosorbent assay (ELISA)(Up to Day 22)
- Plasma area under the concentration-time curve (AUC) of RO6839921.(Up to Day 22)