Phase 1b Study of IDH Inhibition With Enasidenib and MEK Inhibition With Cobimetinib in Patients With Relapsed or Refractory Acute Myeloid Leukemia Who Have Co-Occurring IDH2 and RAS Signaling Gene Mutations
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- 入组人数
- 3
- 试验地点
- 2
- 主要终点
- Incidence of adverse events
研究概览
简要总结
This phase Ib trial tests the safety, side effects, and best dose of a enasidenib in combination with cobimetinib in treating patients with acute myeloid leukemia that has come back (relapsed) or does not respond to treatment (refractory). Enasidenib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Cobimetinib is used in patients whose cancer has a mutated (changed) form of a gene called BRAF. It is in a class of medications called kinase inhibitors. It works by blocking the action of an abnormal protein that signals cancer cells to multiply. This helps slow or stop the spread of cancer cells. Giving enasidenib and cobimetinib may kill more cancer cells in patients with relapsed or refractory acute myeloid leukemia.
详细描述
PRIMARY OBJECTIVES:
I. Assess the safety and tolerability of cobimetinib in combination with enasidenib.
II. Determine the maximum tolerated dose(s) (MTD) and recommended phase 2 dose (RP2D).
SECONDARY OBJECTIVES:
I. Obtain preliminary estimates of clinical activity as measured by the complete remission (complete response [CR], complete response with incomplete hematologic recovery [CRi], or complete response with partial hematologic recovery [CRh]) rate and minimal residual disease (MRD) rate.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 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 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Main Inclusion Criteria
- •Patients with histologically confirmed AML, according to WHO criteria, with refractory/relapsed (R/R) disease who are ineligible for therapies known to be effective for treatment of their AML.
- •Patients with non-central nervous system (CNS) extramedullary disease may be included if they also have marrow involvement
- •Patients with acute promyelocytic leukemia (APL) will not be eligible
- •Patients with IDH2 mutations, who were previously treated with enasidenib are allowed
- •Have a documented IDH2 gene mutation (≥ 2% allele frequency) and a concomitant detectable RAS-pathway mutation (as determined by local testing), involving NRAS, KRAS, HRAS, BRAF, KIT, RIT1, PTPN11, CBL or NF1 genes.
- •Adults aged ≥ 18 years
- •WBC ≤25 x 10^9/L prior to initiation of enasidenib.
排除标准
- •Current or planned use of other investigational agents, antineoplastic, chemotherapy, radiation therapy, biological therapy, immunotherapy or major surgery within 2 weeks or 5 half-lives, whichever is shorter, prior to Day 1 of protocol therapy (exception: hydroxyurea is allowed in cycles 1 and 2 for control of rapidly progressing leukemia or for treatment of enasidenib-related leukocytosis)
- •Systemic steroid therapy > 10 mg/day (≤ 10mg/day prednisone equivalent ok) or any other form of immunosuppressive medication within 28 days, except as required for treatment of differentiation syndrome
- •Strong and moderate CYP3A4 inducers/inhibitors (moderate CYP3A4 inhibitors only allowed on Principal Investigator approval) within 14 days or 5 half-lives, whichever is shorter, prior to Day 1 of protocol therapy
- •Foods/supplements that are strong or moderate inhibitors or inducers of CYP3A (such as grapefruit, Seville oranges, starfruit and St. John's wort) within 7 days prior to initiation of and during study treatment
- •Gastrointestinal disorder such as maladsorption syndrome or any other disorder that may interfere with oral drug absorption
- •Clinically significant cardiac morbidities (Class III/IV cardiovascular disability according to the New York Heart Association Classification, arrhythmia not stable on medical management, acute cardiovascular ischemic event within 6 months of enrollment, etc)
- •Active CNS disease
研究组 & 干预措施
Treatment (cobimetinib, enasidenib mesylate)
Patients receive cobimetinib PO QD on days 1-21 and enasidenib mesylate PO QD on days 1-28 of each cycle. Treatment repeats every 28 days for 12 cycles in the absence of disease progression or unacceptable toxicity.
干预措施: Cobimetinib (Drug)
Treatment (cobimetinib, enasidenib mesylate)
Patients receive cobimetinib PO QD on days 1-21 and enasidenib mesylate PO QD on days 1-28 of each cycle. Treatment repeats every 28 days for 12 cycles in the absence of disease progression or unacceptable toxicity.
干预措施: Enasidenib Mesylate (Drug)
结局指标
主要结局
Incidence of adverse events
时间窗: Up to 30 days after last dose of study drug
Toxicity will be graded according to the NCI- CTCAE version 5.0. Observed toxicities will be summarized in terms of type (organ affected or laboratory determination), severity, time of onset, duration, probable association with the study treatment and reversibility or outcome.
Dose limiting toxicity
时间窗: Cycle 1 (28 days)
Toxicity will be graded according to the National Cancer Institute (NCI)-Common Terminology Criteria for Adverse Events (CTCAE), version 5.0.
次要结局
- Response(Up to 1 year)
- Minimal residual disease (MRD) status(Up to 1 year)
- Complete remission(Up to 1 year)
- Time to first response(From first study does to first documented complete response, assessed up to 3 years)
- Response duration(From first study does to first documented complete response, assessed up to 1 year)
- Event-free survival (EFS)(From first study dose to first documented complete response to relapse/progression (> 5% blasts, reappearance of blasts in blood, or development of extramedullary disease) or death, whichever occurs first, assessed up to 1 year)
- Overall survival (OS)(From first study dose to death from any cause, assessed up to 1 year)