A Phase 2 Study of Single-Agent MLN9708 for the Treatment of Relapsed or Refractory Acute Myeloid Leukemia With Mutated Nucleophosmin-1
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 发起方
- 入组人数
- 4
- 试验地点
- 1
- 主要终点
- Overall Response Rate (ORR)
研究概览
简要总结
This phase 2 trial studies how well ixazomib(MLN9708) works in treating study participants with relapsed or refractory acute myeloid leukemia. Ixazomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.
详细描述
PRIMARY OBJECTIVE:
Determine the best response including complete remission (CR), CR with incomplete recovery (CRi), and partial remission (PR) after 3 cycles of treatment with MLN9708 (ixazomib) in participants with nucleophosmin (NPM)1-mutated acute myeloid leukemia (AML) (following the LeukemiaNet1 guidelines for response criteria).
SECONDARY OBJECTIVES:
- Determine the duration of remission in all responders after treatment with MLN9708 defined as the time of documented remission until relapse.
- Determine the 1 year overall survival, which will be measured from time of study entry to the earlier of death from any cause or end of follow up at 1 year.
- Establish toxicity and tolerability of MLN9708 treatment in AML, including non-hematologic toxicities grade 3 or above as specified by Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.
OUTLINE:
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
- •Diagnosis of relapsed or refractory AML of any French American British (FAB) subtype except M3 and NPM1 genetic mutation detected by molecular assay; AML patients treated at Stanford have NPM1 molecular mutation status checked routinely at time of diagnosis in a Clinical Laboratory Improvement Amendment (CLIA)-certified laboratory
- •Male or female patients and no race-ethnic restrictions
- •Patients are unwilling, or who are determined to be medically unfit for or resistant to standard intensive induction chemotherapy; patients who are medically unfit will be determined by the treating primary hematologist and the principal investigator (including but not limited to evaluation of co-morbidities, and response and complications to previous AML treatment strategy)
- •Eastern Cooperative Oncology Group (ECOG) 0 to 2
- •Ability to understand and the willingness to sign a written informed consent document
- •Female patients who:
- •Are postmenopausal for at least 1 year before the screening visit, OR
- •Are surgically sterile, OR
- •If they are of childbearing potential, agree to practice 2 effective methods of contraception, at the same time, from the time of signing the informed consent form through 90 days after the last dose of study drug, AND
- •Must also adhere to the guidelines of any treatment-specific pregnancy prevention program, if applicable, OR
- •Agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject; (periodic abstinence [eg, calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of contraception)
- •Male patients, even if surgically sterilized (ie, status post-vasectomy), must agree to one of the following:
- •Agree to practice effective barrier contraception during the entire study treatment period and through 90 days after the last dose of study drug, OR
- •Must also adhere to the guidelines of any treatment-specific pregnancy prevention program, if applicable, OR
- •Agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject; (periodic abstinence (eg, calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of contraception)
- •Total bilirubin ≤ 1.5 x the upper limit of the normal range (ULN)
- •Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 x ULN
- •Calculated creatinine clearance ≥ 30 mL/min
排除标准
- •Female patient who are lactating or have a positive serum pregnancy test during the screening period
- •Major surgery within 14 days before enrollment
- •Radiotherapy within 14 days before enrollment; if the involved field is small, 7 days will be considered a sufficient interval between treatment and administration of MLN9708
- •Known active and uncontrolled central nervous system (CNS) involvement of leukemia (a lumbar puncture does not need to be performed as a part of screening)
- •Have a significant uncontrolled infection active infection
- •Have other severe concurrent disease or serious organ dysfunction involving the heart, kidney, liver or other organ system that may place the patient at undue risk to undergo treatment including uncontrolled hypertension, uncontrolled cardiac arrhythmias, symptomatic congestive heart failure, unstable angina, or myocardial infarction within the past 6 months
- •Systemic treatment, within 14 days before the first dose of MLN9708, with strong inhibitors of cytochrome P450, family 1, subfamily A, polypeptide 2 (CYP1A2) (fluvoxamine, enoxacin, ciprofloxacin), strong inhibitors of cytochrome P450, family 3, subfamily A (CYP3A) (clarithromycin, telithromycin, itraconazole, voriconazole, ketoconazole, nefazodone, posaconazole) or strong CYP3A inducers (rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, phenobarbital), or use of Ginkgo biloba or St. John's wort
- •Known ongoing or active systemic infection, active hepatitis B or C virus infection, or known human immunodeficiency virus (HIV) positive
- •Known gastrointestinal (GI) disease or GI procedure that could interfere with the oral absorption or tolerance of MLN9708 including difficulty
- •Diagnosed or treated for another malignancy within 2 years before study enrollment or previously diagnosed with another malignancy and have any evidence of residual disease; patients with nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone complete resection; this does not preclude previous diagnosis of acute myeloid leukemia or myelodysplastic syndrome
- •Patient has ≥ grade 3 peripheral neuropathy, or grade 2 with pain on clinical examination during the screening
- •Participation in other clinical trials, including those with other investigational agents not included in this trial, within 21 days of the start of this trial and throughout the duration of this trial
- •Known allergy to any of the study medications, their analogues, or excipients in the various formulations of any agent
研究组 & 干预措施
Ixazomib (MLN9708)
Participants receive ixazomib PO (orally) on days 1, 4, 8, and 11. Treatment repeats every 21 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.
干预措施: Ixazomib (Drug)
结局指标
主要结局
Overall Response Rate (ORR)
时间窗: 9 weeks
Overall response rate after 3 cycles of treatment (9 weeks) was assessed as complete remission (CR); CR with incomplete recovery (CRi); and partial remission (PR) with MLN9708, in participants with NPM1-mutated AML by LeukemiaNet1 guidelines: Although achievement of complete remission (CR) has unique clinical significance for improved overall survival (OS) and relapse-free survival (RFS) compared to achievement of CRi with incomplete platelet recovery, the latter is still a clinically meaningful response, as it is independently-superior to resistant disease. Partial remission (PR) is defined as meeting all hematologic criteria for CR with an allowance for 5% to 25% bone marrow blasts or decrease of pre-treatment bone marrow blast percentage by at least 50%. Stable disease is defined as a change in bone marrow aspirate blast count within 10% of baseline. Relapsed disease is defined as reappearance of blasts in the blood or bone marrow blasts
次要结局
- Duration of Response (DOR)(1 year)
- Overall Survival (OS)(1 year)
- Serious Adverse Events Related to Ixazomib(1 year)
研究者
Steven E. Coutre
Assistant Professor of Medicine
Stanford University