A Phase I Study of MLN9708 and Vorinostat to Target Autophagy in Patients With Advanced p53 Mutant Malignancies
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 68
- 试验地点
- 1
- 主要终点
- Maximum Tolerated Doses (MTD) of MLN9708 and Vorinostat
研究概览
简要总结
The goal of this clinical research study is to find the highest tolerable dose of the combination of MLN9708 and vorinostat that can be given to patients with advanced solid tumors. The safety of these drugs will also be studied.
详细描述
Study Groups:
If you are found to be eligible to take part in this study, you will be assigned to a dose level of MLN9708 and vorinostat based on when you join this study. Up to 4 dose levels of the MLN9708 and vorinostat combination will be tested. Up to 6 participants will be enrolled at each dose level combination. The first group of participants will receive the lowest dose level combination. Each new group will receive a higher dose of either MLN9708 or vorinostat than the group before it, if no intolerable side effects were seen. This will continue until the highest tolerable dose combination of MLN9708 and vorinostat is found or all 4 dose levels are filled. Up to an additional 14 participants will be enrolled in the highest dose level of the study drug combination.
The dose of the study drug combination that you receive may be lowered if you have intolerable side effects.
Study Drug Administration:
Each study cycle is 28 days.
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
- •Male or female patients 18 years or older.
- •Voluntary written consent must be given before performance of any study related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care.
- •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.)
- •Patients must have a diagnosis with solid tumors and lymphomas, either refractory to standard therapy or for which no effective standard therapy that conveys clinical benefit.
- •Patients must have a p53 mutation which is defined as cytoplasmic positivity by immunohistochemistry and/or next gene mutation sequencing.
- •Eastern Cooperative Oncology Group (ECOG) performance status and/or other performance status 0, 1, or
- •Patients must meet the following clinical laboratory criteria:Absolute neutrophil count (ANC) >/= 1,000/mm^3 and platelet count >/= 75,000/mm^
- •Platelet transfusions to help patients meet eligibility criteria are not allowed within 3 days before study enrollment.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.
- •Patients may receive local palliative radiation therapy immediately before or during the treatment if the radiation therapy is not delivered to the sole target lesions.
- •Measurable or evaluable disease will be included as assessed by RECIST 1.1.
排除标准
- •Female patients who are lactating or have a positive blood pregnancy test during the screening period.
- •Failure to have fully recovered (ie, </= Grade 1 toxicity) from the reversible effects of prior chemotherapy.
- •Major surgery within 14 days before first dose of study drug..
- •Radiotherapy within 14 days before first dose of study drug. If the involved field is small, 7 days will be considered a sufficient interval between treatment and study initiation.
- •Active uncontrolled central nervous system involvement.
- •Infection requiring systemic antibiotic therapy or other serious infection within 14 days before first dose of study drug.
- •Evidence of current uncontrolled cardiovascular conditions, 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 CYP1A2 (fluvoxamine, enoxacin, ciprofloxacin), strong inhibitors of 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.
- •Ongoing or active systemic infection, active hepatitis B or C virus infection, or known human immunodeficiency virus (HIV) positive.
- •Any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to this protocol.
- •Known allergy to any of the study medications, their analogues, or excipients in the various formulations of any agent.
- •Known GI disease or GI procedure that could interfere with the oral absorption or tolerance of MLN9708 including difficulty swallowing.
- •Diagnosed or treated for another malignancy within 2 years before first dose of study drug. 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.
- •Patient has >/= Grade 2 peripheral neuropathy
- •Participation in other clinical trials, including those with other investigational agents not included in this trial, within 21days of the start of this trial and throughout the duration of this trial.
研究组 & 干预措施
MLN9708 and Vorinostat
Dose Escalation Phase: Starting Dose of MLN9708 3 mg by mouth on day 1, 8 and 15. Starting Dose of Vorinostat: 100 mg by mouth twice a day, total of 200 mg/day Days 1 to 21.
Dose Expansion Phase Starting Doses of MLN9708 and Vorinostat: Maximum tolerated dose from Dose Escalation Phase.
干预措施: MLN9708 (Drug)
MLN9708 and Vorinostat
Dose Escalation Phase: Starting Dose of MLN9708 3 mg by mouth on day 1, 8 and 15. Starting Dose of Vorinostat: 100 mg by mouth twice a day, total of 200 mg/day Days 1 to 21.
Dose Expansion Phase Starting Doses of MLN9708 and Vorinostat: Maximum tolerated dose from Dose Escalation Phase.
干预措施: Vorinostat (Drug)
结局指标
主要结局
Maximum Tolerated Doses (MTD) of MLN9708 and Vorinostat
时间窗: After 2, 28 day cycles
Maximum tolerated dose is the highest dose level in which 6 patients have been treated with at most 1 experiencing dose limiting toxicity (DLT). Dose-limiting toxicity defined if the events occur within the first cycle (28 days).
次要结局
- Tumor Response(4 months)