A Phase I/II Study of CPI-613 and Hydroxychloroquine for Patients With High Risk MDS Who Have Failed Hypomethylating Therapy
试验速览
- 阶段
- 1 期
- 状态
- 撤回
- 试验地点
- 2
- 主要终点
- Number of Dose Limiting Toxicities
研究概览
简要总结
This is a phase 1/2 study of the combination of CPI-613 and hydroxychloroquine for the treatment of high risk myelodysplastic syndrome patients who have failed a hypomethylating agent.
详细描述
Primary Objective(s):
- To determine the Maximum Tolerated Dose (MTD) of the combination of CPI-613 and Hydroxychloroquine therapy for patients with high risk MDS who have failed hypomethylating therapy.
- To determine the overall response rate (complete remission (CR), marrow CR, partial remission (PR), Hematologic improvement (HI)) of high risk MDS patients who have failed hypomethylating agents, treated with the combination of CPI-613 and the maximally tolerated dose of hydroxychloroquine
Secondary Objective(s):
- To assess the safety of the combination
- To assess progression-free-survival (PFS)
- To assess the overall survival of MDS patients who have failed hypomethylating agents treated with the combination of CPI-613 and hydroxychloroquine defined as the time from enrolment on study to death from any cause.
- To assess any changes in the frequency of blood transfusions
OUTLINE: This is a phase I, dose-escalation study of hydroxychloroquine, followed by a phase II study.
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
- •Patients must meet all of the following inclusion criteria before enrollment:
- •Histologically documented high risk MDS whose disease has failed to respond, progressed or relapsed while on a hypomethylating agent.
- •IPSS-R score of Intermediate, high or very high at time of enrollment
- •ECOG Performance Status of ≤
- •Men and women 18 years of age or older.
- •Expected survival >2 months.
- •Women of child-bearing potential (i.e., women who are pre-menopausal or not surgically sterile) must use accepted contraceptive methods (abstinence, intrauterine device [IUD], oral contraceptive or double barrier device) during the study, and must have a negative serum or urine pregnancy test within 1 week prior to treatment initiation.
- •Fertile men must practice effective contraceptive methods during the study, unless documentation of infertility exists.
- •Patients must have fully recovered from the acute, non-hematological, non-infectious toxicities of any prior treatment with cytotoxic drugs, radiotherapy or other anti-cancer modalities. Patients with persisting, non-hematologic, non-infectious toxicities from prior treatment ≤ Grade 2 are eligible, but must be documented as such.
- •Laboratory values obtained ≤2 weeks prior to enrollment must demonstrate adequate hepatic function, renal function, and coagulation as defined below:
- •Aspartate aminotransferase [AST/SGOT] ≤3x upper normal limit [UNL]
- •Alanine aminotransferase [ALT/SGPT] ≤3x UNL
- •Bilirubin ≤1.5x UNL
- •Serum creatinine ≤1.5 mg/dL or 133 μmol/L
- •Albumin ≥ 2.0 g/dL or ≥ 20 g/L.
- •Mentally competent, ability to understand and willingness to sign an IRB-approved written informed consent form.
- •Have access via central line (e.g., portacath).
排除标准
- •Patients with the following characteristics are excluded:
- •Serious medical illness, such as significant cardiac disease (e.g. symptomatic congestive heart failure, unstable angina pectoris, symptomatic coronary artery disease, myocardial infarction within the past 3 months, uncontrolled cardiac arrhythmia, pericardial disease or New York Heart Association Class III or IV), or severe debilitating pulmonary disease, that would potentially increase patients' risk for toxicity.
- •Patients with active central nervous system (CNS) or epidural tumor.
- •Any active uncontrolled bleeding or bleeding diathesis (e.g., active peptic ulcer disease).
- •Any condition or abnormality which may, in the opinion of the investigator, compromise his or her safety.
- •Pregnant women, or women of child-bearing potential not using reliable means of contraception.
- •Fertile men unwilling to practice contraceptive methods during the study period.
- •Lactating females.
- •Life expectancy less than 2 months.
- •Unwilling or unable to follow protocol requirements.
- •Evidence of ongoing uncontrolled serious infection.
- •Requirement for immediate palliative treatment of any kind including surgery.
- •Patients with uncontrolled HIV infection. (Note: Patients with known HIV infection are excluded because patients with an immune deficiency are at increased risk of lethal infections when treated with marrow-suppressive therapy, and because there may be unknown or dangerous drug interactions between CPI-613 and anti-retroviral agents used to treat HIV infections).
- •Patients who have received radiotherapy, surgery, treatment with cytotoxic agents (except a hypomethylating agent, i.e. azacytidine or decitabine), treatment with biologic agents, immunotherapy, or any other anti-cancer therapy of any kind, or any other standard or investigational treatment for their cancer, or any other investigational agent for any indication, within the past 2 weeks prior to initiation of CPI-613 treatment.
- •Patients that have received a chemotherapy regimen with stem cell support in the previous 6 months.
研究组 & 干预措施
CPI-613 and hydroxychloroquine
The initial phase of the study will be a dose escalation of hydroxychloroquine from 600 mg to 1,200 mg orally flat dose given 2 hours before the CPI-613 infusion on days 1-5 of every 28 days. CPI-dose will be 2,000 mg/m² and will not be escalated.
干预措施: CPI-613 (Drug)
CPI-613 and hydroxychloroquine
The initial phase of the study will be a dose escalation of hydroxychloroquine from 600 mg to 1,200 mg orally flat dose given 2 hours before the CPI-613 infusion on days 1-5 of every 28 days. CPI-dose will be 2,000 mg/m² and will not be escalated.
干预措施: Hydroxychloroquine (Drug)
结局指标
主要结局
Number of Dose Limiting Toxicities
时间窗: 4 weeks
Dose-limiting toxicities assessed in order to be able to establish the maximum tolerable dose for the combination of CPI-613 and Hydroxychloroquine therapy for patients with high risk myelodysplastic syndrome who have failed hypomethylating therapy. Using the descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 for adverse event reporting (Grade 1 (Mild) - 5 (Death) as well as expectedness (unexpected/expected) and attribution (definitely related to study treatment to unrelated to study treatment).
Overall Response Rate
时间窗: 4 weeks
Measurements for response criteria will be based upon the Modified International Working Group (IWG) 2006 response criteria for altering natural history of myelodysplastic syndrome. Overall response rates criteria - complete remission (CR), partial response (PR) marrow CR, hematologic improvement (HI), or stable disease, failure, relapse after complete response or partial response, cytogenetic response, disease progression and survival) of high risk myelodysplastic syndrome patients who have failed hypomethylating agents treated with the combination of CPI-613 and the maximally tolerated dose of hydroxychloroquine.
次要结局
- Proportion of Patients with Toxicities(4 weeks)
- Progression-free-survival(Up to 5 years or until death)
- Overall Survival(Up to 5 years or until death)
- Changes in the Frequency of Blood Transfusions(Baseline to approximately 6 months)