A Phase I/II, Open-Label, Multi-Center Study Evaluating the Safety and Efficacy of Ruxolitinib and CPX-351 in Combination for the Treatment of Advanced Phase Myeloproliferative Neoplasms
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 12
- 试验地点
- 6
- 主要终点
- Dose limiting toxicity (DLT) (Phase I)
研究概览
简要总结
This phase I/II trial studies the best dose of ruxolitinib when given together with CPX-351 and to see how well they work in treating patients with accelerated phase or blast phase myeloproliferative neoplasm. Ruxolitinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. CPX-351 is a mixture of 2 chemotherapy drugs (daunorubicin and cytarabine) given for leukemia in small fat-based particles (liposomes) to improve the drug getting into cancer cells. Giving ruxolitinib and CPX-351 may work better in treating patients with secondary acute myeloid leukemia compared to CPX-351 alone.
详细描述
PRIMARY OBJECTIVES:
I. To identify the maximum-tolerated dose (MTD) of ruxolitinib in combination with liposome-encapsulated daunorubicin-cytarabine (CPX-351). (Phase I) II. To evaluate the objective response rate in participants with post-myeloproliferative neoplasm (MPN)- accelerated phase (AP)/blast phase (BP) following treatment with the combination of ruxolitinib and CPX-351 (per 2012 MPN-BP criteria). (Phase II)
SECONDARY OBJECTIVES:
I. To evaluate the safety and tolerability of ruxolitinib in combination with CPX-351. (Phase I) II. Assess survival outcomes and proportion of patients receiving transplant associated with ruxolitinib in combination with CPX-351. (Phase II)
EXPLORATORY OBJECTIVES:
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
- •Ability to understand and the willingness to sign a written informed consent document
- •Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2
- •Participants eligible for this study have either MPN in accelerated phase (AP) or blast phase (BP), defined as:
- •MPN-AP is defined by 10% to 19% blasts in the peripheral blood or bone marrow
- •MPN-BP is defined by >= 20% blasts in the blood or bone marrow
- •Either MPN-AP or MPN-BP requires a previous diagnosis of polycythemia vera (PV), essential thrombocythemia (ET), primary or secondary myelofibrosis (MF), or MDS/MPN overlap with intermediate-2 or high risk disease according to IPSS as well as progression on or failure to respond to at least one line of therapy
- •Participants with ET, PV, or MF that have received prior MPN-associated therapy (e.g., hydroxyurea, hypomethylating agents [azacitidine, decitabine], anti-platelet therapies [e.g., aspirin, anagrelide], as well as JAK2 inhibitor therapy [e.g., ruxolitinib or other investigational JAK2 inhibitor]) are eligible. They must discontinue prior to starting therapy; no wash-out is required
- •Female participants of childbearing potential must agree to use adequate contraception (2 forms of contraception or abstinence) from the screening visit until 30 days following the last dose of study treatment. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately
- •Male participants of childbearing potential having intercourse with females of childbearing potential must agree to abstain from heterosexual intercourse or have their partner use 2 forms of contraception from the screening visit until 90 days until the last dose of study treatment. They must also refrain from sperm donation from the screening visit until 90 days following the last dose of study treatment
- •Left ventricular ejection fraction at >= 50% as measured by echocardiogram (ECHO) or multigated acquisition (MUGA) scan (14 days prior to initiating study treatment)
- •Candidate for cytotoxic-intensive induction chemotherapy
- •Willing to take oral medication
- •Serum creatinine =< 2 x the upper limit of normal (ULN), or glomerular filtration rate > 20 ml/min/1.73m^2 as calculated by Cockcroft-Gault formula
- •Serum potassium, magnesium, and calcium (corrected for albumin) within institutional normal limits or can be corrected with supplementation
- •Total serum bilirubin =< 2.5 x ULN
- •Serum aspartate transaminase (AST) and/or alanine transaminase (ALT) =< 2.5 x ULN
排除标准
- •Ongoing participation in another clinical trial
- •Isolated myeloid sarcoma (i.e., participants must have blood or marrow involvement with AML to enter the study)
- •Acute promyelocytic leukemia (French-American-British [FAB] M3 classification)
- •Active central nervous system (CNS) involvement by AML
- •Current treatment or treatment within 2 weeks or 5 half-lives (whichever is longer) prior to the first dose of study medication with another investigational medication or current enrollment in another investigational drug protocol (unless there is evidence of rapidly progressive disease in which case a shorter interval from last therapy may be acceptable)
- •Any unresolved toxicity equal to or greater than grade 2 from previous anticancer therapy, except for stable chronic toxicities not expected to resolve, such as peripheral neurotoxicity
- •Incomplete recovery from any prior surgical procedures or had surgery within 4 weeks prior to study entry, excluding the placement of vascular access
- •Disseminated intravascular coagulopathy with active bleeding or signs of thrombosis
- •Participants with rapidly progressive disease (defined by blast count doubling within 48 hours) or organ dysfunction that would prevent them from receiving these agents
- •Participants with uncontrolled infection will not be enrolled until infection is treated and symptoms controlled
- •Participants with an infection receiving treatment (antibiotic, antifungal or antiviral treatment) may be entered into the study but must be afebrile and hemodynamically stable for >= 72 hours (hrs)
- •Known hypersensitivity to ruxolitinib, cytarabine, daunorubicin, or liposomal products
- •History of Wilson's disease or other copper metabolism disorder
- •Uncontrolled intercurrent illness or any concurrent condition that, in the investigator's opinion, would jeopardize the safety of the participant or compliance with the protocol per investigator's discretion. Including, but not limited to, symptomatic congestive heart failure, unstable angina pectoris, serious cardiac arrhythmia, myocardial infarction within 6 months prior to enrollment, New York Heart Association (NYHA) class III or IV heart failure, severe uncontrolled ventricular arrhythmias
- •Participants with prior cumulative anthracycline exposure of greater than 368 mg/m^2 daunorubicin (or equivalent)
- •All participants must discontinue anti-platelet agents or anticoagulants prior to initiation of study drug, including therapeutic doses of aspirin and clopidogrel
研究组 & 干预措施
Treatment (CPX-351, ruxolitinib, allogeneic SCT)
See Detailed Description.
干预措施: Ruxolitinib (Drug)
Treatment (CPX-351, ruxolitinib, allogeneic SCT)
See Detailed Description.
干预措施: Allogeneic Hematopoietic Stem Cell Transplantation (Procedure)
Treatment (CPX-351, ruxolitinib, allogeneic SCT)
See Detailed Description.
干预措施: Liposome-encapsulated Daunorubicin-Cytarabine (Drug)
结局指标
主要结局
Dose limiting toxicity (DLT) (Phase I)
时间窗: Day 1 to day 42
DLT occurrence after exposure to ruxolitinib and CPX-351.
Proportion of participants that achieve at least an Acute Leukemia Response-Partial response (>= ALR-P, per 2012 myeloproliferative neoplasm - blast phase [MPN-BP] criteria) (Phase 2)
时间窗: Day 1 to end of induction or re-induction cycle (or upon assessment of the bone marrow biopsy performed near the end of these cycles if this occurs later). Cycle length is 28 days.
Will compute the proportion of efficacy-evaluable participants achieving overall response rate (ORR) and the exact binominal 95% confidence interval.
Dose Limiting Toxicity (DLT) (Phase I)
时间窗: Day 1 to day 42
DLT occurrence after exposure to ruxolitinib and CPX-351.
Proportion of Participants That Achieve at Least an Acute Leukemia Response-Partial Response (>= ALR-P, Per 2012 Myeloproliferative Neoplasm - Blast Phase [MPN-BP] Criteria) (Phase 2)
时间窗: Day 1 to end of induction or re-induction cycle (or upon assessment of the bone marrow biopsy performed near the end of these cycles if this occurs later). Cycle length is 28 days.
Will compute the proportion of efficacy-evaluable participants achieving objective response rate (ORR) and the exact binominal 95% confidence interval. The ORR will be calculated as the proportion of participants that achieve at least an Acute Leukemia Response-Partial response (≥ ALR-P, per 2012 MPN-BP criteria).
次要结局
- Incidence of adverse events as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 5.0(Day 1 to end of 6 cycles with study intervention)
- Incidence of adverse events as assessed by CTCAE version 5.0(Up to 30 days after last on-study dose)
- Overall survival (OS)(1 year post treatment)
- Event-free survival (EFS)(Day 1 to treatment failure, progressive disease, relapse, last exam date, or death (whichever is first), up to 2 years)
- Relapse-free survival (RFS)(Date of first documented response (ALR-C) to date of relapse or death from any cause, up to 2 years.)
- Remission duration(Date of first documented response (ALR-C) to date of documented relapse, up to 2 years)
- Proportion of participants proceeding to transplant(Date of enrollment to time of transplant or end of follow-up (if no transplant), up to 2 years)
- Number of Participants With Adverse Events as Assessed by Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0(Up to 30 days after last on-study dose, up to 9 months.)
- Overall Survival (OS)(Up to 4 years.)
- Event-free Survival (EFS)(Day 1 to treatment failure, progressive disease, relapse, last exam date, or death (whichever is first), up to 2 years)
- Relapse-free Survival (RFS)(Date of first documented response (ALR-C) to date of relapse or death from any cause, up to 2 years.)
- Remission Duration(Date of first documented response (ALR-C) to date of documented relapse, up to 2 years)
- Proportion of Participants Proceeding to Transplant(Date of enrollment to time of transplant or end of follow-up (if no transplant), up to 2 years)
研究者
Uma Borate
Principal Investigator
Ohio State University Comprehensive Cancer Center