Phase I Study of Palbociclib Alone and in Combination in Patients With Relapsed and Refractory Leukemias
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 入组人数
- 32
- 试验地点
- 1
- 主要终点
- Maximum tolerated dose (MTD) as determined by dose limiting toxicity (DLT)
研究概览
简要总结
This phase I trial studies the side effects and best dose of palbociclib when given alone and in combination with sorafenib, decitabine, or dexamethasone in treating patients with leukemia that has come back (recurrent) or that does not respond to previous treatment (refractory). Palbociclib, sorafenib, and decitabine may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as dexamethasone, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving palbociclib alone and in combination with sorafenib, decitabine, or dexamethasone may work better in treating patients with recurrent or refractory leukemia.
详细描述
PRIMARY OBJECTIVES:
I. To determine the maximum tolerated dose (MTD) and dose limiting toxicities (DLT) of various combinations with palbociclib in patients with relapsed and refractory leukemias.
SECONDARY OBJECTIVES:
I. To assess pharmacodynamic effects of palbociclib on the Cyclin-CDK-Rb axis in leukemic blasts of patients with relapsed/refractory (R/R) leukemias.
II. To explore the efficacy (complete response [CR], complete remission without platelet recovery [CRp], complete remission without blood count recovery [CRi], partial response [PR], or clinical benefit [CB]) of palbociclib as a single-agent and in combinations in patients with R/R leukemias.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 15 Years 至 —（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Participants with a diagnosis of histologically confirmed relapsed or refractory (R/R) acute myeloid leukemia or R/R acute lymphoblastic leukemia for which no available standard therapies are indicated or anticipated to result in a durable response.
- •Only participants with R/R ALL will be eligible for cohort C
- •Age >/= 15 years.
- •Participants must not have had leukemia therapy for 14 days prior to starting palbociclib. However, participants with rapidly proliferative disease may receive hydroxyurea as needed until 24 hours prior to starting therapy on this protocol and starting the first cycle of study.
- •Adequate organ function as defined below:
- •liver function (bilirubin < 2mg/dL, AST and/or ALT <3 x ULN - or <5 x ULN if related to leukemic involvement)
- •kidney function (creatinine < 1.5 x ULN ).
- •known cardiac ejection fraction of > or = 45% within the past 3 months
- •ECOG performance status of ≤
- •A negative urine pregnancy test is required within 1 week for all women of childbearing potential prior to enrolling on this trial.
- •Participants must have the ability to understand the requirements of the study and signed informed consent. A signed informed consent by the participants or his legally authorized representative is required prior to their enrollment on the protocol.
排除标准
- •Participants women are excluded from this study because the agent used in this study has the potential for teratogenic or abortifacient effects. Because there is a potential risk for adverse events in nursing infants secondary to treatment of the mother with the chemotherapy agents, breastfeeding should also be avoided.
- •Uncontrolled intercurrent illness including, but not limited to active uncontrolled infection, symptomatic congestive heart failure (NYHA Class III or IV), unstable angina pectoris, clinically significant cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
- •Participant with documented hypersensitivity to any of the components of the therapy program.
- •Participants with active, uncontrolled CNS leukemia will not be eligible.
- •Men and women of childbearing potential who do not practice contraception. Women of childbearing potential and men must agree to use contraception prior to study entry and for the duration of study participation.
- •Participants with known history of serous retinopathy will not be eligible.
- •Prior treatment with palbociclib,
研究组 & 干预措施
Arm I (palbociclib, sorafenib)
Patients receive palbociclib PO QD on days 1-28. Patients also receive sorafenib PO QD on days 1-28 beginning on cycle 2. Treatment repeats every 28 days for up to 8 cycles in the absence of disease progression or unacceptable toxicity.
干预措施: Palbociclib (Drug)
Arm I (palbociclib, sorafenib)
Patients receive palbociclib PO QD on days 1-28. Patients also receive sorafenib PO QD on days 1-28 beginning on cycle 2. Treatment repeats every 28 days for up to 8 cycles in the absence of disease progression or unacceptable toxicity.
干预措施: Sorafenib (Drug)
Arm II (palbociclib, decitabine)
Patients receive palbociclib as in Arm I. Beginning cycle 2, patients receive palbociclib PO QC on days 1-7 and decitabine IV QD over 1 hour on days 8-17 of cycle 2 and days 8-12 of cycles 3-8. Treatment repeats every 28 days for up to 8 cycles in the absence of disease progression or unacceptable toxicity.
干预措施: Decitabine (Drug)
Arm II (palbociclib, decitabine)
Patients receive palbociclib as in Arm I. Beginning cycle 2, patients receive palbociclib PO QC on days 1-7 and decitabine IV QD over 1 hour on days 8-17 of cycle 2 and days 8-12 of cycles 3-8. Treatment repeats every 28 days for up to 8 cycles in the absence of disease progression or unacceptable toxicity.
干预措施: Palbociclib (Drug)
Arm III (palbociclib, dexamethasone)
Patients receive palbociclib as in Arm I. Patients also receive dexamethasone PO QD or IV over 15-30 minutes on days 1-4 and 15-18 beginning on cycle 2. Treatment repeats every 28 days for up to 8 cycles in the absence of disease progression or unacceptable toxicity.
干预措施: Dexamethasone (Drug)
Arm III (palbociclib, dexamethasone)
Patients receive palbociclib as in Arm I. Patients also receive dexamethasone PO QD or IV over 15-30 minutes on days 1-4 and 15-18 beginning on cycle 2. Treatment repeats every 28 days for up to 8 cycles in the absence of disease progression or unacceptable toxicity.
干预措施: Palbociclib (Drug)
结局指标
主要结局
Maximum tolerated dose (MTD) as determined by dose limiting toxicity (DLT)
时间窗: Up to cycle 2 (each cycle is 28 days)
MTD is defined as the highest dose level in which 6 patients have been treated with at most 1 instance of dose limiting toxicity using a classic '3+3' dose-escalation design. DLT is defined as drug-related adverse events during cycle two (i.e., the first cycle of palbociclib in combination). The number and proportion of DLTs will be summarized by treatment arm and dose level.
次要结局
- Efficacy as determined by complete response (CR]), complete remission without platelet recovery (CRp), complete remission without blood count recovery (CRi), partial response (PR), or clinical benefit (CB)(Up to 3 years)
- Incidence of adverse events graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0(Up to 3 years)
- Pharmacodynamic (PD) effects of palbociclib(Up to 3 years)
- Assessment of biomarkers of response and resistance(Up to 3 years)