A Phase I Study of Ixabepilone Administered as a Daily Oral Dose on 5 Successive Days Every 21 Days in Subjects With Advanced Cancer
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- 入组人数
- 40
- 试验地点
- 2
- 主要终点
- Maximum Tolerated Dose (MTD) of Ixabepilone
研究概览
简要总结
This study will determine the maximum tolerated dose of oral ixabepilone administered for 5 successive days every 21 days in participants with advanced cancer. The safety, tolerability, and pharmacokinetics of ixabepilone in the body will be studied. In addition, this study will assess preliminary evidence of the effect of food and famotidine on the pharmacokinetics of oral ixabepilone.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Crossover
- 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
- •Confirmed diagnosis of solid tumor malignancy unresponsive to current treatment options
- •Measurable or nonmeasurable disease as defined by Response Evaluation Criteria in Solid Tumors
- •Lapse of at least 1 week since minor surgery and of at least 3 weeks since major surgery and radiation therapy
- •Eastern Cooperative Oncology Group performance status of 0-1
- •Lapse of at least 4 weeks since immunotherapy or chemotherapy
- •Negative pregnancy test result within 72 hours of study drug administration for any woman of childbearing potential (WOCBP)
排除标准
- •WOCBP unable or unwilling to use birth control during study and for up to 4 weeks after study completion
- •Women who are pregnant or breastfeeding
- •Fertile men not using effective birth control with partners who are WOCBP
- •Gastrointestinal(GI) disease or GI tract surgery that could impact drug absorption
- •Inability to swallow capsules
- •Inability to be venipunctured or to tolerate venous access
- •Known symptomatic brain metastases
- •Common Terminology Criteria for Adverse Events Grade 2 or greater neuropathy or history of Grade 3 or greater neuropathy
- •Psychiatric conditions inhibiting compliance with protocol requirements
- •Uncontrolled medical disorder or active infection that would impair participant's ability to receive protocol therapy or whose control may be jeopardized by the study treatment protocol
- •Inadequate hematologic, hepatic, or renal function
- •History of significant drug allergy
- •Previous exposure to ixabepilone
- •Exposure to any investigational drug or placebo within 4 weeks of enrollment
- •Concurrent chemotherapy regimen
- •Use of cytochrome P4503A4 inhibitors or inducers within 2 weeks of treatment initiation (unless approved by medical monitor)
- •Use of steroids (except as antiemetic)
- •Prisoners or subjects involuntarily detained for treatment
研究组 & 干预措施
Ixabepilone, 5 mg/d
If none of first 3 participants experiences a dose-limiting toxicity (DLT) during the first 21-day cycle, a new cohort is opened at the next dose level (5-mg increments). If 2 or more of the first 3 participants experience a DLT within the first 21-day course, the dose level will be considered above the maximum tolerated dose (MTD). If 1 of the first 3 participants experiences a DLT, an additional 3 participants will be enrolled at this dose level for a total of 6 participants. If 2 or more of the 6 participants (or 1/3 or more of a cohort with more than 6 participants) experience a DLT, this dose level will be considered above the MTD.
干预措施: Ixabepilone, 5 mg/d (Drug)
Ixabepilone, 10 mg/d
If none of first 3 participants experiences a DLT during the first 21-day cycle, a new cohort is opened at the next dose level (5-mg increments). If 2 or more of the first 3 participants experience a DLT within the first 21-day course, the dose level will be considered above the MTD. If 1 of the first 3 participants experiences a DLT, an additional 3 participants will be enrolled at this dose level for a total of 6 participants. If 2 or more of the 6 participants (or 1/3 or more of a cohort with more than 6 participants) experience a DLT, this dose level will be considered above the MTD.
干预措施: Ixabepilone, 10 mg/d (Drug)
Ixabepilone, 15 mg/d
If none of first 3 participants experiences a DLT during the first 21-day cycle, a new cohort is opened at the next dose level (5-mg increments). If 2 or more of the first 3 participants experience a DLT within the first 21-day course, the dose level will be considered above the MTD. If 1 of the first 3 participants experiences a DLT, an additional 3 participants will be enrolled at this dose level for a total of 6 participants. If 2 or more of the 6 participants (or 1/3 or more of a cohort with more than 6 participants) experience a DLT, this dose level will be considered above the MTD.
干预措施: Ixabepilone, 15 mg/d (Drug)
Ixabepilone, 25 mg, with food
Following identification of MTD, participants who completed Cycle 1 and treated at the ixabepilone MTD (25 mg/d) will crossover to Cycle 2 in which they receive a low-fat meal on Day 1.
干预措施: Ixabepilone, 25 mg, with food (Drug)
Ixabepilone, 20 mg/d
If none of first 3 participants experiences a DLT during the first 21-day cycle, a new cohort is opened at the next dose level (5-mg increments). If 2 or more of the first 3 participants experience a DLT within the first 21-day course, the dose level will be considered above the MTD. If 1 of the first 3 participants experiences a DLT, an additional 3 participants will be enrolled at this dose level for a total of 6 participants. If 2 or more of the 6 participants (or 1/3 or more of a cohort with more than 6 participants) experience a DLT, this dose level will be considered above the MTD.
干预措施: Ixabepilone, 20 mg/d (Drug)
Ixabepilone, 25 mg/d
If none of first 3 participants experiences a DLT during the first 21-day cycle, a new cohort is opened at the next dose level (5-mg increments). If 2 or more of the first 3 participants experience a DLT within the first 21-day course, the dose level will be considered above the MTD. If 1 of the first 3 participants experiences a DLT, an additional 3 participants will be enrolled at this dose level for a total of 6 participants. If 2 or more of the 6 participants (or 1/3 or more of a cohort with more than 6 participants) experience a DLT, this dose level will be considered above the MTD.
干预措施: Ixabepilone, 25 mg/d (Drug)
Ixabepilone, 30 mg/d
If none of first 3 participants experiences a DLT during the first 21-day cycle, a new cohort is opened at the next dose level (5-mg increments). If 2 or more of the first 3 participants experience a DLT within the first 21-day course, the dose level will be considered above the MTD. If 1 of the first 3 participants experiences a DLT, an additional 3 participants will be enrolled at this dose level for a total of 6 participants. If 2 or more of the 6 participants (or 1/3 or more of a cohort with more than 6 participants) experience a DLT, this dose level will be considered above the MTD.
干预措施: Ixabepilone, 30 mg/d (Drug)
Ixabepilone, 25 mg, with famotidine
Following identification of MTD, participants who completed Cycle 1 and treated at the ixabepilone MTD (25 mg/d) will crossover to Cycle 2 in which they receive famotidine, 40 mg on Day 1.
干预措施: Ixabepilone, 25 mg, with famotidine (Drug)
结局指标
主要结局
Maximum Tolerated Dose (MTD) of Ixabepilone
时间窗: Days 1 through 21 (Cycle 1)
MTD is based on Cycle 1 data only and defined as the maximum dose that can be administered to 6 participants with no more than 1 experiencing a dose-limiting toxicity (DLT) (or fewer than one third of participants if more than 6 receive treatment) with at least 2 participants experiencing a DLT at the next higher dose level. DLT=an event, such as neutropenia; thrombocytopenia; Gr 3 or 4 nausea or diarrhea; Gr 3 fatigue or asthenia; transient arthralgia or recalcitrant myalgia; and prolonged recovery from a toxicity, that occurs during the first course of treatment.
Number of Participants With DLTs by Worst Common Terminology Criteria (CTC) Grade
时间窗: Days 1 through 21 (Cycle 1), continuously
Adverse events (AEs) graded by CTC version 3. Grade (Gr) 1=mild; Gr 2=moderate; Gr 3=severe; Gr 4=life threatening; Gr 5=Death related to AE. DLT is defined as an event related to ixabepilone that occurs during the first course of treatment. Includes neutropenia; thrombocytopenia; Gr 3 or 4 nausea, vomiting, or diarrhea despite adequate medical intervention and prophylaxis; Gr 3 fatigue or asthenia; transient arthralgia or myalgia unresponsive to medical intervention; any Gr 3 nonhematologic toxicity; and prolonged recovery from a toxicity.
次要结局
- Maximum Plasma Concentration (Cmax) of Ixabepilone(Days 1 and 5 of Cycle 1)
- Plasma Half-life (T-Half) of Ixabepilone(Day 5 of Cycle 1)
- Time of Maximum Plasma Concentration (Tmax)of Oral Ixabepilone at MTD in Fasted and Fed Participants in Crossover Cohorts(Up to 24 hours postdose Day 1 of Cycle 1 (21 days) and Day 1 of Cycle 2 (21 days))
- Number of Participants With Death as Outcome, Treatment-related Adverse Events (AEs), and AEs Leading to Discontinuation(Days 1 through 21 (Cycle 1), continuously)
- Area Under the Curve in 1 Dosing Interval (AUC[TAU]) of Oral Ixabepilone at MTD in Fasted and Fed Participants in Crossover Cohorts(Up to 24 hours postdose Day 1 of Cycle 1 (21 days) and Day 1 of Cycle 2 (21 days))
- Number of Participants With Abnormal Laboratory Values by Worst CTC Grade(Baseline and Days 1, 8, and 15 of Cycle 1 (21 days))
- Time of Maximum Plasma Concentration (Tmax) of Ixabepilone(Days 1 and 5 of Cycle 1)
- Area Under the Concentration-time Curve in 1 Dosing Interval (AUC[TAU])of Ixabepilone(Days 1 and 5 of Cycle 1)
- Maximum Plasma Concentration (Cmax) of Oral Ixabepilone at MTD in Fasted and Fed Participants in Crossover Cohorts(Up to 24 hours postdose Day 1 of Cycle 1 (21 days) and Day 1 of Cycle 2 (21 days))
- Maximum Plasma Concentration (Cmax) of Oral Ixabepilone With and Without Famotidine in Crossover Cohorts(Up to 24 hours postdose Day 1 of Cycle 1 (21 days) and Day 1 of Cycle 2 (21 days))
- Number of Participants With Abnormal (CTC Grade 3 or Greater) Serum Chemistry Levels(At screening and predose Day 1, Cycle 1 (21 days))
- Time of Maximum Plasma Concentration (Tmax) of Oral Ixabepilone With and Without Famotidine in Crossover Cohorts(Up to 24 hours postdose Day 1 of Cycle 1 (21 days) and Day 1 of Cycle 2 (21 days))
- Area Under the Curve in 1 Dosing Interval (AUC[TAU]) of Oral Ixabepilone With and Without Famotidine in Crossover Cohorts(Up to 24 hours postdose Day 1 of Cycle 1 (21 days) and Day 1 of Cycle 2 (21 days))
- Number of Participants With Significant Findings on Physical Examination or Electrocardiogram (ECG)(At screening and predose Day 1, Cycle 1 (21 days))