NCT00811070已完成2 期
A Phase 1/2 Study Of SKI-606 Administered As A Single Agent In Japanese Subjects With Philadelphia Chromosome Positive Leukemias
适应症
干预措施
相关药物
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- Pfizer
- 入组人数
- 63
- 试验地点
- 23
- 主要终点
- Number of Participants With Dose-Limiting Toxicity (DLT) - Part 1
研究概览
简要总结
This is a two-part safety and efficacy study of SKI-606 in subjects who have Philadelphia chromosome positive leukemias (CML). Part 1 will be a dose-escalation study, in which an escalating dose of SKI-606 (Bosutinib), up to 600 mg, will be studied in subjects with imatinib resistant/refractory or imatinib intolerant chronic phase CML. Part 2 will evaluate the safety and efficacy of the maximum tolerated dose (MTD) of SKI-606 (Bosutinib)identified in Part 1 of the study.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 20 Years 至 74 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Cytogenetic or Polymerase Chain Reaction based diagnosis of Chronic phase of Philadelphia Chromosome Positive Chronic Myelogenous Leukemia:
- •(Part 1), any phase of Philadelphia Chromosome Positive Chronic Myelogenous Leukemia (Part 2), whose disease is resistant/refractory to full-dose imatinib (400 mg for chronic phase subjects/600 mg for advanced leukemia subjects), or are intolerant of any dose of imatinib.
- •Adequate duration of prior imatinib therapy.
- •No prior exposure to Src, Abl, or Src/Abl kinase inhibitors other than imatinib.
- •Eastern Cooperative Oncology Group Performance Status of 0 or 1 for chronic phase subjects, and 0, 1 or 2 for Advanced Stage subjects.
- •At least 7 days since any anti-proliferative treatment (including intrathecal chemotherapy) before the first dose of SKI-606, (except hydroxyurea).
- •Recovered to National Cancer Institute grade 0-1, or to baseline, from any toxicities of prior anti-tumor treatment, other than alopecia or thrombocytopenia due to active prior treatment (intolerant subjects).
- •At least 3 months post allogeneic stem cell transplantation before the first dose of SKI-
- •Able to take daily oral capsules reliably.
- •Absolute neutrophil count greater than 1,000/mL (Part 1)
- •Adequate hepatic, and renal function.
- •Documented normal INR if not on oral anticoagulant therapy, or, if on oral anticoagulant therapy consistent target INR less than
- •Age should be greater than 20 years and less than 75 years (Part 1), greater than 20 years (Part 2), including women of childbearing potential.
- •Willingness of male and female subjects, who are not surgically sterile or postmenopausal, must agree and commit to the use of reliable methods of birth control (oral contraceptives, intrauterine devices, or barrier methods used with a spermicide) for the duration of the study and for 30 days after the last dose of SKI-606.
排除标准
- •Subjects with Philadelphia chromosome negative Chronic Myelogenous Leukemia.
- •Overt leptomeningeal leukemia. Subjects must be free of CNS involvement according to the symptoms for a minimum of 2 months before the first dose of SKI-
- •Subjects with CNS symptoms must have a diagnostic lumbar puncture prior to study enrollment.
- •Subjects with extramedullary disease only.
- •Ongoing requirement for warfarin or other oral anticoagulant therapy (Part 1).
- •Ongoing requirement for hydroxyurea (Part 1).
- •Graft Versus Host Disease. a. no previous Graft Versus Host Disease allowed (Part 1). b. no treated or untreated Graft Versus Host Disease within 60 days of first dose (Part 2).
- •Major surgery within 14 days or radiotherapy within 7 days before the first dose of SKI-606 (recovery from any previous surgery should be complete before day 1).
- •Ongoing clinical requirement for administration of a strong inhibitor or inducer of CYP-3A4 (Part 1).
- •History of clinically significant or uncontrolled cardiac disease including: a. history of a clinically significant ventricular arrhythmia (such as ventricular tachycardia, ventricular fibrillation, or Torsades de pointes) b. diagnosed or suspected congenital or acquired prolonged QT syndrome c. history of prolonged QTc d. unexplained syncope e. history of or active congestive heart failure f. myocardial infarction within 12 months. g. Uncontrolled angina or hypertension within 3 months.
- •Baseline QTcF greater than 0.45 sec (average of triplicate readings).
- •Concomitant use of or need for medications known to prolong the QT interval.
- •Uncorrected hypomagnesemia or hypokalemia due to potential effects on the QT interval.
- •Recent (within 14 days before the first dose of SKI-606) or ongoing clinically significant gastrointestinal disorder.
- •Pregnant or breastfeeding women.
- •Evidence of serious active infection, or significant medical or psychiatric illness.
研究组 & 干预措施
1
Experimental
干预措施: SKI-606 (Bosutinib) (Drug)
结局指标
主要结局
Number of Participants With Dose-Limiting Toxicity (DLT) - Part 1
时间窗: Baseline up to Day 28 (Part 1 )
DLT was defined as any of the following events occurring during the first 28 days of study medication and considered at least possibly-related to study medication: any grade 3 or 4 clinically-relevant non-hematologic toxicity.
Maximum Tolerated Dose (MTD) - Part 1
时间窗: Baseline up to Day 28 (Part 1 )
MTD was defined as highest dose level for which no more than 1 participant in a dose cohort experienced DLT.
Percentage of Participants With Major Cytogenetic Response (MCyR) at Week 24 in Chronic Phase Second-line Cohort - Part 2
时间窗: Week 24
Cytogenetic response (CyR) is based on the prevalence of Philadelphia chromosome positive (Ph+) cells. Major cytogenetic response was categorized as either complete cytogenetic response (CCyR) or partial cytogenetic response (PCyR). CCyR was achieved when there was 0 percent (%) Ph+ cells and PCyR was achieved when 1 to 35% Ph+ cells.
次要结局
- Percentage of Participants With Major Cytogenetic Response (MCyR) at Week 24 in Chronic Phase Third-line Cohort - Part 2(Week 24)
- Duration of Major Cytogenetic Response (MCyR) in Chronic Phase Second-line and Third-line Cohort - Part 2(204 weeks in the second-line participants and 48 weeks in the third-line participants)
- Area Under the Concentration-Time Curve (AUC) - Part 1(Before and 1, 2, 3, 4, 6, 8, 24 and 48 hours after administration on Day 1, and before and 1, 2, 3, 4, 6, 8, and 24 hours after administration on Day 15)
- Apparent Volume of Distribution (Vz/F) - Part 1(Before and 1, 2, 3, 4, 6, 8, 24 and 48 hours after administration on Day 1)
- Accumulation Ratio (R) - Part 1(Before and 1, 2, 3, 4, 6, 8, 24 and 48 hours after administration on Day 1, and before and 1, 2, 3, 4, 6, 8, and 24 hours after administration on Day 15)
- Time to Reach Maximum Observed Plasma Concentration (Tmax) - Part 1(Before and 1, 2, 3, 4, 6, 8, 24 and 48 hours after administration on Day 1, and before and 1, 2, 3, 4, 6, 8, and 24 hours after administration on Day 15)
- Percentage of Participants With Maintained Major Cytogenetic Response (MCyR) at Week 24 in Chronic Phase Second-line and Third-line Cohort - Part 2(Week 24)
- Time to Treatment Failure (TTF) Rate - Part 2(Date of first dose of study drug up to Week 336 in primary second line participants; up to Week 192 in advanced second line and exploratory third line participants)
- Maximum Observed Plasma Concentration (Cmax) - Part 1(Before and 1, 2, 3, 4, 6, 8, 24 and 48 hours after administration on Day 1, and before and 1, 2, 3, 4, 6, 8, and 24 hours after administration on Day 15)
- Plasma Decay Half-Life (t1/2) - Part 1(Before and 1, 2, 3, 4, 6, 8, 24 and 48 hours after administration on Day 1)
- Apparent Oral Clearance (CL/F) - Part 1(Before and 1, 2, 3, 4, 6, 8, 24 and 48 hours after administration on Day 1, and before and 1, 2, 3, 4, 6, 8, and 24 hours after administration on Day 15)
- Duration of Complete Hematologic Response (CHR) in Advanced Phase Second-line Cohort - Part 2(Baseline up to Week 192)
- Percentage of Participants With Major Cytogenetic Response (MCyR) at Week 24 - Part 1(Week 24)
- Time to Major Cytogenetic Response (MCyR) in Chronic Phase Second-line and Third-line Cohort - Part 2(204 weeks in the second-line participants and 48 weeks in the third-line participants)
- Percentage of Participants With Complete Hematologic Response (CHR) up to Week 192 in Advance Phase Second-line Cohort - Part 2(Baseline up to Week 192)
- Percentage of Participants With Overall Hematologic Response (OHR) Up to Week 192 in Accelerated Phase/Blast Phase Third-line Cohort - Part 2(Baseline up to Week 192)
- Time to Achieve Complete Hematologic Response (CHR) in Advanced Phase Second-line Cohort - Part 2(Baseline up to Week 192)
- Time to Achieve Overall Hematologic Response (OHR) in Accelerated Phase/Blast Phase Third-line Cohort - Part 2(Baseline up to Week 192)
- Duration of Overall Hematologic Response (OHR) in Accelerated Phase/Blast Phase Third-line Cohort - Part 2(Baseline up to Week 192)
- Overall Survival (OS) Rate - Part 2(Date of first dose of study drug up to Week 336 in primary second line participants; up to Week 192 in advanced second line and exploratory third line participants)
- Progression-free Survival (PFS) Rate - Part 2(Date of first dose of study drug up to Week 336 in primary second line participants; up to Week 192 in advanced second line and exploratory third line participants)
研究者
研究点 (23)
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