A Phase I-II Study Evaluating the Safety and Efficacy of Imatinib Mesylate (Gleevec) Combined With Reinduction Chemotherapy Using Mitoxantrone, Etoposide and Cytarabine in Patients With Relapsed/Refractory C-kit Positive Acute Myeloid Leukemia
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 35
- 试验地点
- 1
- 主要终点
- Response rate - CR, MLFS and PR as per section 7.1
研究概览
简要总结
This is a Phase I-II study evaluating the toxicity and efficacy of imatinib combined with mitoxantrone, etoposide and high-dose cytarabine reinduction therapy in relapsed and refractory AML. Patients will be treated initially at a 200 mg dose of imatinib; if tolerated, the imatinib dose will be escalated in subsequent cohorts to 300 mg and 400 mg. Once the recommended dose is determined, the remaining patients will be treated at that dose, to evaluate the antileukemic activity of the regimen. Patients achieving complete remission will receive consolidation therapy with imatinib combined with high-dose cytarabine and mitoxantrone, followed by maintenance imatinib.
详细描述
Induction therapy:
- Imatinib 200-400 mg p.o. daily x 10 days, Days 1-10 (see dose escalation scheme in Section 5.4 below).
- Mitoxantrone 10 mg/m2 daily x 5 days, Days 4-8.
- Etoposide 100 mg/m2 daily x 5 days, Days 4-8.
- Cytarabine 1.5 grams/m2 q12h x 4 doses, Days 9-10 (for patients aged 60 years and over, 1.0 gram/m2).
Only one induction course will be permitted. Only patients achieving CR will proceed to consolidation and maintenance.
Consolidation therapy, maximum 2 cycles (for patients achieving CR):
- Imatinib 200-400 mg p.o. daily x 8 days, Days 1-8 (see dose escalation scheme in Section 5.4 below).
- Mitoxantrone 12 mg/m2 daily x 2 days, Days 4-5.
- Cytarabine 3 grams/m2 q12h x 6 doses, Days 4,6,8. For patients aged 60 years and over, the dose will be reduced to 1.5 grams/m2.
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 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •AML, all subtypes except APL.
- •Prior induction therapy consisting of cytarabine 100-200 mg/m2 plus an anthracycline.
- •One of the following:
- •persistent leukemia after induction therapy.
- •relapse within two years of achieving complete remission with induction therapy. Any consolidation therapy is acceptable, including stem cell transplantation.
- •At least 10% bone marrow blasts, or biopsy confirmed extramedullary disease.
- •Positivity for c-kit (CD117) in at least 30% of blasts as measured by flow cytometry.
- •ECOG performance status < 3 (see Appendix I).
- •No chemotherapy within the previous four weeks, other than hydroxyurea to control counts. If hydroxyurea is used, it must be stopped at least 24 hours prior to starting imatinib.
- •Able to given informed consent.
排除标准
- •Active uncontrolled infection.
- •Active CNS leukemia.
- •Serum creatinine > 200 umol/L.
- •Serum bilirubin > 1.5 x ULN, AST or ALT > 2x ULN.
- •Left ventricular ejection fraction < 50%.
研究组 & 干预措施
one
干预措施: Imatinib (Gleevec) (Drug)
结局指标
主要结局
Response rate - CR, MLFS and PR as per section 7.1
时间窗: 2 years
* Complete response * Morphologic leukemia-free state * Partial remission (PR•No response (NR): Does not meet the criteria for CR, MLFS or PR.
Maximum tolerated dose of Imatinib when given in combination with chemotherapy
时间窗: 2 years
Maximum tolerated dose (MTD) of Imatinib (200, 300, 400 mg) when used in combination with NOVE-HiDAC induction and consolidation. MTD defined as highest dose resulting in up to 2/6 grade III-IV hematologic (as defined above) or non-hematologic DLTs per dose level. Non-hematologic DLTs as defined by NCIC CTC.
Toxicity (hematologic and non-hematologic) of the combination of Imatinib and Chemotherapy consisting of Mitoxantrone, Etoposide and Ara-c
时间窗: 2 years
Hematologic toxicity * Number of days to ANC \> 0.5 and 1.0. * Number of days until platelets \> 20 and \> 50, independent of platelet transfusions. * Number of days until RBC transfusion independent. Non-hematologic toxicity, as per NCI common toxicity criteria Hematologic dose-limiting toxicity (DLT) defined as \> 40 days to ANC \> 0.5 or platelets \> 20 independent of transfusions.
次要结局
- Toxicity of imatinib maintenance therapy.(2 years)
- Number of Participants with adverse events as a measure of safety and tolerability(2 years)
- Remission-free survival and overall survival.(2 years)
- Total and phosphorylated c-kit activity at Days 1 and 4.(2 years)
- Levels of downstream components of c-kit pathway at Days 1 & 4.(2 years)