A Feasibility Assessment and a Phase I/II Trial of MLN518 for Treatment of Patients With Recurrent Glioblastoma
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 60
- 试验地点
- 9
- 主要终点
- Maximum Tolerated Dose of Tandutinib Defined by Dose Limiting Toxicities (Phase 1)
研究概览
简要总结
This phase I/II trial is studying the side effects and best dose of tandutinib and to see how well it works in treating patients with recurrent or progressive glioblastoma.Tandutinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor.
详细描述
PRIMARY OBJECTIVES:
I. Assess the ability of tandutinib to achieve a target tumor/plasma ratio ≥ 0.33 in patients with recurrent glioblastoma undergoing resection. (Feasibility study) II. Detect potential biological effects of tandutinib by measuring platelet-derived growth factor receptor phosphorylation status and downstream activation of Akt and Erk. (Feasibility study) III. Determine the maximum tolerated dose of tandutinib in patients with recurrent or progressive glioblastoma. (Phase I) IV. Estimate the frequency of toxicities associated with tandutinib in patients with recurrent or progressive glioblastoma. (Phase I) V. Describe the pharmacokinetics of this route of administration in patients with recurrent or progressive glioblastoma. (Phase I) VI. Assess tumor response rate in patients with recurrent or progressive glioblastoma. (Phase II)
SECONDARY OBJECTIVES:
I. Estimate overall survival of patients with recurrent or progressive glioblastoma. (Phase II) II. Estimate the 6-month progression-free survival rate in these patients. (Phase II) III. Assess the toxicities associated with tandutinib in these patients. (Phase II) IV. Assess the pharmacokinetic profile of this route of administration in these patients. (Phase II) V. Explore protein-expression patterns that distinguish patients who respond to therapy from those who do not. (Phase II)
OUTLINE: This is a multicenter, prospective, nonrandomized, feasibility study and phase I study (in parallel) followed by an open label phase II 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
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- 未提供
排除标准
- 未提供
研究组 & 干预措施
Arm I - Feasibility
Patients receive oral tandutinib twice daily for 7 days. Patients then undergo biopsy or surgery to remove the tumor. Within 2 weeks after biopsy or surgery, patients receive oral tandutinib twice daily* on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
conventional surgery
oral tandutinib
Pharmacological study
Tissue samples
干预措施: conventional surgery (Procedure)
Arm I - Feasibility
Patients receive oral tandutinib twice daily for 7 days. Patients then undergo biopsy or surgery to remove the tumor. Within 2 weeks after biopsy or surgery, patients receive oral tandutinib twice daily* on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
conventional surgery
oral tandutinib
Pharmacological study
Tissue samples
干预措施: tandutinib (Drug)
Arm I - Feasibility
Patients receive oral tandutinib twice daily for 7 days. Patients then undergo biopsy or surgery to remove the tumor. Within 2 weeks after biopsy or surgery, patients receive oral tandutinib twice daily* on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
conventional surgery
oral tandutinib
Pharmacological study
Tissue samples
干预措施: pharmacological study (Other)
Arm I - Feasibility
Patients receive oral tandutinib twice daily for 7 days. Patients then undergo biopsy or surgery to remove the tumor. Within 2 weeks after biopsy or surgery, patients receive oral tandutinib twice daily* on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
conventional surgery
oral tandutinib
Pharmacological study
Tissue samples
干预措施: Tissue samples (Other)
Arm 2 - Dose Escalation (Phase 1)
Phase I: Patients receive oral tandutinib twice daily* on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Cohorts of 3-6 patients receive escalating doses of tandutinib until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. At least 6 patients are treated at the MTD.
the starting dose for tandtinib is 500mg BID
oral tandutinib
Pharmacological study
Tissue samples
干预措施: tandutinib (Drug)
Arm 2 - Dose Escalation (Phase 1)
Phase I: Patients receive oral tandutinib twice daily* on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Cohorts of 3-6 patients receive escalating doses of tandutinib until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. At least 6 patients are treated at the MTD.
the starting dose for tandtinib is 500mg BID
oral tandutinib
Pharmacological study
Tissue samples
干预措施: pharmacological study (Other)
Arm 2 - Dose Escalation (Phase 1)
Phase I: Patients receive oral tandutinib twice daily* on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Cohorts of 3-6 patients receive escalating doses of tandutinib until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. At least 6 patients are treated at the MTD.
the starting dose for tandtinib is 500mg BID
oral tandutinib
Pharmacological study
Tissue samples
干预措施: Tissue samples (Other)
Arm 3 - Phase 2
Patients receive tandutinib as in phase I at the MTD determined in phase I.
600mg was the determined MTD in Dose Escalation
oral tandutinib
Pharmacological study
Tissue samples
干预措施: tandutinib (Drug)
Arm 3 - Phase 2
Patients receive tandutinib as in phase I at the MTD determined in phase I.
600mg was the determined MTD in Dose Escalation
oral tandutinib
Pharmacological study
Tissue samples
干预措施: pharmacological study (Other)
Arm 3 - Phase 2
Patients receive tandutinib as in phase I at the MTD determined in phase I.
600mg was the determined MTD in Dose Escalation
oral tandutinib
Pharmacological study
Tissue samples
干预措施: Tissue samples (Other)
结局指标
主要结局
Maximum Tolerated Dose of Tandutinib Defined by Dose Limiting Toxicities (Phase 1)
时间窗: cycle 1 - 28 days
To Determine the Tumor/Plasma Ratio of in Subjects With Recurrent GBM Undergoing Resections (Phase 0)
时间窗: 7 days prior to surgery including surgery
participants are administered tandutinib (500mg BID) for 7 days prior to surgery and then undergo resection for recurrent glioblastoma. Tissue samples will be collected for correlative studies - determine tumor/plasma ratio.
Number of Dose Limiting Toxicities Per Dose Level
时间窗: 28 days
cohorts of 3-6 pts will recieve oral tandutinib starting at 500mg BID with a dose escalation in each cohort. Each treatment cycle is 28 days. Evaluation period for MTD is 1st cycle - 28 days. dose limiting toxicity defined as: grades 3-4 severity (except vomiting and diarrhea without sufficient prophylaxis delay of treatment \> 14 days. ANC less/equal 500m/mm3; Plts less/equal 25,000/mm3; febrile neutropenia or delay of treatment \> 14 days
Tumor Response (Complete Response and Partial Response) Rate (Phase II)
时间窗: Up to 4 years
pts receive a scan baseline and prior to every odd cycle. All responses are centrally reviewed Complete response Complete disappearance of all tumor on MRI scan, off all glucocorticoids with stable or improving neurological exam minimum of 4 wks Partial response Greater than or equal 50% reduction in tumor size on MRI, on sable or decreasing glucocorticoids with stable or improving neurological exam for a minimum of 4 wks. Progressive disease Progressive neurological abnormalities not explained by other causes or greater than 25% increase in size of tumor or if new lesion. Stable disease Clinical status and MRI does not qualify for complete response, partial response or progression
Pharmacokinetics (Max Concentration of Plasma) for Tandutinib in Phase 1 and Phase 2
时间窗: 28 days
pre-dose, 1,2,4,6,8 and 24 hrs post dose and days 8,15, 21 of cycle 1 and day one of cycle 2
Pharmacokinetics (Apparent Terminal Phase Half-life) for Tandutinib in Phase 1 and Phase 2
时间窗: 28 days
pre-dose, 1,2,4,6,8 and 24 hrs post dose and days 8,15, 21 of cycle 1 and day one of cycle 2
Pharmacokinetics (Area Under the Plasma Concentration Time Profile From Zero to Infinity (AUC)) for Tandutinib in Phase 1 and Phase 2
时间窗: 28 days
pre-dose, 1,2,4,6,8 and 24 hrs post dose and days 8,15, 21 of cycle 1 and day one of cycle 2
Pharmacokinetics; Apparent Oral Clearance for Tandutinib in Phase 1 and Phase 2
时间窗: 28 days
pre-dose, 1,2,4,6,8 and 24 hrs post dose and days 8,15, 21 of cycle 1 and day one of cycle 2
Pharmacokinetics; Apparent Oral Total Body Volume of Distribution for Tandutinib in Phase 1 and Phase 2
时间窗: 28 days
pre-dose, 1,2,4,6,8 and 24 hrs post dose and days 8,15, 21 of cycle 1 and day one of cycle 2
Pharmacokinetics; Steady-state Trough Concentration for Tandutinib in Phase 1 and Phase 2
时间窗: 28 days
pre-dose, 1,2,4,6,8 and 24 hrs post dose and days 8,15, 21 of cycle 1 and day one of cycle 2
次要结局
- Overall Survival (Phase II)(Up to 4 years)
- Six-month Progression-free Survival Rate (Phase II)(At 6 months)
- Overall Failure Rate (Phase II)(up to 4 years)
- Proportion of Patients With Serious or Life Threatening Toxicities(2 year period)
- Protein Expression Patterns Post Treatment - Loss or Gain(baseline - cycle 2 (28 days))