Phase I Dose Escalation of Gleevec in Combination With RAD001 Plus Hydroxyurea for Patients With Recurrent Malignant Glioma
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- 入组人数
- 78
- 试验地点
- 1
- 主要终点
- To determine MTD & DLT & Imatinib mesylate & RAD001 when combined w Hydroxyurea among pt w GBM
研究概览
简要总结
Primary objective To determine maximum tolerated dose & dose limiting toxicity of imatinib mesylate & RAD001 when combined w fixed doses of hydroxyurea among pts w recurrent GBM who are on & not on enzyme-inducing anti-convulsants including pts not on anti-epileptic drugs Secondary objective To assess safety & tolerability of imatinib mesylate in combo w RAD001 & hydroxyurea in this population To characterize single-dose & repeated-dose pharmacokinetic profiles of imatinib mesylate & RAD001 combo therapy in this pt population.
To assess antiangiogenic effects, pre- and post-treatment, of imatinib mesylate, RAD001 & hydroxyurea combo therapy, using DCE-MRI to evaluate changes in extent of vascular permeability, perfusion & relative tumor blood volume; to explore assessment of tumor cellularity & tumor cell death by changes in DWI-MRI as quantitated by apparent diffusion coefficient maps.
详细描述
This is open-label, single center, 1-arm ph I dose-escalation study of continuous, daily doses of imatinib mesylate & RAD001 administered orally in combination w fixed doses of hydroxyurea in adult pts w recurrent or relapsing glioblastoma multiforme. Study format includes classical "3+3" dose escalation design to determine MTD & DLT of imatinib mesylate + RAD001 when combined w hydroxyurea among GBM pts. Pts will be stratified based on whether they who are receiving EIACD & each stratum will independently dose escalate. Additionally, study will characterize safety, tolerability, biologic activity, & pharmacokinetic profile of this combo therapy.
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
- •Pts w confirmed GBM, GS, AA, AO & AOA are presenting in 1st, 2nd/3rd recurrence/relapse
- •Pts without tumor biopsy <1 wk/surgical resection <2 wks prior to starting study drug
- •For stratum of non-EIAED pts, each pts off all enzyme inducing anticonvulsants for >2 wks prior to starting study drug
- •Pts should be on non-increasing dose of steroids for >7 days prior to obtaining baseline Gd-MRI of brain
- •Pts should be on non-increasing dose of steroids for >7 days prior to starting study drug
- •Pts w previous implantation of Gliadel may be eligible after discussion between investigator & sponsor
- •Multifocal disease is eligible
- •Age >18 yrs
- •Hematology: ANC>1.5 x 10^9/L, Hgb>9 g/dL, Platelets>100 x 10^9/L
- •Biochemistry: K≥ LLN/correctable w supplement, Total Ca≥ LLN/correctable w supplement, Mg≥ LLN/correctable w supplement, P≥ LLN/correctable w supplement, AST/SGOT & ALT/SGPT <2.5 x ULN, Serum bilirubin <1.5 x ULN, Serum creatinine <1.5 x ULN/measured 24hr CrCl<0 mL/min/1.73m2, & Cholesterol≤ 00 mg/dL & triglyceride≤2.5 ULN
- •Life expectancy ≥12wks
- •Written informed consent obtained prior to any screening procedures
排除标准
- •Pts w any peripheral neuropathy ≥CTCAE gr2
- •Pts w unresolved diarrhea ≥CTCAE gr2
- •History of impaired cardiac function
- •Obligate use of cardiac pacemaker, Congenital long QT syndrome, History or presence of ventricular or atrial tachyarrhythmias, Clinically significant resting bradycardia , Right bundle branch block + left anterior hemiblock
- •Other clinically significant cardiac diseases
- •Uncontrolled Db
- •Active or uncontrolled infection requiring intravenous antibiotics
- •Impairment of GI function/GI disease that may significantly alter absorption of Gleevec, hydroxyurea and/or RAD001
- •Acute/chronic liver/renal disease
- •Other concurrent severe and/or uncontrolled medical condition that could cause unacceptable safety risks/compromise compliance w protocol
- •Treatment w any hematopoietic colony-stimulating factor ≤2wks prior to starting study drug. Erythropoietin is allowed
- •Pts w history of CHF/arrhythmias who are receiving treatment w digoxin/verapamil, & treatment cannot be discontinued/switched to different drug prior to starting study drug
- •Pts taking warfarin sodium
- •Pts received treatment w PDGF/mTOR directed therapies
- •Pts received chemo ≤ 4wks prior to starting study drug/have not recovered from side effects of such therapy
- •Pts received immunotherapy ≤2 wks prior to starting study drug/have not recovered from side effects of such therapy
- •Pts received investigational drugs ≤4 wks prior to starting study drug/have not recovered from side effects of such therapy
- •Pts received XRT ≤4 wks prior to starting study drug/have not recovered from side effects of such therapy
- •Pts undergone major non-CNS surgery ≤2 wks prior to starting study drug/pts have not recovered from side effects of such therapy
- •Cardiac pacemaker, Ferromagnetic metal implants other than those approved as safe for use in MR scanners, Claustrophobia, Obesity
- •Female pts are pregnant/breast feeding,/adults of reproductive potential not employing effective method of birth control. Barrier contraceptives must be used throughout trial in both sexes. Oral, implantable/injectable contraceptives may be affected by cytochrome P450 interactions, & are therefore not considered effective for study. Women of childbearing potential have negative serum pregnancy test 48hrs prior to administration of Gleevec, hydroxyurea and/or RAD
- •Known diagnosis of HIV infection
- •Pts w history of another primary malignancy that is currently clinically significant/currently requires active intervention
- •Pts unwilling to/unable to comply w protocol
研究组 & 干预措施
1
Pts receiving EIACDs
干预措施: Gleevec, RAD001, and Hydroxyurea (Drug)
2
Pts not receiving EIACDs
干预措施: Gleevec, RAD001, and Hydroxyurea (Drug)
结局指标
主要结局
To determine MTD & DLT & Imatinib mesylate & RAD001 when combined w Hydroxyurea among pt w GBM
时间窗: 6 months
次要结局
- To further evaluate safety & tolerability & Imatinib mesylate in combo w RAD001 & Hydroxyurea(6 months)
- To evaluate PK on Imatinib mesylate when administered w RAD001 among GBM pt who are on & not on EIAEDs(6 months)
研究者
Annick Desjardins
Assistant Professor of Medicine
Duke University