Phase I/II Study of R04929097 With Bevacizumab in Patients With Recurrent Malignant Glioma

National Cancer Institute (NCI)4 个研究点分布在 1 个国家目标入组 13 人开始时间: 2010年12月最近更新: 2015年12月14日

适应症

干预措施

试验速览

阶段: 1 期
状态: 终止
发起方: National Cancer Institute (NCI)
入组人数: 13
试验地点: 4
主要终点: Maximum-tolerated Dose and the Recommended Phase II Dose of Gamma-secretase Inhibitor RO4929097 in Combination With Bevacizumab Determined by Dose-limiting Toxicity Rate (Phase I)

研究概览研究设计入排标准研究组 & 干预措施结局指标研究者研究点记录与标识符相似试验

研究概览

简要总结

This phase I/II trial is studying the side effects and the best dose of RO4929097 to see how well it works when given together with bevacizumab compared to bevacizumab alone in treating patients with progressive or recurrent malignant glioma. RO4929097 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Giving RO4929097 together with bevacizumab may kill more tumor cells.

详细描述

Phase I

Primary Objective:

To assess the safety profile of R04929097 in combination with bevacizumab and to determine a recommended Phase II dose of R04929097 in combination with bevacizumab in patients with recurrent malignant glioma

Secondary Objectives: 2. To describe the toxicity associated with this combination regimen 3. To assess pharmacokinetics of R04929097 in combination with bevacizumab

Phase II I. Assess the safety profile and the recommended phase II dose of gamma-secretase inhibitor RO4929097 (RO4929097) in combination with bevacizumab in patients with recurrent malignant glioma.

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

•Histologically confirmed malignant glioma (phase I)
•Glioblastoma
•Anaplastic astrocytoma
•Anaplastic oligodendroglioma
•Mixed anaplastic oligoastrocytoma
•Histologically confirmed glioblastoma following radiotherapy and temozolomide (phase II)
•Progressive or recurrent disease after conformal external-beam radiation therapy and concurrent temozolomide, followed by ≥ 1 adjuvant course of temozolomide
•Measurable disease by MRI within the past 2 weeks
•Tumor tissue form indicating availability of archived tissue from initial resection at diagnosis of malignant glioma completed and signed by a pathologist
•Karnofsky performance status 60-100%
•ANC ≥ 1,500/mm³
•Platelet count ≥ 100,000/mm³
•Hemoglobin ≥ 9 g/dL
•Total bilirubin normal
•AST and ALT ≤ 2.5 times upper limit of normal
•Creatinine normal OR creatinine clearance ≥ 60 mL/min
•Urine protein: If proteinuria ≥ +2 protein, a protein level should be < 1,000 mg by a 24-hour urine collection
•Electrolytes (calcium, chloride, magnesium, potassium, phosphorus, sodium) within institutional normal limits
•Fertile patients must use 2 forms of effective contraception before, during, and for ≥ 12 months (6 months phase II, bevacizumab arm only) after treatment
•Negative pregnancy test
•Not pregnant or nursing
•At least 5 years since prior malignancy except nonmelanoma skin cancer, or carcinoma in situ of the cervix, breast, or bladder
•Mini Mental State Exam score of ≥ 15
•Must be able to tolerate MRI

排除标准

•No serious concurrent infection or medical illness that would jeopardize the ability of the patient to receive the treatment outline in this protocol with reasonable safety
•No history of allergic reactions attributed to compounds of similar chemical or biological composition to gamma-secretase inhibitor RO4929097 or bevacizumab
•Must be able to swallow capsules
•No malabsorption syndrome or other condition that would interfere with intestinal absorption
•No baseline QTcF > 450 msec (male) or QTcF > 470 msec (female)
•Not history of being serologically positive for hepatitis A, B, or C
•No history of cirrhosis
•No uncontrolled hypocalcemia, hypomagnesemia, hyponatremia, or hypokalemia despite adequate electrolyte supplementation
•No uncontrolled intercurrent illness including, but not limited to, any of the following:
•Ongoing or active infection
•Symptomatic congestive heart failure
•Unstable angina pectoris
•A history of torsades de pointes or other significant cardiac arrhythmias other than chronic, stable atrial fibrillation
•Psychiatric illness and/or social situations that would limit compliance with study requirements
•No serious or non-healing wound, ulcer, or bone fracture
•No history of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within the past 6 months
•No significant vascular disease (e.g., aortic aneurysm requiring surgical repair or recent peripheral arterial thrombosis) within the past 6 months
•No clinically significant cardiovascular disease, including any of the following:
•Inadequately controlled hypertension (systolic BP > 160 mm Hg and/or diastolic BP > 90 mm Hg) despite antihypertensive medication
•History of cerebrovascular accident or transient ischemic attack at any time
•Myocardial infarction or unstable angina within the past 12 months
•NYHA grade II-IV congestive heart failure
•Serious and inadequately controlled cardiac arrhythmia
•Significant vascular disease (e.g., aortic aneurysm or history of aortic dissection)
•Clinically significant peripheral vascular disease
•No evidence of bleeding diathesis or coagulopathy
•No known hypersensitivity to Chinese hamster ovary cell products or other recombinant human antibodies
•No requirement for antiarrhythmics or other medications known to prolong QTc
•One or 2 prior treatment regimens allowed
•Recovered from severe toxicity of prior therapy
•At least 3 months since prior radiotherapy
•At least 6 weeks since prior nitrosourea
•At least 3 weeks since prior chemotherapy
•At least 4 weeks since prior and no other concurrent investigational agents
•At least 2 weeks since prior non-cytotoxic, FDA-approved agent (e.g., Tarceva [erlotinib hydrochloride], hydroxychloroquine, bevacizumab, etc.)
•At least 28 days since any prior surgery
•No prior γ-secretase inhibitors and/or bevacizumab
•At least 10 days since prior and no concurrent enzyme-inducing anti-epileptic drug
•No concurrent combination antiretroviral therapy for HIV-positive patients

研究组 & 干预措施

Phase I Dose Finding

Experimental

Patients receive oral gamma-secretase/Notch signalling pathway inhibitor RO49290977 on days 1-3, 8-10, 15-17, and 22-24, and bevacizumab IV over 30-90 minutes on days 1 and 15. Other: pharmacological study: correlative studies; laboratory biomarker analysis: correlative studies.

干预措施: gamma-secretase/Notch signalling pathway inhibitor RO4929097 (Drug)

Phase I Dose Finding

Experimental

干预措施: bevacizumab (Biological)

Phase I Dose Finding

Experimental

干预措施: laboratory biomarker analysis (Other)

Phase I Dose Finding

Experimental

干预措施: pharmacological study (Other)

Phase II Stage I

Experimental

Patients receive oral gamma-secretase/Notch signalling pathway inhibitor RO49290977 on days 1-3, 8-10, 15-17, and 22-24, and bevacizumab IV over 30-90 minutes on days 1 and 15.Other: laboratory biomarker analysis: correlative studies.