A Phase 2 Study of RO4929097 (NSC 749225) in Combination With FOLFOX Plus Bevacizumab Versus FOLFOX Plus Bevacizumab Alone for the First-Line Treatment of Patients With Metastatic Colorectal Cancer (NCI #8467)
试验速览
- 阶段
- 2 期
- 状态
- 撤回
- 试验地点
- 3
- 主要终点
- Progression-free survival of patients treated with FOLFOX6 plus bevacizumab with or without gamma-secretase inhibitor RO4929097
研究概览
简要总结
This phase II clinical trial is studying how well giving combination chemotherapy and bevacizumab with or without RO4929097 works in treating patients with metastatic colorectal cancer. Drugs used in chemotherapy, such as oxaliplatin, leucovorin calcium, and fluorouracil, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. 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. RO4929097 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet known whether combination chemotherapy and bevacizumab is more effective with RO4929097 in treating patients with colorectal cancer.
详细描述
PRIMARY OBJECTIVES:
I. To estimate the efficacy, as determined by progression-free survival, of FOLFOX6 and bevacizumab with versus without gamma-secretase inhibitor RO4929097 (RO4929097).
SECONDARY OBJECTIVES:
I. To estimate the clinical benefit of RO4929097 in combination with mFOLFOX6 and bevacizumab, as measured by objective response rate.
II. To evaluate the safety and tolerability of RO4929097 in combination with mFOLFOX6 chemotherapy and bevacizumab.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 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 or cytologically confirmed adenocarcinoma of the colon or adenocarcinoma of the rectum
- •Metastatic disease by imaging
- •Measurable disease, defined as ≥ 1 lesion that can be accurately measured in ≥ 1 dimension (longest diameter to be recorded) as ≥ 20mm by conventional techniques or as ≥ 10 mm by spiral CT scan
- •No known brain metastases
- •ECOG performance status 0-1
- •ANC ≥ 1,500/mm³
- •WBC ≥ 3,000/mm³
- •Platelet count ≥ 100,000/mm³ (without a platelet transfusion ≤ 14 days prior to study)
- •Hemoglobin ≥ 9 g/dL
- •Serum creatinine ≤ 1.5 times upper limit of normal (ULN)
- •Urine protein:creatinine ≤ 0.5 or proteinuria < 1,000 mg on 24-hour urine collection
- •Total bilirubin ≤ 1.5 times ULN
- •AST and ALT ≤ 2.5 times ULN (≤ 5.0 times ULN for patients with liver metastases)
- •Albumin ≥ 2.5 g/dL
- •Amylase ≤ 2 times ULN
- •Lipase ≤ 2 times ULN
- •PTT ≤ 1.2 times ULN
- •INR ≤ 1.2 times ULN
- •No patients with uncontrolled hypophosphatemia, hypocalcemia, hypomagnesemia, hyponatremia, or hypokalemia defined as less than the lower limit of normal for the institution, despite adequateelectrolyte supplementation
- •Not pregnant or nursing
- •Negative pregnancy test
- •Fertile patients must use two forms of contraception (i.e., barrier contraception and one other method of contraception) prior to, during, and for ≥ 12 months after study participation
- •Patients must not have current evidence of or history of another malignancy except adequately treated non-melanoma skin cancer, curatively treated in-situ cancer of the cervix, or other curatively treated solid tumors with no evidence of disease for ≥ 3 years prior to enrollment
- •Able to swallow capsules
- •No malabsorption syndrome or other condition that would interfere with intestinal absorption
- •No history of allergic reactions attributed to compounds of similar chemical or biologic composition to gamma-secretase inhibitor RO4929097 used in the study
- •No clinically important history of liver disease, including known viral, other hepatitis, or cirrhosis
- •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
- •Psychiatric illness and/or social situations that would limit compliance with study requirements
- •No baseline QTcF > 450 msec (male) or QTcF > 470msec (female)
- •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 traumatic injury within the past 28 days
- •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 antihypertension medication)
- •History of cerebrovascular accident within the past 6 months
- •Myocardial infarction or unstable angina within the past 6 months
- •NYHA grade II-IV congestive heart failure
- •Serious and inadequately controlled cardiac arrhythmia
- •No requirement for antiarrhythmics or other medications known to prolong QTc
- •No significant vascular disease (e.g., aortic aneurysm, requiring surgical repair, history of aortic dissection, or recent peripheral arterial thrombosis) within the past 6 months
- •No 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
- •Recovered to < NCI CTCAE grade 2 toxicities related to prior therapy
- •No prior adjuvant or neoadjuvant chemotherapy for colorectal cancers within 12 months of development of metastases
- 另有 7 项未显示
排除标准
- 未提供
研究组 & 干预措施
Arm I (RO4929097, combination chemotherapy, bevacizumab)
Patients receive FOLFOX6 regimen comprising oxaliplatin IV over 2 hours, leucovorin calcium IV over 2 hours, fluorouracil IV continuously over 46 hours, and bevacizumab IV over 30-90 minutes on days 1-2. Patients also receive oral gamma-secretase inhibitor RO4929097 on days 1-3 and 8-10. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.
干预措施: bevacizumab (Biological)
Arm I (RO4929097, combination chemotherapy, bevacizumab)
Patients receive FOLFOX6 regimen comprising oxaliplatin IV over 2 hours, leucovorin calcium IV over 2 hours, fluorouracil IV continuously over 46 hours, and bevacizumab IV over 30-90 minutes on days 1-2. Patients also receive oral gamma-secretase inhibitor RO4929097 on days 1-3 and 8-10. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.
干预措施: oxaliplatin (Drug)
Arm I (RO4929097, combination chemotherapy, bevacizumab)
Patients receive FOLFOX6 regimen comprising oxaliplatin IV over 2 hours, leucovorin calcium IV over 2 hours, fluorouracil IV continuously over 46 hours, and bevacizumab IV over 30-90 minutes on days 1-2. Patients also receive oral gamma-secretase inhibitor RO4929097 on days 1-3 and 8-10. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.
干预措施: leucovorin calcium (Drug)
Arm I (RO4929097, combination chemotherapy, bevacizumab)
Patients receive FOLFOX6 regimen comprising oxaliplatin IV over 2 hours, leucovorin calcium IV over 2 hours, fluorouracil IV continuously over 46 hours, and bevacizumab IV over 30-90 minutes on days 1-2. Patients also receive oral gamma-secretase inhibitor RO4929097 on days 1-3 and 8-10. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.
干预措施: fluorouracil (Drug)
Arm II (combination chemotherapy, bevacizumab)
Patients receive FOLFOX6 regimen and bevacizumab as in arm I. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.
干预措施: FOLFOX regimen (Drug)
Arm II (combination chemotherapy, bevacizumab)
Patients receive FOLFOX6 regimen and bevacizumab as in arm I. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.
干预措施: bevacizumab (Biological)
Arm II (combination chemotherapy, bevacizumab)
Patients receive FOLFOX6 regimen and bevacizumab as in arm I. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.
干预措施: oxaliplatin (Drug)
Arm II (combination chemotherapy, bevacizumab)
Patients receive FOLFOX6 regimen and bevacizumab as in arm I. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.
干预措施: leucovorin calcium (Drug)
Arm I (RO4929097, combination chemotherapy, bevacizumab)
Patients receive FOLFOX6 regimen comprising oxaliplatin IV over 2 hours, leucovorin calcium IV over 2 hours, fluorouracil IV continuously over 46 hours, and bevacizumab IV over 30-90 minutes on days 1-2. Patients also receive oral gamma-secretase inhibitor RO4929097 on days 1-3 and 8-10. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.
干预措施: FOLFOX regimen (Drug)
Arm I (RO4929097, combination chemotherapy, bevacizumab)
Patients receive FOLFOX6 regimen comprising oxaliplatin IV over 2 hours, leucovorin calcium IV over 2 hours, fluorouracil IV continuously over 46 hours, and bevacizumab IV over 30-90 minutes on days 1-2. Patients also receive oral gamma-secretase inhibitor RO4929097 on days 1-3 and 8-10. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.
干预措施: gamma-secretase/Notch signalling pathway inhibitor RO4929097 (Drug)
Arm II (combination chemotherapy, bevacizumab)
Patients receive FOLFOX6 regimen and bevacizumab as in arm I. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.
干预措施: fluorouracil (Drug)
结局指标
主要结局
Progression-free survival of patients treated with FOLFOX6 plus bevacizumab with or without gamma-secretase inhibitor RO4929097
时间窗: From start of treatment to time of progression, assessed up to 12 months
Progression is defined as changes in RECIST 1.1-defined imaging, progression in non-target lesions as defined by RECIST 1.1, unequivocal clinical deterioration, or death from any cause.
次要结局
- Objective response rate (complete or partial response) as measured by RECIST(Assessed up to 12 months)
- Pharmacokinetics and pharmacodynamics of gamma-secretase inhibitor RO4929097(Baseline, and day 1 of courses 1 and 2)
- Incidence of dose-limiting and non-dose-limiting toxicities(Assessed up to 12 months)