A Phase I/II Study of RAD001, FOLFOX and Bevacizumab in Treatment of Colorectal Carcinoma
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 47
- 试验地点
- 2
- 主要终点
- Evaluate Safety of the Combination at a Daily Dosing of 2.5mg RAD001, 5 mg RAD001 or 10 mg RAD001 (Phase 1 Part)
研究概览
简要总结
RAD001 (everolimus) is a novel oral derivative of rapamycin. RAD001 has been in clinical development since 1996 as an immunosuppressant in solid organ transplantation and has obtained marketing authorization (Certican®) for prophylaxis of rejection in renal and cardiac transplantation in a number of countries, including the majority of the European Union. RAD001 has been in development for patients with various malignancies since 2002.
RAD001 is being investigated as an anticancer agent based on its potential to act:
- Directly on the tumor cells by inhibiting tumor cell growth and proliferation
- Indirectly by inhibiting angiogenesis leading to reduced tumor vascularity (via potent inhibition of tumor cell HIF-1 activity, VEGF production and VEGF-induced proliferation of endothelial cells). The role of angiogenesis in the maintenance of solid tumor growth is well established, and the mTOR pathway has been implicated in the regulation of tumor production of proangiogenic factors as well as modulation of VEGFR signaling in endothelial cells.
At weekly and daily schedules and at various doses explored, RAD001 is generally well tolerated. The most frequent adverse events (rash, mucositis, fatigue and headache) associated with RAD001 therapy are manageable. Non-infectious pneumonitis has been reported with mTOR inhibitors but is commonly low-grade and reversible.
Both FOLFOX and bevacizumab are well established for treatment of metastatic colorectal carcinomas. FOLFOX-6 can be combined safely with Bevacizumab and is currently in phase 3 testing for adjuvant therapy and is commonly used as a first line treatment regimen for metastatic colorectal cancers 25. There is an enhanced interest in development of more effective regimens for colorectal cancers. RAD001 is a mTOR inhibitor that has preclinical and clinical activity in colorectal cancers. RAD001 downregulates the mTOR pathway which can lead to direct antiproliferative effects as well as decreased production of Vascular Endothelial Growth Factor. A combination of RAD001 at 10 mg per day in combination with Bevacizumab 10 mg/kg every 2 weeks has been shown to be efficacious and safe. In another trial, RAD001 was shown to have many patients with stable disease and clearly needs to be given in combination therapy.
详细描述
Patient population Phase I portion: Metastatic colorectal cancer. A total of 3 patients on each cohort. Additional 3 patients on the tolerable cohort. Total patient number: Minimum 6, Maximum: 12 Phase II portion: Metastatic colorectal cancer: A total of 33 patients will be treated in this portion. This will include the patients treated on the tolerable dose level from the phase I trial. The statistical justification is indicated in the Statistics section 7.
Overall study design Phase I Study: A three cohort dose escalation will be used. Cycle length will be 28 days.
Bevacizumab FOLFOX-6 RAD001 Cohort 1: 5 mg/ kg Q 2weeks Standard Dose FOLFOX-6 2.5 mg PO qd Cohort 2: 5 mg/ kg Q 2weeks Standard Dose FOLFOX-6 5 mg PO qd Cohort 3: 5mg/kg Q 2 weeks Standard Dose FOLFOX-6 10 mg PO qd
Phase II Study:
For the Phase II portion the primary endpoint is Progression Free Survival at 6 months.
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
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patients with advanced or metastatic colorectal cancers for whom chemotherapy is indicated
- •Patients must not have had prior chemotherapy for advanced or metastatic disease. Patients could have received adjuvant chemotherapy or adjuvant chemo-radiotherapy
- •Patients must have at least one measurable site of disease according to RECIST (version 1.1) criteria that has not been previously irradiated. If the patient has had previous radiation to the marker lesion(s), there must be evidence of progression since the radiation
- •Age ≥ 18 years
- •Minimum of four weeks since any major surgery, completion of radiation, or completion of all prior systemic anticancer therapy (adequately recovered from the acute toxicities of any prior therapy)
- •ECOG performance status £ 2
- •Adequate bone marrow function as shown by: ANC ≥ 1.5 x 109/L, Platelets ≥ 100 x 109/L, Hgb > 9 g/dL
- •Adequate liver function as shown by: serum bilirubin ≤ 1.5 x upper limit of normal (ULN), and serum AST and ALT ≤ 2.5 x ULN. With the exception of serum AST and ALT (< 5 x ULN) if the patient has liver metastases
- •Adequate renal function, serum creatinine < 2 x ULN or creatinine clearance > 50 cc/hr
- •Fasting serum cholesterol ≤300 mg/dL OR ≤ 7.75 mmol/L AND fasting triglycerides ≤ 2.5 x ULN. NOTE: In cases where one or both of these thresholds are exceeded, the patient can only be included after initiation of appropriate lipid lowering medication
- •Signed informed consent
- •INR and PTT < 1.5 (Anticoagulation is allowed if target INR < 1.5 on a stable dose of warfarin or on a stable dose of LMW heparin for > 2 weeks at time of randomization)
排除标准
- •History of severe and uncontrolled allergic reactions to bevacizumab
- •Symptomatic congestive heart failure of New York heart association Class III or IV
- •Patients who have received prior treatment with an mTOR inhibitor (sirolimus, temsirolimus, everolimus)
- •DVT and hypertension controlled < 6 months
- •Prior treatment with any investigational drug within the preceding 4 weeks
- •Chronic treatment with systemic steroids or another immunosuppressive agent; topical or inhaled corticosteroids are allowed
- •Patients should not receive immunization with attenuated live vaccines during study period or within 1 week of study entry
- •Uncontrolled brain or leptomeningeal metastases, including patients who continue to require glucocorticoids for brain or leptomeningeal metastases
- •Other malignancies that are active at the time of enrollment/ treatment on the protocol
- •Patients who have any severe and/or uncontrolled medical conditions or other conditions that could affect their participation in the study such as:
- •unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction ≤ 6 months prior to first study treatment, serious uncontrolled cardiac arrhythmia or any other clinically significant cardiac disease
- •severely impaired lung function as defined as spirometry and DLCO that is 50% of the normal predicted value and/or O2 saturation that is 88% or less at rest on room air
- •uncontrolled diabetes as defined by fasting serum glucose >1.5x ULN
- •any active (acute or chronic) or uncontrolled infection/ disorders
- •nonmalignant medical illnesses that are uncontrolled or whose control may be jeopardized by the treatment with the study therapy
- •known liver disease such as cirrhosis, chronic active hepatitis or chronic persistent hepatitis
- •A known history of HIV seropositivity
- •Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of RAD001 in the judgment of the investigator (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small bowel resection)
- •Patients with an active, bleeding diathesis or on oral anti-vitamin K medication (except low dose Coumadin)
- •Women who are pregnant or breast feeding, or women/men able to conceive and unwilling to practice an effective method of birth control. (Women of childbearing potential must have a negative urine or serum pregnancy test within 7 days prior to administration of RAD001). Oral, implantable, or injectable contraceptives may be affected by cytochrome P450 interactions, and are therefore not considered effective for this study.
- •Patients with a known hypersensitivity to RAD001 (everolimus) or other rapamycins (sirolimus, temsirolimus) or to its excipients
- •History of noncompliance to medical regimens
- •Patients unwilling to or unable to comply with the protocol
研究组 & 干预措施
All patients
All participants enrolled.
干预措施: RAD001 (Drug)
All patients
All participants enrolled.
干预措施: FOLFOX (Drug)
All patients
All participants enrolled.
干预措施: Bevacizumab (Drug)
结局指标
主要结局
Evaluate Safety of the Combination at a Daily Dosing of 2.5mg RAD001, 5 mg RAD001 or 10 mg RAD001 (Phase 1 Part)
时间窗: December 2011
Number of patients who experienced a Dose Limiting Toxicity (DLT). DLT will be assessed in the first 28 days of dosing. Patients need to get dosed with 2 rounds/sessions of all chemotherapy agents in the first 28 days in order to be evaluable for DLT assessment. The primary endpoint is safety as summarized by dose limiting toxicity (DLT).
Progression Free Survival at Six Months
时间窗: 6 months
次要结局
未报告次要终点