Sorafenib and Bevacizumab in Treating Patients With Metastatic Colorectal Cancer

Study Overview
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Brief Summary
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This phase II trial is studying how well giving sorafenib together with bevacizumab works in treating patients with metastatic colorectal cancer. Sorafenib 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. Sorafenib and bevacizumab may also stop the growth of tumor cells by blocking blood flow to the tumor. Giving sorafenib together with bevacizumab may kill more tumor cells

Detailed Description
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PRIMARY OBJECTIVES: I. Evaluate proportion of patients who are progression-free at 3 months (in historic comparison with results for single-agent bevacizumab in ECOG 3200). SECONDARY OBJECTIVES: I. Response rate (RR) II. Overall survival (OS) III. Safety IV. Feasibility OUTLINE: This is a multicenter study. Patients receive sorafenib tosylate orally twice daily on days 1-5 and 8-12 and bevacizumab IV over 30-90 minutes on day 1. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity. Blood samples are collected at baseline and then periodically during study treatment for laboratory biomarker and pharmacogenetic studies. After completion of study treatment, patients are followed periodically for up to 2 years.

Official Title
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Phase II Study of Sorafenib/Avastin® as Salvage Therapy in Patients With Metastatic Colorectal Cancer

Conditions
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Recurrent Colon Cancer, Recurrent Rectal Cancer, Stage IV Colon Cancer, Stage IV Rectal Cancer

Intervention / Treatment
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* Drug: sorafenib tosylate
* Biological: bevacizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of stage IV colorectal cancer (histologic proof is not required) Measurable disease Spiral CT scan required for both pre- and post-treatment tumor assessments of lesions measuring 1-2 cm Progressive disease during or within 6 months of most recent prior chemotherapy regimen (bevacizumab, fluoropyrimidine, oxaliplatin, or irinotecan-based treatment) OR considered ineligible for standard therapy Documentation of submission of tumor material for Kirsten Rat Sarcoma (KRAS) testing available Prior anti-epidermal growth factor receptor (EGFR) antibody therapy (e.g., cetuximab or panitumumab) required for patients with wild-type KRAS tumor No known brain metastasis Patients with neurological symptoms must undergo a CT scan or MRI of the brain to exclude brain metastasis Eastern Cooperative Oncology Group (ECOG) performance status 0-1 Life expectancy ≥ 6 months Hemoglobin ≥ 9.0 g/dL Absolute neutrophil count (ANC) ≥ 1,500/mm³ Platelet count ≥ 100,000/mm³ White blood cell count (WBC) ≥ 3,400/mm³ International normalized ratio (INR) < 1.5 (≤ 3.0 if on anti-coagulation therapy [e.g., warfarin or heparin]) Total bilirubin ≤ 1.5 times upper limit of normal (ULN) Aspartate aminotransferase (AST) ≤ 2.5 times ULN (≤ 5 times ULN if there is liver involvement) Alkaline phosphatase ≤ 3 times ULN Creatinine ≤ 1.5 times ULN Urine protein:creatinine ratio < 1 OR urine dipstick < 2+ OR urine protein < 1,000 mg by 24-hour urine collection Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception during and for ≥ 6 months after completion of study treatment (≥ 2 weeks after completion of treatment with sorafenib tosylate alone) Willing to provide mandatory blood samples for translational research studies Able to swallow whole pills No inadequately controlled hypertension (i.e., systolic BP > 150 mm Hg or diastolic BP > 100 mm Hg on anti-hypertensive medications) No prior hypertensive crisis or hypertensive encephalopathy No myocardial infarction or unstable angina within the past 6 months No congestive heart failure requiring use of ongoing maintenance therapy for life-threatening ventricular arrhythmias No thrombolic or embolic events (e.g., cerebrovascular accident, including transient ischemic attacks) within the past 6 months No hemorrhage or bleeding event > grade 3 within the past 4 weeks No evidence or history of bleeding diathesis or coagulopathy (in the absence of therapeutic anticoagulation) No greater than normal risk of bleeding No active or recent hemoptysis (≥ ½ teaspoon of bright red blood per episode) within the past 30 days No concurrent uncontrolled illness including, but not limited to, any of the following: Ongoing or active infection Symptomatic congestive heart failure Unstable angina pectoris Cardiac arrhythmia requiring anti-arrhythmic drugs Psychiatric illness or social situations that would limit compliance with study requirements No known HIV infection or chronic hepatitis B or C infection No serious, non-healing wound, active ulcer, or untreated bone fracture Patients with fractures secondary to metastatic disease are eligible after appropriate radiotherapy No significant traumatic injury within the past 4 weeks No known or suspected allergy or hypersensitivity to any component of bevacizumab, sorafenib tosylate, or their excipients or to any other agent given in the course of this study No malabsorption problem None of the following within the past 6 months: Significant vascular disease (e.g., aortic aneurysm or aortic dissection) Peripheral arterial thrombosis Symptomatic peripheral vascular disease Abdominal fistula Gastrointestinal perforation Intra-abdominal abscess No other active malignancy within the past 3 years except non melanoma skin cancer or carcinoma in situ of the cervix Prior malignancy allowed provided patient is not receiving other specific treatment for that malignancy (other than hormonal therapy) No other concurrent investigational agent for this cancer Prior radiotherapy allowed No prior sorafenib tosylate No prior discontinuation of bevacizumab due to adverse events More than 4 weeks since prior and no concurrent participation in any other experimental drug study More than 4 weeks since prior St. John's wort or rifampin More than 4 weeks since prior and no concurrent major surgical procedure or open biopsy More than 7 days since prior core biopsy or minor surgical procedure, including placement of a vascular access device No concurrent anticoagulant, except low-dose warfarin or heparin for deep venous thrombosis prophylaxis

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (sorafenib tosylate and bevacizumab)<br>Patients receive sorafenib tosylate orally twice daily on days 1-5 and 8-12 and bevacizumab IV over 30-90 minutes on day 1. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity. Blood samples are collected at baseline and then periodically during study treatment for laboratory biomarker and pharmacogenetic studies | Drug: sorafenib tosylate<br>* Given orally<br>* Other names: SFN;Biological: bevacizumab<br>* Given IV<br>* Other names: rhuMAb VEGF;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival Rate | The primary endpoint of this trial is progression free survival at 3 months. All patients meeting the eligibility criteria who have signed a consent form and have begun treatment will be considered evaluable. Patients lost to follow-up before 3 months (e.g., progression, refusing further treatment, etc.) will be considered treatment failures. All eligible patients will be followed until death or a minimum of 3 years. The proportion of successes will be estimated by the number of successes divided by the total number of evaluable patients. Progression is defined as at least a 20% increase in the sum of longest liameter of target lesions taking as reference the smallest sum longest diameter recorded since the treatment started or the appearance of one or more new lesions. | At 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response Rate | Simple frequency analysis will be conducted to see if response rate is related to prior treatment and the selected tumor biomarkers. Descriptive statistics will be used to investigate how prior treatment affects various other measures as well. | Up to 2 years | 
| Overall Survival | The distribution of overall survival will be estimated using Kaplan-Meier methodology. | Time from registration to death, assessed up to 2 years | 
| Feasibility of Study Treatment | Will be evaluated based on the number of patients who are able to> tolerate the regimen, how long they tolerate it and whether they elect to stop treatment. | Up to 2 years |