Combination Chemotherapy and Bevacizumab in Treating Patients With Stage IV Colon Cancer That Cannot Be Removed By Surgery

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy, such as fluorouracil, leucovorin, and oxaliplatin, 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. Bevacizumab may also stop the growth of colon cancer by blocking blood flow to the tumor. Giving combination chemotherapy together with bevacizumab may kill more tumor cells. PURPOSE: This phase II trial is studying how well giving combination chemotherapy together with bevacizumab works in treating patients with stage IV colon cancer that cannot be removed by surgery.

Detailed Description
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OBJECTIVES: Primary Determine the rate of major morbidity in patients with unresectable stage IV colon cancer and a synchronous asymptomatic primary tumor treated with fluorouracil, leucovorin calcium, and oxaliplatin (mFOLFOX6) in combination with bevacizumab without resection of the primary tumor. Secondary Determine the rate of specific events related to the intact primary tumor requiring hospitalization or a major intervention but not requiring surgery. Determine the rate of ≥ grade 3 toxicity as defined by the Common Terminology Criteria for Adverse Events version 3.0 (CTCAE v3.0) that is related to study therapy prior to disease progression. Determine overall survival of patients treated with this regimen. OUTLINE: This is a multicenter study. Patients receive bevacizumab IV over 30-90 minutes, oxaliplatin IV given concurrently with leucovorin calcium IV over 2 hours on day 1 and fluorouracil IV continuously over 46 hours on days 1 and 2. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed periodically for 5 years after study entry. PROJECTED ACCRUAL: A total of 90 patients will be accrued for this study.

Official Title
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A Phase II Trial of 5-Fluorouracil, Leucovorin, and Oxaliplatin (mFOLFOX6) Chemotherapy Plus Bevacizumab for Patients With Unresectable Stage IV Colon Cancer and a Synchronous Asymptomatic Primary Tumor

Conditions
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Colorectal Cancer

Intervention / Treatment
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* Biological: bevacizumab
* Drug: fluorouracil
* Drug: leucovorin
* Drug: oxaliplatin


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically or cytologically confirmed adenocarcinoma of the colon No histological findings other than adenocarcinoma of the colon If the primary colon tumor and the metastatic lesions have been identified at the same time and it is not possible to biopsy the colonic lesion, the patient will be eligible without histologic confirmation of the primary cancer of the colon as long as other radiographic studies or scans document the characteristics of a colon cancer AND the biopsy of a metastatic site confirms diagnosis of adenocarcinoma suggestive of a primary tumor of the colon Unresected primary tumor of the colon AND radiographically confirmed metastatic colon cancer (single or multiple sites of metastases) that are not considered surgically resectable for cure by chest imaging and CT scan or MRI of the abdomen within the past 4 weeks and by endoscopy within the past 8 weeks Asymptomatic primary tumor No obstruction, perforation, or active bleeding requiring transfusion Distal extent of the tumor must be ≥ 12 cm from the anal verge on endoscopy Not a candidate for curative surgical resection of all metastatic and colon primary tumors No evidence of Central Nervous System (CNS) metastases No recurrent local or metastatic disease after prior adjuvant therapy No diagnosis of rectal carcinoma PATIENT CHARACTERISTICS: Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 Absolute neutrophil count ≥ 1200/mm³ Platelet count ≥ 100,000/mm³ Hemoglobin ≥ 9 g/dL Aspartate aminotransferase (AST) ≤ 2.5 times upper limit of normal (ULN) (≤ 5.0 times ULN if liver metastases are present) Alkaline phosphatase ≤ 3.0 times ULN (≤ 5.0 times ULN if liver metastases are present) Bilirubin ≤ 1.5 times ULN (≤ 2.0 times ULN if liver metastases are present) Creatinine < 1.8 mg/dL Urine dipstick indicating 0-1+ protein If dipstick reading is ≥ 2+, a 24-hour urine collection must demonstrate < 1 g of protein Prothrombin Time and International Normalized Ratio (PT/INR) ≤ 1.5 unless the patient is on therapeutic doses of warfarin, in which case the following criteria must be met: Patient must have an in-range INR (between 2 and 3) on a stable dose of warfarin Patient must not have active bleeding or a pathologic condition that is associated with a high risk of bleeding Patients with a history of non-colorectal malignancies must be disease free for ≥ 5 years prior to study entry and be deemed at low risk for recurrence Patients with the following cancers are eligible if diagnosed and treated within the past 5 years: Carcinoma in situ of the colon Melanoma in situ Basal cell or squamous cell carcinoma of the skin Carcinoma in situ of the cervix Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception during and for 3 months after the completion of study therapy No uncontrolled blood pressure (BP), defined as BP > 150/100 mm Hg No nonmalignant systemic disease that would preclude any of the study therapy drugs, compromise the safety of the patient, or inhibit the patient's ability to participate in the study, including any of the following: New York Heart Association class III or IV cardiac disease Myocardial infarction within the past 6 months Unstable angina within the past 6 months Symptomatic arrhythmia No transient ischemic attack or cerebrovascular accident within the past 6 months No symptomatic peripheral vascular ischemia within the past 6 months No arterial thrombotic event within the past 6 months No gastroduodenal ulcer(s) determined by endoscopy to be active No gastrointestinal perforation within the past 12 months No serious or nonhealing wound, skin ulcer, or bone fracture No significant traumatic injury within the past 28 days No significant episodes of acute bleeding requiring blood transfusion within the past 6 months No clinically significant (≥ grade 2) peripheral neuropathy (neurosensory or neuromotor toxicity) No pulmonary fibrosis or interstitial pneumonitis by chest x-ray No psychiatric or addictive disorders or other conditions that would preclude the patient from meeting study requirements PRIOR CONCURRENT THERAPY: See Disease Characteristics No prior systemic chemotherapy, radiation therapy, or surgery for this malignancy No prior endoscopic management of this malignancy other than biopsy, including endoscopic stent placement, fulguration, or laser treatment More than 30 days since prior investigational drugs More than 28 days since prior major surgical procedure or open biopsy More than 7 days since prior core biopsy or other minor procedure, excluding placement of a vascular access device No concurrent major surgery unrelated to intact primary colon cancer No concurrent radiotherapy No concurrent filgrastim (G-CSF) or pegfilgrastim as primary prophylaxis for neutropenia No concurrent halogenated antiviral agents No other concurrent investigational drugs No other concurrent antineoplastic agents

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: Arm 1: Oxaliplatin + Leucovorin + 5-Fluorouracil + Bevacizumab<br>Oxaliplatin + Leucovorin + 5-Fluorouracil + Bevacizumab | Biological: bevacizumab<br>* bevacizumab 5 mg/kg IV on day 1 every 14 days until excessive toxicity or disease progression<br>Drug: fluorouracil<br>* 5-FU 400 mg/m2 IV bolus over 2-4 minutes then 2400 mg/m2 IV continuous infusion over 46 hours on day 1 every 14 days until excessive toxicity or disease progression<br>* Other names: 5-FU;Drug: leucovorin<br>* leucovorin 400 mg/m2 IV on day 1 every 14 days until excessive toxicity or disease progression<br>* Other names: leucovorin calcium;Drug: oxaliplatin<br>* Oxaliplatin 85 mg/m2 IV on day 1 every 14 days until excessive toxicity or disease progression<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Major Morbidity Related to the Intact Primary Tumor | Cumulative incidence was used to compute percent probability of morbidity. Cumulative incidence at time t measures the probability of a participant having an event (i.e., Colonic bleeding, perforation, bowel obstruction, or fistula formation requiring surgery or resulting in patient death) over the given duration, t. It involves computing the probability of an event at any observed time (i.e., the number of new cases during a period divided by the number of subjects at risk) and multiplying these successive probabilities by any early computed probability to get the final estimate. | 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Local Complications as Assessed by Colonic Obstruction Requiring Hospitalization (But Not Surgery) for Medical Management, Stent Placement, Laser Treatment, or Fulguration |  | Time from start of study through year 5 | 
| Local Complications as Assessed by Gastrointestinal Bleeding Requiring Transfusion But Not Requiring Surgery |  | Time from start of study through year 5 | 
| Local Complications as Assessed by Fistula Formation (Self-draining Enterocutaneous Fistula and Intra-abdominal Abscess Requiring Percutaneous Drainage) Not Requiring Surgery |  | Time from start of study through year 5 | 
| Local Complications as Assessed by Other Events Related to the Intact Primary Tumor Which Require Hospitalization But Not Surgery |  | Time from start of study through year 5 | 
| Serious Adverse Events (Grades 3, 4, and 5) as Defined by CTCAE v3.0 |  | Time from start of study through year 5 | 
| Overall Survival as Measured by Death From Any Cause |  | Time from start of study through year 5 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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adenocarcinoma of the colon, stage IV colon cancer