A Randomized Trial of Avastin + Gemcitabine + 5-Fluorouracil (5FU)/Folinic Acid Versus Avastin + Oxaliplatin + 5FU/Folinic Acid in Metastatic Colorectal Cancer

Study Overview
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Brief Summary
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The purpose of the study is to describe the tumor response rates for the two regimens being studied, and to determine how long patients live after receiving the treatment, how long patients are without return of their disease after they receive treatment, and how long the response they get from the treatment lasts. The amount and type of side effects/toxicities of each regimen will also be evaluated. The regimen including Oxaliplatin + 5FU/Folinic Acid is a current standard of care.

Official Title
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A Multicenter, Randomized Phase II Trial of Avastin Plus Gemcitabine Plus 5FU/Folinic Acid (A + FFG) vs. Avastin Plus Oxaliplatin Plus 5FU/Folinic Acid (A + FOLFOX 4) as Therapy for Patients With Metastatic Colorectal Cancer

Conditions
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Colorectal Cancer

Intervention / Treatment
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* Drug: Gemcitabine
* Drug: avastin
* Drug: 5FU/folinic acid
* Drug: oxaliplatin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must have a histological or cytological diagnosis of the colon or rectum with Stage III unresectable or Stage IV disease. Urinalysis or Urine dipstick for proteinuria of less than 1+ (i.e. either 0 or trace). If urine dipstick is greater than 1+, the 24 hour urine protein must demonstrate less than 500 mg of protein in 24 hours to allow participation. No prior chemotherapy, immunotherapy, or hormonal treatment for metastatic disease is acceptable. However, one prior neo-adjuvant or adjuvant treatment is acceptable, including Capecitabine, Camptothecin-11 (CPT-11), 5 Fluorouracil/Leucovorin (5FU/LV) or Radiation containing regimens, (but no Oxaliplatin), and only if progression > 6 months since last adjuvant treatment. Prior radiation therapy, including radiation to the whole pelvis, is allowed (Cristy and Eckerman 1987) and patients must have recovered from the acute toxic effects of the treatment prior to study enrollment. Prior palliative radiation therapy given to a non-measurable diagnostic site is acceptable if given > 4 weeks prior to treatment or if other non-irradiated measurable disease is present. No known central nervous system (CNS) metastasis. Exclusion Criteria: Histology other than adenocarcinoma Tumors that demonstrate free perforation as manifested by free air or free fluid in the abdomen. Patients with walled-off perforation are eligible. Gastroduodenal ulcer determined as active by endoscopy. Invasive procedures defined as follows; major surgical procedures, open biopsy, or significant traumatic injury within 28 days prior to randomization, anticipation of need for major surgical procedure during the course of study, core biopsy or other minor procedure within 7 days prior to registration. Following cardiac condition; New York Heart Association (NYHA) Class III or IV, myocardial infarction (MI) within 6 months, unstable angina within 6 months and current symptomatic arrhythmia.

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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: A+FFG<br>Avastin + Gemcitabine + 5-Fluorouracil (5FU)/Folinic Acid | Drug: Gemcitabine<br>* 900 mg/m2 IV over 90 minutes after Folinic Acid weekly for 6 weeks every 8 weeks until progression.<br>* Other names: Gemzar;Drug: avastin<br>* 5 milligrams per kilogram (mg/kg)<br>Drug: 5FU/folinic acid<br>* Folinic Acid: 100 milligrams per square meter (mg/m2) intravenous (IV) over 60 minutes (A+FFG). Folinic Acid: 200 mg/m2 as a 2-hr infusion on Days 1 and 2 of a 14-day cycle (A+FOLFOX 4). 5-Fluorouracil: 450 mg/m2 as an IV bolus in middle of Folinic Acid (A+FFG). 5-Fluorouracil: 400 mg/m2 bolus plus a 600 mg/m2 22-hour infusion on Days 1 and 2 of a 14-day cycle (A+FOLFOX 4).<br>|
| Active Comparator: A+FOLFOX 4<br>Avastin + Oxaliplatin + 5-Fluorouracil (5FU)/Folinic Acid | Drug: avastin<br>* 5 milligrams per kilogram (mg/kg)<br>Drug: 5FU/folinic acid<br>* Folinic Acid: 100 milligrams per square meter (mg/m2) intravenous (IV) over 60 minutes (A+FFG). Folinic Acid: 200 mg/m2 as a 2-hr infusion on Days 1 and 2 of a 14-day cycle (A+FOLFOX 4). 5-Fluorouracil: 450 mg/m2 as an IV bolus in middle of Folinic Acid (A+FFG). 5-Fluorouracil: 400 mg/m2 bolus plus a 600 mg/m2 22-hour infusion on Days 1 and 2 of a 14-day cycle (A+FOLFOX 4).<br>Drug: oxaliplatin<br>* 85 mg/m2 as a 2-hour infusion on Day 1 of a 14 day cycle.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tumor Response by Response Evaluation Criteria In Solid Tumors (RECIST) | Response using Response Evaluation Criteria In Solid Tumors (RECIST) criteria. Complete Response=disappearance of all target lesions; Partial Response=30% decrease in sum of longest diameter of target lesions; Progressive Disease=20% increase in sum of longest diameter of target lesions; Stable Disease=small changes that do not meet above criteria. | baseline to measured progressive disease (every 7-8 weeks for 2 cycles, monthly for 3 months, every other month for 6 months, then every 3 months up to 4.4 years) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Progressive Disease | Defined as the time from study enrollment to the first date of disease progression. Time to disease progression was censored at the date of death if death was due to other cause. | randomization to the date of first documented disease progression or death due to disease under study, whichever comes first (every 7-8 weeks for 2 cycles, monthly for 3 months, every other month for 6 months, then every 3 months up to 4.4 years) | 
| Progression-Free Survival | Defined as the time from randomization to the first observation of disease progression, or death due to any cause. | randomization to the first date of progression or death from any cause (every 7-8 weeks for 2 cycles, monthly for 3 months, every other month for 6 months, then every 3 months up to 4.4 years) | 
| Overall Survival | Overall survival is the duration from enrollment to death. For patients who are alive, overall survival is censored at the last contact. | randomization to the date of death from any cause (every 7-8 weeks for 2 cycles, monthly for 3 months, every other month for 6 months, then every 3 months up to 4.4 years) | 
| Duration of Response | The duration of a complete response (CR) or partial response (PR) was defined as the time from first objective status assessment of CR or PR to the first time of progression or death as a result of any cause. | date of first response until the first date of documented progression or death from any cause (every 7-8 weeks for 2 cycles, monthly for 3 months, every other month for 6 months, then every 3 months up to 4.4 years) |