A Study Combining FOLFOX or FOLFIRI With AG-013736 or Bevacizumab (Avastin) in Patients With Metastatic Colorectal Cancer After Failure Of One First Line Regimen

Study Overview
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Brief Summary
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The study is designed to demonstrate that the combination of AG-013736 with either FOLFIRI or FOLFOX is superior to FOLFIRI or FOLFOX in combination with bevacizumab (Avastin) in delaying tumor progression in the second-line treatment of patients with metastatic colorectal cancer after failure of an irinotecan or oxaliplatin-containing first-line regimen.

Official Title
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A Randomized, Phase 2 Study Of FOLFOX Or FOLFIRI With AG-013736 Or Bevacizumab (Avastin) In Patients With Metastatic Colorectal Cancer After Failure Of An Irinotecan Or Oxaliplatin-Containing First-Line Regimen

Conditions
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Colorectal Neoplasms

Intervention / Treatment
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* Drug: Bevacizumab (avastin)
* Drug: FOLFIRI (Irinotecan, leucovorin, 5-fluorouracil [5FU])
* Drug: AG-013736 (axitinib)
* Drug: FOLFOX (oxaliplatin, leucovorin, 5-fluorouracil [5FU])
* Drug: AG-013736 (axitinib)
* Drug: FOLFIRI (irinotecan, leucovorin, 5-fluorouracil [5FU])
* Drug: Bevacizumab (avastin)
* Drug: FOLFOX (oxaliplatin, leucovorin, 5-fluorouracil [5FU])


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically documented colorectal cancer plus one of the following: Failure of one prior irinotecan- or oxaliplatin-containing regimen, or Adjuvant refractory to irinotecan- or oxaliplatin-containing regimen. Exclusion Criteria: Prior treatment in first line metastatic setting with more than one regimen Prior irradiation of more than 25% of bone marrow.

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 |
| --- | --- |
| Active Comparator: B<br>Bevacizumab (avastin) | Drug: Bevacizumab (avastin)<br>* Bevacizumab intravenous [IV] infusion 5 mg/kg every two weeks until disease progression, intolerance or withdrawal of consent.<br>Drug: FOLFIRI (Irinotecan, leucovorin, 5-fluorouracil [5FU])<br>* Irinotecan (180 mg/m²) intravenous infusion [IV] over 90 minutes, concurrently with leucovorin (400 mg/m²) intravenous infusion [IV] over 2 hours followed immediately by 5-FU bolus (400 mg/m²) intravenous [IV] and a subsequent 5-FU infusion (2400 mg/m² over 46-48 hours), repeated every 2 weeks until disease progression, intolerance or withdrawal of consent.<br>|
| Experimental: C<br>AG-013736 (axitinib) | Drug: AG-013736 (axitinib)<br>* Axitinib is given at a starting dose of 5 mg twice daily [BID] continuous dosing until disease progression, intolerance or withdrawal of consent.<br>Drug: FOLFOX (oxaliplatin, leucovorin, 5-fluorouracil [5FU])<br>* Oxaliplatin (85 mg/m²) intravenous infusion [IV] over 120 minutes, concurrently with leucovorin (400 mg/m²) intravenous infusion [IV] over 2 hours followed by 5-FU IV bolus (400 mg/m²) and a subsequent 5-FU IV infusion (2400 mg/m² over 46-48 hours), repeated every 2 weeks until disease progression, intolerance or withdrawal of consent.<br>|
| Experimental: A<br>AG-013736 (axitinib) | Drug: AG-013736 (axitinib)<br>* Axitinib is given at a starting dose of 5 mg twice daily [BID] continuous dosing until disease progression, intolerance or withdrawal of consent.<br>Drug: FOLFIRI (irinotecan, leucovorin, 5-fluorouracil [5FU])<br>* Irinotecan (180 mg/m²) intravenous infusion [IV] over 90 minutes, concurrently with leucovorin (400 mg/m²) intravenous infusion [IV] over 2 hours followed immediately by 5-FU bolus (400 mg/m²) IV and a subsequent 5-FU IV infusion (2400 mg/m² over 46-48 hours), repeated every 2 weeks until disease progression, intolerance or withdrawal of consent.<br>|
| Active Comparator: D<br>bevacizumab (avastin) | Drug: Bevacizumab (avastin)<br>* Bevacizumab intravenous infusion [IV] 5 mg/kg every two weeks until disease progression, intolerance or withdrawal of consent.<br>Drug: FOLFOX (oxaliplatin, leucovorin, 5-fluorouracil [5FU])<br>* Oxaliplatin (85 mg/m²) IV infusion over 120 minutes, concurrently with leucovorin (400 mg/m²) intravenous infusion [IV] over 2 hours followed by 5-FU IV bolus (400 mg/m²) and a subsequent 5-FU IV infusion (2400 mg/m² over 46-48 hours), repeated every 2 weeks until disease progression, intolerance or withdrawal of consent.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) | Time in months from start of study treatment to first documentation of objective tumor progression or death due to any cause. PFS was calculated as (first event date minus the date of first dose of study medication plus 1) divided by 30.4. Tumor progression was determined from oncologic assessment data (where data meet the criteria for progressive disease [PD]), or from adverse event (AE) data (where the outcome was Death). | Baseline until disease progression or discontinuation from the study due to any cause, assessed every 8 week up to 130 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | Time in months from the start of study treatment to date of death due to any cause. OS was calculated as (the death date minus the date of first dose of study medication plus 1) divided by 30.4. Death was determined from adverse event data (where outcome was death) or from follow-up contact data (where the participant current status was death). | Baseline until death or up to 1 year after the randomization of last participant | 
| Percentage of Participants With Objective Response (OR) | Percentage of participants with objective response based assessment of confirmed complete response (CR) or confirmed partial response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST). CR are those that persist on repeat imaging study at least 4 weeks after initial documentation of response. PR are those with at least 30 percent decrease in sum of the longest dimensions of target lesions taking as a reference the baseline sum longest dimensions, with non target lesions not increased or absent. | Baseline until disease progression or discontinuation from the study due to any cause, assessed every 8 weeks up to 130 weeks | 
| Duration of Response (DR) | Time in months from the first documentation of objective tumor response to objective tumor progression or death due to any cause. Duration of tumor response was calculated as (the date of the first documentation of objective tumor progression or death due to cancer minus the date of the first CR or PR that was subsequently confirmed plus 1) divided by 30.4. DR was calculated for the subgroup of participants with a confirmed objective tumor response. | Baseline until disease progression or discontinuation from the study due to any cause, assessed every 8 weeks up to 130 weeks | 
| Change From Baseline in MD Anderson Symptoms Inventory Diarrhea (MDASI-D) Symptom Severity Score at Day 1 of Cycles 2-5, Day 1 of Every Odd-numbered Cycle Throughout the Study and End of Treatment (Cycle 65) or Withdrawal | Symptom severity score is comprised of average of 14 MDASI-D core items (pain, fatigue, nausea, disturbed sleep, distress, shortness of breath, remembering things, lack of appetite, drowsiness, dry mouth, sadness, vomiting, numbness or tingling and diarrhea) and ranges from 0 to 10. Participants were asked to rate severity of each symptom at their worst in last week; each item rated from 0 to 10, with 0 = symptom not present and 10 = as bad as you can imagine. Lower scores indicated better outcome. Total average score range: 0 to 10. | Baseline, Day 1 of cycles 2- 5, Day 1 of every odd-numbered cycle throughout the study and end of treatment (cycle 65) or withdrawal | 
| Change From Baseline in MDASI-D Symptom Interference Score at Day 1 of Cycles 2-5, Day 1 of Every Odd-numbered Cycle Throughout the Study and End of Treatment (Cycle 65) or Withdrawal | Symptom Interference score is comprised of the average of 6 items on feeling or function from the MDASI-D core (general activity, mood, work, relations with others, walking, and enjoyment of life) and ranges from 0 to 10. Participants were asked to rate how much symptoms have interfered in last week; each item rated from 0 to 10, with 0 = did not interfere and 10 = interfered completely. Lower scores indicated better outcome. Total average score range: 0 to 10. | Baseline, Day 1 of cycle 2-5, Day 1 of every odd-numbered cycle throughout the study and end of treatment (cycle 65) or withdrawal |