Phase 2 Study of ABT-869 in Combination With mFOLFOX6 Versus Bevacizumab in Combination With mFOLFOX6 to Treat Advanced Colorectal Cancer

Study Overview
=================
Brief Summary
-----------------
To determine the effect of ABT-869 plus mFOLFOX6 compared to bevacizumab plus mFOLFOX6 on disease progression in advanced colorectal cancer.

Official Title
-----------------
An Open-Label, Randomized Phase 2 Study of ABT-869 in Combination With mFOLFOX6 (Oxaliplatin, 5-Fluorouracil, and Folinic Acid) Versus Bevacizumab in Combination With mFOLFOX6 as Second-line Treatment of Subjects With Advanced Colorectal Cancer

Conditions
-----------------
Advanced Colorectal Cancer, Adenocarcinoma of the Colon, Adenocarcinoma of the Rectum

Intervention / Treatment
-----------------
* Drug: ABT-869
* Drug: bevacizumab
* Drug: oxaliplatin
* Drug: folinic acid
* Drug: fluorouracil
* Drug: ABT-869


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Subject must be >/= 18 years of age. Subject (male or female) must be diagnosed with adenocarcinoma of the colon or rectum. Subject must have metastatic disease or locally recurrent disease that is not amenable to surgical resection with curative intent. Subject must have received one prior chemotherapy regimen containing irinotecan or a fluoropyrimidine for locally recurrent or metastatic colon or rectal cancer. Subject has experienced progressive disease during or following the previous anti-tumor treatment. Subject may have received prior adjuvant treatment for colorectal cancer. Subject has measurable disease by RECIST criteria (randomized portion only). Eastern Cooperative Oncology Group (ECOG) Performance Score of 0-1. Subject must have adequate bone marrow, renal and hepatic function. Subject must have Partial Thromboplastin Time (PTT) < 1.5 x Upper Limit of Normal (ULN) and International Normalized Ratio (INR) < 1.5. Exclusion Criteria: Subject has received more than one prior therapy in the metastatic setting. Lead-in Cohort only: The subject may have received more than one prior therapy in the metastatic setting. Subject has received cytotoxic chemotherapy within 21 days prior to Study Day 1. Subject has received non-cytotoxic, anti-cancer therapy within 21 days or within a period defined by 5 half lives whichever is shorter, prior to Study Day 1. Subject has not recovered to less than or equal to Grade 1 clinically significant adverse effects/toxicities of the previous therapy. Subject has received prior treatment with a tyrosine kinase inhibitor targeting VEGF or PDGF. Subject has received prior treatment with oxaliplatin in the metastatic setting. Lead-in cohort only: Prior treatment with oxaliplatin will be allowed provided that any neuropathy as a result of the oxaliplatin treatment has resolved to less than or equal to Grade 1. Subject has had major surgery within 28 days of Study Day 1. Subject has had radiotherapy within 14 days of Study Day 1. Subject has a history of hypersensitivity to recombinant murine monoclonal antibodies, oxaliplatin or other platinum-containing compounds, fluorouracil, or folinic acid. Subject has a known intolerance to bevacizumab. Subject has untreated brain or meningeal metastases. Subject is receiving therapeutic anticoagulation therapy . Subject has a history of/or currently exhibits clinically significant cancer related events of bleeding. Subject currently exhibits symptomatic or persistent, uncontrolled hypertension. Subject has a history of myocardial infarction, stroke, or transient ischemic attack within six months of Study Day 1. History of another active cancer within the past 5 years except cervical cancer in situ, in situ carcinoma of the bladder, squamous cell or basal cell carcinoma of the skin.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

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: A<br>Open-label to Bevacizumab plus mFOLFOX6 | Drug: bevacizumab<br>* 10 mg/kg QD, IV on Day 1 of each 14-day cycle<br>Drug: oxaliplatin<br>* 85 mg/m2 IV, 120 minutes on Day 1 of each 14-day cycle<br>* Other names: mFOLFOX6 regimen;Drug: folinic acid<br>* 400 mg/m2 IV, 120 minutes on Day 1 of each 14-day cycle<br>* Other names: mFOLFOX6 regimen;Drug: fluorouracil<br>* 400 mg/m2 IV bolus on Day 1 of each 14-day cycle; followed by 2400 mg/m2 IV infusion 46-48 hours<br>* Other names: mFOLFOX6 regimen;|
| Active Comparator: B<br>Open-label to High-dose ABT-869 arm plus mFOLFOX6 | Drug: ABT-869<br>* 12.5 mg QD, tablets taken orally days 1-14 of every 14-day cycle<br>Drug: oxaliplatin<br>* 85 mg/m2 IV, 120 minutes on Day 1 of each 14-day cycle<br>* Other names: mFOLFOX6 regimen;Drug: folinic acid<br>* 400 mg/m2 IV, 120 minutes on Day 1 of each 14-day cycle<br>* Other names: mFOLFOX6 regimen;Drug: fluorouracil<br>* 400 mg/m2 IV bolus on Day 1 of each 14-day cycle; followed by 2400 mg/m2 IV infusion 46-48 hours<br>* Other names: mFOLFOX6 regimen;|
| Active Comparator: C<br>Open-label to low-dose ABT-869 arm plus mFOLFOX6 | Drug: oxaliplatin<br>* 85 mg/m2 IV, 120 minutes on Day 1 of each 14-day cycle<br>* Other names: mFOLFOX6 regimen;Drug: folinic acid<br>* 400 mg/m2 IV, 120 minutes on Day 1 of each 14-day cycle<br>* Other names: mFOLFOX6 regimen;Drug: fluorouracil<br>* 400 mg/m2 IV bolus on Day 1 of each 14-day cycle; followed by 2400 mg/m2 IV infusion 46-48 hours<br>* Other names: mFOLFOX6 regimen;Drug: ABT-869<br>* 7.5 mg QD tablets taken orally days 1-14 of every 14-day cycle<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival |  | Radiographic evaluation every 2 months, clinial evaluation every 2 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival |  | from randomization until patient death or alive at 5 years | 
| 12-month overall survival rate |  | from randomization until patient death or alive at 5 years | 
| Objective response rate |  | from randomization until patient death or alive at 5 years |