Combination of Brivanib With 5-Fluorouracil/Leucovorin (5FU/LV) and 5-Fluorouracil/Leucovorin/Irinotecan (FOLFIRI)

Study Overview
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Brief Summary
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The purpose of this study is to determine a safe and maximum tolerable dose of Brivanib when combined with standard dose 5FU/LV and FOLFIRI.

Official Title
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A Phase Ib Multiple Ascending Dose Study to Evaluate the Safety of Brivanib in Combination With 5-Fluorouracil/Leucovorin (5FU/LV) and Brivanib in Combination With 5-Fluorouracil/Leucovorin/Irinotecan (FOLFIRI) in Subjects With Advanced or Metastatic Gastrointestinal Malignancies

Conditions
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Gastro-Intestinal Cancer

Intervention / Treatment
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* Drug: 5-FU
* Drug: Leucovorin
* Drug: 5-FU
* Drug: Irinotecan
* Drug: Brivanib
* Drug: Brivanib
* Drug: Brivanib


Participation Criteria
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Eligibility Criteria
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For more information regarding BMS clinical trial participation, please visit www.BMSStudyConnect.com Inclusion Criteria: Histological/cytological confirmed diagnosis of Gastrointestinal malignancy, except pancreatic cancer Eligible for 5FU/LV or FOLFIRI chemotherapy ECOG 0-1 Able to swallow and tolerate tablets Life expectancy of 3 months Exclusion Criteria: Unwilling to use acceptable method to avoid pregnancy of partner/self for the entire study period and up to 4 weeks after last dose Women who are pregnant or breastfeeding Pancreatic cancer Known brain metastasis, evidence of leptomeningeal disease History of thrombo-embolic disease Hemorrhage/bleeding events Uncontrolled or significant cardiovascular disease Any 3 or more of the following risk factors: arterial thrombosis , smoking, hypercholesterolemia, hypertension, obesity (BMS>30) and diabetes Pre-existing thyroid abnormality, not maintained with medication QTC (Fridericia) >450 msec on two consecutive ECG's Subjects with concomitant second malignancies ( except adequately treated non-melanoma skin, in situ carcinoma of bladder, cervix or breast, early prostate cancer) Any major surgery within 4 weeks of study drug administration Increased levels of both D-Dimer and Prothrombin fragment 1 +2 Arm B and C only-positive UGT1A1 genotype of TA7/TA7 History of allergy of brivanib or drug class History of severe reactions to fluoropyrimidine therapy or irinotecan Prior therapy with brivanib

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 75 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: Non-Randomized
Intervention Model: Factorial Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1<br> | Drug: 5-FU<br>* IV solution, IV bolus over 2-4 minutes, 400 mg/m², Every 14 days, Until disease progression/toxicity<br>* Other names: Fluorouracil;Drug: Leucovorin<br>* IV solution, IV over 2 hours, 400 mg/m², Every 14 days, Until disease progression/toxicity<br>* Other names: Folinic acid;Drug: 5-FU<br>* IV solution, IV infusion over 46 hours, 2400 mg/m², Every 14 days, Until disease progression/toxicity<br>* Other names: Fluorouracil;Drug: Brivanib<br>* Tablets, Oral, 400 - 800 mg, once daily, Until disease progression/toxicity<br>|
| Experimental: Arm 2<br> | Drug: 5-FU<br>* IV solution, IV bolus over 2-4 minutes, 400 mg/m², Every 14 days, Until disease progression/toxicity<br>* Other names: Fluorouracil;Drug: Leucovorin<br>* IV solution, IV over 2 hours, 400 mg/m², Every 14 days, Until disease progression/toxicity<br>* Other names: Folinic acid;Drug: 5-FU<br>* IV solution, IV infusion over 46 hours, 2400 mg/m², Every 14 days, Until disease progression/toxicity<br>* Other names: Fluorouracil;Drug: Irinotecan<br>* IV solution, IV over 90 minutes, 180 mg/m², Every 14 days, Until disease progression/toxicity<br>* Other names: Camptosar;Drug: Brivanib<br>* Tablets, Oral, 600 - 800 mg, once daily, Until disease progression/toxicity<br>* Other names: BMS-582664;|
| Experimental: Arm 3<br>Japanese Population | Drug: 5-FU<br>* IV solution, IV bolus over 2-4 minutes, 400 mg/m², Every 14 days, Until disease progression/toxicity<br>* Other names: Fluorouracil;Drug: Leucovorin<br>* IV solution, IV over 2 hours, 400 mg/m², Every 14 days, Until disease progression/toxicity<br>* Other names: Folinic acid;Drug: 5-FU<br>* IV solution, IV infusion over 46 hours, 2400 mg/m², Every 14 days, Until disease progression/toxicity<br>* Other names: Fluorouracil;Drug: Irinotecan<br>* IV solution, IV over 90 minutes, 180 mg/m², Every 14 days, Until disease progression/toxicity<br>* Other names: Camptosar;Drug: Brivanib<br>* Tablets, Oral, 800 mg, once daily, Until disease progression/toxicity<br>* Other names: BMS-582664;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety-Toxicity, evaluated according to NCI Common Terminology Criteria for Adverse Events v3.0. Assessments based on medical review of adverse events, results of vital signs, ECGs, echocardiography, physical examinations, and clinical laboratory tests |  | Cycle 4, Day 1 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics (Cmax, Tmax, AUC (TAU), T-HALF) plasma concentration vs time for brivanib given alone and in combination with FOLFIRI. Individual concentrations (C) of 5FU will be calculated from samples on Day 2 in the presence and absence of Brivanib |  | Cycle 2, Day 2 | 
| Efficacy-Tumor BOR determined for treated subjects by radiological responses assessed by CT scan or MRI, by RECIST criteria (v1.1). Radiological tumor assessments to evaluate response & progression will be done every 8 wks or more frequently if indicated |  | Every 8 weeks | 
| Exploratory Measures (Biomarkers for Predictive Analysis): Potential predictive markers, including activity of FGF, VEGF and related pathways as well as K-RAS mutation status, will be evaluated based on blood or tumor samples |  | Cycle 1, Cycle 2, every other cycle | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Gastro-Intestinal Cancer, NOS