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

Sponsor

Bristol-Myers Squibb (Industry)

Overall Status

Completed

CT.gov ID

NCT01046864

Collaborator

(none)

Enrollment

Locations

Arms

51.9

Duration (Months)

8.2

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Gastro-Intestinal Cancer	Drug: 5-FU Drug: Leucovorin Drug: 5-FU Drug: Irinotecan Drug: Brivanib Drug: Brivanib Drug: Brivanib	Phase 1

Study Design

Study Type:

Interventional

Actual Enrollment :

49 participants

Allocation:

Non-Randomized

Intervention Model:

Factorial Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Study Start Date :

Feb 1, 2010

Actual Primary Completion Date :

Jun 1, 2014

Actual Study Completion Date :

Jun 1, 2014

Arms and Interventions

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

Arm

Intervention/Treatment

Experimental: Arm 1

Drug: 5-FU

IV solution, IV bolus over 2-4 minutes, 400 mg/m², Every 14 days, Until disease progression/toxicity

Other Names:

Fluorouracil

Drug: Leucovorin

IV solution, IV over 2 hours, 400 mg/m², Every 14 days, Until disease progression/toxicity

Other Names:

Folinic acid

Drug: 5-FU

IV solution, IV infusion over 46 hours, 2400 mg/m², Every 14 days, Until disease progression/toxicity

Other Names:

Fluorouracil

Drug: Brivanib

Tablets, Oral, 400 - 800 mg, once daily, Until disease progression/toxicity

Experimental: Arm 2

Drug: 5-FU

IV solution, IV bolus over 2-4 minutes, 400 mg/m², Every 14 days, Until disease progression/toxicity

Other Names:

Fluorouracil

Drug: Leucovorin

IV solution, IV over 2 hours, 400 mg/m², Every 14 days, Until disease progression/toxicity

Other Names:

Folinic acid

Drug: 5-FU

IV solution, IV infusion over 46 hours, 2400 mg/m², Every 14 days, Until disease progression/toxicity

Other Names:

Fluorouracil

Drug: Irinotecan

IV solution, IV over 90 minutes, 180 mg/m², Every 14 days, Until disease progression/toxicity

Other Names:

Camptosar

Drug: Brivanib

Tablets, Oral, 600 - 800 mg, once daily, Until disease progression/toxicity

Other Names:

BMS-582664

Experimental: Arm 3

Japanese Population

Drug: 5-FU

IV solution, IV bolus over 2-4 minutes, 400 mg/m², Every 14 days, Until disease progression/toxicity

Other Names:

Fluorouracil

Drug: Leucovorin

IV solution, IV over 2 hours, 400 mg/m², Every 14 days, Until disease progression/toxicity

Other Names:

Folinic acid

Drug: 5-FU

IV solution, IV infusion over 46 hours, 2400 mg/m², Every 14 days, Until disease progression/toxicity

Other Names:

Fluorouracil

Drug: Irinotecan

IV solution, IV over 90 minutes, 180 mg/m², Every 14 days, Until disease progression/toxicity

Other Names:

Camptosar

Drug: Brivanib

Tablets, Oral, 800 mg, once daily, Until disease progression/toxicity

Other Names:

BMS-582664

Outcome Measures

Primary Outcome Measures

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

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]

Eligibility Criteria

Criteria

Ages Eligible for Study:

20 Years to 75 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Usc/Norris Comprehensive Cancer Center	Los Angeles	California	United States	90033
2	Texas Oncology	Dallas	Texas	United States	75246
3	Scott & White Memorial Hospital And Clinic	Temple	Texas	United States	76508
4	Local Institution	Edmonton	Alberta	Canada	T6G 1Z2
5	Local Institution	Ottawa	Ontario	Canada	K1H 8L6
6	Local Institution	Villejuif Cedex		France	94800