Safety and Efficacy Study of BMS-908662 Alone or in Combination With Cetuximab in Subjects With K-RAS or B-RAF Mutation Positive Advanced or Metastatic Colorectal Cancer

Study Overview
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Brief Summary
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The purpose of the study is to identify a safe and tolerable dose of BMS-908662 in combination with cetuximab; and then to evaluate the tumor response to BMS-908662 when administered alone or in combination with cetuximab

Detailed Description
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Phase 1: Single Arm Study Phase 2: Randomized Controlled, Parallel

Official Title
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A Phase 1/2 Study of BMS-908662 (XL281) Alone or in Combination With Cetuximab in Subjects With K-RAS or B-RAF Mutation Positive Advanced or Metastatic Colorectal Cancer

Conditions
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Colorectal Cancer

Intervention / Treatment
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* Drug: BMS-908662
* Drug: BMS-908662
* Drug: Cetuximab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects with K-RAS (codon 12 or 13) or B -RAF (V600E) mutation positive advanced or metastatic colorectal cancer who have relapsed or are refractory to 2 or more standard systemic anticancer regimes for metastatic disease, or are intolerant to existing therapies. Histologic or cytologic confirmation of the diagnosis. Eastern Cooperative Oncology Group (ECOG) ≤ 1 Adequate organ & marrow function. Exclusion Criteria: Uncontrolled or significant cardiovascular disease. Phase 2: Prior therapy with a RAF inhibitor.

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: BMS-908662 (A1)<br>Phase 1 | Drug: BMS-908662<br>* Capsules, Oral, escalating doses starting at 25 mg, every 12 hours (Q 12 h), Continuously<br>|
| Experimental: Cetuximab (A1)<br>Phase 1 | Drug: Cetuximab<br>* Vial, IV, 400 mg/m² loading dose followed by 250 mg/m² maintenance dose, Weekly, Continuously<br>|
| Experimental: BMS-908662 (B1)<br>Phase 2 | Drug: BMS-908662<br>* Capsules, Oral, (TBD) mg, Q 12 h, Continuously<br>|
| Experimental: BMS-908662 + Cetuximab (B2)<br>Phase 2 | Drug: BMS-908662<br>* Capsules, Oral, (TBD) mg, Q 12 h, Continuously<br>Drug: Cetuximab<br>* Vial, IV, 400 mg/m² loading dose followed by 250 mg/m² maintenance dose, Weekly, Continuously<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Toxicity will be evaluated according to the National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (CTCAE) version 3 |  | Assessments every 1-2 weeks while receiving study drug | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy as determined by estimates of objective response rates and response duration |  | Efficacy measured at least every 8 weeks while receiving study drug | 
| Pharmacodynamics (PD) will be assessed by evaluating markers of RAS/RAF pathway activity |  | PD assessed during the first 4 weeks on study | 
| Pharmacokinetics (PK) for BMS-908662 as determined by minimum observed concentrations [Cmin]. |  | PK measured during first 4 weeks on study | 
| Pharmacokinetics (PK) for BMS-908662 as determined by maximum observed concentrations [Cmax]. |  | PK measured during first 4 weeks on study | 
| Pharmacokinetics (PK) for BMS-908662 as determined by time of maximum observed concentration [Tmax]. |  | PK measured during first 4 weeks on study | 
| Pharmacokinetics (PK) for BMS-908662 as determined by area under the concentration-curve for one dosing interval [AUC(TAU)]. |  | PK measured during first 4 weeks on study | 
| Pharmacokinetics (PK) for BMS-908662 as determined by accumulation index [AI]. |  | PK measured during first 4 weeks on study |