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

• Efficacy as determined by estimates of objective response rates and response duration [ Time Frame: Efficacy measured at least every 8 weeks while receiving study drug ] [ Designated as safety issue: No ]
• Pharmacodynamics (PD) will be assessed by evaluating markers of RAS/RAF pathway activity [ Time Frame: PD assessed during the first 4 weeks on study ] [ Designated as safety issue: No ]
• Pharmacokinetics (PK) for BMS-908662 as determined by minimum observed concentrations [Cmin]. [ Time Frame: PK measured during first 4 weeks on study ] [ Designated as safety issue: No ]
• Pharmacokinetics (PK) for BMS-908662 as determined by maximum observed concentrations [Cmax]. [ Time Frame: PK measured during first 4 weeks on study ] [ Designated as safety issue: No ]
• Pharmacokinetics (PK) for BMS-908662 as determined by time of maximum observed concentration [Tmax]. [ Time Frame: PK measured during first 4 weeks on study ] [ Designated as safety issue: No ]
• Pharmacokinetics (PK) for BMS-908662 as determined by area under the concentration-curve for one dosing interval [AUC(TAU)]. [ Time Frame: PK measured during first 4 weeks on study ] [ Designated as safety issue: No ]
• Pharmacokinetics (PK) for BMS-908662 as determined by accumulation index [AI]. [ Time Frame: PK measured during first 4 weeks on study ] [ Designated as safety issue: No ]

• Efficacy as determined by estimates of objective response rates and response duration [ Time Frame: Efficacy measured at least every 8 weeks ] [ Designated as safety issue: No ]
• Pharmacokinetics for BMS-908662 as determined by minimum and maximum observed concentrations, time of maximum observed concentration, area under the concentration-curve for one dosing interval and the accumulation index [ Time Frame: PK measured during first 4 weeks on study ] [ Designated as safety issue: No ]
• Pharmacodynamics will be assessed by evaluating markers of RAS/RAF pathway activity [ Time Frame: PD assessed during the first 4 weeks on study ] [ Designated as safety issue: No ]

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

Phase 1: Single Arm Study

Phase 2: Randomized Controlled, Parallel

• Drug: BMS-908662
  Capsules, Oral, escalating doses starting at 25 mg, every 12 hours (Q 12 h), Continuously
• Drug: BMS-908662
  Capsules, Oral, (TBD) mg, Q 12 h, Continuously
• Drug: Cetuximab
  Vial, IV, 400 mg/m² loading dose followed by 250 mg/m² maintenance dose, Weekly, Continuously

• Experimental: BMS-908662 (A1)
  Phase 1
  Intervention: Drug: BMS-908662
• Experimental: Cetuximab (A1)
  Phase 1
  Intervention: Drug: Cetuximab
• Experimental: BMS-908662 (B1)
  Phase 2
  Intervention: Drug: BMS-908662
• Experimental: BMS-908662 + Cetuximab (B2)
  Phase 2
  Interventions:

  • Drug: BMS-908662
  • Drug: Cetuximab

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.