ARQ 197 or placebo in combination with irinotecan and cetuximab in participants with metastatic colorectal cancer (CRC), in participants with wild-type KRAS alleles who have failed front-line systemic therapy, to evaluate the safety, tolerability, and efficacy of ARQ 197, define the recommended dose for Phase 2.

After the recommended dose is determined for Phase 2, participants receive study drug or placebo with irinotecan and cetuximab.

Phase 1/2 Multicenter study:

• Phase 1 portion is open-label to evaluate the safety of ARQ 197 administered in combination with irinotecan and cetuximab.
• Phase 2 portion is designed as a randomized, double-blind placebo-controlled study to assess the efficacy and safety of ARQ 197 or matching placebo administered in combination with irinotecan and cetuximab.

Inclusion Criteria:

1. Participants with surgically unresectable locally advanced or metastatic disease who have received one prior line of chemotherapy. (The Phase 1 portion of the study will be open for enrollment for subjects who received 1 or more prior therapies). Both relapsed and refractory CRC are allowed.

2. All participants must express the wild-type form of the gene KRAS.

3. Measurable disease according to RECIST (Response Evaluation Criteria In Solid Tumors) criteria, Version 1.1.

4. Male or female >= to 18 years of age.

5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

6. Resolution of any toxic effects of prior therapy (except alopecia) to NCI CTCAE, Version 4.0, grade <= to 1.

7. Adequate bone marrow, liver, and renal functions, defined as:

   • Hemoglobin >= to 9.0 g/dL (transfusion and/or growth factor support allowed).
   • Absolute neutrophil count (ANC) >= to 1.5 x 10^9/L.
   • Platelet count >= to 75 x 10^9/L.
   • Serum creatinine <= to 1.5 x upper limit of normal (ULN) or creatinine clearance >= to 60 mL/min.
   • Alanine transaminase (ALT), aspartate transaminase (AST), and alkaline phosphatase <= to 2.5 x ULN in subjects with no liver metastasis and <= to 5.0 x ULN in participants with liver metastasis.
   • Total bilirubin <= to 1.5 x ULN (<= to 4 x ULN and direct bilirubin <= to 1.5 x ULN is acceptable for subjects with Gilbert's syndrome).

8. Male and female participants of child-bearing potential must agree to use double-barrier contraceptive measures, oral contraception, or avoidance of intercourse during the study and for 90 days after last investigational drug dose received.

9. All female participants of childbearing potential must each have a negative pregnancy test (serum or urine) result before initiating study treatment.

10. Participants must be fully informed about their illness and the investigational nature of the study protocol (including foreseeable risks and possible side effects) and must sign and date an Independent Ethics Committee (IEC) or Institutional Review Board (IRB)-approved informed consent form (ICF) (including HIPAA authorization, if applicable) before performance of any study specific procedures or tests.

Exclusion Criteria:

1. Prior therapy with an Epidermal Growth Factor Receptor (EGFR) inhibitor.

2. History of malignancy other than CRC, unless there is an exception that the malignancy has been cured and no tumor-specific treatment for the malignancy has been administered within the 5 years prior to initiation of study treatment (participants with a history of basal cell carcinoma or benign tumor of cervix can be enrolled if diagnosis and treatment occurred less than 3 years prior to randomization).

3. Anticipation of need for a major surgical procedure or radiation therapy (RT) during the study.

4. Treatment with chemotherapy, radiotherapy, surgery, immunotherapy, biological therapy, or any other investigational anticancer agent within 4 weeks prior to start of study treatment.

5. History of cardiac disease:

   • Congestive heart failure defined as Class II to IV per New York Heart Association (NYHA) classification.
   • Active coronary artery disease (CAD).
   • Previously diagnosed bradycardia or other cardiac arrhythmia defined as Grade 2 or higher according to NCI CTCAE, version 4.0, or uncontrolled hypertension.
   • Myocardial infarction that occurred within 6 months prior to start of study treatment (myocardial infarction that occurred greater than 6 months before the start of study treatment is permitted).

6. Malabsorption syndrome, chronic diarrhea (lasting greater than 4 weeks), inflammatory bowel disease, or partial bowel obstruction.

7. Known metastatic brain or meningeal tumors, unless the participant is greater than 6 months from definitive therapy, has a negative imaging study within 4 weeks of first dose of study treatment, and is clinically stable (no concomitant therapy, including supportive therapy with steroids or anticonvulsant medications) with respect to the tumor at the time of first dose of study treatment.

8. Uncontrolled seizure disorder, spinal cord compression, or carcinomatous meningitis.

9. Pericardial or pleural effusion (eg, requiring drainage) or pericardial involvement with the tumor. Participants with minimal pleural effusion may be eligible upon request by Investigator and approval by Sponsor.

10. Clinically significant active infection that requires antibiotic therapy.

11. Previous administration of ARQ 197.

12. Substance abuse or medical, psychological or social conditions that may, in the opinion of the Investigator, interfere with the participant's participation in the clinical trial or evaluation of the clinical trial results.

13. Any condition that is unstable or that could jeopardize the safety of the subject and the participant's protocol compliance including known human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV) infection.

14. Inability to swallow oral medications.

15. Pregnant or nursing females.