Cetuximab and Savolitinib Treatment of Ras Wild-Type Colorectal Cancer

Inclusion Criteria, Part 1: 1. Progressive metastatic or unresectable CRC or SCCHN. 2. Prior therapy with cetuximab or panitumumab. Cetuximab and panitumumab could have been used either alone or in combination with other agents. 3. If patients were treated with cetuximab in the past, they must have been able to tolerate full doses of cetuximab without dose modifications for toxicity. 4. ECOG performance status 0-2. 5. Life expectancy of at least 3 months. 6. Patient with adequate organ function: * Absolute neutrophil count (ANC) ≥ 1.5 x 109/L * Hemoglobin ≥ 9 g/dL * Platelets (PLT) ≥ 100 x 109/L * AST/ALT ≤ 2.5 x ULN (≤ 5 x ULN in case of liver metastases) * GGT \< 3 x ULN (\< 5 x ULN in case of liver involvement) * Bilirubin ≤ 1.5 x ULN * Albumin ≥ 3 g/dL * Serum creatinine ≤ 1.5 x institutional ULN (Cockcroft and Gault formula) 7. Adequate contraception if applicable. 8. Ability to take oral medication in the opinion of the investigator. 9. Patient able and willing to comply with study procedures as per protocol, including the biopsy at the time of study enrollment. 10. Patient able to understand and willing to sign and date the written voluntary informed consent form (ICF) at screening visit prior to any protocol-specific procedures. Inclusion Criteria, Part 2: 1. Histologically confirmed stage IV colon cancer (AJCC 7th edition) that has progressed after at least one line of standard therapy. 2. Presence of measurable disease per RECIST criteria on imaging studies at the time of trial enrollment. 3. Prior therapy with cetuximab or panitumumab containing regimen and disease progression within 3 months of last dose of cetuximab or panitumumab. Anti-EGFR antibodies could have been used either alone or in combination with other agents. 4. Subjects should be off other disease directed treatments for at least 4 weeks prior to treatment initiation on this study. 5. Absence of K-Ras or N-Ras mutations using extended Ras profiling. 6. ECOG performance status 0-2. 7. Life expectancy of at least 3 months. 8. Patient able to receive adequate oral nutrition of ≥ 1500 calories per day and free of significant nausea and vomiting 9. Patient with adequate organ function: * Absolute neutrophil count (ANC) ≥ 1.5 x 109/L * Hemoglobin ≥ 9 g/dL * Platelets (PTL) ≥ 100 x 109/L * AST/ALT ≤ 2.5 x ULN (≤ 5 x ULN in case of liver metastases) * Bilirubin ≤ 1.5 x ULN * Albumin ≥ 3 g/dL * Serum creatinine ≤ 1.5 x institutional ULN (Cockcroft and Gault formula) 10. Adequate contraception if applicable. 11. Ability to take oral medication in the opinion of the investigator. 12. Patient able and willing to comply with study procedures as per protocol, including a tumor biopsy within 28 days of treatment initiation. 13. Patient able to understand and willing to sign and date the written voluntary informed consent form at screening visit prior to any protocol-specific procedures. Exclusion Criteria (Parts 1 and 2): 1. Previous treatment with MET inhibitor or anti-MET antibody (e.g. foretinib, crizotinib, cabozantinib, onartuzumab). 2. Patients with previous hypersensitivity to cetuximab (Grade 2 or higher, unless controlled to \< Grade 2 with prophylactic measures on subsequent exposures). 3. Active dermatological condition requiring treatment with associated grade 2 or higher skin toxicity. Dermatological condition controlled with treatment with maximum of grade 1 skin toxicity will be allowed for study enrollment. 4. Symptomatic brain metastases requiring treatment. 5. Other active malignancy within the last 3 years (except for non-melanoma skin cancer or a non-invasive/in situ cancer). 6. Patients unable to swallow orally administered medication and patients with gastrointestinal disorders likely to interfere with absorption of the study medication. 7. Persistent toxicities CTCAE grade 2 or higher, with the exception of alopecia, caused by previous cancer therapy. 8. Pregnancy or breast feeding. 9. Current therapy with other investigational agents or participation in another clinical study. 10. History of allergic reactions attributed to compounds of similar chemical or biologic composition to savolitinib. 11. Major surgery within 28 days or minor surgery within 14 days of the start of the study treatment, except for tumor biopsy. 12. Radiotherapy less than two weeks prior to the start of the study treatment 13. Significant current or recent (\< 14 days) gastrointestinal disorders with diarrhea as a major symptom, e.g. Crohn's disease, malabsorption, or CTCAE grade \> 2 diarrhea of any etiology. 14. Psychological, familial, or sociological condition potentially hampering compliance with the study protocol and follow-up schedule. 15. Involvement in the planning and/or conduct of the study. 16. Previous enrolment in the present study. 17. Acute or chronic liver or pancreatic disease. 18. Use of strong inducers or inhibitors of CYP3A4 or strong inhibitors of CYP1A2 within 2 weeks before the first dose of study treatment (3 weeks for St John's Wort). \-