The purpose of this study is to assess the safety and anti-tumor activity of the triple combination of WNT974, LGX818 and cetuximab in BRAFV600-mutant mCRC with RNF43 mutations or RSPO fusions.

The design of this study is based upon the translational and pre-clinical data that suggest that Wnt pathway signals, increased due to RNF43 mutations or RSPO fusions, cooperate with the EGFR and BRAF signals to maintain the growth of BRAFV600 CRCs. Inhibition of these signals with the triple combination of WNT974, LGX818 and cetuximab may result in anti-tumor activity.

Inclusion Criteria:

• Male or female aged ≥ 18 years
• Histological or cytological confirmed metastatic colorectal cancer
• Written documentation of KRAS wild-type status and BRAFV600-mutation with RNF43 mutation and/or RSPO fusion
• Progression of disease after at least one prior standard of care regimen or intolerant to irinotecan based regimens
• Availability of a representative tumor specimen (primary or metastatic, archival or newly obtained)
• Measurable disease as per RECIST v1.1
• Eastern cooperative oncology group (ECOG) performance status ≤ 2

Exclusion Criteria:

• Phase II only: Prior treatment with RAF inhibitors, Wnt pathway inhibitors, cetuximab, panitumumab, and/or other EGFR inhibitors

• Symptomatic brain metastasis. Patients previously treated or untreated for these conditions that are asymptomatic in the absence of corticosteroid and anti-epileptic therapy are allowed to enroll

• Current treatment with medications or consuming foods that are strong inhibitors or inducers of CYP3A4/5 or herbal medications and that cannot be discontinued at least one week prior to the start of treatment.

• Symptomatic or untreated leptomeningeal disease

• Acute or chronic pancreatitis

• Clinically significant cardiac disease

• Patients with any of the following laboratory values at Screening/baseline

  • Absolute neutrophil count (ANC) <1,500/mm3
  • Platelets < 100,000/mm3
  • Hemoglobin < 9.0 g/dL
  • Serum creatinine >1.5 x ULN or calculated or directly measured CrCl < 50% lower limit of normal
  • Serum total bilirubin >1.5 x ULN
  • AST/SGOT and/or ALT/SGPT > 2.5 x ULN, (> 5 x ULN if liver metastases present)

• Patients with impaired hepatic function as defined by Childs-Pugh class B or C

• Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral WNT974/LGX818

Other protocol-defined inclusion/exclusion criteria may apply