Study of WNT974 in Combination With LGX818 and Cetuximab in Patients With BRAF-mutant Metastatic Colorectal Cancer (mCRC) and Wnt Pathway Mutations

Array BioPharma

Status and phase: Completed; Phase 2; Phase 1

Conditions: Metastatic Colorectal Cancer

Treatments: Drug: WNT974; Drug: LGX818; Biological: Cetuximab

Study type: Interventional

Funder types: Industry

Identifiers

NCT02278133

CWNT974X2102C

Details and patient eligibility

About

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.

Enrollment: 20 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: N/A

Interventional model: Single Group Assignment

Masking: None (Open label)

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20 participants in 1 patient group

WNT974, LGX818 and cetuximab combo

Experimental group

Description:

Phase l: Dose Escalation phase; Phase ll: SIngle group assessing the triple combination of WNT974, LGX818 and cetuximab

Treatment:

Biological: Cetuximab

Drug: WNT974

Drug: LGX818