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

NCT02278133 | Completed Phase 1

• 1 other identifier: CWNT974X2102C
• Study Type: interventional
• Target: 20
• Locations: 10 countries
• Sites: 19

Brief Summary

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.

Conditions

Metastatic Colorectal Cancer

Keywords

metastatic,; Colorectal cancer,; WNT974,; LGX818,; cetuximab,; BRAF-mutant,; mCRC,; BRAFV600-mutant,; KRAS

Outcome Measures

Primary Outcomes (2)

• Incidence of Dose Limiting Toxicities and exposure (AUC C1D15) to WNT974 and LGX818 (phase lb)

  Phase Ib: To estimate the MTD(s) and/or RP2D(s) of the triple combination of WNT974, LGX818 and cetuximab in patients with BRAFV600-mutant, KRAS wild-type (WT) mCRC harboring upstream Wnt pathway mutations.

  12 months

• Overall response rate in phase II

  Phase II: To estimate the preliminary anti-tumor activity of the RP2D(s) of the combination of WNT974, LGX818 and cetuximab in patients with BRAFV600-mutant metastatic CRC harboring upstream Wnt pathway mutations

  30 months

Secondary Outcomes (11)

• Overall response rate (ORR) (phase lb)

  36 months

• Overall survival (OS) (phase lb/ll)

  36 months

• Duration of response (DOR) (phase lb/ll)

  36 months

• Time to response (TTR) (phase lb/ll)

  36 months

• Progression free survival (PFS) (phase lb/ll)

  36 months

Study Arms (1)

WNT974, LGX818 and cetuximab combo

EXPERIMENTAL

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

Drug: WNT974; Drug: LGX818; Biological: Cetuximab

Interventions

WNT974 DRUG

WNT974, LGX818 and cetuximab combo

LGX818 DRUG

WNT974, LGX818 and cetuximab combo

Cetuximab BIOLOGICAL

WNT974, LGX818 and cetuximab combo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Array BioPharma: lead

Study Sites (19)

Memorial Sloan-Kettering Cancer Center (MSKCC) MSKCC (3)

New York, New York, 10065, United States

Location

Medical University of South Carolina Oncology Dept

Charleston, South Carolina, 29425, United States

Location

University of Texas/MD Anderson Cancer Center Onc. Dept,

Houston, Texas, 77030-4009, United States

Location

University of Wisconsin / Paul P. Carbone Comp Cancer Center Univ Wisc

Madison, Wisconsin, 53792-6164, United States

Location

Array BioPharma Investigative Site

Parkville, Victoria, 3050, Australia

Location

Array BioPharma Investigative Site

Leuven, 3000, Belgium

Location

Array BioPharma Investigative Site

Edmonton, Alberta, T6G 1Z2, Canada

Location

Array BioPharma Investigative Site

Vancouver, British Columbia, V5Z 4E6, Canada

Location

Array BioPharma Investigative Site

Toronto, Ontario, M5G 2M9, Canada

Location

Array BioPharma Investigative Site

Bordeaux, 33076, France

Location

Array BioPharma Investigative Site

Marseille, 13273, France

Location

Array BioPharma Investigative Site

Tel Aviv, 6423906, Israel

Location

Array BioPharma Investigative Site

Milan, MI, 20133, Italy

Location

Array BioPharma Investigative Site

Amsterdam, 1066 CX, Netherlands

Location

Array BioPharma Investigative Site

Singapore, 169610, Singapore

Location

Array BioPharma Investigative Site

Barcelona, Catalonia, 08035, Spain

Location

Array BioPharma Investigative Site

L'Hospitalet de Llobregat, Catalonia, 08907, Spain

Location

Array BioPharma Investigative Site

Madrid, 28041, Spain

Location

Array BioPharma Investigative Site

Madrid, 28050, Spain

Location

Related Publications (2)

• VAN Bussel MTJ, Bravenboer N, Essen HV, Snaebjornsson P, Appelman-Dijkstra NM, Schellens JH, Opdam FL. Bone Toxicity Case Report Combining Encorafenib, Cetuximab and WNT974 in a Phase I Trial. Anticancer Res. 2025 Jul;45(7):3137-3147. doi: 10.21873/anticanres.17677.

  PMID: 40578933 DERIVED

• Tabernero J, Van Cutsem E, Garralda E, Tai D, De Braud F, Geva R, van Bussel MTJ, Fiorella Dotti K, Elez E, de Miguel MJ, Litwiler K, Murphy D, Edwards M, Morris VK. A Phase Ib/II Study of WNT974 + Encorafenib + Cetuximab in Patients With BRAF V600E-Mutant KRAS Wild-Type Metastatic Colorectal Cancer. Oncologist. 2023 Mar 17;28(3):230-238. doi: 10.1093/oncolo/oyad007.

  PMID: 36811382 DERIVED

MeSH Terms

Conditions

Colorectal Neoplasms; Neoplasm Metastasis

Interventions

LGK974; encorafenib; Cetuximab

Condition Hierarchy (Ancestors)

Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases; Neoplastic Processes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Clinical Trial Call Center

  Array BioPharma, Inc.

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 6, 2014
• First Posted: October 29, 2014
• Study Start: December 1, 2014
• Primary Completion: May 31, 2016
• Study Completion: June 23, 2017
• Last Updated: October 9, 2017

Record last verified: 2017-10

Locations

AU (1); US (4); FR (2); SG (1); IL (1); CA (3); BE (1); ES (4); NL (1); IT (1)