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

A Phase Ib/II Multi-center, Open Label, Dose Escalation Study of WNT974, LGX818 and Cetuximab in Patients With BRAFV600-mutant KRAS Wild-type Metastatic Colorectal Cancer Harboring Wnt Pathway Mutations

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.

Study Overview

• Status: Completed
• Conditions: Metastatic Colorectal Cancer
• Intervention / Treatment: Biological: Cetuximab; Drug: LGX818; Drug: WNT974

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Australia
  • Victoria
    • Parkville, Victoria, Australia, 3050
      • Array BioPharma Investigative Site
• Belgium
  • Leuven, Belgium, 3000
    • Array BioPharma Investigative Site
• Canada
  • Alberta
    • Edmonton, Alberta, Canada, T6G 1Z2
      • Array BioPharma Investigative Site
  • British Columbia
    • Vancouver, British Columbia, Canada, V5Z 4E6
      • Array BioPharma Investigative Site
  • Ontario
    • Toronto, Ontario, Canada, M5G 2M9
      • Array BioPharma Investigative Site
• France
  • Bordeaux, France, 33076
    • Array BioPharma Investigative Site
  • Marseille, France, 13273
    • Array BioPharma Investigative Site
• Israel
  • Tel-Aviv, Israel, 6423906
    • Array BioPharma Investigative Site
• Italy
  • MI
    • Milano, MI, Italy, 20133
      • Array BioPharma Investigative Site
• Netherlands
  • Amsterdam, Netherlands, 1066 CX
    • Array BioPharma Investigative Site
• Singapore
  • Singapore, Singapore, 169610
    • Array BioPharma Investigative Site
• Spain
  • Madrid, Spain, 28041
    • Array BioPharma Investigative Site
  • Madrid, Spain, 28050
    • Array BioPharma Investigative Site
  • Catalunya
    • Barcelona, Catalunya, Spain, 08035
      • Array BioPharma Investigative Site
    • Hospitalet de LLobregat, Catalunya, Spain, 08907
      • Array BioPharma Investigative Site
• United States
  • New York
    • New York, New York, United States, 10065
      • Memorial Sloan-Kettering Cancer Center (MSKCC) MSKCC (3)
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina Oncology Dept
  • Texas
    • Houston, Texas, United States, 77030-4009
      • University of Texas/MD Anderson Cancer Center Onc. Dept,
  • Wisconsin
    • Madison, Wisconsin, United States, 53792-6164
      • University of Wisconsin / Paul P. Carbone Comp Cancer Center Univ Wisc

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: WNT974, LGX818 and cetuximab combo; Phase l: Dose Escalation phase; Phase ll: SIngle group assessing the triple combination of WNT974, LGX818 and cetuximab	Biological: Cetuximab; Drug: LGX818; Drug: WNT974

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall response rate (ORR) (phase lb)	To assess additional parameters of clinical activity of WNT974 in combination with LGX818 and cetuximab in BRAFV600-mutant mCRC with evidence of upstream Wnt pathway activation.	36 months
Overall survival (OS) (phase lb/ll)	To assess additional parameters of clinical activity of WNT974 in combination with LGX818 and cetuximab in BRAFV600-mutant mCRC with evidence of upstream Wnt pathway activation.	36 months
Duration of response (DOR) (phase lb/ll)	To assess additional parameters of clinical activity of WNT974 in combination with LGX818 and cetuximab in BRAFV600-mutant mCRC with evidence of upstream Wnt pathway activation.	36 months
Time to response (TTR) (phase lb/ll)	To assess additional parameters of clinical activity of WNT974 in combination with LGX818 and cetuximab in BRAFV600-mutant mCRC with evidence of upstream Wnt pathway activation.	36 months
Progression free survival (PFS) (phase lb/ll)	To assess additional parameters of clinical activity of WNT974 in combination with LGX818 and cetuximab in BRAFV600-mutant mCRC with evidence of upstream Wnt pathway activation.	36 months
Disease control rate (DCR) (phase lb/ll)	To assess additional parameters of clinical activity of WNT974 in combination with LGX818 and cetuximab in BRAFV600-mutant mCRC with evidence of upstream Wnt pathway activation.	36 months
Plasma concentration of WNT974, LHA333, LGX818 (phase lb/ll)	To characterize the pharmacokinetics (PK) of WNT974, its pharmacologically active metabolite LHA333, and LGX818 when used in combination therapy with cetuximab	30 months
Number of participants with Adverse Events as a measure of safety and tolerability (phase lb/ll)	To characterize the safety and tolerability of WNT974 in combination with LGX818 and cetuximab in patients with BRAFV600-mutant mCRC with evidence of upstream Wnt pathway activation	30 months
Number of participants with Serious Adverse Events as a measure of safety and tolerability(phase lb/ll)	To characterize the safety and tolerability of WNT974 in combination with LGX818 and cetuximab in patients with BRAFV600-mutant mCRC with evidence of upstream Wnt pathway activation	30 months
Biomarker activations for WNT and RTK-MAPK pathways (phase Ib/II)	Phase Ib/II: To assess the pharmacodynamic effect of WNT974, LGX818 in combination with cetuximab and a potential relationship with clinical outcome	32 months
Number of participants with dose interruptions and dose reductions (phase Ib/II)	To characterize the safety and tolerability of WNT974 in combination with LGX818 and cetuximab in patients with BRAFV600-mutant mCRC with evidence of upstream Wnt pathway activation	30 months

Collaborators and Investigators

• Sponsor: Array BioPharma
• Investigators: Study Director: Clinical Trial Call Center, Array BioPharma, Inc.

Study record dates

Study Major Dates

• Study Start: December 1, 2014
• Primary Completion (Actual): May 31, 2016
• Study Completion (Actual): June 23, 2017

Study Registration Dates

• First Submitted: October 6, 2014
• First Submitted That Met QC Criteria: October 27, 2014
• First Posted (Estimate): October 29, 2014

Study Record Updates

• Last Update Posted (Actual): October 9, 2017
• Last Update Submitted That Met QC Criteria: October 3, 2017
• Last Verified: October 1, 2017

More Information

Terms related to this study

• Keywords: Colorectal cancer,; KRAS; metastatic,; WNT974,; LGX818,; cetuximab,; BRAF-mutant,; mCRC,; BRAFV600-mutant,
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Antineoplastic Agents; Antineoplastic Agents, Immunological; Cetuximab
• Other Study ID Numbers: CWNT974X2102C