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

Metastatic Colorectal Cancer Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02278133
• Other study ID #: CWNT974X2102C
• Status: Completed
• Phase: Phase 1/Phase 2
• First received: October 6, 2014
• Last updated: October 3, 2017
• Start date: December 2014
• Est. completion date: June 23, 2017

Study information

• Verified date: October 2017
• Source: Array BioPharma
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 20
• Est. completion date: June 23, 2017
• Est. primary completion date: May 31, 2016
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Colorectal Neoplasms
• Metastatic Colorectal Cancer

Intervention

Drug:
• WNT974

• LGX818

Biological:
• Cetuximab

Locations

Country	Name	City	State
Australia	Array BioPharma Investigative Site	Parkville	Victoria
Belgium	Array BioPharma Investigative Site	Leuven
Canada	Array BioPharma Investigative Site	Edmonton	Alberta
Canada	Array BioPharma Investigative Site	Toronto	Ontario
Canada	Array BioPharma Investigative Site	Vancouver	British Columbia
France	Array BioPharma Investigative Site	Bordeaux
France	Array BioPharma Investigative Site	Marseille
Israel	Array BioPharma Investigative Site	Tel-Aviv
Italy	Array BioPharma Investigative Site	Milano	MI
Netherlands	Array BioPharma Investigative Site	Amsterdam
Singapore	Array BioPharma Investigative Site	Singapore
Spain	Array BioPharma Investigative Site	Barcelona	Catalunya
Spain	Array BioPharma Investigative Site	Hospitalet de LLobregat	Catalunya
Spain	Array BioPharma Investigative Site	Madrid
Spain	Array BioPharma Investigative Site	Madrid
United States	Medical University of South Carolina Oncology Dept	Charleston	South Carolina
United States	University of Texas/MD Anderson Cancer Center Onc. Dept,	Houston	Texas
United States	University of Wisconsin / Paul P. Carbone Comp Cancer Center Univ Wisc	Madison	Wisconsin
United States	Memorial Sloan-Kettering Cancer Center (MSKCC) MSKCC (3)	New York	New York

Sponsors (1)

Lead Sponsor	Collaborator
Array BioPharma

Countries where clinical trial is conducted

United States,  Australia,  Belgium,  Canada,  France,  Israel,  Italy,  Netherlands,  Singapore,  Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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