Clinical trial NCT02278133: Study of WNT974 in Combination With LGX818 and Cetuximab in Patients With BRAF-mutant Metastatic Colorectal Cancer (mCRC) and Wnt Pathway Mutations
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Metastatic Colorectal Cancer
Keywords: metastatic,
Colorectal cancer,
WNT974,
LGX818,
cetuximab,
BRAF-mutant,
mCRC,
BRAFV600-mutant,
KRAS
Lead sponsor: Array BioPharma
Sponsor class: INDUSTRY
First posted: 2014-10-29
Enrollment: 20
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.


Eligibility criteria: 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

Primary outcomes:
measure: Incidence of Dose Limiting Toxicities and exposure (AUC C1D15) to WNT974 and LGX818 (phase lb)
timeFrame: 12 months
measure: Overall response rate in phase II
timeFrame: 30 months
Secondary outcomes:
measure: Overall response rate (ORR) (phase lb)
timeFrame: 36 months
measure: Overall survival (OS) (phase lb/ll)
timeFrame: 36 months
measure: Duration of response (DOR) (phase lb/ll)
timeFrame: 36 months
measure: Time to response (TTR) (phase lb/ll)
timeFrame: 36 months
measure: Progression free survival (PFS) (phase lb/ll)
timeFrame: 36 months
measure: Disease control rate (DCR) (phase lb/ll)
timeFrame: 36 months
measure: Plasma concentration of WNT974, LHA333, LGX818 (phase lb/ll)
timeFrame: 30 months
measure: Number of participants with Adverse Events as a measure of safety and tolerability (phase lb/ll)
timeFrame: 30 months
measure: Number of participants with Serious Adverse Events as a measure of safety and tolerability(phase lb/ll)
timeFrame: 30 months
measure: Biomarker activations for WNT and RTK-MAPK pathways (phase Ib/II)
timeFrame: 32 months
measure: Number of participants with dose interruptions and dose reductions (phase Ib/II)
timeFrame: 30 months
Other outcomes:
Locations:
city: New York
country: United States
facility: Memorial Sloan-Kettering Cancer Center (MSKCC) MSKCC (3)
state: New York
city: Charleston
country: United States
facility: Medical University of South Carolina Oncology Dept
state: South Carolina
city: Houston
country: United States
facility: University of Texas/MD Anderson Cancer Center Onc. Dept,
state: Texas
city: Madison
country: United States
facility: University of Wisconsin / Paul P. Carbone Comp Cancer Center Univ Wisc
state: Wisconsin
city: Parkville
country: Australia
facility: Array BioPharma Investigative Site
state: Victoria
city: Leuven
country: Belgium
facility: Array BioPharma Investigative Site
city: Edmonton
country: Canada
facility: Array BioPharma Investigative Site
state: Alberta
city: Vancouver
country: Canada
facility: Array BioPharma Investigative Site
state: British Columbia
city: Toronto
country: Canada
facility: Array BioPharma Investigative Site
state: Ontario
city: Bordeaux
country: France
facility: Array BioPharma Investigative Site
city: Marseille
country: France
facility: Array BioPharma Investigative Site
city: Tel-Aviv
country: Israel
facility: Array BioPharma Investigative Site
city: Milano
country: Italy
facility: Array BioPharma Investigative Site
state: MI
city: Amsterdam
country: Netherlands
facility: Array BioPharma Investigative Site
city: Singapore
country: Singapore
facility: Array BioPharma Investigative Site
city: Barcelona
country: Spain
facility: Array BioPharma Investigative Site
state: Catalunya
city: Hospitalet de LLobregat
country: Spain
facility: Array BioPharma Investigative Site
state: Catalunya
city: Madrid
country: Spain
facility: Array BioPharma Investigative Site
city: Madrid
country: Spain
facility: Array BioPharma Investigative Site
Study officials:
affiliation: Array BioPharma, Inc.
name: Clinical Trial Call Center
role: STUDY_DIRECTOR
References: