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

Sponsor

Array BioPharma (Industry)

Overall Status

Completed

CT.gov ID

NCT02278133

Collaborator

(none)

Enrollment

Locations

Arm

30.7

Duration (Months)

1.1

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Metastatic Colorectal Cancer	Drug: WNT974 Drug: LGX818 Biological: Cetuximab	Phase 1/Phase 2

Study Design

Study Type:

Interventional

Actual Enrollment :

20 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

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 Start Date :

Dec 1, 2014

Actual Primary Completion Date :

May 31, 2016

Actual Study Completion Date :

Jun 23, 2017

Arms and Interventions

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	Drug: WNT974 Drug: LGX818 Biological: Cetuximab

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

Drug: WNT974

Drug: LGX818

Biological: Cetuximab

Outcome Measures

Primary Outcome Measures

Incidence of Dose Limiting Toxicities and exposure (AUC C1D15) to WNT974 and LGX818 (phase lb) [12 months]
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.
Overall response rate in phase II [30 months]
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

Secondary Outcome Measures

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts 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

Contacts and Locations

Locations

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