Back to resultsStudy of WNT974 in Combination With LGX818 and Cetuximab in Patients With BRAF-mutant Metastatic Colorectal Cancer (mCRC) and Wnt Pathway Mutations
Primary Purpose
Metastatic Colorectal Cancer
Status
Completed
Phase
Phase 1
Locations
International
Study Type
Interventional
Intervention
WNT974
LGX818
Cetuximab
Sponsored by
About this trial
This is an interventional treatment trial for Metastatic Colorectal Cancer focused on measuring metastatic,, Colorectal cancer,, WNT974,, LGX818,, cetuximab,, BRAF-mutant,, mCRC,, BRAFV600-mutant,, KRAS
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
Sites / Locations
- Memorial Sloan-Kettering Cancer Center (MSKCC) MSKCC (3)
- Medical University of South Carolina Oncology Dept
- University of Texas/MD Anderson Cancer Center Onc. Dept,
- University of Wisconsin / Paul P. Carbone Comp Cancer Center Univ Wisc
- Array BioPharma Investigative Site
- Array BioPharma Investigative Site
- Array BioPharma Investigative Site
- Array BioPharma Investigative Site
- Array BioPharma Investigative Site
- Array BioPharma Investigative Site
- Array BioPharma Investigative Site
- Array BioPharma Investigative Site
- Array BioPharma Investigative Site
- Array BioPharma Investigative Site
- Array BioPharma Investigative Site
- Array BioPharma Investigative Site
- Array BioPharma Investigative Site
- Array BioPharma Investigative Site
- Array BioPharma Investigative Site
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
WNT974, LGX818 and cetuximab combo
Arm Description
Phase l: Dose Escalation phase; Phase ll: SIngle group assessing the triple combination of WNT974, LGX818 and cetuximab
Outcomes
Primary Outcome Measures
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.
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
Secondary Outcome Measures
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.
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.
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.
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.
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.
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.
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
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
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
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
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
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT02278133
Brief Title
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
2. Study Status
Record Verification Date
October 2017
Overall Recruitment Status
Completed
Study Start Date
December 2014 (undefined)
Primary Completion Date
May 31, 2016 (Actual)
Study Completion Date
June 23, 2017 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Array BioPharma
4. Oversight
Data Monitoring Committee
No
5. 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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Metastatic Colorectal Cancer
Keywords
metastatic,, Colorectal cancer,, WNT974,, LGX818,, cetuximab,, BRAF-mutant,, mCRC,, BRAFV600-mutant,, KRAS
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
20 (Actual)
8. Arms, Groups, and Interventions
Arm Title
WNT974, LGX818 and cetuximab combo
Arm Type
Experimental
Arm Description
Phase l: Dose Escalation phase; Phase ll: SIngle group assessing the triple combination of WNT974, LGX818 and cetuximab
Intervention Type
Drug
Intervention Name(s)
WNT974
Intervention Type
Drug
Intervention Name(s)
LGX818
Intervention Type
Biological
Intervention Name(s)
Cetuximab
Primary Outcome Measure Information:
Title
Incidence of Dose Limiting Toxicities and exposure (AUC C1D15) to WNT974 and LGX818 (phase lb)
Description
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.
Time Frame
12 months
Title
Overall response rate in phase II
Description
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
Time Frame
30 months
Secondary Outcome Measure Information:
Title
Overall response rate (ORR) (phase lb)
Description
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 Frame
36 months
Title
Overall survival (OS) (phase lb/ll)
Description
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 Frame
36 months
Title
Duration of response (DOR) (phase lb/ll)
Description
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 Frame
36 months
Title
Time to response (TTR) (phase lb/ll)
Description
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 Frame
36 months
Title
Progression free survival (PFS) (phase lb/ll)
Description
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 Frame
36 months
Title
Disease control rate (DCR) (phase lb/ll)
Description
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 Frame
36 months
Title
Plasma concentration of WNT974, LHA333, LGX818 (phase lb/ll)
Description
To characterize the pharmacokinetics (PK) of WNT974, its pharmacologically active metabolite LHA333, and LGX818 when used in combination therapy with cetuximab
Time Frame
30 months
Title
Number of participants with Adverse Events as a measure of safety and tolerability (phase lb/ll)
Description
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
Time Frame
30 months
Title
Number of participants with Serious Adverse Events as a measure of safety and tolerability(phase lb/ll)
Description
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
Time Frame
30 months
Title
Biomarker activations for WNT and RTK-MAPK pathways (phase Ib/II)
Description
Phase Ib/II: To assess the pharmacodynamic effect of WNT974, LGX818 in combination with cetuximab and a potential relationship with clinical outcome
Time Frame
32 months
Title
Number of participants with dose interruptions and dose reductions (phase Ib/II)
Description
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
Time Frame
30 months
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Clinical Trial Call Center
Organizational Affiliation
Array BioPharma, Inc.
Official's Role
Study Director
Facility Information:
Facility Name
Memorial Sloan-Kettering Cancer Center (MSKCC) MSKCC (3)
City
New York
State/Province
New York
ZIP/Postal Code
10065
Country
United States
Facility Name
Medical University of South Carolina Oncology Dept
City
Charleston
State/Province
South Carolina
ZIP/Postal Code
29425
Country
United States
Facility Name
University of Texas/MD Anderson Cancer Center Onc. Dept,
City
Houston
State/Province
Texas
ZIP/Postal Code
77030-4009
Country
United States
Facility Name
University of Wisconsin / Paul P. Carbone Comp Cancer Center Univ Wisc
City
Madison
State/Province
Wisconsin
ZIP/Postal Code
53792-6164
Country
United States
Facility Name
Array BioPharma Investigative Site
City
Parkville
State/Province
Victoria
ZIP/Postal Code
3050
Country
Australia
Facility Name
Array BioPharma Investigative Site
City
Leuven
ZIP/Postal Code
3000
Country
Belgium
Facility Name
Array BioPharma Investigative Site
City
Edmonton
State/Province
Alberta
ZIP/Postal Code
T6G 1Z2
Country
Canada
Facility Name
Array BioPharma Investigative Site
City
Vancouver
State/Province
British Columbia
ZIP/Postal Code
V5Z 4E6
Country
Canada
Facility Name
Array BioPharma Investigative Site
City
Toronto
State/Province
Ontario
ZIP/Postal Code
M5G 2M9
Country
Canada
Facility Name
Array BioPharma Investigative Site
City
Bordeaux
ZIP/Postal Code
33076
Country
France
Facility Name
Array BioPharma Investigative Site
City
Marseille
ZIP/Postal Code
13273
Country
France
Facility Name
Array BioPharma Investigative Site
City
Tel-Aviv
ZIP/Postal Code
6423906
Country
Israel
Facility Name
Array BioPharma Investigative Site
City
Milano
State/Province
MI
ZIP/Postal Code
20133
Country
Italy
Facility Name
Array BioPharma Investigative Site
City
Amsterdam
ZIP/Postal Code
1066 CX
Country
Netherlands
Facility Name
Array BioPharma Investigative Site
City
Singapore
ZIP/Postal Code
169610
Country
Singapore
Facility Name
Array BioPharma Investigative Site
City
Barcelona
State/Province
Catalunya
ZIP/Postal Code
08035
Country
Spain
Facility Name
Array BioPharma Investigative Site
City
Hospitalet de LLobregat
State/Province
Catalunya
ZIP/Postal Code
08907
Country
Spain
Facility Name
Array BioPharma Investigative Site
City
Madrid
ZIP/Postal Code
28041
Country
Spain
Facility Name
Array BioPharma Investigative Site
City
Madrid
ZIP/Postal Code
28050
Country
Spain
12. IPD Sharing Statement
Learn more about this trial
Study of WNT974 in Combination With LGX818 and Cetuximab in Patients With BRAF-mutant Metastatic Colorectal Cancer (mCRC) and Wnt Pathway Mutations
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