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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/show/NCT02278133




Registration number
NCT02278133
Ethics application status
Date submitted
6/10/2014
Date registered
29/10/2014
Date last updated
9/10/2017

Titles & IDs
Public title
Study of WNT974 in Combination With LGX818 and Cetuximab in Patients With BRAF-mutant Metastatic Colorectal Cancer (mCRC) and Wnt Pathway Mutations
Scientific 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
Secondary ID [1] 0 0
CWNT974X2102C
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Metastatic Colorectal Cancer 0 0
Condition category
Condition code
Cancer 0 0 0 0
Bowel - Back passage (rectum) or large bowel (colon)

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - WNT974
Treatment: Drugs - LGX818
Other interventions - Cetuximab

Experimental: WNT974, LGX818 and cetuximab combo - Phase l: Dose Escalation phase; Phase ll: SIngle group assessing the triple combination of WNT974, LGX818 and cetuximab


Treatment: Drugs: WNT974


Treatment: Drugs: LGX818


Other interventions: Cetuximab


Intervention code [1] 0 0
Treatment: Drugs
Intervention code [2] 0 0
Other interventions
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
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.
Timepoint [1] 0 0
12 months
Primary outcome [2] 0 0
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
Timepoint [2] 0 0
30 months
Secondary outcome [1] 0 0
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.
Timepoint [1] 0 0
36 months
Secondary outcome [2] 0 0
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.
Timepoint [2] 0 0
36 months
Secondary outcome [3] 0 0
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.
Timepoint [3] 0 0
36 months
Secondary outcome [4] 0 0
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.
Timepoint [4] 0 0
36 months
Secondary outcome [5] 0 0
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.
Timepoint [5] 0 0
36 months
Secondary outcome [6] 0 0
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.
Timepoint [6] 0 0
36 months
Secondary outcome [7] 0 0
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
Timepoint [7] 0 0
30 months
Secondary outcome [8] 0 0
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
Timepoint [8] 0 0
30 months
Secondary outcome [9] 0 0
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
Timepoint [9] 0 0
30 months
Secondary outcome [10] 0 0
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
Timepoint [10] 0 0
32 months
Secondary outcome [11] 0 0
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
Timepoint [11] 0 0
30 months

Eligibility
Key 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
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key 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 design
Purpose of the study
Treatment
Allocation to intervention
N/A
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Phase 1/Phase 2
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 0 0
Array BioPharma Investigative Site - Parkville
Recruitment postcode(s) [1] 0 0
3050 - Parkville
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
New York
Country [2] 0 0
United States of America
State/province [2] 0 0
South Carolina
Country [3] 0 0
United States of America
State/province [3] 0 0
Texas
Country [4] 0 0
United States of America
State/province [4] 0 0
Wisconsin
Country [5] 0 0
Belgium
State/province [5] 0 0
Leuven
Country [6] 0 0
Canada
State/province [6] 0 0
Alberta
Country [7] 0 0
Canada
State/province [7] 0 0
British Columbia
Country [8] 0 0
Canada
State/province [8] 0 0
Ontario
Country [9] 0 0
France
State/province [9] 0 0
Bordeaux
Country [10] 0 0
France
State/province [10] 0 0
Marseille
Country [11] 0 0
Israel
State/province [11] 0 0
Tel-Aviv
Country [12] 0 0
Italy
State/province [12] 0 0
MI
Country [13] 0 0
Netherlands
State/province [13] 0 0
Amsterdam
Country [14] 0 0
Singapore
State/province [14] 0 0
Singapore
Country [15] 0 0
Spain
State/province [15] 0 0
Catalunya
Country [16] 0 0
Spain
State/province [16] 0 0
Madrid

Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
Name
Array BioPharma
Address
Country

Ethics approval
Ethics application status

Summary
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.
Trial website
https://clinicaltrials.gov/show/NCT02278133
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Clinical Trial Call Center
Address 0 0
Array BioPharma, Inc.
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries

Summary results
Other publications