Metastatic Colorectal CancerPhase 1/2NCT02278133
Study of WNT974 in Combination With LGX818 and Cetuximab in Patients With BRAF-mutant Metastatic Colorectal Cancer (mCRC) and Wnt Pathway Mutations
A Phase 1/2 study testing WNT974, LGX818 and Cetuximab in people with Metastatic Colorectal Cancer, run by Array BioPharma at 19 sites in 10 countries.
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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Metastatic Colorectal Cancer
- What is being tested?
- WNT974, LGX818 and Cetuximab
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 20 participants
- Where
- 19 sitesin 10 countries
- Study dates
- Dec 2014to 23 Jun 2017
- Phase
- Phase 1/2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Who cannot join
- 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
Show all 16Show fewer
- 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
Trial locations and contacts
19 sites in 10 countries.
19 sites in 10 countries
United States4 sites
Medical University of South Carolina Oncology Dept
Charleston, South Carolina, 29425
University of Texas/MD Anderson Cancer Center Onc. Dept,
Houston, Texas, 77030-4009
University of Wisconsin / Paul P. Carbone Comp Cancer Center Univ Wisc
Madison, Wisconsin, 53792-6164
Memorial Sloan-Kettering Cancer Center (MSKCC) MSKCC (3)
New York, New York, 10065
Spain4 sites
Array BioPharma Investigative Site
Barcelona, Catalonia, 08035
Array BioPharma Investigative Site
L'Hospitalet de Llobregat, Catalonia, 08907
Array BioPharma Investigative Site
Madrid, 28041
Array BioPharma Investigative Site
Madrid, 28050
Canada3 sites
Array BioPharma Investigative Site
Edmonton, Alberta, T6G 1Z2
Array BioPharma Investigative Site
Toronto, Ontario, M5G 2M9
Array BioPharma Investigative Site
Vancouver, British Columbia, V5Z 4E6
France2 sites
Array BioPharma Investigative Site
Bordeaux, 33076
Array BioPharma Investigative Site
Marseille, 13273
Australia1 site
Array BioPharma Investigative Site
Parkville, Victoria, 3050
About this study
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
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.
- Conditions
- Metastatic Colorectal Cancer
- Being tested
- WNT974, LGX818, Cetuximab
- Keywords
- metastatic,, Colorectal cancer,, WNT974,, LGX818,, cetuximab,, BRAF-mutant,, mCRC,, BRAFV600-mutant,, KRAS
- Medical subject headings
- Colorectal Neoplasms, Neoplasm Metastasis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
WNT974Drug
LGX818Drug
CetuximabBiological
| Study group | Role | What they receive |
|---|---|---|
| WNT974, LGX818 and cetuximab combo | Experimental | Phase l: Dose Escalation phase; Phase ll: SIngle group assessing the triple combination of WNT974, LGX818 and cetuximab Receives: Drug: WNT974; Drug: LGX818; Biological: Cetuximab |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 12 months
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
Measured: 30 months
Secondary outcomes (11)
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.
Measured: 36 months
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.
Measured: 36 months
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.
Measured: 36 months
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.
Measured: 36 months
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.
Measured: 36 months
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.
Measured: 36 months
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
Measured: 30 months
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
Measured: 30 months
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
Measured: 30 months
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
Measured: 32 months
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
Measured: 30 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted29 Oct 2014 (estimated)
- Study startDec 2014
- Primary completion31 May 2016
- Study completion23 Jun 2017
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for Metastatic Colorectal CancerStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 20 participants (actual)
Sponsor and investigators
- Lead sponsor
- Array BioPharma
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Clinical Trial Call Center, Study director, Array BioPharma, Inc.
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02278133
- Sponsor's protocol ID
- CWNT974X2102C
- Status last verified
- Oct 2017
- First submitted
- 6 Oct 2014
- Last updated
- 9 Oct 2017
- Results posted
- No
- Data monitoring committee
- No
Publications
VAN Bussel MTJ, Bravenboer N, Essen HV, Snaebjornsson P, Appelman-Dijkstra NM, Schellens JH, Opdam FL. Bone Toxicity Case Report Combining Encorafenib, Cetuximab and WNT974 in a Phase I Trial. Anticancer Res. 2025 Jul;45(7):3137-3147. doi: 10.21873/anticanres.17677.
PubMed 40578933Tabernero J, Van Cutsem E, Garralda E, Tai D, De Braud F, Geva R, van Bussel MTJ, Fiorella Dotti K, Elez E, de Miguel MJ, Litwiler K, Murphy D, Edwards M, Morris VK. A Phase Ib/II Study of WNT974 + Encorafenib + Cetuximab in Patients With BRAF V600E-Mutant KRAS Wild-Type Metastatic Colorectal Cancer. Oncologist. 2023 Mar 17;28(3):230-238. doi: 10.1093/oncolo/oyad007.
PubMed 36811382
Study at a glance
From the registry record, last updated by the sponsor on 9 Oct 2017. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT02278133
- Acronym / sponsor ID
- CWNT974X2102C
- Conditions
- Metastatic Colorectal Cancer
- Keywords
- metastatic,, Colorectal cancer,, WNT974,, LGX818,, cetuximab,, BRAF-mutant,, mCRC,, BRAFV600-mutant,
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 20 participants (actual)
- Lead sponsor
- Array BioPharmaIndustry (pharma, biotech, devices)
- Study start
- Dec 2014
- Primary completion
- 31 May 2016 (actual)
- Study completion
- 23 Jun 2017 (actual)
- First posted
- 29 Oct 2014 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| WNT974, LGX818 and cetuximab combo | Experimental | Drug: WNT974, Drug: LGX818, Biological: CetuximabPhase l: Dose Escalation phase; Phase ll: SIngle group assessing the triple combination of WNT974, LGX818 and cetuximab |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (7 listed)
- 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)
Key exclusion criteria (16 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| WNT974 | Drug | WNT974, LGX818 and cetuximab combo |
| LGX818 | Drug | WNT974, LGX818 and cetuximab combo |
| Cetuximab | Biological | WNT974, LGX818 and cetuximab combo |
Primary outcome
Incidence of Dose Limiting Toxicities and exposure (AUC C1D15) to WNT974 and LGX818 (phase lb)
Time frame: 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
Time frame: 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
11 secondary outcomes
Overall response rate (ORR) (phase lb)
Time frame: 36 months
Overall survival (OS) (phase lb/ll)
Time frame: 36 months
Duration of response (DOR) (phase lb/ll)
Time frame: 36 months
Time to response (TTR) (phase lb/ll)
Time frame: 36 months
Progression free survival (PFS) (phase lb/ll)
Time frame: 36 months
Disease control rate (DCR) (phase lb/ll)
Time frame: 36 months
Plasma concentration of WNT974, LHA333, LGX818 (phase lb/ll)
Time frame: 30 months
Number of participants with Adverse Events as a measure of safety and tolerability (phase lb/ll)
Time frame: 30 months
Number of participants with Serious Adverse Events as a measure of safety and tolerability(phase lb/ll)
Time frame: 30 months
Biomarker activations for WNT and RTK-MAPK pathways (phase Ib/II)
Time frame: 32 months
Number of participants with dose interruptions and dose reductions (phase Ib/II)
Time frame: 30 months
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 9 Oct 2017.
- Derived from this study: PubMed 40578933VAN Bussel MTJ, Bravenboer N, Essen HV, Snaebjornsson P, Appelman-Dijkstra NM, Schellens JH, Opdam FL. Bone Toxicity Case Report Combining Encorafenib, Cetuximab and WNT974 in a Phase I Trial. Anticancer Res. 2025 Jul;45(7):3137-3147. doi: 10.21873/anticanres.17677.
- Derived from this study: PubMed 36811382Tabernero J, Van Cutsem E, Garralda E, Tai D, De Braud F, Geva R, van Bussel MTJ, Fiorella Dotti K, Elez E, de Miguel MJ, Litwiler K, Murphy D, Edwards M, Morris VK. A Phase Ib/II Study of WNT974 + Encorafenib + Cetuximab in Patients With BRAF V600E-Mutant KRAS Wild-Type Metastatic Colorectal Cancer. Oncologist. 2023 Mar 17;28(3):230-238. doi: 10.1093/oncolo/oyad007.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Clinical Trial Call Center study director
Array BioPharma, Inc.
19 sites in 10 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing WNT974, LGX818 and Cetuximab in people with Metastatic Colorectal Cancer, run by Array BioPharma at 19 sites in 10 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 7 inclusion and 16 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 9 Oct 2017. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 19 sites in United States, Spain, Canada, France, Australia and 5 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Incidence of Dose Limiting Toxicities and exposure (AUC C1D15) to WNT974 and LGX818 (phase lb) (time frame: 12 months). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02278133, which also lists 2 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 9 Oct 2017.