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

Study Overview
=================
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.

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

Conditions
-----------------
Metastatic Colorectal Cancer

Intervention / Treatment
-----------------
* Drug: WNT974
* Drug: LGX818
* Biological: Cetuximab


Participation Criteria
=================
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: WNT974, LGX818 and cetuximab combo<br>Phase l: Dose Escalation phase; Phase ll: SIngle group assessing the triple combination of WNT974, LGX818 and cetuximab | Drug: WNT974<br> <br> Drug: LGX818<br> <br> Biological: Cetuximab<br> <br> |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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 | 30 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | 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. | 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. | 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. | 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. | 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 | 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 | 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 | 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 | 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 | 30 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
BRAF-mutant,, metastatic,, Colorectal cancer,, WNT974,, LGX818,, cetuximab,, mCRC,, BRAFV600-mutant,, KRAS