Clinical Trials /

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

NCT02278133

Description:

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.

Related Conditions:
  • Colorectal Carcinoma
Recruiting Status:

Completed

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Study of <span class="go-doc-concept go-doc-intervention">WNT974</span> in Combination With <span class="go-doc-concept go-doc-intervention">LGX818</span> and <span class="go-doc-concept go-doc-intervention">Cetuximab</span> in Patients With <span class="go-doc-concept go-doc-biomarker">BRAF</span>-<span class="go-doc-concept go-doc-keyword">mutant</span> Metastatic <span class="go-doc-concept go-doc-disease">Colorectal Cancer</span> (mCRC) and Wnt Pathway <span class="go-doc-concept go-doc-keyword">Mutations</span>

Title

  • 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
  • Clinical Trial IDs

    NCT ID: NCT02278133

    ORG ID: CWNT974X2102C

    Trial Conditions

    Metastatic Colorectal Cancer

    Trial Interventions

    Drug Synonyms Arms
    WNT974 WNT974, LGX818 and cetuximab combo
    LGX818 WNT974, LGX818 and cetuximab combo

    Trial Purpose

    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.

    Detailed Description

    Trial Arms

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

    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

    Minimum Eligible Age: 18 Years

    Maximum Eligible Age: N/A

    Eligible Gender: Both

    Primary Outcome Measures

    Incidence of Dose Limiting Toxicities and exposure (AUC C1D15) to WNT974 and LGX818 (phase lb)

    Overall response rate in phase II

    Secondary Outcome Measures

    Overall response rate (ORR) (phase lb)

    Overall survival (OS) (phase lb/ll)

    Duration of response (DOR) (phase lb/ll)

    Time to response (TTR) (phase lb/ll)

    Progression free survival (PFS) (phase lb/ll)

    Disease control rate (DCR) (phase lb/ll)

    Plasma concentration of WNT974, LHA333, LGX818 (phase lb/ll)

    Number of participants with Adverse Events as a measure of safety and tolerability (phase lb/ll)

    Number of participants with Serious Adverse Events as a measure of safety and tolerability(phase lb/ll)

    Biomarker activations for WNT and RTK-MAPK pathways (phase Ib/II)

    Number of participants with dose interruptions and dose reductions (phase Ib/II)

    Trial Keywords

    metastatic,

    Colorectal cancer,

    WNT974,

    LGX818,

    cetuximab,

    BRAF-mutant,

    mCRC,

    BRAFV600-mutant,

    KRAS