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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02278133
Recruitment Status : Completed
First Posted : October 29, 2014
Last Update Posted : October 9, 2017
Sponsor:
Information provided by (Responsible Party):
Array BioPharma

Tracking Information
First Submitted Date  ICMJE October 6, 2014
First Posted Date  ICMJE October 29, 2014
Last Update Posted Date October 9, 2017
Study Start Date  ICMJE December 2014
Actual Primary Completion Date May 31, 2016   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 27, 2014)
  • 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
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: October 27, 2014)
  • Overall response rate (ORR) (phase lb) [ Time Frame: 36 months ]
    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) [ Time Frame: 36 months ]
    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) [ Time Frame: 36 months ]
    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) [ Time Frame: 36 months ]
    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) [ Time Frame: 36 months ]
    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) [ Time Frame: 36 months ]
    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) [ Time Frame: 30 months ]
    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) [ Time Frame: 30 months ]
    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) [ Time Frame: 30 months ]
    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) [ Time Frame: 32 months ]
    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) [ Time Frame: 30 months ]
    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
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Study of WNT974 in Combination With LGX818 and Cetuximab in Patients With BRAF-mutant Metastatic Colorectal Cancer (mCRC) and Wnt Pathway Mutations
Official Title  ICMJE 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
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.

Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Metastatic Colorectal Cancer
Intervention  ICMJE
  • Drug: WNT974
  • Drug: LGX818
  • Biological: Cetuximab
Study Arms  ICMJE Experimental: WNT974, LGX818 and cetuximab combo
Phase l: Dose Escalation phase; Phase ll: SIngle group assessing the triple combination of WNT974, LGX818 and cetuximab
Interventions:
  • Drug: WNT974
  • Drug: LGX818
  • Biological: Cetuximab
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: October 3, 2017)
20
Original Estimated Enrollment  ICMJE
 (submitted: October 27, 2014)
60
Actual Study Completion Date  ICMJE June 23, 2017
Actual Primary Completion Date May 31, 2016   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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

Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Australia,   Belgium,   Canada,   France,   Israel,   Italy,   Netherlands,   Singapore,   Spain,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02278133
Other Study ID Numbers  ICMJE CWNT974X2102C
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Array BioPharma
Study Sponsor  ICMJE Array BioPharma
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Clinical Trial Call Center Array BioPharma, Inc.
PRS Account Array BioPharma
Verification Date October 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP