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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

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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

Study Description
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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.


Condition or disease Intervention/treatment Phase
Metastatic Colorectal Cancer Drug: WNT974 Drug: LGX818 Biological: Cetuximab Phase 1 Phase 2

Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 20 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Study Start Date : December 2014
Actual Primary Completion Date : May 31, 2016
Actual Study Completion Date : June 23, 2017

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Arms and Interventions
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Arm Intervention/treatment
Experimental: WNT974, LGX818 and cetuximab combo
Phase l: Dose Escalation phase; Phase ll: SIngle group assessing the triple combination of WNT974, LGX818 and cetuximab
 Drug: WNT974
Drug: LGX818
Biological: Cetuximab


Outcome Measures
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Primary Outcome Measures :
  1. 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.

  2. 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


Secondary Outcome Measures :
  1. 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.

  2. 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.

  3. 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.

  4. 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.

  5. 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.

  6. 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.

  7. 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

  8. 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

  9. 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

  10. 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

  11. 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


Eligibility Criteria
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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02278133


Locations
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United States, New York
Memorial Sloan-Kettering Cancer Center (MSKCC) MSKCC (3)
New York, New York, United States, 10065
United States, South Carolina
Medical University of South Carolina Oncology Dept
Charleston, South Carolina, United States, 29425
United States, Texas
University of Texas/MD Anderson Cancer Center Onc. Dept,
Houston, Texas, United States, 77030-4009
United States, Wisconsin
University of Wisconsin / Paul P. Carbone Comp Cancer Center Univ Wisc
Madison, Wisconsin, United States, 53792-6164
Australia, Victoria
Array BioPharma Investigative Site
Parkville, Victoria, Australia, 3050
Belgium
Array BioPharma Investigative Site
Leuven, Belgium, 3000
Canada, Alberta
Array BioPharma Investigative Site
Edmonton, Alberta, Canada, T6G 1Z2
Canada, British Columbia
Array BioPharma Investigative Site
Vancouver, British Columbia, Canada, V5Z 4E6
Canada, Ontario
Array BioPharma Investigative Site
Toronto, Ontario, Canada, M5G 2M9
France
Array BioPharma Investigative Site
Bordeaux, France, 33076
Array BioPharma Investigative Site
Marseille, France, 13273
Israel
Array BioPharma Investigative Site
Tel-Aviv, Israel, 6423906
Italy
Array BioPharma Investigative Site
Milano, MI, Italy, 20133
Netherlands
Array BioPharma Investigative Site
Amsterdam, Netherlands, 1066 CX
Singapore
Array BioPharma Investigative Site
Singapore, Singapore, 169610
Spain
Array BioPharma Investigative Site
Barcelona, Catalunya, Spain, 08035
Array BioPharma Investigative Site
Hospitalet de LLobregat, Catalunya, Spain, 08907
Array BioPharma Investigative Site
Madrid, Spain, 28041
Array BioPharma Investigative Site
Madrid, Spain, 28050
Sponsors and Collaborators
Array BioPharma
Investigators
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Study Director: Clinical Trial Call Center Array BioPharma, Inc.
More Information
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Responsible Party: Array BioPharma
ClinicalTrials.gov Identifier: NCT02278133    
Other Study ID Numbers: CWNT974X2102C
First Posted: October 29, 2014    Key Record Dates
Last Update Posted: October 9, 2017
Last Verified: October 2017
Keywords provided by Array BioPharma:
metastatic,
Colorectal cancer,
WNT974,
LGX818,
cetuximab,
 BRAF-mutant,
mCRC,
BRAFV600-mutant,
KRAS
Additional relevant MeSH terms:
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Colorectal Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
 Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases
Cetuximab
Antineoplastic Agents, Immunological
Antineoplastic Agents