Clinical Trials /

A Study of LGK974 in Patients With Malignancies Dependent on Wnt Ligands

NCT01351103

Description:

This primary purpose of this study is to find the recommended dose of LGK974 as a single agent and in combination with PDR001 that can be safely given to adult patients with selected solid malignancies for whom no effective standard treatment is available.

Related Conditions:
  • Breast Carcinoma
  • Cervical Squamous Cell Carcinoma
  • Colorectal Carcinoma
  • Esophageal Squamous Cell Carcinoma
  • Head and Neck Carcinoma
  • Head and Neck Squamous Cell Carcinoma
  • Malignant Solid Tumor
  • Melanoma
  • Pancreatic Adenocarcinoma
  • Pancreatic Carcinoma
  • Squamous Cell Lung Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: A Study of LGK974 in Patients With Malignancies Dependent on Wnt Ligands
  • Official Title: A Phase I, Open-label, Dose Escalation Study of Oral LGK974 in Patients With Malignancies Dependent on Wnt Ligands

Clinical Trial IDs

  • ORG STUDY ID: CLGK974X2101
  • SECONDARY ID: 2011-000495-33
  • NCT ID: NCT01351103

Conditions

  • Pancreatic Cancer
  • BRAF Mutant Colorectal Cancer
  • Melanoma
  • Triple Negative Breast Cancer
  • Head and Neck Squamous Cell Cancer
  • Cervical Squamous Cell Cancer
  • Esophageal Squamous Cell Cancer
  • Lung Squamous Cell Cancer

Interventions

DrugSynonymsArms
LGK974WNT974LGK974
PDR001LGK974 in combination with PDR001

Purpose

This primary purpose of this study is to find the recommended dose of LGK974 as a single agent and in combination with PDR001 that can be safely given to adult patients with selected solid malignancies for whom no effective standard treatment is available.

Trial Arms

NameTypeDescriptionInterventions
LGK974Experimental
  • LGK974
LGK974 in combination with PDR001Experimental
  • LGK974
  • PDR001

Eligibility Criteria

        Inclusion Criteria:

        Diagnosis of locally advanced or metastatic cancer that has progressed despite standard
        therapy or for which no effective standard therapy exists and histological confirmation of
        one of the following diseases indicated below:

        Single Agent Dose escalation part:documented B-RAF mutant colorectal cancer or pancreatic
        adenocarcinoma. In addition, tumors of any histological origin with documented genetic
        alterations upstream in the Wnt signaling pathway are eligible with prior agreement with
        Novartis.

        Single Agent Dose expansion part: documented B-RAF mutant colorectal cancer with documented
        RNF43 mutation and/or RSPO fusion or pancreatic adenocarcinoma with documented RNF43
        mutation. In addition, patients with tumors of any histological origin with documented
        genetic alterations upstream in the Wnt signaling pathway (e.g. RNF43 or RSPO fusion) are
        eligible with prior agreement with Novartis

        LGK974 with PDR001: Dose escalation: patients with the following cancers that were
        previously treated with anti-PD-1 therapy and whose best response on that therapy was
        progressive disease (i.e. primary refractory): melanoma, lung SCC, HNSCC. Patients with
        esophageal SCC, cervical SCC or TNBC who are either naïve or primary refractory to prior
        anti-PD-1 therapy.

        LGK974 with PDR001: Dose expansion: patients with pancreatic cancer, or TNBC, or melanoma,
        or head and neck cancer.

        Exclusion Criteria:

          -  Impaired cardiac function

          -  Impairment of gastrointestinal function or gastrointestinal disease that may
             significantly alter the absorption of oral LGK974 (e.g., ulcerative diseases,
             uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel
             resection)

          -  Brain metastases that have not been adequately treated

          -  Malignant disease other than that being treated in this study

          -  Laboratory abnormalities as specified in the protocol

          -  Osteoporosis, severe or untreated osteopenia

          -  Bone fractures within the past year

          -  Pathologic bone fracture

          -  Active, known or suspected autoimmune disease or severe hypersensitivity reactions to
             other monoclonal antibodies

        Other protocol-defined inclusion/exclusion criteria may apply
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum Tolerated Dose or Recommended Dose for Expansion of LGK974 as a single agent or in combination with PDR001 in patients treated
Time Frame:34 months
Safety Issue:
Description:Determine the Maximum Tolerated Dose (MTD) or Recommended Dose for Expansion (RDE) of LGK974 as a single agent and in combination with PDR001 when administered orally to adult patients with malignancies dependent on Wnt ligands.

Secondary Outcome Measures

Measure:Type and category of study drug related adverse events (AE)
Time Frame:61 months
Safety Issue:
Description:The incidence of treatment-emergent adverse events (new or worsening from baseline) will be summarized by primary system organ class, severity based on the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03, type of AE, relationship to study drug by dose group. Deaths reportable as SAEs and non-fatal serious adverse events will be listed by patient and tabulated by primary system organ clase, type of AE and dose group.
Measure:Absorption and plasma concentrations of LGK974
Time Frame:61 months
Safety Issue:
Description:Evaluate pharmacokinetic (PK) parameters such as AUClast, AUCtau, Cmax, the apparent elimination T1/2 and Racc for LGK974 and its pharmacologically metabolite. This will include but is not limited to the following timepoints: 8 times at C1D1; C1D2, C1D8, C1D16 and C1D22 pre-dose; 8 times at C1D15; and then pre-dose for each subsequent cycles D1.
Measure:Biomarkers related to the Wnt pathway
Time Frame:61 months
Safety Issue:
Description:Assessing percent change from baseline to post-treatment of biomarkers related to the Wnt pathway.
Measure:Overall response rate of tumor
Time Frame:61 months
Safety Issue:
Description:Patients with an Overall Response Rate(ORR), complete response (CR) or partial response (PR) rate and duration of response (DOR) assessed by RECIST 1.1 for single agent LGK974 and by RECIST1.1 and irRC for LGK974+PDR001.
Measure:Absorportion and plasma concentrations of PDR001
Time Frame:61 months
Safety Issue:
Description:Evaluate pharmacokinetic (PK) parameters such as AUClast, AUCtau, Cmax, the apparent elimination T1/2 and Racc for LGK974, its pharmacologically metabolite and PDR001. Serial timpoints will be obtained on C1D1 and within C1 dosing, pre-dose samples may also be obtained during study treatment..
Measure:Biomarkers related to immunomodulation
Time Frame:61 months
Safety Issue:
Description:Evaluate biomarkers of immunomodulation after treatment with LGK974 and PDR001.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Novartis Pharmaceuticals

Trial Keywords

  • LGK974
  • pancreatic adenocarcinoma
  • BRAF mutant colorectal cancer
  • RNF43 mutation
  • RSPO fusion
  • melanoma
  • triple negative breast cancer
  • PDR001
  • immunotherapy
  • head and neck scc
  • cervical scc
  • esophageal scc
  • lung scc

Last Updated