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

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. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT01351103
Recruitment Status : Recruiting
First Posted : May 10, 2011
Last Update Posted : May 5, 2021
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
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 Drug: LGK974 Biological: PDR001 Phase 1

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 184 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I, Open-label, Dose Escalation Study of Oral LGK974 in Patients With Malignancies Dependent on Wnt Ligands
Actual Study Start Date : December 1, 2011
Estimated Primary Completion Date : November 4, 2022
Estimated Study Completion Date : November 4, 2022

Arm Intervention/treatment
Experimental: LGK974 Drug: LGK974
Other Name: WNT974

Experimental: LGK974 in combination with PDR001 Drug: LGK974
Other Name: WNT974

Biological: PDR001

Primary Outcome Measures :
  1. 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 ]
    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 :
  1. Type and category of study drug related adverse events (AE) [ Time Frame: 61 months ]
    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.

  2. Absorption and plasma concentrations of LGK974 [ Time Frame: 61 months ]
    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.

  3. Biomarkers related to the Wnt pathway [ Time Frame: 61 months ]
    Assessing percent change from baseline to post-treatment of biomarkers related to the Wnt pathway.

  4. Overall response rate of tumor [ Time Frame: 61 months ]
    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.

  5. Absorportion and plasma concentrations of PDR001 [ Time Frame: 61 months ]
    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..

  6. Biomarkers related to immunomodulation [ Time Frame: 61 months ]
    Evaluate biomarkers of immunomodulation after treatment with LGK974 and PDR001.

Information from the National Library of Medicine

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

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

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 identifier (NCT number): NCT01351103

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Contact: Novartis Pharmaceuticals 1-888-669-6682
Contact: Novartis Pharmaceuticals +41613241111

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United States, California
UCLA School of Medicine Recruiting
Los Angeles, California, United States, 90024
Contact: Elizabeth O Laco    310-794-0738   
Principal Investigator: Antoni Ribas         
United States, Maryland
Sidney Kimmel Comprehensive Cancer Center Johns Hopkins Recruiting
Baltimore, Maryland, United States, 21287-0013
Contact: Christina Raynor    410-502-2377   
Principal Investigator: Patrick Forde         
United States, Massachusetts
Dana Farber Cancer Institute SC Withdrawn
Boston, Massachusetts, United States, 02115
Dana Farber Cancer Institute SC-7 Recruiting
Boston, Massachusetts, United States, 02215
Contact: Marios Giannakis, M.D., Ph.D.    617-632-6805   
Principal Investigator: Marios Giannakis, M.D., Ph.D.         
United States, Michigan
University of Michigan Comprehensive Cancer Center Onc Dept. Completed
Ann Arbor, Michigan, United States, 48109-0944
Karmanos Cancer Institute Wayne St Recruiting
Detroit, Michigan, United States, 48201
Contact: Tina Guthrie   
Principal Investigator: Misako Nagasaka         
United States, New York
Columbia University Medical Center Recruiting
New York, New York, United States, 10032
Contact: Swathi Balaji    212-304-5548   
Principal Investigator: Richard Carvajal         
United States, Texas
University of Texas/MD Anderson Cancer Center MD Anderson 2 Recruiting
Houston, Texas, United States, 77030-4009
Contact: Stepanek M. Vanda    713-792-2921   
Principal Investigator: Filip P. Janku         
Novartis Investigative Site Recruiting
Rotterdam, Netherlands, 3075 EA
Novartis Investigative Site Recruiting
Utrecht, Netherlands, 3584CX
Novartis Investigative Site Recruiting
Barcelona, Catalunya, Spain, 08035
Novartis Investigative Site Recruiting
Barcelona, Catalunya, Spain, 08036
Novartis Investigative Site Recruiting
Hospitalet de LLobregat, Catalunya, Spain, 08907
Novartis Investigative Site Recruiting
Valencia, Comunidad Valenciana, Spain, 46010
Novartis Investigative Site Recruiting
Madrid, Spain, 28009
Novartis Investigative Site Recruiting
Madrid, Spain, 28040
Novartis Investigative Site Recruiting
Madrid, Spain, 28050
Sponsors and Collaborators
Novartis Pharmaceuticals
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Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
Publications automatically indexed to this study by Identifier (NCT Number):
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Responsible Party: Novartis Pharmaceuticals Identifier: NCT01351103    
Other Study ID Numbers: CLGK974X2101
2011-000495-33 ( EudraCT Number )
First Posted: May 10, 2011    Key Record Dates
Last Update Posted: May 5, 2021
Last Verified: May 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Novartis ( Novartis Pharmaceuticals ):
pancreatic adenocarcinoma
BRAF mutant colorectal cancer
RNF43 mutation
RSPO fusion
triple negative breast cancer
head and neck scc
cervical scc
esophageal scc
lung scc
Additional relevant MeSH terms:
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Colorectal Neoplasms
Triple Negative Breast Neoplasms
Neoplasms, Squamous Cell
Carcinoma, Squamous Cell
Esophageal Squamous Cell Carcinoma
Breast Neoplasms
Neoplasms by Site
Breast Diseases
Skin Diseases
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms, Nerve Tissue
Nevi and Melanomas
Neoplasms, Glandular and Epithelial
Esophageal Neoplasms
Head and Neck Neoplasms
Esophageal Diseases