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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. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01351103
Recruitment Status : Active, not recruiting
First Posted : May 10, 2011
Last Update Posted : March 15, 2024
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Study Description
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Brief Summary:
The 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 that have progressed despite standard therapy or for which no effective standard therapy exists

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

Detailed Description:

This open-label multicenter phase 1 dose escalation study will be the first to administer LGK974 as a single agent or in combination with PDR001 in humans.

The study will comprise of 2 parts: a dose escalation of LGK974 as a single agent, followed by a safety expansion in specific disease indications; and a dose escalation of LGK974 in combination with PDR001, followed by a safety expansion in cutaneous melanoma.

Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 185 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
Actual Primary Completion Date : June 14, 2021
Estimated Study Completion Date : June 18, 2024

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: LGK974
LGK974
 Drug: LGK974
Other Name: WNT974
Experimental: LGK974 in combination with PDR001
LGK in combination with PDR001
 Drug: LGK974
Other Name: WNT974

Biological: PDR001


Outcome Measures
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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.

  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.

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


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:

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:

  • cutaneous melanoma that was primary refractory to prior anti-PD-1 therapy, defined as a best response of progressive disease or stable disease for <= 4 months, or disease recurrence with the first 6 months of adjuvant therapy. Patients with BRAF V600-mutant melanoma must have also received and been failed by prior systemic therapy with BRAF V600 inhibitor, with or without a MEK inhibitor.
  • Cutaneous melanoma with acquired resistance to prior anti-PD-1 therapy, defined as progressive disease following response (PR or CR) or following stable disease for > 4 months. Patients with BRAF V600-mutant melanoma must have also received and been failed by prior systemic therapy with a BRAF V600 inhibitor, with or without a MEK inhibitor.

Exclusion Criteria:

  • Impaired cardiac function
  • Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of 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, 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

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): NCT01351103


Locations
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United States, California
UCLA School of Medicine
Los Angeles, California, United States, 90024
United States, Maryland
Sidney Kimmel Comprehensive Cancer Center Johns Hopkins
Baltimore, Maryland, United States, 21287-0013
United States, Massachusetts
Dana Farber Cancer Institute SC-7
Boston, Massachusetts, United States, 02215
United States, Michigan
University of Michigan Comprehensive Cancer Center Onc Dept.
Ann Arbor, Michigan, United States, 48109-0944
Karmanos Cancer Institute Wayne St
Detroit, Michigan, United States, 48201
United States, Texas
University of Texas/MD Anderson Cancer Center MD Anderson 2
Houston, Texas, United States, 77030-4009
Canada, Quebec
Novartis Investigative Site
Montreal, Quebec, Canada, H2W 1T8
France
Novartis Investigative Site
Villejuif, France, 94800
Germany
Novartis Investigative Site
Essen, Germany, 45147
Italy
Novartis Investigative Site
Milano, MI, Italy, 20133
Novartis Investigative Site
Napoli, Italy, 80131
Netherlands
Novartis Investigative Site
Rotterdam, Netherlands, 3075 EA
Novartis Investigative Site
Utrecht, Netherlands, 3584CX
Spain
Novartis Investigative Site
Barcelona, Catalunya, Spain, 08035
Novartis Investigative Site
Barcelona, Catalunya, Spain, 08036
Novartis Investigative Site
Hospitalet de LLobregat, Catalunya, Spain, 08907
Novartis Investigative Site
Valencia, Comunidad Valenciana, Spain, 46010
Novartis Investigative Site
Madrid, Spain, 28009
Novartis Investigative Site
Madrid, Spain, 28040
Novartis Investigative Site
Madrid, Spain, 28050
Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
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Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
More Information
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Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: Novartis Pharmaceuticals
ClinicalTrials.gov Identifier: NCT01351103    
Other Study ID Numbers: CLGK974X2101
2011-000495-33 ( EudraCT Number )
First Posted: May 10, 2011    Key Record Dates
Last Update Posted: March 15, 2024
Last Verified: March 2024
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 ):
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
Additional relevant MeSH terms:
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Colorectal Neoplasms
Melanoma
Triple Negative Breast Neoplasms
Neoplasms, Squamous Cell
Carcinoma, Squamous Cell
Esophageal Squamous Cell Carcinoma
Breast Neoplasms
Neoplasms by Site
Neoplasms
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
Skin Neoplasms
Neoplasms, Glandular and Epithelial
Carcinoma
Esophageal Neoplasms
Head and Neck Neoplasms