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

This study is currently recruiting participants. (see Contacts and Locations)
Verified February 2017 by Novartis
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier:
NCT01351103
First received: May 4, 2011
Last updated: February 24, 2017
Last verified: February 2017
  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.

Condition Intervention Phase
Pancreatic Cancer
BRAF Mutant Colorectal Cancer
Other Tumor Types With Documented Genetic Alterations Upstream in the Wnt Signaling Pathway
Melanoma
Triple Negative Breast Cancer
Head and Neck Cancer
Drug: LGK974
Biological: PDR001
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: No masking
Primary Purpose: Treatment
Official Title: A Phase I, Open-label, Dose Escalation Study of Oral LGK974 in Patients With Malignancies Dependent on Wnt Ligands

Resource links provided by NLM:


Further study details as provided by Novartis:

Primary Outcome Measures:
  • 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:
  • 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.

  • 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.

  • 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.

  • Overall response rate of tumor [ Time Frame: 61 months ]
    Patients with an Objective Overall Response (OOR) were those whose best response to treatment was a complete response (CR) or a partial response (PR) assessed by RECIST 1.1 or irRC . A patient had a CR if the target tumors disappeared. A patient had a PR if there was a ≥ 30% reduction in the sum of the products of the largest perpendicular diameters of the target tumors compared to the baseline value. Duration of Response (DOR) will also be summarized and is defined as the time from first observation of response to the first time of progression or death.

  • 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..

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


Estimated Enrollment: 170
Actual Study Start Date: December 1, 2011
Estimated Study Completion Date: January 10, 2020
Estimated Primary Completion Date: September 25, 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: LGK974 Drug: LGK974
Experimental: LGK974 in combination with PDR001 Biological: PDR001

  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
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: melanoma patients primary refractory to anti-PD-1 inhibitor. 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

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01351103

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

Locations
United States, Maryland
Sidney Kimmel Comprehensive Cancer Center Johns Hopkins Recruiting
Baltimore, Maryland, United States, 21287-0013
Contact: Ashley O'Connor    410-502-2377    aoconnor@jhmi.edu   
Principal Investigator: Roisin Connolly         
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: Eunice Kwak, M.D.    617-724-4000      
Principal Investigator: Marios Giannakis         
United States, Michigan
University of Michigan Comprehensive Cancer Center Onc Dept. Not yet recruiting
Ann Arbor, Michigan, United States, 48109-0944
Contact: Cancer AnswerLine    800-865-1125      
Principal Investigator: David Smith         
Karmanos Cancer Institute Wayne St Recruiting
Detroit, Michigan, United States, 48201
Contact: DeQuindalyn Moore    313-576-9371    moored@karmanos.org   
Principal Investigator: Ulka A. Vaishampayan         
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    vstepane@mdanderson.org   
Principal Investigator: Filip P. Janku         
Netherlands
Novartis Investigative Site Recruiting
Rotterdam, Netherlands, 3075 EA
Spain
Novartis Investigative Site Recruiting
Barcelona, Catalunya, Spain, 08035
Novartis Investigative Site Recruiting
Madrid, Spain, 28050
Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
  More Information

Responsible Party: Novartis Pharmaceuticals
ClinicalTrials.gov Identifier: NCT01351103     History of Changes
Other Study ID Numbers: CLGK974X2101
2011-000495-33 ( EudraCT Number )
Study First Received: May 4, 2011
Last Updated: February 24, 2017

Keywords provided by Novartis:
LGK974
pancreatic adenocarcinoma
BRAF mutant colorectal cancer
other tumor types with documented genetic alterations upstream in the Wnt signaling pathway
RNF43 mutation
RSPO fusion
melanoma
triple negative breast cancer
PDR001
immunotherapy
head and neck cancer

Additional relevant MeSH terms:
Melanoma
Colorectal Neoplasms
Pancreatic Neoplasms
Head and Neck Neoplasms
Triple Negative Breast Neoplasms
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Nerve Tissue
Nevi and Melanomas
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases
Endocrine Gland Neoplasms
Pancreatic Diseases
Endocrine System Diseases
Breast Neoplasms
Breast Diseases
Skin Diseases

ClinicalTrials.gov processed this record on March 23, 2017