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

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

The primary purpose of this study was 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 had progressed despite standard therapy or for which no effective standard therapy existed.

Study Overview

• Status: Completed
• Conditions: Melanoma; Pancreatic Cancer; Triple Negative Breast Cancer; Head and Neck Squamous Cell Cancer; Esophageal Squamous Cell Cancer; BRAF Mutant Colorectal Cancer; Cervical Squamous Cell Cancer; Lung Squamous Cell Cancer
• Intervention / Treatment: Drug: LGK974; Biological: PDR001

Detailed Description

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

The study comprised 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 Type: Interventional
• Enrollment (Actual): 185
• Phase: Phase 1

Contacts and Locations

Study Locations

• Canada
  • Quebec
    • Montreal, Quebec, Canada, H2W 1T8
      • Novartis Investigative Site
• France
  • Villejuif, France, 94800
    • Novartis Investigative Site
• Germany
  • Essen, Germany, 45147
    • Novartis Investigative Site
• Italy
  • Napoli, Italy, 80131
    • Novartis Investigative Site
  • MI
    • Milano, MI, Italy, 20133
      • Novartis Investigative Site
• Netherlands
  • Utrecht, Netherlands, 3584CX
    • Novartis Investigative Site
  • Zuid Holland
    • Rotterdam, Zuid Holland, Netherlands, 3015 GD
      • Novartis Investigative Site
• Spain
  • Madrid, Spain, 28050
    • Novartis Investigative Site
  • Madrid, Spain, 28040
    • Novartis Investigative Site
  • Madrid, Spain, 28009
    • Novartis Investigative Site
  • Catalunya
    • Barcelona, Catalunya, Spain, 08035
      • Novartis Investigative Site
    • Barcelona, Catalunya, Spain, 08036
      • Novartis Investigative Site
    • Hospitalet de LLobregat, Catalunya, Spain, 08907
      • Novartis Investigative Site
  • Comunidad Valenciana
    • Valencia, Comunidad Valenciana, Spain, 46010
      • Novartis Investigative Site
• United States
  • California
    • Los Angeles, California, United States, 90024
      • UCLA School of Medicine
  • Maryland
    • Baltimore, Maryland, United States, 21287-0013
      • Sidney Kimmel Comprehensive Cancer Center Johns Hopkins
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Dana Farber Cancer Institute SC-7
  • Michigan
    • Ann Arbor, Michigan, United States, 48109-0944
      • University of Michigan Comprehensive Cancer Center Onc Dept.
    • Detroit, Michigan, United States, 48201
      • Karmanos Cancer Institute Wayne St
  • Texas
    • Houston, Texas, United States, 77030-4009
      • University of Texas/MD Anderson Cancer Center MD Anderson 2

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: LGK974	Drug: LGK974; Other Names: WNT974
Experimental: LGK974 in combination with PDR001; LGK in combination with PDR001	Drug: LGK974; Other Names: WNT974; Biological: PDR001

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of dose limiting toxicities (DLTs) during the first cycle of LGK974 treatment and during the first 2 cycles of LGK974 in combination with PDR001	DLT is defined as an adverse event or abnormal laboratory value that is assessed by the investigator as unrelated to disease, disease progression, intercurrent illness, or concomitant medications and that meets the criteria defined in the study protocol. The objective was to 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.	28 days (LGK974 single agent) and 56 days (LGK974 in combination with PDR001)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Type and category of study drug related adverse events (AE)	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.	61 months
Absorption and plasma concentrations of LGK974	Evaluate pharmacokinetic (PK) parameters such as AUClast, AUCtau, Cmax, the apparent elimination T1/2 and Racc for LGK974 and its pharmacologically metabolite.	61 months
PD related to the Wnt pathway	Assessing percent change from baseline to post-treatment of PD related to the Wnt pathway.	61 months
Overall response rate of tumor	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.	61 months
Absorportion and plasma concentrations of PDR001	Evaluate pharmacokinetic (PK) parameters such as AUClast, AUCtau, Cmax, the apparent elimination T1/2 and Racc for LGK974, its pharmacologically metabolite and PDR001.	61 months

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals
• Investigators: Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Publications and helpful links

General Publications

• Rodon J, Argiles G, Connolly RM, Vaishampayan U, de Jonge M, Garralda E, Giannakis M, Smith DC, Dobson JR, McLaughlin ME, Seroutou A, Ji Y, Morawiak J, Moody SE, Janku F. Phase 1 study of single-agent WNT974, a first-in-class Porcupine inhibitor, in patients with advanced solid tumours. Br J Cancer. 2021 Jul;125(1):28-37. doi: 10.1038/s41416-021-01389-8. Epub 2021 May 3.

Helpful Links

• Link to Study Results

Study record dates

Study Major Dates

• Study Start (Actual): December 1, 2011
• Primary Completion (Actual): June 1, 2021
• Study Completion (Actual): June 17, 2024

Study Registration Dates

• First Submitted: May 4, 2011
• First Submitted That Met QC Criteria: May 9, 2011
• First Posted (Estimated): May 10, 2011

Study Record Updates

• Last Update Posted (Actual): June 13, 2025
• Last Update Submitted That Met QC Criteria: June 10, 2025
• Last Verified: June 1, 2025

More Information

Terms related to this study

• Keywords: immunotherapy; pancreatic adenocarcinoma; melanoma; PDR001; triple negative breast cancer; LGK974; BRAF mutant colorectal cancer; RNF43 mutation; RSPO fusion; head and neck scc; cervical scc; esophageal scc; lung scc
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Intestinal Diseases; Neoplasms by Histologic Type; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Head and Neck Neoplasms; Neoplasms, Glandular and Epithelial; Colonic Diseases; Esophageal Diseases; Skin Diseases; Breast Diseases; Carcinoma; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroendocrine Tumors; Nevi and Melanomas; Skin Neoplasms; Esophageal Neoplasms; Breast Neoplasms; Esophageal Squamous Cell Carcinoma; Colorectal Neoplasms; Carcinoma, Squamous Cell; Melanoma; Triple Negative Breast Neoplasms; Neoplasms, Squamous Cell; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Antineoplastic Agents; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Spartalizumab; LGK974
• Other Study ID Numbers: CLGK974X2101; 2011-000495-33 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No