A Study Of LGK974 In Patients With Malignancies Dependent On Wnt Ligands

Study Overview

A Study of 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.

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.

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

CLGK974X2101
2011-000495-33 (EUDRACT_NUMBER Identifier) (EUDRACT_NUMBER: )

Study Record Dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Registration Dates	Results Reporting Dates	Study Record Updates
First Submitted 2011-05-04	Results First Submitted N/A	Last Update Submitted that met QC Criteria 2024-09-06
First Submitted that Met QC Criteria 2011-05-09	Results First Submitted that Met QC Criteria N/A	Last Update Posted (ACTUAL) 2024-09-19
First Posted (ACTUAL) 2011-05-10	Results First Posted N/A	Last Verified 2024-08

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

Design Details

Primary Purpose:
Treatment

Allocation:
Non Randomized

Interventional Model:
Single Group

Masking:
None

Arms and Interventions

Participant Group/Arm	Intervention/Treatment
EXPERIMENTAL: LGK974 LGK974	DRUG: LGK974 BIOLOGICAL: PDR001
EXPERIMENTAL: LGK974 in combination with PDR001 LGK in combination with PDR001	DRUG: LGK974 BIOLOGICAL: PDR001

Participant Group/Arm

Intervention/Treatment

EXPERIMENTAL: LGK974

LGK974

DRUG: LGK974

BIOLOGICAL: PDR001

EXPERIMENTAL: LGK974 in combination with PDR001

LGK in combination with PDR001

DRUG: LGK974

BIOLOGICAL: PDR001

Primary Outcome Measures	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	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

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person’s general health condition or prior treatments.

Ages Eligible for Study:
ALL

Sexes Eligible for Study:
18 Years

Accepts Healthy Volunteers:

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.

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

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Investigators

STUDY_DIRECTOR: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Publications

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

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.

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Clinical Trial Record