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

Pancreatic Cancer Clinical Trial

Official title:

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT01351103
• Other study ID #: CLGK974X2101
• Secondary ID: 2011-000495-33
• Status: Active, not recruiting
• Phase: Phase 1
• Start date: December 1, 2011
• Est. completion date: June 18, 2024

Study information

• Verified date: May 2024
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 185
• Est. completion date: June 18, 2024
• Est. primary completion date: June 14, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• BRAF Mutant Colorectal Cancer
• Carcinoma, Squamous Cell
• Cervical Squamous Cell Cancer
• Colorectal Neoplasms
• Esophageal Squamous Cell Cancer
• Esophageal Squamous Cell Carcinoma
• Head and Neck Squamous Cell Cancer
• Lung Squamous Cell Cancer
• Melanoma
• Neoplasms, Squamous Cell
• Pancreatic Cancer
• Triple Negative Breast Cancer
• Triple Negative Breast Neoplasms

Intervention

Drug:
• LGK974

Biological:
• PDR001

Locations

Country	Name	City	State
Canada	Novartis Investigative Site	Montreal	Quebec
France	Novartis Investigative Site	Villejuif
Germany	Novartis Investigative Site	Essen
Italy	Novartis Investigative Site	Milano	MI
Italy	Novartis Investigative Site	Napoli
Netherlands	Novartis Investigative Site	Rotterdam
Netherlands	Novartis Investigative Site	Utrecht
Spain	Novartis Investigative Site	Barcelona	Catalunya
Spain	Novartis Investigative Site	Barcelona	Catalunya
Spain	Novartis Investigative Site	Hospitalet de LLobregat	Catalunya
Spain	Novartis Investigative Site	Madrid
Spain	Novartis Investigative Site	Madrid
Spain	Novartis Investigative Site	Madrid
Spain	Novartis Investigative Site	Valencia	Comunidad Valenciana
United States	University of Michigan Comprehensive Cancer Center Onc Dept.	Ann Arbor	Michigan
United States	Sidney Kimmel Comprehensive Cancer Center Johns Hopkins	Baltimore	Maryland
United States	Dana Farber Cancer Institute SC-7	Boston	Massachusetts
United States	Karmanos Cancer Institute Wayne St	Detroit	Michigan
United States	University of Texas/MD Anderson Cancer Center MD Anderson 2	Houston	Texas
United States	UCLA School of Medicine	Los Angeles	California

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Countries where clinical trial is conducted

United States,  Canada,  France,  Germany,  Italy,  Netherlands,  Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Maximum Tolerated Dose or Recommended Dose for Expansion of LGK974 as a single agent or in combination with PDR001 in patients treated	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.	34 months
Secondary	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
Secondary	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
Secondary	PD related to the Wnt pathway	Assessing percent change from baseline to post-treatment of PD related to the Wnt pathway.	61 months
Secondary	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
Secondary	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