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

Primary Purpose

Pancreatic Cancer, BRAF Mutant Colorectal Cancer, Melanoma

Status
Active
Phase
Phase 1
Locations
International
Study Type
Interventional
Intervention
LGK974
PDR001
Sponsored by
Novartis Pharmaceuticals
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Pancreatic Cancer focused on measuring 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

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • UCLA School of Medicine
  • Sidney Kimmel Comprehensive Cancer Center Johns Hopkins
  • Dana Farber Cancer Institute SC-7
  • University of Michigan Comprehensive Cancer Center Onc Dept.
  • Karmanos Cancer Institute Wayne St
  • University of Texas/MD Anderson Cancer Center MD Anderson 2
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

LGK974

LGK974 in combination with PDR001

Arm Description

LGK974

LGK in combination with PDR001

Outcomes

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
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)
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.
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.
PD related to the Wnt pathway
Assessing percent change from baseline to post-treatment of PD related to the Wnt pathway.
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.
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.

Full Information

First Posted
May 4, 2011
Last Updated
October 16, 2023
Sponsor
Novartis Pharmaceuticals
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1. Study Identification

Unique Protocol Identification Number
NCT01351103
Brief Title
A Study of LGK974 in Patients With Malignancies Dependent on Wnt Ligands
Official Title
A Phase I, Open-label, Dose Escalation Study of Oral LGK974 in Patients With Malignancies Dependent on Wnt Ligands
Study Type
Interventional

2. Study Status

Record Verification Date
October 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
December 1, 2011 (Actual)
Primary Completion Date
June 14, 2021 (Actual)
Study Completion Date
June 28, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Novartis Pharmaceuticals

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

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
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
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
Keywords
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

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
185 (Actual)

8. Arms, Groups, and Interventions

Arm Title
LGK974
Arm Type
Experimental
Arm Description
LGK974
Arm Title
LGK974 in combination with PDR001
Arm Type
Experimental
Arm Description
LGK in combination with PDR001
Intervention Type
Drug
Intervention Name(s)
LGK974
Other Intervention Name(s)
WNT974
Intervention Type
Biological
Intervention Name(s)
PDR001
Primary Outcome Measure Information:
Title
Maximum Tolerated Dose or Recommended Dose for Expansion of LGK974 as a single agent or in combination with PDR001 in patients treated
Description
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.
Time Frame
34 months
Secondary Outcome Measure Information:
Title
Type and category of study drug related adverse events (AE)
Description
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.
Time Frame
61 months
Title
Absorption and plasma concentrations of LGK974
Description
Evaluate pharmacokinetic (PK) parameters such as AUClast, AUCtau, Cmax, the apparent elimination T1/2 and Racc for LGK974 and its pharmacologically metabolite.
Time Frame
61 months
Title
PD related to the Wnt pathway
Description
Assessing percent change from baseline to post-treatment of PD related to the Wnt pathway.
Time Frame
61 months
Title
Overall response rate of tumor
Description
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.
Time Frame
61 months
Title
Absorportion and plasma concentrations of PDR001
Description
Evaluate pharmacokinetic (PK) parameters such as AUClast, AUCtau, Cmax, the apparent elimination T1/2 and Racc for LGK974, its pharmacologically metabolite and PDR001.
Time Frame
61 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Novartis Pharmaceuticals
Organizational Affiliation
Novartis Pharmaceuticals
Official's Role
Study Director
Facility Information:
Facility Name
UCLA School of Medicine
City
Los Angeles
State/Province
California
ZIP/Postal Code
90024
Country
United States
Facility Name
Sidney Kimmel Comprehensive Cancer Center Johns Hopkins
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21287-0013
Country
United States
Facility Name
Dana Farber Cancer Institute SC-7
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02215
Country
United States
Facility Name
University of Michigan Comprehensive Cancer Center Onc Dept.
City
Ann Arbor
State/Province
Michigan
ZIP/Postal Code
48109-0944
Country
United States
Facility Name
Karmanos Cancer Institute Wayne St
City
Detroit
State/Province
Michigan
ZIP/Postal Code
48201
Country
United States
Facility Name
University of Texas/MD Anderson Cancer Center MD Anderson 2
City
Houston
State/Province
Texas
ZIP/Postal Code
77030-4009
Country
United States
Facility Name
Novartis Investigative Site
City
Montreal
State/Province
Quebec
ZIP/Postal Code
H2W 1T8
Country
Canada
Facility Name
Novartis Investigative Site
City
Villejuif
ZIP/Postal Code
94800
Country
France
Facility Name
Novartis Investigative Site
City
Essen
ZIP/Postal Code
45147
Country
Germany
Facility Name
Novartis Investigative Site
City
Milano
State/Province
MI
ZIP/Postal Code
20133
Country
Italy
Facility Name
Novartis Investigative Site
City
Napoli
ZIP/Postal Code
80131
Country
Italy
Facility Name
Novartis Investigative Site
City
Rotterdam
ZIP/Postal Code
3075 EA
Country
Netherlands
Facility Name
Novartis Investigative Site
City
Utrecht
ZIP/Postal Code
3584CX
Country
Netherlands
Facility Name
Novartis Investigative Site
City
Barcelona
State/Province
Catalunya
ZIP/Postal Code
08035
Country
Spain
Facility Name
Novartis Investigative Site
City
Barcelona
State/Province
Catalunya
ZIP/Postal Code
08036
Country
Spain
Facility Name
Novartis Investigative Site
City
Hospitalet de LLobregat
State/Province
Catalunya
ZIP/Postal Code
08907
Country
Spain
Facility Name
Novartis Investigative Site
City
Valencia
State/Province
Comunidad Valenciana
ZIP/Postal Code
46010
Country
Spain
Facility Name
Novartis Investigative Site
City
Madrid
ZIP/Postal Code
28009
Country
Spain
Facility Name
Novartis Investigative Site
City
Madrid
ZIP/Postal Code
28040
Country
Spain
Facility Name
Novartis Investigative Site
City
Madrid
ZIP/Postal Code
28050
Country
Spain

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
33941878
Citation
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.
Results Reference
derived

Learn more about this trial

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

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