Description:
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.
Title
- 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
Clinical Trial IDs
- ORG STUDY ID:
CLGK974X2101
- SECONDARY ID:
2011-000495-33
- NCT ID:
NCT01351103
Conditions
- 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
Interventions
Drug | Synonyms | Arms |
---|
LGK974 | WNT974 | LGK974 |
PDR001 | | LGK974 in combination with PDR001 |
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.
Trial Arms
Name | Type | Description | Interventions |
---|
LGK974 | Experimental | | |
LGK974 in combination with PDR001 | Experimental | | |
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 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
Maximum Eligible Age: | N/A |
Minimum Eligible Age: | 18 Years |
Eligible Gender: | All |
Healthy Volunteers: | No |
Primary Outcome Measures
Measure: | 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 |
Safety Issue: | |
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. |
Secondary Outcome Measures
Measure: | Type and category of study drug related adverse events (AE) |
Time Frame: | 61 months |
Safety Issue: | |
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. 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. |
Measure: | Absorption and plasma concentrations of LGK974 |
Time Frame: | 61 months |
Safety Issue: | |
Description: | 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. |
Measure: | Biomarkers related to the Wnt pathway |
Time Frame: | 61 months |
Safety Issue: | |
Description: | Assessing percent change from baseline to post-treatment of biomarkers related to the Wnt pathway. |
Measure: | Overall response rate of tumor |
Time Frame: | 61 months |
Safety Issue: | |
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. |
Measure: | Absorportion and plasma concentrations of PDR001 |
Time Frame: | 61 months |
Safety Issue: | |
Description: | 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.. |
Measure: | Biomarkers related to immunomodulation |
Time Frame: | 61 months |
Safety Issue: | |
Description: | Evaluate biomarkers of immunomodulation after treatment with LGK974 and PDR001. |
Details
Phase: | Phase 1 |
Primary Purpose: | Interventional |
Overall Status: | Recruiting |
Lead Sponsor: | Novartis Pharmaceuticals |
Trial 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
Last Updated
July 27, 2021