BRAF Mutant Colorectal Cancer, Cervical Squamous Cell Cancer, Esophageal Squamous Cell Cancer, Head and Neck Squamous Cell Cancer, Lung Squamous Cell Cancer, Melanoma, Pancreatic Cancer, Triple Negative Breast Cancer
Conditions
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
Brief summary
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.
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.
Interventions
DRUGLGK974
BIOLOGICALPDR001
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 | 28 days (LGK974 single agent) and 56 days (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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Type and category of study drug related adverse events (AE) | 61 months | 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 | 61 months | 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 | 61 months | Assessing percent change from baseline to post-treatment of PD related to the Wnt pathway. |
| Overall response rate of tumor | 61 months | 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 | 61 months | Evaluate pharmacokinetic (PK) parameters such as AUClast, AUCtau, Cmax, the apparent elimination T1/2 and Racc for LGK974, its pharmacologically metabolite and PDR001. |
Countries
Canada, France, Germany, Italy, Netherlands, Spain, United States
Outcome results
None listed