Neoplasms

Respiratory Tract (Lung and Bronchial) Diseases

All Conditions

Lung Neoplasms

Carcinoma, Non-Small-Cell Lung

Carcinoma

Respiratory Tract Neoplasms

Thoracic Neoplasms

Lung Diseases

Respiratory Tract Diseases

Carcinoma, Bronchogenic

Bronchial Neoplasms

Antineoplastic Agents

All Drugs and Chemicals

Trametinib

Protein Kinase Inhibitors

Enzyme Inhibitors

Patients receive 200 - 400 mg capmatinib orally, twice a day and 1.0 or 1.5 mg trametinib orally once a day on days 1-28 of each cycle. Cycles repeat every 28 days for 2 years in the absence of disease progression or unacceptable toxicity.

Patients will receive the recommended phase 2 dose (RP2D) or capmatinib in combination with trametinib determined by the safety profile of the Phase 1 group. Cycles repeat every 28 days for 2 years in the absence of disease progression or unacceptable toxicity.

Capmatinib

Lisa Tan

Collin M. Blakely, MD, PhD

Johnathan Riess, MD, MS

Collin M Blakely, MD, PhD

This phase I/Ib trial studies the side effects and best doses of capmatinib plus trametinib when given together for the treatment of patients with MET exon 14 skipping mutation non-small cell lung cancer that has spread to other places in the body (metastatic). Capmatinib is in a class of medications called kinase inhibitors. It works by blocking the action of an abnormal protein that signals cancer cells to multiply. This helps slow or stop the spread of cancer cells. Trametinib is in a class of medications called kinase inhibitors. It works by blocking the action of an abnormal protein that signals cancer cells to multiply. This helps stop the spread of cancer cells. Capmatinib and trametinib are "targeted therapies." These targeted therapies work by detecting and targeting a mutation in the MET gene. Giving Capmatinib and trametinib may kill more tumor cells in patients with metastatic non-small cell lung cancer.

PRIMARY OBJECTIVES:

I. To identify recommended phase II dose (RP2D) of capmatinib in combination with trametinib in non-small cell lung cancer (NSCLC) with MET 14 exon mutation, MET amplification, or MET fusion (Phase I).

II. To further characterize the safety profile of the RP2D of capmatinib in combination with trametinib in MET-exon14 mutated NSCLC (Phase Ib).

SECONDARY OBJECTIVES:

I. To further characterize the safety profile of the combination of capmatinib and trametinib in NSCLC with MET exon 14 mutation, MET amplification, or MET fusion (Phase I).

II. To determine preliminary efficacy ofcapmatinib in combination with trametinib in MET-exon14 mutated NSCLC (Phase Ib)

EXPLORATORY OBJECTIVES:

I. To evaluate the pharmacokinetics of capmatinib in combination with trametinib.

II. To identify biomarkers of response to capmatinib and trametinib. III. To identify mechanisms of resistance tocapmatinib and trametinib.

OUTLINE: This is a phase I dose-escalation study of capmatinib and trametinib followed by a phase Ib dose expansion study.

Patients receive capmatinib orally (PO) twice daily (BID) and trametinib PO once daily (QD) on days 1-28 of each cycle. Cycles repeat every 28 days for 2 years in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for up to 12 months.

Capmatinib Plus Trametinib for the Treatment of Metastatic Non-small Cell Lung Cancer With MET Exon 14 Skipping Mutation

A Multicenter Phase I/Ib Study of Capmatinib Plus Trametinib in Patients With Metastatic MET Exon 14 Skipping Mutation Positive NSCLC

Proportion of participants who experience a DLT for capmatinib in combination with trametinib in Phase I. A dose limiting toxicity (DLT) will be defined as any adverse event that are considered by the investigator to be at least possibly related to capmatinib or trametinib and are observed during the first 28 days of treatment (Cycle 1).

Proportion of participants with treatment-emergent Adverse Events, will be reported as preferred terms using Medical Dictionary for Regulatory Activities (MedDRA).as graded by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE version 5.0) in Phase Ib (Dose Expansion).

Proportion of participants with Adverse Events, as graded by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE version 5.0 in Phase Ib

The ORR is defined as the best overall response recorded from the start of the treatment until disease progression or recurrence assessed over a 1-year period from the start of treatment using RECIST version 1.1 criteria. The percentages of patients with a best overall response rate of complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD) will be determined.

DCR will be defined as the percentage of patients who have achieved CR, PR, or SD (based on RECIST 1.1 criteria) for at least 12 weeks. The mean DCR and the standard deviation of DCR will be summarized.

PFS will be calculated as 1+ the number of days from the first dose of study drugs to documented radiographic progression or death due to any cause. For patients who continue treatment post-progression, the date of radiographic progression will be used for PFS analysis. The Kaplan-Meier analysis will be used to calculate the median PFS with 95% confidence interval.

OS will be calculated as 1+ the number of days from the first dose of study drugs to death due to any cause. The Kaplan-Meier analysis will be used to calculate the median PFS with 95% confidence interval.

Spots Global Cancer Trial Database for mutation positive