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

NCT05435846 | Terminated Phase 1 DMC FDA Drug

• 2 other identifiers: 22653NCI-2022-04800
• Study Type: interventional
• Target: 3
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Metastatic Lung Non-Small Cell Carcinoma; Stage IV Lung Cancer

Keywords

MET exon 14 skipping mutation; Mutation Positive

Outcome Measures

Primary Outcomes (2)

• Proportion of participants with reported dose limiting toxicity (DLT) (Phase I)

  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).

  1 cycle (each cycle is 28 days)

• Proportion of participants with treatment-emergent adverse events (Phase Ib)

  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).

  Up to 12 months

Secondary Outcomes (5)

• Proportion of participants with treatment-emergent adverse events (Phase I)

  From initiation of study treatment until 30 days post-treatment discontinuation

• Overall Response Rate (ORR) (Phase Ib)

  Up to 12 months

• Mean Disease Control Rate (DCR) (Phase Ib)

  Up to 12 months

• Median Progression Free Survival (PFS) (Phase Ib)

  Up to 12 months

• Overall survival (OS) (Phase Ib)

  Up to 12 months

Study Arms (2)

Phase 1: Dose Escalation

EXPERIMENTAL

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.

Drug: Capmatinib; Drug: Trametinib

Phase 1b: Dose Expansion

EXPERIMENTAL

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.

Drug: Capmatinib; Drug: Trametinib

Interventions

Capmatinib DRUG

Given orally

Also known as: INC280

Phase 1: Dose Escalation; Phase 1b: Dose Expansion

Trametinib DRUG

Given orally

Also known as: TMT212, Mekinist

Phase 1: Dose Escalation; Phase 1b: Dose Expansion

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Participants must have histologically or cytologically confirmed, non-small cell lung cancer.
• Documented MET exon 14 skipping mutation by tumor DNA sequencing or cell-free DNA assay by Clinical Laboratory Improvement Act (CLIA) - approved laboratory AND previously received treatment with a MET inhibitor (capmatinib crizotinib, savolitinib, or tepotinib) with evidence of disease progression, in the opinion of the investigator.
• Note - MET inhibitor therapy is NOT required to be the most recent anti-cancer therapy. Prior treatment with platinum-based chemotherapy or anti-programmed cell death protein 1 (PD-1) /programmed death-ligand 1 (PD-L1) therapy (alone or in combination with chemotherapy) is allowed, but not required.
• \- or (For dose escalation only): MET amplification or fusion detected in tumor sample or cell-free DNA by next generation sequencing (NGS) or Fluorescent in situ hybridisation (FISH) by CLIA-approved laboratory AND prior treatment with a MET inhibitor (capmatinib crizotinib, savolitinib, or tepotinib) with at least 5 months of clinical benefit, followed by disease progression, in the opinion of the investigator.
• Archived tissue available or willingness to undergo new tumor biopsy.
• Measurable disease defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria.
• Life expectancy of at least 3 months.
• Age \>= 18 years.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 (Karnofsky) \> 60%.
• Resolution of all acute toxic effects (other than alopecia, or non-clinically significant lab abnormalities) of prior chemotherapy, targeted therapy, immunotherapy, radiotherapy, or surgical procedures to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0 grade 1.
• Absolute neutrophil count \>= 1,500/microliter (mcL)
• Platelets \>= 100,000/mcL
• Hemoglobin (Hgb) \>= 9 g/dl
• Total bilirubin within 1.2 X institutional upper limit of normal, unless elevated due to Gilbert's syndrome and direct bilirubin is within normal limits.
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase (SGOT)) =\< 3 X institutional upper limit of normal if no known liver metastases.

You may not qualify if:

• Known activating mutations or oncogenic fusions in Epithelial Growth Factor Receptor (EGFR), KRAS g12c, ALK, ROS1, Neurotrophic tyrosine receptor kinase (NTRK), BRAF V600E, or RET or known on-target MET mutations on residues D1228 or Y1230.
• Phase Ib patients enrolling into the dose expansion cohort must have previously tolerated the RP2D of capmatinib if they have received prior capmatinib treatment.
• Pregnant women are excluded from this study because capmatinib and trametinib are tyrosine kinase inhibitors (TKIs) with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with capmatinib and trametinib, breastfeeding should be discontinued if the mother is treated with capmatinib and trametinib.
• Patients who have received systemic anti-cancer therapies within the following time periods prior to the first dose of study drug: within 3 weeks of cytotoxic chemotherapy or antibody therapy, radiation within 2 weeks, targeted therapy within 7 days.
• Note: Concomitant administration of Luteinizing hormone-releasing hormone (LHRH) analogues for prostate cancer and somatostatin analogues for neuroendocrine tumors are allowed as per standard of care. Patients who are currently receiving and progressing on capmatinib monotherapy will be allowed to continue treatment without interruption
• History of interstitial lung disease or pneumonitis.
• Note: History of radiation pneumonitis not requiring steroids is allowed.
• Known Hepatitis B Virus (HBV), Hepatitis C Virus (HCV) infection, or human immunodeficiency virus (HIV) with inadequate CD4+ T cell counts or a history of acquired immunodeficiency syndrome (AIDS)-defining opportunistic infections.
• Note: Participants with laboratory evidence of cleared HBV and HCV infection will be permitted). Patients living with HIV, with adequate CD4+ T cell counts, and without a history of AIDS-defining opportunistic infections will be permitted.
• Known active COVID-19 infection.
• Note: Patients who have recovered from an infection and test negative for viral ribonucleic acid (RNA) will be allowed.
• History or evidence of cardiovascular risk including any of the following:
• Left ventricular ejection fraction (LVEF) \< lower limit of normal (LLN) by echocardiogram (ECHO) or multigated acquisition scan (MUGA).
• A QT interval corrected for heart rate using the Fridericia's formula (QTcF) 470 msec.
• History or evidence of current clinically significant uncontrolled arrhythmias.

Sponsors & Collaborators

• Collin Blakely: lead
• Novartis: collaborator

Study Sites (1)

University of California San Francisco

San Francisco, California, 94143, United States

Location

MeSH Terms

Conditions

Carcinoma, Non-Small-Cell Lung; Lung Neoplasms

Interventions

capmatinib; trametinib

Condition Hierarchy (Ancestors)

Carcinoma, Bronchogenic; Bronchial Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases

Study Officials

• Collin M Blakely, MD, PhD

  University of California, San Francisco

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: June 22, 2022
• First Posted: June 28, 2022
• Study Start: August 10, 2022
• Primary Completion: November 30, 2023
• Study Completion: May 31, 2024
• Last Updated: June 11, 2024

Record last verified: 2024-06

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)