CNS Dose Escalation/Expansion of Tepotinib in MET-driven NSCLC

NCT04739358 | Terminated Phase 1 DMC FDA Drug

• 1 other identifier: 01AT21-MET
• Study Type: interventional
• Target: 2
• Locations: 1 country
• Sites: 5

Brief Summary

This study will look at how effective the study drug (tepotinib) is at stopping the growth and spread of lung cancer with central nervous system metastasis. In some patients, who have developed resistance to their tyrosine kinase inhibitors (TKIs), this study will look at how effective tepotinib is in combination with TKIs. This study will also measure a number of other things including safety of the study drug and the side effects, how body processes the study drug, or how the study drug affects your quality of life.

Conditions

Advanced Non-Small Cell Lung Cancer With MET Mutations

Keywords

Non-Small Cell Lung Cancer, NSCLC

Outcome Measures

Primary Outcomes (4)

• ARM 1 (Monotherapy) Dose Limiting Toxicity (DLT)

  Dose Escalation Phase: DLT: This is defined as any ≥ to Grade 3 study drug-related toxicity (CTCAE v5.0) occurring within the first cycle of dosing at a given dose level without resolution within 7 days of holding study drug and appropriate supportive care.

  1 year

• Arm 1 (Monotherapy) Intracranial Objective Response Rate (ORR)

  Dose Expansion Phase: Intracranial ORR (RECIST 1.1)

  6 years

• Arm 2 (Combination Therapy) Dose Limiting Toxicity (DLT)

  Dose Escalation Phase: DLT: This is defined as any ≥ to Grade 3 study drug-related toxicity (CTCAE v5.0) occurring within the first cycle of dosing at a given dose level without resolution within 7 days of holding study drug and appropriate supportive care.

  1 year

• Arm 2 (Combination Therapy) Overall and Extracranial Objective Response Rate

  Dose Expansion Phase: Overall and extracranial ORR among patients treated with the combination of tepotinib and concurrent TKI.

  6 years

Secondary Outcomes (9)

• ARM 1 (Monotherapy) Blood PK Parameters

  1 year

• ARM 1 (Monotherapy) CSF PK Parameters

  1 year

• Arm 1 (Monotherapy) Graded drug-related AEs

  1 year

• Arm 1 (Monotherapy) Overall, intracranial and extracranial ORR, PFS, DOR and DCR

  6 years

• Arm 1 (Monotherapy) Graded drug-related AEs in CNS efficacy evaluation cohort

  6 years

Other Outcomes (3)

• Resistance to MET inhibition

  6 years

• Overall survival

  6 years

• Quality of Life Score

  6 years

Study Arms (2)

Monotherapy

EXPERIMENTAL

* Dose Escalation Phase for participants with MET-driven NSCLC. * Dose Expansion Phase: CNS Efficacy Dose Expansion Cohort for participants with MET-driven NSCLC and measurable CNS disease.

Drug: Tepotinib

Combination Therapy

EXPERIMENTAL

* Dose Escalation Phase for participants with evidence of MET-driven acquired -resistance. * Dose Expansion Phase for participants with evidence of MET-driven acquired -resistance with or without measurable CNS disease.

Drug: Tepotinib

Interventions

Tepotinib DRUG

Subjects will receive tepotinib daily in cycles of 21-day duration. Subjects in the Combination Therapy arm will continue to receive their last tolerable dose of tyrosine kinase inhibitor (TKI) together with tepotinib.

Also known as: Tepmetko

Combination Therapy; Monotherapy

Eligibility Criteria

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

You may qualify if:

• Participants who meet ALL of the following criteria are eligible
• Arm 1 (Monotherapy) Participant has histologic or cytologic confirmation of metastatic MET-driven NSCLC which will be defined by presence of one of the following:
• MET Exon 14 skipping mutation as determined by CLIA certified NGS assay. This can be ascertained either by ctDNA based assay or through local testing of tissue samples.
• MET amplifications (defined as MET/CEP7 ≥ 4 using FISH)
• MET fusions as determined by CLIA certified NGS assay. This can be ascertained either by ctDNA based assay or through local testing for tissue samples.
• Other MET driven cases may be considered after consultation and approval by the principal investigator (PI).
• Arm 2 (Combination) Participant has histologic or cytologic confirmation of metastatic NSCLC with documented other driver (eg EGFR or ALK alterations) in which there is evidence of MET-driven acquired resistance (including any of the MET mechanisms noted for dose escalation/CNS expansion monotherapyarms, however due to the potential sub-clonal nature of acquired resistance MET/CEP7 ≥3 or equivalent will explicitly be permitted, or other potential cases with plausible biological evidence after consultation and approval by PI).
• The participant is able to understand and voluntarily sign a written informed consent and is willing and able to comply with the protocol requirements.
• Participant is a male or female and at least 18 years of age.
• Participant has at least 1 measurable lesion by RECIST v1.1 criteria using computed tomography (CT) scan or magnetic resonance image (MRI). Evaluable disease alone will be permitted in the dose escalation cohort. In the CNS efficacy cohort at least one measurable lesion must be intracranial. CNS measurability is defined as below. Measurable CNS lesions ≥10mm in any cohort must be captured as overall and intracranial RECIST target lesions. CNS lesions 5-9mm may be included in intra-cranial data set alone.
• Participant has an Eastern Cooperative Oncology Group (ECOG) score of 0-2 or Karnofsky score of ≥ 60.
• Participant has a life expectancy of greater than 12 weeks.
• Participant is able to ingest oral medications.
• Participant has received the final dose of any of the following treatments/procedures with the specified minimum intervals before first dose of study drug (unless in the opinion of Investigator and Medical Monitor, the medication will not interfere with study or compromise participant safety).
• Chemotherapy 28 days Antibody drug conjugate (ADC)\* 28 days Immune checkpoint inhibitors (ICI) 28 days Stereotactic radiotherapy (SRS) 14 days Tyrosine kinase inhibitor (TKI) † 7 days

You may not qualify if:

• Participants who meet ANY of the following criteria are not eligible for entry to the study
• Participant has received an investigational drug within a 28-day period (or within 5 half-lives, whichever is shorter) before the first dose of study drug or is currently participating in another interventional clinical trial, unless in the opinion of the Investigator and Medical Monitor, the medication will not interfere with the study procedures or compromise subject safety.
• Participants with isolated leptomeningeal disease are not eligible. Patients with symptomatic brain metastases may be potentially eligible provided that all the following criteria are met: 1) they are not on prednisolone 20mg equivalents daily prior to enrolling in the study and 2) anticonvulsants will be permitted provided the patient has been on a stable dose for a period of 2 weeks prior to the first dose of study drug.
• Participant has clinical evidence or history of ongoing significant bowel obstruction limiting oral intake, active uncontrolled malabsorption syndromes, or any other gastrointestinal disorder or defect that would interfere with absorption, distribution, metabolism, or excretion of the study drug and/or predispose the subject to an increased risk of gastrointestinal toxicity.
• Participant has New York Association Class III or IV heart failure.
• Participant has symptomatic acute coronary syndrome, unstable angina, or active ischemia requiring coronary artery stenting, angioplasty, or bypass grafting within 12 weeks prior to starting investigational drug.
• Participant has evidence of current, uncontrolled, clinically significant, unstable arrhythmias. Participants receiving active anti-arrhythmic therapy are not eligible with the following exceptions:
• Participants with atrial fibrillation medically controlled for greater than 1 month prior to Study Day 1.
• Participants who have medical pacemakers for control of arrhythmias.
• Participant has medically uncontrolled hypertension (defined as \> 160 mmHg systolic blood pressure (SBP) and \> 100 mmHg diastolic blood pressure (DBP).
• Participant has active/chronic, uncontrolled pancreatitis with serum amylase / lipase ≥ 1.5 ULN.
• Participant has untreated known HIV/AIDS. Patients with treated and stable HIV (defined as CD4 count \>200 cells/mm3 and undetectable HIV viral load) with active, chronic, known outpatient follow up with an HIV specialist will be eligible.
• Participant has active/chronic, known, untreated, hepatitis B or C infection.
• Participant has a concurrent and uncontrolled medical illness which would preclude study conduct and assessment, including, but not limited to the following medical conditions: an active infection requiring systemic therapy, bleeding disorder, diabetes mellitus, pulmonary diseases, or alcoholic liver disease.
• Participant is a pregnant or lactating woman.

Sponsors & Collaborators

• Criterium, Inc.: lead
• EMD Serono Research & Development Institute, Inc.: collaborator

Study Sites (5)

UC Davis Comprehensive Cancer Center

Sacramento, California, 95817, United States

Location

University of Colorado Cancer Center

Aurora, Colorado, 80045, United States

Location

Georgetown Lombardi Comprehensive Cancer Center

Washington D.C., District of Columbia, 20007, United States

Location

UPMC Hillman Cancer Center

Pittsburgh, Pennsylvania, 15232, United States

Location

University of Washington

Seattle, Washington, 98195, United States

Location

Related Publications (1)

• Tyler LC, Le AT, Chen N, Nijmeh H, Bao L, Wilson TR, Chen D, Simmons B, Turner KM, Perusse D, Kasibhatla S, Christiansen J, Dudek AZ, Doebele RC. MET gene amplification is a mechanism of resistance to entrectinib in ROS1+ NSCLC. Thorac Cancer. 2022 Nov;13(21):3032-3041. doi: 10.1111/1759-7714.14656. Epub 2022 Sep 13.

  PMID: 36101520 DERIVED

MeSH Terms

Conditions

Carcinoma, Non-Small-Cell Lung

Interventions

tepotinib

Condition Hierarchy (Ancestors)

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

Study Officials

• David R Camidge, MD, PhD

  University of Colorado, Denver

  PRINCIPAL INVESTIGATOR

• Tejas Patil, MD

  University of Colorado, Denver

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: Phase I - Two arms (Monotherapy and Combination therapy) with a primary endpoint of Dose Limiting Toxicity Phase II - Two arms Monotherapy Cohort: Primary endpoint is Intracranial Objective Response Rate; Combination Cohort: Primary endpoint is overall and extracranial ORR among patients treated with the combination of tepotinib and concurrent TKI.

Study Record Dates

• First Submitted: January 25, 2021
• First Posted: February 4, 2021
• Study Start: May 25, 2022
• Primary Completion: June 23, 2023
• Study Completion: June 23, 2023
• Last Updated: October 18, 2023

Record last verified: 2023-10

Locations

US (5)