Clinical Trials /

A Study of Tepotinib Plus Osimertinib in Osimertinib Relapsed MET Amplified NSCLC (INSIGHT 2)

NCT03940703

Description:

This study will assess the antitumor activity, safety, tolerability, and pharmacokinetics (PK) of the Mesenchymal-epithelial Transition Factor (MET) inhibitor tepotinib combined with the 3rd generation EGFR inhibitor osimertinib in participants with advanced or metastatic non-small cell lung cancer (NSCLC).

Related Conditions:
  • Non-Small Cell Lung Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: A Study of Tepotinib Plus Osimertinib in Osimertinib Relapsed Mesenchymal-epithelial Transition Factor (MET) Amplified Non-small Cell Lung Cancer (NSCLC) (INSIGHT 2)
  • Official Title: A Phase II, Two-arm Study to Investigate Tepotinib Combined With Osimertinib in MET Amplified, Advanced or Metastatic Non-small Cell Lung Cancer (NSCLC) Harboring Activating EGFR Mutations and Having Acquired Resistance to Prior Osimertinib Therapy (INSIGHT 2 Study)

Clinical Trial IDs

  • ORG STUDY ID: MS200095_0031
  • SECONDARY ID: 2019-001538-33
  • NCT ID: NCT03940703

Conditions

  • Non-small Cell Lung Cancer

Interventions

DrugSynonymsArms
TepotinibTepotinib Mono-therapy
OsimertinibTagrisso®Tepotinib and Osimertinib

Purpose

This study will assess the antitumor activity, safety, tolerability, and pharmacokinetics (PK) of the MET inhibitor tepotinib combined with the 3rd generation EGFR inhibitor osimertinib in participants with advanced or metastatic NSCLC..

Trial Arms

NameTypeDescriptionInterventions
Tepotinib and OsimertinibExperimentalParticipants will receive a combination of tepotinib and osimertinib. The combination will be applied in cycles of 21 days until disease progression, death, adverse event leading to discontinuation, study withdrawal or consent withdrawal.
  • Tepotinib
  • Osimertinib
Tepotinib Mono-therapyExperimentalParticipants will receive once daily dose of tepotinib. The mono therapy will be applied in cycles of 21 days until disease progression, death, adverse event leading to discontinuation, study withdrawal or consent withdrawal.
  • Tepotinib

Eligibility Criteria

        Inclusion Criteria:

          -  Locally advanced or metastatic Non-small Cell Lung Cancer (NSCLC) histology (confirmed
             by either histology or cytology) with documented activating Epidermal Growth Factor
             Receptor (EGFR) mutation

          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and a minimum
             life expectancy of 12 weeks

          -  Acquired resistance on previous first-line osimertinib. Participants must meet both of
             the following 2 criteria:

          -  Radiological documentation of disease progression on first-line osimertinib

          -  Objective clinical benefit documented during previous osimertinib therapy, defined by
             either partial or complete radiological response, or durable stable disease (SD) (SD
             should last less than 6 months after initiation of osimertinib

          -  Have received only first-line osimertinib as a prior line of therapy in the non
             curative advanced or metastatic NSCLC setting

          -  MET amplification as determined by either FISH testing (central or local) on tumor
             tissue (TBx) or central blood-based next generation sequencing (LBx). Tumor and blood
             samples must be collected following progression on prior first-line osimertinib at
             Prescreening

          -  Submission of tumor tissue and blood sample obtained after progression on first-line
             osimertinib, is mandatory for all patients for MET amplification testing

          -  Submission of tumor tissue during Prescreening or Screening is mandatory for patients
             with tumor tissue tested by local FISH, to confirm MET amplification status. Central
             confirmation is not mandated prior to the start of study treatment

          -  Other protocol defined inclusion criteria could apply

        Exclusion Criteria:

          -  Spinal cord compression or brain metastasis unless asymptomatic, stable or not
             requiring steroids for at least 2 weeks prior to start of study intervention

          -  Any unresolved toxicity Grade 2 or more according to National cancer institute common
             terminology criteria for adverse events( NCI-CTCAE) version 5, from previous
             anticancer therapy with the exception of alopecia

          -  Inadequate hematological, liver and renal function

          -  Impaired cardiac function

          -  History of interstitial lung disease(ILD) or interstitial pneumonitis including
             radiation pneumonitis that required steroid treatment

          -  Hypertension uncontrolled by standard therapies (not stabilized to < 150/90 millimeter
             of mercury (mmHg)

          -  Contraindication to the administration of osimertinib

          -  Other protocol defined exclusion criteria could apply.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Safety run-in: Number of Participants Experiencing Dose-Limiting Toxicities (DLTs) According to National Cancer Institute Common Terminology Criteria for Adverse Events Version (NCI-CTCAE v 5.0)
Time Frame:Up to Day 21 of Cycle 1 (each Cycle is of 21 days)
Safety Issue:
Description:Participants are identified as having an objective response if they achieve either a confirmed complete response (CR) or partial response (PR) from first administration of study treatment to first observation of progression disease (PD) according to determined according to RECIST 1.1 as adjudicated by the IRC. CR: Complete Response defined as disappearance of all target and non target lesions and any pathological lymph nodes (whether target or non target) must have reduction in short axis to less than (<) 10 mm. Partial response defined as at least a 30 percent (%) decrease in the sum of diameters of target lesions taking as reference the baseline sum diameters. PD defined as an increase of at least 20% in the sum of the diameters of target lesions, taking as reference the smallest sum of the diameters of target lesions recorded since treatment started. PD: At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study.

Secondary Outcome Measures

Measure:Objective Response According to RECIST Version 1.1 as per IRC for Combined Therapy in Participants With MET Amplification Determined Centrally by Blood-Based Next Generation Sequencing
Time Frame:Every 6 weeks following the Cycle 1 Day 1 visit until 9 months; every 12 weeks thereafter until disease progression, death, study withdrawal, or withdrawal of consent (each Cycle is of 21 days) (approximately 42 months)
Safety Issue:
Description:Participants are identified as having an objective response if they achieve either a confirmed CR or PR from first administration of study treatment to first observation of PD according to determined according to RECIST 1.1 as adjudicated by the IRC. CR: Complete Response defined as disappearance of all target and non target lesions and any pathological lymph nodes (whether target or non target) must have reduction in short axis to less than (<) 10 mm. Partial response defined as at least a 30 percent (%) decrease in the sum of diameters of target lesions taking as reference the baseline sum diameters. PD defined as an increase of at least 20% in the sum of the diameters of target lesions, taking as reference the smallest sum of the diameters of target lesions recorded since treatment started. PD: At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study.
Measure:Objective Response According to RECIST Version 1.1 as per IRC for Tepotinib Monotherapy in Participants With MET Amplification Determined Centrally by FISH
Time Frame:Every 6 weeks following the Cycle 1 Day 1 visit until 9 months; every 12 weeks thereafter until disease progression, death, study withdrawal, or withdrawal of consent (each Cycle is of 21 days) (approximately 42 months)
Safety Issue:
Description:Participants are identified as having an objective response if they achieve either a confirmed CR or PR from first administration of study treatment to first observation of PD according to determined according to RECIST 1.1 as adjudicated by the IRC. CR: Complete Response defined as disappearance of all target and non target lesions and any pathological lymph nodes (whether target or non target) must have reduction in short axis to less than (<) 10 mm. Partial response defined as at least a 30 percent (%) decrease in the sum of diameters of target lesions taking as reference the baseline sum diameters. PD defined as an increase of at least 20% in the sum of the diameters of target lesions, taking as reference the smallest sum of the diameters of target lesions recorded since treatment started. PD: At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study.
Measure:Number of Participants With Adverse Events (AEs) and Treatment-Related Adverse Events According to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v5.0, and Deaths
Time Frame:Baseline up to 30 days after the last dose of study treatment
Safety Issue:
Description:
Measure:Percentage of Participants With Abnormal greater Than or Equal to (>=) Grade 3 Laboratory Findings
Time Frame:Baseline up to 30 days after the last dose of study treatment
Safety Issue:
Description:
Measure:Percentage of Participants With Abnormal Vital Signs, Electrocardiograms (ECGs) and Eastern Cooperative Oncology Group (ECOG) Performance Status
Time Frame:Baseline up to 30 days after the last dose of study treatment
Safety Issue:
Description:Percentage of participants with abnormalities in vital signs; clinically significant electrocardiograms (ECGs), change in body weight and change in Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) will be analyzed.
Measure:Objective Response According to RECIST Version 1.1 Assessed by Investigator for Combined Therapy in Participants with MET Amplification Determined Centrally by FISH
Time Frame:Every 6 weeks following the Cycle 1 Day 1 visit until 9 months; every 12 weeks thereafter until disease progression, death, study withdrawal, or withdrawal of consent (each Cycle is of 21 days) (approximately 42 months)
Safety Issue:
Description:Participants are identified as having an objective response if they achieve either a confirmed CR or PR from first administration of study treatment to first observation of PD according to RECIST 1.1 as adjudicated by the Investigator. CR: CR defined as disappearance of all target and non-target lesions and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm. PR defined as at least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum diameters. PD defined as an increase of at least 20% in the sum of the diameters of target lesions, taking as reference the smallest sum of the diameters of target lesions recorded since treatment started.
Measure:Confirmed Complete Response Assessed by IRC and by Investigator for Combined Therapy in Participants with MET Amplification Determined Centrally by FISH
Time Frame:Every 6 weeks following the Cycle 1 Day 1 visit until 9 months; every 12 weeks thereafter until disease progression, death, study withdrawal, or withdrawal of consent (each Cycle is of 21 days) (approximately 42 months)
Safety Issue:
Description:Complete Response (CR) defined as disappearance of all target and non-target lesions and any pathological lymph nodes (whether target or non target) must have reduction in short axis to < 10 mm. Participants will be assessed who have confirmed CR if they achieve a confirmed CR from first administration of study treatment to first observation of PD. Participants are identified as having a confirmed CR if they achieve a confirmed CR from first administration of study treatment to first observation of PD.
Measure:Duration of Response Assessed by Independent Review Committee (IRC) and by Investigator for Combined Therapy in Participants with MET Amplification Determined Centrally by FISH
Time Frame:Approximately 42 months
Safety Issue:
Description:Duration of response is the time from when the CR/PR (whichever is first) criteria are first met until PD or death due to any cause of the last tumor assessment, whichever occurs first.
Measure:Percentage of Participants With Disease Control Assessed by IRC and by Investigator for Combined Therapy in Participants with MET Amplification Determined Centrally by FISH
Time Frame:Approximately 42 months
Safety Issue:
Description:Participants are identified as having objective disease control if they achieve either a confirmed CR or PR (confirmation needs to take place after the tumor assessments initially indicating CR or PR), or stable disease (SD).
Measure:Progression-Free Survival Assessed by the IRC and Investigator for Combined Therapy According to RECIST v1.1 in Participants with MET Amplification Determined Centrally by FISH
Time Frame:Approximately 42 months
Safety Issue:
Description:Progression free survival is defined as the time (in months) from first administration of study treatment to the date of the first documentation of PD or death due to any cause of the last tumor assessment, whichever occurs first.
Measure:Overall Survival for Combined Therapy in Participants With MET Amplification Determined Centrally by FISH
Time Frame:Approximately 42 months
Safety Issue:
Description:Overall survival is defined as the time (in months) from first administration of study treatment to the date of death.
Measure:Objective Response Assessed by IRC According to RECIST v1.1 for Tepotinib Monotherapy in Participants with MET Amplification Determined Centrally by FISH
Time Frame:Every 6 weeks following the Cycle 1 Day 1 visit until 9 months; every 12 weeks thereafter until disease progression, death, study withdrawal, or withdrawal of consent (each Cycle is of 21 days) (approximately 42 months)
Safety Issue:
Description:Participants are identified as having an objective response if they achieve either a confirmed CR or PR from first administration of study treatment to first observation of PD according to RECIST 1.1 as adjudicated by the Investigator. CR: CR defined as disappearance of all target and non-target lesions and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm. PR defined as at least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum diameters. PD defined as an increase of at least 20% in the sum of the diameters of target lesions, taking as reference the smallest sum of the diameters of target lesions recorded since treatment started.
Measure:Confirmed Complete Response Assessed by IRC and by Investigator for Tepotinib Monotherapy in Participants With MET Amplification Determined Centrally by FISH
Time Frame:Every 6 weeks following the Cycle 1 Day 1 visit until 9 months; every 12 weeks thereafter until disease progression, death, study withdrawal, or withdrawal of consent (each Cycle is of 21 days) (approximately 42 months)
Safety Issue:
Description:Complete Response (CR) defined as disappearance of all target and non-target lesions and any pathological lymph nodes (whether target or non target) must have reduction in short axis to < 10 mm. Participants will be assessed who have confirmed CR if they achieve a confirmed CR from first administration of study treatment to first observation of PD. Participants are identified as having a confirmed CR if they achieve a confirmed CR from first administration of study treatment to first observation of PD.
Measure:Duration of Response Assessed by IRC and by Investigator for Tepotinib Monotherapy in Participants with MET Amplification Determined Centrally by FISH
Time Frame:Approximately 42 months
Safety Issue:
Description:Duration of response is the time from when the CR/PR (whichever is first) criteria are first met until PD or death due to any cause of the last tumor assessment, whichever occurs first.
Measure:Percentage of Participants With Disease Control Assessed by IRC and Investigator for Tepotinib Monotherapy in Participants with MET Amplification Determined Centrally by FISH
Time Frame:Approximately 42 months
Safety Issue:
Description:Participants are identified as having objective disease control if they achieve either a confirmed CR or PR (confirmation needs to take place after the tumor assessments initially indicating CR or PR), or stable disease (SD).
Measure:Progression-Free Survival Assessed by the IRC and Investigator for Tepotinib Monotherapy According to RECIST v1.1 in Participants with MET Amplification Determined Centrally by FISH
Time Frame:Approximately 42 months
Safety Issue:
Description:Progression free survival is defined as the time (in months) from first administration of study treatment to the date of the first documentation of PD or death due to any cause of the last tumor assessment, whichever occurs first.
Measure:Health-Related Quality of Life as Assessed by EuroQol Five Dimension Five Level (EQ-5D-5L) Scale Score in Combination Therapy
Time Frame:Approximately 42 months
Safety Issue:
Description:
Measure:Health-Related Quality of Life as assessed by European Organisation For Research And Treatment of Cancer Quality of Life Questionnaire Core 3D (EORTC-QLQ-C30) in Combination Therapy
Time Frame:Every 6 weeks following the Cycle 1 Day 1 visit until 9 months; every 12 weeks thereafter until disease progression, death, study withdrawal, or withdrawal of consent (each Cycle is of 21 days) (approximately 42 months)
Safety Issue:
Description:
Measure:Health-Related Quality of Life as assessed by Non-Small Cell Lung Cancer Symptom Assessment Questionnaire (NSCLC-SAQ) in Combination Therapy
Time Frame:Every 6 weeks following the Cycle 1 Day 1 visit until 9 months; every 12 weeks thereafter until disease progression, death, study withdrawal, or withdrawal of consent (each Cycle is of 21 days) (approximately 42 months)
Safety Issue:
Description:
Measure:Area Under the Plasma Concentration-Time Curve From Time Zero to the Last Sampling Time (AUC 0-t) of Tepotinib and Osimertinib and Their Metabolities
Time Frame:Predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours after tepotinib and Osimertinib administration at Day 1 of Cycle 1 and Day 15 of Cycle 1 (each Cycle is of 21 days)
Safety Issue:
Description:
Measure:Maximum Observed Plasma Concentration (Cmax) of Tepotinib and Osimertinib and Their Metabolities
Time Frame:Predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours after tepotinib and Osimertinib administration at Day 1 of Cycle 1 and Day 15 of Cycle 1 (each Cycle is of 21 days)
Safety Issue:
Description:
Measure:Time to Reach Maximum Observed Plasma Concentration (tmax) of Tepotinib and Osimertinib and Their Metabolities
Time Frame:Predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours after tepotinib and Osimertinib administration at Day 1 of Cycle 1 and Day 15 of Cycle 1 (each Cycle is of 21 days)
Safety Issue:
Description:
Measure:Apparent Total Body Clearance (CL/f) of Tepotinib and Osimertinib and Their Metabolities
Time Frame:Predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours after tepotinib and Osimertinib administration at Day 1 of Cycle 1 and Day 15 of Cycle 1 (each Cycle is of 21 days)
Safety Issue:
Description:The apparent total body clearance of study intervention following extravascular administration, taking into account the fraction of dose absorbed. CL/f = Dose p.o. /AUC0-infinity (AUC0-inf).
Measure:Apparent Volume Of Distribution (Vz/F) of Tepotinib and Osimertinib and Their Metabolities
Time Frame:Predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours after tepotinib and Osimertinib administration at Day 1 of Cycle 1 and Day 15 of Cycle 1 (each Cycle is of 21 days)
Safety Issue:
Description:The apparent volume of distribution during the terminal phase following extravascular administration, based on the fraction of dose absorbed. The Vz/f was calculated by dividing the dose with area under the concentration time curve from time zero to infinity multiplied with terminal elimination rate constant Lambda(z). Vz/f=Dose/AUC(0-inf)* Lambda(z).
Measure:Percentage of Participants With resistant Mutations of the Epidermal Growth Factor Receptor (EGFR) gene or other pathways as Assessed in Circulating Tumor Deoxyribonucleic Acid (ctDNA
Time Frame:From Day 1 of Cycle 3 up to end of treatment (14 days after last dose) (each Cycle is for 21 days)
Safety Issue:
Description:

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:EMD Serono Research & Development Institute, Inc.

Trial Keywords

  • Tepotinib
  • Osimertinib
  • Non-Small Cell Lung Cancer
  • INSIGHT 2
  • MET amplified

Last Updated

July 3, 2020