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Clinical trial information and results are updated daily from ClinicalTrials.gov. The latest data update was conducted on 06/14/2021.

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

Clinicaltrials.gov identifier NCT03940703

Recruitment Status Recruiting

First Posted May 7, 2019

Last update posted April 9, 2021

Study Description

Brief summary:

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).

  • Condition or Disease:Non-small Cell Lung Cancer
  • Intervention/Treatment: Drug: Tepotinib
    Drug: Osimertinib
  • Phase: Phase 2
Detailed Description

N/A

Study Design
  • Study Type: Interventional
  • Estimated Enrollment: 120 participants
  • Allocation: Non-Randomized
  • Intervention Model: Parallel Assignment
  • Masking: None (Open Label) ()
  • Primary Purpose: Treatment
  • Official Title: A Phase II, Two-arm Study to Investigate Tepotinib Combined With Osimertinib in MET Amplified, Advanced or Metastatic NSCLC Harboring Activating EGFR Mutations and Having Acquired Resistance to Prior Osimertinib Therapy (INSIGHT 2)
  • Actual Study Start Date: September 2019
  • Estimated Primary Completion Date: November 2022
  • Estimated Study Completion Date: March 2023
Arms and interventions
Arm Intervention/treatment
Experimental: Tepotinib Mono-therapy
Participants 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.
Drug: Tepotinib
Participants will be administered Tepotinib orally once daily at an initial dose of 500 milligram (mg). A safety monitoring committee (SMC) may decide to confirm or adapt the dose.
Experimental: Tepotinib and Osimertinib
Participants 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.
Drug: Tepotinib
Participants will be administered Tepotinib orally once daily at an initial dose of 500 milligram (mg). A safety monitoring committee (SMC) may decide to confirm or adapt the dose.

Drug: Osimertinib
Participants will receive Osimertinib at a dose of 80 mg orally once daily.
Outcome Measures
  • Primary Outcome Measures: 1. 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) ]
  • 2. Objective Response According to Response Evaluation Criteria in Solid Tumors(RECIST)Version1.1as per Independent Review Committee for Combined Therapy in Participants With MET Amplification Determined Centrally by Fluorescence in situ Hybridization(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 38 months) ]
    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: 1. 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 ]
    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).
  • 2. 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 ]
    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.
  • 3. 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) ]
    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.
  • 4. 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) ]
    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.
  • 5. 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 ]
  • 6. 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 ]
  • 7. 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 ]
    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.
  • 8. 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) ]
    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.
  • 9. 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) ]
    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.
  • 10. 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 ]
    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.
  • 11. Overall Survival for Combined Therapy in Participants With MET Amplification Determined Centrally by FISH [ Time Frame: Approximately 42 months ]
    Overall survival is defined as the time (in months) from first administration of study treatment to the date of death.
  • 12. Objective Response Assessed by Investigator 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) ]
    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.
  • 13. 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) ]
    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.
  • 14. 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 ]
    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.
  • 15. 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 ]
    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).
  • 16. 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 ]
    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.
  • 17. 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 ]
  • 18. 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) ]
  • 19. 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) ]
  • 20. 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) ]
  • 21. 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) ]
  • 22. 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) ]
  • 23. 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) ]
    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).
  • 24. 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) ]
    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).
  • 25. 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) ]
Eligibility Criteria
  • Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
  • Sexes Eligible for Study: All
  • Accepts Healthy Volunteers: No
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 greater 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.

Contacts and Locations
Contacts

Contact: US Medical Information 888-275-7376 eMediUSA@emdserono.com

Contact: Communication Center +49 6151 72 5200 service@emdgroup.com

Locations
Show 106 Study Locations
Sponsors and Collaborators

EMD Serono Research & Development Institute, Inc.

Merck KGaA, Darmstadt, Germany

Investigators

Study Director: Medical Responsible Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany

More Information
  • Responsible Party: EMD Serono Research & Development Institute, Inc.
  • ClinicalTrials.gov Identifier: NCT03940703 History of Changes
  • Other Study ID Numbers: MS200095_0031, 2019-001538-33
  • First Posted: May 7, 2019 Key Record Dates
  • Last Update Posted: April 9, 2021
  • Last Verified: April 2021
  • Individual Participant
    Data (IPD) Sharing
    Statement:
  • Plan to Share IPD: Yes
  • Plan Description: Per company policy, following approval of a new product or a new indication for an approved product in both the EU and the US, EMD Serono will share study protocols, anonymized patient level and study level data and redacted clinical study reports from clinical trials in patients with qualified scientific and medical researchers, upon request, as necessary for conducting legitimate research. Further information on how to request data can be found on our website https://www.emdgroup.com/en/research/our-approach-to-research-and-development/healthcare/clinical-trials/commitment-responsible-data-sharing.html
  • Studies a U.S. FDA-regulated Drug Product: Yes
  • Studies a U.S. FDA-regulated Device Product: No
  • Keywords provided by EMD Serono Research & Development Institute, Inc.: Tepotinib
    Osimertinib
    Non-Small Cell Lung Cancer
    MET amplified
    INSIGHT 2
  • Additional relevant MeSH terms: Carcinoma, Non-Small-Cell Lung