Tepotinib With Gefitinib in Participants With Locally Advanced or Metastatic NSCLC (INSIGHT)

NCT ID: NCT01982955

Last Updated: 2022-11-08

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 88 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2013-12-23
• Study Completion Date: 2021-10-14

Brief Summary

This is a multi-center, open-label, randomized, Phase 1b/2 study to determine the recommended phase 2 dose (RP2D) and to evaluate the efficacy in terms of progression free survival (PFS) of Tepotinib when used in combination with gefitinib in partcipants with T790M negative, MET positive locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutation and having acquired resistance to Prior EGFR-Tyrosine Kinase Inhibitor (EGFR-TKI) Therapy. This study has 2:1 randomization (Tepotinib/Gefitinib arm versus Chemotherapy arm).

Conditions

Non-small Cell Lung Cancer

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg

Participants received Tepotinib 300 milligram (mg) along with 250 mg Gefitinib tablets orally once daily over a 21-day treatment cycle until progressive disease, intolerable toxicity or withdrawal from treatment.

Group Type: EXPERIMENTAL

Tepotinib

Intervention Type: DRUG

Tepotinib was administered at a dose range of 300 or 500 milligram (mg) (Phase 1b) and the recommended phase II dose (RP2D) determined in the Phase 1b in Phase II orally once daily over a 21-day cycle until progressive disease, intolerable toxicity, participants withdrawal from treatment. RP2D was determined as per safety monitoring committee (SMC) discretion.

Gefitinib

Intervention Type: DRUG

Gefitinib was administered at a dose of 250 mg orally as once daily over a 21-day cycle until progressive disease, intolerable toxicity, participants withdrawal from treatment.

Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg

Participants received Tepotinib 500 milligram (mg) along with 250 mg Gefitinib tablets orally once daily over a 21-day treatment cycle until progressive disease, intolerable toxicity or withdrawal from treatment.

Group Type: EXPERIMENTAL

Tepotinib

Intervention Type: DRUG

Tepotinib was administered at a dose range of 300 or 500 milligram (mg) (Phase 1b) and the recommended phase II dose (RP2D) determined in the Phase 1b in Phase II orally once daily over a 21-day cycle until progressive disease, intolerable toxicity, participants withdrawal from treatment. RP2D was determined as per safety monitoring committee (SMC) discretion.

Gefitinib

Intervention Type: DRUG

Gefitinib was administered at a dose of 250 mg orally as once daily over a 21-day cycle until progressive disease, intolerable toxicity, participants withdrawal from treatment.

Phase 2: Tepotinib 500 mg + Gefitinib 250 mg (MET + T790 negative)

Participants randomized to receive Tepotinib recommended Phase 2 dose 500 mg once daily along with 250 mg Gefitinib tablets orally once daily over a 21-day cycle until progressive disease, intolerable toxicity or withdrawal from treatment.

Group Type: EXPERIMENTAL

Tepotinib

Intervention Type: DRUG

Tepotinib was administered at a dose range of 300 or 500 milligram (mg) (Phase 1b) and the recommended phase II dose (RP2D) determined in the Phase 1b in Phase II orally once daily over a 21-day cycle until progressive disease, intolerable toxicity, participants withdrawal from treatment. RP2D was determined as per safety monitoring committee (SMC) discretion.

Gefitinib

Intervention Type: DRUG

Gefitinib was administered at a dose of 250 mg orally as once daily over a 21-day cycle until progressive disease, intolerable toxicity, participants withdrawal from treatment.

Phase 2: Pemetrexed and Cisplatin/Carboplatin (MET + T790 negative)

Participants randomized to receive 500 milligram per square meter (mg/m\^2) of Pemetrexed as intravenous infusion over 10 minutes in combination with Cisplatin (75 mg/m2 as an intravenous infusion over 2 hours) or Carboplatin (intravenously at a dose of area under curve (AUC) 5 or AUC6 at the discretion of the Investigator) on Day 1 of each 21-day cycle until progressive disease, intolerable toxicity or withdrawal from treatment or up to 6 cycles if or 4 cycles followed by Pemetrexed maintenance monotherapy.

Group Type: EXPERIMENTAL

Pemetrexed

Intervention Type: DRUG

Pemetrexed was administered at a dose of 500 milligram per square meter (mg/m\^2) as intravenous infusion over 10 minutes on Day 1 of each 21-day cycle until progressive disease, intolerable toxicity, participants withdrawal from treatment or up to 6 cycles if pemetrexed maintenance is not considered.

Cisplatin

Intervention Type: DRUG

Cisplatin was administered at a dose of 75 mg/m\^2 as intravenous infusion over 2 hours on Day 1 of each 21-day cycle until progressive disease, intolerable toxicity, participants withdrawal from treatment or up to 6 cycles if pemetrexed maintenance is not considered.

Carboplatin

Intervention Type: DRUG

Carboplatin was administered intravenously on Day 1 of each 21-day cycle at a dose of area under curve (AUC) 5 or AUC6 at the discretion of the Investigator until progressive disease, intolerable toxicity, participants withdrawal from treatment or up to 6 cycles if pemetrexed maintenance is not considered.

Phase 2: Single-arm Cohort (MET+ T790M positive)

Participants with MET+ T790M positive Non-small Cell Lung Cancer (NSCLC) received a Tepotinib recommended Phase 2 dose 500 mg once daily along with 250 mg Gefitinib tablets orally once daily over a 21-day treatment cycle until progressive disease, intolerable toxicity or withdrawal from treatment.

Group Type: EXPERIMENTAL

Tepotinib

Intervention Type: DRUG

Tepotinib was administered at a dose range of 300 or 500 milligram (mg) (Phase 1b) and the recommended phase II dose (RP2D) determined in the Phase 1b in Phase II orally once daily over a 21-day cycle until progressive disease, intolerable toxicity, participants withdrawal from treatment. RP2D was determined as per safety monitoring committee (SMC) discretion.

Gefitinib

Intervention Type: DRUG

Gefitinib was administered at a dose of 250 mg orally as once daily over a 21-day cycle until progressive disease, intolerable toxicity, participants withdrawal from treatment.

Interventions

Tepotinib

Tepotinib was administered at a dose range of 300 or 500 milligram (mg) (Phase 1b) and the recommended phase II dose (RP2D) determined in the Phase 1b in Phase II orally once daily over a 21-day cycle until progressive disease, intolerable toxicity, participants withdrawal from treatment. RP2D was determined as per safety monitoring committee (SMC) discretion.

Intervention Type: DRUG

Gefitinib

Gefitinib was administered at a dose of 250 mg orally as once daily over a 21-day cycle until progressive disease, intolerable toxicity, participants withdrawal from treatment.

Intervention Type: DRUG

Pemetrexed

Pemetrexed was administered at a dose of 500 milligram per square meter (mg/m\^2) as intravenous infusion over 10 minutes on Day 1 of each 21-day cycle until progressive disease, intolerable toxicity, participants withdrawal from treatment or up to 6 cycles if pemetrexed maintenance is not considered.

Intervention Type: DRUG

Cisplatin

Cisplatin was administered at a dose of 75 mg/m\^2 as intravenous infusion over 2 hours on Day 1 of each 21-day cycle until progressive disease, intolerable toxicity, participants withdrawal from treatment or up to 6 cycles if pemetrexed maintenance is not considered.

Intervention Type: DRUG

Carboplatin

Carboplatin was administered intravenously on Day 1 of each 21-day cycle at a dose of area under curve (AUC) 5 or AUC6 at the discretion of the Investigator until progressive disease, intolerable toxicity, participants withdrawal from treatment or up to 6 cycles if pemetrexed maintenance is not considered.

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• Histologically or cytologically confirmed advanced non-small cell lung cancer (NSCLC), regardless of histology subtype, which failed on gefitinib for reasons other than toxicity or compliance;
• Availability of a fresh or archived pre treatment tumor biopsy (excluding fine needle aspiration and cytology samples). For participants who have had at least 1 prior anticancer treatment, a biopsy obtained between failure of the most recent anticancer treatment and enrolment is mandatory;
• Mesenchymal-epithelial transition diagnostic-positive (status) (MET+ status), as determined by the central laboratory
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1

Phase II

• Locally advanced or metastatic NSCLC other than predominantly squamous histology (confirmed by either histology or cytology);
• Activating mutation of the epidermal growth factor (EGFR) receptor (documented, or as determined by the central laboratory)
• Acquired resistance on first-line EGFR-Tyrosine Kinase Inhibitors (EGFR-TKI) therapy including gefitinib, erlotinib, icotinib, or afatinib
• EGFR T790M status after acquired resistance to first line EGFR-TKI therapy including gefitinib, erlotinib, icotinib, or afatinib treatment (as determined by the central laboratory, using a validated PCR test);
• T790M negative status for the randomized part
• T790M positive status for the single-arm cohort (mainland China sites only)
• Availability of a fresh or archived tumor tissue (excluding fine needle aspiration and cytology samples) obtained between documentation of acquired resistance to gefitinib, erlotinib, icotinib, or afatinib and enrollment is mandatory
• MET+ status, as determined by the central laboratory i.e. c-Met overexpression as determined by IHC (i.e., IHC 2+ or IHC 3+) and/or c-Met amplification and/or increased c-Met gene copy number (GCN), both determined by ISH;
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

Exclusion Criteria

• Estimated life expectancy less than (<) 3 months
• Inadequate bone marrow, liver or renal functions
• Prior chemotherapy, biological therapy, radiation therapy, or other investigational anticancer therapy (not including palliative radiotherapy at focal sites) within 21 days prior to the first dose of study treatment (Phase 1b only)
• Prior systemic anticancer treatment with chemotherapy or other agents targeting the EGFR pathway excluding gefitinib, erlotinib, icotinib, and afatinib for advanced NSCLC (one course of chemotherapy regimen for [neo] adjuvant purpose, or one course of chemoradiation for Stage IIIa disease is allowed) (Phase 2 only)

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Merck KGaA, Darmstadt, Germany

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Medical Responsible

Role: STUDY_DIRECTOR

Merck KGaA, Darmstadt, Germany

Locations

Beijing Cancer Hospital

Beijing, , China

Beijing Chest Hospital

Beijing, , China

Peking Union Medical College Hospital

Beijing, , China

Jilin Cancer Hospital

Changchun, , China

Jilin University

Changchun, , China

Fuzhou General Hospital

Fuzhou, , China

Guangdong Provincial People's Hospital

Guangzhou, , China

Sir Run Run Shaw Hospital Cardiology

Hangzhou, , China

The First Affiliated Hospital of College of Medicine

Hangzhou, , China

Shanghai Chest Hospital

Shanghai, , China

Tongji Hospital

Wuhan, , China

Fourth Military Medical University

Xi'an, , China

Zhejiang Cancer Hospital

Zhejiang, , China

Azienda Ospedaliero Universitaria Mater Domini-Campus Universitario

Catanzaro, , Italy

IEO Istituto Europeo di Oncologia

Milan, , Italy

University Malaya Medical Centre

Kuala Lumpur, , Malaysia

Beacon International Specialist Centre Sdn Bhd

Petaling Jaya, , Malaysia

National Cancer Center

Singapore, , Singapore

National University Hospital

Singapore, , Singapore

Raffles Hospital

Singapore, , Singapore

Chungbuk National University Hospital

Cheongju-si, , South Korea

Kyungpook National University Hospital

Daegu, , South Korea

Chonnam National University Hwasun Hospital

Hwasun, , South Korea

CHA Bundang Medical Center, CHA University

Seongnam-si, , South Korea

Seoul National University Bundang Hospital

Seongnam-si, , South Korea

Severance Hospital Yonsei University Health System

Seongnam-si, , South Korea

Asan medical Centre

Seoul, , South Korea

Gangnam Severance Hospital Yonsei University

Seoul, , South Korea

Korea University Anam Hospital

Seoul, , South Korea

Samsung Medical Center

Seoul, , South Korea

Seoul National Universtiy Hospital

Seoul, , South Korea

The Catholic University of Korea St Mary s Hospital

Seoul, , South Korea

The Catholic University of Korea St. Vincent's Hospital

Suwon, , South Korea

Hospital Universitari Vall d'Hebron

Barcelona, , Spain

Hospital General Universitario Gregorio Marañon

Madrid, , Spain

Hospital Clinico Universitario

Valencia, , Spain

Hospital Alvaro Cunqueiro

Vigo, , Spain

Chang Gung Memorial Hospital-Kaohsiung

Kaohsiung City, , Taiwan

China Medical University Hospital

Taichung, , Taiwan

Taichung Veterans General Hospital

Taichung, , Taiwan

National Taiwan University Hospital

Taipei, , Taiwan

Taipei Veterans General Hospital

Taipei, , Taiwan

Tri-Service General Hospital

Taipei, , Taiwan

Chang Gung Memorial Hospital Linkou

Taoyuan District, , Taiwan

Countries

China; Italy; Malaysia; Singapore; South Korea; Spain; Taiwan

References

Wu YL, Cheng Y, Zhou J, Lu S, Zhang Y, Zhao J, Kim DW, Soo RA, Kim SW, Pan H, Chen YM, Chian CF, Liu X, Tan DSW, Bruns R, Straub J, Johne A, Scheele J, Park K, Yang JC; INSIGHT Investigators. Tepotinib plus gefitinib in patients with EGFR-mutant non-small-cell lung cancer with MET overexpression or MET amplification and acquired resistance to previous EGFR inhibitor (INSIGHT study): an open-label, phase 1b/2, multicentre, randomised trial. Lancet Respir Med. 2020 Nov;8(11):1132-1143. doi: 10.1016/S2213-2600(20)30154-5. Epub 2020 May 29.

Reference Type: RESULT

PMID: 32479794 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Related Links

https://clinicaltrials.merckgroup.com/en/trial-details/?id=EMR%20200095-006

Trial Awareness and Transparency website

https://www.merckgroup.com/en/company/contact-us/medinfo-contact-map.html

Medical Information Location Map - Med Info Contacts

Other Identifiers

2016-001604-28

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

EMR 200095-006

Identifier Type: -

Identifier Source: org_study_id