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

NCT01982955 | Completed Phase 1 Results DMC

• 2 other identifiers: EMR 200095-0062016-001604-28
• Study Type: interventional
• Target: 88
• Locations: 7 countries
• Sites: 44

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

Keywords

MSC2156119J; Gefitinib; Pemetrexed; Cisplatin; MET positive; Tepotinib; Carboplatin; INSIGHT

Outcome Measures

Primary Outcomes (3)

• Phase 1b: Number of Participants Experiencing at Least One Dose Limiting Toxicity (DLT)

  Dose limiting toxicity (DLT) using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 4.0 was defined as toxicities at any dose level and judged to be related to the study treatment by investigator and/or the sponsor. DLTs included Grade 4 neutropenia for more than 7 days; Grade greater than or equal to (\>=) 3 febrile neutropenia for more than 1 day; Grade 4 thrombocytopenia or Grade 3 thrombocytopenia with non-traumatic bleeding; Grade \>= 3 uncontrolled nausea/vomiting and/or diarrhea despite adequate and optimal treatment and Grade \>= 3 any non-hematological adverse event (AE), except the aforementioned gastrointestinal events and alopecia. Number of participants who experienced DLT during Phase 1b were reported.

  Day 1 to Day 21 of Cycle 1 (each cycle is 21 days)

• Phase 1b: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs

  An AE was defined as any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of study drug, whether or not considered related to the study drug. A serious AE was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. The term TEAE is defined as AEs starting or worsening after the first intake of the study drug. TEAEs include both Serious TEAEs and non-serious TEAEs. Number of Participants with TEAEs and serious TEAEs were reported.

  Up to 175 weeks

• Phase 2 (Randomized Part Only): Progression-free Survival (PFS) Based on Tumor Assessment by the Investigator

  Progression-free survival (assessed by the Investigator) time was defined as the time in months from randomization to either first observation of radiologically confirmed progression disease (PD) by the investigator or occurrence of death due to any cause within 84 days of either randomization or the last tumor assessment. PD is defined as at least a 20 percent (%) increase in the sum of diameters of target lesions, taking as reference the smallest sum on study; and/or unequivocal progression of existing non-target lesions and/or the presence of new lesions. The sum must also demonstrate an absolute increase of at least 5 millimeter (mm). PFS was measured using Kaplan-Meier (KM) estimates.

  Up to 328 weeks

Secondary Outcomes (41)

• Phase 1b: Area Under the Plasma Concentration Versus Time Curve From Time Zero to the Last Sampling Time AUC (0-t) of Tepotinib, Its Metabolites and Gefitinib

  Pre dose, 0.25, 0.5, 1, 2, 4, 8, 10 and 24 hours post dose on Day 1 and 15 of Cycle 1 (each Cycle is 21 days)

• Phase 1b: Area Under the Plasma Concentration-Time Curve Within 1 Dosing Interval (AUC 0-tau) of Tepotinib, Its Metabolites and Gefitinib

  Pre dose, 0.25, 0.5, 1, 2, 4, 8, 10 and 24 hours post dose on Day 1 and 15 of Cycle 1 (each Cycle is 21 days)

• Phase 1b: Maximum Observed Plasma Concentration (Cmax) of Tepotinib, Its Metabolites and Gefitinib

  Pre dose, 0.25, 0.5, 1, 2, 4, 8, 10 and 24 hours post dose on Day 1 and 15 of Cycle 1 (each Cycle is 21 days)

• Phase 1b: Average Observed Plasma Concentration (Cavg) of Tepotinib, Its Metabolites and Gefitinib

  Pre dose, 0.25, 0.5, 1, 2, 4, 8, 10 and 24 hours post dose on Day 15 of Cycle 1 (each Cycle is 21 days)

• Phase 1b: Minimum Observed Plasma Concentration (Cmin) of Tepotinib, Its Metabolites and Gefitinib

  Pre dose, 0.25, 0.5, 1, 2, 4, 8, 10 and 24 hours post dose on Day 15 of Cycle 1 (each Cycle is 21 days)

Study Arms (5)

Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg

EXPERIMENTAL

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.

Drug: Tepotinib; Drug: Gefitinib

Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg

EXPERIMENTAL

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.

Drug: Tepotinib; Drug: Gefitinib

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

EXPERIMENTAL

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.

Drug: Tepotinib; Drug: Gefitinib

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

EXPERIMENTAL

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.

Drug: Pemetrexed; Drug: Cisplatin; Drug: Carboplatin

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

EXPERIMENTAL

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.

Drug: Tepotinib; Drug: Gefitinib

Interventions

Tepotinib 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.

Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg; Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg; Phase 2: Single-arm Cohort (MET+ T790M positive); Phase 2: Tepotinib 500 mg + Gefitinib 250 mg (MET + T790 negative)

Gefitinib 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 300 mg + Gefitinib 250 mg; Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg; Phase 2: Single-arm Cohort (MET+ T790M positive); Phase 2: Tepotinib 500 mg + Gefitinib 250 mg (MET + T790 negative)

Pemetrexed 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.

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

Cisplatin 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.

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

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

Eligibility Criteria

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

You may qualify if:

• 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

You may not qualify if:

• 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)

Sponsors & Collaborators

• Merck KGaA, Darmstadt, Germany: lead

Study Sites (44)

Beijing Cancer Hospital

Beijing, China

Location

Beijing Chest Hospital

Beijing, China

Location

Peking Union Medical College Hospital

Beijing, China

Location

Jilin Cancer Hospital

Changchun, China

Location

Jilin University

Changchun, China

Location

Fuzhou General Hospital

Fuzhou, China

Location

Guangdong Provincial People's Hospital

Guangzhou, China

Location

Sir Run Run Shaw Hospital Cardiology

Hangzhou, China

Location

The First Affiliated Hospital of College of Medicine

Hangzhou, China

Location

Shanghai Chest Hospital

Shanghai, China

Location

Tongji Hospital

Wuhan, China

Location

Fourth Military Medical University

Xi'an, China

Location

Zhejiang Cancer Hospital

Zhejiang, China

Location

Azienda Ospedaliero Universitaria Mater Domini-Campus Universitario

Catanzaro, Italy

Location

IEO Istituto Europeo di Oncologia

Milan, Italy

Location

University Malaya Medical Centre

Kuala Lumpur, Malaysia

Location

Beacon International Specialist Centre Sdn Bhd

Petaling Jaya, Malaysia

Location

National Cancer Center

Singapore, Singapore

Location

National University Hospital

Singapore, Singapore

Location

Raffles Hospital

Singapore, Singapore

Location

Chungbuk National University Hospital

Cheongju-si, South Korea

Location

Kyungpook National University Hospital

Daegu, South Korea

Location

Chonnam National University Hwasun Hospital

Hwasun, South Korea

Location

CHA Bundang Medical Center, CHA University

Seongnam-si, South Korea

Location

Seoul National University Bundang Hospital

Seongnam-si, South Korea

Location

Severance Hospital Yonsei University Health System

Seongnam-si, South Korea

Location

Asan medical Centre

Seoul, South Korea

Location

Gangnam Severance Hospital Yonsei University

Seoul, South Korea

Location

Korea University Anam Hospital

Seoul, South Korea

Location

Samsung Medical Center

Seoul, South Korea

Location

Seoul National Universtiy Hospital

Seoul, South Korea

Location

The Catholic University of Korea St Mary s Hospital

Seoul, South Korea

Location

The Catholic University of Korea St. Vincent's Hospital

Suwon, South Korea

Location

Hospital Universitari Vall d'Hebron

Barcelona, Spain

Location

Hospital General Universitario Gregorio Marañon

Madrid, Spain

Location

Hospital Clinico Universitario

Valencia, Spain

Location

Hospital Alvaro Cunqueiro

Vigo, Spain

Location

Chang Gung Memorial Hospital-Kaohsiung

Kaohsiung City, Taiwan

Location

China Medical University Hospital

Taichung, Taiwan

Location

Taichung Veterans General Hospital

Taichung, Taiwan

Location

National Taiwan University Hospital

Taipei, Taiwan

Location

Taipei Veterans General Hospital

Taipei, Taiwan

Location

Tri-Service General Hospital

Taipei, Taiwan

Location

Chang Gung Memorial Hospital Linkou

Taoyuan District, Taiwan

Location

Related Publications (1)

• 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.

  PMID: 32479794 RESULT

Related Links

• Trial Awareness and Transparency website
• Medical Information Location Map - Med Info Contacts

MeSH Terms

Conditions

Carcinoma, Non-Small-Cell Lung

Interventions

tepotinib; Gefitinib; Pemetrexed; Cisplatin; Carboplatin

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

Quinazolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Guanine; Hypoxanthines; Purinones; Purines; Glutamates; Amino Acids, Acidic; Amino Acids; Amino Acids, Peptides, and Proteins; Amino Acids, Dicarboxylic; Chlorine Compounds; Inorganic Chemicals; Nitrogen Compounds; Platinum Compounds; Coordination Complexes; Organic Chemicals

Results Point of Contact

• Title: Communication Center
• Organization: Merck KGaA, Darmstadt, Germany

service@emdgroup.com

+49-6151-72-5200

Study Officials

• Medical Responsible

  Merck KGaA, Darmstadt, Germany

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

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

Study Record Dates

• First Submitted: October 29, 2013
• First Posted: November 13, 2013
• Study Start: December 23, 2013
• Primary Completion: December 12, 2017
• Study Completion: October 14, 2021
• Last Updated: November 8, 2022
• Results First Posted: July 23, 2020

Record last verified: 2022-10

Locations

CN (13); IT (2); MY (2); KR (13); ES (4); TW (7); SG (3)