Clinical trial NCT01982955: Tepotinib With Gefitinib in Participants With Locally Advanced or Metastatic NSCLC (INSIGHT)
Official title: A Phase Ib/II Multicenter, Randomized, Open Label Trial to Compare Tepotinib (MSC2156119J) Combined With Gefitinib Versus Chemotherapy as Second-Line Treatment in Subjects With MET Positive, Locally Advanced or Metastatic NSCLC Harboring EGFR Mutation and Having Acquired Resistance to Prior EGFR-TKI Therapy (INSIGHT)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Non-small Cell Lung Cancer
Keywords: MSC2156119J
Gefitinib
Pemetrexed
Cisplatin
MET positive
Tepotinib
Carboplatin
INSIGHT
Lead sponsor: Merck KGaA, Darmstadt, Germany
Sponsor class: INDUSTRY
First posted: 2013-11-13
Enrollment: 88
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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).


Eligibility criteria: Phase Ib

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
* Other protocol defined inclusion criteria could apply.

Phase II

Inclusion criteria:

* 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
* Other protocol defined inclusion criteria could apply

Exclusion Criteria (Phase I and II):

* 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)
* Other protocol defined exclusion criteria could apply.

Primary outcomes:
measure: Phase 1b: Number of Participants Experiencing at Least One Dose Limiting Toxicity (DLT)
timeFrame: Day 1 to Day 21 of Cycle 1 (each cycle is 21 days)
measure: Phase 1b: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs
timeFrame: Up to 175 weeks
measure: Phase 2 (Randomized Part Only): Progression-free Survival (PFS) Based on Tumor Assessment by the Investigator
timeFrame: Up to 328 weeks
Secondary outcomes:
measure: 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
timeFrame: 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)
measure: Phase 1b: Area Under the Plasma Concentration-Time Curve Within 1 Dosing Interval (AUC 0-tau) of Tepotinib, Its Metabolites and Gefitinib
timeFrame: 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)
measure: Phase 1b: Maximum Observed Plasma Concentration (Cmax) of Tepotinib, Its Metabolites and Gefitinib
timeFrame: 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)
measure: Phase 1b: Average Observed Plasma Concentration (Cavg) of Tepotinib, Its Metabolites and Gefitinib
timeFrame: 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)
measure: Phase 1b: Minimum Observed Plasma Concentration (Cmin) of Tepotinib, Its Metabolites and Gefitinib
timeFrame: 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)
measure: Phase 1b: Time to Reach Maximum Plasma Concentration (Tmax) of Tepotinib, Its Metabolites and Gefitinib
timeFrame: 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)
measure: Phase 1b: Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUC 0-infinity) of Tepotinib, Its Metabolites and Gefitinib
timeFrame: 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)
measure: Phase 1b: Apparent Total Body Clearance From Plasma (CL/F) of Tepotinib and Gefitinib
timeFrame: 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)
measure: Phase 1b: Apparent Volume of Distribution (Vz/F) During the Terminal Phase of Tepotinib, Its Metabolites and Gefitinib
timeFrame: 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)
measure: Phase 1b: Apparent Volume of Distribution During the Steady State (Vss/F) of Tepotinib, Its Metabolites and Gefitinib
timeFrame: 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)
measure: Phase 1b: Apparent Terminal Elimination Rate Constant Lambda(z) of Tepotinib, Its Metabolites and Gefitinib
timeFrame: 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)
measure: Phase 1b: Apparent Terminal Half-Life (t1/2) of Tepotinib, Its Metabolites and Gefitinib
timeFrame: 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)
measure: Phase 1b: Percentage of Participants With Objective Response Based on Tumor Response Assessment According to Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST v1.1) Criteria
timeFrame: Up to 328 weeks
measure: Phase 1b: Percentage of Participants With Disease Control Based on Tumor Response Assessment According to Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST v1.1) Criteria
timeFrame: Up to 328 weeks
measure: Phase 1b: Number of Participants With Treatment-Related Treatment-Emergent Adverse Events (TEAEs) and Treatment-Related Serious TEAEs According to National Cancer Institute Common Toxicity Criteria for Adverse Events Version 4.03
timeFrame: Up to 175 weeks
measure: Phase 1b: Number of Participants With Grade 3/4 Treatment-Emergent Adverse Events (TEAEs) and Grade 3/4 Treatment-Related TEAEs According to National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI-CTCAE) Version 4.03
timeFrame: Up to 175 weeks
measure: Phase 1b: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) Leading to Permanent Treatment Discontinuation
timeFrame: Up to 175 weeks
measure: Phase 1b: Number of Participants With Death and Reasons
timeFrame: Up to 175 weeks
measure: Phase 1b: Number of Participants With Laboratory Test Abnormalities of Grade 3 or Higher Severity Based on NCI-CTCAE Version 4.03 Reported as Treatment-Emergent Adverse Events (TEAEs)
timeFrame: Up to 175 weeks
measure: Phase 1b: Number of Participants With Clinically Significant Abnormalities in Vital Signs
timeFrame: Up to 175 weeks
measure: Phase 1b: Number of Participants With Clinically Significant Abnormalities in 12-Lead Electrocardiograms (ECG) Findings
timeFrame: Up to 175 weeks
measure: Phase 1b: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status Score of 2 or Higher Than 2
timeFrame: Up to 175 weeks
measure: Phase 2: Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, Treatment-Related TEAEs and Treatment-Related Serious TEAEs According to National Cancer Institute Common Toxicity Criteria for Adverse Events Version 4.03
timeFrame: Up to 328 weeks
measure: Phase 2: Number of Participants With Greater Than or Equal to (>=) Grade 3 Treatment-Emergent Adverse Events (TEAEs) and >= Grade 3 Treatment-Related TEAEs According to National Cancer Institute Common Toxicity Criteria for Adverse Events Version 4.03
timeFrame: Up to 328 weeks
measure: Phase 2: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) Leading to Permanent Treatment Discontinuation
timeFrame: Up to 328 weeks
measure: Phase 2: Number of Participants With Death and Reasons
timeFrame: Up to 328 weeks
measure: Phase 2: Number of Participants With Laboratory Test Abnormalities of Grade 3 or Higher Severity Based on NCI-CTCAE Version 4.03 Reported as Treatment-Emergent Adverse Events (TEAEs)
timeFrame: Up to 328 weeks
measure: Phase 2: Number of Participants With Clinically Significant Abnormalities in Vital Signs
timeFrame: Up to 328 weeks
measure: Phase 2: Number of Participants With Clinically Significant Abnormalities in 12-Lead Electrocardiograms (ECG) Findings
timeFrame: Up to 328 weeks
measure: Phase 2: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status Score of 2 or Higher Than 2
timeFrame: Up to 328 weeks
measure: Phase 2 (Randomized Part Only): Progression-free Survival (PFS) Based on Tumor Assessment by Independent Review Committee (IRC)
timeFrame: Up to 328 weeks
measure: Phase 2: (Randomized Part Only): Overall Survival (OS) Time
timeFrame: Up to 328 weeks
measure: Phase 2 (Randomized Part Only): Percentage of Participants With Objective Response Based on Tumor Response Assessment According to Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST v1.1) Criteria
timeFrame: Up to 328 weeks
measure: Phase 2 (Randomized Part Only): Percentage of Participants With Disease Control Based on Tumor Response Assessment According to Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST v1.1) Criteria
timeFrame: Up to 328 weeks
measure: Phase 2 (Non-Randomized Part Only): Progression-free Survival (PFS) Based on Tumor Assessment by Investigator
timeFrame: Up to 328 weeks
measure: Phase 2 (Non-Randomized Part Only): Progression-free Survival (PFS) Based on Tumor Assessment by Independent Review Committee (IRC)
timeFrame: Up to 328 weeks
measure: Phase 2: (Non-Randomized Part Only): Overall Survival (OS) Time
timeFrame: Up to 328 weeks
measure: Phase 2 (Non-Randomized Part Only): Percentage of Participants With Objective Response Based on Tumor Response Assessment According to Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST v1.1) Criteria
timeFrame: Up to 328 weeks
measure: Phase 2 (Non-Randomized Part Only): Percentage of Participants With Disease Control Based on Tumor Response Assessment According to Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST v1.1) Criteria
timeFrame: Up to 328 weeks
measure: Phase 2: Change From Baseline in European Organization for the Research and Treatment of Cancer Quality of Life (EORTC QLQ-C30) Global Health Status Scale Score at End of Treatment (EOT)
timeFrame: Baseline and EOT (up to 110 weeks)
measure: Phase 2: Time-to-Symptom Progression (TTSP)
timeFrame: Up to 328 weeks
Other outcomes:
Locations:
city: Beijing
country: China
facility: Beijing Cancer Hospital
city: Beijing
country: China
facility: Beijing Chest Hospital
city: Beijing
country: China
facility: Peking Union Medical College Hospital
city: Changchun
country: China
facility: Jilin Cancer Hospital
city: Changchun
country: China
facility: Jilin University
city: Fuzhou
country: China
facility: Fuzhou General Hospital
city: Guangzhou
country: China
facility: Guangdong Provincial People's Hospital
city: Hangzhou
country: China
facility: Sir Run Run Shaw Hospital Cardiology
city: Hangzhou
country: China
facility: The First Affiliated Hospital of College of Medicine
city: Shanghai
country: China
facility: Shanghai Chest Hospital
city: Wuhan
country: China
facility: Tongji Hospital
city: Xi'an
country: China
facility: Fourth Military Medical University
city: Zhejiang
country: China
facility: Zhejiang Cancer Hospital
city: Catanzaro
country: Italy
facility: Azienda Ospedaliero Universitaria Mater Domini-Campus Universitario
city: Milano
country: Italy
facility: IEO Istituto Europeo di Oncologia
city: Cheongju-si
country: Korea, Republic of
facility: Chungbuk National University Hospital
city: Daegu
country: Korea, Republic of
facility: Kyungpook National University Hospital
city: Hwasun
country: Korea, Republic of
facility: Chonnam National University Hwasun Hospital
city: Seongnam-si
country: Korea, Republic of
facility: CHA Bundang Medical Center, CHA University
city: Seongnam-si
country: Korea, Republic of
facility: Seoul National University Bundang Hospital
city: Seongnam-si
country: Korea, Republic of
facility: Severance Hospital Yonsei University Health System
city: Seoul
country: Korea, Republic of
facility: Asan medical Centre
city: Seoul
country: Korea, Republic of
facility: Gangnam Severance Hospital Yonsei University
city: Seoul
country: Korea, Republic of
facility: Korea University Anam Hospital
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center
city: Seoul
country: Korea, Republic of
facility: Seoul National Universtiy Hospital
city: Seoul
country: Korea, Republic of
facility: The Catholic University of Korea St Mary s Hospital
city: Suwon
country: Korea, Republic of
facility: The Catholic University of Korea St. Vincent's Hospital
city: Kuala Lumpur
country: Malaysia
facility: University Malaya Medical Centre
city: Petaling Jaya
country: Malaysia
facility: Beacon International Specialist Centre Sdn Bhd
city: Singapore
country: Singapore
facility: National Cancer Center
city: Singapore
country: Singapore
facility: National University Hospital
city: Singapore
country: Singapore
facility: Raffles Hospital
city: Barcelona
country: Spain
facility: Hospital Universitari Vall d'Hebron
city: Madrid
country: Spain
facility: Hospital General Universitario Gregorio Marañon
city: Valencia
country: Spain
facility: Hospital Clinico Universitario
city: Vigo
country: Spain
facility: Hospital Alvaro Cunqueiro
city: Kaohsiung
country: Taiwan
facility: Chang Gung Memorial Hospital-Kaohsiung
city: Taichung
country: Taiwan
facility: China Medical University Hospital
city: Taichung
country: Taiwan
facility: Taichung Veterans General Hospital
city: Taipei
country: Taiwan
facility: National Taiwan University Hospital
city: Taipei
country: Taiwan
facility: Taipei Veterans General Hospital
city: Taipei
country: Taiwan
facility: Tri-Service General Hospital
city: Taoyuan
country: Taiwan
facility: Chang Gung Memorial Hospital Linkou
Study officials:
affiliation: Merck KGaA, Darmstadt, Germany
name: Medical Responsible
role: STUDY_DIRECTOR
References:
citation: 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.