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)
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 88
- 试验地点
- 44
- 主要终点
- Phase 1b: Number of Participants Experiencing at Least One Dose Limiting Toxicity (DLT)
研究概览
简要总结
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).
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
- •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.
排除标准
- 未提供
研究组 & 干预措施
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.
干预措施: Tepotinib (Drug)
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.
干预措施: Gefitinib (Drug)
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.
干预措施: Tepotinib (Drug)
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.
干预措施: Gefitinib (Drug)
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.
干预措施: Tepotinib (Drug)
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.
干预措施: Gefitinib (Drug)
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.
干预措施: Pemetrexed (Drug)
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.
干预措施: Cisplatin (Drug)
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.
干预措施: Carboplatin (Drug)
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.
干预措施: Tepotinib (Drug)
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.
干预措施: Gefitinib (Drug)
结局指标
主要结局
Phase 1b: Number of Participants Experiencing at Least One Dose Limiting Toxicity (DLT)
时间窗: Day 1 to Day 21 of Cycle 1 (each cycle is 21 days)
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.
Phase 2 (Randomized Part Only): Progression-free Survival (PFS) Based on Tumor Assessment by the Investigator
时间窗: Up to 328 weeks
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.
Phase 1b: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs
时间窗: Up to 175 weeks
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.
次要结局
- 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))
- 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: 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: 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(Up to 175 weeks)
- Phase 1b: Number of Participants With Death and Reasons(Up to 175 weeks)
- 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: 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(Up to 328 weeks)
- 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: Apparent Total Body Clearance From Plasma (CL/F) of Tepotinib 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 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(Up to 328 weeks)
- Phase 1b: Apparent Terminal Half-Life (t1/2) 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: Time to Reach Maximum Plasma Concentration (Tmax) 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 From Time Zero to Infinity (AUC 0-infinity) 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: Apparent Volume of Distribution (Vz/F) During the Terminal Phase 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: Apparent Volume of Distribution During the Steady State (Vss/F) 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: Apparent Terminal Elimination Rate Constant Lambda(z) 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: Number of Participants With Clinically Significant Abnormalities in 12-Lead Electrocardiograms (ECG) Findings(Up to 175 weeks)
- 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(Up to 328 weeks)
- 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(Up to 328 weeks)
- Phase 1b: Number of Participants With Clinically Significant Abnormalities in Vital Signs(Up to 175 weeks)
- 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(Up to 175 weeks)
- 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)(Up to 175 weeks)
- Phase 2: Number of Participants With Death and Reasons(Up to 328 weeks)
- Phase 2 (Non-Randomized Part Only): Progression-free Survival (PFS) Based on Tumor Assessment by Investigator(Up to 328 weeks)
- Phase 1b: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) Leading to Permanent Treatment Discontinuation(Up to 175 weeks)
- Phase 1b: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status Score of 2 or Higher Than 2(Up to 175 weeks)
- 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(Up to 328 weeks)
- Phase 2: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) Leading to Permanent Treatment Discontinuation(Up to 328 weeks)
- Phase 2 (Randomized Part Only): Progression-free Survival (PFS) Based on Tumor Assessment by Independent Review Committee (IRC)(Up to 328 weeks)
- Phase 2 (Non-Randomized Part Only): Progression-free Survival (PFS) Based on Tumor Assessment by Independent Review Committee (IRC)(Up to 328 weeks)
- 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)(Up to 328 weeks)
- Phase 2: Number of Participants With Clinically Significant Abnormalities in Vital Signs(Up to 328 weeks)
- 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(Up to 328 weeks)
- Phase 2: Number of Participants With Clinically Significant Abnormalities in 12-Lead Electrocardiograms (ECG) Findings(Up to 328 weeks)
- Phase 2: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status Score of 2 or Higher Than 2(Up to 328 weeks)
- Phase 2: (Randomized Part Only): Overall Survival (OS) Time(Up to 328 weeks)
- 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(Up to 328 weeks)
- 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(Up to 328 weeks)
- 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)(Baseline and EOT (up to 110 weeks))
- Phase 2: (Non-Randomized Part Only): Overall Survival (OS) Time(Up to 328 weeks)
- Phase 2: Time-to-Symptom Progression (TTSP)(Up to 328 weeks)