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Report for Clinical Trial NCT01982955

Developed by Shray Alag, 2020.
SNP Clinical Trial Gene

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 Non‑Small Cell Lung Cancer (NSCLC) Harboring EGFR Mutation and Having Acquired Resistance to Prior EGFR-Tyrosine Kinase Inhibitor (EGFR‑TKI) Therapy

This is a multi-center, open-label, randomized, Phase 1b/2 trial 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 subjects 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).

NCT01982955 Non-small Cell Lung Cancer
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

5 Interventions

Name: Tepotinib

Description: Tepotinib will be 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, subject's withdrawal from treatment. RP2D will be determined as per safety monitoring committee (SMC) discretion.
Type: Drug
Group Labels: 1

Tepotinib plus Gefitinib

Name: Gefitinib

Description: Gefitinib will be administered at a dose of 250 mg orally as once daily over a 21-day cycle until progressive disease, intolerable toxicity, subject's withdrawal from treatment.
Type: Drug
Group Labels: 1

Tepotinib plus Gefitinib

Name: Pemetrexed

Description: Pemetrexed will be 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, subject's withdrawal from treatment or up to 6 cycles if pemetrexed maintenance is not considered.
Type: Drug
Group Labels: 1

Pemetrexed plus Cisplatin/Carboplatin

Name: Cisplatin

Description: Cisplatin will be 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, subject's withdrawal from treatment or up to 6 cycles if pemetrexed maintenance is not considered.
Type: Drug
Group Labels: 1

Pemetrexed plus Cisplatin/Carboplatin

Name: Carboplatin

Description: Carboplatin will be 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, subject's withdrawal from treatment or up to 6 cycles if pemetrexed maintenance is not considered
Type: Drug
Group Labels: 1

Pemetrexed plus Cisplatin/Carboplatin


Primary Outcomes

Measure: Phase 1b: Number of subjects experiencing at least one dose limiting toxicity (DLT)

Time: Up to Day 21 of Cycle 1

Measure: Phase 1b: Percentage of subjects with adverse events (AEs)

Time: Baseline up to Day 30 after the last dose of study treatment

Description: PFS (assessed by investigator/site radiologist) time is defined as the time (in months) from randomization to either the first disease progression (PD) per RECIST Version 1.1 or death in T790M negative, MET+ subjects due to any cause within 84 days of either randomization or last tumor assessment. If no progression or death is observed, or if death without previously documented PD is observed after more than 84 days of last tumor assessment without progression, the PFS time will be censored on the date of last tumor assessment/date of randomization, whatever occurs later.

Measure: Phase 2 (randomized): Progression free survival (PFS) time: Investigator assessments or site radiologist assessment

Time: Up to 8 months

Secondary Outcomes

Description: PFS time is defined as the time (in months) from randomization either the first observation of PD (as assessed by the independent review committee) or occurrence of death due to any cause within 84 days of either randomization or the last tumor assessment.

Measure: Phase 2 (randomized): Progression free survival (PFS) time: Independent review assessments

Time: Time from randomization to the date of death or up to 8 months whichever occur first

Description: PFS time is defined as the time (in months) from the first administration of the trial treatment to either the first observation of documented PD per RECIST Version 1.1 or occurrence of death due to any cause within 84 days of either the first administration of the trial treatment or the last tumor assessment.

Measure: Phase 2 (single arm cohort): Progression free survival (PFS) time: Investigator and Independent review assessment

Time: Time from first administration of trial treatment to the date of death or up to 8 months whichever occur first

Description: OS time is defined as the time (in months) from randomization/the first administration of the trial treatment to the date of death in the randomized part of Phase 2/the single-arm cohort of Phase 2

Measure: Overall Survival (OS) Time

Time: Time from randomization to the date of death or up to 10 months whichever occur first

Description: Objective response is defined as complete response (CR) or partial response (PR) as the best overall response according to local radiological assessments from randomization/the first administration of the trial treatment to the first observation of PD.

Measure: Percentage of subjects with objective response according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v 1.1) criteria

Time: Every 6 weeks until Week 72 and every 12 weeks after Week 72 until radiologically documented progressive disease, death, end of trial, or starting a new treatment, whichever occurs first (assessed up to 3.5 years)

Description: Disease control is defined as CR, PR, or stable disease (SD) as the best overall response according to local radiological assessments from the date of randomization/the first administration of the trial treatment to the first observation of PD. In the case of SD, measurements must have met the SD criteria at least once after entry at a minimum interval of 42 days after randomization/the first administration of the trial treatment;

Measure: Percentage of subjects with disease control according to RECIST version 1.1 criteria

Time: Time Frame: Every 6 weeks until Week 72 and every 12 weeks after Week 72 until radiologically documented progressive disease, death, end of trial, or starting a new treatment, whichever occurs first (assessed up to 3.5 years)

Measure: Phase 1b: Area Under the Plasma Concentration Versus Time Curve from Time Zero to the Last Sampling Time AUC (0-t)

Time: Pre dose, 0.25, 0.5, 1, 2, 4, 8, 10 and 24 hours post dose on Day 1 and 15 of Cycle 1

Measure: Percentage of subject with treatment emergent adverse events (TEAEs), treatment related TEAEs, SAEs, treatment related SAEs, TEAEs with toxicity >= 3, treatment related TEAEs >= 3, and TEAEs leading to permanent treatment discontinuation

Time: Baseline up to Day 30 after the last dose of study treatment

Measure: Phase 1b: Area Under the Plasma Concentration Versus Time Curve within 1 dosing interval (AUC 0-tau)

Time: Pre dose, 0.25, 0.5, 1, 2, 4, 8, 10 and 24 hours post dose on Day 1 and 15 of Cycle 1

Measure: Phase 1b: Maximum Observed Plasma Concentration (Cmax)

Time: Pre dose, 0.25, 0.5, 1, 2, 4, 8, 10 and 24 hours post dose on Day 1 and 15 of Cycle 1

Measure: Phase 1b: Average Plasma Concentration (Cavg)

Time: Pre dose, 0.25, 0.5, 1, 2, 4, 8, 10 and 24 hours post dose on Day 1 and 15 of Cycle 1

Measure: Phase 1b: Minimum Concentration (Cmin)

Time: Pre dose, 0.25, 0.5, 1, 2, 4, 8, 10 and 24 hours post dose on Day 1 and 15 of Cycle 1

Measure: Phase 1b:Time to Maximum Concentration (Tmax)

Time: Pre dose, 0.25, 0.5, 1, 2, 4, 8, 10 and 24 hours post dose on Day 1 and 15 of Cycle 1

Measure: Phase 1b: Area Under the Curve From Time Zero to Infinity (AUC 0-inf)

Time: Pre dose, 0.25, 0.5, 1, 2, 4, 8, 10 and 24 hours post dose on Day 1 and 15 of Cycle 1

Measure: Phase 1b: Apparent Body Clearance of the drug from Plasma (CL/F)

Time: Pre dose, 0.25, 0.5, 1, 2, 4, 8, 10 and 24 hours post dose on Day 1 and 15 of Cycle 1

Measure: Phase 1b: Apparent Volume of Distribution (Vz/F)

Time: Pre dose, 0.25, 0.5, 1, 2, 4, 8, 10 and 24 hours post dose on Day 1 and 15 of Cycle 1

Measure: Phase 1b: Volume of Distribution at Steady State (Vss/F)

Time: Pre dose, 0.25, 0.5, 1, 2, 4, 8, 10 and 24 hours post dose on Day 1 and 15 of Cycle 1

Measure: Phase 1b: Apparent Terminal Rate Constant (λ z)

Time: Pre dose, 0.25, 0.5, 1, 2, 4, 8, 10 and 24 hours post dose on Day 1 and 15 of Cycle 1

Measure: Phase 1b: Apparent Terminal Half-Life (t1/2)

Time: Pre dose, 0.25, 0.5, 1, 2, 4, 8, 10 and 24 hours post dose on Day 1 and 15 of Cycle 1

Measure: Percentage of subjects with death with reasons within 30 (±3) days after the last dose of study drug

Time: 30 days after the last dose of study drug

Measure: Percentage of subjects with abnormalities in safety laboratory tests as graded by NCI-CTCAE (Version 4.0)

Time: Baseline up to Day 30 after the last dose of study treatment

Measure: Percentage of subjects with abnormalities incl. vital signs, 12-lead ECG changes, physical examination, body weight, and Eastern Cooperative Oncology Group (ECOG) PS

Time: Baseline up to Day 30 after the last dose of study treatment

Measure: Health related quality of life (HRQoL)

Time: Day 1 of Cycles 1, 3, 5, 7, 9, 11, 13, 15, 17 and every 4 cycles thereafter until disease progression or end of treatment (up to 14 days after the last dose of study drug, assessed up to 3.5 years)

Measure: Time-to-Symptom Progression (TTSP) measured by Lung Cancer Symptom Scale (LCSS)

Time: Day 1 of Cycles 1, 3, 5, 7, 9, 11, 13, 15, 17 and every 4 cycles thereafter until disease progression or end of treatment (up to 14 days after the last dose of study drug, assessed up to 3.5 years)

Purpose: Treatment

Allocation: Randomized

Parallel Assignment


There is one SNP

SNPs


1 T790M

Tepotinib With Gefitinib in Subjects With Locally Advanced or Metastatic Non-small Cell Lung Cancer (NSCLC) This is a multi-center, open-label, randomized, Phase 1b/2 trial 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 subjects 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. --- T790M ---

PFS (assessed by investigator/site radiologist) time is defined as the time (in months) from randomization to either the first disease progression (PD) per RECIST Version 1.1 or death in T790M negative, MET+ subjects due to any cause within 84 days of either randomization or last tumor assessment. --- T790M ---

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 trial 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. --- T790M ---

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 trial 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. --- T790M --- --- T790M ---

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 trial 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. --- T790M --- --- T790M --- --- T790M ---



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