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Tepotinib With Gefitinib in Subjects With Locally Advanced or Metastatic Non-small Cell Lung Cancer (NSCLC) (INSIGHT)

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ClinicalTrials.gov Identifier: NCT01982955
Recruitment Status : Active, not recruiting
First Posted : November 13, 2013
Last Update Posted : August 8, 2018
Sponsor:
Information provided by (Responsible Party):
Merck KGaA, Darmstadt, Germany

Brief Summary:
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).

Condition or disease Intervention/treatment Phase
Non-small Cell Lung Cancer Drug: Tepotinib Drug: Gefitinib Drug: Pemetrexed Drug: Cisplatin Drug: Carboplatin Phase 1 Phase 2

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 70 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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 Non‑Small Cell Lung Cancer (NSCLC) Harboring EGFR Mutation and Having Acquired Resistance to Prior EGFR-Tyrosine Kinase Inhibitor (EGFR‑TKI) Therapy
Actual Study Start Date : December 23, 2013
Actual Primary Completion Date : December 12, 2017
Estimated Study Completion Date : October 16, 2018

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Lung Cancer

Arm Intervention/treatment
Experimental: Tepotinib plus Gefitinib Drug: Tepotinib
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.

Drug: Gefitinib
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.

Active Comparator: Pemetrexed plus Cisplatin/Carboplatin
Subjects will either receive Pemetrexed plus Cisplatin combination or Pemetrexed plus Carboplatin combination.
Drug: Pemetrexed
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.

Drug: Cisplatin
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.

Drug: Carboplatin
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




Primary Outcome Measures :
  1. Phase 1b: Number of subjects experiencing at least one dose limiting toxicity (DLT) [ Time Frame: Up to Day 21 of Cycle 1 ]
  2. Phase 1b: Percentage of subjects with adverse events (AEs) [ Time Frame: Baseline up to Day 30 after the last dose of study treatment ]
  3. Phase 2 (randomized): Progression free survival (PFS) time: Investigator assessments or site radiologist assessment [ Time Frame: Up to 8 months ]
    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.


Secondary Outcome Measures :
  1. Phase 2 (randomized): Progression free survival (PFS) time: Independent review assessments [ Time Frame: Time from randomization to the date of death or up to 8 months whichever occur first ]
    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.

  2. Phase 2 (single arm cohort): Progression free survival (PFS) time: Investigator and Independent review assessment [ Time Frame: Time from first administration of trial treatment to the date of death or up to 8 months whichever occur first ]
    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.

  3. Overall Survival (OS) Time [ Time Frame: Time from randomization to the date of death or up to 10 months whichever occur first ]
    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

  4. Percentage of subjects with objective response according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v 1.1) criteria [ 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) ]
    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.

  5. Percentage of subjects with disease control according to RECIST version 1.1 criteria [ Time Frame: 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) ]
    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;

  6. Phase 1b: Area Under the Plasma Concentration Versus Time Curve from Time Zero to the Last Sampling Time AUC (0-t) [ Time Frame: Pre dose, 0.25, 0.5, 1, 2, 4, 8, 10 and 24 hours post dose on Day 1 and 15 of Cycle 1 ]
  7. 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 Frame: Baseline up to Day 30 after the last dose of study treatment ]
  8. Phase 1b: Area Under the Plasma Concentration Versus Time Curve within 1 dosing interval (AUC 0-tau) [ Time Frame: Pre dose, 0.25, 0.5, 1, 2, 4, 8, 10 and 24 hours post dose on Day 1 and 15 of Cycle 1 ]
  9. Phase 1b: Maximum Observed Plasma Concentration (Cmax) [ Time Frame: Pre dose, 0.25, 0.5, 1, 2, 4, 8, 10 and 24 hours post dose on Day 1 and 15 of Cycle 1 ]
  10. Phase 1b: Average Plasma Concentration (Cavg) [ Time Frame: Pre dose, 0.25, 0.5, 1, 2, 4, 8, 10 and 24 hours post dose on Day 1 and 15 of Cycle 1 ]
  11. Phase 1b: Minimum Concentration (Cmin) [ Time Frame: Pre dose, 0.25, 0.5, 1, 2, 4, 8, 10 and 24 hours post dose on Day 1 and 15 of Cycle 1 ]
  12. Phase 1b:Time to Maximum Concentration (Tmax) [ Time Frame: Pre dose, 0.25, 0.5, 1, 2, 4, 8, 10 and 24 hours post dose on Day 1 and 15 of Cycle 1 ]
  13. Phase 1b: Area Under the Curve From Time Zero to Infinity (AUC 0-inf) [ Time Frame: Pre dose, 0.25, 0.5, 1, 2, 4, 8, 10 and 24 hours post dose on Day 1 and 15 of Cycle 1 ]
  14. Phase 1b: Apparent Body Clearance of the drug from Plasma (CL/F) [ Time Frame: Pre dose, 0.25, 0.5, 1, 2, 4, 8, 10 and 24 hours post dose on Day 1 and 15 of Cycle 1 ]
  15. Phase 1b: Apparent Volume of Distribution (Vz/F) [ Time Frame: Pre dose, 0.25, 0.5, 1, 2, 4, 8, 10 and 24 hours post dose on Day 1 and 15 of Cycle 1 ]
  16. Phase 1b: Volume of Distribution at Steady State (Vss/F) [ Time Frame: Pre dose, 0.25, 0.5, 1, 2, 4, 8, 10 and 24 hours post dose on Day 1 and 15 of Cycle 1 ]
  17. Phase 1b: Apparent Terminal Rate Constant (λ z) [ Time Frame: Pre dose, 0.25, 0.5, 1, 2, 4, 8, 10 and 24 hours post dose on Day 1 and 15 of Cycle 1 ]
  18. Phase 1b: Apparent Terminal Half-Life (t1/2) [ Time Frame: Pre dose, 0.25, 0.5, 1, 2, 4, 8, 10 and 24 hours post dose on Day 1 and 15 of Cycle 1 ]
  19. Percentage of subjects with death with reasons within 30 (±3) days after the last dose of study drug [ Time Frame: 30 days after the last dose of study drug ]
  20. Percentage of subjects with abnormalities in safety laboratory tests as graded by NCI-CTCAE (Version 4.0) [ Time Frame: Baseline up to Day 30 after the last dose of study treatment ]
  21. Percentage of subjects with abnormalities incl. vital signs, 12-lead ECG changes, physical examination, body weight, and Eastern Cooperative Oncology Group (ECOG) PS [ Time Frame: Baseline up to Day 30 after the last dose of study treatment ]
  22. Health related quality of life (HRQoL) [ Time Frame: 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) ]
  23. Time-to-Symptom Progression (TTSP) measured by Lung Cancer Symptom Scale (LCSS) [ Time Frame: 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) ]


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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 subjects 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 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01982955


Locations
Germany
Please contact the Merck KGaA Communication Center located in
Darmstadt, Germany
Sponsors and Collaborators
Merck KGaA, Darmstadt, Germany
Investigators
Study Director: Medical Responsible Merck KGaA, Darmstadt, Germany

Responsible Party: Merck KGaA, Darmstadt, Germany
ClinicalTrials.gov Identifier: NCT01982955     History of Changes
Other Study ID Numbers: EMR 200095-006
2016-001604-28 ( EudraCT Number )
First Posted: November 13, 2013    Key Record Dates
Last Update Posted: August 8, 2018
Last Verified: August 2018

Keywords provided by Merck KGaA, Darmstadt, Germany:
MSC2156119J
Gefitinib
Pemetrexed
Cisplatin
MET positive
Tepotinib
Carboplatin
INSIGHT

Additional relevant MeSH terms:
Lung Neoplasms
Carcinoma, Non-Small-Cell Lung
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Neoplasms
Lung Diseases
Respiratory Tract Diseases
Carcinoma, Bronchogenic
Bronchial Neoplasms
Gefitinib
Cisplatin
Carboplatin
Pemetrexed
Antineoplastic Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Folic Acid Antagonists
Nucleic Acid Synthesis Inhibitors
Protein Kinase Inhibitors