Locally Advanced or Metastatic Non-small Cell Lung Cancer (NSCLC) MedDRA version: 19.1 Level: PT Classification code 10059515 Term: Non-small cell lung cancer metastatic System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Conditions
Interventions
Product Name: Tepotinib
Product Code: MSC2156119J
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: tepotinib
Current Sponsor code: MSC2156119J
Other descriptive name: MSC2156119J
Concentra
Sponsors
Merck KGaA
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Phase Ib a) Histologically or cytologically confirmed advanced NSCLC, regardless of histology subtype, which failed on gefitinib for reasons other than toxicity or compliance; b) Availability of a fresh or archived pretreatment 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 enrollment is mandatory; c) MET+ status, as determined by the central laboratory, i.e. c-Met overexpression as determined by immunohistochemistry (IHC) (i.e., IHC 2+ or IHC 3+); d) Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1. Phase II a) Locally advanced or metastatic NSCLC other than predominantly squamous histology (confirmed by either histology or cytology); b) Activating mutation of the EGFR receptor (documented, or as determined by the central laboratory); c) Acquired resistance on first line EGFR-TKI therapy including gefitinib, erlotinib, icotinib, or afatinib; d) EGFR T790M status (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) e) Availability of a fresh or archived tumor tissue (excluding fine needle aspiration and cytology samples) obtained between documentation of acquired resistance to EGFR-TKI therapy including gefitinib, erlotinib, icotinib, or afatinib and enrollment is mandatory; f) 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; g) ECOG PS of 0 or 1. Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 80 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 112
Exclusion criteria
Exclusion criteria: Phase Ib .Subjects are not eligible for Phase Ib if they fulfill any of the following exclusion criteria: Cancer Related 1.Symptomatic metastasis of brain and/or CNS, uncontrolled with antiepileptics and requiring steroids, unless treated and stable without steroids for at least 10 days within 4 weeks prior to the first dose of trial treatment; 2.Any unresolved toxicity more than National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) (Version 4.0) Grade 2 from previous anticancer therapy; 3.Estimated life expectancy 1.5 × upper limit of normal (ULN)Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) > 3 × ULN; For subjects with liver metastases:Total bilirubin > 1.5 × ULNAST/ALT > 5 × ULN 3.Known pre-existing interstitial lung disease 4.Inadequate renal function: 6.Renal impairment as evidenced by serum creatinine ? 1.5 × ULN, or creatinine clearance (CrCl) < 60 mL/min calculated by the Cockcroft-Gault formula (24 hour CrCl might be requested by the investigator for confirmation, if calculated CrCl is < 60 mL/min. In such case, subjects with 24 hour CrCl < 60 mL/min should be excluded 5.Subjects who have ongoing medical history of acute pancreatitis and/or chronic pancreatitis, with concomitant elevated lipase and/or amylase, clinical symptoms, and/or imaging studies that are indicative of the diagnosis (subjects in mainland China only) General 1.Impaired cardiac function Left ventricular ejection fraction (LVEF) < 45% defined by echocardiography (a screening LVEF assessment without history of congestive heart failure [CHF] is not required) Serious arrhythmia Unstable angina pectoris CHF New York Heart Association (NYHA) III and IV (Appendix E) Myocardial infarction within the last 12 months prior to trial entry Signs of pericardial effusion 2.Hypertension uncontrolled by standard therapies (not stabilized to <150/90 mmHg) 3.Contraindication to the administration of gefitinib 4.Medical history of liver fibrosis/cirrhosis 5.Past or current history of neoplasm other than NSCLC, except for curatively treated non melanoma skin cancer, in situ carcinoma of the cervix, or other cancer curatively treated and with no evidence of disease for at least 5 years; 6.Medical history of difficulty swallowing, malabsorption, or other chronic gastrointestinal disease, or conditions that may hamper compliance and/or absorption of the tested product 7.Major surgery within 28 days prior to Day 1 of trial treatment 8.Known human immunodeficiency virus positivity 9.Substance abuse, active infection, or other acute or chronic medical or psychiatric condition or laboratory abnormalities that might increase the risk associated with study participation at the discretion of investigators 10.Female subjects who are pregnant or lactating, or men and women of reproductive potential not willing or not able to employ a highly effective method of birth control/contraception to prevent pregnancy until the
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Phase Ib ? To determine the RP2D of tepotinib when used in combination with gefitinib (at the approved standard dose of 250 mg) when administered orally once daily over a 21-day cycle in subjects with MET+ advanced NSCLC. Phase II To evaluate whether the efficacy in terms of progression free survival (PFS) of second-line tepotinib in combination with gefitinib is superior to pemetrexed+cisplatin/carboplatin in subjects with T790M negative, MET+ locally advanced or metastatic NSCLC harboring an EGFR mutation and having acquired resistance to first-line EGFR-TKI therapy including gefitinib, erlotinib, icotinib, or afatinib;Secondary Objective: Phase Ib To characterize the PK of tepotinib when given in combination with gefitinib To characterize the PK of gefitinib when given in combination with tepotinib To assess the safety and tolerability of tepotinib in combination with gefitinib To evaluate preliminary antitumor activity of tepotinib in combination with gefitinib Phase II To evaluate the safety and tolerability of tepotinib in comb with gefitinib To evaluate the efficacy of tepotinib in combination with gefitinib in T790M negative, MET+ subjects To evaluate the antitumor activity of tepotinib in combination with gefitinib in T790M positive, MET+ subjects in a separate single-arm cohort (mainland China sites only) To assess patient-reported outcomes (PROs) with respect to quality of life (QoL), as measured by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) and time-to-symptom progression (TTSP), as measured by Lung Cancer Symptom Scale (LCSS);Primary end point(s): 1- Phase 1b: Number of subjects experiencing at least one dose limiting toxicity (DLT) 2- Phase 1b: Percentage of subjects with adverse events (AEs) 3- Phase 2 (randomized): Progression free survival (PFS) time: Investigator assessments or site radiologist assessment;Timepoint(s) of evaluation of this end point: 1- Up to | — |
Secondary
| Measure | Time frame |
|---|---|
| Timepoint(s) of evaluation of this end point: 1- Time from randomiz. to death or up to 8 mo whichever occur first 2- Time from 1st drug adm. to death or up to 8 mo whichever occur 1st 3- Time from random. to death or up to 10 mo whichever occur 1st 4- endpoint number 7 and 8: Every 6 wks until Wk 72 and every 12 weeks after Wk 72 til radiol. documented PD, death, end of trial, or starting a new treatment, whichever occurs first 5- Pre dose, 0.25, 0.5, 1, 2, 4, 8, 10 and 24 h post dose on D 1 and 15 of Cycle 1 6- 0 up to D 30 after the last dose 7 to 18- Pre dose, 0.25, 0.5, 1, 2, 4, 8, 10 and 24 h post dose on D 1 and 15 of Cycle 1 19- 30 days after the last dose 20, and 21- 0 up to Day30 after the last dose 22 and 23- D 1 of Cycles 1, 3, 5, 7, 9, 11, 13, 15, 17 and every 4 cycles thereafter until PD, and end of treatment ;Secondary end point(s): 1. Phase 2 (randomized): Progression free survival (PFS) time: Independent review assessments 2. Phase 2 (single arm cohort): Progression free survival (PFS) time: Investigator and Independent review assessment 3. Overall Survival (OS) Time 4. Percentage of subjects with objective response according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v 1.1) criteria 5. Percentage of subjects with disease control according to RECIST version 1.1 criteria 6. Phase 1b: Area Under the Plasma Concentration Versus Time Curve from Time Zero to the Last Sampling Time AUC (0-t) 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 8. Phase 1b: Area Under the Plasma Concentration Versus Time Curve within 1 dosing interval (AUC 0-tau) 9. Phase 1b: Maximum Observed Plasma Concentration (Cmax) 10. Phase 1b: Average Plasma Concentration (Cavg) 11. Phase 1b: Minimum Concentration (Cmin) 12. Phase 1b:Time to Maximum Co | — |
Countries
Austria, Bosnia and Herzegovina, Bulgaria, Canada, China, Czech Republic, France, Germany, Hungary, Israel, Italy, Japan, Korea, Democratic People's Republic of, Malaysia, Netherlands, Poland, Portugal, Romania, Singapore, Slovakia, Slovenia, Spain, Taiwan, United Kingdom, United States
Contacts
Public ContactCommunication Center Merck KGaA
Merck KGaA
Outcome results
None listed