Phase Ia:
A. To determine the recommended phase II dose (RP2D) of tepotinib for patients with brain metastasis and MET alterations (Group A)
B. To determine RP2D of tepotinib in patients with GLIOBLASTOMA with MET alterations (Group B)
C. To determine RP2D of tepotinib in combination with osimertinib in patients with EGFR+ NSCLC with EGFR TKI resistance and MET amplification (Group C)
Phase 1b:
A. To determine intracranial clinical benefit of tepotinib in brain mets, as measured by RANO-BM, in patients with NSCLC and METex14-skipping mutations (Group A) C. To determine intracranial clinical benefit of tepotinib in combination with osimertinib, in brain metastasis, as measured by RANO-BM, in patients with EGFR+ NSCLC with EGFR TKI resistance and MET amplification (Group C)
2.2 Secondary Objectives:
Phase 1a:
A1. To evaluate the safety and toxicity of tepotinib in treating brain metastasis in patients with MET alterations in Group A, as measured by CTCAE, version 5.0 A2. To evaluate the PK/PD (including phosphomet level) of tepotinib in brain metastasis tissue and CSF in patients with MET alterations in Group A A3. To determine overall survival in Group A A4. To determine progression-free survival for intracranial disease and extracranial disease in Group A A5. To determine intracranial objective response rate according to RANO-BM and the modified Response Evaluation Criteria in Solid Tumors (mRECIST) \[Qianet al., 2017\] of Group A A6. To determine extracranial objective reponse rate as assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 of Group A A7. To identify the site of first progression (intracranial vs extracranial) in Group A A8.To determine the duration of intracranial response by BM-RANO and by mRECIST in Group A A9. To determine the duration of extracranial response by RECIST 1.1 in Group A A10. To determine the time to intracranial progression (defined as progression of existing lesions and development of new lesions) in Group A A11. To explore the patient experience with treatment using patient-reported outcomes (PROs) using the MDASI-BT and EQ-5D-5L questionnaires in Group A A12. To identify the frequency of grade 3+ toxicities at 4 weeks, and 3, 6, 9, 12 and 18 months in Group A A13. To determine changes in dose, duration and frequency of steroid use for symptomatic management in Group A
B1. To evaluate the safety and toxicity of tepotinib in treating glioblastoma in patients with MET alterations (Group B), as measured by CTCAE, version 5.0 B2. To evaluate the PK/PD (including phosphomet level) of tepotinib in glioblastoma tissue and CSF in patients with MET alterations in Group B B3. To determine survival (PFS, OS) of Group B B4. To determine objective response rate according to RANO of Group B B5.To determine the duration of response by RANO in Group B B6. To determine the time to progression (defined as progression of existing lesions and development of new lesions) in Group B B7. To explore the patient experience with treatment using patient-reported outcomes (PROs) using the MDASI-BT and EQ-5D-5L questionnaires in Group B B8. To identify the frequency of grade 3+ toxicities at 4 weeks, and 3, 6, 9, 12 and 18 months in Group B B9. To determine changes in dose, duration and frequency of steroid use for symptomatic management in Group B
C1. To evaluate the safety and toxicity of the combination of osimertinib and tepotinib in treating patients with EGFR+ NSCLC with EGFR TKI resistance and MET amplification, with (Group C), as measured by CTCAE, version 5.0 C2. To evaluate the PK/PD (including phosphomet level) of tepotinib in CSF in patients with EGFR+ NSCLC with EGFR TKI resistance and MET amplification treated with the combination of osimertinib and tepotinib (Group C) C3. To determine overall survival in Group C C4. To determine progression-free survival for intracranial disease and extracranial disease in Group C C5. To determine intracranial objective response rate according to RANO-BM and mRECIST of Group C C6. To determine extracranial objective response rate as assessed by RECIST v1.1 for Group C C7. To identify the site of first progression (intracranial vs extracranial) in Group C C8.To determine the duration of intracranial response by BM-RANO and by mRECIST in Group C C9. To determine the duration of extracranial response by RECIST 1.1 in Group C C10. To determine the time to intracranial progression (defined as progression of existing lesions and development of new lesions) in Group C C11. To explore the patient experience with treatment using patient-reported outcomes (PROs) using the MDASI-BT and EQ-5D-5L questionnaires in Group C C12. To identify the frequency of grade 3+ toxicities at 4 weeks, and 3, 6, 9, 12 and 18 months in Group C C13. To determine changes in dose, duration and frequency of steroid use for symptomatic management in Group C
Phase 1b:
A1. To evaluate the safety and toxicity of tepotinib as measured by CTCAE, version 5.0 in patients with NSCLC and METex14-skipping mutations (Group A) A2. To evaluate the PK/PD (including phosphomet level) of tepotinib in the CSF in patients with NSCLC and METex14-skipping mutations (Group A) A3. To determine overall survival in Group A A4. To determine progression-free survival for intracranial disease and extracranial disease in Group A A5. To determine intracranial objective response rate according to RANO-BM and mRECIST of Group A A6. To determine extracranial objective reponse rate as assessed by RECIST v1.1 of Group A A7. To identify the site of first progression (intracranial vs extracranial) in Group A A8.To determine the duration of intracranial response by BM-RANO and by mRECIST in Group A A9. To determine the duration of extracranial response by RECIST 1.1 in Group A A10. To determine the time to intracranial progression (defined as progression of existing lesions and development of new lesions) in Group A A11. To explore the patient experience with treatment using patient-reported outcomes (PROs) using the MDASI-BT and EQ-5D-5L questionnaires in Group A A12. To identify the frequency of grade 3+ toxicities at 4 weeks, and 3, 6, 9, 12 and 18 months in Group A A13. To determine changes in dose, duration and frequency of steroid use for symptomatic management in Group A
C1. To evaluate the safety andtoxicity as measured by CTCAE, version 5.0, in patients with EGFR+ NSCLC with EGFR TKI resistance and MET amplification (Group C) C2. To evaluate the PK/PD (including phosphomet level) of tepotinib in CSF in patients with EGFR TKI resistance and MET amplification (Group C) C3. To determine overall survival in Group C C4. To determine progression-free survival for intracranial disease and extracranial disease in Group C C5. To determine intracranial objective response rate according to RANO-BM and mRECIST of Group C C6. To determine extracranial objective reponse rate as assessed by RECIST v1.1 for Group C C7. To identify the site of first progression (intracranial vs extracranial) in Group C C8.To determine the duration of intracranial response by BM-RANO and by mRECIST in Group C C9. To determine the duration of extracranial response by RECIST 1.1 in Group C C10. To determine the time to intracranial progression (defined as progression of existing lesions and development of new lesions) in Group C C11. To explore the patient experience with treatment using patient-reported outcomes (PROs) using the MDASI-BT and EQ-5D-5L questionnaires in Group C C12. To identify the frequency of grade 3+ toxicities at 4 weeks, and 3, 6, 9, 12 and 18 months in Group C C13. To determine changes in dose, duration and frequency of steroid use for symptomatic management in Group C
