Neoplasms

Nervous System Diseases

All Conditions

Brain Neoplasms

Central Nervous System Neoplasms

Nervous System Neoplasms

Brain Diseases

Central Nervous System Diseases

Antineoplastic Agents

All Drugs and Chemicals

Amino Acids

Osimertinib

Tepotinib

Tyrosine Kinase Inhibitors

Protein Kinase Inhibitors

Enzyme Inhibitors

Tyrosine

tepotinib

tepotinib plus osimertinib

Barbara O'Brien, MD

This is a single center, multi-arm, biomarker-driven phase 1 study to assess the RP2D, PK/PD, safety, and activity of tepotinib in participants with MET alterations and brain tumors. Eligible patients include those with brain metastases or glioblastoma, including patients who are surgical candidates. In patients with EGFR+ NSCLC with EGFR-TKI resistance and MET amplification, tepotinib will be given in combination with osimertinib. This phase 1 study will be conducted in 2 parts, Phase 1a (dose exploration) and Phase 1b (dose expansion). Phase 1a will include a surgical resection window of opportunity component. Phase 1b (dose expansion) can open once the relevant RP2D has been estimated in Phase 1a (dose exploration). Phase 1a (Dose Exploration): Patients will be assigned to dose levels within a Group as outlined in the Statistical Analysis Plan. Group A will be comprised of patients who are surgical resection candidates with newly-diagnosed or recurrent brain metastases and MET alteration. Group B will be comprised of patients who are surgical resection candidates with recurrent glioblastoma and MET alteration. Group C will be comprised of patients with newly-diagnosed or recurrent brain metastases and epidermal growth factor receptor mutated (EGFR+) non-small cell lung cancer (NSCLC). Phase 1b (Dose Expansion): Upon completion of the Phase 1a (dose exploration) component and estimation of a RP2D, dose expansion may proceed within Group A (consisting of patients with brain metastasis and MET alteration) and Group C (EGFR+ NSCLC brain metastasis, TKI resistance, and MET amplification). Dose expansion in these 2 groups may be done concurrently, but enrollment in each group does not require completion of the entire Phase 1a component of the study. There will not be a Group B (glioblastoma) in Phase 1b. Patients in Phase 1b will not undergo surgical resection.

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

A Phase 1a/1b Study to Determine the Recommended Phase 2 Dose, of Tepotinib in Participants With MET Alterations and Brain Tumors

M.D. Anderson Cancer Center

Spots Global Cancer Trial Database for tepotinib plus osimertinib