Nonclinical There were no non-clinical (toxicology) objections to registration of either trametinib as monotherapy or trametinib in combination with dabrafenib. Clinical The clinical evaluator recommended rejection of the application. Overview of data Table 17: Studies relevant to this application Study ID Phase Study drug/s Population Endpoints / comments MEK111054 1 trametinib Solid tumours, FTIH; dose escalation; lymphomas anti-tumour activity. MEK113709 1 trametinib Solid tumours Food effect MEK113708 1 trametinib tumours Mass balance MEK115064 1 trametinib Solid tumours Absolute bioavailability MEK113583 2 trametinib BRAF mutant PK, efficacy, safety. melanoma, 2nd line MEK114267 3 trametinib BRAF PK, efficacy, safety. versus mutant advanced Pivotal for “METRIC” chemotherapy melanoma monotherapy. BRF113220 1-2 trametinib, BRAF mutant PK / interaction study dabrafenibA melanoma Part A BRF113220 1-2 trametinib, BRAF mutant PK, dose escalation dabrafenibA melanoma or Part B colorectal cancer BRF113220 2 dabrafenibA + BRAF V600E/K Pivotal for trametinib mutant advanced combination therapy. Part C versus melanoma dabrafenibA BRF113220 1-2 dabrafenibB; BRAF mutant PK dabrafenibB + melanoma Part D trametinib A: gelatin capsule; B: HPMC capsule (commercial dabrafenib uses the HPMC capsule) Some aspects of BRF113220, unrelated to combination therapy, were evaluated in the CER for dabrafenib (PM-2012-02231-3-4).
Nonclinical There were no non-clinical (toxicology) objections to registration of either trametinib as monotherapy or trametinib in combination with dabrafenib. Clinical The clinical evaluator recommended rejection of the application. Overview of data Table 17: Studies relevant to this application Study ID Phase Study drug/s Population Endpoints / comments MEK111054 1 trametinib Solid tumours, lymphomas FTIH; dose escalation; anti-tumour activity. MEK113709 1 trametinib Solid tumours Food effect MEK113708 1 trametinib tumours Mass balance MEK115064 1 trametinib Solid tumours Absolute bioavailability MEK113583 2 trametinib BRAF mutant melanoma, 2nd line PK, efficacy, safety. MEK114267 “METRIC” 3 trametinib versus chemotherapy BRAF mutant advanced melanoma PK, efficacy, safety. Pivotal for monotherapy. BRF113220 Part A 1-2 trametinib, dabrafenibA BRAF mutant melanoma PK / interaction study BRF113220 Part B 1-2 trametinib, dabrafenibA BRAF mutant melanoma or colorectal cancer PK, dose escalation BRF113220 Part C 2 dabrafenibA + trametinib versus dabrafenibA BRAF V600E/K mutant advanced melanoma Pivotal for combination therapy. BRF113220 Part D 1-2 dabrafenibB; dabrafenibB + trametinib BRAF mutant melanoma PK A: gelatin capsule; B: HPMC capsule (commercial dabrafenib uses the HPMC capsule) Some aspects of BRF113220, unrelated to combination therapy, were evaluated in the CER for dabrafenib (PM-2012-02231-3-4).
auspar-trametinib-140317.docx