Phase 1 study of the p53-MDM2 inhibitor AMG 232 combined with trametinib plus dabrafenib or trametinib in patients (Pts) with TP53 wild type (TP53WT) metastatic cutaneous melanoma (MCM).
Stergios J Moschos, Shahneen Kaur Sandhu, Karl D Lewis, Ryan J Sullivan, Douglas Buckner Johnson, Yilong Zhang, Erik Rasmussen, Haby A Henary, Georgina V Long
JOURNAL OF CLINICAL ONCOLOGY | AMER SOC CLINICAL ONCOLOGY | Published : 2017
2575 Background: Large sequencing studies in MCM have shown a TP53WT incidence of approximately 80%. In preclinical TP53WT melanoma models, the oral p53-MDM2 inhibitor AMG 232 exhibited synergistic, cytotoxic-type antitumor activity when combined with MAPK inhibitors. This phase 1 study assessed the toxicity (CTCAE 4.03), maximum tolerated dose (MTD), pharmacokinetics (PK), and preliminary antitumor activity (RECIST 1.1) of AMG 232 plus trametinib (T) and dabrafenib (D) (BRAFV600-mutant) or T (BRAFV600-WT) in pts with TP53WT MCM. Methods: Using 3+3 dose escalation design, pts with advanced TP53WT (using a CLIA-approved assay) MCM received AMG 232 PO QD for seven days of each 3-week cycle (7..View full abstract