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) (BRAF^V600-mutant) or T (BRAF^V600-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 (7/21) at 120, 240, or 480 mg plus either T 2 mg PO QD and D 150 mg PO BID (Arm 1; BRAF^V600-mutant) or T 2 mg QD (Arm 2; BRAF^{nonV600-mutant}). Results: At the time of this analysis, 21 pts (median age, 58 y [range 24–76]; male, n = 11; at least 2 systemic treatments, n = 15) were treated. Arm 2 enrolled first: AMG 232 120 mg (n = 6), then 240 mg (n = 6). Due to chronic grade (G) 2 gastrointestinal toxicity, an intermediate dose (180 mg; n = 3) was determined as the preliminary MTD. Arm 1 enrolled at AMG 232 120 mg (n = 4), then 180 mg (n = 2). The most common reasons for AMG 232 withdrawal were disease progression (n = 8) and AEs (n = 4); 6 pts remain on AMG 232. All 21 pts had treatment-related AEs (TRAEs); the most common TRAEs were nausea (n = 18), fatigue (n = 17), diarrhea (n = 14), and vomiting (n = 13). The only DLT (Arm 2; 240 mg) was G 3 pulmonary embolism. Preliminary PK analysis suggests that AMG 232 exposure (area under the curve) is similar to that as monotherapy at the same dose, with no apparent drug-drug interaction between AMG 232 and T; analysis of D and T PK is ongoing. Of 21 pts, 6 had partial response (Arm 1/2, n = 4 [67%]/2 [13%]), 13 had stable disease (Arm 1/2, n = 2 [33%]/11 [73%]), and 2 progressed (Arm 1/2, n = 0/2 [13%]) as best response; 17 had tumor reduction (Arm 1/2, n = 6 [100%]/11 [73%]). Conclusions: In this population of pts with MCM, AMG 232 combined with D and/or T during DE was tolerable up to 180 mg QD 7/21 days, showing an acceptable PK profile and early antitumor activity. Clinical trial information: NCT02110355