A phase I pharmacokinetic (PK) and pharmacodynamic (PD) study of PLX9486 alone and in combination (combo) with the KIT inhibitors pexidartinib (pexi) or sunitinib (su) in patients (Pts) with advanced solid tumors and gastrointestinal stromal tumor (GIST).

11509Background: Most metastatic GISTs have primary (10) mut in KIT exons (ex) 9 or 11, which confer sensitivity to imatinib and other agents. Tumors develop clonal secondary (2y) resistance mut, typically in ex 13, 14, 17, and 18. PLX9486 inhibits KIT 10 mut and ex 17 and 18 2y mut. Pexi (PLX3397) and su inhibit 10 mut and ex 13 and 14 2y mut. Combo of PLX9486 with pexi or su may have activity against a broader spectrum of mutations. Methods: 3 + 3 dose escalation study in pts with solid tumors and GIST who had progressed on imatinib and other TKI. Safety, efficacy per RECIST, and PK were assessed. Ct DNA was assessed as a biomarker. Part (P) 1: single agent PLX9486 dose escalation once (QD) and twice daily (BID). P2: combos of PLX9486 500 mg QD with pexi 600 mg QD fed and fasted or su 25 mg QD with food. Results: As of January 8, 2018, 36 pts (31 GIST; Part 1-20 pts, part 2-11 pts) were enrolled; median age was 63 years (range 49-82). GIST pts had a median of 4 prior therapies (range 1-7), and all progr...