A phase I pharmacological and pharmacodynamic study of MK-1775, a Wee1 tyrosine kinase inhibitor, in monotherapy and combination with gemcitabine, cisplatin, or carboplatin in patients with advanced solid tumors.

Abstract

3067 Background: MK-1775 (MK) is an inhibitor of the Wee1 kinase regulating the G2 checkpoint leading to chemo-sensitization in p53 deficient tumor cells. Down-regulation of pCDC2 upon treatment with MK and chemotherapy serves as biomarker in this study. Methods: Evaluation of safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of MK administered PO as monotherapy and combination with gemcitabine (G), cisplatin (P), or carboplatin (C). Part 1 is a single dose of MK followed by 1 of 3 treatment arms in PART 2A: single MK dose in combination with: 1) 1,000 mg/m2 G, 2) 75 mg/m2 P, or 3) C AUC 5. In Part 2B, 5BID doses of MK are explored in the same 3 arms. Part 3 is a cohort expansion to confirm maximum tolerated dose (MTD). PD biomarkers include pCDC2 and Wee1 signature. Results: To date, 91 pts (41 in monotherapy, 50 in combination therapy) were treated with MK. No DLTs were observed in monotherapy; 7 (single dose) and 13 pts (multiple dose) experienced DLTs in combination therapy. Most common AEs are hematological, nausea/vomiting, fatigue. PK was linear from 25 to 1,300 mg MK. MTDs of MK in combination with G, C, P as a single dose and as multiple dose in combination with G were identified; dose finding with C and P is ongoing. Marker responses were observed in 3 melanoma, 1 pancreatic, and 3 ovarian cancer pts. 50% reduction of pCDC2 in mono and combination therapy and significant changes in Wee1 signature in monotherapy substantiate target engagement. Conclusions: MK is a first-in-class Wee1 inhibitor that is well tolerated in monotherapy and in combination with chemotherapy; it shows strong target engagement along with clinical and biomarker responses in previously treated pts. MK+G single dose MK+P single dose MK+C single dose MK+G multiple dose MK+P multiple dose MK+C multiple dose N 14 13 16 21 13 16 MTD 200 mg 200 mg 325 mg 50/25 mg* 125 mg** 225 mg** PR (%) 0 (0) 1 0 0 2 0 SD (%) 4 (28.6) 4 (30.8) 3 (18.8) 6 (28.6) 1 (7.7) 2 (12.5) Target engagement Y Y Y marginal Y Y Related AEs≥grade 3 (%) 5 (35.7) 4 (30.8) 1 (6.3) 12 (57.1) 4 (30.8) 6 (37.5) * 50 BID day 1, 25 mg BID day 2, 25 mg QD day 3. ** Tolerable, escalation ongoing at next dose level. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Merck Merck Merck