Update on a phase I pharmacologic 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

3068 Background: MK-1775 (MK) is an investigational 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, 5-BID doses of MK are explored in the same 3 arms. PART 3 is a cohort expansion to confirm Maximum Tolerated Dose (MTD). 50% reduction of pCDC2 in skin biopsies post-MK vs pre-treatment is considered evidence of target engagement (TE). Results: To date, 156 pts (44 in monotherapy/single-dose combination, 112 in multi-dose combination therapy) were treated with MK. No DLTs were observed in monotherapy; 7 (single dose) and 17 pts (multiple dose) experienced DLTs in combination therapy. Most common AEs are hematologic, 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 C and P were identified. TE by pCDC2 occurred in 55% of pts at doses of MK > 100 mg across treatment arms. Conclusions: MK is a first-in-class Wee1 inhibitor that is well tolerated in combination with chemotherapy, with evidence of TE. Clinical and biomarker responses were observed 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 26 28 37 MTD 200 mg 200 mg 225 mg 50/50/25/25/25mg* 200 mg 225 mg PR (%) 0(0) 2 (15.4) 0 0 2 (7.1) 1 (2.7) SD (%) 9 (64.3) 7 (53.8) 5 (31.3) 12 (46.2) 10 (35.7) 19 (51.4) Target engagement Y Y Y N Y Y Related AEs ≥grade 3 (%) 7 (50.0) 4 (30.8) 2 (12.5) 16 (61.5) 9 (32.1) 26 (70.3) * Dose escalation ongoing with an attenuated schedule facilitating use of higher MK doses of > 100 mg.