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

Abstract

3510 Background: MK-1775 is an inhibitor of Wee1, a kinase that phosphorylates CDC2 to inactivate the CDC2/cyclin B complex (regulating the G2 checkpoint). Since most human cancers harbor p53-dependent G1 checkpoint abnormalities, they are dependent on the G2 checkpoint. G2 checkpoint abrogation may therefore sensitize p53 deficient tumor cells to anti-cancer agents. Methods: This study is evaluating the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of MK-1775 administered as both monotherapy (MT) and combination therapy (CT) with gemcitabine (G), cisplatin (P), or carboplatin (C). PART 1 consists of a single dose of MK-1775 followed by 14 days observation. If well tolerated, the same pt continues on to one of three treatment arms in PART 2: a single lower dose of MK-1775 in combination with: 1) 1000 mg/m2 G, 2) 75 mg/m2 P or 3) C AUC 5. Maximum Tolerated Doses (MTDs) will be established for MK-1775 as both monotherapy and in combination. PD biomarkers include IHC analysis for pCDC2/CDC2 in plucked hair and skin biopsies, peripheral blood, and tumor biopsies. Wee1 gene expression signature is measured in plucked hair and tumor biopsies by qPCR. Results: To date, 37 pts (median age 61; up to 4 prior therapies) have been treated with MK-1775. 4 pts experienced DLT. One pt on G + 200mg MK-1775 had gr3 leucopenia and neutropenia; one pt on P + 200mg MK-1775 had gr3, fatigue, diarrhea and hypokalemia and another pt gr2 nausea/vomiting > 48hrs requiring hospitalization. One pt on C + 325mg MK-1775 was hospitalized for gr3 bilirubin. Linear PK was demonstrated at 100, 200, 325, 650 and 1300 mg MK-1775. Terminal T½ of MK-1775 was 7.6–12.2 hrs and Tmax was 1.0–6.0 hrs. Preliminary MTDs of MK-1775 in combination with G, C and P were 200, 325 and 200mg, respectively. Significant changes in Wee1 signature gene expression were observed in plucked hair. Of 28 evaluable pts, >50% regression of axillary lymphadenopathy was seen in 1 pt with melanoma on the P arm, and stable disease in 14 other pts (median duration). Conclusions: MK-1775 is a first in class Wee1 inhibitor that is well tolerated and shows promising anti-tumor activity in previously treated pts. [Table: see text]