Phase I trial of AZD1775 (MK1775), a wee1 kinase inhibitor, in patients with refractory solid tumors.

2503 Background: Wee1 tyrosine kinase phosphorylates and inactivates Cdk1, causing G2 cell cycle arrest in response to DNA damage. AZD1775 is a novel inhibitor of Wee1 kinase with single-agent anti-tumor activity in preclinical models. Objectives of this study were to establish the safety, toxicity, maximum tolerated dose (MTD) of single agent AZD1775; determine the pharmacokinetics (PK) of AZD1775; evaluate for target modulation in paired tumor biopsies. Methods: Eligible adult patients (pts) had refractory cancers that had progressed on standard therapy; ECOG PS 0-2; adequate organ function. Dose level (DL) 1 was 225 mg BID x 5 doses, q 21d cycles. Dose escalation: 225 mg (DL 2) or 300 mg (DL 3) BID x 5 doses for 2 wks, q21d cycles; 3 + 3 design. Blood sampling for PK and circulating tumor cells (CTCs) occurred on C1D1 and C1D3. Tumor biopsies at MTD were performed at baseline and C1D3 (2-5 hrs post-drug) and were evaluated for pTyr15-Cdk to assess target modulation. Results: 18 pts treated; median age ...