AZD1775（MK1775）针对wee1的靶点的

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

Abstract:

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 54; median # of prior therapies 4; cancer dx (#pts): sarcoma (8); NSCLC (2); head and neck (3); fallopian tube (1); cervical (1); granulosa cell tumor (1); breast (1); appendiceal cancer (1). One pt with BRCA mutated head and neck cancer had a confirmed PR. Common toxicities were myelosuppression and diarrhea. Two DLTs occurred at DL 3: 1 pt had Gr 4 myelosuppression, developed pneumonia, and died; a second pt had SVT. At the MTD of DL 2, average Cmax was 1650 nM on D3; total exposure on D3 was 2-3 fold higher than on D1. Reduction in phosphorylated Tyr15-Cdk levels was shown in 3 of 5 paired tumor biopsies; quantitation of γH2AX, a DNA damage marker, is ongoing in CTCs and tumor biopsies. Conclusions: This is the first single-agent trial of AZD1775 in pts with refractory solid tumors. MTD was established at 225mg BID x 5 doses/week, 2 of 3 wks, with evidence of antitumor activity in a pt with BRCA mutated head and neck cancer. Accrual is ongoing for BRCA+ pts. The accumulation of drug on the BID regimen is consistent with a t1/2 of ~ 24 hrs, which supports a QD schedule for future trials. Target modulation was demonstrated in paired tumor biopsies. CTCs were isolated from 2 pts with non-epithelial cancers. Analysis of tumor biopsies and CTCs for γH2AX is ongoing. Clinical trial information: NCT01748825.

目前有个2期的临床联合培美+卡铂的不知效果如何

http://www.selleck.cn/wee1-kinase.html

顶 之前还真没听说过这个

二师兄呀，俺真的是看不懂呀，是化疗药吗？

请问是靶向药么？

和NSCLC有关吗？