ZD-9331 AstraZeneca.

Abstract

AstraZeneca (formerly Zeneca) is developing ZD-9331, a non-polyglutamatable thymidylate synthase inhibitor, as a potential treatment for solid tumors and other neoplasia, including colorectal tumors [216476,179954,179955]. ZD-9331 is being developed as both an oral and an i.v. formulation, both of which are in phase II trials as of December 1999 [349551,352095]. As of June 1998, ZD-9331 was in phase II trials for advanced colorectal and other solid tumors [315489], with drug filings not expected until 2002 [349551]. A clinical study presented at the 36th Annual Meeting of the American Society of Clinical Oncology (ASCO) demonstrated that treatment with ZD-9331 resulted in a period of intracellular 2'-deoxyuridine (dUrd) elevation, a surrogate marker of thymidylate synthase inhibition, with observed myelosuppression being no greater than that seen with raltitrexed and less than with bolus 5-FU [369475]. Results from a 56-patient phase I study were presented at the 1999 ASCO meeting. Dose escalation followed a two-stage procedure. As in previous studies myelosuppression was the dose-limiting toxicity, occurring at 4.8 and 7.5 mg/m2/day, with one patient at each of these two doses experiencing a DLT. The MTD was not achieved until 12 to 16 mg/m2/day, based on which a fixed dose of 25 mg/day was being evaluated [326935]. A number of other studies are ongoing, comparing once to twice daily dosages as well as the pharmacokinetics of the compound. Encouraging phase I data have been seen in melanoma, ovarian, colon and breast cancer; myelosuppression is the dose limiting toxicity in the majority of these studies [326938,326943,326945,327399]. A phase I dose-escalation trial was conducted to evaluate the feasibility of a once 3-weekly 30-min i.v. infusion of ZD-9331, with doses ranging from 4.8 to 370 mg/m2. The regimen was overall well tolerated up to 370 mg/m2, with grade IV myelosuppression and grade IV diarrhea being observed in a small number of patients [288959,377842]. In June 2000, Deutsche Bank predicted sales of $12 million in 2002 [374500]. In January 1999, ABN Amro predicted sales of US $8 million in 2002 rising to $66 million in 2005 [316250, 328676]. In March 1999, Lehman Brothers predicted a 30% probability that the drug would reach the worldwide markets, and be launched in 2002 [336599].