Biomarker measurements have become an essential component of oncology drug development, particularly so in this era of targeted therapies. Such measurements ensure that clinical studies are testing our biological hypotheses and can help make the difficult decisions required to choose which drugs to stop developing or de-prioritise. For those drugs taken forward, biomarker measurements may also help choose the appropriate dose, schedule and patient population. In this review we discuss the intrinsic properties of biological sample based efficacy measurements and how these relate to their implementation in oncology drug development by way of points to consider and examples.

AZD0530, an orally available Src inhibitor, demonstrated potent antimigratory and anti-invasive effects in vitro, and inhibited metastasis in a murine model of bladder cancer. Antiproliferative activity of AZD0530 in vitro varied between cell lines (IC(50) 0.2 ->10μM). AZD0530 inhibited tumor growth in 4/10 xenograft models tested and dynamically inhibited in vivo phosphorylation of Src substrates paxillin and FAK in both growth-inhibition-resistant and -sensitive xenografts. The activity of AZD0530 in NBT-II bladder cancer cells in vitro was consistent with inhibition of cell migration and stabilization of cell-cell adhesion. These data suggest a dominant anti-invasive pharmacology for AZD0530 that may limit tumor progression in a range of cancers. AZD0530 is currently in Phase II clinical trials.

A254 Aberrant function of the erbB family of receptor tyrosine kinases and their ligands has been described in many human cancers. Within this family, erbB2 plays a central role: mis-regulation of erbB2, for example by over-expression/gene amplification, has been observed to varying degrees in a range of tumours, particularly breast cancer. Medicinal chemistry effort at AstraZeneca has identified certain 5-substitued anilinoquinazolines as kinase inhibitors for Src, EGF and erbB2. We previouly described 11 as a potent and selective inhibitor of erbB2, showing antitumor efficacy after oral administration in mouse xenograft models. However, this compound was subsequently found to exhibit modest pharmacokinetics in other species (especially dog) and mild to severe effects in liver and lung in rat toxicological studies attributed to phospholipidosis, which precluded its progression towards clinical trials. SAR around generic structure A was developed by introducing a wide range of substituents at C4 and C5 positions to optimize the potency and incorporate desirable pharmaceutical properties. We will describe the lead candidate which was selected from this series, based on its potent erbB2 kinase inhibition profile, its physical and pharmacokinetic properties and its anti-tumor efficacy after oral administration in xenograft models with erbB2 overexpression. 1 Ballard, P.; Bradbury, R.H.; Hennequin, L.F.A.; Hickinson, D.M.; Johnson, P.D.; Kettle, J.G.; Klinowska, T.; Morgentin, R.; Ogilvie, D.J.; Olivier, A. Bioorg. Med. Chem. Lett.2005, 15, 4226-4229.

5989 AZD0530 is a highly selective, dual-specific small molecule inhibitor of Src family kinases and Bcr-Abl. A series of studies were performed to characterize the distribution, pharmacokinetics and tumor growth inhibitory effects of AZD0530 in rats bearing Src 3T3 xenografts (3T3 mouse fibroblast transfected with a constitutively active human c-Src kinase in an overexpressing vector). Src 3T3 xenograft growth is driven by Src. In study 1, tumor growth inhibition was assessed at dose levels of 1, 3, 6 and 10 mg/kg/day (per os administration). AZD0530 produced a dose-related inhibition of tumor growth, with more than 90% of tumor growth inhibition at 6 and 10 mg/kg, 19% inhibition at 3 mg/kg and no effect at 1 mg/kg compared to a vehicle control group. In study 2, a single 10 mg/kg [14] C-labeled dose of AZD0530 was administered per os to rats and tissue distribution assessed by quantitative whole body autoradiography. Drug-related material was extensively distributed to many tissues with high and protracted levels in the xenograft. The third study assessed the pharmacokinetics of AZD0530 in plasma and tumor following a 25 mg/kg single dose (per os administration). Maximum tumor levels of AZD0530 (∼44 μg/g) were approximately 40-fold higher than those in plasma. The shapes of the plasma and tumor AZD0530 concentration versus time curves were similar though the tumor curve lagged behind that of plasma. AZD0530 is in early clinical development.