ARRY-543 is a novel, oral, ErbB-2 / EGFR inhibitor that is safe, effective and convenient for treating ErbB-2 / EGFR expressing tumors. ARRY-543 is a reversible ATP-competitive inhibitor with nanomolar potency both in vitro and in cell-based proliferation assays. ARRY-543 has demonstrated efficacy in certain preclinical models where Tarceva or Herceptin are not active and has shown equivalent or improved efficacy compared to Tykerb.
About ErbB-2 and EGFR Inhibition for Cancer
ErbB-2 and EGFR are receptor kinase targets that are over-expressed in a number of malignancies, including breast, lung, pancreas, colon and head and neck cancers. Stimulation of ErbB-2 and EGFR is associated with cell proliferation and with multiple processes involved in tumor progression, invasion and metastases. Herceptin® (trastuzumab) is an intravenously-dosed protein therapeutic currently on the market for the treatment of breast cancers that over-express ErbB-2. Herceptin has also been reported to show promising therapeutic benefits in early, post-surgery, breast cancer patients being treated chronically. We believe these results suggest a high potential value for an orally active drug that regulates ErbB-2 and that can be conveniently dosed for extended periods of time. Erbitux® (cetuximab), an intravenously-dosed protein therapeutic, and Tarceva® (erlotinib), a small molecule inhibitor, are currently marketed drugs that modulate EGFR only. Tykerb® (lapatinib), a small molecule drug that modulates ErbB-2 and EGFR, has been approved for the treatment of certain Herceptin-resistant breast cancers and is still undergoing clinical trials for other cancers. There is evidence that the concurrent inhibition of ErbB-2 and EGFR provides enhanced efficacy in treatment of some cancers.
Phase 1 Clinical Trial
We initiated Phase 1 clinical testing of ARRY-543 in January 2006. The open-label, dose-escalation trial was designed to evaluate safety, tolerability and pharmacokinetics of ARRY-543 following oral administration to patients with advanced cancer. In addition, the trial was designed to examine indicators of therapeutic activity in these patients. As reported at the 2007 EORTC-NCI-AACR and SABC conferences, ARRY-543, produced stable disease in refractory patients with advanced solid tumors in the Phase 1 clinical trial. ARRY-543 was well-tolerated up to 300 mg BID (twice daily). The maximally tolerated dose was 400 mg BID. The most common adverse events included fatigue, nausea, anorexia, diarrhea and rash, which are all typically seen with tyrosine kinase inhibitors. Systemic concentrations of ARRY-543 increased with escalating doses at all dose levels tested and it was able to achieve blood levels that are predicted to provide continuous and profound inhibition of the molecular targets. In completed cohorts, sixty percent of patients receiving doses of 200 mg BID and higher had prolonged stable disease.
Future Milestones
During fiscal 2009, we plan to initiate a Phase 1b/2 trial of ARRY-543 in combination with Taxotere (docetaxel) and continue a Phase 1b/2 trial in combination with Xeloda (capecitabine).
Scientific Posters
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