Kosan Biosciences Incorporated has initiated a Phase II clinical trial in patients with HER2-positive metastatic breast cancer, administering KOS-953 in combination with trastuzumab (Herceptin).

In addition, interim data from the Phase Ib dose-escalating clinical trial using this combination was presented at the 28th Annual San Antonio Breast Cancer Symposium. KOS-953 is the Company's proprietary formulation of the heat shock protein 90 (Hsp90) inhibitor, 17-AAG.

According to the company release, the Phase Ib dose-escalating and Phase II clinical trials of KOS-953 in combination with trastuzumab are being conducted at Memorial Sloan-Kettering Cancer Centre and Arizona Cancer Centre. The Phase II trial will enrol patients with HER2-positive metastatic breast cancer whose disease has progressed following treatment with trastuzumab in either the adjuvant or metastatic setting. In this Phase II trial, patients will receive weekly doses of KOS-953 following the infusion of trastuzumab. The primary objective of the protocol is to assess tumour response using standard RECIST criteria.

"Preclinical research conducted in the laboratory of Dr. Neal Rosen at Memorial Sloan-Kettering Cancer Centre demonstrated the anti-tumour potential of Hsp90 inhibition in HER2-positive animal models," Clifford Hudis, Chief of the Breast Cancer Medicine Service and Associate Attending Physician at Memorial Sloan-Kettering Cancer Centre, New York said adding, "The encouraging anti-tumour activity observed in the dose-escalating trial among heavily pre-treated patients supports continuation of this combination into a Phase II clinical trial."

The Phase Ib clinical trial was designed to determine the recommended Phase II dose and toxicity of KOS-953 in combination with standard doses of trastuzumab. According to the trial protocol, patients received standard weekly doses of trastuzumab followed by KOS-953 in escalating doses. Ten patients received the final recommended Phase II dose of KOS-953. Drug-related toxicities were primarily fatigue and gastrointestinal (nausea, vomiting, diarrhoea) that were amenable to supportive care. There was no marrow suppression and minimal hepatoxicity. No cardiovascular toxicity was observed. Pharmacokinetic parameters for KOS-953 in this combination were similar to KOS-953 administered as a single agent; KOS-953 had no effect on the kinetics of trastuzumab.

KOS-953 is a proprietary formulation of 17-AAG -- an analog of the polyketide geldanamycin that inhibits Hsp90 (heat shock protein 90). Found in high levels in tumour cells, Hsp90 is a molecular "chaperone" which maintains the stability of numerous "client proteins" implicated in tumour growth and metastasis, including protein kinases and transcription factors.

In addition to the KOS-953/Herceptin combination trial in metastatic breast cancer reported on today, KOS-953 is also being evaluated in a Phase I single-agent and Phase Ib combination clinical trial with bortezomib (Velcade) in patients with multiple myeloma. The original formulation of 17-AAG is being evaluated in multiple Phase I, Phase Ib and Phase II clinical trials in a variety of tumour types. These trials are sponsored by the National Cancer Institute (NCI) under a Cooperative Research and Development Agreement (CRADA) between Kosan and the NCI Cancer Therapy Evaluation Program (CTEP). In 2004, Kosan obtained orphan drug designation for 17-AAG from both the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMEA) for the treatment of multiple myeloma as well as another hematologic cancer, chronic myelogenous leukaemia.