Kosan Initiates 17-AAG PII Trial

Kosan Biosciences has initiated the first Phase II monotherapy clinical trial of 17-allylamino-17-demethoxy-geldanamycin (17-AAG).

The trial will evaluate anti-tumour efficacy in cancer patients with metastatic melanoma. The clinical trial is 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).

'We are particularly enthusiastic about this study because of the important pre-clinical observation that the MAPK pathway is critical for melanoma growth,' said Dr Paul Chapman, head of the melanoma section of the clinical immunology service in the department of medicine at Memorial Sloan-Kettering Cancer Center (MSKCC). 'By enhancing the degradation of B-Raf protein, we hypothesise that 17-AAG will interrupt this pathway effectively.'

The Phase II study will be undertaken at three major cancer centres under the supervision of Dr. Chapman as the principal investigator. The Phase II trial will establish if treatment with 17-AAG results in measurable anti-tumour effects in patients with Stage III or IV metastatic melanoma who have failed up to one prior regimen. Patients will be dosed at 450 mg/m² weekly for 6 weeks on an 8-week cycle. The pharmacodynamics of 17-AAG in blood cells and in tumour tissue will be investigated, particularly 17-AAG's effect on B-Raf, which is a putative Hsp90 client protein.

17-AAG inhibits Hsp90 (heat shock protein 90), a protein chaperone that binds to signalling proteins, known as 'client proteins.' These client proteins include a 'who's who' list of cancer-relevant targets such as mutated p53, Bcr-Abl, Her2, Akt, Raf-1, B-Raf, and others. When 17-AAG binds to Hsp90, it disrupts the Hsp90-client protein complexes, leading to degradation of the client proteins. This study is the first of multiple planned Phase II monotherapy trials with 17-AAG.