A Phase II trial of 17allylamino 17demethoxygel

Authors: Simon Pacey Martin Gore David Chao Udai Banerji James Larkin Sarah Sarker Karen Owen Yasmin Asad Florence Raynaud Mike Walton Ian Judson Paul Workman Tim Eisen

Publish Date: 2010/08/05

Volume: 30, Issue: 1, Pages: 341-349

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Abstract

Purpose A Phase II study to screen for antimelanoma activity of the heat shock protein 90 HSP90 inhibitor 17AAG 17allylamino17demethoxygeldanamycin was performed The primary endpoint was the rate of disease stabilisation in patients with progressive metastatic melanoma treated with 17AAG Secondary endpoints were to determine the toxicity of 17AAG the duration of responses median survival and further study the pharmacokinetics and pharmacodynamics of 17AAG Patients and Methods Patients with metastatic melanoma progressive disease documented ≤6 months of entering study were treated with weekly intravenous 17AAG A Simon one sample two stage minimax design was used A stable disease rate of ≥25 at 6 months was considered compatible with 17AAG having activity Results Fourteen patients 8 male 6 female were entered eleven received 17AAG performance status 0 or 1 Median age was 60 range 29–81 years The majority 93 received prior chemotherapy and had stage M1c disease 71 Toxicity was rarely ≥ Grade 2 in severity and commonly included fatigue headache and gastrointestinal disturbances One of eleven patients treated with 17AAG had stable disease for 6 months and median survival for all patients was 173 days The study was closed prematurely prior to completion of the first stage of recruitment and limited planned pharmacokinetic and pharmacodynamic analyses Conclusion Some evidence of 17AAG activity was observed although early study termination meant study endpoints were not reached Stable disease rates can be incorporated into trials screening for antimelanoma activity and further study of HSP90 inhibitors in melanoma should be consideredThis trial was performed under the sponsorship and management of Cancer Research UK’s Drug Development Office The authors would like to acknowledge the contribution of the staff of the Melanoma and the Drug Development Units Royal Marsden Hospital UK the Melanoma unit The Royal Free Hospital London UK as well as the staff of the pharmacy units at both hospitals and the Drug Development Office of Cancer Research UK London UK In particular we acknowledge Sarah Stapleton Maggie James Jane Vincent and Lindsey Gumbrell The protocol concept was developed at the 2002 NCI/EORTC/AACR Protocol Development Workshop Flims Switzerland by Dr Udai Banerji This work was supported by Cancer Research UK programme grant numbers C309/A8274 C212/A5720 C212/A7324 C212/A7324 and C212/A11342 Paul Workman is a Cancer Research UK Life Fellow and Simon Pacey was the grateful recipient of a Cancer Research UK New Agents Committee Clinical Research Fellowship With respect to conflict of interest the following are noted in the paper Professor Paul Workman and his team received research funding on the development of HSP90 inhibitors from Vernalis Ltd and intellectual property from this programme was licensed to Vernalis Ltd and Novartis Pacey Judson Banerji Raynaud Asad Walton and Workman are/were employees of The Institute of Cancer Research which has a commercial interest in HSP90 inhibitors under development by Novartis Ltd 17AAG was supplied by the NCI and Kosan Biosciences Ltd Most of all we thank our patients their families and friends for their support and participation in our early clinical trials

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