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Final results of a phase I study of the Heat Shock Protein 90 inhibitor Alvespimycin (17-DMAG) in patients with advanced, solid tumours
Simon Pacey1, Richard Wilson4, Mike Walton1, Martin Eatock4, Anna Zetterlund1, Hendrik-Tobias Arkenau2, Belle Roels3, Florence Raynaud1, Jooern Ang2, Samantha Costigan1, David Olmos2, Rebecca Gallagher4, Paul Workman1, Ian Judson1
1The Institute of Cancer Research, Sutton, UK, 2The Royal Marsden Hospital, Sutton, UK, 3Cancer Research UK, London, UK, 4N. Ireland Cancer Clinical Trials Unit, Belfast, UK
Method and Results
Alvespimycin [17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG)] inhibits N-terminal ATPase activity of Heat Shock Protein 90 (HSP90). Chaperone interactions are altered such that client proteins are targeted for degradation. The multitude of HSP90 client proteins offers the potential of simultaneous blockade across multiple, oncogenic signalling pathways.
The maximum tolerated dose, at which ≤ 1/6 patients experienced dose limiting toxicity (DLT) was determined by dose-doubling (3+3) design. Pharmacokinetic (PK) and pharmacodynamic (PD) biomarker data and a planned dose de-escalation phase were used in an attempt to define a biologically effective dose (BED). PK (LC/MS/MS) and PD (western blot) assays were validated and compliant with European clinical trial legislation. Twenty five patients, median age 58 (range 38 - 78) years, received 559 infusions at doses between 2.5 and 106mg/m2. Dose doubling was performed up to 80mg/m2, at which dose grade 2 toxicity, including dry eye and blurred vision (2/5 patients) occurred.
At the subsequent dose level (106mg/m2) DLT were observed (grade 3 fatigue, diarrhoea, dehydration and grade 4 hypotension, AST rise) in 2/4 patients, one patient died from cardiac arrest. PK data were as follows; plasma t 24.6 8.6 hr, Vss 468 383 L (mean SD) and clearance 27.7 L/hr (range 8.26 - 153). Maximum plasma concentration increased proportionally with alvespimycin dose, area under the curve was only linear at doses ≤ 80mg/m2 above which greater than proportional increases were observed. PD changes (HSP72 induction) in surrogate tissue, peripheral blood mononuclear cells, were detected at doses of 20mg/m2 and above. Evidence of HSP90 inhibition (client protein depletion and HSP72 induction) was not commonly detected until 106mg/m2. HSP90 inhibition in tumour samples was confirmed 24 hours after 17-DMAG in 1/1 and 3/5 patients given 106 and 80mg/m2, respectively. One patient with castrate-resistant prostate cancer had a confirmed complete response (on study 33 months) and one, investigator assessed, partial response occurred in a patient with metastatic melanoma (who remains on study after 26 months). Eleven patients have been on trial ≥12 weeks.
Conclusion
In conclusion the recommended phase II dose of alvespimycin is 80mg/m2 weekly. PK and PD data support this as a BED. Clinical activity was observed at doses up to and including the recommended dose and further investigation is warranted.
Acknowledgements
The study was co-sponsored by Cancer Research UK and the NCI
