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A Phase II trial of 17-allylamino, 17-demethoxygeldanamycin (17-AAG, tanespimycin) in patients with metastatic melanoma

  • PHASE II STUDIES
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Summary

Purpose A Phase II study to screen for anti-melanoma activity of the heat shock protein 90 (HSP90) inhibitor, 17-AAG (17-allylamino-17-demethoxygeldanamycin) was performed. The primary endpoint was the rate of disease stabilisation in patients with progressive, metastatic melanoma treated with 17-AAG. Secondary endpoints were to determine: the toxicity of 17-AAG, the duration of response(s), median survival and further study the pharmacokinetics and pharmacodynamics of 17-AAG. Patients and Methods Patients with metastatic melanoma (progressive disease documented ≤6 months of entering study) were treated with weekly, intravenous 17-AAG. A Simon one sample two stage minimax design was used. A stable disease rate of ≥25% at 6 months was considered compatible with 17-AAG having activity. Results Fourteen patients (8 male: 6 female) were entered, eleven received 17-AAG (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 17-AAG 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 17-AAG activity was observed although early study termination meant study endpoints were not reached. Stable disease rates can be incorporated into trials screening for anti-melanoma activity and further study of HSP90 inhibitors in melanoma should be considered.

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References

  1. Eigentler TK, Caroli UM, Radny P et al (2003) Palliative therapy of disseminated malignant melanoma: a systematic review of 41 randomised clinical trials. Lancet Oncol 4:748–759

    Article  PubMed  CAS  Google Scholar 

  2. Pearl LH, Prodromou C, Workman P (2008) The Hsp90 molecular chaperone: an open and shut case for treatment. Biochem J 410:439–453

    Article  PubMed  CAS  Google Scholar 

  3. Neckers L, Neckers K (2005) Heat-shock protein 90 inhibitors as novel cancer chemotherapeutics—an update. Expert Opin Emerg Drugs 10:137–149

    Article  PubMed  CAS  Google Scholar 

  4. Workman P, Burrows F, Neckers L et al (2007) Drugging the cancer chaperone HSP90: combinatorial therapeutic exploitation of oncogene addiction and tumor stress. Ann NY Acad Sci 1113:202–216

    Article  PubMed  CAS  Google Scholar 

  5. Powers MV, Workman P (2007) Inhibitors of the heat shock response: biology and pharmacology. FEBS Lett 581:3758–3769

    Article  PubMed  CAS  Google Scholar 

  6. Banerji U, Walton M, Raynaud F, Grimshaw R, Kelland L, Valenti M, Judson I, Workman P (2005) Pharmacokinetic-pharmacodynamic relationships for the heat shock protein 90 molecular chaperone inhibitor 17-allylamino, 17-demethoxygeldanamycin in human ovarian cancer xenograft models. Clin Cancer Res 11(19 Pt 1):7023–7032

    Google Scholar 

  7. Banerji U, Sain N, Sharp SY, Valenti M, Asad Y, Ruddle R, Raynaud F, Walton M, Eccles SA, Judson I, Jackman AL, Workman P (2008) An in vitro and in vivo study of the combination of the heat shock protein inhibitor 17-allylamino-17-demethoxygeldanamycin and carboplatin in human ovarian cancer models. Cancer Chemother Pharmacol 62(5):769–778

    Google Scholar 

  8. Solit DB, Zheng FF, Drobnjak M et al (2002) 17-Allylamino-17-demethoxygeldanamycin induces the degradation of androgen receptor and HER-2/neu and inhibits the growth of prostate cancer xenografts. Clin Cancer Res 8:986–993

    PubMed  CAS  Google Scholar 

  9. Sharp SY, Boxall K, Rowlands M, Prodromou C, Roe SM, Maloney A, Powers M, Clarke PA, Box G, Sanderson S, Patterson L, Matthews TP, Cheung KM, Ball K, Hayes A, Raynaud F, Marais R, Pearl L, Eccles S, Aherne W, McDonald E, Workman P (2007) In vitro biological characterization of a novel, synthetic diaryl pyrazole resorcinol class of heat shock protein 90 inhibitors. Cancer Res 67(5):2206–2216

    Google Scholar 

  10. Sharp SY, Prodromou C, Boxall K et al (2007) Inhibition of the heat shock protein 90 molecular chaperone in vitro and in vivo by novel, synthetic, potent resorcinylic pyrazole/isoxazole amide analogues. Mol Cancer Ther 6:1198–1211

    Article  PubMed  CAS  Google Scholar 

  11. Banerji U, O’Donnell A, Scurr M et al (2005) Phase I pharmacokinetic and pharmacodynamic study of 17-allylamino, 17-demethoxygeldanamycin in patients with advanced malignancies. J Clin Oncol 23:4152–4161

    Article  PubMed  CAS  Google Scholar 

  12. Solit DB, Ivy SP, Kopil C et al (2007) Phase I trial of 17-allylamino-17-demethoxygeldanamycin in patients with advanced cancer. Clin Cancer Res 13:1775–1782

    Article  PubMed  CAS  Google Scholar 

  13. Workman P (2003) Auditing the pharmacological accounts for Hsp90 molecular chaperone inhibitors: unfolding the relationship between pharmacokinetics and pharmacodynamics. Mol Cancer Ther 2:131–138

    PubMed  CAS  Google Scholar 

  14. Moreno-Farre J, Asad Y, Pacey S et al (2006) Development and validation of a liquid chromatography/tandem mass spectrometry method for the determination of the novel anticancer agent 17-DMAG in human plasma. Rapid Commun Mass Spectrom 20:2845–2850

    Article  PubMed  CAS  Google Scholar 

  15. Pacey S, Walton M, Eisen T et al (2006) Validation and use of western blotting to measure pharmacodynamic endpoints in Cancer Research UK clinical trials of Heat Shock Protein (HSP90) inhibitors. Abstract A161. Presented at the NCRI meeting, Birmingham, UK

  16. Smith V, Sausville EA, Camalier RF et al (2005) Comparison of 17-dimethylaminoethylamino-17-demethoxy-geldanamycin (17DMAG) and 17-allylamino-17-demethoxygeldanamycin (17AAG) in vitro: effects on Hsp90 and client proteins in melanoma models. Cancer Chemother Pharmacol 56:126–137

    Article  PubMed  CAS  Google Scholar 

  17. Burger AM, Fiebig HH, Stinson SF et al (2004) 17-(Allylamino)-17-demethoxygeldanamycin activity in human melanoma models. Anticancer Drugs 15:377–387

    Article  PubMed  CAS  Google Scholar 

  18. Flaherty K, Puzanov I, Sosman J et al (2009) Phase I study of PLX4032: Proof of concept for V600E BRAF mutation as a therapeutic target in human cancer. J Clin Oncol 27:9000

    Google Scholar 

  19. da Rocha Dias S, Friedlos F, Light Y, Springer C, Workman P, Marais R (2005) Activated B-RAF is an Hsp90 client protein that is targeted by the anticancer drug 17-allylamino-17-demethoxygeldanamycin. Cancer Res 65(23):10686–10691

  20. Modi S, Stopeck AT, Gordon MS et al (2007) Combination of trastuzumab and tanespimycin (17-AAG, KOS-953) is safe and active in trastuzumab-refractory HER-2 overexpressing breast cancer: a phase I dose-escalation study. J Clin Oncol 25:5410–5417

    Article  PubMed  CAS  Google Scholar 

  21. Davies H, Bignell GR, Cox C (2002) et al Mutations of the BRAF gene in human cancer. Nature 417:949–954

    Article  PubMed  CAS  Google Scholar 

  22. Banerji U, Affolter A, Judson I, Marais R, Workman P (2008) BRAF and NRAS mutations in melanoma: potential relationships to clinical response to HSP90 inhibitors. Mol Cancer Ther 7(4):737–739

    Google Scholar 

  23. Nowakowski GS, McCollum AK, Ames MM et al (2006) A phase I trial of twice-weekly 17-allylamino-demethoxy-geldanamycin in patients with advanced cancer. Clin Cancer Res 12:6087–6093

    Article  PubMed  CAS  Google Scholar 

  24. Gelmon KA, Eisenhauer EA, Harris AL et al (1999) Anticancer agents targeting signaling molecules and cancer cell environment: challenges for drug development? J Natl Cancer Inst 91:1281–1287

    Article  PubMed  CAS  Google Scholar 

  25. Michaelis LC, Ratain MJ (2007) Phase II trials published in 2002: a cross-specialty comparison showing significant design differences between oncology trials and other medical specialties. Clin Cancer Res 13:2400–2405

    Article  PubMed  Google Scholar 

  26. Middleton MR, Grob JJ, Aaronson N et al (2000) Randomized phase III study of temozolomide versus dacarbazine in the treatment of patients with advanced metastatic malignant melanoma. J Clin Oncol 18:158–166

    PubMed  CAS  Google Scholar 

  27. Richards JM, Gale D, Mehta N et al (1999) Combination of chemotherapy with interleukin-2 and interferon alfa for the treatment of metastatic melanoma. J Clin Oncol 17:651–657

    PubMed  CAS  Google Scholar 

  28. Balch CM, Soong SJ, Gershenwald JE et al (2001) Prognostic factors analysis of 17, 600 melanoma patients: validation of the American Joint Committee on Cancer melanoma staging system. J Clin Oncol 19:3622–3634

    PubMed  CAS  Google Scholar 

  29. Manola J, Atkins M, Ibrahim J et al (2000) Prognostic factors in metastatic melanoma: a pooled analysis of Eastern Cooperative Oncology Group trials. J Clin Oncol 18:3782–3793

    PubMed  CAS  Google Scholar 

  30. Gogas HJ, Kirkwood JM, Sondak VK (2007) Chemotherapy for metastatic melanoma: time for a change? Cancer 109:455–464

    Article  PubMed  CAS  Google Scholar 

  31. Simon R (1989) Optimal two-stage designs for phase II clinical trials. Control Clin Trials 10:1–10

    Article  PubMed  CAS  Google Scholar 

  32. Therasse P (2002) Evaluation of response: new and standard criteria. Ann Oncol 13(Suppl 4):127–129

    PubMed  Google Scholar 

  33. Egorin MJ, Zuhowski EG, Rosen DM et al (2001) Plasma pharmacokinetics and tissue distribution of 17-(allylamino)-17-demethoxygeldanamycin (NSC 330507) in CD2F1 mice1. Cancer Chemother Pharmacol 47:291–302

    Article  PubMed  CAS  Google Scholar 

  34. Kamal A, Thao L, Sensintaffar J et al (2003) et al A high-affinity conformation of Hsp90 confers tumour selectivity on Hsp90 inhibitors. Nature 425:407–410

    Article  PubMed  CAS  Google Scholar 

  35. Chung YL, Troy H, Banerji U et al (2003) Magnetic Resonence Spectroscopic Pharmacodynamic Markers of the Heat Shock Protien Inhibitor 17-Allyamino, 17-Demethoxygeldanamycin (17-AAG) in Human Colon Cancer Models. J Natl Cancer Inst 95:1624–1633

    Article  PubMed  CAS  Google Scholar 

  36. Smith-Jones PM, Solit D, Afroze F et al (2006) Early tumor response to Hsp90 therapy using HER2 PET: comparison with 18F-FDG PET. J Nucl Med 47:793–796

    PubMed  CAS  Google Scholar 

  37. Taldone T, Gozman A, Maharaj R et al (2008) Targeting Hsp90: small-molecule inhibitors and their clinical development. Curr Opin Pharmacol 8:370–374

    Article  PubMed  CAS  Google Scholar 

  38. Kefford R, Millwars M, Hersey P et al (2007) Phase 2 Trial of Tanespimycin (KOS-953), a Heat Shock Protein-90 (Hap90) Inhibitor in Patients with Metastatic Melanoma. J Clin Oncol 25:8558

    Google Scholar 

  39. Pacey S, Wilson R, Walton M et al (2007) A Phase I Trial Of The Heat Shock Protein 90 (HSP90) Inhibitor 17-Dimethylaminoethylamino-17-Demethoxygeldanamycin (17-DMAG, Alvespimycin) Administered Weekly. J Clin Oncol 25

  40. Flaherty KT, Gore L, Avadhani A et al (2008) First use of an oral Hsp90 inhibitor in patients (Pts) with solid tumors: Alvespimycin (A) administered QOD or QD. J Clin Oncol 26:2502

    Google Scholar 

  41. Solit DB, Osman I, Polsky D et al (2008) Phase II trial of 17-allylamino-17-demethoxygeldanamycin in patients with metastatic melanoma. Clin Cancer Res 14:8302–8307

    Article  PubMed  CAS  Google Scholar 

  42. Korn EL, Liu PY, Lee SJ et al (2008) Meta-analysis of phase II cooperative group trials in metastatic stage IV melanoma to determine progression-free and overall survival benchmarks for future phase II trials. J Clin Oncol 26:527–534

    Article  PubMed  Google Scholar 

  43. Elfiky A, Saif MW, Beeram M et al (2008) BIIB021, an oral, synthetic non-ansamycin Hsp90 inhibitor: Phase I experience. J Clin Oncol 26:2503

    Google Scholar 

  44. Sessa C, Sharma SK, Britten CD et al (2009) A phase I dose escalation study of AUY922, a novel HSP90 inhibitor, in patients with advanced solid malignancies. J Clin Oncol 27:3532

    Google Scholar 

  45. Bryson JC, Infante JR, Ramanathan RK et al (2008) A phase 1 dose-escalation study for the safety and pharmacokinetics (PK) of the oral Hsp90 inhibitor SNX-4522. J Clin Oncol 26:14613

    Google Scholar 

  46. Eccles SA, Massey A, Raynaud FI, Sharp SY, Box G, Valenti M, Patterson L, de Haven Brandon A, Gowan S, Boxall F, Aherne W, Rowlands M, Hayes A, Martins V, Urban F, Boxall K, Prodromou C, Pearl L, James K, Matthews TP, Cheung KM, Kalusa A, Jones K, McDonald E, Barril X, Brough PA, Cansfield JE, Dymock B, Drysdale MJ, Finch H, Howes R, Hubbard RE, Surgenor A, Webb P, Wood M, Wright L, Workman P (2008) NVP-AUY922: a novel heat shock protein 90 inhibitor active against xenograft tumor growth, angiogenesis, and metastasis. Cancer Res 68(8):2850–2860

    Google Scholar 

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Acknowledgements

This 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. 17-AAG 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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Authors and Affiliations

  1. Cancer Research UK Centre for Cancer Therapeutics, The Institute of Cancer Research, Sutton, Surrey, SM2 5NG, UK

    Simon Pacey, Udai Banerji, Yasmin Asad, Florence Raynaud, Mike Walton, Ian Judson & Paul Workman

  2. The Royal Marsden Foundation NHS Trust, Sutton, Surrey, SM2 5PT, UK

    Simon Pacey, Martin Gore, Udai Banerji, James Larkin, Sarah Sarker & Ian Judson

  3. The Royal Free Hospital, Pond Street, London, NW3 2QG, UK

    David Chao

  4. Cancer Research UK, 61 Lincolns Inn Fields (Albany House), London, WC2A 3PX, UK

    Karen Owen

  5. Department of Oncology, University of Cambridge, Box 193, (R4) Addenbrooke’s Hospital, Cambridge, CB2 0QQ, UK

    Tim Eisen

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  1. Simon Pacey
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Correspondence to Tim Eisen.

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Pacey, S., Gore, M., Chao, D. et al. A Phase II trial of 17-allylamino, 17-demethoxygeldanamycin (17-AAG, tanespimycin) in patients with metastatic melanoma. Invest New Drugs 30, 341–349 (2012). https://doi.org/10.1007/s10637-010-9493-4

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