Abstract
Purpose
To define maximum tolerated dose (MTD), clinical toxicities, and pharmacokinetics of 17-allylamino-17-demethoxygeldanamycin (17-AAG) when administered in combination with docetaxel once every 21 days in patients with advanced solid tumor malignancies.
Experimental design
Docetaxel was administered over 1 h at doses of 55, 70, and 75 mg/m2. 17-AAG was administered over 1–2 h, following the completion of the docetaxel infusion, at escalating doses ranging from 80 to 650 mg/m2 in 12 patient cohorts. Serum was collected for pharmacokinetic and pharmacodynamic studies during cycle 1. Docetaxel, 17-AAG, and 17-AG levels were determined by high-performance liquid chromatography. Biologic effects of 17-AAG were monitored in peripheral blood mononuclear cells by immunoblot.
Results
Forty-nine patients received docetaxel and 17-AAG. The most common all-cause grade 3 and 4 toxicities were leukopenia, lymphopenia, and neutropenia. An MTD was not defined; however, three dose-limiting toxicities were observed, including 2 incidences of neutropenic fever and 1 of junctional bradycardia. Dose escalation was halted at docetaxel 75 mg/m2-17-AAG 650 mg/m2 due to delayed toxicities attributed to patient intolerance of the DMSO-based 17-AAG formulation. Of 46 evaluable patients, 1 patient with lung cancer experienced a partial response. Minor responses were observed in patients with lung, prostate, melanoma, and bladder cancers. A correlation between reduced docetaxel clearance and 17-AAG dose level was observed.
Conclusions
The combination of docetaxel and 17-AAG was well tolerated in adult patients with solid tumors, although patient intolerance to the DMSO formulation precluded further dose escalation. The recommended phase II dose is docetaxel 70 mg/m2 and 17-AAG 500 mg/m2.
References
Solit DB, Rosen N (2006) Hsp90: a novel target for cancer therapy. Curr Top Med Chem 6:1205–1214
Trepel J, Mollapour M, Giaccone G, Neckers L (2010) Targeting the dynamic HSP90 complex in cancer. Nat Rev Cancer 10:537–549
Banerji U, O’Donnell A, Scurr M, Pacey S, Stapleton S, Asad Y 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
Goetz MP, Toft D, Reid J, Ames M, Stensgard B, Safgren S et al (2005) Phase I trial of 17-allylamino-17-demethoxygeldanamycin in patients with advanced cancer. J Clin Oncol 23:1078–1087
Grem JL, Morrison G, Guo XD, Agnew E, Takimoto CH, Thomas R et al (2005) Phase I and pharmacologic study of 17-(allylamino)-17-demethoxygeldanamycin in adult patients with solid tumors. J Clin Oncol 23:1885–1893
Ramanathan RK, Trump DL, Eiseman JL, Belani CP, Agarwala SS, Zuhowski EG et al (2005) Phase I pharmacokinetic-pharmacodynamic study of 17-(allylamino)-17-demethoxygeldanamycin (17AAG, NSC 330507), a novel inhibitor of heat shock protein 90, in patients with refractory advanced cancers. Clin Cancer Res 11:3385–3391
Solit DB, Ivy SP, Kopil C, Sikorski R, Morris MJ, Slovin SF et al (2007) Phase I trial of 17-allylamino-17-demethoxygeldanamycin in patients with advanced cancer. Clin Cancer Res 13:1775–1782
Stebbins CE, Russo AA, Schneider C, Rosen N, Hartl FU, Pavletich NP (1997) Crystal structure of an Hsp90-geldanamycin complex: targeting of a protein chaperone by an antitumor agent. Cell 89:239–250
Schulte TW, Neckers LM (1998) The benzoquinone ansamycin 17-allylamino-17-demethoxygeldanamycin binds to HSP90 and shares important biologic activities with geldanamycin. Cancer Chemother Pharmacol 42:273–279
Mimnaugh EG, Chavany C, Neckers L (1996) Polyubiquitination and proteasomal degradation of the p185c-erbB-2 receptor protein-tyrosine kinase induced by geldanamycin. J Biol Chem 271:22796–22801
Sepp-Lorenzino L, Ma Z, Lebwohl DE, Vinitsky A, Rosen N (1995) Herbimycin A induces the 20 S proteasome- and ubiquitin-dependent degradation of receptor tyrosine kinases. J Biol Chem 270:16580–16587
Solit DB, Zheng FF, Drobnjak M, Munster PN, Higgins B, Verbel D 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
Solit DB, Basso AD, Olshen AB, Scher HI, Rosen N (2003) Inhibition of heat shock protein 90 function down-regulates Akt kinase and sensitizes tumors to Taxol. Cancer Res 63:2139–2144
Basso AD, Solit DB, Chiosis G, Giri B, Tsichlis P, Rosen N (2002) Akt forms an intracellular complex with heat shock protein 90 (Hsp90) and Cdc37 and is destabilized by inhibitors of Hsp90 function. J Biol Chem 277:39858–39866
Schulte TW, Blagosklonny MV, Ingui C, Neckers L (1995) Disruption of the Raf-1-Hsp90 molecular complex results in destabilization of Raf-1 and loss of Raf-1-Ras association. J Biol Chem 270:24585–24588
Munster PN, Basso A, Solit D, Norton L, Rosen N (2001) Modulation of Hsp90 function by ansamycins sensitizes breast cancer cells to chemotherapy-induced apoptosis in an RB- and schedule-dependent manner. See: Sausville EA, Combining cytotoxics and 17-allylamino, 17-demethoxygeldanamycin: sequence and tumor biology matters. Clin Cancer Res 7:2155–2158, 2228–2236
Sain N, Krishnan B, Ormerod MG, De Rienzo A, Liu WM, Kaye SB et al (2006) Potentiation of paclitaxel activity by the HSP90 inhibitor 17-allylamino-17-demethoxygeldanamycin in human ovarian carcinoma cell lines with high levels of activated AKT. Mol Cancer Ther 5:1197–1208
Nguyen DM, Lorang D, Chen GA, Stewart JHt, Tabibi E, Schrump DS (2001) Enhancement of paclitaxel-mediated cytotoxicity in lung cancer cells by 17-allylamino geldanamycin: in vitro and in vivo analysis. Ann Thorac Surg 72:371–378; discussion 8–9
Nguyen DM, Chen A, Mixon A, Schrump DS (1999) Sequence-dependent enhancement of paclitaxel toxicity in non-small cell lung cancer by 17-allylamino 17-demethoxygeldanamycin. J Thorac Cardiovasc Surg 118:908–915
Egorin MJ, Zuhowski EG, Rosen DM, Sentz DL, Covey JM, Eiseman JL (2001) Plasma pharmacokinetics and tissue distribution of 17-(allylamino)-17-demethoxygeldanamycin (NSC 330507) in CD2F1 mice1. Cancer Chemother Pharmacol 47:291–302
Parise RA, Ramanathan RK, Zamboni WC, Egorin MJ (2003) Sensitive liquid chromatography-mass spectrometry assay for quantitation of docetaxel and paclitaxel in human plasma. J Chromatogr B Anal Technol Biomed Life Sci 783:231–236
Yeh KC, Kwan KC (1978) A comparison of numerical integrating algorithms by trapezoidal, Lagrange, and spline approximation. J Pharmacokinet Biopharm 6:79–98
Rocci ML Jr, Jusko WJ (1983) LAGRAN program for area and moments in pharmacokinetic analysis. Comput Programs Biomed 16:203–216
Ficker E, Dennis AT, Wang L, Brown AM (2003) Role of the cytosolic chaperones Hsp70 and Hsp90 in maturation of the cardiac potassium channel HERG. Circ Res 92:e87–e100
Vilenchik M, Solit D, Basso A, Huezo H, Lucas B, He H et al (2004) Targeting wide-range oncogenic transformation via PU24FCl, a specific inhibitor of tumor Hsp90. Chem Biol 11:787–797
Kamal A, Thao L, Sensintaffar J, Zhang L, Boehm MF, Fritz LC et al (2003) A high-affinity conformation of Hsp90 confers tumour selectivity on Hsp90 inhibitors. Nature 425:407–410
Xu W, Mimnaugh E, Rosser MF, Nicchitta C, Marcu M, Yarden Y et al (2001) Sensitivity of mature Erbb2 to geldanamycin is conferred by its kinase domain and is mediated by the chaperone protein Hsp90. J Biol Chem 276:3702–3708
Chandarlapaty S, Scaltriti M, Angelini P, Ye Q, Guzman M, Hudis CA et al (2010) Inhibitors of HSP90 block p95-HER2 signaling in Trastuzumab-resistant tumors and suppress their growth. Oncogene 29:325–334
Normant E, Paez G, West KA, Lim AR, Slocum KL, Tunkey C et al (2011) The Hsp90 inhibitor IPI-504 rapidly lowers EML4-ALK levels and induces tumor regression in ALK-driven NSCLC models. Oncogene 30:2581–2586
Sequist LV, Gettinger S, Senzer NN, Martins RG, Janne PA, Lilenbaum R et al (2010) Activity of IPI-504, a novel heat-shock protein 90 inhibitor, in patients with molecularly defined non-small-cell lung cancer. J Clin Oncol 28:4953–4960
Modi S, Stopeck A, Linden H, Solit D, Chandarlapaty S, Rosen N et al (2011) HSP90 Inhibition Is Effective in Breast Cancer: A Phase II Trial of Tanespimycin (17-AAG) Plus Trastuzumab in Patients with HER2-Positive Metastatic Breast Cancer Progressing on Trastuzumab. Clin Cancer Res 17:5132–5139
Sydor JR, Normant E, Pien CS, Porter JR, Ge J, Grenier L et al (2006) Development of 17-allylamino-17-demethoxygeldanamycin hydroquinone hydrochloride (IPI-504), an anti-cancer agent directed against Hsp90. Proc Natl Acad Sci USA 103:17408–17413
Acknowledgments
We would like to thank Kin Tse for his assistance with data collection and analysis. National Cancer Institute grants P50-CA92629 and U01-CA69856 and the generous support of the Prostate Cancer Foundation.
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Iyer, G., Morris, M.J., Rathkopf, D. et al. A phase I trial of docetaxel and pulse-dose 17-allylamino-17-demethoxygeldanamycin in adult patients with solid tumors. Cancer Chemother Pharmacol 69, 1089–1097 (2012). https://doi.org/10.1007/s00280-011-1789-3
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DOI: https://doi.org/10.1007/s00280-011-1789-3