Abstract
Purpose
To translate promising preclinical data on the combination of vorinostat and ixabepilone for metastatic breast cancer (MBC) into clinical trials.
Methods
We conducted a randomized two-arm Phase IB clinical trial of ascending doses of vorinostat and ixabepilone in prior -treated MBC patients. To determine the maximum tolerated dose (MTD), 37 patients were randomized to schedule A: every-3-week ixabepilone + vorinostat (days 1–14), or schedule B: weekly ixabepilone + vorinostat (days 1–7; 15–21) Pharmacokinetics were assessed. Nineteen additional patients were randomized to schedule A or B and objective response rate (ORR), clinical benefit rate (CBR), toxicity, progression-free survival (PFS), and overall survival (OS) were assessed.
Results
The schedule A MTD was vorinostat 300 mg daily (days 1–14), ixabepilone 32 mg/m2 (day 2); 21-day cycle 27% dose-limiting toxicities (DLTs). The schedule B MTD was vorinostat 300 mg daily (days 1–7; 15–21), ixabepilone 16 mg/m2 (days 2, 9, 16); 28-day cycle; no DLTs. Vorinostat and ixabepilone clearances were 194 L/h and 21.3 L/h/m2, respectively. Grade 3 peripheral sensory neuropathy was reported in 8% (A) and 21% (B) of patients. The ORR and CBR were 22 and 22% (A); 30 and 35% (B). Median PFS was 3.9 (A) and 3.7 (B) months. OS was 14.8 (A) and 17.1 (B) months.
Conclusions
We established the MTD of vorinostat and ixabepilone. This drug combination offers a novel therapy for previously treated MBC patients. The potential for lower toxicity and comparable efficacy compared to current therapies warrants further study.
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References
Siegel R, DeSantis C, Virgo K, Stein K, Mariotto A, Smith T, Cooper D, Gansler T, Lerro C, Fedewa S, Lin C, Leach C, Cannady RS, Cho H, Scoppa S, Hachey M, Kirch R, Jemal A, Ward E (2012) Cancer treatment and survivorship statistics, 2012. CA Cancer J Clin 62(4):220–241. doi:10.3322/caac.21149
Andreopoulou E, Sparano JA (2013) Chemotherapy in patients with anthracycline- and taxane-pretreated metastatic breast cancer: an overview. Curr Breast Cancer Rep 5(1):42–50. doi:10.1007/s12609-012-0097-1
Colozza M, de Azambuja E, Personeni N, Lebrun F, Piccart MJ, Cardoso F (2007) Achievements in systemic therapies in the pregenomic era in metastatic breast cancer. Oncologist 12(3):253–270. doi:10.1634/theoncologist.12-3-253
Jones SE, Erban J, Overmoyer B, Budd GT, Hutchins L, Lower E, Laufman L, Sundaram S, Urba WJ, Pritchard KI, Mennel R, Richards D, Olsen S, Meyers ML, Ravdin PM (2005) Randomized phase III study of docetaxel compared with paclitaxel in metastatic breast cancer. J Clin Oncol 23(24):5542–5551. doi:10.1200/JCO.2005.02.027
Sledge GW, Neuberg D, Bernardo P, Ingle JN, Martino S, Rowinsky EK, Wood WC (2003) Phase III trial of doxorubicin, paclitaxel, and the combination of doxorubicin and paclitaxel as front-line chemotherapy for metastatic breast cancer: an intergroup trial (E1193). J Clin Oncol 21(4):588–592. doi:10.1200/JCO.2003.08.013
Paridaens R, Biganzoli L, Bruning P, Klijn JG, Gamucci T, Houston S, Coleman R, Schachter J, Van Vreckem A, Sylvester R, Awada A, Wildiers J, Piccart M (2000) Paclitaxel versus doxorubicin as first-line single-agent chemotherapy for metastatic breast cancer: a European Organization for Research and Treatment of Cancer Randomized Study with cross-over. J Clin Oncol 18(4):724–733. doi:10.1200/JCO.2000.18.4.724
Lee FY, Borzilleri R, Fairchild CR, Kamath A, Smykla R, Kramer R, Vite G (2008) Preclinical discovery of ixabepilone, a highly active antineoplastic agent. Cancer Chemother Pharmacol 63(1):157–166. doi:10.1007/s00280-008-0724-8
Yardley DA (2008) Activity of ixabepilone in patients with metastatic breast cancer with primary resistance to taxanes. Clin Breast Cancer 8(6):487–492. doi:10.3816/CBC.2008.n.058
Thomas E, Tabernero J, Fornier M, Conte P, Fumoleau P, Lluch A, Vahdat LT, Bunnell CA, Burris HA, Viens P, Baselga J, Rivera E, Guarneri V, Poulart V, Klimovsky J, Lebwohl D, Martin M (2007) Phase II clinical trial of ixabepilone (BMS-247550), an epothilone B analog, in patients with taxane-resistant metastatic breast cancer. J Clin Oncol 25(23):3399–3406. doi:10.1200/JCO.2006.08.9102
Thomas ES, Gomez HL, Li RK, Chung HC, Fein LE, Chan VF, Jassem J, Pivot XB, Klimovsky JV, de Mendoza FH, Xu B, Campone M, Lerzo GL, Peck RA, Mukhopadhyay P, Vahdat LT, Roche HH (2007) Ixabepilone plus capecitabine for metastatic breast cancer progressing after anthracycline and taxane treatment. J Clin Oncol 25(33):5210–5217. doi:10.1200/JCO.2007.12.6557
Thomas ES (2008) Ixabepilone plus capecitabine for metastatic breast cancer progressing after anthracycline and taxane treatment. J Clin Oncol 26(13):2223. doi:10.1200/JCO.2008.16.5019
Jones PA, Baylin SB (2002) The fundamental role of epigenetic events in cancer. Nat Rev Genet 3(6):415–428. doi:10.1038/nrg816
Minucci S, Pelicci PG (2006) Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer. Nat Rev Cancer 6(1):38–51. doi:10.1038/nrc1779
Paris M, Porcelloni M, Binaschi M, Fattori D (2008) Histone deacetylase inhibitors: from bench to clinic. J Med Chem 51(6):1505–1529. doi:10.1021/jm7011408
Marks P, Rifkind RA, Richon VM, Breslow R, Miller T, Kelly WK (2001) Histone deacetylases and cancer: causes and therapies. Nat Rev Cancer 1(3):194–202. doi:10.1038/35106079
Fuino L, Bali P, Wittmann S, Donapaty S, Guo F, Yamaguchi H, Wang HG, Atadja P, Bhalla K (2003) Histone deacetylase inhibitor LAQ824 down-regulates Her-2 and sensitizes human breast cancer cells to trastuzumab, taxotere, gemcitabine, and epothilone B. Mol Cancer Ther 2(10):971–984
Munster PN, Troso-Sandoval T, Rosen N, Rifkind R, Marks PA, Richon VM (2001) The histone deacetylase inhibitor suberoylanilide hydroxamic acid induces differentiation of human breast cancer cells. Can Res 61(23):8492–8497
Finnin MS, Donigian JR, Cohen A, Richon VM, Rifkind RA, Marks PA, Breslow R, Pavletich NP (1999) Structures of a histone deacetylase homologue bound to the TSA and SAHA inhibitors. Nature 401(6749):188–193. doi:10.1038/43710
Kim MS, Blake M, Baek JH, Kohlhagen G, Pommier Y, Carrier F (2003) Inhibition of histone deacetylase increases cytotoxicity to anticancer drugs targeting DNA. Can Res 63(21):7291–7300
Rikiishi H, Shinohara F, Sato T, Sato Y, Suzuki M, Echigo S (2007) Chemosensitization of oral squamous cell carcinoma cells to cisplatin by histone deacetylase inhibitor, suberoylanilide hydroxamic acid. Int J Oncol 30(5):1181–1188
Marchion DC, Bicaku E, Daud AI, Richon V, Sullivan DM, Munster PN (2004) Sequence-specific potentiation of topoisomerase II inhibitors by the histone deacetylase inhibitor suberoylanilide hydroxamic acid. J Cell Biochem 92(2):223–237. doi:10.1002/jcb.20045
Luu TH, Morgan RJ, Leong L, Lim D, McNamara M, Portnow J, Frankel P, Smith DD, Doroshow JH, Wong C, Aparicio A, Gandara DR, Somlo G (2008) A phase II trial of vorinostat (suberoylanilide hydroxamic acid) in metastatic breast cancer: a California Cancer Consortium study. Clin Cancer Res 14(21):7138–7142. doi:10.1158/1078-0432.CCR-08-0122
Ji Y, Liu P, Li Y, Bekele BN (2010) A modified toxicity probability interval method for dose-finding trials. Clin Trials 7(6):653–663. doi:10.1177/1740774510382799
Perez EA, Lerzo G, Pivot X, Thomas E, Vahdat L, Bosserman L, Viens P, Cai C, Mullaney B, Peck R, Hortobagyi GN (2007) Efficacy and safety of ixabepilone (BMS-247550) in a phase II study of patients with advanced breast cancer resistant to an anthracycline, a taxane, and capecitabine. J Clin Oncol 25(23):3407–3414. doi:10.1200/JCO.2006.09.3849
Sparano JA, Vrdoljak E, Rixe O, Xu B, Manikhas A, Medina C, Da Costa SC, Ro J, Rubio G, Rondinon M, Perez Manga G, Peck R, Poulart V, Conte P (2010) Randomized phase III trial of ixabepilone plus capecitabine versus capecitabine in patients with metastatic breast cancer previously treated with an anthracycline and a taxane. J Clin Oncol 28(20):3256–3263. doi:10.1200/JCO.2009.24.4244
Kelly WK, O’Connor OA, Krug LM, Chiao JH, Heaney M, Curley T, MacGregore-Cortelli B, Tong W, Secrist JP, Schwartz L, Richardson S, Chu E, Olgac S, Marks PA, Scher H, Richon VM (2005) Phase I study of an oral histone deacetylase inhibitor, suberoylanilide hydroxamic acid, in patients with advanced cancer. J Clin Oncol 23(17):3923–3931. doi:10.1200/JCO.2005.14.167
Sparreboom A, Scripture CD, Trieu V, Williams PJ, De T, Yang A, Beals B, Figg WD, Hawkins M, Desai N (2005) Comparative preclinical and clinical pharmacokinetics of a cremophor-free, nanoparticle albumin-bound paclitaxel (ABI-007) and paclitaxel formulated in Cremophor (Taxol). Clin Cancer Res 11(11):4136–4143. doi:10.1158/1078-0432.CCR-04-2291
Rischin D, Webster LK, Millward MJ, Linahan BM, Toner GC, Woollett AM, Morton CG, Bishop JF (1996) Cremophor pharmacokinetics in patients receiving 3-, 6-, and 24-hour infusions of paclitaxel. J Natl Cancer Inst 88(18):1297–1301
Aghajanian C, Burris HA 3rd, Jones S, Spriggs DR, Cohen MB, Peck R, Sabbatini P, Hensley ML, Greco FA, Dupont J, O’Connor OA (2007) Phase I study of the novel epothilone analog ixabepilone (BMS-247550) in patients with advanced solid tumors and lymphomas. J Clin Oncol 25(9):1082–1088. doi:10.1200/JCO.2006.08.7304
Cohen M, Mould D, Roy A, Mandava M, Pfister M (2008) A population pharmacokinetic analysis of ixabepilone in patients with cancer. J Clin Oncol 15S:2521 2008 ASCO Annual Meeting Proceedings
U.S. Department of Health and Human Services Food and Drug Administration (2007) Ixabepilone clinical pharmacology and biopharmaceutics review. U.S. Department of Health and Human Services; Food and Drug Administration; Center for Drug Evaluation and Research
Beumer JH, Chu E, Salamone SJ (2012) Body-surface area-based chemotherapy dosing: appropriate in the 21st century? J Clin Oncol 30(31):3896–3897. doi:10.1200/JCO.2012.44.2863
Chou TC, Talalay P (1984) Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv Enzym Regul 22:27–55
Chen LH, Sun YT, Chen YF, Lee MY, Chang LY, Chang JY, Shen MR (2015) Integrating image-based high-content screening with mouse models identifies 5-hydroxydecanoate as a neuroprotective drug for paclitaxel-induced neuropathy. Mol Cancer Ther 14(10):2206–2214. doi:10.1158/1535-7163.MCT-15-0268
Parise RA, Holleran JL, Beumer JH, Ramalingam S, Egorin MJ (2006) A liquid chromatography-electrospray ionization tandem mass spectrometric assay for quantitation of the histone deacetylase inhibitor, vorinostat (suberoylanilide hydroxamicacid, SAHA), and its metabolites in human serum. J Chromatogr, B 840(2):108–115. doi:10.1016/j.jchromb.2006.04.044
Xu XS, Zeng J, Mylott W, Arnold M, Waltrip J, Iacono L, Mariannino T, Stouffer B (2010) Liquid chromatography and tandem mass spectrometry for the quantitative determination of ixabepilone (BMS-247550, Ixempra) in human plasma: method validation, overcoming curve splitting issues and eliminating chromatographic interferences from degradants. J Chromatogr B 878(5–6):525–537. doi:10.1016/j.jchromb.2009.12.014
Mosteller RD (1987) Simplified calculation of body-surface area. N Engl J Med 317(17):1098. doi:10.1056/NEJM198710223171717
D’Argenio DZ (1981) Optimal sampling times for pharmacokinetic experiments. J Pharmacokinet Biopharm 9(6):739–756
D’Argenio DZA, Schumitzky A, Wang X (2009) ADAPT 5 user’s guide: pharmacokinetic/pharmacodynamic systems analysis software. Biomedical Simulations Resource, Los Angeles
Acknowledgements
The authors thank all participating patients and their families, as well as the network of investigators, research nurses, study coordinators, and operational staff. The authors also thank Nicola Solomon, PhD for assistance in editing the manuscript. This study was supported by Merck and Bristol-Myers Squibb. This project used the UPCI Cancer Pharmacokinetics and Pharmacodynamics Facility (CPPF) and was supported in part by National Institutes of Health award P30CA047904. This study was previously reported at the San Antonio Breast Cancer Symposium 2012; J Clin Oncol 30, 2012 (suppl; abstr 1070).
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JHB received funding from Bristol-Myers Squibb to perform PK analyses. AH has consulted for Pierian Biosciences and Boehringer Ingelheim and received funding from Celgen, Novartis, and GSK. GS has consulted for Genentech, Novartis, AstraZeneca, AbbVie, Pfizer, Nanostring, Celgene, and PUMA, and received funding from Celgene and Genentech.
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Experiments comply with the current laws of the USA. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments. Informed consent was obtained from all individual participants included in the study.
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Luu, T., Kim, Kp., Blanchard, S. et al. Phase IB trial of ixabepilone and vorinostat in metastatic breast cancer. Breast Cancer Res Treat 167, 469–478 (2018). https://doi.org/10.1007/s10549-017-4516-x
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DOI: https://doi.org/10.1007/s10549-017-4516-x