Phase IB trial of ixabepilone and vorinostat in metastatic breast cancer
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To translate promising preclinical data on the combination of vorinostat and ixabepilone for metastatic breast cancer (MBC) into clinical trials.
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.
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.
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.
KeywordsPhase IB clinical trial Ixabepilone Vorinostat Metastatic breast cancer Histone deacetylation inhibitors (HDACIs)
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).
Compliance with ethical standards
Conflict of interest
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.
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.
- 1.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 CrossRefPubMedGoogle Scholar
- 4.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 CrossRefPubMedGoogle Scholar
- 5.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 CrossRefPubMedGoogle Scholar
- 6.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 CrossRefPubMedGoogle Scholar
- 9.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 CrossRefPubMedGoogle Scholar
- 10.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 CrossRefPubMedGoogle Scholar
- 16.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):971–984PubMedGoogle Scholar
- 17.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):8492–8497Google Scholar
- 19.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):7291–7300Google Scholar
- 22.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 CrossRefPubMedPubMedCentralGoogle Scholar
- 24.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 CrossRefPubMedGoogle Scholar
- 25.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 CrossRefPubMedPubMedCentralGoogle Scholar
- 26.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 CrossRefPubMedPubMedCentralGoogle Scholar
- 27.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 CrossRefPubMedGoogle Scholar
- 29.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 CrossRefPubMedGoogle Scholar
- 31.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 ResearchGoogle Scholar
- 34.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 CrossRefPubMedGoogle Scholar
- 35.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 CrossRefGoogle Scholar
- 36.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 CrossRefGoogle Scholar
- 39.D’Argenio DZA, Schumitzky A, Wang X (2009) ADAPT 5 user’s guide: pharmacokinetic/pharmacodynamic systems analysis software. Biomedical Simulations Resource, Los AngelesGoogle Scholar