Breast Cancer Research and Treatment

, Volume 167, Issue 2, pp 469–478 | Cite as

Phase IB trial of ixabepilone and vorinostat in metastatic breast cancer

  • Thehang Luu
  • Kyu-pyo Kim
  • Suzette Blanchard
  • Bean Anyang
  • Arti Hurria
  • Lixin Yang
  • Jan H. Beumer
  • George Somlo
  • Yun Yen
Clinical trial



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.


Phase 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.

Ethical approval

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.

Supplementary material

10549_2017_4516_MOESM1_ESM.doc (784 kb)
Supplementary material 1 (DOC 784 kb)


  1. 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
  2. 2.
    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 CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    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 CrossRefPubMedGoogle Scholar
  4. 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. 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. 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
  7. 7.
    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 CrossRefPubMedGoogle Scholar
  8. 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 CrossRefPubMedGoogle Scholar
  9. 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. 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
  11. 11.
    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 CrossRefPubMedGoogle Scholar
  12. 12.
    Jones PA, Baylin SB (2002) The fundamental role of epigenetic events in cancer. Nat Rev Genet 3(6):415–428. doi: 10.1038/nrg816 PubMedGoogle Scholar
  13. 13.
    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 CrossRefPubMedGoogle Scholar
  14. 14.
    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 CrossRefPubMedGoogle Scholar
  15. 15.
    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 CrossRefPubMedGoogle Scholar
  16. 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. 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
  18. 18.
    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 CrossRefPubMedGoogle Scholar
  19. 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
  20. 20.
    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):1181–1188PubMedGoogle Scholar
  21. 21.
    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 CrossRefPubMedGoogle Scholar
  22. 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
  23. 23.
    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 CrossRefPubMedPubMedCentralGoogle Scholar
  24. 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. 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. 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. 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
  28. 28.
    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):1297–1301CrossRefPubMedGoogle Scholar
  29. 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
  30. 30.
    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 CrossRefGoogle Scholar
  31. 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
  32. 32.
    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 CrossRefPubMedGoogle Scholar
  33. 33.
    Chou TC, Talalay P (1984) Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv Enzym Regul 22:27–55CrossRefGoogle Scholar
  34. 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. 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. 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
  37. 37.
    Mosteller RD (1987) Simplified calculation of body-surface area. N Engl J Med 317(17):1098. doi: 10.1056/NEJM198710223171717 PubMedGoogle Scholar
  38. 38.
    D’Argenio DZ (1981) Optimal sampling times for pharmacokinetic experiments. J Pharmacokinet Biopharm 9(6):739–756CrossRefPubMedGoogle Scholar
  39. 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

Copyright information

© Springer Science+Business Media, LLC 2017

Authors and Affiliations

  1. 1.Department of Medical OncologyCity of Hope Medical CenterDuarteUSA
  2. 2.OncoGambit, LLCIrvineUSA
  3. 3.Cancer Therapeutics ProgramUniversity of Pittsburgh Cancer InstitutePittsburghUSA
  4. 4.Department of Oncology, Asan Medical CenterUniversity of Ulsan College of MedicineSeoulSouth Korea
  5. 5.Department of BiostatisticsCity of HopeDuarteUSA
  6. 6.Department of MolecularCity of HopeDuarteUSA
  7. 7.Department of Pharmaceutical SciencesUniversity of Pittsburgh School of PharmacyPittsburghUSA
  8. 8.Division of Hematology/Oncology, Department of MedicineUniversity of Pittsburgh School of MedicinePittsburghUSA
  9. 9.Pharmacology, Beckman Research InstituteCity of HopeDuarteUSA
  10. 10.Cancer Research and Drug Discovery Medical Technology CollegeTaipei Medical UniversityTaipeiTaiwan

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