Skip to main content
Erschienen in: Breast Cancer Research and Treatment 2/2018

27.09.2017 | Clinical trial

Phase IB trial of ixabepilone and vorinostat in metastatic breast cancer

verfasst von: Thehang Luu, Kyu-pyo Kim, Suzette Blanchard, Bean Anyang, Arti Hurria, Lixin Yang, Jan H. Beumer, George Somlo, Yun Yen

Erschienen in: Breast Cancer Research and Treatment | Ausgabe 2/2018

Einloggen, um Zugang zu erhalten

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.
Anhänge
Nur mit Berechtigung zugänglich
Literatur
1.
Zurück zum Zitat 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 CrossRefPubMed 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 CrossRefPubMed
4.
Zurück zum Zitat 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 CrossRefPubMed 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 CrossRefPubMed
5.
Zurück zum Zitat 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 CrossRefPubMed 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 CrossRefPubMed
6.
Zurück zum Zitat 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 CrossRefPubMed 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 CrossRefPubMed
7.
Zurück zum Zitat 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 CrossRefPubMed 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 CrossRefPubMed
9.
Zurück zum Zitat 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 CrossRefPubMed 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 CrossRefPubMed
10.
Zurück zum Zitat 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 CrossRefPubMed 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 CrossRefPubMed
13.
15.
16.
Zurück zum Zitat 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):971–984PubMed 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):971–984PubMed
17.
Zurück zum Zitat 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 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
18.
Zurück zum Zitat 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 CrossRefPubMed 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 CrossRefPubMed
19.
Zurück zum Zitat 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 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
20.
Zurück zum Zitat 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):1181–1188PubMed 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):1181–1188PubMed
21.
Zurück zum Zitat 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 CrossRefPubMed 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 CrossRefPubMed
22.
Zurück zum Zitat 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 CrossRefPubMedPubMedCentral 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 CrossRefPubMedPubMedCentral
24.
Zurück zum Zitat 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 CrossRefPubMed 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 CrossRefPubMed
25.
Zurück zum Zitat 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 CrossRefPubMedPubMedCentral 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 CrossRefPubMedPubMedCentral
26.
Zurück zum Zitat 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 CrossRefPubMedPubMedCentral 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 CrossRefPubMedPubMedCentral
27.
Zurück zum Zitat 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 CrossRefPubMed 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 CrossRefPubMed
28.
Zurück zum Zitat 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):1297–1301CrossRefPubMed 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):1297–1301CrossRefPubMed
29.
Zurück zum Zitat 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 CrossRefPubMed 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 CrossRefPubMed
30.
Zurück zum Zitat 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 CrossRef 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 CrossRef
31.
Zurück zum Zitat 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 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
33.
Zurück zum Zitat Chou TC, Talalay P (1984) Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv Enzym Regul 22:27–55CrossRef Chou TC, Talalay P (1984) Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv Enzym Regul 22:27–55CrossRef
34.
Zurück zum Zitat 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 CrossRefPubMed 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 CrossRefPubMed
35.
Zurück zum Zitat 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 CrossRef 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 CrossRef
36.
Zurück zum Zitat 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 CrossRef 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 CrossRef
38.
Zurück zum Zitat D’Argenio DZ (1981) Optimal sampling times for pharmacokinetic experiments. J Pharmacokinet Biopharm 9(6):739–756CrossRefPubMed D’Argenio DZ (1981) Optimal sampling times for pharmacokinetic experiments. J Pharmacokinet Biopharm 9(6):739–756CrossRefPubMed
39.
Zurück zum Zitat D’Argenio DZA, Schumitzky A, Wang X (2009) ADAPT 5 user’s guide: pharmacokinetic/pharmacodynamic systems analysis software. Biomedical Simulations Resource, Los Angeles D’Argenio DZA, Schumitzky A, Wang X (2009) ADAPT 5 user’s guide: pharmacokinetic/pharmacodynamic systems analysis software. Biomedical Simulations Resource, Los Angeles
Metadaten
Titel
Phase IB trial of ixabepilone and vorinostat in metastatic breast cancer
verfasst von
Thehang Luu
Kyu-pyo Kim
Suzette Blanchard
Bean Anyang
Arti Hurria
Lixin Yang
Jan H. Beumer
George Somlo
Yun Yen
Publikationsdatum
27.09.2017
Verlag
Springer US
Erschienen in
Breast Cancer Research and Treatment / Ausgabe 2/2018
Print ISSN: 0167-6806
Elektronische ISSN: 1573-7217
DOI
https://doi.org/10.1007/s10549-017-4516-x

Weitere Artikel der Ausgabe 2/2018

Breast Cancer Research and Treatment 2/2018 Zur Ausgabe

Update Onkologie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.