Cancer Chemotherapy and Pharmacology

, Volume 66, Issue 1, pp 181–189

A phase I study of oral panobinostat alone and in combination with docetaxel in patients with castration-resistant prostate cancer

  • Dana Rathkopf
  • Bryan Y. Wong
  • Robert W. Ross
  • Aseem Anand
  • Erika Tanaka
  • Margaret M. Woo
  • Jing Hu
  • Andy Dzik-Jurasz
  • Wei Yang
  • Howard I. Scher
Clinical Trial Report

Abstract

Purpose

Histone deacetylase inhibitors have demonstrated anticancer activity against a range of tumors. We aimed to define the maximum tolerated dose, toxicity, activity, and pharmacokinetics of oral panobinostat, a pan-deacetylase inhibitor, alone and in combination with docetaxel for the treatment of castration-resistant prostate cancer (CRPC).

Methods

Sixteen patients were enrolled, eight in each arm. Eligible patients had CRPC and adequate organ function. In arm I, oral panobinostat (20 mg) was administered on days 1, 3, and 5 for 2 consecutive weeks followed by a 1-week break. In arm II, oral panobinostat (15 mg) was administered on the same schedule in combination with docetaxel 75 mg/m2 every 21 days.

Results

Dose-limiting toxicities were grade 3 dyspnea (arm I) and grade 3 neutropenia >7 days (arm II). In arm I, all patients developed progressive disease despite accumulation of acetylated histones in peripheral blood mononuclear cells. In arm II, five of eight patients (63%) had a ≥50% decline in prostate-specific antigen (PSA), including one patient whose disease had previously progressed on docetaxel.

Conclusions

Oral panobinostat with and without docetaxel is feasible, and docetaxel had no apparent effect on the pharmacokinetics of panobinostat. Since preclinical studies suggest a dose-dependent effect of panobinostat on PSA expression, and other phase I data demonstrate that intravenous panobinostat produces higher peak concentrations (>20- to 30-fold) and area under the curve (3.5x–5x), a decision was made to focus the development of panobinostat on the intravenous formulation to treat CRPC.

Keywords

Prostate cancer Castration-resistant Histone deacetylase inhibitor Panobinostat Docetaxel 

References

  1. 1.
    Rasheed W, Bishton M, Johnstone RW, Primce HM (2008) Histone deacetylase inhibitors in lymphoma and solid malignancies. Expert Rev Anticancer Ther 8:413–432CrossRefPubMedGoogle Scholar
  2. 2.
    Butler LM, Agus DB, Scher HI, Higgins B, Rose A, Cordon-Cardo C, Thaler HT, Rifkind RA, Marks PA, Richon VM (2000) Suberoylanilide hydroxamic acid, an inhibitor of histone deacetylase, suppresses the growth of prostate cancer cells in vitro and in vivo. Cancer Res 60:5165–5170PubMedGoogle Scholar
  3. 3.
    Qian DZ, Kato Y, Shabbeer S, Wei Y, Verheul HM, Salumbides B, Sanni T, Atadja P, Pili R (2006) Targeting tumor angiogenesis with histone deacetylase inhibitors: the hydroxamic acid derivative LBH589. Clin Cancer Res 12:634–642CrossRefPubMedGoogle Scholar
  4. 4.
    Kulp SK, Chen CS, Wang DS, Cheng CY, Chen CS (2006) Antitumor effects of a novel phenylbutyrate-based histone deacetylase inhibitor, (S)-HDAC-42, in prostate cancer. Clin Cancer Res 12:5199–5206CrossRefPubMedGoogle Scholar
  5. 5.
    Kuefer R, Hofer MD, Altug V, Zorn C, Genze F, Kunzi-Rapp K, Hautmann RE, Gschwend JE (2004) Sodium butyrate and tributyrin induce in vivo growth inhibition and apoptosis in human prostate cancer. Br J Cancer 90:535–541CrossRefPubMedGoogle Scholar
  6. 6.
    Chen L, Meng S, Wang H, Bali P, Bai W, Li B, Atadja P, Bhalla KN, Wu J (2005) Chemical ablation of androgen receptor in prostate cancer cells by the histone deacetylase inhibitor LAQ824. Mol Cancer Ther 4:1311–1319CrossRefPubMedGoogle Scholar
  7. 7.
    Shao W, Growney J, O’Connor G, Feng Y, Scher H, Yao Y, Fawell S, Atadja P (2008) Efficacy of panobinostat (LBH589) in prostate cancer cell models: targeting the androgen receptor in hormone-refractory prostate cancer (HRPC). Presented at the Genitourinary Cancers Symposium, San FranciscoGoogle Scholar
  8. 8.
    Giles F, Fischer T, Cortes J, Garcia-Manero G, Beck J, Ravandi F, Masson E, Rae P, Laird G, Sharma S, Kantarjian H, Dugan M, Albitar M, Bhalla K (2006) A phase I study of intravenous LBH589, a novel cinnamic hydroxamic acid analogue histone deacetylase inhibitor, in patients with refractory hematologic malignancies. Clin Cancer Res 12:4628–4635CrossRefPubMedGoogle Scholar
  9. 9.
    Prince HM, George D, Patnaik A et al (2007) Phase I study of oral panobinostat (LBH589) in advanced solid tumors and non-Hodgkin’s lymphoma. Presented at the ECCO Poster, Barcelona, Spain, September 23–27, 2007 (abstr 701)Google Scholar
  10. 10.
    Sharma S, Vogelzang N, Beck J et al (2007) Phase I pharmacokinetic and pharmacodynamic study of once-weekly i.v. panobinostat (LBH589). Presented at the ECCO Poster, Barcelona, Spain, September 23–27, 2007 (abstr 702)Google Scholar
  11. 11.
    Scher HI, Morris MJ, Kelly WK, Schwartz LH, Heller G (2005) Prostate cancer clinical trial end points: “RECIST”ing a step backwards. Clin Cancer Res 11:5223–5232CrossRefPubMedGoogle Scholar
  12. 12.
    Babb J, Rogatko A, Zacks S (1998) Cancer phase I clinical trials: efficient dose escalation with overdose control. Stat Med 17:1103–1120CrossRefPubMedGoogle Scholar
  13. 13.
    Cristofanilli M, Budd GT, Ellis MJ, Stopeck A, Matera J, Miller MC, Reuben JM, Doyle GV, Allard WJ, Terstappan LW, Hayes DF (2004) Circulating tumor cells, disease progression, and survival in metastatic breast cancer. N Engl J Med 351:781–791CrossRefPubMedGoogle Scholar
  14. 14.
    Danila DC, Heller G, Gignac GA, Gonzalez-Espinoza R, Anand A, Tanaka E, Lilja H, Schwartz L, Larson S, Fleisher M, Scher HI (2007) Circulating tumor cell number and prognosis in progressive castration-resistant prostate cancer. Clin Cancer Res 13:7053–7058CrossRefPubMedGoogle Scholar
  15. 15.
    Young H, Baum R, Cremerius U, Herholz K, Hoekstra O, Lammertsma AA, Pruim J, Price P (1999) Measurement of clinical and subclinical tumour response using [18F]-fluorodeoxyglucose and positron emission tomography: review and 1999 EORTC recommendations. European organization for research and treatment of cancer (EORTC) PET study group. Eur J Cancer 35:1773–1782CrossRefPubMedGoogle Scholar
  16. 16.
    Minn H, Zasadny KR, Quint LE, Wahl RL (1995) Lung cancer: reproducibility of quantitative measurements for evaluating 2-[F-18]-fluoro-2-deoxy-D-glucose uptake at PET. Radiology 196:167–173PubMedGoogle Scholar
  17. 17.
    Weber WA, Ziegler SI, Thödtmann R, Hanauske AR, Schwaiger M (1999) Reproducibility of metabolic measurements in malignant tumors using FDG PET. J Nucl Med 40:1771–1777PubMedGoogle Scholar
  18. 18.
    Kelloff GJ, Krohn KA, Larson SM, Weissleder R, Mankoff DA, Hoffman JM, Link JM, Guyton KZ, Eckelman WC, Scher HI, O’Shaughnessy J, Cheson BD, Sigman CC, Tatum JL, Mills GQ, Sullivan DC, Woodcock J (2005) The progress and promise of molecular imaging probes in oncologic drug development. Clin Cancer Res 11:7967–7985CrossRefPubMedGoogle Scholar
  19. 19.
    Tannock IF, de Wit R, Berry WR, Horti J, Pluzanska A, Chi KN, Oudard S, Théodore C, James ND, Turesson I, Rosenthal MA, Eisenberger MA, TAX 327 Investigators (2004) Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 351:1502–1512CrossRefPubMedGoogle Scholar
  20. 20.
    de Bono JS, Scher HI, Montgomery RB, Parker C, Miller MC, Tissing H, Doyle GV, Terstappen LW, Pienta KJ, Raghavan D (2008) Circulating tumor cells predict survival benefit from treatment in metastatic castration-resistant prostate cancer. Clin Cancer Res 14:6302–6309CrossRefPubMedGoogle Scholar
  21. 21.
    Rokhlin OW, Glover RB, Guseva NV, Taghiyev AF, Kohlgraf KG, Cohen MB (2006) Mechanisms of cell death induced by histone deacetylase inhibitors in androgen receptor-positive prostate cancer cells. Mol Cancer Res 4:113–123CrossRefPubMedGoogle Scholar
  22. 22.
    Tomlins SA, Mehra R, Rhodes DR et al (2006) TMPRSS2: ETV4 gene fusions define a third molecular subtype of prostate cancer. Cancer Res 66:3396–3400CrossRefPubMedGoogle Scholar
  23. 23.
    Welsbie DS, Xu J, Chen Y et al (2009) Histone deacetylases are required for androgen receptor function in hormone-sensitive and castrate-resistant prostate cancer. Cancer Res 69:958–966CrossRefPubMedGoogle Scholar
  24. 24.
    Scher HI, Halabi S, Tannock I, Morris M, Sternberg CN, Carducci MA et al (2008) Design and end points of clinical trials for patients with progressive prostate cancer and castrate levels of testosterone: recommendations of the Prostate Cancer Clinical Trials Working Group. J Clin Oncol 26(7):1148–1159Google Scholar
  25. 25.
    Kelly WK, O’Connor OA, Krug LM et al (2005) Phase I study of an oral histone deacetylase inhibitor, suberoylanilide hydroxamic acid, in patients with advanced cancer. J Clin Oncol 23:3923–3931CrossRefPubMedGoogle Scholar
  26. 26.
    Sharma S, Vogelzang NJ, Beck J et al (2007) Phase I pharmacokinetic (PK) and pharmacodynamic (PD) study of LBH589, a novel deacetylase (DAC) inhibitor given intravenously on a new once weekly schedule. J Clin Oncol, 2007 ASCO Annual Meeting Proceedings Part I. Vol 25, No. 18S (June 20, 2007, Supplement) (abstr 14019)Google Scholar
  27. 27.
    Zanzonico PB, Finn R, Pentlow KS et al (2004) PET-based radiation dosimetry in man of 18F-fluorodihydrotestosterone, a new radiotracer for imaging prostate cancer. J Nucl Med 45:1966–1971PubMedGoogle Scholar
  28. 28.
    Larson SM, Morris M, Gunther I et al (2004) Tumor localization of 16beta-18F-fluoro-5alpha-dihydrotestosterone versus 18F-FDG in patients with progressive, metastatic prostate cancer. J Nucl Med 45:366–373PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Dana Rathkopf
    • 1
    • 2
  • Bryan Y. Wong
    • 3
  • Robert W. Ross
    • 4
  • Aseem Anand
    • 1
    • 2
  • Erika Tanaka
    • 1
    • 2
  • Margaret M. Woo
    • 5
  • Jing Hu
    • 5
  • Andy Dzik-Jurasz
    • 5
  • Wei Yang
    • 5
  • Howard I. Scher
    • 1
    • 2
  1. 1.Genitourinary Oncology Service, Department of MedicineSidney Kimmel Center for Prostate and Urologic Cancers, Memorial Sloan-Kettering Cancer CenterNew YorkUSA
  2. 2.Department of MedicineJoan and Sanford I. Weill Medical College of Cornell UniversityNew YorkUSA
  3. 3.Mayo ClinicScottsdaleUSA
  4. 4.Dana-Farber Cancer InstituteBostonUSA
  5. 5.Novartis OncologyFlorham ParkUSA

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