Phase I clinical, pharmacokinetic and pharmacodynamic study of SB939, an oral histone deacetylase (HDAC) inhibitor, in patients with advanced solid tumours

A R A Razak, S J Hotte, L L Siu, E X Chen, H W Hirte, J Powers, W Walsh, L-A Stayner, A Laughlin, V Novotny-Diermayr, J Zhu, E A Eisenhauer, A R A Razak, S J Hotte, L L Siu, E X Chen, H W Hirte, J Powers, W Walsh, L-A Stayner, A Laughlin, V Novotny-Diermayr, J Zhu, E A Eisenhauer

Abstract

Background: SB939 is an orally available, competitive histone deacetylase (HDAC) inhibitor selective for class I, II and IV histone deacetylases. Preclinical evaluation of SB939 revealed a profile suggesting improved efficacy compared to other HDAC inhibitors. This phase I study was carried out to determine the safety, dose-limiting toxicity, recommended phase II dose (RPTD), as well as pharmacokinetic (PK) and pharmacodynamic (PD) profiles of SB939 in a daily × 5 schedule in advanced solid tumours.

Methods: Sequential dose-escalating cohorts of patients were enrolled into 8 dose levels. At dose level 1, SB939 was taken on days 1-3 and 15-17 every 4 weeks, then on days 1-5 and 15-19 for other dose levels. Detailed PK sampling was performed in cycle 1, days 1 and 5. Peripheral blood mononuclear cells (PBMCs) were collected on cycle 1 at various time points for determination of acetylated histone H3 (AcH3) levels.

Results: In total, 38 patients received a total of 96 cycles of treatment. The maximal administered dose was 90 mg and the RPTD was 60 mg given 5 consecutive days every 2 weeks. The most frequent non-hematologic adverse events (AEs) of at least possible attribution to SB939 were fatigue, nausea, vomiting, anorexia and diarrhoea. Pharmacokinetic analysis showed dose-proportional increases in AUC across the doses evaluated. Elimination half-life was 5.6-8.9 h. There was no clear relationship between AcH3 changes and dose level or anti-tumour response.

Conclusions: SB939 is well tolerated in patients with advanced solid tumours. The RPTD of this drug is 60 mg on a schedule of 5 consecutive days every 2 weeks. The toxicities of SB939 are consistent with other HDAC inhibitors.

Figures

Figure 1
Figure 1
(A) Mean Cmax and (B) AUC0–∞ of SB939 by dose level.

References

    1. Bjorkman M, Iljin K, Halonen P, Sara H, Kaivanto E, Nees M, Kallioniemi OP (2008) Defining the molecular action of HDAC inhibitors and synergism with androgen deprivation in ERG-positive prostate cancer. Int J Cancer 123: 2774–2781
    1. Carey N, La Thangue NB (2006) Histone deacetylase inhibitors: gathering pace. Curr Opin Pharmacol 6: 369–375
    1. Chambers AE, Banerjee S, Chaplin T, Dunne J, Debernardi S, Joel SP, Young BD (2003) Histone acetylation-mediated regulation of genes in leukaemic cells. Eur J Cancer 39: 1165–1175
    1. Chan HM, Krstic-Demonacos M, Smith L, Demonacos C, La Thangue NB (2001) Acetylation control of the retinoblastoma tumour-suppressor protein. Nat Cell Biol 3: 667–674
    1. Furuyama T, Banerjee R, Breen TR, Harte PJ (2004) SIR2 is required for polycomb silencing and is associated with an E(Z) histone methyltransferase complex. Curr Biol 14: 1812–1821
    1. Garcia-Manero G, Assouline S, Cortes J, Estrov Z, Kantarjian H, Yang H, Newsome WM, Miller Jr WH, Rousseau C, Kalita A, Bonfils C, Dubay M, Patterson TA, Li Z, Besterman JM, Reid G, Laille E, Martell RE, Minden M (2008) Phase 1 study of the oral isotype specific histone deacetylase inhibitor MGCD0103 in leukemia. Blood 112: 981–989
    1. 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: 4628–4635
    1. Iljin K, Wolf M, Edgren H, Gupta S, Kilpinen S, Skotheim RI, Peltola M, Smit F, Verhaegh G, Schalken J, Nees M, Kallioniemi O (2006) TMPRSS2 fusions with oncogenic ETS factors in prostate cancer involve unbalanced genomic rearrangements and are associated with HDAC1 and epigenetic reprogramming. Cancer Res 66: 10242–10246
    1. Johnstone RW, Licht JD (2003) Histone deacetylase inhibitors in cancer therapy: is transcription the primary target? Cancer Cell 4: 13–18
    1. 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: 3923–3931
    1. Lin HY, Chen CS, Lin SP, Weng JR (2006) Targeting histone deacetylase in cancer therapy. Med Res Rev 26: 397–413
    1. Lubieniecka JM, de Bruijn DR, Su L, van Dijk AH, Subramanian S, van de Rijn M, Poulin N, van Kessel AG, Nielsen TO (2008) Histone deacetylase inhibitors reverse SS18-SSX-mediated polycomb silencing of the tumor suppressor early growth response 1 in synovial sarcoma. Cancer Res 68: 4303–4310
    1. Marshall JL, Rizvi N, Kauh J, Dahut W, Figuera M, Kang MH, Figg WD, Wainer I, Chaissang C, Li MZ, Hawkins MJ (2002) A phase I trial of depsipeptide (FR901228) in patients with advanced cancer. J Exp Ther Oncol 2: 325–332
    1. Novotny-Diermayr V, Nayangam NM, Hentze HH, Liang AL, Loh YK, Sausgruber N, Yeo P, Ethirajulu K, Wood JM (2008) A robust and quantitative biomarker assay for SB939, a potent, orally-active HDAC inhibitor (Abstract). Eur J Cancer (Supplements) 6: 28–29
    1. Novotny-Diermayr V, Sangthongpitag K, Hu CY, Wu X, Sausgruber N, Yeo P, Greicius G, Pettersson S, Liang AL, Loh YK, Bonday Z, Goh KC, Hentze H, Hart S, Wang H, Ethirajulu K, Wood JM (2010) SB939, a novel potent and orally active histone deacetylase inhibitor with high tumor exposure and efficacy in mouse models of colorectal cancer. Mol Cancer Ther 9: 642–652
    1. Pandolfi PP (2001) Histone deacetylases and transcriptional therapy with their inhibitors. Cancer Chemother Pharmacol 48(Suppl 1): S17–S19
    1. Ryan QC, Headlee D, Acharya M, Sparreboom A, Trepel JB, Ye J, Figg WD, Hwang K, Chung EJ, Murgo A, Melillo G, Elsayed Y, Monga M, Kalnitskiy M, Zwiebel J, Sausville EA (2005) Phase I and pharmacokinetic study of MS-275, a histone deacetylase inhibitor, in patients with advanced and refractory solid tumors or lymphoma. J Clin Oncol 23: 3912–3922
    1. Sandor V, Bakke S, Robey RW, Kang MH, Blagosklonny MV, Bender J, Brooks R, Piekarz RL, Tucker E, Figg WD, Chan KK, Goldspiel B, Fojo AT, Balcerzak SP, Bates SE (2002) Phase I trial of the histone deacetylase inhibitor, depsipeptide (FR901228, NSC 630176), in patients with refractory neoplasms. Clin Cancer Res 8: 718–728
    1. Siu LL, Pili R, Duran I, Messersmith WA, Chen EX, Sullivan R, MacLean M, King S, Brown S, Reid GK, Li Z, Kalita AM, Laille EJ, Besterman JM, Martell RE, Carducci MA (2008) Phase I study of MGCD0103 given as a three-times-per-week oral dose in patients with advanced solid tumors. J Clin Oncol 26: 1940–1947
    1. Soulez M, Saurin AJ, Freemont PS, Knight JC (1999) SSX and the synovial-sarcoma-specific chimaeric protein SYT-SSX co-localize with the human Polycomb group complex. Oncogene 18: 2739–2746
    1. Steele NL, Plumb JA, Vidal L, Tjornelund J, Knoblauch P, Rasmussen A, Ooi CE, Buhl-Jensen P, Brown R, Evans TR, DeBono JS (2008) A phase 1 pharmacokinetic and pharmacodynamic study of the histone deacetylase inhibitor belinostat in patients with advanced solid tumors. Clin Cancer Res 14: 804–810
    1. Stimson L, Wood V, Khan O, Fotheringham S, La Thangue NB (2009) HDAC inhibitor-based therapies and haematological malignancy. Ann Oncol 20: 1293–1302
    1. Strahl BD, Allis CD (2000) The language of covalent histone modifications. Nature 403: 41–45
    1. Terry J, Saito T, Subramanian S, Ruttan C, Antonescu CR, Goldblum JR, Downs-Kelly E, Corless CL, Rubin BP, van de Rijn M, Ladanyi M, Nielsen TO (2007) TLE1 as a diagnostic immunohistochemical marker for synovial sarcoma emerging from gene expression profiling studies. Am J Surg Pathol 31: 240–246
    1. Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van Glabbeke M, van Oosterom AT, Christian MC, Gwyther SG (2000) New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92: 205–216
    1. Timmermann S, Lehrmann H, Polesskaya A, Harel-Bellan A (2001) Histone acetylation and disease. Cell Mol Life Sci 58: 728–736
    1. Tomlins SA, Rhodes DR, Perner S, Dhanasekaran SM, Mehra R, Sun XW, Varambally S, Cao X, Tchinda J, Kuefer R, Lee C, Montie JE, Shah RB, Pienta KJ, Rubin MA, Chinnaiyan AM (2005) Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer. Science 310: 644–648
    1. van der Vlag J, Otte AP (1999) Transcriptional repression mediated by the human polycomb-group protein EED involves histone deacetylation. Nat Genet 23: 474–478
    1. Yochum GS, Ayer DE (2001) Pf1, a novel PHD zinc finger protein that links the TLE corepressor to the mSin3A-histone deacetylase complex. Mol Cell Biol 21: 4110–4118
    1. Yong W, Goh B, Toh R, Soo R, Diermayr V, Goh A, Ethirajulu K, Lee S, Seah E, Zhu J (2009) Phase I study of SB939 three times weekly for 3 weeks every 4 weeks in patients with advanced solid malignancies (Abstract). J Clin Oncol 27: 2560
    1. Yong WP, Goh BC, Ethirajulu K, Yeo P, Otheris O, Chao SM, Soo R, Yeo WL, Seah E, Zhu J (2008) A phase I dose escalation study of oral SB939 when administered thrice weekly (every other day) for 3 weeks in a 4-week cycle in patients with advanced solid malignancies (Abstract). Eur J Cancer (Supplements) 6: 130

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe