Cancer Chemotherapy and Pharmacology

, Volume 84, Issue 6, pp 1201–1208 | Cite as

Phase I trial of belinostat in combination with 13-cis-retinoic acid in advanced solid tumor malignancies: a California Cancer Consortium NCI/CTEP sponsored trial

  • Thehang Luu
  • Paul Frankel
  • Jan H. Beumer
  • Dean Lim
  • Mihaela Cristea
  • Leonard J. Appleman
  • Heinz J. Lenz
  • David R. Gandara
  • Brian F. Kiesel
  • Richard L. Piekarz
  • Edward M. NewmanEmail author
Original Article



The reported maximum tolerated dose (MTD) of single-agent belinostat is 1000 mg/m2 given days 1–5, every 21 days. Pre-clinical evidence suggests histone deacetylase inhibitors enhance retinoic acid signaling in a variety of solid tumors. We conducted a phase I study of belinostat combined with 50–100 mg/m2/day 13-cis-retinoic acid (13-cRA) in patients with advanced solid tumors.


Belinostat was administered days 1–5 and 13-cRA days 1–14, every 21 days. Dose-limiting toxicity (DLT) was defined as cycle 1 hematologic toxicity grade ≥ 3 not resolving to grade ≤ 1 within 1 week or non-hematologic toxicity grade ≥ 3 (except controlled nausea and vomiting and transient liver function abnormalities) attributable to belinostat.


Among 51 patients, two DLTs were observed: grade 3 hypersensitivity with dizziness and hypoxia at 1700 mg/m2/day belinostat with 100 mg/m2/day 13-cRA, and grade 3 allergic reaction at 2000 mg/m2/day belinostat with 100 mg/m2/day 13-cRA. The MTD was not reached. Pharmacokinetics of belinostat may be non-linear at high doses. Ten patients had stable disease, including one with neuroendocrine pancreatic cancer for 56 cycles, one with breast cancer for 12 cycles, and one with lung cancer for 8 cycles. Partial responses included a patient with keratinizing squamous cell carcinoma of the tonsils, and a patient with lung cancer.


The combination of belinostat 2000 mg/m2 days 1–5 and 13-cRA 100 mg/m2 days 1–14, every 21 days, was well-tolerated and an MTD was not reached despite doubling the established single-agent MTD of belinostat.


Histone deacetylase (HDAC) inhibitors Retinoids Phase I clinical trial Pharmacokinetics 



The authors thank all of the participating patients and their families, as well as the network of investigators, research nurses, study coordinators, and operation staffs.


The research reported was supported by the National Cancer Institute of the National Institutes of Health under Award numbers U01CA062505, UM1CA186717 and P30CA033572 to City of Hope; and UM1CA186690 and P30CA047904 to University of Pittsburgh. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Compliance with ethical standards

Conflict of interest

Jan H. Beumer received research support from Spectrum Pharmaceuticals.


  1. 1.
    Plumb JA et al (2003) Pharmacodynamic response and inhibition of growth of human tumor xenografts by the novel histone deacetylase inhibitor PXD101. Mol Cancer Ther 2(8):721–728PubMedGoogle Scholar
  2. 2.
    Marks PA, Richon VM, Rifkind RA (2000) Histone deacetylase inhibitors: inducers of differentiation or apoptosis of transformed cells. J Natl Cancer Inst 92(15):1210–1216CrossRefGoogle Scholar
  3. 3.
    Altucci L, Gronemeyer H (2001) The promise of retinoids to fight against cancer. Nat Rev Cancer 1(3):181–193CrossRefGoogle Scholar
  4. 4.
    Lippman SM et al (1992) 13-cis-retinoic acid plus interferon alpha-2a: highly active systemic therapy for squamous cell carcinoma of the cervix. J Natl Cancer Inst 84(4):241–245CrossRefGoogle Scholar
  5. 5.
    Lippman SM et al (1993) 13-cis-retinoic acid plus interferon-alpha 2a in locally advanced squamous cell carcinoma of the cervix. J Natl Cancer Inst 85(6):499–500CrossRefGoogle Scholar
  6. 6.
    Lippman SM et al (1992) 13-cis-retinoic acid and interferon alpha-2a: effective combination therapy for advanced squamous cell carcinoma of the skin. J Natl Cancer Inst 84(4):235–241CrossRefGoogle Scholar
  7. 7.
    Yoshida M et al (1990) Potent and specific inhibition of mammalian histone deacetylase both in vivo and in vitro by trichostatin A. J Biol Chem 265(28):17174–17179PubMedGoogle Scholar
  8. 8.
    Richon VM et al (2000) Histone deacetylase inhibitor selectively induces p21WAF1 expression and gene-associated histone acetylation. Proc Natl Acad Sci USA 97(18):10014–10019CrossRefGoogle Scholar
  9. 9.
    Steele NL et al (2008) A phase 1 pharmacokinetic and pharmacodynamic study of the histone deacetylase inhibitor belinostat in patients with advanced solid tumors. Clin Cancer Res 14(3):804–810CrossRefGoogle Scholar
  10. 10.
    Yeo W et al (2012) Epigenetic therapy using belinostat for patients with unresectable hepatocellular carcinoma: a multicenter phase I/II study with biomarker and pharmacokinetic analysis of tumors from patients in the Mayo Phase II Consortium and the Cancer Therapeutics Research Group. J Clin Oncol 30(27):3361–3367CrossRefGoogle Scholar
  11. 11.
    Giaccone G et al (2011) Phase II study of belinostat in patients with recurrent or refractory advanced thymic epithelial tumors. J Clin Oncol 29(15):2052–2059CrossRefGoogle Scholar
  12. 12.
    Dizon DS et al (2012) A phase II evaluation of belinostat and carboplatin in the treatment of recurrent or persistent platinum-resistant ovarian, fallopian tube, or primary peritoneal carcinoma: a Gynecologic Oncology Group study. Gynecol Oncol 125(2):367–371CrossRefGoogle Scholar
  13. 13.
    Dizon DS et al (2012) Phase II activity of belinostat (PXD-101), carboplatin, and paclitaxel in women with previously treated ovarian cancer. Int J Gynecol Cancer 22(6):979–986CrossRefGoogle Scholar
  14. 14.
    Kizaki M et al (1993) Effects of novel retinoic acid compound, 9-cis-retinoic acid, on proliferation, differentiation, and expression of retinoic acid receptor-alpha and retinoid X receptor-alpha RNA by HL-60 cells. Blood 82(12):3592–3599CrossRefGoogle Scholar
  15. 15.
    Chambon P (1996) A decade of molecular biology of retinoic acid receptors. FASEB J 10(9):940–954CrossRefGoogle Scholar
  16. 16.
    Armstrong JL, Redfern CP, Veal GJ (2005) 13-cis retinoic acid and isomerisation in paediatric oncology–is changing shape the key to success? Biochem Pharmacol 69(9):1299–1306CrossRefGoogle Scholar
  17. 17.
    Blaner WS (2001) Cellular metabolism and actions of 13-cis-retinoic acid. J Am Acad Dermatol 45(5):S129–S135CrossRefGoogle Scholar
  18. 18.
    Yung WK et al (1996) Treatment of recurrent malignant gliomas with high-dose 13-cis-retinoic acid. Clin Cancer Res 2(12):1931–1935PubMedGoogle Scholar
  19. 19.
    Connolly RM, Nguyen NK, Sukumar S (2013) Molecular pathways: current role and future directions of the retinoic acid pathway in cancer prevention and treatment. Clin Cancer Res 19(7):1651–1659CrossRefGoogle Scholar
  20. 20.
    Ferrara FF et al (2001) Histone deacetylase-targeted treatment restores retinoic acid signaling and differentiation in acute myeloid leukemia. Cancer Res 61(1):2–7PubMedGoogle Scholar
  21. 21.
    Demary K, Wong L, Spanjaard RA (2001) Effects of retinoic acid and sodium butyrate on gene expression, histone acetylation and inhibition of proliferation of melanoma cells. Cancer Lett 163(1):103–107CrossRefGoogle Scholar
  22. 22.
    Fitzgerald P et al (1997) Retinoic acid receptor alpha expression correlates with retinoid-induced growth inhibition of human breast cancer cells regardless of estrogen receptor status. Cancer Res 57(13):2642–2650PubMedGoogle Scholar
  23. 23.
    Bovenzi V, Momparler RL (2001) Antineoplastic action of 5-aza-2′-deoxycytidine and histone deacetylase inhibitor and their effect on the expression of retinoic acid receptor beta and estrogen receptor alpha genes in breast carcinoma cells. Cancer Chemother Pharmacol 48(1):71–76CrossRefGoogle Scholar
  24. 24.
    Minucci S et al (1997) A histone deacetylase inhibitor potentiates retinoid receptor action in embryonal carcinoma cells. Proc Natl Acad Sci USA 94(21):11295–11300CrossRefGoogle Scholar
  25. 25.
    Sirchia SM et al (2002) Endogenous reactivation of the RARbeta2 tumor suppressor gene epigenetically silenced in breast cancer. Cancer Res 62(9):2455–2461PubMedGoogle Scholar
  26. 26.
    Cassidy J et al (1982) Phase II trial of 13-cis-retinoic acid in metastatic breast cancer. Eur J Cancer Clin Oncol 18(10):925–928CrossRefGoogle Scholar
  27. 27.
    Kiesel BF et al (2013) LC-MS/MS assay for the quantitation of the HDAC inhibitor belinostat and five major metabolites in human plasma. J Pharm Biomed Anal 81–82:89–98CrossRefGoogle Scholar
  28. 28.
    Wang K et al (2008) Retinoids induce cytochrome P450 3A4 through RXR/VDR-mediated pathway. Biochem Pharmacol 75(11):2204–2213CrossRefGoogle Scholar
  29. 29.
    Lassen U et al (2010) A phase I study of the safety and pharmacokinetics of the histone deacetylase inhibitor belinostat administered in combination with carboplatin and/or paclitaxel in patients with solid tumours. Br J Cancer 103(1):12–17CrossRefGoogle Scholar
  30. 30.
    Fontana JA, Rishi AK (2002) Classical and novel retinoids: their targets in cancer therapy. Leukemia 16(4):463–472CrossRefGoogle Scholar
  31. 31.
    Boyle JO (2001) Retinoid mechanisms and cyclins. Curr Oncol Rep 3(4):301–305CrossRefGoogle Scholar
  32. 32.
    Beleodaq® (belinostat) (2019) Beleodaq® (belinostat) for injection, for intravenous administration [package insert]. Spectrum Pharmaceuticals, Henderson, NVGoogle Scholar
  33. 33.
    Lamb JG, Franklin MR (2000) Early events in the induction of rat hepatic UDP-glucuronosyltransferases, glutathione S-transferase, and microsomal epoxide hydrolase by 1,7-phenanthroline: comparison with oltipraz, tert-butyl-4-hydroxyanisole, and tert-butylhydroquinone. Drug Metab Dispos 28(9):1018–1023PubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Thehang Luu
    • 1
  • Paul Frankel
    • 2
  • Jan H. Beumer
    • 3
  • Dean Lim
    • 1
  • Mihaela Cristea
    • 1
  • Leonard J. Appleman
    • 3
  • Heinz J. Lenz
    • 4
  • David R. Gandara
    • 5
  • Brian F. Kiesel
    • 3
  • Richard L. Piekarz
    • 6
  • Edward M. Newman
    • 7
    Email author
  1. 1.Department of Medical OncologyCity of HopeDuarteUSA
  2. 2.Department of BiostatisticsCity of HopeDuarteUSA
  3. 3.UPMC Hillman Cancer CenterPittsburghUSA
  4. 4.University of Southern California/Norris Comprehensive Cancer CenterLos AngelesUSA
  5. 5.University of California Davis Cancer CenterSacramentoUSA
  6. 6.Cancer Therapy Evaluation ProgramNational Cancer InstituteBethesdaUSA
  7. 7.Beckman Research Institute City of HopeDuarteUSA

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