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Cancer Chemotherapy and Pharmacology

, Volume 70, Issue 2, pp 251–258 | Cite as

Phase I study of bevacizumab, everolimus, and panobinostat (LBH-589) in advanced solid tumors

  • John H. Strickler
  • Alexander N. Starodub
  • Jingquan Jia
  • Kellen L. Meadows
  • Andrew B. Nixon
  • Andrew Dellinger
  • Michael A. Morse
  • Hope E. Uronis
  • P. Kelly  Marcom
  • S. Yousuf  Zafar
  • Sherri T. Haley
  • Herbert I. Hurwitz
Original Article

Abstract

Purpose

To define the maximum tolerated dose, clinical toxicities, and pharmacodynamics of bevacizumab, everolimus, and panobinostat (LBH-589) when administered in combination to patients with advanced solid tumor malignancies.

Experiment design

Subjects received 10 mg of panobinostat three times weekly, 5 or 10 mg everolimus daily, and bevacizumab at 10 mg/kg every 2 weeks. Dose-limiting toxicities (DLTs) were assessed in cycle 1; toxicity evaluation was closely monitored throughout treatment. Treatment continued until disease progression or undesirable toxicity. Protein acetylation was assessed in peripheral blood mononuclear cells (PBMC) both at baseline and on treatment.

Results

Twelve subjects were evaluable for toxicity and nine subjects for response. DLTs in cohort 1 included grade 2 esophagitis and grade 3 oral mucositis; DLTs in cohort -1 were grade 2 ventricular arrhythmia and grade 2 intolerable skin rash. Common adverse events were diarrhea (50 %), headache (33 %), mucositis/stomatitis (25 %), hyperlipidemia (25 %), and thrombocytopenia (25 %). There was 1 partial response; an additional 2 subjects had stable disease as best response. No consistent changes in protein acetylation in PBMC were observed in samples available from eight patients on treatment compared with baseline.

Conclusions

Bevacizumab, everolimus, and panobinostat in combination at the lowest proposed doses did not have an acceptable safety and tolerability profile and did not consistently inhibit HDAC activity; therefore, we do not recommend further evaluation.

Keywords

Bevacizumab Everolimus Panobinostat Phase I Advanced cancer 

Notes

Acknowledgments

We gratefully acknowledge the invaluable contributions of the patients and their families. We would also like to acknowledge the Duke University GI Oncology clinical trials team. This research was supported by National Institute of Health Grant 5K24-CA113755-05 (H Hurwitz).

References

  1. 1.
    Affinitor [package insert]. Novartis Pharmaceuticals Corporation, East Hanover, NJ (2011)Google Scholar
  2. 2.
    NCT01037257: A Safety Study of LBH589 (Panobinostat) and RAD001 (Everolimus) to Stabilize Kidney Cancer. http://clinicaltrials.gov/ct2/show/NCT01037257
  3. 3.
    Adams RH, Alitalo K (2007) Molecular regulation of angiogenesis and lymphangiogenesis. Nat Rev Mol Cell Biol 8:464–478PubMedCrossRefGoogle Scholar
  4. 4.
    Altomare I, Bendell JC, Bullock KE, Uronis HE, Morse MA, Hsu SD, Zafar SY, Blobe GC, Pang H, Honeycutt W, Sutton L, Hurwitz HI (2011) A phase II trial of bevacizumab plus everolimus for patients with refractory metastatic colorectal cancer. Oncologist 16:1131–1137PubMedCrossRefGoogle Scholar
  5. 5.
    Bergers G, Hanahan D (2008) Modes of resistance to anti-angiogenic therapy. Nat Rev Cancer 8:592–603PubMedCrossRefGoogle Scholar
  6. 6.
    Borgstrom P, Bourdon MA, Hillan KJ, Sriramarao P, Ferrara N (1998) Neutralizing anti-vascular endothelial growth factor antibody completely inhibits angiogenesis and growth of human prostate carcinoma micro tumors in vivo. Prostate 35:1–10PubMedCrossRefGoogle Scholar
  7. 7.
    Borgstrom P, Gold DP, Hillan KJ, Ferrara N (1999) Importance of VEGF for breast cancer angiogenesis in vivo: implications from intravital microscopy of combination treatments with an anti-VEGF neutralizing monoclonal antibody and doxorubicin. Anticancer Res 19:4203–4214PubMedGoogle Scholar
  8. 8.
    Borgstrom P, Hillan KJ, Sriramarao P, Ferrara N (1996) Complete inhibition of angiogenesis and growth of microtumors by anti-vascular endothelial growth factor neutralizing antibody: novel concepts of angiostatic therapy from intravital videomicroscopy. Cancer Res 56:4032–4039PubMedGoogle Scholar
  9. 9.
    Bruegge K, Jelkmann W, Metzen E (2007) Hydroxylation of hypoxia-inducible transcription factors and chemical compounds targeting the HIF-alpha hydroxylases. Curr Med Chem 14:1853–1862PubMedCrossRefGoogle Scholar
  10. 10.
    Bullock KE, Petros WP, Younis I, Uronis HE, Morse MA, Blobe GC, Zafar SY, Gockerman JP, Lager JJ, Truax R, Meadows KL, Howard LA, O’Neill MM, Broadwater G, Hurwitz HI, Bendell JC (2011) A phase I study of bevacizumab (B) in combination with everolimus (E) and erlotinib (E) in advanced cancer (BEE). Cancer Chemother Pharmacol 67:465–474PubMedCrossRefGoogle Scholar
  11. 11.
    Ceradini DJ, Kulkarni AR, Callaghan MJ, Tepper OM, Bastidas N, Kleinman ME, Capla JM, Galiano RD, Levine JP, Gurtner GC (2004) Progenitor cell trafficking is regulated by hypoxic gradients through HIF-1 induction of SDF-1. Nat Med 10:858–864PubMedCrossRefGoogle Scholar
  12. 12.
    Conte P, Campone M, Pronzato P, Amadori D, Frank R, Schuetz F, Rea D, Wardley A, Britten C, Elias A (2009) Phase I trial of panobinostat (LBH589) in combination with trastuzumab in pretreated HER2-positive metastatic breast cancer (mBC): preliminary safety and tolerability results. J Clin Oncol 27:15s (suppl; abstr 1081)CrossRefGoogle Scholar
  13. 13.
    De Falco E, Porcelli D, Torella AR, Straino S, Iachininoto MG, Orlandi A, Truffa S, Biglioli P, Napolitano M, Capogrossi MC, Pesce M (2004) SDF-1 involvement in endothelial phenotype and ischemia-induced recruitment of bone marrow progenitor cells. Blood 104:3472–3482PubMedCrossRefGoogle Scholar
  14. 14.
    Deroanne CF, Bonjean K, Servotte S, Devy L, Colige A, Clausse N, Blacher S, Verdin E, Foidart JM, Nusgens BV, Castronovo V (2002) Histone deacetylases inhibitors as anti-angiogenic agents altering vascular endothelial growth factor signaling. Oncogene 21:427–436PubMedCrossRefGoogle Scholar
  15. 15.
    Dimicoli S, Jabbour E, Borthakur G, Kadia T, Estrov Z, Yang H, Kelly M, Pierce S, Kantarjian H, Garcia-Manero G (2012) Phase II study of the histone deacetylase inhibitor panobinostat (LBH589) in patients with low or intermediate-1 risk myelodysplastic syndrome. Am J Hematol 87:127–129PubMedCrossRefGoogle Scholar
  16. 16.
    Drappatz J, Lee EQ, Hammond S, Grimm SA, Norden AD, Beroukhim R, Gerard M, Schiff D, Chi AS, Batchelor TT, Doherty LM, Ciampa AS, Lafrankie DC, Ruland S, Snodgrass SM, Raizer JJ, Wen PY (2011) Phase I study of panobinostat in combination with bevacizumab for recurrent high-grade glioma. J Neurooncol. Oct 8 [Epub ahead of print]Google Scholar
  17. 17.
    Escudier B, Pluzanska A, Koralewski P, Ravaud A, Bracarda S, Szczylik C, Chevreau C, Filipek M, Melichar B, Bajetta E, Gorbunova V, Bay JO, Bodrogi I, Jagiello-Gruszfeld A, Moore N (2007) Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. Lancet 370:2103–2111PubMedCrossRefGoogle Scholar
  18. 18.
    Fath DM, Kong X, Liang D, Lin Z, Chou A, Jiang Y, Fang J, Caro J, Sang N (2006) Histone deacetylase inhibitors repress the transactivation potential of hypoxia-inducible factors independently of direct acetylation of HIF-alpha. J Biol Chem 281:13612–13619PubMedCrossRefGoogle Scholar
  19. 19.
    Ferrari AC, Stein MN, Alumkal JJ, Gomez-Pinillos A, Catamero DD, Mayer TM, Collins F, Beer TM, DiPaola RS (2011) A phase I/II randomized study of panobinostat and bicalutamide in castration-resistant prostate cancer (CRPC) patients progressing on second-line hormone therapy. J Clin Oncol 29: (suppl 7; abstr 156)Google Scholar
  20. 20.
    Folkman J (1995) Seminars in medicine of the Beth Israel Hospital, Boston. Clinical applications of research on angiogenesis. N Engl J Med 333:1757–1763PubMedCrossRefGoogle Scholar
  21. 21.
    Franz DN, Krueger DA, Care MM, Holland-Bouley K, Agricola K, Tudor C, Mangeshkar P, Byars AW, Sahmoud T (2010) Everolimus for subependymal giant-cell astrocytomas (SEGAs) in tuberous sclerosis (TS). J Clin Oncol 28:15s (suppl; abstr 2004)Google Scholar
  22. 22.
    Fukutomi A, Hatake K, Matsui K, Sakajiri S, Hirashima T, Tanii H, Kobayashi K, Yamamoto N (2011) A phase I study of oral panobinostat (LBH589) in Japanese patients with advanced solid tumors. Invest New Drugs. Apr 12 [Epub ahead of print]Google Scholar
  23. 23.
    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 12:4628–4635PubMedCrossRefGoogle Scholar
  24. 24.
    Giver CR, Jaye DL, Waller EK, Kaufman JL, Lonial S (2011) Rapid recovery from panobinostat (LBH589)-induced thrombocytopenia in mice involves a rebound effect of bone marrow megakaryocytes. Leukemia 25:362–365PubMedCrossRefGoogle Scholar
  25. 25.
    Hainsworth JD, Infante JR, Spigel DR, Arrowsmith ER, Boccia RV, Burris HA (2011) A phase II trial of panobinostat, a histone deacetylase inhibitor, in the treatment of patients with refractory metastatic renal cell carcinoma. Cancer Invest 29:451–455PubMedGoogle Scholar
  26. 26.
    Hainsworth JD, Infante JR, Spigel DR, Peyton JD, Thompson DS, Lane CM, Clark BL, Rubin MS, Trent DF, Burris HA 3rd (2010) Bevacizumab and everolimus in the treatment of patients with metastatic melanoma: a phase 2 trial of the Sarah Cannon Oncology Research Consortium. Cancer 116:4122–4129PubMedCrossRefGoogle Scholar
  27. 27.
    Hainsworth JD, Spigel DR, Burris HA 3rd, Waterhouse D, Clark BL, Whorf R (2010) Phase II trial of bevacizumab and everolimus in patients with advanced renal cell carcinoma. J Clin Oncol 28:2131–2136PubMedCrossRefGoogle Scholar
  28. 28.
    Hanahan D, Folkman J (1996) Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 86:353–364PubMedCrossRefGoogle Scholar
  29. 29.
    Hudson CC, Liu M, Chiang GG, Otterness DM, Loomis DC, Kaper F, Giaccia AJ, Abraham RT (2002) Regulation of hypoxia-inducible factor 1alpha expression and function by the mammalian target of rapamycin. Mol Cell Biol 22:7004–7014PubMedCrossRefGoogle Scholar
  30. 30.
    Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, Berlin J, Baron A, Griffing S, Holmgren E, Ferrara N, Fyfe G, Rogers B, Ross R, Kabbinavar F (2004) Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350:2335–2342PubMedCrossRefGoogle Scholar
  31. 31.
    Jones SF, Bendell JC, Infante JR, Spigel DR, Thompson DS, Yardley DA, Greco FA, Murphy PB, Burris HA 3rd (2011) A phase I study of panobinostat in combination with gemcitabine in the treatment of solid tumors. Clin Adv Hematol Oncol 9:225–230PubMedGoogle Scholar
  32. 32.
    Kaur B, Khwaja FW, Severson EA, Matheny SL, Brat DJ, Van Meir EG (2005) Hypoxia and the hypoxia-inducible-factor pathway in glioma growth and angiogenesis. Neuro Oncol 7:134–153PubMedCrossRefGoogle Scholar
  33. 33.
    Kim MS, Kwon HJ, Lee YM, Baek JH, Jang JE, Lee SW, Moon EJ, Kim HS, Lee SK, Chung HY, Kim CW, Kim KW (2001) Histone deacetylases induce angiogenesis by negative regulation of tumor suppressor genes. Nat Med 7:437–443PubMedCrossRefGoogle Scholar
  34. 34.
    Levy AP, Levy NS, Wegner S, Goldberg MA (1995) Transcriptional regulation of the rat vascular endothelial growth factor gene by hypoxia. J Biol Chem 270:13333–13340PubMedCrossRefGoogle Scholar
  35. 35.
    Liu T, Kuljaca S, Tee A, Marshall GM (2006) Histone deacetylase inhibitors: multifunctional anticancer agents. Cancer Treat Rev 32:157–165PubMedCrossRefGoogle Scholar
  36. 36.
    Mie Lee Y, Kim SH, Kim HS, Jin Son M, Nakajima H, Jeong Kwon H, Kim KW (2003) Inhibition of hypoxia-induced angiogenesis by FK228, a specific histone deacetylase inhibitor, via suppression of HIF-1alpha activity. Biochem Biophys Res Commun 300:241–246PubMedCrossRefGoogle Scholar
  37. 37.
    Morita S, Oizumi S, Minami H, Kitagawa K, Komatsu Y, Fujiwara Y, Inada M, Yuki S, Kiyota N, Mitsuma A, Sawaki M, Tanii H, Kimura J, Ando Y (2011) Phase I dose-escalating study of panobinostat (LBH589) Administered intravenously to Japanese patients with advanced solid tumors. Invest New Drugs. Oct 1 [Epub ahead of print]Google Scholar
  38. 38.
    Motzer RJ, Escudier B, Oudard S, Hutson TE, Porta C, Bracarda S, Grunwald V, Thompson JA, Figlin RA, Hollaender N, Urbanowitz G, Berg WJ, Kay A, Lebwohl D, Ravaud A (2008) Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet 372:449–456PubMedCrossRefGoogle Scholar
  39. 39.
    Patnaik A, Chiorean EG, Tolcher A, Papadopoulos K, Beeram M, Kee D, Waddell M, Gilles E, Buchbinder A (2009) EZN-2968, a novel hypoxia-inducible factor-1α (HIF-1α) messenger ribonucleic acid (mRNA) antagonist: results of a phase I, pharmacokinetic (PK), dose-escalation study of daily administration in patients (pts) with advanced malignancies. J Clin Oncol 27:15s (suppl; abstr 2564)CrossRefGoogle Scholar
  40. 40.
    Peacock NW, Jones SF, Yardley DA, Bendell JC, Infante JR, Murphy PB, Burrris HA (2010) A phase I study of panobinostat (LBH589) with capecitabine with or without lapatinib. J Clin Oncol 28:15s (suppl; abstr 1115)Google Scholar
  41. 41.
    Prince HM, Bishton MJ, Harrison SJ (2009) Clinical studies of histone deacetylase inhibitors. Clin Cancer Res 15:3958–3969PubMedCrossRefGoogle Scholar
  42. 42.
    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 12:634–642PubMedCrossRefGoogle Scholar
  43. 43.
    Qian DZ, Wang X, Kachhap SK, Kato Y, Wei Y, Zhang L, Atadja P, Pili R (2004) The histone deacetylase inhibitor NVP-LAQ824 inhibits angiogenesis and has a greater antitumor effect in combination with the vascular endothelial growth factor receptor tyrosine kinase inhibitor PTK787/ZK222584. Cancer Res 64:6626–6634PubMedCrossRefGoogle Scholar
  44. 44.
    Rapisarda A, Hollingshead M, Uranchimeg B, Bonomi CA, Borgel SD, Carter JP, Gehrs B, Raffeld M, Kinders RJ, Parchment R, Anver MR, Shoemaker RH, Melillo G (2009) Increased antitumor activity of bevacizumab in combination with hypoxia inducible factor-1 inhibition. Mol Cancer Ther 8:1867–1877PubMedCrossRefGoogle Scholar
  45. 45.
    Rathkopf D, Wong BY, Ross RW, Anand A, Tanaka E, Woo MM, Hu J, Dzik-Jurasz A, Yang W, Scher HI (2010) A phase I study of oral panobinostat alone and in combination with docetaxel in patients with castration-resistant prostate cancer. Cancer Chemother Pharmacol 66:181–189PubMedCrossRefGoogle Scholar
  46. 46.
    Recanatini M, Poluzzi E, Masetti M, Cavalli A, De Ponti F (2005) QT prolongation through hERG K(+) channel blockade: current knowledge and strategies for the early prediction during drug development. Med Res Rev 25:133–166PubMedCrossRefGoogle Scholar
  47. 47.
    Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, Lilenbaum R, Johnson DH (2006) Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 355:2542–2550PubMedCrossRefGoogle Scholar
  48. 48.
    Semenza GL (2003) Targeting HIF-1 for cancer therapy. Nat Rev Cancer 3:721–732PubMedCrossRefGoogle Scholar
  49. 49.
    Semenza GL (2007) Evaluation of HIF-1 inhibitors as anticancer agents. Drug Discov Today 12:853–859PubMedCrossRefGoogle Scholar
  50. 50.
    Shultz MD, Cao X, Chen CH, Cho YS, Davis NR, Eckman J, Fan J, Fekete A, Firestone B, Flynn J, Green J, Growney JD, Holmqvist M, Hsu M, Jansson D, Jiang L, Kwon P, Liu G, Lombardo F, Lu Q, Majumdar D, Meta C, Perez L, Pu M, Ramsey T, Remiszewski S, Skolnik S, Traebert M, Urban L, Uttamsingh V, Wang P, Whitebread S, Whitehead L, Yan-Neale Y, Yao YM, Zhou L, Atadja P (2011) Optimization of the in vitro cardiac safety of hydroxamate-based histone deacetylase inhibitors. J Med Chem 54:4752–4772PubMedCrossRefGoogle Scholar
  51. 51.
    Suessbrich H, Waldegger S, Lang F, Busch AE (1996) Blockade of HERG channels expressed in Xenopus oocytes by the histamine receptor antagonists terfenadine and astemizole. FEBS Lett 385:77–80PubMedCrossRefGoogle Scholar
  52. 52.
    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 92:205–216PubMedCrossRefGoogle Scholar
  53. 53.
    Unruh A, Ressel A, Mohamed HG, Johnson RS, Nadrowitz R, Richter E, Katschinski DM, Wenger RH (2003) The hypoxia-inducible factor-1 alpha is a negative factor for tumor therapy. Oncogene 22:3213–3220PubMedCrossRefGoogle Scholar
  54. 54.
    Vredenburgh JJ, Desjardins A, Herndon JE 2nd, Marcello J, Reardon DA, Quinn JA, Rich JN, Sathornsumetee S, Gururangan S, Sampson J, Wagner M, Bailey L, Bigner DD, Friedman AH, Friedman HS (2007) Bevacizumab plus irinotecan in recurrent glioblastoma multiforme. J Clin Oncol 25:4722–4729PubMedCrossRefGoogle Scholar
  55. 55.
    Yao JC, Shah MH, Ito T, Bohas CL, Wolin EM, Van Cutsem E, Hobday TJ, Okusaka T, Capdevila J, de Vries EG, Tomassetti P, Pavel ME, Hoosen S, Haas T, Lincy J, Lebwohl D, Oberg K (2011) Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med 364:514–523PubMedCrossRefGoogle Scholar
  56. 56.
    Zhang L, Lebwohl D, Masson E, Laird G, Cooper MR, Prince HM (2008) Clinically relevant QTc prolongation is not associated with current dose schedules of LBH589 (panobinostat). J Clin Oncol 26: 332–333; discussion 333–334Google Scholar

Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • John H. Strickler
    • 1
  • Alexander N. Starodub
    • 1
    • 2
  • Jingquan Jia
    • 1
  • Kellen L. Meadows
    • 1
  • Andrew B. Nixon
    • 1
  • Andrew Dellinger
    • 1
  • Michael A. Morse
    • 1
  • Hope E. Uronis
    • 1
  • P. Kelly  Marcom
    • 1
  • S. Yousuf  Zafar
    • 1
  • Sherri T. Haley
    • 1
  • Herbert I. Hurwitz
    • 1
  1. 1.Duke University Medical CenterDurhamUSA
  2. 2.Goshen Center for Cancer CareGoshenUSA

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