Download PDF
Klin Padiatr 2012; 224(06): 398-403
DOI: 10.1055/s-0032-1323692
Bericht
© Georg Thieme Verlag KG Stuttgart · New York

Phase I/II Intra-patient Dose Escalation Study of Vorinostat in Children with Relapsed Solid Tumor, Lymphoma or Leukemia

Phase I/II intra-individuelle Dosiseskalationstudie von Vorinostat bei Kindern mit rezidivierten soliden Tumoren, Lymphomen oder Leukämien
O. Witt
1   Department of Pediatric Oncology, Hematology, Immunology and Pneumonology and CCU Pediatric Oncology, University Hospital of Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany
,
T. Milde
1   Department of Pediatric Oncology, Hematology, Immunology and Pneumonology and CCU Pediatric Oncology, University Hospital of Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany
,
H. E. Deubzer
1   Department of Pediatric Oncology, Hematology, Immunology and Pneumonology and CCU Pediatric Oncology, University Hospital of Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany
,
I. Oehme
2   CCU Pediatric Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany
,
R. Witt
3   Department of Pediatric Oncology, Hematology, Immunology and Pneumonology, CCU Pediatric Oncology, Clinical Trial Center, University Hospital of Heidelberg, German Cancer Research Center (DKFZ), National Center for Tumor Diseases (NCT), Heidelberg, Germany
,
A. Kulozik
4   Department of Pediatric Oncology, Hematology, Immunology and Pneumonology, Heidelberg, Germany
,
A. Eisenmenger
5   National Center for Tumor Diseases (NCT), Clinical Trial Center, Heidelberg, Germany
,
U. Abel
5   National Center for Tumor Diseases (NCT), Clinical Trial Center, Heidelberg, Germany
,
I. Karapanagiotou-Schenkel
5   National Center for Tumor Diseases (NCT), Clinical Trial Center, Heidelberg, Germany
› Author Affiliations
Further Information

Publication History

Publication Date:
22 August 2012 (online)

Also available at
    Permissions and Reprints

Abstract

Members of the histone deacetylase (HDAC) family exhibit great promise as potential drug targets in pediatric tumors including neuroblastoma, medulloblastoma, ependymoma and Ewing’s sarcoma. HDAC inhibitors of various structural classes have shown anti-tumoral effects in pre-clinical pediatric tumor models as single agents or in combination treatments. Suberoylanilidehydroxamic acid (SAHA=vorinostat) is the most clinical advanced compound of the class and was approved by the US FDA in October 2006 for the treatment of refractory cutaneous T-cell lymphoma. In this phase I/II trial, pediatric patients with relapsed solid tumors, lymphoma or leukemias are treated according to an individualized dose escalation concept ensuring each individual patient to receive his optimal dose with respect to toxicity and efficacy. The study is accompanied by an extensive pharmacokinetic, pharmacodynamic and biomarker program.

Zusammenfassung

Mitglieder der Histondeacetylase (HDAC)-Familie stellen vielversprechende therapeutische Zielstrukturen für pädiatrische Tumoren inklusive Neuroblastome, Medulloblastome, Ependymome und Ewing-Sarkome dar. HDAC-Inhibitoren verschiedener struktureller Klassen haben als Monosubstanz oder in Kombination eine anti-tumorale Wirksamkeit in prä-klinischen pädiatrischen Tumormodellen gezeigt. Suberoylanilid-Hydroxamsäure (SAHA=Vorinostat) ist die in klinischen Studien am weitesten entwickelte Substanz und wurde im Oktober 2006 zur Behandlung des refraktären kutanen T-Zell-Lymphoms zugelassen. In der Phase I/II Studie werden pädiatrische Patienten mit rezidivierten soliden Tumoren, Lymphomen oder Leukämien nach einem individualisierten Dosiseskalations-Konzept behandelt. Dieses soll sicher stellen, dass jeder einzelne Patient seine optimale Dosis bezüglich Toxizität und Wirksamkeit erhält. Die Studie wird von einem detaillierten Pharmakokinetik- und Biomarker-Programm begleitet. .

Key words

vorinostat - HDAC - phase I/II - pediatric oncology

Schlüsselwörter

Vorinostat - HDAC - Phase I/II - pädiatrische Onkologie
 

  • References

  • 1 ZOLINZA (Vorinostat). Food and Drug Administration 2006; http://www.fda.gov/cder/foi/label/2006/021991lbl.pdf
    PubMed
  • 2 Berthold F, Burdach S, Kremens B et al. The role of chemotherapy in the treatment of children with neuroblastoma stage IV: the GPO (German Pediatric Oncology Society) experience. Klin Padiatr 1990; 202: 262-269 DOI: 10.1055/s-2007-1025531.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 3 Blattmann C, Oertel S, Ehemann V et al. Enhancement of radiation response in osteosarcoma and rhabdomyosarcoma cell lines by histone deacetylase inhibition. Int J Radiat Oncol Biol Phys 2010; 78: 237-245 DOI: 10.1016/j.ijrobp.2010.03.010.
    CrossrefPubMedGoogle Scholar
  • 4 Brodeur GM, Pritchard J, Berthold F et al. Revisions of the international criteria for neuroblastoma diagnosis, staging, and response to treatment. J Clin Oncol 1993; 11: 1466-1477
    CrossrefPubMedGoogle Scholar
  • 5 Creutzig U, Jurgens H, Herold R et al. Concepts of the Society of Paediatric Oncology and Haematology (GPOH) and the German Competence Network in Paediatric Oncology and Haematology for the quality controlled development in paediatric oncology. Klin Padiatr 2004; 216: 379-383 DOI: 10.1055/s-2004-832383.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 6 Deubzer H, Busche B, Ronndahl G et al. Novel valproic acid derivatives with potent differentiation-inducing activity in myeloid leukemia cells. Leuk Res 2006; 30: 1167-1175 DOI: 10.1016/j.leukres.2006.01.009.
    CrossrefPubMedGoogle Scholar
  • 7 Deubzer HE, Ehemann V, Kulozik AE et al. Anti-neuroblastoma activity of Helminthosporium carbonum (HC)-toxin is superior to that of other differentiating compounds in vitro. Cancer Lett 2008; 264: 21-28 DOI: 10.1016/j.canlet.2008.01.002.
    CrossrefPubMedGoogle Scholar
  • 8 Deubzer HE, Ehemann V, Westermann F et al. Histone deacetylase inhibitor Helminthosporium carbonum (HC)-toxin suppresses the malignant phenotype of neuroblastoma cells. Int J Cancer 2008; 122: 1891-1900 DOI: 10.1002/ijc.23295.
    CrossrefPubMedGoogle Scholar
  • 9 Ecke I, Petry F, Rosenberger A et al. Antitumor effects of a combined 5-aza-2'deoxycytidine and valproic acid treatment on rhabdomyosarcoma and medulloblastoma in Ptch mutant mice. Cancer Res 2009; 69: 887-895 DOI: 10.1158/0008-5472.CAN-08-0946.
    CrossrefPubMedGoogle Scholar
  • 10 Einsiedel HG, Kawan L, Eckert C et al. Histone deacetylase inhibitors have antitumor activity in two NOD/SCID mouse models of B-cell precursor childhood acute lymphoblastic leukemia. Leukemia 2006; 20: 1435-1436 DOI: 10.1038/sj.leu.2404282.
    CrossrefPubMedGoogle Scholar
  • 11 Fouladi M, Park JR, Stewart CF et al. Pediatric phase I trial and pharmacokinetic study of vorinostat: a Children’s Oncology Group phase I consortium report. J Clin Oncol 2010; 28: 3623-3269 DOI: 10.1200/JCO.2009.25.9119.
    CrossrefPubMedGoogle Scholar
  • 12 Fruhwald MC, Witt O. The epigenetics of cancer in children. Klin Padiatr 2008; 220: 333-341 DOI: 10.1055/s-0028-1086026.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 13 Furchert SE, Lanvers-Kaminsky C, Juurgens H et al. Inhibitors of histone deacetylases as potential therapeutic tools for high-risk embryonal tumors of the nervous system of childhood. Int J Cancer 2007; 120: 1787-1794 DOI: 10.1002/ijc.22401.
    CrossrefPubMedGoogle Scholar
  • 14 Grunewald TGP, Greulich N, Kontny U, Frühwald M et al. Targeted Therapeutics in Treatment of Children and Young Adults with Solid Tumors: an Expert Survey and Review of the Literature. Klin Padiatr 2012; 224: 124-131 DOI: 10.1055/s-0032-1301930.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 15 Hahn H, Nitzki F, Uhmann A, Ecke I et al. Hedgehog Signaling: A Therapeutic Target in Embryonal Rhabdomyosarcoma?. Klin Padiatr 2011; 33: 47-48
    PubMedGoogle Scholar
  • 16 Hahnen E, Eyupoglu IY, Brichta L et al. In vitro and ex vivo evaluation of second-generation histone deacetylase inhibitors for the treatment of spinal muscular atrophy. J Neurochem 2006; 98: 193-202
    CrossrefPubMedGoogle Scholar
  • 17 Hockly E, Richon VM, Woodman B et al. Suberoylanilide hydroxamic acid, a histone deacetylase inhibitor, ameliorates motor deficits in a mouse model of Huntington’s disease. Proc Natl Acad Sci USA 2003; 100: 2041-2046
    CrossrefPubMedGoogle Scholar
  • 18 Kelly WK, O’Connor OA, Krug LM et al. Phase I study of an oral histone deacetylase inhibitor, suberoylanilide hydroxamic acid, in patients with advanced cancer. J Clin Oncol 2005; 23: 3923-3931 DOI: 10.1200/JCO.2005.14.167.
    CrossrefPubMedGoogle Scholar
  • 19 Kelly WK, Richon VM, O’Connor O et al. Phase I clinical trial of histone deacetylase inhibitor: suberoylanilide hydroxamic acid administered intravenously. Clin Cancer Res 2003; 9: 3578-3588
    PubMedGoogle Scholar
  • 20 Kruchen AJPD, Handgretinger R, Mueller I. I. Effect of the HDAC inhibitor SAHA on the immunomodulatory properties of MSC and tumor stroma cells. Klin Padiatr 2010; 03: A50 DOI: 10.1055/s-0030-1254501.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 21 Kuhl J. A study group on brain tumors in childhood. Introduction, establishment and aims. Klin Padiatr 1987; 199: 196-199 DOI: 10.1055/s-2008-1026789.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 22 Kumar KS, Sonnemann J, Beck JF. Histone deacetylase inhibitors induce cell death in supratentorial primitive neuroectodermal tumor cells. Oncol Rep 2006; 16: 1047-1052
    PubMedGoogle Scholar
  • 23 Kumar KS, Sonnemann J, Hong le TT et al. Histone deacetylase inhibitors, but not vincristine, cooperate with radiotherapy to induce cell death in medulloblastoma. Anticancer Res 2007; 27: 465-470
    PubMedGoogle Scholar
  • 24 Milde T, Kleber S, Korshunov A et al. A novel human high-risk ependymoma stem cell model reveals the differentiation-inducing potential of the histone deacetylase inhibitor Vorinostat. Acta neuropathologica 2011; 122: 637-650 DOI: 10.1007/s00401-011-0866-3.
    CrossrefPubMedGoogle Scholar
  • 25 Milde T, Oehme I, Korshunov A et al. HDAC5 and HDAC9 in medulloblastoma: novel markers for risk stratification and role in tumor cell growth. Clin Cancer Res 2010; 16: 3240-3252 DOI: 10.1158/1078-0432.CCR-10-0395.
    CrossrefPubMedGoogle Scholar
  • 26 Minucci S, Pelicci PG. Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer. Nat Rev Cancer 2006; 6: 38-51
    CrossrefPubMedGoogle Scholar
  • 27 Oehme I, Deubzer HE, Lodrini M et al. Targeting of HDAC8 and investigational inhibitors in neuroblastoma. Expert Opin Investig Drugs 2009; 18: 1605-1617 DOI: 10.1517/14728220903241658.
    CrossrefPubMedGoogle Scholar
  • 28 Oehme I, Deubzer HE, Wegener D et al. Histone deacetylase 8 in neuroblastoma tumorigenesis. Clin Cancer Res 2009; 15: 91-99 DOI: 10.1158/1078-0432.CCR-08-0684.
    CrossrefPubMedGoogle Scholar
  • 29 Padhani AR, Ollivier L. The RECIST (Response Evaluation Criteria in Solid Tumors) criteria: implications for diagnostic radiologists. Br J Radiol 2001; 74: 983-986
    PubMedGoogle Scholar
  • 30 Schäfer B. Therapeutic Strategies Targeting Oncogenic Fusion Proteins in Sarcomas. Klin Padiatr 2011; 01: A11 DOI: 10.1055/s-0030-1270304.
    PubMedGoogle Scholar
  • 31 Sonnemann J, Kumar KS, Heesch S et al. Histone deacetylase inhibitors induce cell death and enhance the susceptibility to ionizing radiation, etoposide, and TRAIL in medulloblastoma cells. Int J Oncol 2006; 28: 755-766
    PubMedGoogle Scholar
  • 32 Therasse P, Arbuck SG, Eisenhauer EA et al. 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 2000; 92: 205-216
    CrossrefPubMedGoogle Scholar
  • 33 Wegener D, Deubzer HE, Oehme I et al. HKI 46F08, a novel potent histone deacetylase inhibitor, exhibits antitumoral activity against embryonic childhood cancer cells. Anticancer Drugs 2008; 19: 849-857 DOI: 10.1097/CAD.0b013e32830efbeb.
    CrossrefPubMedGoogle Scholar
  • 34 Witt O, Deubzer HE, Lodrini M et al. Targeting histone deacetylases in neuroblastoma. Current pharmaceutical design 2009; 15: 436-447
    CrossrefPubMedGoogle Scholar
  • 35 Witt O, Deubzer HE, Milde T et al. HDAC family: What are the cancer relevant targets?. Cancer Lett 2009; 277: 8-21 DOI: 10.1016/j.canlet.2008.08.016.
    CrossrefPubMedGoogle Scholar
  • 36 Witt O, Monkemeyer S, Ronndahl G et al. Induction of fetal hemoglobin expression by the histone deacetylase inhibitor apicidin. Blood 2003; 101: 2001-2007
    CrossrefPubMedGoogle Scholar
  • 37 Witt O, Schweigerer L, Driever PH et al. Valproic acid treatment of glioblastoma multiforme in a child. Pediatr Blood Cancer 2004; 43: 181
    CrossrefPubMedGoogle Scholar