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

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

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