Vorinostat in Children
Condition: Children With Relapsed Solid Tumor, Lymphoma or Leukemia
MeSH terms: Lymphoma; Leukemia
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      The aim of this study is to define a dose recommendation of vorinostat in pediatric oncology,
      to determine pharmacokinetics of vorinostat in children, determine response rates, safety and
      feasibility.
    

Detailed description: 
      Relapsed or progressive solid tumors and leukemias have a very poor prognosis in children
      despite intense multimodal treatment protocols involving polychemotherapy, surgery, and
      radiation. Therefore, innovative treatment strategies targeting specific molecular mechanisms
      are urgently required. A novel class of compounds with promising anti-tumoral activities is
      histone deacetylase (HDAC)-inhibitors. HDACs are key enzymes involved in regulation of
      chromatin-structure and function of several proteins, and aberrant activities of HDACs are
      found in many cancer cells. Pharmacological inhibition of HDACs causes cell cycle arrest,
      apoptosis, differentiation, inhibition of clonogenic growth, and anti-angiogenic effects in
      numerous cancer cells. In addition, promising anti-tumoral activity has been shown in several
      pre-clinical pediatric tumor models such as neuroblastoma, medulloblastoma, glioblastoma,
      retinoblastoma, rhabdomyosarcoma, osteosarcoma, Ewing's sarcoma, ATRT, and acute
      lymphoblastic leukemia. Several HDAC inhibitors are now in Phase I-III clinical trials in
      adult patients demonstrating a good safety profile and promising anti-neoplastic activity.
      The first of these compounds, suberoylanilide hydroxamic acid (SAHA, vorinostat, Zolinza),
      was recently approved by the FDA for the treatment of refractory cutaneous T-cell lymphoma.
      Vorinostat showed linear pharmacokinetics, good oral bioavailability and a broad range of
      anti-tumor activity in a Phase I clinical trial including 73 adult relapsed tumor patients.
      The determined peak plasma levels were in the range of 658±439 ng/ml (corresponding to
      2.5±1.7 µM). At these concentrations, anti-tumoral effects on pediatric cancer cells and
      leukemias have been documented in vitro. Furthermore, vorinostat passes the blood brain
      barrier in mice, thus making it a suitable compound for the treatment of brain tumors.

      The aim of this study is to define a dose recommendation of vorinostat in pediatric oncology,
      to determine pharmacokinetics of vorinostat in children, determine response rates, safety and
      feasibility. The design is an open, multicenter Phase I/II trial. Children and adolescents
      (3-18 years) with relapsed or therapy-refractory solid tumor, lymphoma or leukemia following
      standard treatment protocols in pediatric oncology will be included. 50 patients will be
      recruited over 2 years. Vorinostat will be taken orally once per day on an outpatient basis
      and the dose will be escalated until the individual maximum tolerated dose is established.
      This dose will then be applied for 3 months, when tumor response will be evaluated. Patients
      without progression at first response evaluation will continue treatment for a maximum of 9
      months. After end of treatment (EOT) follow-up evaluations will be performed for 3 months.
      Pharmacokinetic studies will be performed in plasma, and in optional cerebrospinal fluid
      samples. Biomarkers (BMP4, IL-6, IL10 induction following Vorinostat treatment, basal histone
      acetylation, HDACs and H23B in archived tumor samples) will be determined and correlated with
      treatment response.
    

Intervention name(s): zolinza/vorinostat
Intervention type(s): Drug
Intervention description(s): orally once per day (suspension of 50mg/ml or capsules of 100 mg vorinostat); starting dose will be 180 mg/m²/d; escalated with increments of 50 mg/m²/d every two weeks until dose limiting toxicity (grade 3 or 4 toxicity according to CTC) occurs or up to a maximum dose of 580 mg/m²/d; This dose will then be applied for 3 months. Patients without progression at first response evaluation will continue treatment for a maximum of 9 months.
Intervention MeSH terms: Vorinostat
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: pediatric oncology; relapsed solid tumor; lymphoma; leukemia; vorinostat