Phase I/II Intra-patient Dose Escalation Study of Vorinostat in Children With Relapsed Solid Tumor, Lymphoma or Leukemia
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.
Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
To determine a safe dose recommended (SDR) for the routine application of oral vorinostat (involving dose escalation) in children and adolescents (3-18 years) with relapsed/refractory solid tumor, lymphoma or leukemia.
A SDR is defined as the highest dose with no ≥ grade 3 toxicity according to CTC criteria (Dose Limiting Toxicity) in no more than 1/50 patient in this study. Dose Limiting Toxicity (DLT) is defined as any grade 3 or 4 toxicity according the CTCAE version 4.0 and judged by the investigator as definitely, probably or possibly related to the study drug. However, all DLTs will be subject to a second assessment by the Coordinating Investigator or a designated person.
After finding the individual MTD this dose will be applied for 3 months. Patients without progression at first response evaluation will continue treatment for a maximum of 9 months.
Olaf Witt, Prof. Dr.
University Hospital Heidelberg and German Cancer Research Center (DKFZ)
Germany: Federal Institute for Drugs and Medical Devices