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

Phase 1/Phase 2
3 Years
18 Years
Open (Enrolling)
Children With Relapsed Solid Tumor, Lymphoma or Leukemia

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Trial Information

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.

Inclusion Criteria:

- Children and adolescents (3-18 years) with relapsed or therapy-refractory solid
tumor, lymphoma or leukemia following standard first-line or relapse protocols in
pediatric oncology

- Diagnosis confirmed by one of the Pathological, Radiological or Study Reference
Centers recognized by the GPOH

- No other simultaneous anti-neoplastic treatment or radiation during the study and 1
months before enrolment

- Sufficient general condition (Lansky Score >50%)

- Life expectancy > 3 months

- Liver enzymes (ALT or AST) < 5x upper limit of normal reference value, bilirubin and
creatinine < 3x upper limit of normal reference value

- Solid tumors: leukocytes > 2000/µl, thrombocytes > 50.000/µl and adequate bone marrow
function to permit evaluations of hematopoietic toxicity

- No CTC grade 3 or 4 toxicity from previous treatments

- Normal ECG

- Written informed consent of the legal representatives and the patient if the patient
is able to understand the study situation and to give consent (must be available
before enrolment in the trial)

- Women with childbearing potential agree to use adequate contraception or to abstain
from heterosexual activity throughout the study, starting with Visit 1.

- Sexually active male patient agrees to use an adequate method of contraception for
the duration of the study

- Solid tumors: measurable disease activity according to RECIST criteria

Exclusion Criteria:

- History of deep vein thrombosis or pulmonary embolism

- Pregnancy and lactation

- Patient with concomitant treatments and/or anti-neoplastic treatment such as
chemotherapy, immune therapy, and differentiation therapy, other targeted therapy,
radiation. The use of valproic acid as prior antiepileptic therapy is allowed with a
30-day washout period.

- Prior exposure to Histone Deacetylase Inhibitors

- Known active HBV, HCV or HIV infection

- Patient with concomitant treatments such as amber [Hypericum perforatum], plant
extracts, vitamins, and other anti-oxidative compounds

- Participation in other clinical trials or observation period of competing trials,

- Patient is unable to swallow vorinostat suspension or capsules

- Patient on coumarin-derivative anticoagulants

- Any other medication which could accentuate known dose-dependent adverse effects of
the study drug, for instance bone marrow depression or QT-prolongation

Type of Study:


Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

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.

Outcome Description:

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.

Outcome Time Frame:

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.

Safety Issue:


Principal Investigator

Olaf Witt, Prof. Dr.

Investigator Role:

Principal Investigator

Investigator Affiliation:

University Hospital Heidelberg and German Cancer Research Center (DKFZ)


Germany: Federal Institute for Drugs and Medical Devices

Study ID:




Start Date:

March 2012

Completion Date:

December 2015

Related Keywords:

  • Children With Relapsed Solid Tumor, Lymphoma or Leukemia
  • pediatric oncology
  • relapsed solid tumor
  • lymphoma
  • leukemia
  • vorinostat
  • Leukemia
  • Lymphoma