Vorinostat in Children

This study is currently recruiting participants. (see Contacts and Locations)
Verified April 2014 by National Center for Tumor Diseases, Heidelberg
Sponsor:
Collaborators:
University Hospital Heidelberg
Merck Sharp & Dohme Corp.
Information provided by (Responsible Party):
National Center for Tumor Diseases, Heidelberg
ClinicalTrials.gov Identifier:
NCT01422499
First received: August 3, 2011
Last updated: April 24, 2014
Last verified: April 2014
  Purpose

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.


Condition Intervention Phase
Children With Relapsed Solid Tumor, Lymphoma or Leukemia
Drug: zolinza/vorinostat
Phase 1
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase I/II Intra-patient Dose Escalation Study of Vorinostat in Children With Relapsed Solid Tumor, Lymphoma or Leukemia

Resource links provided by NLM:


Further study details as provided by National Center for Tumor Diseases, Heidelberg:

Primary Outcome Measures:
  • 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. [ 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. ] [ Designated as safety issue: Yes ]

    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.



Secondary Outcome Measures:
  • pharmacokinetics [ Time Frame: d 8, when maximum tolerated dose (MTD) ist reached and after 3 months treatment at MTD ] [ Designated as safety issue: No ]

    Quantification of vorinostat concentration by mass spectrometry and enzymatically (AUC, Cmax, Cmin, tmax, Clearance, and t1/2).

    The pharmacokinetic study will investigate the correlation between dose administered, plasma concentration, CSF concentrations, intracellular inhibition of HDAC activity and glucuronosyltransferase polymorphisms as well as observed treatment responses and toxicities.

    Additionally:Intracellular HDAC activity in leukocytes using a fluorescence based enzymatic assay


  • antitumor effectiveness [ Time Frame: three months after start of treatment with the individual MTD ] [ Designated as safety issue: No ]
    antitumor effectiveness of vorinostat as measured by treatment response rate

  • association of the histone deacetylase (HDAC)-inhibiting activity with the dose administered, toxicity, and treatment response [ Time Frame: d8, after reaching the MTD and after 3 months treatment at MTD ] [ Designated as safety issue: No ]
    Intracellular vorinostat concentrations and pharmacologic target (HDAC) inhibition in peripheral leukocytes will be determined as a pharmacodynamic surrogate parameter. The latter assay is based on conversion of a fluorigenic acetyl-substrate by the enzymatic activity of HDACs which is specifically inhibited by vorinostat in a concentration dependent manner. The performance of the assay in patient plasma samples has been validated according to the FDA recommendations "Guidance for Industry Bioanalytical Method Validation".

  • safety [ Time Frame: during dose escalation and during 3 months treatment at MTD every week; during prolongation of treatment and follow-up every second week ] [ Designated as safety issue: Yes ]

    The analysis of safety assessments will include summaries of the following categories of safety and tolerability data collected for each subject:

    • Drug Exposure(s)
    • Adverse Events (AEs and SAEs, AEs leading to withdrawal)
    • Clinical Laboratory Investigations
    • Hemodynamics (vital signs)
    • ECG Investigations

    Frequencies of patients experiencing at least one AE will be displayed. Severity of the AEs will be graded according to the CTCAEv4.0. Summary tables will present the number of patients observed with AEs, the corresponding percentages and 95% CI.


  • duration of response in responding patients [ Time Frame: every 3 months until progression of tumor ] [ Designated as safety issue: No ]
    MRI and MIBG (in case of neuroblastoma)


Estimated Enrollment: 50
Study Start Date: March 2012
Estimated Study Completion Date: December 2015
Estimated Primary Completion Date: November 2015 (Final data collection date for primary outcome measure)
Intervention Details:
    Drug: zolinza/vorinostat
    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.
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.

  Eligibility

Ages Eligible for Study:   3 Years to 18 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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, respectively
  • 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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01422499

Contacts
Contact: Olaf Witt, Prof. Dr. +49 6221 56 38786 o.witt@dkfz.de

Locations
Germany
Clinic for Pediatric Oncology, Hematology, Immunology and Clinical Cooperation Unit Pediatric Oncology Recruiting
Heidelberg, BW, Germany, 69198
Contact: Olaf Witt, MD    +49 6221 56 38786 or 06221 42    o.witt@dkfz.de   
Principal Investigator: Olaf Witt, MD         
Sub-Investigator: Till Milde, MD         
Sub-Investigator: Hedwig Deubzner, MD         
Childrens's Hospital, Pediatric Oncology and Hematology Recruiting
Augsburg, Germany, 86156
Contact: Michael Frühwald, MD       Michael.Fruehwald@klinikum-augsburg.de   
Prof. Hess Childrens's Hospital, Pediatric Oncology and Hematology Recruiting
Bremen, Germany, 28205
Contact: Arnulf Pekrun, MD       Arnulf.Pekrun@klinikum-bremen-mitte.de   
University Childrens's Hospital, Pediatric Oncology and Hematology Recruiting
Essen, Germany, 45122
Contact: Regina Wieland, MD       Regina.Wieland@uk-essen.de   
University Children's Hospital, Clinic IV Recruiting
Freiburg, Germany, 79106
Contact: Christian Flotho, MD       christian.flotho@uniklinik-freiburg.de   
Department of Pediatric Oncology and Hematology University Hospital Eppendorf (UKE) Recruiting
Hamburg, Germany, 20246
Contact: Uwe Kordes, MD       kordes@uke.de   
University Children's Hospital, Pediatric Oncology and Hematology, MHH Recruiting
Hannover, Germany, 30625
Contact: Christin Linderkamp, MD       linderkamp.christin@mh-hannover.de   
University Childrens's Hospital, Pediatric Oncology and Hematology Recruiting
Jena, Germany, 07743
Contact: James F. Beck, MD       James.Beck@med.uni-jena.de   
University Children's Hospital, Pediatric Oncology and Hematology Recruiting
Köln, Germany, 50937
Contact: Frank Berthold, MD       frank.berthold@uk-koeln.de   
Department of Pediatric Oncology and Hematology University Children's Hospital Recruiting
Münster, Germany, 48149
Contact: Heribert Jürgens, MD       jurgh@uni-muenster.de   
Sponsors and Collaborators
National Center for Tumor Diseases, Heidelberg
University Hospital Heidelberg
Merck Sharp & Dohme Corp.
Investigators
Principal Investigator: Olaf Witt, Prof. Dr. University Hospital Heidelberg and German Cancer Research Center (DKFZ)
  More Information

No publications provided by National Center for Tumor Diseases, Heidelberg

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: National Center for Tumor Diseases, Heidelberg
ClinicalTrials.gov Identifier: NCT01422499     History of Changes
Other Study ID Numbers: NCT-2007-11-02-1004
Study First Received: August 3, 2011
Last Updated: April 24, 2014
Health Authority: Germany: Federal Institute for Drugs and Medical Devices

Keywords provided by National Center for Tumor Diseases, Heidelberg:
pediatric oncology
relapsed solid tumor
lymphoma
leukemia
vorinostat

Additional relevant MeSH terms:
Lymphoma
Leukemia
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Vorinostat
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Histone Deacetylase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on September 30, 2014