Clinical trial NCT01422499: Vorinostat in Children
Official title: Phase I/II Intra-patient Dose Escalation Study of Vorinostat in Children With Relapsed Solid Tumor, Lymphoma or Leukemia
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Children With Relapsed Solid Tumor, Lymphoma or Leukemia
Keywords: pediatric oncology
relapsed solid tumor
lymphoma
leukemia
vorinostat
Lead sponsor: National Center for Tumor Diseases, Heidelberg
Sponsor class: OTHER
Collaborators: name: University Hospital Heidelberg
name: Merck Sharp & Dohme LLC
First posted: 2011-08-24
Enrollment: 50
Sex: ALL
Minimum age (years): 3
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief 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.

Eligibility 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

Primary outcomes:
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.
timeFrame: 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.
Secondary outcomes:
measure: pharmacokinetics
timeFrame: d 8, when maximum tolerated dose (MTD) ist reached and after 3 months treatment at MTD
measure: antitumor effectiveness
timeFrame: three months after start of treatment with the individual MTD
measure: association of the histone deacetylase (HDAC)-inhibiting activity with the dose administered, toxicity, and treatment response
timeFrame: d8, after reaching the MTD and after 3 months treatment at MTD
measure: safety
timeFrame: during dose escalation and during 3 months treatment at MTD every week; during prolongation of treatment and follow-up every second week
measure: duration of response in responding patients
timeFrame: every 3 months until progression of tumor
Other outcomes:
Locations:
city: Heidelberg
country: Germany
facility: Clinic for Pediatric Oncology, Hematology, Immunology and Clinical Cooperation Unit Pediatric Oncology
state: BW
city: Augsburg
country: Germany
facility: Childrens's Hospital, Pediatric Oncology and Hematology
city: Bremen
country: Germany
facility: Prof. Hess Childrens's Hospital, Pediatric Oncology and Hematology
city: Essen
country: Germany
facility: University Childrens's Hospital, Pediatric Oncology and Hematology
city: Freiburg
country: Germany
facility: University Children's Hospital, Clinic IV
city: Hamburg
country: Germany
facility: Department of Pediatric Oncology and Hematology University Hospital Eppendorf (UKE)
city: Hannover
country: Germany
facility: University Children's Hospital, Pediatric Oncology and Hematology, MHH
city: Jena
country: Germany
facility: University Childrens's Hospital, Pediatric Oncology and Hematology
city: Köln
country: Germany
facility: University Children's Hospital, Pediatric Oncology and Hematology
city: Münster
country: Germany
facility: Department of Pediatric Oncology and Hematology University Children's Hospital
Study officials:
affiliation: University Hospital Heidelberg and German Cancer Research Center (DKFZ)
name: Olaf Witt, Prof. Dr.
role: PRINCIPAL_INVESTIGATOR
References:
citation: van Tilburg CM, Milde T, Witt R, Ecker J, Hielscher T, Seitz A, Schenk JP, Buhl JL, Riehl D, Fruhwald MC, Pekrun A, Rossig C, Wieland R, Flotho C, Kordes U, Gruhn B, Simon T, Linderkamp C, Sahm F, Taylor L, Freitag A, Burhenne J, Foerster KI, Meid AD, Pfister SM, Karapanagiotou-Schenkel I, Witt O. Phase I/II intra-patient dose escalation study of vorinostat in children with relapsed solid tumor, lymphoma, or leukemia. Clin Epigenetics. 2019 Dec 10;11(1):188. doi: 10.1186/s13148-019-0775-1.
citation: Witt O, Milde T, Deubzer HE, Oehme I, Witt R, Kulozik A, Eisenmenger A, Abel U, Karapanagiotou-Schenkel I. Phase I/II intra-patient dose escalation study of vorinostat in children with relapsed solid tumor, lymphoma or leukemia. Klin Padiatr. 2012 Oct;224(6):398-403. doi: 10.1055/s-0032-1323692. Epub 2012 Aug 22.