Children With Relapsed Solid Tumor, Lymphoma or Leukemia Clinical Trial
Official title:
Phase I/II Intra-patient Dose Escalation Study of Vorinostat in Children With Relapsed Solid Tumor, Lymphoma or Leukemia
| Verified date | April 2018 |
| Source | National Center for Tumor Diseases, Heidelberg |
| Contact | n/a |
| Is FDA regulated | No |
| Health authority | |
| Study type | Interventional |
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.
| Status | Completed |
| Enrollment | 50 |
| Est. completion date | March 24, 2017 |
| Est. primary completion date | March 24, 2017 |
| Accepts healthy volunteers | No |
| Gender | All |
| Age group | 3 Years to 18 Years |
| Eligibility |
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 |
| Country | Name | City | State |
|---|---|---|---|
| Germany | Childrens's Hospital, Pediatric Oncology and Hematology | Augsburg | |
| Germany | Prof. Hess Childrens's Hospital, Pediatric Oncology and Hematology | Bremen | |
| Germany | University Childrens's Hospital, Pediatric Oncology and Hematology | Essen | |
| Germany | University Children's Hospital, Clinic IV | Freiburg | |
| Germany | Department of Pediatric Oncology and Hematology University Hospital Eppendorf (UKE) | Hamburg | |
| Germany | University Children's Hospital, Pediatric Oncology and Hematology, MHH | Hannover | |
| Germany | Clinic for Pediatric Oncology, Hematology, Immunology and Clinical Cooperation Unit Pediatric Oncology | Heidelberg | BW |
| Germany | University Childrens's Hospital, Pediatric Oncology and Hematology | Jena | |
| Germany | University Children's Hospital, Pediatric Oncology and Hematology | Köln | |
| Germany | Department of Pediatric Oncology and Hematology University Children's Hospital | Münster |
| Lead Sponsor | Collaborator |
|---|---|
| National Center for Tumor Diseases, Heidelberg | Merck Sharp & Dohme Corp., University Hospital Heidelberg |
Germany,
| Type | Measure | Description | Time frame | Safety issue |
|---|---|---|---|---|
| Primary | 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. | |
| Secondary | pharmacokinetics | 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 |
d 8, when maximum tolerated dose (MTD) ist reached and after 3 months treatment at MTD | |
| Secondary | antitumor effectiveness | antitumor effectiveness of vorinostat as measured by treatment response rate | three months after start of treatment with the individual MTD | |
| Secondary | association of the histone deacetylase (HDAC)-inhibiting activity with the dose administered, toxicity, and treatment response | 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". | d8, after reaching the MTD and after 3 months treatment at MTD | |
| Secondary | safety | 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. |
during dose escalation and during 3 months treatment at MTD every week; during prolongation of treatment and follow-up every second week | |
| Secondary | duration of response in responding patients | MRI and MIBG (in case of neuroblastoma) | every 3 months until progression of tumor |