E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Relapsed of progressive solid tumor, lymphoma, or leukemia in children and adolescents aage 3-18 years |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 18.0 |
E.1.2 | Level | HLGT |
E.1.2 | Classification code | 10024324 |
E.1.2 | Term | Leukaemias |
E.1.2 | System Organ Class | 10005329 - Blood and lymphatic system disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 18.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10025310 |
E.1.2 | Term | Lymphoma |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To determine a safe dose 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 |
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E.2.2 | Secondary objectives of the trial |
To determine the distribution of individual maximum tolerated doses (MTD), which is the maximum dose with no grade 3 or 4 toxicity according to CTC criteria.
To determine the pharmacokinetics of oral vorinostat in children and adolescents (3 – 18 years) with relapsed/refractory solid tumor, lymphoma or leukemia
To determine antitumor effectiveness of vorinostat as measured by objective response rate in children and adolescents (3-18 years) with relapsed/refractory solid tumor, lymphoma or leukemia. Response (CR, PR, SD) will be evaluated in every patient three months after start of treatment with the individual maximum tolerated dose (MTD).
To correlate the (HDAC)-inhibiting activity with the dose administered, toxicity, and treatment response.
To determine feasibility and safety of oral vorinostat in children and adolescents (3-18 years) with solid tumor, lymphoma or leukaemia.
To determine duration of response in responding patients
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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 two weeks 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 (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
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E.4 | Principal 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 14-day washout period. Washout will be ensured by determining valproic acid plasma level before enrolment.
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
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E.5 End points |
E.5.1 | Primary end point(s) |
safe dose 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 |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
pharmacokinetics and the distribution of individual maximum tolerated doses (MTD), which is the maximum dose with no grade 3 or 4 toxicity according to CTC criteria.
antitumor effectiveness of vorinostat as measured by treatment response rate. Response will be evaluated in each patient three months after start of treatment with the individual MTD.
association of the histone deacetylase (HDAC)-inhibiting activity with the dose administered toxicity, and treatment response.
feasibility and safety
duration of response in responding patients.
Additional biomarker studies for the prediction of vorinostat response (IL-6, IL-10, BMP) induction, basal histone acetylation level) will be performed. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
response 3 months after start of treatment |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | Yes |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
E.8.2.2 | Placebo | Information not present in EudraCT |
E.8.2.3 | Other | Information not present in EudraCT |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 10 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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until 50 patients are enrolled and the last subject has received the last visit |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |