Background: In preclinical pediatric cancer models, the HDAC inhibitor vorinostat showed significant activity only at higher concentrations compared with those achieved with currently recommended dosing regimens. The aim of this trial was to intra-individually dose escalate to an individual maximum tolerated dose (MTD) in order to increase the likelihood of response whilst keeping toxicity acceptable. Methods: Children 3 – 18 years old with relapsed or therapy-refractory solid tumor, lymphoma or leukemia were eligible. In phase 1 an intra-patient dose (de)escalation was performed until the MTD was reached. After identification of MTD, patients did continue treatment in phase 2 at their individual MTD until progression. Results: Fifty-two patients were enrolled and 50 received treatment. 27/50 patients completed the intra-patient (de)escalation phase 1 part and entered phase 2. A safe starting dose of 130mg/m²/day with weekly increments of 50mg/m² was determined (maximum: 580mg/m²/day). 46/50 (92%) patients experienced treatment related AEs, in 44 patients (88%) ≥ CTCAE grade 3. Of the patients who reached phase 2, 24/27 patients (89%) experienced treatment related AEs, in 17 patients (63%) ≥ grade 3. Most of the grade 3-4 AEs were reversible hematologic toxicity (mostly thrombocytopenia), fatigue, nutrition and gastrointestinal disorders and weight loss. The median MTD was 280mg/m²/day (range 130 - 580mg/m²/day). Overall response rate (CR + PR + SD) in the phase 2 was 6/27 (22%). 5 patients stayed on treatment for > 12 months receiving doses of 280 – 580mg/m²/day. 3 patients with histological high grade glioma and one with metastasized SETTLE tumor showed PR, one with a medulloblastoma showed prolonged SD. 1 patient was on drug for > 4 years. Conclusions: A safe starting dose of 130mg/m²/day for individual dose escalation with weekly increments of 50mg/m² was identified. This resulted in higher drug exposure associated with responses and long-term disease stabilization confirming that activity can only be expected at doses higher than currently recommended. The toxicity profile was compatible with published adult and pediatric safety data. PK, PD and biomarker analysis are ongoing. Clinical trial information: NCT01422499