A phase I study of panobinostat in pediatric patients with refractory solid tumors, including CNS tumors.

Background: Deregulated acetylation of histones plays a key role in the pathogenesis of haematological and solid tumors by changing the transcription of genes involved in cell cycle control, differentiation or apoptosis. Thus, there is considerable interest in HDAC inhibition as a potential therapeutic modality in the treatment of hematological and solid tumor malignancies, including pediatric malignancies. Method(s): This is an open label, Phase I, multi-centre study evaluating panobinostat in pediatric patients with refractory solid tumours. Primary endpoints were to define and describe associated toxicities, and to characterize its pharmacokinetics (PK). Secondary endpoints included assessing the anti-tumour activity of panobinostat, and also to assess its biologic activity by measuring the histone acetylation status in peripheral blood mononuclear cells (PBMNC). Result(s): Nine patients were enrolled and treated with intravenous panobinostat at a dosing level of 15mg/m2. Three patients were removed from study prior to completion of course one due to tumour progression. A dose of 15mg/m2 was tolerated with one dose limiting toxicity (DLT) observed in the six patients evaluated for DLT. Two (22%) patients experienced grade 3-4 thrombocytopenia, 1 (11%) experienced grade 3 anemia, and 2 (22%) experienced grade 3 neutropenia. Grade 4 drug related pain occurred in 2 (22%) of patients studied. Vomiting (44%), nausea (33%) and hypokalaemia (22%) were also common adverse events. Two (22%) of patients experienced a Grade II QTcF change (0.478 +/- 0.006 msec). One cardiac DLT (T wave changes) was reported. PK values for 15mg/m2 (n=9) dosing were: Tmax 0.8 hours, Cmax 235.2 ng/ml, AUC0-t 346.8h.ng/ml and t1/2 7.3 hours. Pooled flow cytometry results of all nine patient samples confirm that panobinostat significantly induced acetylation of histone H3 and H4 at 6 hours (p< 0.001), 24 hours (P<0.01) and 28-70 hours (p<0.05) post dose. Conclusion(s): A significant, sustained