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

This was an open label, phase I (3 + 3 design), multi-centre study evaluating panobinostat in pediatric patients with refractory solid tumors. Primary endpoints were to establish MTD, define and describe associated toxicities, including dose limiting toxicities (DLT) and to characterize its pharmacokinetics (PK). Secondary endpoints included assessing the anti-tumour activity of panobinostat, and its biologic activity, by measuring acetylation of histones in peripheral blood mononuclear cells. Nine patients were enrolled and treated with intravenous panobinostat at a dosing level of 15 mg/m(2) which was tolerated. Six were evaluable for adverse events. Two (33%) patients experienced Grade 3-4 thrombocytopenia, 1 (17%) experienced Grade 3 anemia, and 2 (33%) experienced Grade 3 neutropenia. Grade 4 drug related pain occurred in 2 (33%) of the patients studied. Two (33%) patients experienced a Grade 2 QTcF change (0.478 +/- 0.006 ms). One cardiac DLT (T wave changes) was reported. PK values for 15 mg/m(2) (n = 9) dosing were: T (max) 0.8 h, C (max) 235.2 ng/mL, AUC(0-t) 346.8 h ng/mL and t (1/2) 7.3 h. Panobinostat significantly induced acetylation of histone H3 and H4 at all time points measured when compared to pre-treatment samples (p < 0.05). Pooled quantitative Western blot data confirmed that panobinostat significantly induced acetylation of histone H4 at 6 h (p < 0.01), 24 h (p < 0.01) and 28-70 h (p < 0.01) post dose. A significant biological effect of panobinostat, measured by acetylation status of histone H3 and H4, was achieved at a dose of 15 mg/m(2). PK data and drug tolerability at 15 mg/m(2) was similar to that previously published.