A phase I trial of the histone deacetylase inhibitor panobinostat (LBH589) and epirubicin in patients with solid tumor malignancies.

Abstract

3036 Background: Preclinical and clinical data suggest that pre-exposure of cancer cells to histone deacetylase inhibitors (HDACi) reverses resistance to topoisomerase (topo) inhibitors by facilitating DNA access for topo II inhibitors and inhibiting DNA repair leading to apoptosis. Methods: Dose-escalation and -expansion study to explore safety, tolerability, and maximum tolerated dose (MTD) of oral panobinostat given on days 1, 3, 5 followed by epirubicin 75 mg/m2 day 5 in 21-day cycles. White blood cell counts, histone acetylation (H3, H4) and HDAC2 expression in pre- and post-treatment peripheral blood mononuclear cells and in tumor cells of patients treated in the dose expansion cohort are evaluated on day 1 and 5. Results: 26 patients have enrolled [7M/19F, median age 48 years (22-80)] in 5 panobinostat cohorts: 20, 30, 40, 50, 60 mg. Tumor types included melanoma (n=6), breast (n=5), sarcoma (n=7), ovarian (n=2), lung (n=2), and one each of neuroblastoma, pancreatic, testicular, and colon cancer. Prior to enrollment, patients received a median of 3 (0-8) prior chemotherapy regimens and 50% had anthracyclines. Dose-limiting toxicities (DLTs) included 1/3 grade 3 fatigue and 1/3 grade 4 thrombocytopenia at 60 mg of panobinostat, 1/6 patient experienced grade 3 atrial fibrillation at 50 mg, defining 50 mg panobinostat and 75 mg of epirubicin as the MTD for this combination. Non-dose–limiting grade 3/4 toxicities include neutropenia (n=12, 55%), febrile neutropenia (n=3, 13%), thrombocytopenia (n=4, 18%), and anemia (n=3, 13%). Of 22 evaluable patients, 5 had partial responses and 7 had stable disease in doxorubicin refractory sarcoma, ovarian, breast and small cell lung cancer. Histone acetylation and day 5 neutropenia will be correlated with HDAC2 expression and panobinostat activity. Conclusions: A sequence-specific combination of panobinostat and epirubicin shows early activity without potentiating epirubicin toxicity. A phase IB study in anthracycline pretreated sarcoma patients is ongoing.