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

Abstract

3058 Background: Preclinical and clinical data suggest pre-exposure of cancer cells to a histone deacetylase inhibitor (HDACi) potentiates topoisomerase inhibitors. HDACi-induced histone acetylation and chromatin modulation facilitates DNA access and target recruitment for topo II inhibitors. In vitro data further suggest effective inhibition of HDAC2 is necessary for enhanced epirubicin-induced apoptosis. Methods: This phase I trial explores the safety, tolerability, and maximum tolerated dose (MTD) of escalating doses of panobinostat given orally on days 1, 3, and 5 followed by epirubicin administered intravenously at 75 mg/m2 on day 5 in 21-day cycles. Histone acetylation and HDAC2 expression are evaluated in pre- and post-treatment peripheral blood mononuclear cells (PBMCs) in all patients and in tumor cells of 16 patients treated at the MTD. Results: 36 patients have enrolled [10M/26F, median age 47 years (22-80)] in 5 panobinostat cohorts: 20, 30, 40, 50, 60 mg. Tumor types include melanoma (n=6), breast (n=6), sarcoma (n=16), 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 40% 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 as the MTD. Non-dose–limiting grade 3/4 hematological toxicities include neutropenia (n=19, 53%), febrile neutropenia (n=6, 17%), thrombocytopenia (n=6, 17%), and anemia (n=4, 11%). Of 34 evaluable patients, 5 had partial responses and 14 had stable disease in anthracycline-refractory sarcomas (4) and Her2neu positive breast cancer (2), and small cell lung cancer. Correlative studies demonstrate increased H4 acetylation in PBMCs on day 3 and 5 suggesting sufficient histone deacetylase inhibition. Conclusions: Sequence-specific combination of panobinostat and epirubicin shows early activity without potentiating epirubicin toxicity. Dose expansion in anthracycline-pretreated sarcoma patients is ongoing.