Phase I Trial of Panobinostat (LBH589) in Combination with Trastuzumab in Pretreated HER2-Positive Metastatic Breast Cancer (mBC): Preliminary Safety, Efficacy and Pharmacokinetic Results.
Authors: Campone M. , Conte P. , Amadori D. , Pronzato P. , Wardley A. , McBride K. , Fandi A. 
Published: December 2010

Abstract
Background: Panobinostat (LBH589), a potent inhibitor of histone deacetylases (HDACs), has demonstrated single-agent activity and synergistic effects when administered in combination with trastuzumab or docetaxel in HER2-positive breast cancer xenografts.Methods: This multicenter study is enrolling patients with metastatic breast cancer (mBC) who have progressed on or within 6 months of trastuzumab-based therapy. Patients receive panobinostat either intravenously (i.v.) (Day 1+8 every 3 weeks) or orally (three times per week, continuously) in combination with trastuzumab 2 mg/kg weekly. Phase Ib of the study evaluates the maximum tolerated dose (MTD) for each formulation, three i.v. dose cohorts (10, 15 and 20 mg/m2) and four oral dose cohorts (15, 20, 30 and 40 mg) are planned. Once the MTDs are established, Phase IIa of the study will assess the efficacy of these doses. The pharmacokinetic (PK) profile is also being determined.Results: In this ongoing trial, 33 patients have received treatment. At baseline these patients had a median age of 52 y (33–65). All breast cancers were HER2-positive and 16 (48%) were ER and PR negative. Lung (45%), liver (33%) and the central nervous system (21%) were the most common sites of metastatic disease. Most patients had received prior taxanes and/or anthracyclines. For the i.v. arm, the 10 mg/m2 (n=7) and 15 mg/m2 (n=7) cohorts completed with no dose-limiting toxicity (DLT), while two out of six patients experienced DLTs in the 20 mg/m2 cohort. One patient experienced Grade (G) 4 thrombocytopenia, and one patient had G4 nausea, vomiting and diarrhea. The 20 mg/m2 cohort is currently being expanded to a total of 12 patients to confirm the MTD. For the oral arm, one of six patients experienced a DLT in the 15 mg cohort (uncomplicated G4 thrombocytopenia) and two of eight patients experienced DLTs in the 20 mg cohort. One patient had G3 unstable angina and G3 thrombocytopenia, and the second patient experienced G3 thrombocytopenia and G3 anorexia. The 20 mg cohort has been expanded to 12 patients. Overall the most frequent adverse events reported included gastrointestinal events of nausea, vomiting and diarrhea, and hematologic events of thrombocytopenia and neutropenia. To date, no clinically significant ECG changes have been observed from the 820 ECGs performed. Two patients experienced tumor reduction of 29% (one patient each in the i.v. 10 mg/m2 and oral 20 mg cohorts); both patients had liver metastasis. Eight of the 25 patients (32%) with tumor measurements had a best response of stable disease, across all cohorts. Five of these patients received over 18 weeks of treatment with the combination.Conclusions: These preliminary results demonstrate that the combination of panobinostat and trastuzumab is well tolerated and shows promising activity. Additional patient safety, efficacy and PK data will be presented.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6101.