Abstract P5-06-06: The Safety and Tolerability of Panobinostat (LBH589) in Combination with Capecitabine +/− Lapatinib: A Phase I Study in HER2+ Breast Cancer

Abstract

Abstract Background: Panobinostat is a histone deacetylase (HDAC) inhibitor, for which in vitro studies have suggested activity in breast cancer lines. This phase I study was designed to assess the safety, tolerability, and efficacy of panobinostat in combination with lapatinib and capecitabine in 3 parts. Part 1, for which we have previously reported findings (Peacock et al, ASCO 2010), established the maximum tolerated dose (MTD) of panobinostat (30mg twice weekly) in combination with capecitabine (1000mg/m2 BID). Part 2, reported here, was designed to assess the QTc prolongation and overall toxicity of panobinostat in combination with lapatinib in patients with HER2+ breast cancer. Part 3 will assess the tolerability and efficacy of the triplet combination based on doses defined in Parts 1 and 2. Method: Patients aged ≥18 years with incurable, locally recurrent or metastatic HER2+ breast cancer were eligible. Additional eligibility criteria included: < 3 prior treatments in the metastatic setting; ECOG PS 0-1; measurable disease by RECIST; no impairment of cardiac function; no prior treatment with HDAC inhibitors; informed consent. Lapatinib doses of 1000mg daily were administered with panobinostat doses of 15mg and 20mg three times weekly, following 1 week of 2 doses of panobinostat alone to assess QTc prolongation. Cycles were repeated every 21 days until disease progression or toxicity warranted drug discontinuation. Patients were reevaluated for response every 2 cycles. Results: 5 female patients with HER2+ metastatic breast cancer were accrued to Part 2, with a median age of 66 years (range: 64 — 67); 80% of patients were ECOG PS 0. To date, patients have received 17 cycles of treatment (median 4 cycles), and 2 patients have stable disease (progression1, unevaluable 1, and too early to assess 1), with one patient remaining on treatment. There have been no dose-limiting toxicities. One patient was hospitalized for grade 3 peripheral neuropathy (unrelated). No grade 2/3/4 toxicities have occurred in >1 patient; no QTc prolongation has been observed. Conclusions: Our preliminary findings suggest that the combination of panobinostat and lapatinib is safe and tolerable. No QTc prolongation or cardiotoxicity has been observed. Part 3 will evaluate the triplet combination using the dosages established in Parts 1 and 2. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P5-06-06.