Phase II study of oral panobinostat in patients with relapsed/refractory hodgkin lymphoma after high-dose chemotherapy with autologous stem cell transplant

Abstract

Background. Panobinostat (LBH589) is a pan-deacetylase inhibitor (pan-DACi) targeting epigenetic and non-epigenetic oncogenic pathways. In vitro, panobinostat decreases proliferation and induces apoptosis in HL cell lines at low nanomolar concentrations. Encouraging clinical activity, with a CT scan-based response rate of 42% in patients with HL, has been demonstrated in an ongoing Phase I study in patients with hematologic malignancies (Ottmann OG et al. ASH 2008 Abstract #958). Aims.The aim of this open-label Phase II study is to confirm the efficacy of panobinostat in HL. Methods. Utilizing a Simon two-stage design, patients with hodgkin lymphoma (HL), whose disease is refractory to, or has progressed after ASCT are being enrolled in the study. The primary objective of the study is to determine the overall response rate using the modified Cheson criteria. Secondary objectives include time to and duration of response, progression-free survival (PFS) and overall survival; clinical and laboratory safety data will be collected. To be included in the study, patients must have adequate organ function, no other significant medical conditions, and ECOG PS (less-than or equal to)2. Panobinostat is administered orally at a dose of 40 mg three-times weekly in a 21-day cycle. Treatment is continued until disease progression or intolerance. Dose delay and modification for toxicity is allowed. CT/MRI scans are conducted at the end of every two cycles. The in vivo effect of panobinostat on the expression of programmed cell death protein 1 (PD-1) on peripheral blood T-lymphocytes was evaluated by multicolor FACS analysis. Results. As of Feb 20, 2009, 30 patients have been enrolled, of whom 14 have completed at least 2 months of therapy and for whom preliminary data are available (median age 27.5 years [range 18-51]; six male, eight female; median number of prior regimens five [range one to six]). The more common AEs have been thrombocytopenia (n=6/14, all Grade 3 or 4), diarrhea (n=6/14), and nausea (n=8/14). Among the 295 ECGs analyzed, there have been no (greater-than or equal to)Grade 2 QTc abnormalities. Efficacy data are available for six of the 14 patients who had tumor reductions ranging between 18% and 68%, including two partial responses. All these patients continue on study. Serial blood samples were obtained from four patients, and in all cases panobinostat significantly decreased the expression of PD-1 on CD8+ T cells after 7 and 15 days of therapy. Summary. Panobinostat has encouraging clinical activity in heavily pretreated patients with relapsed classical HL. In addition to its direct antitumor effect, our data suggest that panobinostat may enhance the antitumor immune response by downregulating PD-1 on patients' T lymphocytes. Panobinostat is generally well tolerated, and thrombocytopenia is managed by dose delay or dose reduction. Enrollment into the study is ongoing; efficacy and safety data available at the time of the meeting will be presented.