Abstract 5590: A phase I/II study of decitabine with pegylated interferon α-2b in advanced melanoma: clinical results and impact on DNA methylation and immune modulation
Authors: Plimack Elizabeth R. , Issa Jean-Pierre , Jelinek Jaroslav , Sharma Padmanee , Vence Luis , Bassett Roland L. , Ilagan Joseph L. , Papadopoulos Nicholas E. , Hwu Wen-Jen 
Published: August 2012

Abstract
Background: Melanoma cell lines treated with decitabine (DAC) show significant upregulation of cancer antigens. Interferon-α is known to up-regulate MHC Class I antigens in cancer cells, leading to enhanced T cell recognition and subsequent T cell mediated apoptosis. This hypothesized synergy between the hypomethylating effects of DAC and the immune modulatory effects of interferon was tested in this trial. Methods: Patients with advanced melanoma and no more than one prior therapy were eligible. Using a modified 3+3 design, patients were treated with escalating doses of DAC (IV daily days 1-5) and pegylated interferon α-2b (PGI) (SC weekly). Cycles were repeated every 28 days. Patients were imaged for response assessment every 12 weeks (3 cycles). Global DNA methylation was measured in peripheral blood by LINE assays on days 1 and 5 of cycles 1 and 3. Cytokine profiling and quantification of T-cell sub-populations by FACS were performed at baseline and after cycle 3. Results: 17 patients were enrolled between 10/2008 and 4/2010 to one of the four dose levels: DAC 5 mg/m2/d + PGI 1.5 µg/kg, DAC 10 mg/m2/d + PGI 3 µg/kg, DAC 15 mg/m2/d + PGI 3 µg/kg, DAC 10 mg/m2/d + PGI 4.5 µg/kg. Patients received a median of three cycles of therapy. At DAC 10 + PGI 4.5, two DLTs were noted among 5 patients: intracranial hemorrhage and persistent grade 4 thrombocytopenia. DAC 15 mg/m2/d + PGI 3 µg/kg was determined to be the MTD. Subsequently, two patients were enrolled to the phase II portion of the study before it was closed due to slow accrual. Grade 3/4 cytopenias were seen across all dose levels: anemia (1), neutropenia (7), thrombocytopenia (2). Other common toxicities included fatigue, rigors/chills, and fevers, all grade 1/2. One patient had stable disease at the first scheduled restaging assessment at 12 weeks, and remained progression free for a total of 37 weeks. The other 16 patients progressed at or before 12 weeks. The median PFS was 12 weeks, the median overall survival was 39 weeks. Hypomethylation ranging from 0.3% - 9.9% at day 5 was seen in 14/15 patients for whom data is available. Percent hypomethylation did not correlate with DAC dose, dose level or percent decrease in absolute neutrophils Analyses of immune modulation in blood samples are ongoing. Conclusion: This combination regimen is characterized by significant myelosuppression, particularly neutropenia. No clinical responses were seen and all but one patient progressed at or before the first disease assessment. Disappointing efficacy and slow accrual led to early closure of the study. Measured hypomethylation shows pharmacodynamic evidence of DAC drug effect. Investigations into the effects of treatment on cellular immunity may reveal mechanisms of toxicity/poor efficacy associated with this combination therapy. Supported by Schering-Plough and NIH grants UL1 RR024148 and KL2 RR024149. DAC provided by Eisai.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5590. doi:1538-7445.AM2012-5590