Abstract 2414: A phase I/II clinical trial to evaluate the efficacy of combined epigenetic therapy for improving temozolomide chemosensitivity in metastatic melanoma.
Authors: Xia Chang , Deutsch Jeremy M. , Milhem Mohammed M. , Smith Brian J. , Laux Douglus , Hohl Raymond 
Published: August 2014

Abstract
Background: Cancer epigenomes are characterized by global changes in DNA methylation and covalent histone modification patterns. The disruption of epigenetic mechanisms is a hallmark of cancer development and has strong implications in cancer treatment. Emerging evidence indicates that epigenetics may also play a key role in the development of chemoresistance in melanoma. Keeping the toxicity to a minimum may allow for repeated dosing when combine epigenetic and cytotoxic therapy in the treatment of solid tumors. We proposed combining the histone deacetylase inhibitor panobinostat and the demethylator decitabine to epigenetically regulate apoptotic process and overcome temozolomide resistance in metastatic melanoma
Methods: Eligible patients must be ≥18, stage IV melanoma, and naïve or previously treated, with good performance status (ECOG Performance Status of ≤ 2) and normal organ functions. The study includes the dose escalation of Decitabine and Panobinostat followed by expansion cohorts. Decitabine (0.1mg/kg SQ, 0.2mg/kg SQ) on days 1,3,5,8,10,12, Panobinostat (10mg PO, 20mg PO, 30mg PO) Q96h starting day 8, and Temozolomide 150mg/m2 PO daily on days 9-13 of each 42 day cycle. Temozolomide was increased to 200mg/m2 in the absence of grade 2 thrombocytopenia. Primary endpoints of phase I study are to determine the toxicity, safety and maximum tolerated dose (MTD) of the Decitabine, Panobinostat and Temozolomide combination.
Results: To date, the phase I study of this trial is completed. 17 patients were enrolled (1st cohort: 5; 2nd cohort: 4; 3rd cohort: 4; 4th cohort: 4). M:F 11:6. Median age: 56 (32-77); ECOG PS: 1; 82% of the patients received at least one cycle (n=14). Median number of cycles given: 2 (0-6). To date, no DLTs have occurred. The MTD was not reached. The only G4 adverse event (AE) is neutropenia on a patient in cohort 3 and it resolved within 3 days. G3 AEs included lymphopenia (n=4, 23%), anemia (n=2, 12%), leukopenia (n=2, 12%) and fatigue (n=2, 12%). Common G2 toxicities were leukocyte (n=5, 30%), neutropenia (n=4, 23%), nausea (n=4, 23%) and lymphopenia (n=3, 18%).
Conclusions: The combination of decitabine, panobinostat, and temozolomide appears to be safe and well-tolerated. The recommended dosing regimen for phase II studies is Decitabine 0.2 mg/kg SQ 3x weekly, on days 1,3,5,8,10,12, Panobinostat 30mg PO Q96h starting day 8, and Temozolomide 200mg/m2 PO daily on days 9-13 of each 42 day cycle.
Citation Format: Chang Xia, Jeremy M. Deutsch, Mohammed M. Milhem, Brian J. Smith, Douglus Laux, Raymond Hohl. A phase I/II clinical trial to evaluate the efficacy of combined epigenetic therapy for improving temozolomide chemosensitivity in metastatic melanoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2414. doi:10.1158/1538-7445.AM2013-2414
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.