Treatment of resistant metastatic melanoma using sequential epigenetic therapy (decitabine and panobinostat) combined with chemotherapy (temozolomide)

Abstract

PurposeTo explore the safety and tolerability of combining two epigenetic drugs: decitabine (a DNA methyltransferase inhibitor) and panobinostat (a histone deacetylase inhibitor), with chemotherapy with temozolomide (an alkylating agent). The purpose of such combination is to evaluate the use of epigenetic priming to overcome resistance of melanoma to chemotherapy.MethodsA Phase I clinical trial enrolling patients aged 18 years or older, with recurrent or unresectable stage III or IV melanoma of any site. This trial was conducted with full Institutional Review Board approval and was registered with the National Institutes of Health under the clinicaltrials.gov identifier NCT00925132. Patients were treated with subcutaneous decitabine 0.1 or 0.2 mg/kg three times weekly for 2 weeks (starting on day 1), in combination with oral panobinostat 10, 20, or 30 mg every 96 h (starting on day 8), and oral temozolomide 150 mg/m2/day on days 9 through 13. In cycle 2, temozolomide was increased to 200 mg/m2/day if neutropenia or thrombocytopenia had not occurred. Each cycle lasted 6 weeks, and patients could receive up to six cycles. Patients who did not demonstrate disease progression were eligible to enter a maintenance protocol with combination of weekly panobinostat and thrice-weekly decitabine until tumor progression, unacceptable toxicity, or withdrawal of consent.ResultsTwenty patients were initially enrolled, with 17 receiving treatment. The median age was 56 years. Eleven (65 %) were male, and 6 (35 %) were female. Eleven (64.7 %) had cutaneous melanoma, 4 (23.5 %) had ocular melanoma, and 2 (11.8 %) had mucosal melanoma. All patients received at least one treatment cycle and were evaluable for toxicity. Patients received a median of two 6-week treatment cycles (range 1–6). None of the patients experienced DLT. MTD was not reached. Adverse events attributed to treatment included grade 3 lymphopenia (24 %), anemia (12 %), neutropenia (12 %), and fatigue (12 %), as well as grade 2 leukopenia (30 %), neutropenia (23 %), nausea (23 %), and lymphopenia (18 %). The most common reason for study discontinuation was disease progression.ConclusionsThis triple agent of dual epigenetic therapy in combination with traditional chemotherapy was generally well tolerated by the cohort and appeared safe to be continued in a Phase II trial. No DLTs were observed, and MTD was not reached.

A phase I trial of panobinostat (LBH589) in patients with metastatic melanoma

“…Bortezomib has not proven to be particularly effective in melanoma and is not a candidate for combination as witnessed by the negative phase I trial combining sorafenib and bortezomib in this disease . A combination of decitabine, panobinostat, and temozolomide in metastatic melanoma was well tolerated in a phase I clinical trial with some evidence of activity with a 75% disease‐control rate .…”

“…MART-1 SOX10 pERK TUNEL the negative phase I trial combining sorafenib and bortezomib in this disease [23]. A combination of decitabine, panobinostat, and temozolomide in metastatic melanoma was well tolerated in a phase I clinical trial with some evidence of activity with a 75% disease-control rate [24]. Immunotherapy has revolutionized the treatment of melanoma and is yielding exciting results in the treatment of other malignancies as well [2,[25][26][27][28].…”

Enhanced Histone Deacetylase Activity in Malignant Melanoma Provokes RAD51 and FANCD2-Triggered Drug Resistance

“…In melanoma, pan-HDAC inhibitors in combination with temozolomide have shown promise (19,20). For these reasons, we addressed the role of class I HDACs in melanoma and determined the molecular mechanism whereby these HDACs influence the response of melanomas to temozolomide.…”

New Frontiers in Melanoma Epigenetics—The More We Know, the More We Don’t Know

“…Several chemicals that interfere with DNA methylation or demethylation, and a few more drugs that cause histone acetylation or deacetylation have been already studied even in preclinical or early clinical trials, and some of them (such as decitabine, azacytidine, vorinostat, valproic acid) are already in use [159]. Some researchers try to combine novel epigenetic therapies with currently used chemotherapy and personalised medicine innovations, especially in case of resistant metastatic melanoma [160]. Over a decade ago, the identification of molecules and specific, highly recurrent mutations involved in the altered pathway of apoptosis in melanoma, such as BCL-2, EZH2 and BRAF V600E , provided an insight into molecular basis of chemoresistance in this cancer type, and led to the discovery of personalised medicine drugs, with the most spectacular success of vemurafenib [161][162][163].…”