Abstract
BackgroundWhile recent years have seen a revolution in the treatment of metastatic cutaneous melanoma, no treatment has yet been able to demonstrate any prolonged survival in metastatic uveal melanoma. Thus, metastatic uveal melanoma remains a disease with an urgent unmet medical need. Reports of treatment with immune checkpoint inhibitors have thus far been disappointing. Based on animal experiments, it is reasonable to hypothesize that the effect of immunotherapy may be augmented by epigenetic therapy. Proposed mechanisms include enhanced expression of HLA class I and cancer antigens on cancer cells, as well as suppression of myeloid suppressor cells.MethodsThe PEMDAC study is a multicenter, open label phase II study assessing the efficacy of concomitant use of the PD1 inhibitor pembrolizumab and the class I HDAC inhibitor entinostat in adult patients with metastatic uveal melanoma. Primary endpoint is objective response rate. Eligible patients have histologically confirmed metastatic uveal melanoma, ECOG performance status 0–1, measurable disease as per RECIST 1.1 and may have received any number of prior therapies, with the exception of anticancer immunotherapy. Twenty nine patients will be enrolled. Patients receive pembrolizumab 200 mg intravenously every third week in combination with entinostat 5 mg orally once weekly. Treatment will continue until progression of disease or intolerable toxicity or for a maximum of 24 months.DiscussionThe PEMDAC study is the first trial to assess whether the addition of an HDAC inhibitor to anti-PD1 therapy can yield objective anti-tumoral responses in metastatic UM.Trial registrationClinicalTrials.gov registration number: NCT02697630. (Registered 3 March 2016). EudraCT registration number: 2016–002114-50.
Highlights
While recent years have seen a revolution in the treatment of metastatic cutaneous melanoma, no treatment has yet been able to demonstrate any prolonged survival in metastatic uveal melanoma
Changes in molecular characteristics of uveal melanoma metastases when treated with entinostat and pembrolizumab
Being a rare disease and of low commercial value, drug discovery in Uveal malignant melanoma (UM) is of lower priority by the pharmaceutical industry
Summary
Study design The PEMDAC study is a prospective multicenter, non-randomized, open label study, in which patients with stage IV UM are concomitantly treated with pembrolizumab 200 mg administered intravenously every third week and entinostat 5 mg administered orally once weekly. IrRECIST will be used for assessment of tumor response for managing subjects on protocol treatment and decision making for discontinuation of study therapy due to disease progression. Patients that are deemed clinically unstable or who have biopsy proven new metastatic lesions are not required to have repeat imaging for confirmation This decision will be based on clinical judgment of a patient’s overall clinical condition, including performance status, clinical symptoms, and laboratory data. Patients must meet the following criteria for continued treatment on study after disease progression is identified at a tumor assessment: Absence of new or worsening symptoms No decline in ECOG performance status Absence of rapid progression of disease or of Absence of progressive tumor at critical anatomical sites (e.g., cord compression) requiring urgent alternative medical intervention. Quality of life (QoL) difference from baseline QoL difference will be analyzed using non-parametric methods, e.g. Mann-Whitney-Wilcoxon test
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