Clinical Development of MGCD0103, An Isotype-Selective HDAC Inhibitor: Pericarditis/Pericardial Effusion in the Context of Overall Safety and Efficacy.

MGCD0103 is a potent small molecule histone deacetylase (HDAC) inhibitor that inhibits Class I and IV HDACs involved in human cancers. MGCD0103 is being developed as an anticancer therapeutic and has been evaluated in 437 patients with solid tumors and hematologic malignancies in 13 clinical trials. To date, MGCD0103 has shown evidence of single agent activity in individual studies of patients with Hodgkin lymphoma (HL) (RR=33%), diffuse large B cell lymphoma (RR=17%), follicular lymphoma (RR=11%) and acute myelogenous leukemia (AML)/high-risk myelodysplastic syndrome (MDS), as well as in combination with azacitidine in AML and MDS patients (RR=36%) and in combination with gemcitabine in pancreatic cancer patients. The most frequent drug-related grade 3/4 adverse events (AE) occurring in at least 5% of patients were: fatigue (23%), neutropenia (14%) thrombocytopenia (14%), anemia (9%), nausea (8%), febrile neutropenia (7%), vomiting (5%), and anorexia (5%). New enrollment into all MGCD0103 studies was voluntarily suspended for an investigation of a possible association of MGCD0103 with pericarditis/pericardial effusion, while the ongoing patients remained on treatment provided there were no pericardial findings.

All patients who experienced a pericardial serious AE (SAE) were identified across the trials. The frequency, nature and severity of these SAEs as well as the potential associated risks were evaluated.

Of the 437 patients treated with MGCD0103, there were 19 patients (4.3%) with an SAE where one of the listed terms involved the pericardium. Patients with HL were more likely (9.5%) to experience a pericardial SAE as compared to other diagnoses, while patients with solid tumors had an incidence of only 0.9%. Of the 19 patients with a pericardial SAE, 8 had cardiac tamponade. A majority of pericardial SAEs (14) occurred during Cycle 1 of treatment, however the nature of presentations suggested a non-acute process. Interventions included pericardial window (6), and pericardiocentesis ± drain (8), antiinflammatory agents (5), and antibacterial agents (3). The majority of pericardial SAEs resolved without sequelae (14) and no pericardial event was considered fatal. There were no clear relationships with the starting dose level, exposure, cumulative dose, drug lots, prior history of chest pain/arrhythmia or other cardiac diseases, prior therapies, prior mediastinal or thoracic radiotherapy, presence of mediastinal lesions, pharmacodynamic markers of HDAC activity or inflammation, low albumin levels at baseline, pneumonia, sepsis, or infection. Trends were seen with some variables. Statistically significant associations with pericardial events were found with patients who had a history of pericardial disease, presence of lung lesions, and on-study reports of chest pain or pleural effusion.

Based on the literature and Investigator-driven preliminary reviews, rates of pericardial findings can vary from 3% to approximately 40% in patients with advanced cancers who may have received multiple previous anticancer therapies. Very recent literature indicates that, in leukemias, most pericardial effusions occur after some therapy. However, no chemotherapeutic class, including HDAC inhibitors, appears to be directly related to causing more severe pericardial effusions. While the role of MGCD0103 in pericarditis/pericardial effusion cannot be ruled out, numerous confounding factors make the interpretation uncertain. Implementation of careful safety monitoring will allow safe treatment and prompt intervention for this very treatable condition in the rare instances of significant of pericarditis/pericardial effusion. Considering that the exploratory trials have indicated therapeutic activity, continued clinical development of MGCD0103 is warranted.

Martell:MethylGene Inc: Consultancy, Employment, Equity Ownership. Off Label Use: MGCD0103 is a drug under development for treatment of hematologic malignancies. It is not yet approved.. Younes:MethylGene: Honoraria, Research Funding. Ewer:MethylGene: Consultancy. Drouin:MethylGene: Employment, Equity Ownership. Hunt:MethylGene Inc: Consultancy. Lortie:MethylGene Inc: Employment. Wilhelm:MethylGene: Employment. Besterman:MethylGene Inc: Employment, Equity Ownership, Patents & Royalties.