HDAC inhibitors are a new class of anti-cancer agents and are being evaluated for the treatment of a variety of malignancies. Malignant mesothelioma is a refractory neoplasm that does not have any proven treatment options for progressive disease following combination chemotherapy with cisplatin and pemetrexed. The outcome for these patients is poor and is therefore an unmet medical need. The promising single agent activity noted with vorinostat in this setting prompted our phase II study to evaluate the anti-cancer activity of belinostat, another novel HDAC inhibitor, for second line therapy of malignant mesothelioma. Our study failed to note objective tumor response in any of the 13 patients enrolled to the first stage of accrual and was therefore closed for lack of efficacy. Encouraging disease stabilization was noted in two patients who received therapy for 4 and 6 cycles respectively. Belinostat was tolerated well at the dose and schedule used for the study. Some of the common adverse events noted in our study such as anemia, hyperglycemia and hyponatremia have all been documented with the use of belinostat. Three patients had supraventricular tachycardia during the course of the study. While this toxicity has also been reported with the use of belinostat, other factors such as hypoxia, concomitant medications and prior cardiac disease could have also been the causal factors.
Since the time of initiation of our study, new data have become available with HDAC inhibitor monotherapy in various solid organ tumors. In a phase II study for patients with metastatic breast cancer, vorinostat was not associated with single agent activity (personal communication, Luu et al). Similarly, in a study for patients with advanced head and neck cancer, no confirmed responses were noted in a cohort of 12 patients who were treated with vorinostat as monotherapy 19
. Vorinostat also failed to demonstrate single agent activity in 14 patients with advanced stage non-small cell lung cancer that had progressed following standard treatment options 20
. Taken together, these results demonstrate that HDAC inhibitors are not active as monotherapy in the treatment of solid tumors.
Despite this, certain aspects of belinostat and our study patient characteristics warrant further mention as potential reasons behind the negative results of our study. Our study included a patient group with aggressive disease as evidenced by the fact that half the patients had progressive disease within 1 month of initiation of study treatment. The biological aggressiveness of the disease could have rendered this patient population to be resistant to any therapy. Furthermore, vorinostat and other HDAC inhibitors that are administered orally are being given on a continuous daily schedule as monotherapy. Belinostat is an intravenously administered agent and has been developed on an intermittent schedule (5 continuous days of therapy every 3 weeks). Pharmacodynamic modulation of the targets with belinostat has been documented to last for approximately 24 hours after exposure to the drug 15
. Therefore, under the current schedule, the tumors are exposed to the drug for only a third of the duration of each treatment cycle. This could also have contributed to the lack of efficacy noted with belinostat in our study. An oral formulation of the agent is under development and will be conducive for continuous administration in future studies.
Though inactive as monotherapy, HDAC inhibitors have demonstrated promising activity when given in combination with cytotoxic or other targeted agents. In a phase I study, the combination of vorinostat with carboplatin and paclitaxel resulted in robust anti-cancer activity in patients with advanced NSCLC. An ongoing randomized phase II/III study will evaluate if the addition of vorinostat improves the survival of NSCLC patients treated with carboplatin and paclitaxel. Belinostat has also demonstrated promising activity in combination with carboplatin and paclitaxel in solid tumors. A randomized clinical trial is currently underway for patients with carcinoma of unknown primary to determine if the addition of belinostat to carboplatin and paclitaxel results in improved survival.
Our study included collection of archived tumor tissues to evaluate for potential biomarker evaluation. However, the planned exploratory studies were not conducted in light of the lack of single agent activity. Sequential pre- and post-treatment biopsies could have been helpful to establish if the experimental agent effected the changes on target protein as anticipated.
In summary, belinostat is not active as monotherapy when given on the present schedule for second line therapy of malignant pleural mesothelioma. Further studies should evaluate novel combinations of HDAC inhibitors with either cytotoxic agents or other molecularly targeted agents for the treatment of this disease.