Radiation and cisplatin-based chemotherapy constitute the standard treatment for locally advanced non-small cell lung cancer (NSCLC); however the prognosis of patients unable to tolerate cisplatin is poor. Recent pre-clinical studies have demonstrated the histone deacetylase (HDAC) inhibitor, vorinostat, enhances radiosensitivity of non-small cell cancer cell lines, and offers the potential of low toxicity and a novel mechanism of efficacy. This phase I clinical trial combines a therapeutic combination of vorinostat with paclitaxel and radiation therapy (RT) for the treatment of NSCLC, in a treatment combination not previously described. This phase I trial was an open-label, dose-escalating study to establish the maximum tolerated dose of vorinostat when given with concurrent chemotherapy and radiotherapy. The first patient cohort received a starting dose of 200 mg/day, taken 5 days a week, during radiotherapy. The dose was to be increased in the following patient cohorts until the maximum tolerated dose (MTD) was reached. Patients were administered concurrent paclitaxel at a dose of 60 mg/m2 and RT at 1.8 Gy per day to a total dose of 63 Gy. Between July 2008 and September 2009, 5 patients were enrolled on this study. Four of five patients enrolled completed the planned treatment. Although most patients were able to complete the study therapy, many experienced grade 3+ toxicities. A dose-limiting toxicity triggered the expansion of the 200 mg vorinostat cohort to six patients. Due to slow accrual and significant toxicities, the investigators and the sponsor decided to close the study in July, 2010. There is a strong need to investigate better therapeutic options for patients with NSCLC who cannot receive cisplatin. This patient population is growing and should not be overlooked even though their disease process poses significant challenge for trials.
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