Phase I trial of romidepsin, a histone deacetylase inhibitor, given on days one, three and five in patients with thyroid and other advanced cancers

Abstract

3571 Background: Romidepsin (FK228 or depsipeptide) is a potent histone deacetylase inhibitor (HDI) with cytotoxic activity in preclinical models and significant activity in patients with cutaneous and peripheral T-cell lymphoma. As responses have been infrequently observed in solid tumors it is important to test HDIs in combination therapy. One strategy is to use HDIs to induce expression of genes that can be targeted therapeutically. Metastatic thyroid cancer refractory to RAI offers one such opportunity. In vitro, HDIs restore expression of the sodium iodine symporter in refractory cells and sensitivity to RAI. Methods: We initiated a phase I trial of romidepsin in a new schedule, administered on days 1, 3 and 5 with the goal of enhancing gene expression and evaluating RAI uptake in patients with RAI-refractory thyroid cancer. Results: We have completed the dose escalation stage of the protocol with 26 patients with solid tumors enrolled, including 9 patients with thyroid cancer. Doses tested were 1, 2, 3.3, 5, 7, 9 mg/m2. Patients received a median of 2.5 cycles (1–24); those with thyroid cancer a median of 8 (range 1–24). Twelve of 19 patients treated on the first 5 dose levels tolerated drug well enough to have the dose escalated. Two patients experienced DLTs, one patient with pulmonary metastasis at the 2 mg/m2 experienced worsening hypoxia associated with atrial fibrillation and another at 9 mg/m2 had refractory grade 3 nausea and vomiting. No grade 4 toxicities were observed. Grade 3 toxicities included leucopenia (2), lymphopenia (4), granulocytopenia (2), thrombocytopenia (2), anorexia (4), nausea (3), and vomiting (2). Based on observed toxicities, we concluded that 9 mg/m2 represented the MTD on this schedule. Eleven patients had stable disease, median 28 wks; 6 with thyroid cancer, median 33 wks. Four patients with RAI refractory thyroid cancer have undergone follow up diagnostic RAI scans; none had increased RAI uptake. Evaluation of histone acetylation in PBMCs demonstrated a greater than 2-fold increase even at dose levels well below the MTD. Conclusions: The MTD was reached on a new schedule of romidepsin administered on days 1, 3, and 5; this protocol is now exclusively evaluating patients with non-medullary thyroid cancer. No significant financial relationships to disclose.