Phase II study of depsipeptide (DEP) in radioiodine (RAI)-refractory metastatic nonmedullary thyroid carcinoma

Abstract

6059 Background: Historically, systemic therapy for radioactive iodine (RAI)-refractory thyroid cancer has been understudied. Available drugs have modest efficacy. Depsipeptide (DEP) is a histone deacetylase inhibitor with potent anti-tumor effects both in vitro and in vivo. In thyroid cancer cell lines, DEP increases expression of both thyroglobulin and the sodium/iodine symporter messenger RNAs, offering the possibility of improved iodine concentrating ability of radioactive iodine (RAI)-resistant tumors. Methods: Eligible patients (pts) must have progressive, RAI-refractory, recurrent/metastatic, non-medullary, non-anaplastic thyroid cancer; RECIST measurable disease; and adequate organ/marrow function. Exclusionary criteria include prior chemotherapy in the recurrent/metastatic setting; cardiac disease or dysfunction; QTc prolongation or co-administration of drugs that prolong the QTc. DEP 13 mg/m 2 IV is administered on days 1, 8, 15, every 28 days. The primary endpoint is response rate by RECIST criteria; change in RAI avidity is a secondary endpoint. The study closed early due to poor accrual after an unexpected grade 5 adverse event (AE) that prompted protocol suspension. Results: 20 pts were enrolled: female-50%; median age-64 years; histology-papillary (8)/follicular (1)/Hürthle (11). Grade 4–5 AE possibly related to drug: grade 5 sudden death (1); grade 4 -pulmonary embolus (1). Twelve of 20 subjects had a reported AE. No RECIST major responses have been seen. Evaluation of response: stable disease (10); progression (3); early death (1); unknown/inevaluable (6: 5 - temporary protocol suspension; 1 - withdrew consent). Restoration of RAI avidity was documented in 2 pts. For evaluable patients (14) only, median overall survival and time on study was 36 (.5–45+) months and 1.7 (0.46–12) months, respectively. Conclusions: We observed preliminary signs of in vivo reversal of RAI resistance after treatment with DEP. However, no major responses were observed and accrual was poor after the grade 5 AE. (Study funded by grant N01 CM 62206) No significant financial relationships to disclose.