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/m2 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.

Thyroid cancer: pathogenesis and targeted therapy

“…It was studied in 20 patients with radioiodinerefractory DTC (PTC, n ¼ 8; FTC, n ¼ 1; HTC, n ¼ 11) in a phase II study administered at a dose of 13 mg/m 2 intravenously on days 1, 8, and 15 every 28 days. Two patients (10%) demonstrated restoration of radioiodine reuptake [Sherman et al 2009]. No radiographic objective responses were documented.…”

Solid Tumor Differentiation Therapy - Is It Possible?

“…This trial also evaluated the ability of depsipeptide to promote differentiation via assessment of increased RAI avidity in these tumors. Importantly, in a proof of principle event, clinically observed differentiation of thyroid tumor cells was observed with significant restoration of RAI avidity in two patients [ 56 ].…”

Diagnostic and Prognostic Markers in Differentiated Thyroid Cancer

“…Epigenetic changes in tumor-promoting and tumor-suppressor genes also contribute to the dysregulation of thyrocyte growth and other aspects of tumorigenesis, such as apoptosis, motility and invasiveness [ 57 , 78 ]. Progress in the field of thyroid cancer genetics has produced a novel class of drugs known as ‘targeted therapeutics’, which act selectively on cancer cells harboring particular genetic aberrations [ 78 ], and these agents are undergoing clinical testing for the treatment of aggressive thyroid carcinomas [ 79 ]. The differentiation and proliferation properties of thyroid cancer cells are also strongly influenced by epigenetic alterations [ 80 ], which are thought to be equally, if not more, important than mutational events in the generation and progression of human cancer [ 81 ].…”

“…Preclinical studies have furnished convincing evidence that deacetylation inhibitors and demethylating agents are beneficial in the treatment of thyroid cancer, and these drugs are now being tested against metastatic radioiodine-refractory thyroid carcinomas. Despite promising phase-I results, however, histone deacetylases treatment of 16 patients with differentiated thyroid carcinoma produced no partial or complete responses that met response evaluation criteria in solid tumors [ 79 ] and in a phase-II study, i.v. injection of depsipeptide restored radioiodine avidity in 2 of the 20 patients treated, but there were no objective responses even after 131I treatment [ 79 ].…”

“…Despite promising phase-I results, however, histone deacetylases treatment of 16 patients with differentiated thyroid carcinoma produced no partial or complete responses that met response evaluation criteria in solid tumors [ 79 ] and in a phase-II study, i.v. injection of depsipeptide restored radioiodine avidity in 2 of the 20 patients treated, but there were no objective responses even after 131I treatment [ 79 ]. In light of these preliminary data, epigenetic strategies seem far less promising than approaches that target protein kinases.…”