5554 Background: RAI-refractory thyroid cancer carries a poor prognosis, and no effective systemic therapy exists. DEP is a potent histone deacetylase inhibitor with broad in vitro and phase I anti-tumor activity, and has restored sodium-iodide symporter expression and RAI avidity in thyroid cancer cell lines.
METHODS
Eligible pts have confirmed papillary, follicular, or Hürthle cell carcinoma, progressive measurable disease, and adequate hepatic/renal function. All pts are RAI-refractory by diagnostic RAI whole body scan (WBS). Prior chemotherapy in the recurrent/metastatic setting, and history of significant cardiac disease are exclusions. DEP 13 mg/m2 IV is given on day 1, 8, and 15, every 28 days. A novel Simon 2-stage design specifies an initial accrual of 21 pts, with expansion to 41 total pts if 2 RECIST responses or 6 pts with PFS at 6 months are observed. Primary outcome is RECIST response rate. Change in RAI avidity (by diagnostic RAI WBS) is a secondary outcome.
RESULTS
To date, 14 pts have been enrolled: female 50%, median age 62 (42-78), median Karnofsky 90 (70-100), papillary/follicular/Hürthle histology (7/1/6). Grade 3-5 toxicities possibly related to drug: grade 5 sudden death (1); no grade 4 toxicity; grade 3 toxicity - fatigue (1), dysphagia (1), dyspnea (1). No grade 3 thrombocytopenia (phase I DLT) has been observed. Grade 1 (6) and grade 2 (4) fatigue have been common. As a result of the grade 5 event, protocol accrual and treatment were suspended temporarily. After NCI-CTEP review, more restrictive cardiac exclusions were added and protocol accrual was resumed. Response at 2 months: stable disease (4); progression (2); inevaluable (6, due to protocol suspension); withdrew consent (1); too early (1). In a proof-of-principle event, clinically significant restoration of RAI avidity was observed in a 78 year-old woman with papillary carcinoma. Per protocol, she was taken off study and given treatment-dose RAI; post-therapy WBS confirmed dramatic RAI avidity.
CONCLUSIONS
Preliminary signs of in vivo reversal of RAI resistance have been observed. Accrual continues with more restrictive cardiac exclusions, and close surveillance for cardiac events. No significant financial relationships to disclose.