Background: 17-allylaminogeldanamycin (17-AAG) is a benzoquinone ansamycin antibiotic that destabilizes heat shock protein 90 (HSP-90) complexes, including RET and multiple cancer-involved proteins. 17-AAG promotes apoptosis and down-regulates RET in thyroid cancer cell lines. Methods: Two one-stage phase II clinical trials were conducted to assess whether the 1 year (yr) treatment failure-free (TFF) rate with 17-AAG was at least 20% in patients (pts) with locoregionally advanced/metastatic MTC or in pts with DTC. Eligibility criteria included: measurable disease by RECIST criteria; ECOG status 0-2; adequate laboratory values, no significant cardiac disease, and no active CNS metastases. 17-AAG dosing was 220 mg/m² IV over 2 hours (days 1, 4, 8, and 11 of a 21-day cycle). Treatment was discontinued for disease progression, unacceptable toxicity or refusal. If 4 or more of 33 pts in a given cohort remained on treatment at 1 yr, 17-AAG would be considered promising in that cohort. Both trials were discontinued due to slow accrual. Results: 41 pts were enrolled (Table). All pts were followed until death or a minimum of 13 months. The median number of cycles administered was 7 for MTC and 4 for DTC. Severe (≥grade 3) toxicities possibly related to treatment occurred in 4 MTC pts and 9 DTC pts, the most common being grade 3 AST/ALT elevations. Reasons for discontinuation were: disease progression (MTC:10; DTC:8); refusal (MTC:4; DTC:2); toxicity (MTC:2; DTC:3); desire for surgery (DTC:1); or death (MTC:1). 1 MTC and 3 DTC completed one year of treatment. 1 MTC pt had a partial response. 15 pts (10 DTC) died within one year of entry. Conclusions: 17-AAG appears to have only modest single agent activity in advanced MTC and DTC. Supported by NCI N01-CM62205.