Update on the phase II trial and correlative studies of depsipeptide in patients with cutaneous T-cell lymphoma and relapsed peripheral T-cell lymphoma

Abstract

3028 Background: Depsipeptide, FK228 (Fujisawa Pharmaceuticals), is the first of a new generation of histone deacetylase inhibitors to demonstrate consistent clinical activity in a specific tumor type. As a result, we are currently conducting a multi-institutional phase II trial in patients with CTCL, PTCL, or other mature T cell lymphomas. Methods: This trial is accruing patients into 4 separate arms based on histology and prior therapy. Depsipeptide is administered as a 4 hr infusion on days 1, 8, and 15 of a 28 d cycle. Results: Thirty-nine patients have been enrolled. In Arm 1, comprised of patients with CTCL who had not previously received more than 2 cytotoxic chemotherapy regimens, objective responses were observed in 7 of 14 patients, including 3 patients with complete response and 4 patients with partial response, for a response rate of 50%. Duration of response ranged from 6 to continuing over 34 months. Of the 17 patients with PTCL enrolled, 4 (24%) achieved a PR lasting 9 and 12 months in 2 patients, and ongoing over 4 months in 2 patients. Overall the drug is well tolerated, with observed toxicities including nausea, vomiting, fatigue, neutropenia, thrombocytopenia, and hypocalcemia. Non-specific ST-T wave changes are noted by ECG, without changes in cardiac function. Six patients, all with objective responses, have received depsipeptide for 12 to 34 months without evidence of cumulative toxicity. Molecular endpoints have been studied in patient normal and malignant cells. Increased acetylation of histone H3 has been observed in patient samples obtained 4 hr after initiation of the depsipeptide infusion. Inductions ranging from 2 to 24-fold were observed in 19 out of 24 paired samples obtained from individual patients, with 13 patients demonstrating a greater than 4-fold induction. Changes in gene expression have also been noted. Conclusions: These results suggest that histone deacetylase inhibitors such as depsipeptide are active in patients with T cell lymphoma. All 4 arms remain open to accrual at the NCI and extramural sites. Molecular effects can be assayed in patients treated with HDIs. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Fujisawa Pharmaceutical Company