Panobinostat, a novel histone deacetylase inhibitor, in advanced medullary and iodine-refractory differentiated thyroid cancer: A Wisconsin Oncology Network trial.

Abstract

e17025 Background: Histone deacetylase (HDAC) inhibitors suppress tumor cell proliferation in medullary thyroid cancer (MTC) and differentiated thyroid cancer (DTC) in vivo. We conducted a multicenter single arm phase II trial of panobinostat, a potent inhibitor of Class I, II, and IV HDAC enzymes, in MTC and radioactive iodine (RAI)-refractory DTC. Methods: We enrolled 13 patients (pts) with progressive metastatic MTC or RAI-refractory DTC. Panobinostat was given at 20 mg orally TIW until disease progression or intolerable toxicities. The primary objective was anti-tumor response rate; secondary objectives included overall survival (OS), progression-free survival (PFS), tolerability, and changes in serum thyroglobulin (Tg) concentration. Results: Mean age was 61±13 yrs; 7 pts were female. 11 pts had DTC; 2 had MTC. Median study follow-up was 11.8 months (mos). 9 pts required dose holds/reductions due to thrombocytopenia (n=7), hypocalcemia (n=3), neutropenia (n=2), diarrhea (n=1), bone pain (n=1), or asthenia (n=1). Due to protocol specified rules, 2 pts were withdrawn from therapy with thrombocytopenia or neutropenia, both asymptomatic. Of the 3 pts with ≥ grade 3 thrombocytopenia, 2 had no bleeding. The third pt continued to bleed from her chronically erosive tumor without exacerbation. Median duration of treatment was 2.1 mos (range, 0.8-11.8). Stable disease (SD) was seen in 7 pts, with a median duration of 5.8 mos (range,1.8-13.8). All 7 SD pts are currently alive, including 2 with SD 4.9 mo and 11.8 mo on treatment. Progressive disease (PD) occurred, and was the cause of death, in 6 pts.No anti-tumor responses were observed. Median PFS for the 13 pts was 3.6 mos (95% CI, 1.8-5.8), with 2 pts having a PFS longer than 6 mos.Median OS for the 13 pts was 18.4 mos (95% CI, 5.8-not estimable). 5 of 11 pts had reductions of their serum Tg on study; however, changes in serial Tg values did not distinguish PD from SD pts. Conclusions: 20 mg TIW was not tolerated by most pts. However, dose modified treatment yielded SD in half of our previously progressing pts. This promising disease stabilization warrants further evaluation, possibly in combination with a VEGFR TKI. Clinical trial information: NCT01013597.