A phase I/II trial of belinostat in combination with cisplatin, doxorubicin, and cyclophosphamide in thymic epithelial tumors: A clinical and translational study

Anish Thomas, Arun Rajan, Eva Szabo, Yusuke Tomita, Corey A. Carter, Barbara Scepura, Ariel Lopez-Chavez, Min Jung Lee, Christophe E. Redon, Ari Frosch, Cody J. Peer, Yuanbin Chen, Richard Piekarz, Seth M. Steinberg, Jane B. Trepel, William D. Figg, David S. Schrump, Giuseppe Giaccone

Research output: Contribution to journalArticlepeer-review

51 Scopus citations

Abstract

Purpose: This phase I/II study sought to determine the safety and maximum tolerated dose (MTD) of a novel schedule of belinostat, a histone deacetylase inhibitor (HDAC) administered before and in combination with cisplatin (P), doxorubicin (A), and cyclophosphamide (C) in thymic epithelial tumors (TET). Antitumor activity, pharmacokinetics, and biomarkers of response were also assessed. Experimental Design: Patients with advanced, unresectable TET received increasing doses of belinostat as a continuous intravenous infusion over 48 hours with chemotherapy in 3-week cycles. In phase II, belinostat at the MTD was used. Results: Twenty-six patients were enrolled (thymoma, 12; thymic carcinoma, 14). Dose-limiting toxicities at 2,000 mg/m2 belinostat were grade 3 nausea and diarrhea and grade 4 neutropenia and thrombocytopenia, respectively, in two patients. Twenty-four patients were treated at the MTD of 1,000 mg/m2 with chemotherapy (P, 50 mg/m2 on day 2; A, 25 mg/m2 on days 2 and 3; C, 500 mg/m2 on day 3). Objective response rates in thymoma and thymic carcinoma were 64% (95% confidence interval, 30.8%-89.1%) and 21% (4.7%-50.8%), respectively. Modulation of pharmacodynamic markers of HDAC inhibition and declines in regulatory T cell (Treg) and exhausted CD8+ T-cell populations were observed. Decline in Tregs was associated with response (P = 0.0041) and progression-free survival (P = 0.021). Declines in TIM3+ CD8+ T cells were larger in responders than nonresponders (P = 0.049). Conclusion: This study identified the MTD of belinostat in combination with PAC and indicates that the combination is active and feasible in TETs. Immunomodulatory effects on Tregs and TIM3+ CD8+ T cells warrant further study.

Original languageEnglish (US)
Pages (from-to)5392-5402
Number of pages11
JournalClinical Cancer Research
Volume20
Issue number21
DOIs
StatePublished - Nov 1 2014

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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