Journal article
A phase I/II trial of belinostat in combination with cisplatin, doxorubicin, and cyclophosphamide in thymic epithelial tumors: a clinical and translational study
Clinical cancer research, v 20(21), pp 5392-5402
01 Nov 2014
PMID: 25189481
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
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.
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.
Twenty-six patients were enrolled (thymoma, 12; thymic carcinoma, 14). Dose-limiting toxicities at 2,000 mg/m(2) 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/m(2) with chemotherapy (P, 50 mg/m(2) on day 2; A, 25 mg/m(2) on days 2 and 3; C, 500 mg/m(2) 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).
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.
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Details
- Title
- A phase I/II trial of belinostat in combination with cisplatin, doxorubicin, and cyclophosphamide in thymic epithelial tumors: a clinical and translational study
- Creators
- Anish Thomas - National Cancer InstituteArun Rajan - National Cancer InstituteEva Szabo - National Cancer InstituteYusuke Tomita - National Cancer InstituteCorey A Carter - Walter Reed National Military Medical CenterBarbara Scepura - National Cancer InstituteAriel Lopez-Chavez - National Cancer InstituteMin-Jung Lee - National Cancer InstituteChristophe E Redon - National Cancer InstituteAri Frosch - National Cancer InstituteCody J Peer - National Cancer InstituteYuanbin Chen - National Cancer InstituteRichard Piekarz - National Cancer InstituteSeth M Steinberg - National Cancer InstituteJane B Trepel - National Cancer InstituteWilliam D Figg - National Cancer InstituteDavid S Schrump - National Cancer InstituteGiuseppe Giaccone - National Cancer Institute
- Publication Details
- Clinical cancer research, v 20(21), pp 5392-5402
- Grant note
- Z01 BC010854 / Intramural NIH HHS
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- General Internal Medicine
- Web of Science ID
- WOS:000344759100009
- Scopus ID
- 2-s2.0-84908689205
- Other Identifier
- 991022060044104721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Oncology