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 journalArticle

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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
Externally publishedYes

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Maximum Tolerated Dose
Doxorubicin
Cyclophosphamide
Cisplatin
Thymoma
Histone Deacetylase Inhibitors
T-Lymphocytes
Drug Therapy
Regulatory T-Lymphocytes
Neutropenia
Intravenous Infusions
Nausea
Disease-Free Survival
Diarrhea
Appointments and Schedules
Research Design
Pharmacokinetics
Biomarkers
Thymic epithelial tumor
Clinical Studies

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

A phase I/II trial of belinostat in combination with cisplatin, doxorubicin, and cyclophosphamide in thymic epithelial tumors : A clinical and translational study. / Thomas, Anish; Rajan, Arun; Szabo, Eva; Tomita, Yusuke; Carter, Corey A.; Scepura, Barbara; Lopez-Chavez, Ariel; Lee, Min Jung; Redon, Christophe E.; Frosch, Ari; Peer, Cody J.; Chen, Yuanbin; Piekarz, Richard; Steinberg, Seth M.; Trepel, Jane B.; Figg, William D.; Schrump, David S.; Giaccone, Giuseppe.

In: Clinical Cancer Research, Vol. 20, No. 21, 01.11.2014, p. 5392-5402.

Research output: Contribution to journalArticle

Thomas, A, Rajan, A, Szabo, E, Tomita, Y, Carter, CA, Scepura, B, Lopez-Chavez, A, Lee, MJ, Redon, CE, Frosch, A, Peer, CJ, Chen, Y, Piekarz, R, Steinberg, SM, Trepel, JB, Figg, WD, Schrump, DS & Giaccone, G 2014, '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, vol. 20, no. 21, pp. 5392-5402. https://doi.org/10.1158/1078-0432.CCR-14-0968
Thomas, Anish ; Rajan, Arun ; Szabo, Eva ; Tomita, Yusuke ; Carter, Corey A. ; Scepura, Barbara ; Lopez-Chavez, Ariel ; Lee, Min Jung ; Redon, Christophe E. ; Frosch, Ari ; Peer, Cody J. ; Chen, Yuanbin ; Piekarz, Richard ; Steinberg, Seth M. ; Trepel, Jane B. ; Figg, William D. ; Schrump, David S. ; Giaccone, Giuseppe. / A phase I/II trial of belinostat in combination with cisplatin, doxorubicin, and cyclophosphamide in thymic epithelial tumors : A clinical and translational study. In: Clinical Cancer Research. 2014 ; Vol. 20, No. 21. pp. 5392-5402.
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T1 - A phase I/II trial of belinostat in combination with cisplatin, doxorubicin, and cyclophosphamide in thymic epithelial tumors

T2 - A clinical and translational study

AU - Thomas, Anish

AU - Rajan, Arun

AU - Szabo, Eva

AU - Tomita, Yusuke

AU - Carter, Corey A.

AU - Scepura, Barbara

AU - Lopez-Chavez, Ariel

AU - Lee, Min Jung

AU - Redon, Christophe E.

AU - Frosch, Ari

AU - Peer, Cody J.

AU - Chen, Yuanbin

AU - Piekarz, Richard

AU - Steinberg, Seth M.

AU - Trepel, Jane B.

AU - Figg, William D.

AU - Schrump, David S.

AU - Giaccone, Giuseppe

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N2 - 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.

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