Published OnlineFirst September 4, 2014; DOI: 10.1158/1078-0432.CCR-14-0968 Clinical Cancer Cancer Therapy: Clinical Research A Phase I/II Trial of Belinostat in Combination with Cisplatin, Doxorubicin, and Cyclophosphamide in Thymic Epithelial Tumors: A Clinical and Translational Study Anish Thomas1, Arun Rajan1, Eva Szabo2, Yusuke Tomita1, Corey A. Carter3, Barbara Scepura1, Ariel Lopez-Chavez1, Min-Jung Lee1, Christophe E. Redon4, Ari Frosch1, Cody J. Peer1, Yuanbin Chen1, Richard Piekarz5, Seth M. Steinberg6, Jane B. Trepel1, William D. Figg1, David S. Schrump7, and Giuseppe Giaccone1 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 combi- nation 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 chemo- therapy (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 þ regulatory T cell (Treg) and exhausted CD8 T-cell populations were observed. Decline in Tregs was associated þ þ with response (P ¼ 0.0041) and progression-free survival (P ¼ 0.021). Declines in TIM3 CD8 T cells were larger in responders than nonresponders (P ¼ 0.049). Conclusion: This study identified the MTD of belinostat in combination with PAC and indicates that the þ þ combination is active and feasible in TETs. Immunomodulatory effects on Tregs and TIM3 CD8 T cells warrant further study. Clin Cancer Res; 20(21); 5392–402. Ó2014 AACR. Introduction United States (1). Depending on morphology and atypia Thymic epithelial tumors (TET) are rare malignancies of the neoplastic epithelial cells and their relative pro- with an incidence of 0.13 per 100,000 person-years in the portion compared with lymphocytes, the World Health Organization (WHO) classification groups TETs into a continuum of tumors with increasing degrees of aggres- 1Medical Oncology Branch, National Cancer Institute, NIH, Bethesda, siveness:typesA,AB,B1,B2,B3,andC,thelatteralso Maryland. 2Division of Cancer Prevention, National Cancer Institute, NIH, Bethesda, Maryland. 3Department of Hematology and Oncology, Walter referred to as thymic carcinoma (2). The WHO classifi- Reed National Military Medical Center, Bethesda, Maryland. 4Laboratory of cation and the Masaoka staging system (3), which takes Molecular Pharmacology, National Cancer Institute, NIH, Bethesda, Mary- into account the integrity of the thymic capsule, degree of land. 5Cancer Therapy Evaluation Program, National Cancer Institute, NIH, Bethesda, Maryland. 6Biostatistics and Data Management Section, local tumor invasion, and presence of distant metastases National Cancer Institute, NIH, Bethesda, Maryland. 7Thoracic Surgery are useful predictors of the biologic behavior and prog- Section, Thoracic and Gastrointestinal Oncology Branch, National Cancer nosis of TETs. Type A thymoma has an excellent overall Institute, NIH, Bethesda, Maryland. survival (OS) rate of more than 95% at 10 years, whereas Note: Supplementary data for this article are available at Clinical Cancer the 5-year survival for types B2, B3, and thymic carcinoma Research Online (http://clincancerres.aacrjournals.org/). are 75%, 70%, and 48%, respectively (4). Thymic carci- Corresponding Author: Giuseppe Giaccone, Lombardi Cancer Center, Georgetown University, Research Building Room W503, 3970 Reservoir nomas account for less than 1% of TETs and display a Road NW, Washington, DC 20057. Phone: 202-687-7072; Fax: 202-687- more aggressive phenotype with higher likelihood of 0313; E-mail: [email protected] distant metastases than thymomas (5). doi: 10.1158/1078-0432.CCR-14-0968 Chemotherapy is used in patients with unresectable Ó2014 American Association for Cancer Research. or recurrent disease. Several regimens have been used, but 5392 Clin Cancer Res; 20(21) November 1, 2014 Downloaded from clincancerres.aacrjournals.org on September 24, 2021. © 2014 American Association for Cancer Research. Published OnlineFirst September 4, 2014; DOI: 10.1158/1078-0432.CCR-14-0968 Belinostat plus Chemotherapy for Thymic Epithelial Tumors had stable disease (SD), but no responses were seen in Translational Relevance patients with thymic carcinoma. Median times to progres- Belinostat is a histone deacetylase (HDAC) inhibitor sion and OS were 5.8 and 19.1 months, respectively, in the that inhibits both HDAC class I and II enzymes in overall population. nanomolar concentrations in vitro. Belinostat’s antitu- Belinostat has been shown to potentiate the antitumor mor activity is documented in previously treated patients activity of platinum-containing agents in vitro (12). Poten- with thymoma with minimal toxicity. In preclinical tiation of chemotherapy by HDAC inhibition is likely studies, belinostat potentiated antitumor activity of plat- secondary to altered gene expression patterns allowing inum-containing chemotherapy. In this phase I/II trial, increased chemotherapy sensitivity (13). Chromatin decon- belinostat was administered as a continuous intravenous densation could also facilitate increased access to DNA- infusion before and in combination with cisplatin, damaging agents and target drug-tolerant subpopulations doxorubicin, and cyclophosphamide (PAC) treatment which evolve via an altered chromatin state in response to in patients with advanced or recurrent thymic epithelial stressful exposures such as chemotherapy (14). tumors (TET). This trial identified the maximum toler- Here, we report results of a phase I/II study of belinostat ated dose (MTD) of belinostat in combination with PAC in combination with PAC in the first-line treatment of and demonstrated that the combination is active and advanced or recurrent TETs. We also evaluated the phar- feasible in TETs. Modulation of pharmacodynamic mar- macokinetics of belinostat when administered with chemo- kers of HDAC inhibition and declines in regulatory T cell þ therapy and pharmacodynamic effects in peripheral blood. (Treg) and exhausted CD8 T-cell populations were þ observed with belinostat. Declines in Tregs and TIM3 þ CD8 T cells were associated with responses. The immu- Materials and Methods nomodulatory effects of this novel schedule of belinostat Patients administration need further evaluation. Eligible patients were those more than 18 years of age with histologically confirmed advanced (Masaoka stage III or IV) TETs who had not received prior systemic therapy for advanced disease with Eastern Cooperative Oncology a combination of cisplatin, doxorubicin, and cyclophos- Group (ECOG) performance status score 0 or 1, life expec- phamide (PAC) is one of the most commonly used regi- tancy more than 3 months, and adequate organ function. mens (5, 6). In a phase II trial of 30 patients among Patients at increased cardiac risk were excluded, including whom only one patient had thymic carcinoma, this those with unstable angina, myocardial infarction within combination resulted in an objective response rate (ORR) the previous 12 months, baseline prolongation of QT/QTc of 50% (7). The median duration of response (DOR) and interval as demonstrated by repeated QTc interval > 500 ms OS were 12 and 38 months, respectively. Largely due to and long QT syndrome. Other exclusion criteria included: the rarity of the disease, there are no randomized control resectable disease, untreated brain metastases, radiotherapy trials comparing chemotherapies (5). or chemotherapy within 3 weeks before study drug admin- Acetylation and deacetylation of histones, the protein istration, or positive serology for HIV. component of the nucleosome core particle, play an impor- The study was approved by the National Cancer Institute tant role in the regulation of gene expression. The inhibition Institutional Review Board. The study was overseen by a of histone deacetylase (HDAC) enzymes by HDAC inhibi- Safety Monitoring Committee. All patients provided written tors (HDACi) shifts the dynamic equilibrium between the informed consent to participate in the study before under- deacetylation activity of HDACs, which has been associated going any study-related procedures. This trial was registered with gene silencing, and the acetylation activity of histone with ClinicalTrials.gov with the identifier NCT01100944. acetyltransferases (HAT), which has been associated with chromatin decondensation and gene expression. In partic- Study design ular, HDACi have been reported to induce the expression of Patients received 250 or 500 mg/m2 of belinostat via genes suppressing the malignant phenotype and have dem- 4 consecutive 12-hour continuous intravenous infusions onstrated promising anticancer activity against a variety of (CIVI)