Andrea B Apolo1, Fatima H Karzai2, Jane B Trepel3, Sylvia Alarcon3, Sunmin Lee3, Min-Jung Lee3, Yusuke Tomita3, Liang Cao4, Yunkai Yu4, Maria J Merino5, Ravi A Madan2, Howard L Parnes2, Seth M Steinberg6, Beatriz Walter Rodriguez5, Ben K Seon7, James L Gulley2, Philip M Arlen2, Nancy A Dawson8, William D Figg2, William L Dahut2. 1. Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD. Electronic address: andrea.apolo@nih.gov. 2. Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD. 3. Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD. 4. Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD. 5. Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD. 6. Biostatistics and Data Management Section, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD. 7. Roswell Park Cancer Institute, Buffalo, NY. 8. Medstar Georgetown University Hospital, Lombardi Comprehensive Cancer Center, Washington, DC.
Abstract
BACKGROUND: In this trial we assessed the efficacy and tolerability of TRC105, a chimeric monoclonal antibody that targets CD105 (endoglin) in patients with advanced, previously treated urothelial carcinoma (UC). PATIENTS AND METHODS: Patients received TRC105 15 mg/kg every 2 weeks on days 1 and 15 of each 28-day cycle. The primary end point was progression-free survival (PFS) at 6 months. Secondary end points included safety, toxicity, and overall survival (OS). CD105 expression was evaluated using immunohistochemistry (IHC) in a separate cohort of 50 UC patients. Biomarker studies included immune subsets, circulating tumor cells (CTCs), circulating endothelial cells (CECs), circulating endothelial progenitor cells (CEPs), and osteopontin. RESULTS: Of 13 patients enrolled, 12 were evaluable for OS and PFS. The 3-month PFS probability was 18.2% (median PFS, 1.9 months [95% confidence interval (CI), 1.8-2.1 months). This met the criterion for ending accrual on the basis of the 2-stage design. Median OS was 8.3 months (95% CI, 3.3-17.0 months). IHC for CD105 scores was not associated with T stage (P = .26) or presence of lymph nodes (P = .64). Baseline levels of regulatory T and B cells, CEPs, and changes in CEC level after TRC105 exhibited trends toward an association with PFS or OS. CTCs pre- and post-TRC105 were detected in 4 of 4 patients. CONCLUSION: Although TRC105 was well tolerated, it did not improve 6-month PFS in heavily pretreated patients with advanced UC. CD105 staining was present in 50% of UC tumors at different intensities. Our observations on the pharmacodynamic significance of immune subsets, CECs, and CTCs warrant further study.
BACKGROUND: In this trial we assessed the efficacy and tolerability of TRC105, a chimeric monoclonal antibody that targets CD105 (endoglin) in patients with advanced, previously treated urothelial carcinoma (UC). PATIENTS AND METHODS: Patients received TRC105 15 mg/kg every 2 weeks on days 1 and 15 of each 28-day cycle. The primary end point was progression-free survival (PFS) at 6 months. Secondary end points included safety, toxicity, and overall survival (OS). CD105 expression was evaluated using immunohistochemistry (IHC) in a separate cohort of 50 UC patients. Biomarker studies included immune subsets, circulating tumor cells (CTCs), circulating endothelial cells (CECs), circulating endothelial progenitor cells (CEPs), and osteopontin. RESULTS: Of 13 patients enrolled, 12 were evaluable for OS and PFS. The 3-month PFS probability was 18.2% (median PFS, 1.9 months [95% confidence interval (CI), 1.8-2.1 months). This met the criterion for ending accrual on the basis of the 2-stage design. Median OS was 8.3 months (95% CI, 3.3-17.0 months). IHC for CD105 scores was not associated with T stage (P = .26) or presence of lymph nodes (P = .64). Baseline levels of regulatory T and B cells, CEPs, and changes in CEC level after TRC105 exhibited trends toward an association with PFS or OS. CTCs pre- and post-TRC105 were detected in 4 of 4 patients. CONCLUSION: Although TRC105 was well tolerated, it did not improve 6-month PFS in heavily pretreated patients with advanced UC. CD105 staining was present in 50% of UC tumors at different intensities. Our observations on the pharmacodynamic significance of immune subsets, CECs, and CTCs warrant further study.
Authors: Andrea B Apolo; Rosa Nadal; Yusuke Tomita; Nicole N Davarpanah; Lisa M Cordes; Seth M Steinberg; Liang Cao; Howard L Parnes; Rene Costello; Maria J Merino; Les R Folio; Liza Lindenberg; Mark Raffeld; Jeffrey Lin; Min-Jung Lee; Sunmin Lee; Sylvia V Alarcon; Akira Yuno; Nancy A Dawson; Kimaada Allette; Arpita Roy; Dinuka De Silva; Molly M Lee; Tristan M Sissung; William D Figg; Piyush K Agarwal; John J Wright; Yangmin M Ning; James L Gulley; William L Dahut; Donald P Bottaro; Jane B Trepel Journal: Lancet Oncol Date: 2020-07-06 Impact factor: 41.316
Authors: Keina M C Dourado; June Baik; Vanessa K P Oliveira; Miriam Beltrame; Ami Yamamoto; Charles P Theuer; Camila A V Figueiredo; Michael R Verneris; Rita C R Perlingeiro Journal: Blood Date: 2017-03-28 Impact factor: 22.113
Authors: Yonghua Zhan; Sixiang Shi; Emily B Ehlerding; Stephen A Graves; Shreya Goel; Jonathan W Engle; Jimin Liang; Jie Tian; Weibo Cai Journal: ACS Appl Mater Interfaces Date: 2017-10-24 Impact factor: 9.229
Authors: Fatima Karzai; David VanderWeele; Ravi A Madan; Helen Owens; Lisa M Cordes; Amy Hankin; Anna Couvillon; Erin Nichols; Marijo Bilusic; Michael L Beshiri; Kathleen Kelly; Venkatesh Krishnasamy; Sunmin Lee; Min-Jung Lee; Akira Yuno; Jane B Trepel; Maria J Merino; Ryan Dittamore; Jennifer Marté; Renee N Donahue; Jeffrey Schlom; Keith J Killian; Paul S Meltzer; Seth M Steinberg; James L Gulley; Jung-Min Lee; William L Dahut Journal: J Immunother Cancer Date: 2018-12-04 Impact factor: 13.751
Authors: Maria Catalina Gomez-Puerto; Prasanna Vasudevan Iyengar; Amaya García de Vinuesa; Peter Ten Dijke; Gonzalo Sanchez-Duffhues Journal: J Pathol Date: 2018-11-27 Impact factor: 7.996