Patrick Grierson1, Andrea Teague2, Rama Suresh1, Kian-Huat Lim1, Manik Amin1, Katrina Pedersen1, Benjamin Tan1, Jesse Huffman1, Nick Boice1, Lingling Du3, Jingxia Liu4, A Craig Lockhart5, Andrea Wang-Gillam1. 1. Department of Internal Medicine, Division of Medical Oncology, Washington University in St. Louis, St. Louis, MO, USA. 2. New Mexico Cancer Care Associates, Santa Fe, NM, USA. 3. Ochsner Health System, New Orleans, LA, USA. 4. Department of Surgery, Division of Public Health Sciences, Section of Oncologic Biostatistics, Washington University in St. Louis, St. Louis, MO, USA. 5. University of Miami, Miller School of Medicine, Sylvester Comprehensive Cancer Center, Miami, FL, USA.
Abstract
BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with limited therapeutic options. We evaluated the safety and efficacy of the aminopeptidase inhibitor tosedostat with capecitabine in advanced PDAC. METHODS: We conducted a phase Ib/II trial of tosedostat with capecitabine as second-line therapy for advanced PDAC. Planned enrollment was 36 patients. Eligible patients were treated with capecitabine 1,000 mg/m2 oral twice-daily days 1-14 and oral tosedostat in a dose de-escalation design on days 1-21 of each 21-day cycle. Primary endpoints were the recommended phase 2 dose (RP2D) and progression-free survival (PFS). RESULTS: Sixteen patients were enrolled. Tosedostat 120 mg oral twice daily with capecitabine 1,000 mg/m2 oral twice daily was the RP2D. There was one dose-limiting toxicity (DLT) (grade 3 acute coronary syndrome) during phase Ib. The most common treatment-related adverse events were gastrointestinal (nausea, diarrhea), cardiac [QTc prolongation, decreased ejection fraction (EF)], and fatigue. The median PFS was 7.1 months, and the median treatment failure free survival was 3 months. Eight patients experienced stable disease for greater than 3 months. The study was closed early due to lack of drug availability. CONCLUSIONS: Tosedostat with capecitabine displayed tolerable toxicity, and prolonged disease control in a subset of patients. These data encourage further exploration of aminopeptidase inhibitors in pancreatic cancer. 2020 Journal of Gastrointestinal Oncology. All rights reserved.
BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with limited therapeutic options. We evaluated the safety and efficacy of the aminopeptidase inhibitor tosedostat with capecitabine in advanced PDAC. METHODS: We conducted a phase Ib/II trial of tosedostat with capecitabine as second-line therapy for advanced PDAC. Planned enrollment was 36 patients. Eligible patients were treated with capecitabine 1,000 mg/m2 oral twice-daily days 1-14 and oral tosedostat in a dose de-escalation design on days 1-21 of each 21-day cycle. Primary endpoints were the recommended phase 2 dose (RP2D) and progression-free survival (PFS). RESULTS: Sixteen patients were enrolled. Tosedostat 120 mg oral twice daily with capecitabine 1,000 mg/m2 oral twice daily was the RP2D. There was one dose-limiting toxicity (DLT) (grade 3 acute coronary syndrome) during phase Ib. The most common treatment-related adverse events were gastrointestinal (nausea, diarrhea), cardiac [QTc prolongation, decreased ejection fraction (EF)], and fatigue. The median PFS was 7.1 months, and the median treatment failure free survival was 3 months. Eight patients experienced stable disease for greater than 3 months. The study was closed early due to lack of drug availability. CONCLUSIONS: Tosedostat with capecitabine displayed tolerable toxicity, and prolonged disease control in a subset of patients. These data encourage further exploration of aminopeptidase inhibitors in pancreatic cancer. 2020 Journal of Gastrointestinal Oncology. All rights reserved.
Authors: Andrea Wang-Gillam; Chung-Pin Li; György Bodoky; Andrew Dean; Yan-Shen Shan; Gayle Jameson; Teresa Macarulla; Kyung-Hun Lee; David Cunningham; Jean F Blanc; Richard A Hubner; Chang-Fang Chiu; Gilberto Schwartsmann; Jens T Siveke; Fadi Braiteh; Victor Moyo; Bruce Belanger; Navreet Dhindsa; Eliel Bayever; Daniel D Von Hoff; Li-Tzong Chen Journal: Lancet Date: 2015-11-29 Impact factor: 79.321
Authors: Thierry Conroy; Françoise Desseigne; Marc Ychou; Olivier Bouché; Rosine Guimbaud; Yves Bécouarn; Antoine Adenis; Jean-Luc Raoul; Sophie Gourgou-Bourgade; Christelle de la Fouchardière; Jaafar Bennouna; Jean-Baptiste Bachet; Faiza Khemissa-Akouz; Denis Péré-Vergé; Catherine Delbaldo; Eric Assenat; Bruno Chauffert; Pierre Michel; Christine Montoto-Grillot; Michel Ducreux Journal: N Engl J Med Date: 2011-05-12 Impact factor: 91.245
Authors: Jorge Cortes; Eric Feldman; Karen Yee; David Rizzieri; Anjali S Advani; Anthony Charman; Richard Spruyt; Martin Toal; Hagop Kantarjian Journal: Lancet Oncol Date: 2013-02-28 Impact factor: 41.316
Authors: David Krige; Lindsey A Needham; Lindsay J Bawden; Nicolas Flores; Hannah Farmer; Lauren E C Miles; Erica Stone; Juliana Callaghan; Stephen Chandler; Vanessa L Clark; Patricia Kirwin-Jones; Valérie Legris; Jo Owen; Thakor Patel; Steve Wood; Gary Box; David Laber; Rajesh Odedra; Annette Wright; L Michael Wood; Suzanne A Eccles; Elisabeth A Bone; Andrew Ayscough; Alan H Drummond Journal: Cancer Res Date: 2008-08-15 Impact factor: 12.701
Authors: Alison H M Reid; Andrew Protheroe; Gerhardt Attard; Nikki Hayward; Laura Vidal; James Spicer; Heather M Shaw; Elizabeth A Bone; Joanne Carter; Leon Hooftman; Adrian Harris; Johann S De Bono Journal: Clin Cancer Res Date: 2009-07-28 Impact factor: 12.531
Authors: Daniel D Von Hoff; Thomas Ervin; Francis P Arena; E Gabriela Chiorean; Jeffrey Infante; Malcolm Moore; Thomas Seay; Sergei A Tjulandin; Wen Wee Ma; Mansoor N Saleh; Marion Harris; Michele Reni; Scot Dowden; Daniel Laheru; Nathan Bahary; Ramesh K Ramanathan; Josep Tabernero; Manuel Hidalgo; David Goldstein; Eric Van Cutsem; Xinyu Wei; Jose Iglesias; Markus F Renschler Journal: N Engl J Med Date: 2013-10-16 Impact factor: 91.245
Authors: Xiaohu Tang; Melissa M Keenan; Jianli Wu; Chih-An Lin; Laura Dubois; J Will Thompson; Stephen J Freedland; Susan K Murphy; Jen-Tsan Chi Journal: PLoS Genet Date: 2015-04-07 Impact factor: 5.917