TY - JOUR
T1 - Phase Ib/II study combining tosedostat with capecitabine in patients with advanced pancreatic adenocarcinoma
AU - Grierson, Patrick
AU - Teague, Andrea
AU - Suresh, Rama
AU - Lim, Kian Huat
AU - Amin, Manik
AU - Pedersen, Katrina
AU - Tan, Benjamin
AU - Huffman, Jesse
AU - Boice, Nick
AU - Du, Lingling
AU - Liu, Jingxia
AU - Lockhart, A. Craig
AU - Wang-Gillam, Andrea
N1 - Publisher Copyright:
© Journal of Gastrointestinal Oncology. All rights reserved.
PY - 2020/2/1
Y1 - 2020/2/1
N2 - 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.
AB - 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.
KW - Aminopeptidase inhibitor
KW - Pancreatic cancer
KW - Tosedostat
UR - http://www.scopus.com/inward/record.url?scp=85081268462&partnerID=8YFLogxK
U2 - 10.21037/jgo.2019.11.06
DO - 10.21037/jgo.2019.11.06
M3 - Article
C2 - 32175106
AN - SCOPUS:85081268462
SN - 2078-6891
VL - 11
SP - 61
EP - 67
JO - Journal of Gastrointestinal Oncology
JF - Journal of Gastrointestinal Oncology
IS - 1
ER -