Phase I study of a combination therapy of gemcitabine and candesartan in patients with advanced pancreatic cancer: GECA-1 study.

Abstract

e14555 Background: Increasing evidence indicates a role of the local rennin-angitensin system (RAS) in tumor growth, suggesting potential of RAS as a target for cancer treatment. Our retrospective analysis showed inhibition of RAS was associated with better progression-free survival and overall survival in patients with advanced pancreatic cancer receiving gemcitabine (Br J Cancer. 2010;103:1644-8). This study was conducted to investigate the maximum-tolerated dose (MTD) of candesartan, an angiotensin receptor blocker, in combination with gemcitabine in patients with advanced pancreatic cancer (UMIN-CTR 000002152). Methods: Candesartan was administered orally at escalating dose (4 mg, 8 mg, 16 mg and 32 mg) qd daily and gemcitabine was administered 1,000 mg/m2 30min i.v. day 1, 8, 15, repeated every 4 weeks. There were no dose escalations within each patient. Eligible criteria were unresectable locally advanced or metastatic pancreatic cancer without any prior treatment, ECOG PS 0-2, normal renal function and without hypertension or hypotension. DLT was defined as grade 4 hematological toxicities, Grade 2 hypotension, abnormal creatinine or potassium and grade 3 or 4 other non-hematological toxicities. MTD was defined when 2 or more patients in a cohort of 3 patients or when 3 or more patients in a cohort of 6 patients experienced DLT. Results: Between July 2009 and Oct 2010, 14 patients (4 mg: 3 patients, 8 mg: 3 patients, 16 mg: 6 patients, 32 mg: 2 patients) were enrolled in this trial. The median age, 60, male:female, 5:9, PS 0:1, 8:6, locally advanced, 43%. One of 6 patients at 16 mg demonstrated DLT of grade 4 neutropenia and 2 of 2 patients at 32mg demonstrated DLT of grade 2 hypotension. Tumor response by RECIST was SD in 11, PD in 1, and NE in 2. Response rate was 0% but disease control rate (DCR) was 79%. Median progression-free survival (PFS) was 8.1 months and 1-year survival was 65% after a median observational period of 9.8 months. Conclusions: The recommended dose of candesartan in combination with gemcitabine was 16 mg. The results of DCR and PFS appeared promising.