Inhibition of renin-angiotensin (RA) system is one of the attractive targets in the treatment of pancreatic cancer (PaC). Our retrospective analysis showed the association of inhibition of RA system with better prognosis in advanced PaC (Br J Cancer. 2010;103: 1644–8). Here we reported the results of phase 1 and 2 trials of gemcitabine and candesartan (GECA) therapy in advanced PaC.Patients
In phase 1 trial in normotensive patients, candesartan was administered orally at escalating dose (4, 8, 16 and 32 mg) qd daily and gemcitabine was administered 1000 mg/m2 30 min i.v. day 1, 8, 15, repeated every 4 weeks. DLT was defined as grade 4 hematological toxic effects, Grade 2 hypotension, abnormal creatinine or potassium and grade 3 or 4 other non-hematological toxic effects. In phase 2 trial, candesartan was administered 16 mg in normotensive patients and 8 mg in patients with hypertension, followed by increase up to 16 mg in cases without adverse events. Eligible criteria were unresectable locally advanced or metastatic PaC without any prior treatment, ECOG PS 0-2, normal renal function and without hypotension.Results
In phase 1 trial, 14 patients (locally advanced/metastatic 7/7, candesartan 4 mg: 3 patients, 8 mg: 3 patients, 16 mg: 6 patients, 32 mg: 2 patients) were enrolled between July 2009 and October 2010. One of six patients at 16 mg demonstrated DLT of grade 4 neutropenia and two of two patients at 32 mg demonstrated DLT of grade 2 hypotension. The response rate (RR) and the disease control rate (DCR) were 0% and 79%. Progression-free survival and overall survival were 7.6 and 22.9 months. In phase 2 trial, 35 patients (locally advanced/metastatic 9/26) were enrolled between May 2011 and December 2011. Major severe adverse events were neutropenia 24% and thrombocytopenia 18%. Grade 2 hypotension was seen in three patients. RR and DCR were 11% and 63%. Median PFS and OS were 4.3 and 7.7 months.Conclusion
GECA in advanced PaC appeared safe and promising, though a phase 2 study failed to meet our primary objective of 5-month median PFS.