Clinical and pharmacokinetic study of gemcitabine (GEM) - oxaliplatin (OXA) association in metastatic or locally advanced pancreatic adenocarcinoma

Abstract

2059 Background: Combination of gemcitabine (GEM) with oxaliplatin (OXA) is among the most active chemotherapy for advanced and metastatic pancreatic adenocarcinoma. Based on preclinical data, a supra-additive effect was observed when tumor cells were exposed to GEM first and to OXA 24 h later. Study aim was to evaluate clinical benefits and tolerability of GEM-OXA association in MTS/LA pancreatic carcinoma. By administering sequence-dependent combinations of the two drugs (GEM d1-OXA d2 or OXA d1-GEM d2), pharmacokinetic (PK) interactions were also evaluated. Methods: 30 patients (median age 60.7 yr; ECOG PS = 1) affected by MTS (67%) or LA pancreatic carcinoma (33%) were enrolled. Pts received GEM 1,000 mg/m2 as 10 mg/m2/min infusion and OXA 100 mg/m2 as 2 h infusion q 2 wks (median cycles/patient = 10). For PK study, 15 patients (28 cycles) were enrolled following two alternated protocols: A (GEM-OXA) (9 pts, 16 cycles) received 1st-3rd-5th cicle GEM on day 1 and OXA on day 2; B (OXA-GEM) (6 pts, 12 cycles) received OXA in 2nd-4th-6th cycle on day 1 and GEM on day 2. Results: 30 pts were evaluable for response and toxicity. Response rate was 30%, superimposable in LA and MTS pts; 50% of patients had clinical benefit. Median PFS and OS were 5.5 and 9.5 months, with 40% of pts alive at 1 year. Grade 3/4 toxicity per patient: 10% neutropenia and thrombocytopenia, 13% nausea/vomiting, 7% diarrhea and 10% peripheral neuropathy. By evaluating GEM and OXA PK parameters in arms A and B, no statistically significant difference was revealed between two protocols (Mann-Whitney test). GEM AUC and Cl (A vs B, p 0.84 and 0.87); OXA tot AUC and Cl (p 0.87 and 0.80); OXA ultr AUC and Cl (p 0.91 and 0.84). Pt though level progressively accumulated, from 1st to 6th cycle (Cmin 74.7–321.35 ng/ml). Conclusions: This phase II study showed that biweekly GEM-OXA as a first line chemotherapy in MTS/LA pancreatic carcinoma is well tolerated and has a excellent clinical activity. PK profile of both drugs does not show statistically significant differences between GEM-OXA and OXA-GEM alternate schedules. No significant financial relationships to disclose.