Phase I dose-escalating study of bi-weekly pemetrexed (MTA) with fixed dose rate gemcitabine (gem) in patients with advanced cancer

Abstract

2049 Background: Fixed dose rate (FDR) gem may optimize the documented benefit of gem in pancreatic, NSCL, head and neck, and breast cancers. Preclinical data of the combination of MTA and gem indicate synergy. We studied a bi-weekly combination of MTA and FDR gem to improve tolerance over the previous “Day 1, 8” regimen. Methods: MTA followed by FDR gem infusion was given every 14 days in a dose-escalation design below. Dose-limiting toxicities (DLT) is defined as: grade 4 neutropenia ≥ 5 days, febrile neutropenia, grade 4 thrombocytopenia, or grade 3–4 non-hematological toxicities in 1st cycle. 27 patients were enrolled with median age 59 (range 41–82), males/females 18/9, and ECOG PS 0/1 (5/22). All received Vitamin B12 (1 mg IM prior to study & q9 weeks) and folic acid (350–1000 mcg po qd) supplementation 1–2 weeks prior and during study plus dexamethasone 4 mg po BID day before, of, and after chemotherapy. Results: Dose level 7 has been reached and is being expanded with DLT in 1 patient. Toxicities per patient during all cycles include grade 3–4 neutropenia (8/27 patients), grade 3 anemia (3), brief febrile neutropenia (6), grade 3 rash (1 patient), grade 3 low back pain (1), grade 3 renal failure (1), grade 5 perforated duodenal stent (1). In 19 patients evaluable for response, there were 11 stable disease and 8 progression of disease. Conclusion: Recommended phase II dose for bi-weekly MTA with FDR gem is likely to be 800 mg/m2 and 1,200 mg/m2 × 120 minutes. This regimen allows full doses and dose intensity of both drugs to be administered on a simple schedule with excellent tolerance. A phase II study in biliary cancer is planned. This study is supported in part by Eli Lilly.a This toxicity was at baseline, therefore not drug related.b, c These toxicities were in one patient and were not drug related, rather related to the individual patient’s status going into therapy. [Table: see text] [Table: see text]