Phase I trial of pemetrexed plus paclitaxel administered every 21 days in patients with advanced solid tumors

Abstract

2053 Background: Pemetrexed (a novel multitargeted antifolate) and paclitaxel are active in various solid tumors. The primary objective was maximum tolerated dose (MTD) determination. Secondary objectives included: dose-limiting toxicities (DLTs) in cycle 1, recommended phase II dose, antitumor activity, and pharmacokinetics (PK) assessments. Methods: Patients (pts) with advanced cancer received on d1 pemetrexed (10 min iv) followed by paclitaxel (3h) q21d. Protocol was amended requiring vitamin supplementation (VS): folic acid (0.4 mg po) and B12 (1 mg im q9 weeks). Serial plasma samples were drawn for PK. Results: Prior to VS, 17 pts were enrolled into 3 dose levels (mg/m2): 7 pts 400/135 (one DLT: febrile neutropenia, FN); 6 pts 400/175 (one DLT: G4 diarrhea); 4 pts 500/135 (two DLTs: neutropenic sepsis, G4 neurotoxicity). Toxicities included (all grades/G3/G4): anemia (17/7/0 pts), neutropenia (15/3/8), thrombocytopenia (7/2/0), mucositis (12/0/0), diarrhea (7/1/1), and rash (10/0/0). Post VS amendment, 12 pts [8 M, 4 F; median age 49; prior chemotherapy (11 pts)] were enrolled at 500/135. 40 total cycles (range 1–7) with a median 3 cycles were given. No dose reductions, omissions, or drug-related deaths reported. Of the first 6 pts, 1 experienced FN (DLT). Dose level expanded to evaluate 3 pts treated with ≤1 prior systemic regimen; 1 pt experienced G4 neutropenia (DLT). Dose level was expanded to evaluate 3 pts with PS=0 and treated with ≤1 prior systemic regimen; 1 pt experienced G4 FN (DLT). Toxicities included: neutropenia (7/2/3), anemia (11/1/0), thrombocytopenia (3/0/0), mucositis (2/0/0); diarrhea (0/0/0), and rash (2/0/0). Stable disease reported in 5 pts: head/neck (2), mesothelioma (2), stomach (1). PK evaluation indicates no paclitaxel effect on pemetrexed PK. Conclusions: : The MTD of pemetrexed with VS and paclitaxel q21d is 500/135. VS appears to decrease mucositis, diarrhea, rash, and myelosuppresion. There was no significant change in exposure of either drug when given concomitantly. In a phase 2 study of this combination, pts should have vitamin supplementation, good PS and bone marrow reserve, and minimal prior chemotherapy. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Eli Lilly & Co. Eli Lilly & Co.; Novartis; Pfizer; Aventis; Lilly; Roche; Pharmamar Eli Lilly & Co. Eli Lilly Eli Lilly & Co.