A phase I study of pemetrexed (P) plus gemcitabine (G) in relapsed ovarian cancer (OC): Dosing results and evidence of activity

Abstract

5083 Background: High expression of folate receptors on ovarian cancer cells may provide excellent targets for P. Preclinical data support synergism with G. Optimal doses of q 14 day P+G with vitamin support in pre-treated OC pts are not known. We sought to determine the maximally tolerated doses (MTD) and to assess for toxicity and activity in relapsed OC. Methods: Pts with relapsed OC, no prior P or G, KPS ≥ 70, and adequate organ function were eligible. Pts were enrolled in cohorts of 3, expanding to 6 if dose-limiting toxicity (DLT) was observed during the first 4 cycles. Pts received P at 300 (cohort 1) or 400 (cohort 2) or 500 (cohort 3) or 600 (cohort 4) mg/m2 followed by G 1500 mg/m2 q 14 d without GCSF. B12 and folic acid were given 1 week prior and continued throughout. DLT was defined as grade (gr) 4 neutropenia (ANC) lasting >7d or neutropenic fever (NF); gr 4 thrombocytopenia or gr 3 with bleeding; ≥gr 3 nonhematologic toxicity, except ALT, AST, alopecia, fatigue; treatment delay ≥1 week due to any unresolved toxicity. Response assessed by RECIST. Results: 16 pts (median age 55, range 43–75; median number prior cytotoxic regimens 2, range 1–4) have enrolled in 4 cohorts. 15 are evaluable for response (1 treated after resection of recurrence); 13 of these15 had a platinum-free interval <6 months. 1 pt in cohort 1 had global deterioration during cycle 1 and was replaced, with best response counted as progressive disease (PD). 1 pt in cohort 3 had dose delay ≥1 week, meeting DLT criteria. Cohort 3 was expanded to 6 pts with no further DLT. 3 pts enrolled in cohort 4 with no DLTs observed. Toxicities per cycle (n = 108): gr 3 ANC 31%; gr 4 ANC 27%; gr 3 dehydration 0.9%; gr 3 platelets 0.9%; 0 pts had NF. Median # cycles/pt was 6, range 1–16, median cycle length 14 d. Objective response was observed in 27% (4/15 pts: 4 PR; 7 SD; 4 PD). All 4 responses were among pts with platinum resistant disease. >50% decrease in CA125 for more than two measurements was observed in 9/15 (60%) pts with evaluable CA125s. Median time to progression is 15 wks (95% confidence interval 10–32 wks). Conclusions: MTD is not yet reached. P 500 mg/m2 + G 1500 mg/m2 with vitamin supplementation is safe in pts with previously treated OC. 27% of patients with platinum-resistant disease had objective responses. [Table: see text]