Phase I study of pemetrexed (P) and pegylated liposomal doxorubicin (PLD) in patients with refractory breast, ovarian, primary peritoneal, or fallopian tube cancer

Abstract

e13515 Background: P and PLD are clinically active as single agents and synergistic in preclinical models. This phase I, open-label trial determined the maximum tolerated dose (MTD) and safety profile of P followed by PLD in patients (pts) with breast or gynecologic cancers. Methods: Using standard phase I (3+3 dose escalation) study design, cohorts of 3–9 pts received escalating doses of P followed by PLD in 28-day cycles: P 400–500 mg/m2 on Days 1 and 15 and PLD 30–45 mg/m2 on Day 1. All pts received folic acid (350–1000 μg daily) and vitamin B12 (1000 μg) until 21 days after last dose of P. Pts continued until dose-limiting toxicity (DLT) or disease progression (PD) occurred. Results: From 11/05 to 1/08, 29 pts were registered/treated. Median age: 60.6 years (range, 47.5–80.1); ECOG performance status 0/1: 28%/72%; primary disease sites: ovarian (55%), breast (35%), peritoneal (10%); prior therapies: chemotherapy (100%), surgery (72%), hormones/biologics (35%), radiation (21%). Dosing results are shown below. At dose level (L) 2 and L3, 1 pt/cohort had DLTs; L5 was added and 3/3 pts had DLTs; 4 more pts were treated at L4 (1 pt replaced). Most frequent drug-related Grade 3–4 hematologic toxicities: neutropenia (86%), leukopenia (59%), thrombocytopenia (48%), anemia (41%). Most frequent drug-related Grade 3–4 nonhematologic toxicities: hand-foot syndrome (14%), hypokalaemia (10%). Major reasons for discontinuation: PD (48%), toxicity (28%), pt request (14%). Overall best responses (n=24): 5 pts (21%) had partial response (PR), 14 pts (58%) had stable disease (SD), 2 pts (8%) had PD, 3 pts (13%) were not evaluable. All 5 PR and 8 SD pts were ovarian; 5 SD and both PD pts were breast. Conclusions: P followed by PLD was reasonably tolerated in this heavily-pretreated population. The MTD was P 500 mg/m2 and PLD 40 mg/m2. These dose levels may be carried forward to phase II studies in more specific patient populations. [Table: see text] [Table: see text]