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

Purpose: Pemetrexed and pegylated liposomal doxorubicin (PLD) are clinically active as single agents and preclinically synergistic. This phase I, open-label trial evaluated the maximum tolerated dose (MTD) and safety of pemetrexed followed by PLD in patients with breast or gynecologic cancers. Patients: Using 3 + 3 dose escalation, cohorts of 3–9 patients received escalating doses of pemetrexed 400–500 mg/m² on days 1 and 15 and PLD 30–45 mg/m² on day 1 of a 28-day cycle. All patients received folic acid and vitamin B₁₂ until 21 days after last pemetrexed dose. Patients continued until dose-limiting toxicity (DLT) or progression (PD). Results: From 11/05 to 2/08, 29 patients entered treatment; median age: 60.6 years (range, 47.5–80.1); ECOG PS 0/1: 27.6%/72.4%; primary disease site: ovarian (55.2%), breast (34.5%), peritoneum (10.3%); prior therapies: chemotherapy (100.0%), surgery (72.4%), hormones/biologics (35%), and radiation (20.7%). Pemetrexed/PLD dose levels: L1 = 400/30 (n = 4), L2 = 400/35 (n = 6), L3 = 500/35 (n = 9), L4 = 500/40 (n = 7), and L5 = 500/45 (n = 3). Treatment-related grade 3-4 toxicities: hematologic—neutropenia (86.2%), leukopenia (58.6%), thrombocytopenia (48.3%), anemia (41.4%); nonhematologic—mucosal inflammation (24.1%), febrile neutropenia (24.1%), hand-foot syndrome (13.8%), hypokalaemia (10.3%). Reasons for discontinuation: PD (48.3%), toxicity (27.6%), patient request (13.8%), and investigator request (10.3%). Efficacy: 5 ovarian patients (20.8%) achieved partial response; median time to progression (TTP) was 6.1 months (range, 1.2–12.5). Conclusion: Pemetrexed plus PLD was reasonably tolerated in this heavily–pretreated population. MTD: pemetrexed 500 mg/m² and PLD 40 mg/m² may be carried forward to phase II studies in specific patient populations. TTP in platinum-refractory ovarian patients was greater than expected.