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/m 2 on days 1 and 15 and PLD 30-45 mg/m 2 on day 1 of a 28-day cycle. All patients received folic acid and vitamin B 12 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/m 2 and PLD 40 mg/m 2 may be carried forward to phase II studies in specific patient populations. TTP in platinum-refractory ovarian patients was greater than expected.
- Pegylated liposomal doxorubicin
- Phase I
- Solid tumors
ASJC Scopus subject areas
- Pharmacology (medical)