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

Donald A. Richards, David Loesch, Svetislava J. Vukelja, Hillary Wu, William J. Hyman, Jeffery Nieves, Yunfei Wang, Simin Hu, Oluwatoyin O. Shonukan, Datchen F. Tai

Research output: Contribution to journalArticle

10 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)963-970
Number of pages8
JournalInvestigational New Drugs
Volume29
Issue number5
DOIs
StatePublished - Oct 1 2011
Externally publishedYes

Keywords

  • Chemotherapy
  • Pegylated liposomal doxorubicin
  • Pemetrexed
  • Phase I
  • Solid tumors

ASJC Scopus subject areas

  • Oncology
  • Pharmacology
  • Pharmacology (medical)

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