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


METHODS
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%).


RESULTS
5 ovarian patients (20.8%) achieved partial response; median time to progression (TTP) was 6.1 months (range, 1.2-12.5).


CONCLUSIONS
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.
Richards
Donald A
DA
US Oncology Research, Inc, Texas Oncology-Tyler, 910 E. Houston Street, Suite 100, Tyler, TX 75702, USA. Donald.Richards@USOncology.com
Loesch
David
D
Vukelja
Svetislava J
SJ
Wu
Hillary
H
Hyman
William J
WJ
Nieves
Jeffery
J
Wang
Yunfei
Y
Hu
Simin
S
Shonukan
Oluwatoyin O
OO
Tai
Datchen F
DF
D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm; D005185:Fallopian Tube Neoplasms / Q000188:drug therapy; D005260:Female; D005971:Glutamates / Q000008:administration & dosage / Q000627:therapeutic use*; D006147:Guanine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D060787:Neoplasm Grading; D009369:Neoplasms / Q000188:drug therapy*; D010051:Ovarian Neoplasms / Q000188:drug therapy; D000068437:Pemetrexed; D010534:Peritoneal Neoplasms / Q000188:drug therapy; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000627:therapeutic use*; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D005971:Glutamates; C506643:liposomal doxorubicin; D000068437:Pemetrexed; D011092:Polyethylene Glycols; D006147:Guanine; D004317:Doxorubicin