Overview of phase I/II pemetrexed studies.
Pemetrexed (Alimta) is an antifolate that is effective in the inhibition of multiple enzyme targets including thymidylate synthase, dihydrofolate reductase, and glycinamide ribonucleotide formyl transferase. The compound has been evaluated in several phase I trials, both as single agent and in combination with other cytotoxic agents. The initial schedule selected for further investigation in phase II trials was pemetrexed 600 mg/m2 as a 10-minute infusion on day 1 every 21 days. During the subsequent phase II development the dose of pemetrexed was adjusted to 500 mg/m2 due to bone marrow and gastrointestinal toxicities. The adjusted dose of pemetrexed was well tolerated throughout the late-phase drug development program. Preclinical evidence suggests that pemetrexed has additive or synergistic activity when combined with many other clinically important anticancer agents, including gemcitabine (Gemzar), fluorouracil, carboplatin (Paraplatin), oxaliplatin (Eloxatin), paclitaxel, and vinorelbine (Navelbine). Dose-limiting toxicities in these studies were primarily hematologic, and there was no evidence of cumulative hematologic toxicity. During the drug development program it was discovered that supplementation with folic acid and vitamin B12 profoundly increased the tolerability of pemetrexed. The studies discussed in this review demonstrate that pemetrexed is well tolerated as a single agent and will be an important contribution to combination chemotherapy regimens.
Hanauske
Axel R
AR
AK St. Georg, Department of Medicine, Hamburg, Germany. Hanauske.IND-Synergen@t-online.de
Dittrich
Christian
C
Otero
Jorge
J
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy; D016190:Carboplatin / Q000008:administration & dosage; D002945:Cisplatin / Q000008:administration & dosage; D017321:Clinical Trials, Phase I as Topic; D017322:Clinical Trials, Phase II as Topic; D003520:Cyclophosphamide / Q000008:administration & dosage; D004334:Drug Administration Schedule; D004357:Drug Synergism; D005260:Female; D005493:Folic Acid Antagonists / Q000008:administration & dosage*; D005971:Glutamates / Q000008:administration & dosage*; D006147:Guanine / Q000008:administration & dosage* / Q000031:analogs & derivatives*; D006801:Humans; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D000077150:Oxaliplatin; D000068437:Pemetrexed; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors*; D014747:Vinblastine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D000077235:Vinorelbine
D005493:Folic Acid Antagonists; D005971:Glutamates; D009944:Organoplatinum Compounds; D000068437:Pemetrexed; D000077150:Oxaliplatin; D014747:Vinblastine; D006147:Guanine; D003520:Cyclophosphamide; D016190:Carboplatin; D013940:Thymidylate Synthase; D002945:Cisplatin; D000077235:Vinorelbine