This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. This is a phase I study of pemetrexed (LY231514, Alimta) in children and adolescents with recurrent solid tumors. Pemetrexed is a novel antifolate that inhibits multiple targets. Antimetabolites are cytotoxic drugs structurally similar to naturally occurring molecules necessary for the synthesis of pyrimidines, purines, and nucleic acids. Pemetrexed has anti-tumor activity through inhibition of several key folate-requiring enzymes, including thymidylate synthase (TS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyl transferase (GARFT). Pediatric and adolescent patients with recurrent solid tumors will be eligible for study if they have adequate hematologic, hepatic, renal, and pulmonary status. Informed consent will be required. Participants will be given pemetrexed as a 10 minute IV infusion every 21 days. The starting dose will be 400 mg/m 2, and subsequent levels will be 30% higher. Pharmacokinetics and pharmacogenetics studies will be performed. Other correlative studies include a preliminary assessment of the correlation of the expression of TS, DHFR, GARFT, reduced folate carrier (RFC), folylpolyglutamate synthetase (FPGS) and gamma glutamyl hydrolase (GGH) as well as methylthioadenosine phosphorylase (MTAP) deletion with pemetrexed response, as is possible within the confines of a Phase I trial.
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