A phase I study of nolatrexed dihydrochloride in children with advanced cancer. A United Kingdom Children’s Cancer Study Group Investigation

Abstract

Summary A phase I study of nolatrexed, administered as a continuous 5 day intravenous infusion every 28 days, has been undertaken for children with advanced malignancy. 16 patients were treated at 3 dose levels; 420, 640 and 768 mg/m 2 24 h −1 . 8 patients were evaluable for toxicity. In the 6 patients treated at 768 mg/m 2 24 h −1 , dose-limiting oral mucositis and myelosuppression were observed. Plasma nolatrexed concentrations and systemic exposure, measured in 14 patients, were dose related, with mean AUC values of 36 mg −1 ml −1 min −1 , 50 mg ml −1 min −1 and 80 mg ml −1 min −1 at the 3 dose levels studied. Whereas no toxicity was encountered if the nolatrexed AUC was <45 mg ml −1 min − 1 , Grade 3 or 4 toxicity was observed with AUC values of >60 mg ml −1 min −1 . Elevated plasma deoxyuridine levels, measured as a surrogate marker of thymidylate synthase inhibition, were seen at all of the dose levels studied. One patient with a spinal primitive neuroectodermal tumour had stable disease for 11 cycles of therapy, and in two patients with acute lymphoblastic leukaemia a short-lived 50% reduction in peripheral lymphoblast counts was observed. Nolatrexed can be safely administered to children with cancer, and there is evidence of therapeutic activity as well as antiproliferative toxicity. Phase II studies of nolatrexed in children at the maximum tolerated dose of 640 mg/m 2 24 h −1 are warranted.

A phase I trial of MK‐2206 in children with refractory malignancies: A Children's Oncology Group study

“…The key DLTs in both schedules were rash, similar to adults. In contrast to adult studies , dose‐limiting stomatitis was not observed in this pediatric trial.…”

Regulations of expressions of rat/human sulfotransferases (SULTs) by anti-cancer drug, nolatrexed and micronutrients

“…Not only for adult cancers, but NTs use for children cancer is reported to be safe. So the therapeutic activity is correlated to its antiproliferative toxicity (19). For metastatic hepatocellular carcinoma (HCC), treated with nolatrexed (NT) or doxorubicin (DOX) showed minimal activity in this phase III trial (20).…”

Pemetrexed pharmacokinetics and pharmacodynamics in a phase I/II study of doublet chemotherapy with vinorelbine: implications for further optimisation of pemetrexed schedules

“…Accumulation of dUMP occurs as a direct consequence of TS inhibition and also as a result of increased activity of other enzymes, including ribonucleotide reductase (RR) and deoxycytidylate (dCMP) deaminase (Maybaum et al, 1981). A number of studies have indicated that plasma dUrd is an important pharmacodynamic (PD) marker of TS inhibition (Mitchell et al, 1997;de Jonge et al, 2002;Ford et al, 2002;Rees et al, 2003) especially with the use of the TS inhibitors AG337 (Nolatrexed) (Jodrell et al, 1999;Estlin et al, 2001), ZD9331 (de Jonge et al, 2002;Ford et al, 2002;Rees et al, 2003) and ZD1964 (raltitrexed) (Ford et al, 2002;Horton et al, 2005); however, similar studies have not been performed with pemetrexed.…”