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

Estlin, E. J., Pinkerton, C. R., Lewis, I. J., Lashford, L., McDowell, H., Morland, B., Kohler, J., Newell, D. R., Boddy, A. V., Taylor, G. A., Price, L., Ablett, S., Hobson, R., Pitsiladis, M., Brampton, M., Clendeninn, N., Johnston, A. and Pearson, A. D. J. (2001) A phase I study of nolatrexed dihydrochloride in children with advanced cancer. A United Kingdom Children's Cancer Study Group investigation. British Journal of Cancer, 84 1: 11-18. doi:10.1054/bjoc.2000.1569


Author Estlin, E. J.
Pinkerton, C. R.
Lewis, I. J.
Lashford, L.
McDowell, H.
Morland, B.
Kohler, J.
Newell, D. R.
Boddy, A. V.
Taylor, G. A.
Price, L.
Ablett, S.
Hobson, R.
Pitsiladis, M.
Brampton, M.
Clendeninn, N.
Johnston, A.
Pearson, A. D. J.
Title A phase I study of nolatrexed dihydrochloride in children with advanced cancer. A United Kingdom Children's Cancer Study Group investigation
Journal name British Journal of Cancer   Check publisher's open access policy
ISSN 0007-0920
1532-1827
Publication date 2001
Sub-type Article (original research)
DOI 10.1054/bjoc.2000.1569
Open Access Status DOI
Volume 84
Issue 1
Start page 11
End page 18
Total pages 8
Place of publication London, United Kingdom
Publisher Nature Publishing Group
Language eng
Formatted abstract
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/m2 24 h-1. 8 patients were evaluable for toxicity. In the 6 patients treated at 768 mg/m2 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/m2 24 h-1 are warranted.
Keyword Acute lymphoblastic leukaemia
Deoxyuridine
Methotrexate resistance
Pharmacokinetics
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: School of Medicine Publications
 
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