• Assessment of circulating biomarkers for potential pharmacodynamic utility in patients with lymphoma.

      Greystoke, Alastair; O'Connor, James P B; Linton, Kim M; Taylor, M Ben; Cummings, Jeffrey; Ward, Timothy H; Maders, Fran; Hughes, Anthony; Ranson, Malcolm R; Illidge, Timothy M; et al. (2011-02-15)
      Treatment efficacy and toxicity are difficult to predict in lymphoma patients. In this study, the utility of circulating biomarkers in predicting and/or monitoring treatment efficacy/toxicity were investigated.
    • Biomarker method validation in anticancer drug development.

      Cummings, Jeffrey; Ward, Timothy H; Greystoke, Alastair; Ranson, Malcolm R; Dive, Caroline; Clinical and Experimental Pharmacology, Paterson Institute for Cancer Research, University of Manchester, Manchester, UK. jcummings@picr.man.ac.uk (2008-02)
      Over recent years the role of biomarkers in anticancer drug development has expanded across a spectrum of applications ranging from research tool during early discovery to surrogate endpoint in the clinic. However, in Europe when biomarker measurements are performed on samples collected from subjects entered into clinical trials of new investigational agents, laboratories conducting these analyses become subject to the Clinical Trials Regulations. While these regulations are not specific in their requirements of research laboratories, quality assurance and in particular assay validation are essential. This review, therefore, focuses on a discussion of current thinking in biomarker assay validation. Five categories define the majority of biomarker assays from 'absolute quantitation' to 'categorical'. Validation must therefore take account of both the position of the biomarker in the spectrum towards clinical end point and the level of quantitation inherent in the methodology. Biomarker assay validation should be performed ideally in stages on 'a fit for purpose' basis avoiding unnecessarily dogmatic adherence to rigid guidelines but with careful monitoring of progress at the end of each stage. These principles are illustrated with two specific examples: (a) absolute quantitation of protein biomarkers by mass spectrometry and (b) the M30 and M65 ELISA assays as surrogate end points of cell death.
    • Predicting the myelotoxicity of chemotherapy: the use of pretreatment O6-methylguanine-DNA methyltransferase determination in peripheral blood mononuclear cells.

      Sabharwal, A; Waters, R; Danson, Sarah; Clamp, Andrew R; Lorigan, Paul C; Thatcher, Nick; Margison, Geoffrey P; Middleton, Mark R; Department of Medical Oncology, University of Oxford, Oxford, UK. (2011-12-21)
      To assess the value of pretreatment O-methylguanine-DNA methyltransferase (MGMT) expression in peripheral blood mononuclear cells (PBMCs) in predicting haematological toxicity with O-alkylating agent chemotherapy, we explored this relationship retrospectively in melanoma patients. Ninety-three patients treated with temozolomide or dacarbazine in four clinical trials were assessed, and a model of the interaction between MGMT expression and haematological toxicity was constructed. Nadir white-cell and platelet counts were related to, and hence could be predicted from, pretreatment MGMT. Leucopenia and thrombocytopenia were more prevalent amongst patients with low pretreatment MGMT, according to the highest grades of toxicity experienced and/or the dose intensity patients could sustain. Addition of interferon to chemotherapy or compression of the temozolomide schedule increased the toxicity. The model also predicts significant myelotoxicity where PBMC MGMT is inactivated, consistent with the experience in the clinic with lomeguatrib and O-benzylguanine. Determination of MGMT in PBMC can identify patients at greatest risk of toxicity or who are suitable for dose intensification.