Research Article| Volume 40, ISSUE 6, P899-906, April 2004

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The Cancer Research UK experience of pre-clinical toxicology studies to support early clinical trials with novel cancer therapies


      Pre-clinical toxicology studies in rodents and Phase I clinical trial data are summarised for 14 novel anticancer therapies. With only one exception, an antifolate antimetabolite, rodent toxicology predicted a safe Phase I trial starting dose and the majority of the dose limiting toxicities, in particular haematological toxicity. For targeted agents with well-defined pharmacodynamic markers, illustrated in the current study by 3 anti-endocrine drugs and one resistance modifier, the definition of a maximum tolerated dose can be avoided. Together with earlier data, the current study confirms that pre-clinical toxicology studies in a non-rodent species are not routinely needed for the safe conduct of early clinical trials with new cancer chemotherapies.
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      1. Directive 2001/20/EC of the European Parliament and of the Council of 4 April 2001 on the approximation of the laws, regulations and administrative provisions of the Member States relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use Official Journal L 121, 01/05/2001 P. 0034 - 0044.

        • Newell D.R.
        • Burtles S.S.
        • Fox B.W.
        • Jodrell D.I.
        • Connors T.A.
        Evaluation of rodent-only toxicology for early clinical trials with novel cancer therapeutics.
        British Journal of Cancer. 1999; 1999 (760-768): 81
      2. Tomaszewski JE. Multi-species toxicology approaches for oncology drugs: The US perspective. European Journal of Cancer, 2004.

      3. Committee for Proprietary Medicinal Products. Notes for Guidance on the Pre-clinical Evaluation of Anticancer Medicinal Products. CPMP/SWP/997/96.

        • Joint Steering Committee of the EORTC and CRC
        General guidelines for the preclinical toxicology of new cytotoxic anticancer agents in Europe.
        European Journal of Cancer. 1990; 26: 411-414
        • Burtles S.S.
        • Newell D.R.
        • Henrar R.E.C.
        • Connors T.A.
        Revisions of general guidelines for the preclinical toxicology of new cytotoxic anticancer agents in Europe.
        European Journal of Cancer. 1995; 31A: 408-410
        • Haynes B.P.
        • Jarman M.
        • Dowsett M.
        • et al.
        Pharmacokinetics and pharmacodynamics of the aromatase inhibitor 3-ethyl-3-(4-pyridyl)piperidine-2,6-dione in patients with postmenopausal breast cancer.
        Cancer Chemotherapy and Pharmacology. 1991; 27: 367-372
      4. O'Donnell A, Judson I, Dowsett M, et al. Hormonal impact of the 17α-hydroxylase/C17,20-lyase inhibitor abiraterone acetate (CB7630) in patients with prostate cancer. British Journal of Cancer 2004, In press.

        • Coombes R.C.
        • Haynes B.P.
        • Dowsett M.
        • et al.
        Cancer Research. 1995; 55: 1070-1074
        • Bissett D.
        • McLeod H.L.
        • Sheedy B.
        • et al.
        Phase I dose-escalation and pharmacokinetic study of a novel folate analogue.
        British Journal of Cancer. 2001; 84: 308-312
        • Rustin G.J.S.
        • Galbraith S.M.
        • Anderson H.
        • et al.
        Phase I clinical trial of weekly combretastain A4 phosphate.
        Journal of Clinical Oncology. 2003; 21: 2815-2822
        • Rustin G.J.S.
        • Bradley C.
        • Galbraith S.M.
        • et al.
        5,6-Dimethylxanthone acetic acid (DMXAA), a novel antivascular agent.
        British Journal of Cancer. 2003; 88: 1160-1167
        • Middleton M.R.
        • Ransom M.
        • Bowen R.
        • et al.
        Phase I study of 4-bromothenyl-guanine (4BTG) and temozolomide.
        Proceedings American Association of Cancer Research. 2000; 41: 609
        • Beale P.
        • Judson I.
        • O'Donnell A.
        • et al.
        A Phase I and pharmacological study of cis-diamminedichloro(2-methylpyridine) platinum II (AMD473).
        British Journal of Cancer. 2003; 88: 1128-1134
        • Seymour L.W.
        • Ferry D.R.
        • Anderson D.
        • et al.
        Hepatic drug targeting.
        Journal of Clinical Oncology. 2002; 20: 1668-1676
        • Boddy A.V.
        • Todd R.
        • Verrill M.
        • et al.
        Pharmacological study of CT- (XytoaxTM), a poly(L-glutamic acid)-paclitaxel conjugate administered every 3 weeks or every 2 weeks in a Phase I study.
        European Journal of Cancer. 2002; 38: S34
      5. Bissett D, Cassidy J, de Bono JS, et al. Phase I and pharmacokinetic (PK) study of MAG-CPT (PNU 166148) a polymeric derivative of camptothecin (CPT). Journal of Clinical Oncology 2004, In press.

        • Vigushin D.M.
        • Poon G.K.
        • Boddy A.
        • et al.
        Phase I and pharmacokinetic study of D-limonene in patients with advanced cancer.
        Cancer Chemotherapy and Pharmacology. 1998; 42: 111-117
        • Clive S.
        • Webb D.J.
        • MacLellan A.
        • et al.
        Forearm blood flow and local responses to peptide vasodilators.
        Clinical Cancer Research. 2001; 7: 3071-3078
      6. Danson S, Ferry D, Alakhov V, et al. Phase I dose escalation and pharmacokinetic study of pluronic polymer-bound doxorubicin (SP4019C) in patients with advanced cancer. British Journal of Cancer 2004, In press.

        • Newell D.R.
        • Searle K.M.
        • Westwood N.B.
        • Burtles S.S.
        Professor Tom Connors and the development of novel cancer therapies by the Phase I/II Clinical Trials Committee of Cancer Research UK.
        British Journal of Cancer. 2003; 89: 437-454
        • Double J.
        • Barrass N.
        • Barnard N.D.
        • Navaratnam V.
        Toxicity testing in the development of anticancer drugs.
        The Lancet Oncology. 2002; 3: 438-442