Multi-species toxicology approaches for oncology drugs

the US perspective
  • Joseph E. Tomaszewski
    Tel.: +1-301-496-8777 (T&PB Office)/+1-301-435-9162 (Direct Line); fax: +1-301-480-4836
    Chief, Toxicology & Pharmacology Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Executive Plaza North, Room 8034, 6130 Executive Boulevard, Rockville, MD 20852, USA
    Search for articles by this author


      The Toxicology and Pharmacology Branch (T&PB) of the National Cancer Institute (NCI) performs pharmacological and toxicological evaluations of new oncology agents according to an agent-directed paradigm in which all studies are tailored to each agent. The United States Food and Drug Administration (US FDA) requires that preclinical toxicology studies be conducted in two species, a rodent and a non-rodent for all small molecules, and T&PB has successfully used this formula. While pharmacokinetic (PK) studies are considered optional, T&PB routinely develops new methods for plasma/tissue drug analysis and employs this methodology throughout development to determine kinetics in various species and toxicokinetics in the toxicity studies. In the current era of molecular target-based development, the T&PB also develops or employs methodology to evaluate effects of the new chemical entity on appropriate biomarkers in tumour and normal tissues. In this comprehensive programme, T&PB is able to correlate safety and toxicity with both plasma drug levels and biomarker modulation in two species for a seamless entry into Phase I.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to European Journal of Cancer
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Double J.
        Toxicity testing in the development of anticancer drugs.
        Lancet Oncol. 2002; 3: 438-439
        • Druker B.J.
        • Talpaz M.
        • Resta D.J.
        • Peng B.
        • et al.
        Efficacy and safety of a specific inhibitor of BCR-ABL tyrosine kinase in chronic myeloid leukemia.
        N. Engl. J. Med. 2001; 344: 1031-1037
        • Druker B.J.
        • Sawyers C.L.
        • Kantarjian H.
        • et al.
        Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia Chromosome.
        N. Engl. J. Med. 2001; 344: 1038-1042
      1. Gleevec™ prescribing information. Physicians' Desk Reference, Medical Economics Company, Montvale, NJ, 2002, 2357–2360.

        • Adjei A.A.
        • Erlichman C.
        • Davis J.N.
        • et al.
        A phase I trial of the farnesyl transferase inhibitor SCH66336.
        Cancer Res. 2000; 60: 1871-1877
        • Zujewski J.
        • Horak I.D.
        • Bol C.J.
        • et al.
        Phase I and pharmacokinetic study of farnesyl protein transferase inhibitor R115777 in advanced cancer.
        J. Clin. Oncol. 2000; 18: 927-941
      2. ICH Guidance to Industry: M3, Nonclinical Safety Studies for the Conduct of Human Clinical Trials for Pharmaceuticals (July 1997).

        • DeGeorge J.J.
        • Ahn C.
        • Andrews P.A.
        • et al.
        Regulatory considerations for preclinical development of anticancer drugs.
        Cancer Chemother. Pharmacol. 1998; 41: 173-185
        • Burtles S.S.
        • Newell D.R.
        • Henrar R.E.
        • Connors T.A.
        Revisions of general guidelines for the preclinical toxicology of new cytotoxic anticancer agents in Europe. The Cancer Research Campaign (CRC) Phase I/II Clinical Trials Committee and the European Organization for Research and Treatment of Cancer (EORTC) New Drug Development Office.
        Eur. J. Cancer. 1995; 31: 408-410
        • Grieshaber C.K.
        • Marsoni S.
        Relation of preclinical toxicology to findings in early clinical trials.
        Cancer Treat. Rep. 1986; 70: 65-72
        • Olson H.
        • Betton G.
        • Robinson D.
        • et al.
        Concordance of the toxicity of pharmaceuticals in humans and in animals.
        Regul. Toxicol. Pharmacol. 2000; 32: 56-67
        • Parkinson C.
        • Grasso P.
        The use of the dog in toxicity tests on pharmaceutical compounds.
        Hum. Exp. Toxicol. 1993; 12: 99-109
        • Broadhead C.L.
        • Benton G.
        • Combes R.
        • et al.
        Prospects for reducing and refining the use of dogs in the regulatory toxicity testing of pharmaceuticals.
        Hum. Exp. Toxicol. 2000; 19: 440-447
        • Kennedy T.
        Managing the drug discovery/development interface.
        Drug Discov. Today. 1997; 2: 436-444
        • Grieshaber C.K.
        Agent-directed preclinical toxicology for new antineoplastic drugs.
        in: Valeriote F.A. Corbett T.H. Baker L.H. Cytotoxic Anticancer Drugs: Models and Concepts for Drug Discovery and Development. Kluwer Academic Publishers, Boston1992: 247-260
        • Tomaszewski J.E.
        • Smith A.C.
        Chapter 23, Safety testing of antitumor agents.
        in: Williams P.D. Hottendorf G.H. Comprehensive Toxicology, Toxicity Testing and Evaluation, Vol. 2. Elsevier Science Ltd, Oxford, England1997: 299-309
        • Tomaszewski J.E.
        • Smith A.C.
        • Covey J.M.
        • Donohue S.J.
        • Rhie J.K.
        • Schweikart K.M.
        Chapter 17, Relevance of preclinical pharmacology and toxicology to phase I trial extrapolation techniques. Relevance of animal toxicology.
        in: Baguley B.C. Anti-Cancer Drug Design. Academic Press, San Diego, CA2001: 301-328
        • Joint Steering Committee of the EORTC and CRC
        General guidelines for the preclinical toxicology of new cytotoxic anticancer agents in Europe.
        Eur. J. Cancer. 1990; 26: 411-414
        • 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.
        Br. J. Cancer. 1999; 81: 760-768
        • Dent S.F.
        • Eisenhauer E.A.
        Phase I trial design.
        Ann. Oncol. 1996; 7: 561-566
      3. Verweij J. Starting dose levels for phase I studies. Proceedings of the 9TH NCI-EORTC Symposium on New Drugs in Cancer Therapy, Amsterdam, 1996, 13 (Abstract).

        • Arbuck S.G.
        Workshop on phase I study design. Ninth NCI/EORTC New Drug Development Symposium, Amsterdam, March 12, 1996.
        Ann. Oncol. 1996; 7: 567-573
      4. Smith AC, Tomaszewski JE. Correlation of human toxicity and MTDs with preclinical animal data, presented at the preclinical pharmacology and toxicology workshop at the EORTC/NCI/AACR Meeting, Frankfurt Germany, 2002.

        • Clark D.L.
        • Andrews P.A.
        • Smith D.D.
        • DeGeorge J.J.
        • Justice R.L.
        • Beitz J.G.
        Predictive value of preclinical toxicology studies for platinum anticancer drugs.
        Clin. Cancer Res. 1999; 5: 1161-1167
        • Adams J.
        • Palombella V.J.
        • Sausville E.A.
        • et al.
        Proteasome inhibitors.
        Cancer Res. 1999; 59: 2615-2622
        • Adams J.
        Development of the proteasome inhibitor PS-341.
        Oncologist. 2002; 7: 9-16
        • Millar A.W.
        • Brown P.D.
        • Moore J.
        • et al.
        Results of single and repeat dose studies of the oral matrix metalloproteinase inhibitor marimastat in healthy male volunteers.
        Br. J. Clin. Pharmacol. 1998; 45: 21-26
        • Pilaro A.M.
        • Serabian M.A.
        Preclinical development strategies for novel gene therapy products.
        Toxicol. Pathol. 1999; 27: 4-7
      5. Pilaro AM. Preclinical animal models in gene therapy research. Biological Response Modifiers Advisory Committee Meeting, November 17, 2000.

        • Black L.E.
        • DeGeorge J.J.
        • Cavagnaro J.A.
        • Jordan A.
        • Ahn C.H.
        Regulatory considerations for evaluating the pharmacology and toxicology of antisense drugs.
        Antisense Res. Dev. 1993; 3: 399-404
        • Black L.E.
        • Farrelly J.G.
        • Cavagnaro J.A.
        • et al.
        Regulatory considerations for oligonucleotide drugs.
        Antisense Res. Dev. 1994; 4: 299-301
      6. ICH Guidance to Industry: S7A, Safety Pharmacology Studies for Human Pharmaceuticals (July 2001).

      7. ICH Guidance to Industry: S7B, Guideline on Safety Pharmacology Studies for Assessing the Potential for Delayed Ventricular Repolarization (QT Interval Prolongation) by Human Pharmaceuticals (February 2002).

        • Schweikart K.M.
        • Parchment R.
        • Osborn B.
        • et al.
        In vitro/in vivo bone marrow toxicity.
        Proc. Amer. Assoc. Cancer Res. 1995; 36 (abstr 2185): 367
      8. Tomaszewski JE, Schweikart KM, Parchment RE. Correlation of clinical and preclinical bone marrow toxicity data for selected anticancer drugs. First International Symposium on Hematotoxicology in New Drug Development, Lugano, Switzerland, 1997.

      9. Tomaszewski JE, Schweikart KM, Parchment RE. Correlation of clinical and preclinical bone marrow toxicity data for selected anticancer drugs. In Vitro Human Tissue Models in Risk Assessment Workshop of the Society of Toxicology, Ellicot Ciity, MD, 1999.

        • Parchment R.
        • Tomaszewski J.
        • Schweikart K.
        • LoRusso P.
        Success in predicting human maximum tolerated dose from in vitro data and mouse MTD.
        Proc. Amer. Assoc. Cancer Res. 2002; 43 (abstr 1046).: 208-209
        • Pessina A.
        • Albella B.
        • Bayo M.
        • et al.
        Application of the CFU-GM assay to predict acute drug-induced neutropenia.
        Toxicol. Sci. 2003; 75: 355-367
        • Hollingshead M.G.
        • Alley M.C.
        • Camalier R.F.
        • et al.
        In vivo cultivation of tumor cells in hollow fibers.
        Life Sci. 1995; 57: 131-141
        • Hollingshead M.
        • Roberson J.
        • Decker W.
        • et al.
        In vivo drug screening applications of HIV-infected cells cultivated within hollow fibers in two physiologic compartments of mice.
        Antiviral. Res. 1995; 28: 265-279