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Envisioning the future of early anticancer drug development

Nature Reviews Cancer volume 10, pages 514–523 (2010)Cite this article

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Abstract

The development of novel molecularly targeted cancer therapeutics remains slow and expensive with many late-stage failures. There is an urgent need to accelerate this process by improving early clinical anticancer drug evaluation through modern and rational trial designs that incorporate predictive, pharmacokinetic, pharmacodynamic, pharmacogenomic and intermediate end-point biomarkers. In this article, we discuss current approaches and propose strategies that will potentially maximize benefit to patients and expedite the regulatory approvals of new anticancer drugs.

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Figure 1: The shifting focus of old versus new Phase I clinical trial designs.
Figure 2: Updating the pharmacological audit trail.
Figure 3: Future clinical track for early-phase clinical trials.

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Acknowledgements

The Drug Development Unit of the Royal Marsden NHS Foundation Trust and The Institute of Cancer Research is supported in part by a programme grant from Cancer Research UK. Support was also provided by the Experimental Cancer Medicine Centre (to The Institute of Cancer Research) and the National Institute for Health Research Biomedical Research Centre (jointly to the Royal Marsden NHS Foundation Trust and The Institute of Cancer Research). T.A.Y. is a Cancer Research UK Clinical Research Fellow and P.W. is a Cancer Research UK Life Fellow.

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Authors and Affiliations

  1. Timothy A. Yap, Shahneen K. Sandhu and Johann S. de Bono are at the Drug Development Unit, Royal Marsden NHS Foundation Trust, Downs Road, Sutton, Surrey, SM2 5PT, United Kingdom.,

    Timothy A. Yap, Shahneen K. Sandhu & Johann S. de Bono

  2. Timothy A. Yap, Shahneen K. Sandhu, Paul Workman and Johann S. de Bono are at the Section of Medicine and Cancer Research UK Centre for Cancer Therapeutics, The Institute of Cancer Research, 15 Cotswold Road, Sutton, Surrey SM2 5NG, United Kingdom.,

    Timothy A. Yap, Shahneen K. Sandhu, Paul Workman & Johann S. de Bono

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Correspondence to Johann S. de Bono.

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Competing interests

All the authors are employees of the Institute of Cancer Research, which has a commercial interest in the development of inhibitors of HSP90, PI3K, AKT, BRAF, PARP, CYP17, CDK and chromatin-modifying enzymes. The authors have potentially relevant commercial interactions with Vernalis Ltd, Novartis, Piramed Pharma (acquired by Roche), Astex Therapeutics, AstraZeneca, GSK, Cougar Biotechnology Inc. (acquired by Johnson & Johnson), Merck Serona and Cyclacel Pharmaceuticals.

Related links

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DATABASES

clinicaltrials.gov

NCT00638690

National Cancer Institute Drug Dictionary

5-fluorouracil

abiraterone acetate

cetuximab

FOLFIRI regimen

GDC-0941

gefitinib

imatinib

irinotecan

lapatinib

olaparib

panitumumab

pertuzumab

PF-02341066

PLX4032

sorafenib

tanespimycin

trastuzumab

trastuzumab-DM1

Glossary

Biologically active dose range

The range of drug doses required to result in the modulation of the cellular target of the drug to produce its expected effect.

Continual reassessment method

This tool uses statistical modelling and is employed in dose-finding clinical trials to estimate the dose at which the desired toxicity level can be expected to minimize risk of toxicity to patients.

Maximum tolerated dose

The highest dose of a drug or treatment that does not cause unacceptable side effects.

Pharmacodynamics

The relationship between drug concentration and its biological effects (what the drug does to the body).

Pharmacogenetics

This term was coined in 1959 and represents the study of genetic factors that influence response to drugs and chemicals18.

Pharmacogenomics

Recent advances and improvements in large genome-scale sequencing and bioinformatic tools for processing data have led to the transition of pharmacogenetics to pharmacogenomics, which involves studies of the entire spectrum of genes in the human genome18.

Pharmacokinetics

The concentration of drugs in the body over a period of time, including the processes by which drugs are absorbed, distributed in the body, localized in tissues, metabolized and excreted (what the body does to the drug).

Predictive biomarker

Any measurement associated with response to or lack of response to a particular therapy.

Response Evaluation Criteria In Solid Tumours

A set of published rules that define when cancer patients improve (respond), stay the same (stable) or worsen (progress) during treatments.

Single-arm Phase II trial

A trial that demonstrates the safety and activity of a drug in a selected group of patients. This is in contrast to randomized clinical trials, which involve the random allocation of different treatments (including placebo) to patients in different groups.

Surrogate threshold effect

The minimum treatment effect on the surrogate end point necessary to predict a non-zero effect on the true end point.

Synthetic lethality

In genetics, a phenomenon in which the combination of two otherwise non-lethal mutations results in a non-viable cell.

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Yap, T., Sandhu, S., Workman, P. et al. Envisioning the future of early anticancer drug development. Nat Rev Cancer 10, 514–523 (2010). https://doi.org/10.1038/nrc2870

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