Phase I Cancer Clinical Trials: A Practical Guide

Phase I trials are a vital initial step in the study of novel therapeutic approaches. They stick to years of development in the laboratory, and precede Phase II and III trials where testing of the drug becomes far more focused yet is conducted on a wider scale. The major targets of Phase I trials are to determine the advised dose, schedule and pharmacologic behaviour of new agents or new combinations of agents, and to describe the adverse effects of therapy. In cancer therapeutics, such scientific studies

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One response to “Phase I Cancer Clinical Trials: A Practical Guide”

  1. Tom Brody Avatar
    Tom Brody
    2 of 2 people found the following review helpful
    5.0 out of 5 stars
    Excellent source of orientation and perspective for people at any level., May 2, 2009
    Tom Brody (Berkeley, CA) –

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    PHASE I CANCER CLINICAL TRIALS by E. Eisenhauer, C. Twelves, and M. Buyse, is 343 pages long, and contains three schemas showing procedures for administering drugs (pages 144, 149, 156), and contains four graphs showing titrations resulting in drug toxicity (pages 49, 56, 143, and 147). There is also a valuable appendix containing a sample CONSENT FORM.

    Overall, the book is very clearly written. The book can be an excellent source of orientation for any person about to embark on a career relating to oncology clinical trials, as well as clinical trials in other fields. In short, this book can provide a well-appreciated groundwork for any physician, nurse, clinical study monitor, clinical study associate, statistician, medical writer, and marketing personnel.

    INVESTIGATOR’S BROCHURE (IB). We learn that the IB initially contains only preclinical data, but is updated annually as clinical data emerges. We learn that guidance on the IB is provided by the Good Clinical Practice Guidelines (E6) of the ICH (pages 33-34, 199).

    ENDPOINTS. We learn that clinical study endpoints can include pharmacodynamic (PD) endpoints and pharmacokinetic (PK endpoints). PD endpoints include toxicity endpoints, proof-of-principle endpoints, and efficacy endpoints. We learn that the WHO scale for toxicity was replaced by the CTC scale of the National Cancer Institute, and that this was replaced by CTCAE (Common Terminology Criteria for Adverse Events). We learn that each CTCAE term is correlated with a MedRA term (MedRA was developed by ICH) (pages 50-52, 177).

    DESIGNING THE TRIAL. We learn that trials can include different cohorts, each cohort receiving a different dose in escalated doses. We learn that data on the drug can take the form of effect on toxicity, expected effect on targeted tissues, non-expected effects on targeted and non-targeted tissues, and efficacy on tumor lesions. Data can be taken from samples of tissues, cells, enzymes, or metabolites. (pages 48-70, 155). We learn that in Phase I trials, toxicity can be used as a surrogate for toxicity (this means that people believe that a drug used at a dose high enough to exhibit toxicity, or at higher doses, is the dose expected to be effective against cancer).

    ANIMAL STUDIES. We learn how doses for humans are derived from animal studies (pages 71-72). The information provided in this book is scant. Perhaps the next edition reproduce the following document as an appendix: GUIDANCE FOR INDUSTRY AND REVIEWERS – ESTIMATING THE SAFE STARTING DOSE IN CLINICAL TRIALS FOR THERAPEUTICS IN ADULT HEALTHY VOLUNTEERS (FDA Dec. 2002).

    PD versus PK. We learn about differences between “pharmacokinetics” (PK) and “pharmacodynamics” (PD), and the fine point that in some cases, dose (as measured by mg/m squared) or pharmacokinetics (as measured by AUC) may more accurately predict toxicity, depending on the drug. In other words, the choice for predicting toxicity may be between using a PK parameter (e.g., AUC) or using dose (e.g., mg/m squared) (pages 48, 105-107, 209-243).

    DETAILS OF DESIGNING DRUG ADMINISTRATION. We learn about food effect studies, bioavailability studies, and drug-drug interaction studies (pages 117-132). We learn that for 2-drug combination regimens, if the 2 drugs have overlapping toxicities, the starting doses for Phase I human studies that are chosen are half that of a single drug study, but if there is no overlapping toxicity (as found in previous single drug studies), the 2-drug study will start out with the full doses used for the previous single dose studies (page 131). We learn that preclinical evidence for synergy of 2 drugs can be accurate or misleading (page 127-128).

    ESCALATING DOSES. We learn various approaches to escalating doses, where the goal is to find the dose-response relationship of an anti-cancer drug and to arrive at a value for the maximum tolerated dose (MTD) (a surrogate for efficacious dose). We learn that it may be a poor idea to conduct intrasubject dose escalation studies, because certain subjects tend to be responders (responding by a toxic reaction), while other human subjects tend to be responders. This means that any attempt to arrive at a MTD by focusing on one particular human subject, using the technique of escalating the dose stepwise, may be fruitless or misleading, because of the fact that some subjects simply do not response by exhibiting toxicity to a given drug. We learn that intrasubject dose escalation is also a poor idea because of the possibility of cumulative toxicity (pages 139-154).

    CLINICAL STUDY PROTOCOL (CSP). The CSP states if the drug is a member of an established class of drugs, and if earlier data on humans with the other drugs can help predict outcome with the new drug being presently tested. We learn that proof-of-principle refers to evidence that the drug is inhibiting its target (tissue,…

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