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(More customer reviews)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, cell, or enzyme) as determined by biopsies, serum samples, or cell samples, during the course of the clinical study. We learn that the CSP must state instructions for dose-discontinuation or dose-reduction. We learn that the CSP must disclose all inclusion criteria and exclusion criteria, and that appropriate tests be disclosed for each and every one of these criteria. We learn that the CSP must disclose endpoints, e.g., for toxicity, for proof-of-principle assays, for expected toxicities, and for efficacy (RECIST criteria discloses guidance for endpoints for efficacy in tumor trials) (pages 163-179).
CONCLUSION. This book is nicely written. The writing is not mannered and does not digress by reciting trivial anecdotes. The book can be an excellent source of orientation for any person involved in clinical trials.
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Phase I Cancer Clinical Trials: A Practical GuidePhase I trials are a critical first step in the study of novel therapeutic approaches. They follow years of development in the laboratory, and precede Phase II and III trials where testing of the drug becomes more focused yet is conducted on a wider scale. The primary goals of Phase I trials are to identify the recommended dose, schedule and pharmacologic behaviour of new agents or new combinations of agents, and to describe the adverse effects of treatment. In cancer therapeutics, such studies have particular challenges. In general, because of the nature of the effects of treatment, most studies are conducted in patients with advanced malignancy, rather than in healthy volunteers. Furthermore, the endpoints of these trials are usually measures of adverse effects, but increasingly investigators are interested in assessment of the effects of new drugs on their molecular target. These factors render the design, conduct, analysis and ethical aspects of Phase I cancer clinical trials unique. This book provides a practical guide to Phase I cancer trials and is appropriate for oncology trainees or specialists interested in understanding cancer drug development.Topics covered include preclinical requirements needed for first-in-man investigation of new agents, principles and statistical design, ethical considerations of Phase I studies, pharmacokinetics, pharmacodynamics, and studies in special populations. Practical information on protocol development, study activation and conduct, as well as how to write reports of the results, are incorporated. Numerous appendices offer document templates to use in Phase I study development, and examples from actual Phase I trials are interspersed throughout, making this a true 'hands-on' guide. In an exciting time in cancer research, as the number and type of new potential anti-cancer drugs is increasing dramatically, this book provides much needed information on the first stage in getting a drug approved.
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