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Journal of Clinical Oncology, Vol 24, No 32 (November 10), 2006: pp. 5178-5179 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.09.1207
Dynamic and Modern: Bringing the Ethics of Phase I Trials Up to DateDevelopmental Therapeutics Program, Colorado Cancer Center, Aurora, Denver, CO To the Editor: We read with interest the recent Journal of Clinical Oncology article on the ethics of phase I oncology trials and would like to comment on a number of the arguments raised by Joffe and Miller,1 based on our own experience of many such trials. In addition, the authors1 concentrated largely on classical cytotoxic trials; in order to reflect today's practice, further comment on the emerging predominance of biologic agents in phase I trials would seem appropriate. Joffe and Miller1 focused primarily on the issue of whether the risk-benefit ratio in phase I trials is reasonable, in order to explore the larger question: are phase I oncology studies ethical? They discuss at length where to acquire the appropriate yardstick for measuring reasonableness. The choices discussed were best supportive care, US Food and Drug Administration-approved treatments, or non-US Food and Drug Administration approved off-study treatments. This last category is most commonly in the form of single agent cytotoxics, what some might call D-list chemotherapy drugs. What was not discussed was that the appropriate comparison depends on where in the patient's treatment journey phase I trials are introduced. The appropriate comparator is therefore not an absolute, but may be viewed as a dynamic variable to be selected on an individual basis during the informed consent process. On occasion we treat patients who reject all, or most, standard treatment involving cytotoxics and are only interested in trying phase I trials of biologic agents, in which case US Food and Drug Administration-approved treatments are the informative comparator. However, this is the exception and most of our patients do not usually have these standards left as options. While some have tended to refer patients to us for phase I studies when their only other option—and therefore the relevant comparator—is hospice care, we are increasingly emphasizing the importance of earlier consultations from our referral base. In part, this is to allow patients to gather all the facts in order to make informed ordering decisions in their therapeutic agenda (eg, whether to try phase I studies or D-list drugs first). While we would certainly support the publication of data on the risks and benefits of these kinds of D-list drugs in these heavily pretreated settings to facilitate the decision-making process, from a practical perspective, when the patient is well, there is a certain logic to trying phase I studies first. As the patient's performance status deteriorates—because most phase I trials have relatively strict inclusion and exclusion criteria—there may be a limited window of opportunity for phase I options, whereas the time window for administration of D-list drugs is likely to be wider. Therefore, ordering phase I studies before the D-list drugs may maximize the number of lines of defense potentially open to the patient. Noting that the relevant risk-benefit comparator is a dynamic variable that depends on where the patient is in their personal cancer journey and because of the dose-escalation nature of phase I trials, the baseline risks and benefits to compare against will also be dynamic depending on where the phase I trial is in its accrual when the patient enters. Given that US Food and Drug Administration guidance would suggest one tenth of the no adverse event level in the most sensitive preclinical animal species as the starting dose in humans, 2 and that most efficacy, at least for traditional cytotoxics, occurs within 80% to 120% of the maximum-tolerated dose (MTD), the informed consent discussion on the absolute and comparative risks and benefits cannot sensibly be the same throughout the full course of a phase I trial.3
Joffe and Miller allude to the lower toxicities of many of the newer biologic agents in phase I trials compared with traditional cytotoxics and the possibility of terminating studies below the MTD due to evidence of biomarker activity; although, in our experience, this second point is still the exception and not the rule.4 However, what should also be mentioned is that given that certain tumors appear highly addicted to some biologic pathways, clinical efficacy may also be apparent in key populations with these agents at doses well below the MTD.5 As a consequence, good performance status patients rotating through a series of well-tolerated phase I trials, looking for their own magic bullet, or more realistically buying periods of stable disease in Part of any modern rethinking of the risk-benefit assessment for phase I trials should reflect all of the aforementioned points. Authors' Disclosures of Potential Conflicts of Interest The authors indicated no potential conflicts of interest. REFERENCES
1. Joffe S, Miller F: Rethinking risk-benefit assessment for phase I clinical trials. J Clin Oncol 24
: 2987
-2990, 2006 2. US Food and Drug Administration. http://www.fda.gov/cber/gdlns/dose.htm 3. Von Hoff DD, Turner J: Response rates, duration of response, and dose response effects in phase I studies of antineoplastics. Invest New Drugs 9 : 115 -122, 1991[Medline] 4. Roberts TG, Goulart BH, Squitieri L, et al: Trends in the risks and benefits to patients with cancer participating in phase I clinical trials. JAMA 292
: 2130
-2140, 2004 5. Ranson M, Hammond LA, Ferry D, et al: ZD1839, a selective oral epidermal growth factor receptor-tyrosine kinase inhibitor, is well tolerated and active in patients with solid malignant tumors: Results of a phase I trial. J Clin Oncol 20
: 2240
-2250, 2002 6. Druker BJ, Talpaz M, Resta DJ, et al: Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukaemia. N Engl J Med 344
: 1031
-1037, 2001
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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6-month blocks, with much less risk to themselves from the different treatments is becoming the new reality, at least for a subset of phase I patients. Recognition of such biologic differences between malignancies has also lead to the deliberate enriching of many novel agent phase I clinical trial populations with patients in whom the biologic rationale is strongest, in a bid to improve each trial's risk-benefit ratio even further. The fact that the first safety and efficacy phase I trials of imatinib, which lead to its rapid US Food and Drug Administration approval, only occurred in patients with chronic myeloid leukemia (the final target population), is testimony to the potential benefits of this approach.
