Maurie Markman, MD
The critical role of phase I clinical trials in the development of effective systemic antineoplastic therapy is well established. Further, it is understood that because the fundamental purpose of administering these agents is to kill or at least temporarily prevent the growth or progression of the malignant cell population, drugs that prove successful in fulfilling this goal also may produce serious adverse events (AEs). Although preclinical evaluation hopefully will alert clinicians and research participants to the range and expected severity of predicted toxic events, the full spectrum of drug-associated AEs and the severity of the risk may be a daunting unknown.
In fact, reviews of the appropriately designed and monitored phase I trial experience during the first 4-plus decades of cancer drug development that began shortly after the end of World War II noted objective response rates (ORRs) in these studies of 5% or less, with most reported tumor regressions being only a few months in duration.1
Overall, the majority of tested drugs were essentially of no clinical utility, resulting in far more harm than good, as measured by toxicity and evidence of objective response, for patients with cancer who elected to participate in these early-phase clinical investigative efforts.
There were rare, but critically relevant, exceptions to this general statement, such as the phase I trial of cisplatin, which produced an objective response in 9 of 11 patients with testicular tumors treated with the drug in one such early study.2
All oncologists know the subsequent history of this agent, which continues to play a major role in the management germ cell cancers.
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