Early-Stage Oncology Trials Increasingly Yield Therapeutic Benefits

Maurie Markman, MD
Published: Friday, Sep 28, 2018
Maurie Markman, MD
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.

Until the dawn of the molecular era of modern oncology, much of the biological rationale supporting antineoplastic drug development and the justification for delivering a particular agent in a given setting was far from robust. To put it bluntly, it was a shot-in-the dark. Thus, it is not surprising that most antineoplastic agents that reached the clinic failed to achieve even a modest degree of clinical utility and certainly, compared with their toxicity, could not support further exploration in phase II or III trials.

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.

As a result of the history of most early trial experience, it is not surprising that clinical investigators, drug regulatory agencies, institutional review boards, and medical ethicists emphasize the truly experimental nature of phase I oncology studies which, at best, offered a minimal opportunity for an individual patient to achieve even limited short-term clinical benefit through study participation. The overall risk-to-benefit ratio was far to the side of risk and any patient contemplating phase I trial entry needed to be clearly informed of these sobering facts.

Biomarkers Improve Outcomes

Over the past 20-plus years, and certainly during the past decade, this sobering ratio of risk-to-benefit associated with phase I trial participation has changed dramatically. In a landmark analy- sis summarizing the experience of National Cancer Institute–sponsored clinical trials from 1991 through 2002, an overall ORR of 17.8% was observed when a given phase I trial included at least 1 antineoplastic agent already approved for noninvestigative use.1

There has been a fundamental shift from the consideration of any advanced, previously treated patient with cancer refractory to standard-of-care therapy as an appropriate candidate for inclusion in a phase I trial to a focus on attempting to target therapy even in early-stage studies to patient populations where a scientifically rational biomarker has been validated. The presence of a molecular biomarker has the potential to strengthen substantially the biological rationale for treating that specific patient with the specific drug being examined. One needs to look no further than the truly paradigm-changing phase I study of imatinib (Gleevec) in chronic myeloid leukemia (CML), a cancer with a molecular abnormality strongly predictive of a favorable outcome, to appreciate the relevance of this strategy. In the study, 53 of the first 54 patients treated at an initial daily dose of ≥300-mg imatinib achieved a complete hematologic response.3

Although it would be quite inappropriate to declare that the imatinib story in CML is the new norm when it comes to predicting the benefits that patients participating in early-stage antineoplastic drug trials may experience, it would be equally incorrect to dispute that this new focus on more rational delivery of novel agents is resulting in genuinely meaningful clinical benefit, including in early-phase trials, in an increasing number of cases.

Multiple examples supporting this statement could be provided, but a highly provocative report stands out: an analysis of the phase I clinical trials program at The University of Texas MD Anderson Cancer Center. The study examined the clinical utility of early-stage therapy if a given patient was treated with an agent potentially targeting a molecular abnormality present within their cancer versus patients who participated in the program but could not be matched with clinical trials through molecular targeting.4 Not surprisingly, the nontargeted population experienced the historically distressing “standard objective response rate of 5%.” In striking contrast, for individuals who were able to be treated with a phase I drug in this program where a hypothesized “target” was present, the measured objective response was almost 3 times greater, with superior time to disease progression and overall survival compared with the unmatched population.4

That brings us to this question: Is it time to modify the existing rhetoric regarding the legitimate therapeutic intent associated with early-phase clinical trials, at least for studies where a solid molecular-based rationale for an individual patient’s participation can be provided?


  1. Horstmann E, McCabe MS, Grochow L, et al. Risks and benefits of phase 1 oncology trials, 1991-2002. N Engl J Med. 2005;352(9):895-904. doi: 10.1056/NEJMsa042220.
  2. Higby DJ, Wallace HJ, Albert DJ, Holland JF. Diaminodichloroplatinum: a phase I study showing responses in testicular and other tumors. Cancer. 1974;33(5):1219-1225.
  3. Druker BJ, Talpaz, Resta DJ, et al. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med. 2001;344(14):1031-1037. doi: 10.1056/NEJM200104053441401.
  4. Tsimberidou AM, Wen S, Hong DS, et al. Personalized medicine for patients with advanced cancer in the phase I program at MD Anderson: validation and landmark analysis. Clin Cancer Res. 2014;20(18):4827-4836.doi: 10.1158/1078-0432.CCR-14-0603.

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