Phase 1 Trials: Therapy, Not Just Science

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Phase 1 trials should be considered therapeutic options for some patients.
Phase 1 trials should be considered therapeutic options for some patients.

A growing chorus of patients and leading researchers from around the world believe that phase 1 clinical trials should be considered viable therapy options, rather than merely as tests aimed at determining the safety or toxicity levels of the treatment in question. 

It's a dramatic change from years past, coinciding with the increased focus on targeted therapies and immunotherapies.

“We have a deeper understanding of tumour biology and can better select patients for trials, leading to higher response rates and increased clinical benefit,” Markus Joerger, MD, PhD, of the St Gallen Cancer Center in Switzerland, said in a release announcing the results of new research at the European Society for Medical Oncology (ESMO)'s Targeted Anticancer Therapies International Congress.1

The ethics of phase 1 trials have long been debated, as a paper in The New England Journal of Medicine pointed out, “because of the many unknown factors that participants in the trials face and because of the critical role the trials have in the development of new cancer treatments.”2

Among the primary criticisms was the perception that the relatively low rates of response offered exceedingly limited benefits, especially in light of the risks associated with being treated with an experimental therapy.

“Some contend that the enrollment of patients with advanced disease in risky research studies with little chance of direct benefit exploits a vulnerable population,” the authors of a 2005 review wrote.3

But, the review's authors found, the statistical evidence used to support that argument underreported overall response rates by focusing on single-agent trials.

While earlier reports found response rates of 4% to 6%, their analysis of 460 phase 1 trials involving 11,935 participants between 1991 and 2002 found complete or partial responses “exceeded 10 percent, with stable disease or less-than-partial response having been achieved in an additional 34.1 percent of participants.”

They argued, furthermore, that other factors need to be weighed in considering the value of phase 1 trials.

“Investigational treatments may have clinically meaningful benefits – reduced pain, increased appetite, energy, and activity, weight gain, reduced fatigue, or increased ability to perform daily activities,” they wrote. “Some of these benefits might accrue from research participation itself; for some persons, contributing to research and potentially helping future cancer patients may also be an important benefit.”

Another important benefit may be the effect on patient attitude, as the editorial published in The New England Journal of Medicine, which accompanied the review, noted:

“Our clinical experience with such patients – who often tell us that they have sought out a phase 1 trial, even if the chances of a response are small, because their quality of life is improved by ‘not giving up' – confirms this point.”

Since then, continuing advances in therapeutic agents have resulted in markedly improved quantifiable results at the trial level, especially in cases focusing on carefully selected patient participants.

In fact, a 2016 review of “all non-pediatric phase 1 oncology trials published in English in 2014 and 2015” found a significant leap in those statistics.4

“The overall response rate, ORR (i.e., for both complete and partial responses),” they wrote, “was 19.3%, and was significantly higher in clinical trials focusing on a specific population than in [an] ‘all comers' one.”

In part, that's a result of the ever-more specific selection criteria employed in choosing participants to test increasingly precise targeted therapies. Participants most likely to benefit from a therapy — because of their tumor biology or identifiable biomarkers, for example — become the ones chosen to participate in trials of those drugs.

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