Phase I Oncology Trials: An Evolving Paradigm

Phase I studies are the cornerstone of translating findings from preclinical research into clinical practice and are used to determine the recommended dose and schedule of an experimental therapeutic (1). For decades, phase I oncology trials have been termed ‘toxicity trials’ or ‘safety trials’ and were considered to have low clinical utility other than that of establishing the toxicity profile of emerging therapeutics. Why? This is because phase I trials were thought to be solely aimed at elucidating the toxicity and pharmacokinetic profiles of investigational therapeutics with limited or no therapeutic intent.  Efficacy was not addressed.

The traditional distinction of the three-phase trial algorithm has been challenged in the past few years, most notably in the oncology space by the introduction of targeted therapies and immunotherapies into the cancer care model.  This transformation has especially affected early phase trials, leading to the current situation in which response rates are increasingly addressed and reported from phase I trials. A recent analysis shows that, despite their focus on safety, phase 1 trials of new cancer treatments may benefit participants more than previously thought.  This analysis revealed that over the past 2 decades, the number of phase I solid tumor trial participants whose tumors shrank or disappeared nearly doubled and the percentage of patients whose tumors stopped growing for a time also increased. The risk of death caused by a new treatment being tested, however, remained steady and very low, at less than 1% (2).

We all bear witness to the progressive evolution of perceptions, acceptance, and in many of opinion, the value of phase I trials, especially in the oncology setting.  Still yet, the perception of the potential benefit to patients has not caught up with current drug development. Historically, patients in phase 1 trials generally have had suboptimal tumor response rates, at roughly 4%–5%. Moreover, the primary purpose of phase 1 trials remains all about the assessment of safety with elements of supportive ADME data. So, some doctors have lacking in support in referring patients to phase 1 trials.

But we and others have now shown that things have changed. Participating in phase 1 trials has more potential for clinical benefit than is commonly believed, largely due to the development of modern cancer drugs, like targeted therapies, immunotherapies, regenerative medicines, such as cell and gene therapeutics as well as new combination therapies.

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This is not to say safety does not still rule the roost in phase I trials. The determination of the toxicity/safety profile of a novel therapeutic will always be the crux of phase I clinical trials; yet, as ‘Precision Medicine’ continues to evolve and bring increasing access to biomarker-based, molecularly targeted therapeutics which further refine patient selection, more and more phase I trials can have a therapeutic aim. Not to forget, there is a move to incorporate phase II extensions to demonstrate efficacy in the phase I setting.  We also better understand our therapeutics at an earlier stage in drug development, especially in oncology which has been driven by having sequenced the entire genome and the readily available next generation sequencing.  In such, oncologic drug development, investigation products have well-defined mechanisms of action (MOA) and targets having potential of rapid determination of efficacy through creative phase I trials designed to enrolling much larger volumes of patients than we have seen in the past.

You can see this trend yourself, just look at FDA approvals in the past few years where several investigational products have been approved on the basis of results from phase I studies.   Yes, approved, on the basis of PHASE I TRIALS (pembrolizumab/melanoma, ceritinib/NSCLC et al).  This is such a massive evolution to bringing novel and potentially beneficial therapies to patients sooner.  We applaud the FDA for so boldly prioritizing the critical and timely needs of cancer patients, but are keenly aware, we are still lacking a overall consensus on whether or not a favorable ORR translates into a survival advantage, as even promising phase II ORRs are not always predictive of survival benefits in subsequent phase III trials.

It is important to mention, OncoBay recognizes that phase I oncology trials encompass a variety of study designs and therapeutics with unique MOAs.  Add the potential benefit of adding surrogate end points, especially threshold values, to the trial design.

Efficacy outcomes may differ depending on the ‘n’ of the trial (did it include a large expansion cohort) and if the therapies tested involve combinations including approved agents versus non-approved agents as monotherapy. But, it is hard to argue the promise with Overall Response Rates are reaching around 40% (up from <5%) in current targeted phase I investigational therapeutics (those driven by a genomic biomarker being the highest).  Recall, the ORRs of approved oncology drugs as monotherapy are typically >20%, and FDA accelerated approval for oncologic agents generally sits around >30% (1).

Additionally, there are statistical considerations which have also evolved in the phase I setting. Randomized phase I study designs, and or those which incorporate dose-expansion cohorts are additional strategies to improve the statistical power and potentially enhance the readout of potential phase I therapeutic efficacy.

What are your thoughts around; the therapeutic intent of phase I trials, your perspective of if and how these trials have evolved, how this evolution has contributed to the concept that current phase I trials can be a therapeutic option for cancer patients, and what are the ethical considerations we should be addressing. We look forward to hearing from you.


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OncoBay is now Kapadi


Once three entities – OncoBay Clinical, Clinscience, and Exom Group s.r.l – now we stand as one, bringing forth a symphony of expertise and seamless operations. To celebrate our unity, we re-brand under the banner of Kapadi, and embark on a new chapter of exceptional service in oncology clinical research.

Kapadi is not just a name; it's a testament to our fusion. It signifies the our standing as a global CRO powerhouse committed to accelerating groundbreaking cancer therapies that uplift patients worldwide. From conceptualizing studies, navigating regulations, and analyzing data, we provide a comprehensive array of services designed to empower your oncology clinical trials.




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