Cancer continues to be the leading cause of death worldwide, even though there have been ostensibly major advances in the diagnosis, prevention, and treatment of cancer.  Researchers continue to investigate possible new therapies, but the drug development process is costly, lengthy, and complicated. As part of any new drug development, studies that are called “phase I studies” (or “first-in-human studies”) are designed to determine the pharmacological qualities of a new investigational component, assess safety and possible toxicity, and at times gain initial valuable information on effectiveness. Phase I studies are of great prominence because they serve to determine drug dosing as well as the merit in proceeding to further evaluation of a new molecule in subsequent well-controlled trials (i.e., phase II, III).

Phase I studies in oncology pose challenges unlike any other early phase study. Most phase I studies begin with healthy volunteers, but because of the unique nature of the trial compounds, participants in oncology phase I studies are typically patients with cancer rather than healthy volunteers. This presents ethical and practical challenges. Furthermore, the methodology in phase I oncology studies, with distinctive new investigational drugs (such as toxic chemotherapy, monoclonal antibody targeted therapy, and most recently immunotherapy with adoptive cell transfer), pose challenges that must be overcome before embarking on scientifically sound phase II and III.

Ethical Concerns With Phase I Oncology Studies

The ethical issues surrounding phase I studies in oncology are immense and a source of controversy for almost a century. A significant proportion of these trials seek enrollment of cancer patients with advanced disease, usually at a late stage of their illness or with metastases, and their options for standard treatment are limited and frequently include palliative care. Thus, recruiting these patients into a phase I trial may be seen as exploiting their circumstances. Management of what is commonly referred to as the “therapeutic misconception” weaves its way through these studies, as individuals may view them less as research and more as a treatment option. While phase I trials may show some benefit, that is not the primary purpose of a phase I study.

A study conducted in the 1990s clarified the fact that deriving a benefit from a phase I study is not very likely. Researchers reviewed 460 phase I oncology trials with almost 12,000 participants, with 46% of the studies using at least one FDA-approved drug and 20% using a single chemotherapy. This study showed an overall response rate to the phase I investigational therapy of 10.6%, with significant variability between trials. Another third of patients had less than a partial response to the investigational therapy or simply a stable, unchanged disease.

Beyond their noble willingness to tolerate study-related activities, such as additional blood draws, injections, imaging tests, and study-related visits, participants’ quality of life may be compromised due to the investigational therapy. Phase I studies may subject patients to toxicity from new drugs (especially if the maximum tolerated dose is yet to be found), potentially worsening their quality of life. In the study referenced above, researchers found the rate of toxicity resulting in death was 0.5%. There may also be an inherently unfavorable risk-benefit ratio in phase I oncology research.

With new types of therapies, new data is required to ensure effectiveness and risks are communicated to potential subjects so they can appropriately weigh participation in such phase I studies. The informed consent and disclosure process need to be streamlined, so risk-benefit ratios are clearly described. Supportive therapy during the trial is critical, and the use of approved standard of care should be made available if appropriate.

Need for New Methodologies

Additionally, to ensure that new drugs reach patients with oncological conditions at a faster pace, and to address some of the ethical issues, phase I studies need to employ better methodologies. One such advancement is the first-in-human multiple expansion cohort trials. These studies involve an initial dose escalation phase, where participants are enrolled in cohorts (or batches) that each receive increasing doses of the investigational therapy to determine the maximum tolerated dose in humans. Each dose cohort is evaluated before the next increased dose can be delivered, and this approach can help researchers more quickly understand dosing parameters while also minimizing potential negative effects on participants. First-in-human multiple expansion cohort trials include more patients’ cohorts as well as specific objectives for each one of them. These tend to support assessment of anti-tumor activity, biomarker evaluation, different schedule of administration or dose, and unique patient populations. Some of these trials may include several hundred patients at any given time, a large number in the phase I world.

Design and implementation of such studies is complex and needs to ensure safety of subjects, evaluate potential alternatives, and require appropriate (not too small, not too large) sample size. Recently, the FDA embarked on work to provide guidance on this type of study design to sponsors and sites alike and include some recommendations for the evaluation of studies by IRBs with expertise in the field.

Phase I oncology studies are unique, and it is thanks to patients, study participants, and their families that we constantly realize innovation in the field, for the benefit of future generations.

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