Unfortunately, not all oncology trials succeed. In fact, the phase success and likelihood of approval (LOA) rates for oncology are the lowest across major therapeutic areas. Although there are many reasons for these relatively poor success rates, issues determining dose, schedule, and regimen in early phase trials are among the most prominent.
Why and Where Early Oncology Trials Fail
The main failure in oncology trials happens in Phase II. According to research published by M. Hay et al. in 2014, oncology trials have phase success and LOA rates comparable to other therapeutic areas, such as infectious disease and endocrinology, between Phase I and II trials. It’s between Phases II and III that success rates for oncology dip, a discrepancy that is then compounded in the following Phase III to regulatory approval transition.
1. Failure to demonstrate significant efficacy
To demonstrate sufficient efficacy of a drug for a given indication is the main goal of Phase II trials and their biggest stumbling block. With a sample size that is big enough to derive statistically significant efficacy data for a given indication, why do so many Phase II trials of apparently promising therapies fail to do so?
The answer can be found in how Phase I trials are conducted. Early Phase I trials are focused on safety and often move too quickly without optimizing dose, regimen, indication, regulatory path, and potential combination partners. The result is often an investigational agent that isn’t ready for Phase II to be pushed forward unprepared.
The solution? More rigorous novel early phase trials before Phase II that supply enough data to provide some statistical confidence that the drug will work in the selected indication. Inclusion of a comparator arm when possible, ideally by randomization and double blinding, should be seriously considered.
2. Inaccurate maximum tolerated dose
Another holdover from too-hasty Phase I to II transitions, some Phase II trials begin with inaccurate maximum tolerated doses (MTDs). Phase II dosing is partly dependent on an MTD defined by Phase I trials, but approximately 30% of historical early phase studies that have attempted to define MTD failed to do so. This means that Phase II studies may use doses that are either too toxic or not at a high enough dosage to actually work. To address this issue, dose optimization studies should be done prior to designing Phase II.
3. A lack of tailoring
Some of the biggest failures in oncology drug development in recent years have come from a failure to adhere to the progressive “5R” framework for long-term success in early trials. The foundation for this philosophy is a focus on five considerations for Phase II trials that have to be just “right” for a specific drug and/or indication: target, tissue, safety, patients, and commercial potential. For an in-depth rundown of what each of these means for oncology trials, you can read our blog post focusing on them here.
4. A trial size not right for the investigational agent and indication
You can think of this as a sixth “R.” There’s a fine line between involving too many institutions and too few. Too many can result in safety issues, while too few (e.g., one) can mean lengthier development times. Make sure study designers can make an informed and accurate call long before recruitment begins.
5. Not exploring combinations that include standard of care
Oncology trial designs that incorporate standard of care (SOC) help to ensure that all patients involved receive effective treatment. Although not always possible, the ideal Phase II trial should be SOC with placebo measured against SOC with study drug.
6. Not having a clinically tested biomarker for pre-screening patients
In the modern oncology landscape with its — justifiably! — heavy emphasis on personalized medicine, not using a clinically tested biomarker to pre-screen patients for likely study drug responders can easily hamstring Phase II and III trials. Targeted therapies need to be targeted at the appropriate patients and indications.
Better Ways of Assessing Efficacy in Early Clinical Oncology Trials
By now, you may have noticed a running theme: Oncology trial failure can often be traced back to mistakes and oversights in Phase I/II study design, especially when it comes to dosing considerations. One way to address this is through a focus on understanding the mechanism of an investigational agent and its translation through animal studies and in human cells. When this fundamental data is not available, however, early clinical trials should attempt to establish and/or elucidate drug mechanisms.
Fundamentally, early trials should be designed to obtain pharmacokinetic (Cmax, Cmin, AUC) and pharmacodynamic data (if possible) to optimize dose and dosing regimen. Wherever feasible, early studies should employ non-invasive procedures, such as blood and circulating tumor cells, to obtain samples. Study designers should remember that serial tumor biopsies are not preferred and should be collected only if there are no other methods of assessing mechanism of action or activity, or when indicated for SOC assessment. Smaller studies exploring mechanism of action or other assessments of effect with a subgroup of trial participants are another option for early phase oncology trials.
Dose Expansion Cohort
A study specifically designed to find the recommended Phase II dose (RP2D) is an important foundation for successful Phase II oncology trials. In this dose expansion cohort, the goal is to confirm a dose and treatment regimen for use in a planned randomized comparative — and ideally powered — Phase II decision-enabling trial. This data can also be used to identify indications of interest. Promising doses determined in dose-ranging studies are tested in a larger number of patients at a fixed dose and interval. To learn more about dose-finding design strategies in early oncology trials, be sure to check out our previous blog.
Ensure Success Through Bespoke Trial Design
Always remember that there is no one-size-fits-all approach to clinical research, especially when it comes to a complex and quickly changing therapeutic area such as oncology. Make sure your trial’s planned dose, schedule, and regimen are all right for your trial. Watch our webinar, Preparing for Phase II: Finding the Right Dose, Schedule, and Combination for Phase I/II Oncology Trials, for more information on how.