There are questionable practices informing the design of modern oncology clinical trials.

A clinical trial may be underpowered because it enrolls too few patients, thereby precluding investigators from reliably assessing meaningful endpoints like overall survival. Conversely, a trial can be overpowered by enrolling more patients than needed, leading investigators to detect differences that may be statistically — but not necessarily clinically — significant, as was the case for the 2007 study that showed that adding erlotinib to gemcitabine in metastatic pancreatic cancer led to a statistically significant, approximately 10-day difference in overall survival.1,2

Trials can also randomize patients to control arms that are arguably worse than the current standard of care, such as what occurred in the POLO trial ( Identifier: NCT02184195), which led to the approval of olaparib as a maintenance therapy for patients with BRCA-mutated metastatic pancreatic cancer. For that study, the patients on the comparator arm received placebo, and critics of the reported results argued that patients typically would have been given more chemotherapy, rather than merely undergoing observation.3,4

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Although questionable, these practices remain the exception, not the rule, in oncology clinical trials — but the same cannot be said about a practice that permeates phase 1 clinical trials: a practice known as the 3-plus-3 approach, which is a type of rule-based design.

Time to Break the Rules

Rule-based designs identify the maximum-tolerated dose (MTD) on the basis of toxicity seen in a very small group of patients, and of the rule-based designs, the 3-plus-3 approach has been the most popular choice for decades.5 “It’s ludicrous,” Mark Ratain, MD, University of Chicago, Illinois, told Cancer Therapy Advisor. “That’s the way we did things 35 years ago.”

The 3-plus-3 approach has helped investigators identify doses for chemotherapeutics and continues to be used today, despite it being widely known that the 3-plus-3 approach is suboptimal for identifying dosages for newer agents — for example, agents such as small-molecule kinase inhibitors, as drugs like these can have delayed dose-limiting adverse reactions.6 

The 3-plus-3 approach works like this: 3 patients are given a dose, which is often based on preclinical data, and if no dose-limiting toxicity (DLT) occurs, the next-higher dose is given to 3 different patients. This continues until one or more DLTs is seen.5

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For instance, if 2 or 3 patients have a DLT, the previous dose is deemed the MTD. However, if only 1 patient has a DLT, an additional 3 patients receive that same dose. If no DLT is seen in this additional set of 3 patients, the trial moves on to the next higher dose, but if 1 or more patients in this set of 3 does have a DLT, the previous dose is deemed the MTD.5

“For the hundreds, if not thousands, of patients that are then being treated in later-stage trials, you’re sort of stuck with that dose that’s really based on 6 patients,” Jan Beumer, PharmD, PhD, director of cancer pharmacokinetics and pharmacodynamics at University of Pittsburgh Medical Center (UPMC) Hillman Cancer Center, told Cancer Therapy Advisor.