‘Broader and more inclusive design’ needed for novel cancer trials

ByJosh Friedman

Fact checked byMindy Valcarcel, MS

Key takeaways:

Patients who received waivers for a clinical trial testing off-label targeted therapies had similar response rates as those without waivers.
Serious adverse events did not differ between the groups.

Individuals with therapy-refractory cancer who received waivers to participate in a clinical trial for off-label targeted therapies achieved similar clinical benefits as those who took part in the study without an exception.

Additionally, patients granted a waiver did not have a higher likelihood of experiencing adverse events, according to study results published in Clinical Cancer Research.

Median OS in the DRUP basket trial infographic — Data derived from van Berge Henegouwen JM, et al. *Clin Cancer Res*. 2024;doi:10.1158/1078-0432.CCR-23-3917.

“If an experienced team looks at waiver requests and grants waiver after thorough review, then it is of benefit to the patients,” Hans Gelderblom, MD, chair of the department of medical oncology at Leiden University Medical Center in the Netherlands, told Healio.

Background and methodology

Eligibility criteria for clinical trials ensure individuals who may have adverse reactions to a therapy are not put at risk for additional harm, according to background information researchers provided. They also help researchers keep homogeneous study populations, which allows them to determine the efficacy of treatment.

Not all eligibility criteria are equal, however. Some restrict inclusion beyond necessity.

For example, a study in JCO Oncology Practice in 2015 found 39% of patients with renal cell carcinoma would not have been eligible for a phase 3 trial of a drug approved for them.

Also, 62% of patients with non-small cell lung cancer who receive osimertinib (Tagrisso, AstraZeneca) would not have been eligible for the phase 3 trial.

“It is well known that results in an ‘ideal’ population do not always translate to the real-world population,” Gelderblom said in an AACR-issued press release. “Eligibility criteria are often too strict, and educated exemptions by experienced investigators can help individual patients, especially in a last-resort trial.”

The FDA in 2020 and ASCO recently proposed broadening eligibility criteria, whereas regulatory agencies have opposed deviations and protocol waivers, researchers wrote.

Gelderblom and colleagues decided to investigate whether these waivers resulted in poorer outcomes using the ongoing Drug Rediscovery Protocol (DRUP), a pan-cancer basket/umbrella trial where patients with treatment-refractory cancer get matched to therapies not meant for them based on the tumor’s molecular profile.

“This academic-led study allowed us to grant, after thorough review of the medical steering committee, waiver for specific occasions,” Gelderblom said. “The importance of this study is that it showed the process in detail for the first time ever.”

DRUP researchers enrolled 1,019 patients between September 2016 and September 2021. Of that cohort, 82 received a waiver. They only granted waivers if two of the three principal investigators approved.

Both the waiver and nonwaiver groups had similar characteristics (median age, 63/62 years; both 54% men).

Researchers separated 88 total granted waivers into four categories — eligibility criteria (44.3%), testing exception (26.1%), treatment exception (19.3%) and out-of-window testing (10%).

Gelderblom and colleagues evaluated treatment efficacy and patient safety in those who received waivers as the study’s primary endpoints.

Results and next steps

Of the patients who received waivers, 40% achieved a clinical benefit, which researchers defined as either confirmed objective tumor response (17%) or no disease progression for at least 16 weeks (23%) following treatment.

In the rest of the cohort, 45% had a best response of progressive disease and 14% could not be evaluated.

For patients who did not need a waiver, 33% derived a clinical benefit.

Individuals who received a waiver had a median OS of 11 months compared with 8 months for the nonwaiver cohort.

Researchers did not find a statistically significant difference for either response or survival between the two groups.

Serious adverse events occurred in 39% participants with waivers (49 total serious adverse events) and 41% of the nonwaiver cohort.

Gelderblom and colleagues did not find statistically significant differences in the amount or grade of serious adverse events between the two groups.

They did find that granted waivers possibly contributed to 14% of the serious adverse events. Two patients granted waivers died, one of which possibly related to the waiver.

Most of the 12 individuals who received waivers (17 total) who could not be evaluated had stopped therapy due to toxicity or progressive disease prior to the conclusion of their first treatment cycle.

“These findings advocate for a broader and more inclusive design when establishing novel trials, paving the way for a more effective and tailored application of cancer therapies in patients with advanced or refractory disease,” Gelderblom said in the release.

Researchers noted limitations of the study included the multitude of tumor types, molecular profiles, assigned treatments and reasons for waivers in DRUP. They also did not have data on why waivers had been denied.

“It is important to submit amendments to the study when the same type of waivers are requested and appear to be safe after allowing them,” Gelderblom told Healio. “I hope this is a first step towards a more dynamic and realistic system for including patients in studies.”