Impact of protocol waivers on safety and outcome in the Drug Rediscovery Protocol study

Although eligibility criteria are essential in trial design, overly restrictive criteria contribute to low accrual and limited generalizability. The Drug Rediscovery Protocol (DRUP) study in The Netherlands is a multicenter, non-randomized clinical basket trial treating therapy-refractory cancer patients with molecularly targeted and immunotherapies outside their registered indications. In DRUP, protocol exceptions are frequently requested and occasionally granted. Between september 2016 and september 2021, protocol waivers were granted for 82 patients (8%) out of 1019 included patients. Most waivers (45%) were granted for general or drug-related eligibility criteria; other categories were out-of-window testing, treatment and testing exceptions. Serious adverse event rate was similar between group of patients who received a waiver (39%) and group of patients who did not receive a waiver (41%; p=0.81). Clinical benefit (objective response or stable disease for at least 16 weeks) was 40% among patients receiving a waiver versus 33% among patients not receiving a waiver (p=0.43). The authors conclude that safety and clinical benefit were preserved in patients receiving a waiver. These data support a more personalized approach in assessing eligibility criteria, especially in trials with widely used and approved drugs accruing patients without other treatment options.