1710P - Protocol waivers and consequences on treatment safety and efficacy in the Drug Rediscovery Protocol (DRUP)

Background

Although eligibility criteria are an essential component of clinical trial design, overly restrictive criteria contribute to low accrual and poor generalizability of study results. To make trials more inclusive, there has been an increasing interest in broadening eligibility criteria, but how this affects patient safety remains unclear. In the Drug Rediscovery Protocol (DRUP, NCT02925234), protocol exceptions that were granted by the study team, taking into account the balance of potential benefits and risks, were analyzed. Here we describe the impact of these protocol waivers on patient safety and treatment efficacy.

Methods

DRUP is a Dutch multicentred, non-randomized, pan-cancer platform trial in which treatment-refractory patients are treated with targeted- and immunotherapies outside their registered indications, based on their tumor molecular profile. We collected data of all included patients for whom a waiver was granted and analyzed them in terms of treatment safety and efficacy. Also, safety and efficacy outcomes of these patients were compared to those of patients that did not need a waiver to participate.

Results

Between September 1, 2016, and September 1, 2021, 1019 patients were included in DRUP. In total, 88 protocol waivers were granted for 82 patients (8%). Most waivers were granted for general- or drug-related eligibility criteria (44%). For 32 of 82 patients that received a waiver (39%), 49 SAEs regardless of relationship to study treatment, were reported. For the included patients without a waiver (n=937), 666 SAEs were reported in 385 patients (41%, p = 0.81). The clinical benefit rate (CBR; either objective response or stable disease (SD) ≥ 16 weeks) of patients for whom a waiver was granted was 40% (14 patients (17%) with a partial response and 19 (23%) with SD ≥ 16 weeks), compared to a CBR of 33% in the non-waiver population (p = 0.43).

Conclusions

Safety and clinical benefit were preserved in patients for whom a waiver was granted in DRUP. Our data advocate omittance of ‘old’ unnecessarily strict safety criteria when setting up molecularly driven trials and support a more personalized approach in assessing eligibility criteria, especially in trials with therapeutic intent for patients without other treatment options.

Clinical trial identification

NCT02925234.

Editorial acknowledgement

Legal entity responsible for the study

The Netherlands Cancer Institute.

Funding

Stelvio for Life Foundation: funding; Dutch Cancer Society (KWF): funding; Hartwig Medical Foundation (HMF): genome sequencing; Pharmaceutical partners (Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Clovis, Eisai, Janssen, Lilly, Merck, Novartis, Pfizer, Roche): funding and study drugs.

Disclosure

All authors have declared no conflicts of interest.