Exclusion of patients with brain metastases from early-phase systemic therapy trials: a cross-sectional analysis of eligibility criteria.

PURPOSE: Patients with brain metastases (BrM) are frequently excluded from early-phase clinical trials, limiting evaluation of central nervous system (CNS) efficacy of novel therapies. We aimed to determine the proportion of phase I systemic therapy trials for patients with metastatic solid tumours that permit enrolment of patients with BrM and to characterise BrM-specific eligibility criteria. METHODS: ClinicalTrials.gov was searched in July 2024 for phase I systemic therapy trials for patients with advanced solid tumours and publicly available protocols. Trial characteristics and BrM eligibility criteria were independently abstracted by paired reviewers, with third-reviewer adjudication. RESULTS: Of 3,210 studies screened, 873 with protocols were analysed. Patients with BrM were eligible with stipulations in 70.3%, excluded in 13.2%, and unspecified in 16.5% of phase I trials. Genitourinary trials excluded patients with BrM more frequently than trials for other tumour types (26.4%). Among trials permitting enrolment of patients with BrM (n = 614), patients with active, unstable, and/or progressing BrM (84.0%), those with previously untreated (75.9%) and/or symptomatic (58.5%) BrM were excluded. Corticosteroid use and antiseizure medication use were completely prohibited in 19.4% and 9.4% of these trials, respectively. The proportion of trials permitting enrolment of patients with BrM varied without a consistent temporal trend (66.2% in 2010-2014, 72.8% in 2015-2019, and 67.6% from 2020 onwards). Trials combining immunotherapy and targeted therapy most frequently permitted enrolment (85.1%) of patients with BrM, whereas cytotoxic chemotherapy trials were least permissive (40.9%). CONCLUSION: Inclusion of patients with BrM in phase I trials remains variable, with the greatest permissiveness observed in trials combining immunotherapy and targeted therapy. However, restrictive eligibility criteria for active and/or symptomatic BrM remain common.