Heterogeneity of BCG unresponsive bladder cancer clinical trials limits patients' access to novel therapeutics

Introduction: Effective therapies for patients with nonmuscle invasive bladder cancer that recurs or progresses after Bacille Calmette-Guérin (BCG) are lacking. This unmet need is the focus of many drug development efforts, reflected in many completed/ongoing/planned clinical trials for patients with BCG unresponsive bladder cancer. Though BCG unresponsive criteria are well defined, enrollment criteria are variable such that, even at centers with several open trials in this space, a given patient with BCG unresponsive bladder cancer might not qualify for any. To understand the scope of this dilemma, we systematically analyzed enrollment criteria for all BCG unresponsive protocols registered on ClinicalTrials.gov to quantify heterogeneity in enrollment criteria and to determine what proportion of trials were inclusive to patients meeting U.S. Food and Drug Administration (FDA) BCG unresponsive criteria.

Methods: The ClinicalTrials.gov search tool was queried for relevant trials using the terms "bladder cancer" "nonmuscle invasive bladder cancer" and "BCG". Previously published review articles were cross-referenced to ensure that search results were comprehensive. Inclusion and exclusion criteria for the resulting 31 protocols pertaining to distinct categories such as performance status, laboratory parameters, co-morbidities, active medications, and prior therapies were recorded. Based on enrollment criteria, the trial was assessed as fully inclusive or not to patients considered to be BCG unresponsive by the 2018 FDA criteria.

Results: Of 31 trials, 15 (48%) had inclusion/exclusion criteria that were fully consistent with (inclusive of patients that met) the BCG unresponsive bladder cancer definition. 18 (58%) of trials excluded patients with a history of prior pelvic radiation therapy. 14 (45%) of trials excluded patients with ECOG performance status >2 (or Karnofsky Performance Status equivalent). The most common disease specific exclusion for patients with BCG unresponsive bladder cancer was a requirement for stage Tis (carcinoma in situ, CIS), which pertained to 7 (23%) of trials.

Conclusions: Enrollment criteria for patients with BCG unresponsive bladder cancer are highly variable. Over half of trials evaluated do not meet stringent criteria for this disease state based upon treatment history and cancer staging requirements. For patients who desire to enroll in clinical trials, this restricts access to novel agents. For bladder cancer treating physicians and regulatory bodies, this also hinders comparisons across agents.