A critical analysis of neuro-oncology clinical trials

Abstract

Background: Limitations in trial design, accrual, and data reporting impact efficient and reliable drug evaluation in cancer clinical trials. These concerns have been recognized in neuro-oncology but have not been comprehensively evaluated. We conducted a semi-automated survey of adult interventional neuro-oncology trials, examining design, interventions, outcomes, and data availability trends.

Methods: Trials were selected programmatically from ClinicalTrials.gov using primary malignant central nervous system tumor classification terms. Regression analyses assessed design and accrual trends; effect size analysis utilized survival rates among trials investigating survival.

Results: Of 3038 reviewed trials, most trials reporting relevant information were nonblinded (92%), single group (65%), nonrandomized (51%), and studied glioblastomas (47%) or other gliomas. Basic design elements were reported by most trials, with reporting increasing over time (OR = 1.24, P < .00001). Trials assessing survival outcomes were estimated to assume large effect sizes of interventions when powering their designs. Forty-two percent of trials were completed; of these, 38% failed to meet their enrollment target, with worse accrual over time (R = -0.94, P < .00001) and for US versus non-US based trials (OR = 0.5, P < .00001). Twenty-eight percent of completed trials reported partial results, with greater reporting for US (34.6%) versus non-US based trials (9.3%, P < .00001). Efficacy signals were detected by 15%-23% of completed trials reporting survival outcomes.

Conclusion: Low randomization rates, underutilization of controls, and overestimation of effect size, particularly pronounced in early-phase trials, impede generalizability of results. Suboptimal designs may be driven by accrual challenges, underscoring the need for cooperative efforts and novel designs. The limited results reporting highlights the need to incentivize data reporting and harmonization.

Keywords: clinical trial design trends; leveraging of trial registry data; primary central nervous system malignancies; treatment effect size assumptions; trial accrual.

Figure 1.

Overview of trial landscape. (A) Number and trial status and (B) Data reporting over years. (The plots exclude depiction of 5 pre-1990 trials).

Figure 2.

Enrollment trends. (A) Proportion of completed trials meeting at least 90% of their target enrollment stratified by US versus non-US location. (B) Comparison of target and actual enrollment for completed trials, by phase. Significance levels for P-adj: 0 < *** ≤ .001 ≤ ** ≤ .01 ≤ * ≤ .05.

Figure 3.

Effect size assumption analysis. The minimum ES that each trial is sufficiently powered to assess was computed for trials reporting anticipated enrollment and primary endpoints of OS, PFS, or ORR. For OS/PFS calculations, trials studying multiple diagnoses were assessed based on the diagnosis with poorest prognosis to allow for most lenient assessment. Therefore, survival information for 100% of low survival category trials was based on Glioblastoma; for moderate survival category trials, survival information was based on survival for Glioma for 56.2%, Neuroectodermal Neoplasm for 9.0%, Astrocytoma for 7.7%, Meningioma for 7.7%, CNS Lymphoma for 7.2%, and other diagnoses for <7% of the trials; for high survival category trials, survival information was based on Germ Cell Neoplasm for 46.6%, Pituitary Neoplasm for 24.6%, Medulloblastoma for 16.7%, Ependymoma for 8.5%, Craniopharyngioma for 5.6%, and other diagnoses for <1% of trials. The percentage of trials that failed to meet their target enrollment was computed for completed trials reporting anticipated and actual enrollment.

Figure 4.

Overview of reported efficacy and toxicity. (A) Median responses were compared for experimental and control arms using one-sided Wilcoxon test for completed trials reporting response in either or both arms. One comparison is significant after FDR correction. (B) Proportion of patients experiencing serious and other AEs among trials reporting both experimental and control arm toxicity data.

Figure 5.

Trends of Intervention Mechanisms of Action. Proportion of most common mechanisms of action among interventions over years. Significance levels for P-adj: 0 < *** ≤ .001 ≤ ** ≤ .01 ≤ * ≤ .05.