Endpoints and statistics
toxicity
INFILTRATE, ADVERSE EVENTS
The primary endpoint of this trial was safety and feasibility of different combinations of neoadjuvant nivolumab ± ipilimumab with domatinostat, as measured by surgery timelines. Surgery was not on-time if it was not performed at week 6 ± 1 wk due to trAEs. Feasibility was monitored with stopping boundaries using the Bayesian method. For this, the maximum allowed probability of delayed surgery (p0) was set to 20% and the prior distribution of that probability to the non-informative β (0.5, 0.5). A treatment arm was deemed unfeasible if there was at least 70% probability that p0 >20%. The data were evaluated with the DSMB after inclusion of 5 and 10 patients in each arm. In case of two delays out of five patients or three delays out of 10 patients, the treatment arm would stop for safety. These stopping boundaries were calculated using the software for Bayesian toxicity monitoring at Secondary endpoints were pathologic response rate, radiologic response rate, all grade and grade 3–4 trAEs, RFS, and quality of life. Translational endpoints included identification and comparison of RNA signatures associated with pathologic response, changes in immune infiltrate, expansion of tumor-resident T cell clones, and feces microbiome analyses. The pathologic and radiologic responses as well as adverse events were summarized as proportions among all patients in treatment arm, and their corresponding two-sided 95% confidence intervals were calculated using the Clopper-Pearson method. Survival curves for every treatment arm were generated using the Kaplan-Meier method, and overall comparisons across arms were done with the log-rank test. For confidence intervals of survival rates, the standard error was computed using Greenwood’s formula. No adjustments for multiple comparisons were performed. Median follow-up was computed using the reverse Kaplan-Meier method. Analyses were performed using R (v 3.5.1).