Trial design, endpoints and assessments, sample size calculation
toxicity, Klinikum der Universität, death, SD
ADVERSE EVENTS, DISEASE PROGRESSION, DISEASE
The CheCUP trial was investigator-initiated and was designed as a phase II, open-label, non-randomized, multi-center study evaluating the efficacy and safety of combined nivolumab and ipilimumab in previously treated patients with CUP. The trial was planned to include 194 patients and was performed at ten sites throughout Germany. After failure of platinum-based therapy, eligible patients were stratified based on TMB (high vs low, cut-off 12 mutations/Mb) following comprehensive genomic profiling and treated with combined nivolumab (240 mg biweekly) and ipilimumab (1 mg/kg every 6 weeks) until disease progression, loss of clinical benefit, unacceptable toxicity, death from any cause or withdrawal of consent. Treatment continuation beyond progression was permitted if the patient had investigator-assessed clinical benefit and continued to tolerate treatment. Patients were followed up for overall survival and safety objectives at day 100 and every 3 months thereafter via phone contact after discontinuation of study drug treatment. The study design aimed at balanced strata sizes with 50% of patients belonging to the TMBThe primary endpoint was progression-free survival (PFS), defined as the time from treatment start to the first occurrence of disease progression as assessed by the investigator according to RECIST v1.1 or death from any cause, whichever occurs first. Secondary endpoints included overall survival, defined as the time between start of therapy and death from any cause, overall response rate (ORR), defined as the proportion of patients who exhibit a complete (CR) or partial response (PR) to study treatment and duration of clinical benefit (DOB), defined as the time from the first occurrence of a CR, PR or stable disease (SD) after treatment start until disease progression or death from any cause. Safety and tolerability endpoints included incidence, nature and severity of adverse events (AEs), incidence and reasons for any dose reductions, interruptions or premature discontinuation of any component of the study treatment, as well as clinically significant laboratory values and vital sings.Sample size was calculated with R package gsDesign (The study was conducted on a national, multicenter basis and took place at the following German sites: University Hospital Jena, Evangelische Kliniken Essen-Mitte, Marienhospital Stuttgart, Kliniken Ostholstein ohO Onkologie, Uniklinikum Augsburg, Klinikum der Universität München, Universitätsklinikum Leipzig, Universitätsklinikum Tübingen, Onkologische Praxis Gütersloh, Universitätsklinikum Heidelberg. All sites are large university hospitals, community hospitals or oncological practices with dedicated, high-volume oncology units and large numbers of CUP subjects. In addition, each of the sites has a clinical trial center and study nurses specifically dedicated to execution and documentation of the CheCUP study.For the purpose of this study, sex as a biological attribute was determined based on self-reporting. As there were no preferences on the selection of gender to be included, it was anticipated that the study will result in a representative gender distribution, which should reflect the natural gender distribution in the underlying disease. There are no study findings that apply to only one sex. Since no specific findings were expected according to gender, this information was not collected. Based on previous observations, sex was not expected to affect survival of the trial participants. For this reason, no analyses apart from descriptive frequency analysis were performed regarding sex.