Statistical considerations and analysis populations
tumour, RCC
DISEASE, EVENT, TUMOUR, RCC
For phase 1b, data were summarised by dose level for each cohort separately. For Phase 2, efficacy and safety data were summarised by RP2D dose level of ibrutinib for each cohort. The safety population included all patients who received at least one dose of any study drug. The DLT-evaluable population was defined as patients from phase 1b who completed ≥ 21 days of treatment or discontinued treatment before 21 days due to a DLT event. Efficacy analyses were performed in the efficacy-evaluable population, defined as eligible patients (including DLT-inevaluable) who received at least one dose of ibrutinib at the RP2D in combination with at least one dose of the companion drug and had at least 1 post-baseline tumour assessment, regardless of treatment duration, or had died prior to the first adequate post-baseline assessment (RCC cohort) or had measurable disease and at least 1 post-baseline tumour assessment (GC and CRC cohorts). When analysing efficacy at the RP2D, the data from patients in phase 1 treated with the RP2D phase 2 were merged prior to analysis.For the RCC cohort, a single interim analysis for PFS futility was conducted when the twenty-fifth patient of 55 total dosed at the RP2D level had completed 6 months of follow-up. The study was designed to detect a 75% increase in median PFS to 8.6 months for ibrutinib plus everolimus with a sample size of 55 efficacy-evaluable patients. Phase 2 of the GC and CRC cohorts followed a Simon’s 2-stage design for patients treated at the RP2D. For the GC cohort, 39 patients were to be enrolled in two stages; if ≥ 2 of 21 patients had a tumour response (PR or CR) in stage 1, whereupon an additional 18 patients were enrolled in stage 2. Treatment was deemed acceptable for further clinical development if ≥ 6 patients responded. The Simon’s 2-stage design provided 80% power to test the historical ORR of 7% against the target ORR of 20%. In the CRC cohort, 40 patients were to be enrolled in two stages; if ≥ 3 of 22 patients were responders in stage 1, then an additional 18 patients were enrolled in stage 2. The Simon’s 2-stage design provided 80% power to test the historical ORR of 10% against the target ORR of 25%.