Determination of sample size
toxicity, toxicities, HCC
ADVERSE EVENTS, EVENT, RECRUITMENT
A total of 105 patients will be randomized using a 2:1 randomization ratio to allocate patients to either the experimental arm (Arm A: atezolizumab plus bevacizumab and UCPVax) or the control arm (Arm B: atezolizumab plus bevacizumab).In the experimental Arm (Arm A), the aim is to demonstrate that the rate of patients with an objective response at 6 months post randomization (P) is clearly higher than 30% [According to a Simon two-stage Optimum design (with a one-sided 5% type I error and power of 80%, Fig. H0: 30% (P0) of patients with an objective response is uninterestingH1: 47% (P1) of patients with an objective response is interestingIn terms of statistic the study was elaborated to test the following hypotheses in the experimental arm: H0: P ≤ P0 versus H1: P ≥ P1Simon two-stage Optimum design fixed in the experimental armStage 1:After randomization of the first 21 patients with a follow-up of 6 months from the date of randomization:if ≤ 7 (33.3%) patients are identified with an objective response, the intervention could be declared uninteresting. No more additional patient will be included and the study will be stopped.if ≥ 8 patients are identified with an objective response, 42 additional patients will be randomized.Stage 2:After recruitment of 63 evaluable patients with a follow-up of 6 months from the date of the randomization:if ≤ 24 (38.1%) patients are identified with an objective response, the intervention will be declared uninterestingif ≥ 25 (39.7%) patients are identified with an objective response, the intervention will be regarded as interestingWith an expected 10% rate of patients not evaluable at 6 months or drop out patients, it will be necessary to randomize a total of 70 patients in the experimental Arm (Arm A).Considering the randomization ratio 2:1, it will be necessary to randomize 35 patients in the control Arm (Arm B) and then to randomized a total of 105 patients in the phase II.The control arm will serve to verify the good calibration of the P0 hypothesis made in the experimental arm and to provide true controls for translational investigations. No statistical comparison is planned between the two arms.Randomization will be done using minimization technique (hazard compound 0.9) with stratification according to:CenterMacrovascular invasion and/or extrahepatic spread: absence versus presenceBaseline alpha-foetoprotein (AFP): < 400 versus ≥ 400 ng/mLECOG-PS: 0 versus 1At the stage 1, in parallel given that the safety profile of UCPVax and atezolizumab plus bevacizumab combination has not been evaluated in patients with HCC so far, a semi-continuous monitoring for toxicity using Pocock-type boundary will be performed (probability of early stopping: 0.05, targeted dose-limiting toxicity [DLT] rate: 0.20). Patient recruitment will be stopped and discussed with the DSMB (Data Safety Monitoring Board) after the 21 first patients included in the experimental arm (Arm A) with a minimal follow-up of 6 months.The trial will be stopped if the number of dose limiting toxicities is equal to or exceeds bn out of n patients with completed follow-up. This boundary is equivalent to testing the null hypothesis, after each patient, that the event rate is equal to 0.2, using a one-sided level 0.019493 test [Pocock-type stoppingAn Independent Data and Safety Monitoring Committee (IDMC) will be constituted and will meet for the validation of the passage from stage 1 to stage 2; for the monitoring of toxicities and also for the reviewing of serious adverse events (SAE). DSMB will meet also in case of unexpected toxicities or in demand.