IMMUNOSABR will include 138 patients. The trialpopulation will be divided in two cohorts: patients eligible for ablative stereotactic body radiotherapy to all metastatic sites (treatment with curative intent) and patients not eligible for stereotactic body radiotherapy to all sites (life prolongation).In this single stage phase II trial we aim to demonstrate absolute increase in progression free survival at two years. . PFS will be determined as the time between randomization and disease progression, according to RECIST 1.1, death due to any cause or last patient contact alive and progression-free. Patients will be randomized between control (no L19-IL2) and experimental arms (with L19-IL2) in a 1:1 ratio. The accrual period will be 29 months (or 2.41 years) and the minimum follow-up will be 24 months (or 2 years), making the total study duration 53 months (or 4.41 years). Comparison between control and experimental arms will be done using the Log-Rank statistic. This test for superiority will be one-sided with a desired type I error of 0.10 and power of 0.80. The randomization allocation is 1:1.
Primary endpoint and power calculation For the ablative cohort: the expected 2-year PFS is 20% in the control arm (arm A) and 40% in the experimental arm ( arm B). The study is therefore powered to test for a difference in PFS at 2 years of 20%. The null hypothesis (H0) is that there is no difference in PFS between arm A and arm B. This results in a sample size of 72 patients evenly divided over two arms with 36 patient per arm. Considering a dropout rate of 10% from current experience, the actual amount of patients will be 40 per arm or 80 in total.
For the non-ablative cohort: the expected 2-year PFS is 10% in the control arm (arm C) and 30% in the experimental arm (arm D) The study is therefore powered to test for a difference in PFS at 2 years of 20%. The null hypothesis (H0) is that there is no difference in PFS between arm C and arm D. This resuls in a sample size of 52 patients evenly divided over two arms with 26 patient per arm. Considering a dropout rate of 10% from current experience, the actual amount of patients will be 29 per arm or 58 in total.
The total number of patients needed for the trial is the sum of the amount of patients in the ablative cohort (80 patients) and the amount of patients in the non-ablative cohort (58 patients): 138 patients.
Secondary endpoints Simple univariate comparisons of outcome and toxicity will be made between both treatment arms in each cohort using Chi-square tests for categorical data and independent samples t-tests for scale data. Secondary study parameter(s): Overall survival (OS) will be assessed using survival tables and Kaplan-Meier curves. OS will be calculated from the day of randomisation. Abscopal response, which can only be measured in the non-ablative cohort (with at least one non-irradiated target lesion) will measured as best response between experimental and standard treatment arms. Quality of life (EORTC QLQ-C30 version 3.0 and QLQ-LC13 questionnaires) will be recorded at regular intervals. Average changes in quality of life will be reported in terms of absolute differences in scores, and also in terms of minimally clinically relevant changes.
