STIMULI: A randomised open-label phase II trial of consolidation with nivolumab and ipilimumab in limited-stage SCLC after standard of care chemo-radiotherapy conducted by ETOP and IFCT

Preliminary results from trial CheckMate 032, targeting two distinct inhibitory immune checkpoints combining nivolumab, an anti-PD1 IgG1 monoclonal antibody and ipilimumab, an anti-CTLA4 IgG1 monoclonal antibody, demonstrate very promising 31% objective response rate (ORR) and 48% one-year overall survival (OS) in pre-treated advanced SCLC. This treatment option will be explored in a consolidation setting after curative-intent chemotherapy, chest radiotherapy (RT) and prophylactic cranial irradiation (PCI) for LD-SCLC. Trial design: STIMULI is an open-label, randomised, two-arm, phase II clinical trial. Inclusion is restricted to stage I-IIIB untreated LD-SCLC patients (pts) with adequate organ and pulmonary function, and no history of auto-immune disease. Hyper- or conventionally fractionated chest RT is administered concomitantly to 4 cycles of Cis-/carboplatin plus etoposide, followed by PCI. After completion of this standard treatment, non-progressing pts are randomised 1:1 to consolidation (induction and maintenance) or observation. Induction consists of four 3-week cycles of ipilimumab 3mg/kg plus nivolumab 1mg/kg, and is followed by maximally 12 months of nivolumab 240mg every 2 weeks. OS and progression-free survival (PFS) are co-primary endpoints. ORR, time to treatment failure and tolerability are secondary endpoints. A total of 325 pts are expected to be enrolled in the standard treatment phase, in order for 260 pts to be randomised, with a target hazard ratio of .70 for OS and .57 for PFS. The overall one-sided significance level of .05 is split to .04 for OS and .01 for PFS, with power 78% for OS and 80% for PFS. A safety evaluation for pneumonitis will take place after the first 30 patients reach the 12 weeks follow-up on the experimental arm. Safety will be monitored by the Independent Data Monitoring Committee every 3 months. Translational research will be done on formalin-fixed, paraffin-embedded tumour tissue, PBMCs, whole blood and serum samples at the Centre Hospitalier Universitaire Vaudois in Lausanne, Switzerland. Up to April 2016, 7 pts have been randomised, and enrolment is ongoing. Clinical trial identification: EudraCT number: 2013-002609-78 Legal entity responsible for the study: European Thoracic Oncology Platform ETOP Bristol-Myers Squibb