Immunotherapy is expanding like a novel treatment option for HCC. (27.1%) and a low discontinuation rate (2%) in patients with HCC. Here, we describe the design and rationale of PRIME-HCC, a two-part, multi-centre, phase Ib study to assess safety and bioactivity of the nivolumab/ipilimumab combination prior to LR in early-stage HCC. Methods The study involves an initial safety run-in phase (Part 1) to allow for preliminary safety characterisation within the first 6 patients enrolled and a subsequent expansion (Part 2). Ipilimumab will be administered once only on Day 1. Nivolumab will be administered on Day 1 and Day 22 ( 3?days) for a total of two 21-day?cycles (i.e. 6?weeks of treatment). The primary objective of the study is to determine the safety and tolerability of the nivolumab/ipilimumab combination prior to LR. The secondary objective is to preliminarily characterize the efficacy of the combination prior to LR, including objective response rate (ORR) and pathologic response rates. Additional exploratory objectives include preliminary evidence of long-term disease control and to identify predictive correlates of response to the nivolumab/ipilimumab combination in HCC. Discussion The results of this study will help define the positioning of neoadjuvant nivolumab/ipilimumab combination in the perioperative management of HCC, with potential to improve survival outcomes in this patient population. Trial registration EudraCT Number: 2018C000987-27 Clinical trial registry & ID: ClinicalTrials.gov: “type”:”clinical-trial”,”attrs”:”text”:”NCT03682276″,”term_id”:”NCT03682276″NCT03682276. Supplementary Information The online version contains supplementary material available at 10.1186/s12885-021-08033-x. Computed tomography; Magnetic resonance imaging; Eastern cooperative oncology group-performance status; White blood cells; Absolute neutrophil count; Upper limit of normal; Alanine/aspartate aminotransferase; Investigational medicinal product; Partial thromboplastin time/prombin time; a Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy, Rabbit polyclonal to TranscriptionfactorSp1 or in situ cervical cancer; breplacement therapy (eg. thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment; c with the exceptions relating to Hepatitis B and C virus Participants will require a full hepatitis serology screen prior to enrolment into the study, this includes Hepatitis B and Hepatitis C Virus serology. In patients with positive serology for either virus, baseline HBV DNA and HCV quantitative RNA levels will be requested. Participants who are confirmed to have chronic and active hepatitis B and/or C (i.e. with detectable HBV DNA or HCV RNA at baseline) will have their viral load (HCV RNA and/or HBV DNA as appropriate) monitored at each cycle and at the end of treatment follow-up visit. Planned sample size and study period We designed the study as a safety-oriented trial and considered enrolling a cohort of up to 32 participants to: Comprehensively characterise the safety profile of nivolumab and ipilimumab co-administration in patients with early-stage HCC; Preliminarily document the efficacy of treatment to inform subsequent efficacy-testing in a future adequately powered trial; Obtain adequate information regarding the disease-modulating effects from treatment reflected by the proposed exploratory endpoints. With the primary endpoint being safety, no power calculation for hypothesis testing is required to formally power the study: the upper 95% confidence interval for toxicity events will inform the decision to proceed to a future, adequately powered, phase II trial. Part 1 of the study will initially require a total of 6 patients. If 2 surgical. Delays are observed (primary safety endpoint), the study will continue to Part 2 following Independent Safety Data Monitoring Committee review of preliminary safety data. A second HG-14-10-04 interim analysis will be performed when 100% of the recruited patients have completed study follow-up visit 2 (FU2) to evaluate general safety and tolerability of the combination. Study procedures Patients will undergo baseline tumour imaging including computed tomography (CT) scan of the chest, abdomen and pelvis, and by contrast enhanced magnetic resonance imaging (MRI) scan of the liver at screening. At post-treatment time-points prior to surgery (on Day 43), after surgery (on Day 127) and 4-monthly thereafter, tumour imaging will be repeated using contrast enhanced MRI. A triple-phase CT of the liver is an acceptable alternative for intrahepatic staging in patients with contraindications to MRI. Baseline CT/MRI scans do not need to be repeated if obtained within 35?days of first dose. The same method HG-14-10-04 used for assessment at baseline must HG-14-10-04 then be used at all subsequent time points. RECIST v1.1 criteria will be used to determine patient response to treatment, progression-free survival (PFS) and ORR. A baseline core tumor biopsy will be collected from participants at screening and patients will have a parcel of leftover tissue from their LR specimen stored for correlative studies. Treatment will consist of a maximum of 2?cycles of nivolumab 3?mg/kg and 1?cycle of ipilimumab 1?mg/kg administered intravenously Q3W. Patients will be reviewed following completion of IMP treatment (Follow-up visit 1; FU1) on Day 43 +/? 3, prior to surgery. LR will be performed.