PRISM protocol: a randomised phase II trial of nivolumab in combination with alternatively scheduled ipilimumab in first-line treatment of patients with advanced or metastatic renal cell carcinoma

Abstract

BackgroundThe combination of nivolumab, a programmed death-1 (PD-1) targeted monoclonal antibody, with the cytotoxic T-lymphocyte antigen-4 (CTLA-4) targeted antibody, ipilimumab, represents a new standard of care in the first-line setting for patients with intermediate- and poor-risk metastatic renal cell carcinoma (mRCC) based on recent phase III data. Combining ipilimumab with nivolumab increases rates of grade 3 and 4 toxicity compared with nivolumab alone, and the optimal scheduling of these agents when used together remains unknown. The aim of the PRISM study is to assess whether less frequent dosing of ipilimumab (12-weekly versus 3-weekly), in combination with nivolumab, is associated with a favourable toxicity profile without adversely impacting efficacy.MethodsThe PRISM trial is a UK-based, open label, multi-centre, phase II, randomised controlled trial. The trial population consists of patients with untreated locally advanced or metastatic clear cell RCC, and aims to recruit 189 participants. Participants will be randomised on a 2:1 basis in favour of a modified schedule of 4 doses of 12-weekly ipilimumab versus a standard schedule of 4 doses of 3-weekly ipilimumab, both in combination with standard nivolumab. The proportion of participants experiencing a grade 3 or 4 adverse reaction within 12 months forms the primary endpoint of the study, but with 12-month progression free survival a key secondary endpoint. The incidence of all adverse events, discontinuation rates, overall response rate, duration of response, overall survival rates and health related quality of life will also be analysed as secondary endpoints. In addition, the potential of circulating and tissue-based biomarkers as predictors of therapy response will be explored.DiscussionThe combination of nivolumab with ipilimumab is active in patients with mRCC. Modifying the frequency of ipilimumab dosing may mitigate toxicity rates and positively impact quality of life without compromising efficacy, a hypothesis being explored in other tumour types such as non-small cell lung cancer. The best way to give this combination to patients with mRCC must be similarly established.Trial registrationPRISM is registered with ISRCTN (reference ISRCTN95351638, 19/12/2017).Trial statusAt the time of submission, PRISM is open to recruitment and data collection is ongoing.

Immune checkpoint-targeted antibodies: a room for dose and schedule optimization?

“…The objective of this study is to determine whether extending the dosing interval of ipilimumab (1 mg/kg Q3W or Q12W for a total of 4 doses) in combination with nivolumab will reduce toxicity without compromising the efficacy in the first-line treatment of renal cell carcinoma. The results could impact the clinical practice in renal cell carcinoma in addition to the current regimen in melanoma [ 48 ].…”

Combination of Ipilimumab and Nivolumab in Cancers: From Clinical Practice to Ongoing Clinical Trials

“…Recently, ipilimumab received FDA approval in renal cell carcinoma therapy. The combination of ipilimumab and nivolumab was first investigated in a phase II study in patients with metastatic RCC, on various dosing plans [ 68 ]. Yang JC et al in a phase II clinical trial, investigated the role of ipilimumab (3 mg/kg, three weeks) in two cohorts with RCC.…”

Immune checkpoint inhibitor–associated myocarditis

“…Immunotherapy with ipilimumab (human monoclonal anti-CTLA-4 antibody) 1 mg/kg and nivolumab (human monoclonal anti-PD-1 antibody) 3 mg/kg intra-Fig. 1 Electrocardiogram showing a third-degree atrioventricular block, initially without escape rhythm, but after several seconds an escape beat is visible venously, every 3 weeks for four cycles, was initiated [2][3][4]. On day 2 of the second cycle, the patient collapsed and was subsequently brought to the emergency department.…”

“…A 58-year-old man with a history of hypertension and diabetes mellitus was diagnosed with poor-risk metastatic clear cell renal cell carcinoma. Immunotherapy with ipilimumab (human monoclonal anti–CTLA‑4 antibody) 1 mg/kg and nivolumab (human monoclonal anti–PD‑1 antibody) 3 mg/kg intravenously, every 3 weeks for four cycles, was initiated [ 2 – 4 ]. On day 2 of the second cycle, the patient collapsed and was subsequently brought to the emergency department.…”