David J Pinato1,2, Alessio Cortellini3, Ajithkumar Sukumaran4, Tom Cole4, Madhava Pai5, Nagy Habib5, Duncan Spalding5, Mikael H Sodergren5, Maria Martinez6, Tony Dhillon7, Paul Tait8, Robert Thomas8, Caroline Ward6, Hemant Kocher9,10, Vincent Yip9, Sarah Slater11, Rohini Sharma6. 1. Division of Cancer, Department of Surgery & Cancer, Imperial College London, Hammersmith Campus, Du Cane Road, W120HS, London, UK. david.pinato@imperial.ac.uk. 2. Department of Translational Medicine, Università del Piemonte Orientale "A. Avogadro", Via Paolo Solaroli, 17, 28100, Novara, NO, Italy. david.pinato@imperial.ac.uk. 3. Department of Biotechnology and Applied Clinical Sciences, University of L'Aquila, Via Vetoio, 67100, L'Aquila, Italy. 4. NIHR Imperial CRF, Imperial College London, Hammersmith Hospital, Du Cane Road, W120HS, London, UK. 5. Division of Surgery, Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, Du Cane Road, W120HS, London, UK. 6. Division of Cancer, Department of Surgery & Cancer, Imperial College London, Hammersmith Campus, Du Cane Road, W120HS, London, UK. 7. Faculty of Health and Medical Sciences, University of Surrey and Department of Oncology, The Royal Surrey Hospital, Egerton Rd, Guildford, GU2 7XX, UK. 8. Department of Radiology, Imperial College NHS Trust, Hammersmith Hospital, Du Cane Road, W120HS, London, UK. 9. Barts and The London HPB Centre, The Royal London Hospital, Barts Health NHS Trust, London, UK. 10. Centre for Tumour Biology, Barts Cancer Institute, Queen Mary University of London, London, UK. 11. Department of Medical Oncology, Barts Health NHS Trust, London, UK.
Abstract
BACKGROUND: After liver resection (LR), patients with hepatocellular cancer (HCC) are at high risk of recurrence. There are no approved anti-cancer therapies known to affect such risk, highlighting the acute need for novel systemic therapies to control the probability of disease relapse. Immunotherapy is expanding as a novel treatment option for HCC. Emerging data from cohort 4 of the CA209-040 study, which investigated the safety and preliminary efficacy of nivolumab/ipilimumab co-administration in advanced HCC, suggest that the combination can be delivered safely with an acceptable proportion of reversible grade 3-4 toxicities (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: 2018-000987-27 Clinical trial registry & ID: ClinicalTrials.gov : NCT03682276 .
BACKGROUND: After liver resection (LR), patients with hepatocellular cancer (HCC) are at high risk of recurrence. There are no approved anti-cancer therapies known to affect such risk, highlighting the acute need for novel systemic therapies to control the probability of disease relapse. Immunotherapy is expanding as a novel treatment option for HCC. Emerging data from cohort 4 of the CA209-040 study, which investigated the safety and preliminary efficacy of nivolumab/ipilimumab co-administration in advanced HCC, suggest that the combination can be delivered safely with an acceptable proportion of reversible grade 3-4 toxicities (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: 2018-000987-27 Clinical trial registry & ID: ClinicalTrials.gov : NCT03682276 .
Authors: Giorgio Ercolani; Gian Luca Grazi; Matteo Ravaioli; Massimo Del Gaudio; Andrea Gardini; Matteo Cescon; Giovanni Varotti; Francesco Cetta; Antonino Cavallari Journal: Ann Surg Date: 2003-04 Impact factor: 12.969
Authors: Matthew D Hellmann; Naiyer A Rizvi; Jonathan W Goldman; Scott N Gettinger; Hossein Borghaei; Julie R Brahmer; Neal E Ready; David E Gerber; Laura Q Chow; Rosalyn A Juergens; Frances A Shepherd; Scott A Laurie; William J Geese; Shruti Agrawal; Tina C Young; Xuemei Li; Scott J Antonia Journal: Lancet Oncol Date: 2016-12-05 Impact factor: 41.316
Authors: Andrew X Zhu; Richard S Finn; Julien Edeline; Stephane Cattan; Sadahisa Ogasawara; Daniel Palmer; Chris Verslype; Vittorina Zagonel; Laetitia Fartoux; Arndt Vogel; Debashis Sarker; Gontran Verset; Stephen L Chan; Jennifer Knox; Bruno Daniele; Andrea L Webber; Scot W Ebbinghaus; Junshui Ma; Abby B Siegel; Ann-Lii Cheng; Masatoshi Kudo Journal: Lancet Oncol Date: 2018-06-03 Impact factor: 41.316
Authors: Scott J Antonia; José A López-Martin; Johanna Bendell; Patrick A Ott; Matthew Taylor; Joseph Paul Eder; Dirk Jäger; M Catherine Pietanza; Dung T Le; Filippo de Braud; Michael A Morse; Paolo A Ascierto; Leora Horn; Asim Amin; Rathi N Pillai; Jeffry Evans; Ian Chau; Petri Bono; Akin Atmaca; Padmanee Sharma; Christopher T Harbison; Chen-Sheng Lin; Olaf Christensen; Emiliano Calvo Journal: Lancet Oncol Date: 2016-06-04 Impact factor: 41.316
Authors: Andrea Necchi; Andrea Anichini; Daniele Raggi; Alberto Briganti; Simona Massa; Roberta Lucianò; Maurizio Colecchia; Patrizia Giannatempo; Roberta Mortarini; Marco Bianchi; Elena Farè; Francesco Monopoli; Renzo Colombo; Andrea Gallina; Andrea Salonia; Antonella Messina; Siraj M Ali; Russell Madison; Jeffrey S Ross; Jon H Chung; Roberto Salvioni; Luigi Mariani; Francesco Montorsi Journal: J Clin Oncol Date: 2018-10-20 Impact factor: 44.544
Authors: Antonio Omuro; Gordana Vlahovic; Michael Lim; Solmaz Sahebjam; Joachim Baehring; Timothy Cloughesy; Alfredo Voloschin; Shakti H Ramkissoon; Keith L Ligon; Robert Latek; Ricardo Zwirtes; Lewis Strauss; Prashni Paliwal; Christopher T Harbison; David A Reardon; John H Sampson Journal: Neuro Oncol Date: 2018-04-09 Impact factor: 12.300
Authors: Yelena Y Janjigian; Johanna Bendell; Emiliano Calvo; Joseph W Kim; Paolo A Ascierto; Padmanee Sharma; Patrick A Ott; Katriina Peltola; Dirk Jaeger; Jeffry Evans; Filippo de Braud; Ian Chau; Christopher T Harbison; Cecile Dorange; Marina Tschaika; Dung T Le Journal: J Clin Oncol Date: 2018-08-15 Impact factor: 44.544
Authors: Josep M Llovet; Florian Castet; Mathias Heikenwalder; Mala K Maini; Vincenzo Mazzaferro; David J Pinato; Eli Pikarsky; Andrew X Zhu; Richard S Finn Journal: Nat Rev Clin Oncol Date: 2021-11-11 Impact factor: 65.011
Authors: Tim F Greten; Ghassan K Abou-Alfa; Ann-Lii Cheng; Austin G Duffy; Anthony B El-Khoueiry; Richard S Finn; Peter R Galle; Lipika Goyal; Aiwu Ruth He; Ahmed O Kaseb; Robin Kate Kelley; Riccardo Lencioni; Amaia Lujambio; Donna Mabry Hrones; David J Pinato; Bruno Sangro; Roberto I Troisi; Andrea Wilson Woods; Thomas Yau; Andrew X Zhu; Ignacio Melero Journal: J Immunother Cancer Date: 2021-09 Impact factor: 13.751
Authors: Julian L Goggi; Boominathan Ramasamy; Yun Xuan Tan; Siddesh V Hartimath; Jun Rong Tang; Peter Cheng; Rasha Msallam; Ann-Marie Chacko; You Yi Hwang; Edward G Robins Journal: Mol Imaging Date: 2021-12-09 Impact factor: 3.250