Durvalumab (MEDI 4736) in combination with extended neoadjuvant regimens in rectal cancer: a study protocol of a randomised phase II trial (PRIME-RT)

Hanna, C. R. et al. (2021) Durvalumab (MEDI 4736) in combination with extended neoadjuvant regimens in rectal cancer: a study protocol of a randomised phase II trial (PRIME-RT). Radiation Oncology, 16, 163. (doi: 10.1186/s13014-021-01888-1) (PMID:34446053)

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Abstract

Background: Advances in multi-modality treatment of locally advanced rectal cancer (LARC) have resulted in low local recurrence rates, but around 30% of patients will still die from distant metastatic disease. In parallel, there is increasing recognition that with radiotherapy and systemic treatment, some patients achieve a complete response and may avoid surgical resection, including in many cases, the need for a permanent stoma. Extended neoadjuvant regimes have emerged to address these concerns. The inclusion of immunotherapy in the neoadjuvant setting has the potential to further enhance this strategy by priming the local immune microenvironment and engaging the systemic immune response. Methods: PRIME-RT is a multi-centre, open label, phase II, randomised trial for patients with newly diagnosed LARC. Eligible patients will be randomised to receive either: short course radiotherapy (25 Gray in 5 fractions over one week) with concomitant durvalumab (1500 mg administered intravenously every 4 weeks), followed by FOLFOX (85 mg/m2 oxaliplatin, 350 mg folinic acid and 400 mg/m2 bolus 5-fluorouracil (5-FU) given on day 1 followed by 2400 mg/m2 5-FU infusion over 46–48 h, all administered intravenously every 2 weeks), and durvalumab, or long course chemoradiotherapy (50 Gray to primary tumour in 25 fractions over 5 weeks with concomitant oral capecitabine 825 mg/m2 twice per day on days of radiotherapy) with durvalumab followed by FOLFOX and durvalumab. The primary endpoint is complete response rate in each arm. Secondary endpoints include treatment compliance, toxicity, safety, overall recurrence, proportion of patients with a permanent stoma, and survival. The study is translationally rich with collection of bio-specimens prior to, during, and following treatment in order to understand the molecular and immunological factors underpinning treatment response. The trial opened and the first patient was recruited in January 2021. The main trial will recruit up to 42 patients with LARC and commence after completion of a safety run-in that will recruit at least six patients with LARC or metastatic disease. Discussion: PRIME-RT will explore if adding immunotherapy to neoadjuvant radiotherapy and chemotherapy for patients with LARC can prime the tumour microenvironment to improve complete response rates and stoma free survival. Sequential biopsies are a key component within the trial design that will provide new knowledge on how the tumour microenvironment changes at different time-points in response to multi-modality treatment. This expectation is that the trial will provide information to test this treatment within a large phase clinical trial. Trial registration: Clinicaltrials.gov NCT04621370 (Registered 9th Nov 2020) EudraCT number 2019-001471-36 (Registered 6th Nov 2020).

Item Type:Articles
Additional Information:PRIME-RT is funded by Astrazeneca and receives core funding from CRUK Clinical Trials Unit Glasgow for the purposes of trial set-up and data collection. The trial is co-sponsored by the University Of Glasgow and NHS Greater Glasgow and Clyde.
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Gaya, Mr Daniel and Gourlay, Mrs Jacqueline and Roxburgh, Dr Campbell and Dinnett, Miss Louise and Edwards, Professor Joanne and Hanna, Catherine and Dillon, Miss Susan and Kelly, Mrs Caroline and Lewsley, Ms Liz-Anne and O'Cathail, Dr Sean and Graham, Dr Janet and Thomson, Dr Fiona
Authors: Hanna, C. R., O'Cathail, S. M., Graham, J. S., Saunders, M., Samuel, L., Harrison, M., Devlin, L., Edwards, J., Gaya, D. R., Kelly, C. A., Lewsley, L.-A., Maka, N., Morrison, P., Dinnett, L., Dillon, S., Gourlay, J., Platt, J. J., Thomson, F., Adams, R. A., and Roxburgh, C. S.D.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing
Journal Name:Radiation Oncology
Publisher:BioMed Central
ISSN:1748-717X
ISSN (Online):1748-717X
Copyright Holders:Copyright © 2021 The Authors
First Published:First published in Radiation Oncology 16: 163
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
174279CRUK CTU Glasgow - Clinical Trial FellowshipCatherine HannaCancer Research UK (CRUK)C61974/A24293Institute of Cancer Sciences