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

Catherine R Hanna, Sean M O'Cathail, Janet S Graham, Mark Saunders, Leslie Samuel, Mark Harrison, Lynsey Devlin, Joanne Edwards, Daniel R Gaya, Caroline A Kelly, Liz-Anne Lewsley, Noori Maka, Paula Morrison, Louise Dinnett, Susan Dillon, Jacqueline Gourlay, Jonathan J Platt, Fiona Thomson, Richard A Adams, Campbell S D Roxburgh, Catherine R Hanna, Sean M O'Cathail, Janet S Graham, Mark Saunders, Leslie Samuel, Mark Harrison, Lynsey Devlin, Joanne Edwards, Daniel R Gaya, Caroline A Kelly, Liz-Anne Lewsley, Noori Maka, Paula Morrison, Louise Dinnett, Susan Dillon, Jacqueline Gourlay, Jonathan J Platt, Fiona Thomson, Richard A Adams, Campbell S D Roxburgh

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).

Keywords: Chemotherapy; Clinical trial; Immune-oncology; Immunotherapy; Neoplasm; Radiotherapy; Rectal.

Conflict of interest statement

Catherine R. Hanna, Sean M. O’Cathail, Janet S. Graham, Mark Saunders, Les Samuel, Mark Harrison, Lynsey Devlin, Joanne Edwards, Caroline A. Kelly, Liz-Anne Lewsley, Noori Maka, Paula Morrison, Louise Dinnett, Susan Dillon, Jacqueline Gourlay, Jonathan J. Platt : None. Fiona Thomson: Shareholder: MSD and AstraZeneca, Richard A Adams: Speakers fees/consultancy: Amgen, AZ, MSD, Merck Serono, Bayer. Research funding: MSD, AZ. The PRIME-RT trial is partly supported by Astra Zeneca.

© 2021. The Author(s).

Figures

Fig. 1
Fig. 1
Process of recruitment of patients to PRIME-RT and random allocation of patients between treatment arms
Fig. 2
Fig. 2
Treatment schema for Arm A and Arm B of PRIME-RT

References

    1. Cancer Research UK. Bowel cancer incidence statistics 2020 [Available from: .
    1. McCall JL, Cox MR, Wattchow DA. Analysis of local recurrence rates after surgery alone for rectal cancer. Int J Colorectal Dis. 1995;10(3):126–132. doi: 10.1007/BF00298532.
    1. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology Non-small cell lung cancer Version 3.2020. 2020 11th February 2020.
    1. National Institute for Health and Care Excellence. Colorectal Cancer Guidelines [NG151]. 2020 29th Janurary 2020.
    1. Glehen O, Chapet O, Adham M, Nemoz JC, Gerard JP. Long-term results of the Lyons R90–01 randomized trial of preoperative radiotherapy with delayed surgery and its effect on sphincter-saving surgery in rectal cancer. Br J Surg. 2003;90(8):996–998. doi: 10.1002/bjs.4162.
    1. Erlandsson J, Holm T, Pettersson D, Berglund A, Cedermark B, Radu C, et al. Optimal fractionation of preoperative radiotherapy and timing to surgery for rectal cancer (Stockholm III): a multicentre, randomised, non-blinded, phase 3, non-inferiority trial. Lancet Oncol. 2017;18(3):336–346. doi: 10.1016/S1470-2045(17)30086-4.
    1. Gambacorta MA, Masciocchi C, Chiloiro G, Meldolesi E, Macchia G, van Soest J, et al. Timing to achieve the highest rate of pCR after preoperative radiochemotherapy in rectal cancer: a pooled analysis of 3085 patients from 7 randomized trials. Radiother Oncol. 2021;154:154–160. doi: 10.1016/j.radonc.2020.09.026.
    1. Hospers G, Bahadoer RR, Dijkstra EA, van Etten B, Marijnen C, Putter H, et al. Short-course radiotherapy followed by chemotherapy before TME in locally advanced rectal cancer: The randomized RAPIDO trial. J Clin Oncol. 2020;38(15_suppl):4006. doi: 10.1200/JCO.2020.38.15_suppl.4006.
    1. Bujko K, Wyrwicz L, Rutkowski A, Malinowska M, Pietrzak L, Kryński J, et al. Long-course oxaliplatin-based preoperative chemoradiation versus 5 × 5 Gy and consolidation chemotherapy for cT4 or fixed cT3 rectal cancer: results of a randomized phase III study. Ann Oncol Off J Eur Soc Med Oncol. 2016;27(5):834–842. doi: 10.1093/annonc/mdw062.
    1. Fernandez-Martos C, Garcia-Albeniz X, Pericay C, Maurel J, Aparicio J, Montagut C, et al. Chemoradiation, surgery and adjuvant chemotherapy versus induction chemotherapy followed by chemoradiation and surgery: long-term results of the Spanish GCR-3 phase II randomized trial†. Ann Oncol. 2015;26(8):1722–1728. doi: 10.1093/annonc/mdv223.
    1. Cercek A, Roxburgh CSD, Strombom P, Smith JJ, Temple LKF, Nash GM, et al. Adoption of total neoadjuvant therapy for locally advanced rectal cancer adoption of total neoadjuvant therapy for locally advanced rectal cancer adoption of total neoadjuvant therapy for locally advanced rectal cancer. JAMA Oncol. 2018;4(6):e180071-e. doi: 10.1001/jamaoncol.2018.0071.
    1. Conroy T, Bosset J-F, Etienne P-L, Rio E, François É, Mesgouez-Nebout N, et al. Neoadjuvant chemotherapy with FOLFIRINOX and preoperative chemoradiotherapy for patients with locally advanced rectal cancer (UNICANCER-PRODIGE 23): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2021;22(5):702–715. doi: 10.1016/S1470-2045(21)00079-6.
    1. Habr-Gama A, Perez RO, Wynn G, Marks J, Kessler H, Gama-Rodrigues J. Complete clinical response after neoadjuvant chemoradiation therapy for distal rectal cancer: characterization of clinical and endoscopic findings for standardization. Diseases of the colon & rectum U6 - ctx_ver=Z3988-2004&ctx_enc=info%3Aofi%2Fenc%3AUTF-8&rfr_id=info%3Asid%2Fsummonserialssolutionscom&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rftgenre=article&rftatitle=Complete+clinical+response+after+neoadjuvant+chemoradiation+therapy+for+distal+rectal+cancer%3A+characterization+of+clinical+and+endoscopic+findings+for+standardization&rftjtitle=Diseases+of+the+colon+%26+rectum&rftau=Habr-Gama%2C+Angelita&rftau=Perez%2C+Rodrigo+O&rftau=Wynn%2C+Gregory&rftau=Marks%2C+John&rftdate=2010-12-01&rfteissn=1530-0358&rftvolume=53&rftissue=12&rftspage=1692&rft_id=info%3Apmid%2F21178866&rft_id=info%3Apmid%2F21178866&rftexternalDocID=21178866&paramdict=en-US U7 - Journal Article. 2010;53(12):1692.
    1. Ngan SY, Burmeister B, Fisher RJ, Solomon M, Goldstein D, Joseph D, et al. Randomized trial of short-course radiotherapy versus long-course chemoradiation comparing rates of local recurrence in patients with T3 rectal cancer: Trans-Tasman Radiation Oncology Group trial 01.04. J Clin Oncol Off J Am Soc Clin Oncol. 2012;30(31):3827–3833. doi: 10.1200/JCO.2012.42.9597.
    1. Probst CP, Becerra AZ, Aquina CT, Tejani MA, Wexner SD, Garcia-Aguilar J, et al. Extended intervals after neoadjuvant therapy in locally advanced rectal cancer: the key to improved tumor response and potential organ preservation. J Am Coll Surg. 2015;221(2):430–440. doi: 10.1016/j.jamcollsurg.2015.04.010.
    1. Nagtegaal ID, Glynne-Jones R. How to measure tumour response in rectal cancer? An explanation of discrepancies and suggestions for improvement. Cancer Treat Rev. 2020;84:101. doi: 10.1016/j.ctrv.2020.101964.
    1. Smith JJ, Strombom P, Chow OS, Roxburgh CS, Lynn P, Eaton A, et al. Assessment of a watch-and-wait strategy for rectal cancer in patients with a complete response after neoadjuvant therapy. JAMA Oncol. 2019;5(4):e185896. doi: 10.1001/jamaoncol.2018.5896.
    1. Renehan AG, Malcomson L, Emsley R, Gollins S, Maw A, Myint AS, et al. Watch-and-wait approach versus surgical resection after chemoradiotherapy for patients with rectal cancer (the OnCoRe project): a propensity-score matched cohort analysis. Lancet Oncol. 2016;17(2):174–183. doi: 10.1016/S1470-2045(15)00467-2.
    1. Bujko K, Nowacki MP, Nasierowska-Guttmejer A, Michalski W, Bebenek M, Kryj M. Long-term results of a randomized trial comparing preoperative short-course radiotherapy with preoperative conventionally fractionated chemoradiation for rectal cancer. Br J Surg. 2006;93(10):1215–1223. doi: 10.1002/bjs.5506.
    1. Fokas E, Ströbel P, Fietkau R, Ghadimi M, Liersch T, Grabenbauer GG, Hartmann A, Kaufmann M, Sauer R, Graeven U, Hoffmanns H, Raab HR, Hothorn T, Wittekind C, Rödel C. German rectal cancer study group. tumor regression grading after preoperative chemoradiotherapy as a prognostic factor and individual-level surrogate for disease-free survival in rectal cancer. J Natl Cancer Inst. 2017;109(12). 10.1093/jnci/djx095.
    1. Tiernan J, Cook A, Geh I, George B, Magill L, Northover J, et al. Use of a modified Delphi approach to develop research priorities for the association of coloproctology of Great Britain and Ireland. Colorectal Dis off J Assoc Coloproctol Great Britain Ireland. 2014;16(12):965–970. doi: 10.1111/codi.12790.
    1. Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H, Eyring AD, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med. 2015;372(26):2509–2520. doi: 10.1056/NEJMoa1500596.
    1. Overman MJ, Lonardi S, Wong KYM, Lenz HJ, Gelsomino F, Aglietta M, et al. Durable clinical benefit with nivolumab plus ipilimumab in DNA mismatch repair-deficient/microsatellite instability-high metastatic colorectal cancer. J Clin Oncol Off J Am Soc Clin Oncol. 2018;36(8):773–779. doi: 10.1200/JCO.2017.76.9901.
    1. Lenz H-J, Lonardi S, Zagonel V, Van Cutsem E, Limon ML, Wong KYM, et al. Nivolumab plus low-dose ipilimumab as first-line therapy in microsatellite instability-high/DNA mismatch repair deficient metastatic colorectal cancer: clinical update. J Clin Oncol. 2020;38(4):11. doi: 10.1200/JCO.2020.38.4_suppl.11.
    1. Dovedi SJ, Cheadle EJ, Popple AL, Poon E, Morrow M, Stewart R, et al. Fractionated radiation therapy stimulates antitumor immunity mediated by both resident and infiltrating polyclonal T-cell populations when combined with PD-1 blockade. Clin Cancer Res. 2017;23(18):5514. doi: 10.1158/1078-0432.CCR-16-1673.
    1. Teng F, Meng X, Kong L, Mu D, Zhu H, Liu S, et al. Tumor-infiltrating lymphocytes, forkhead box P3, programmed death ligand-1, and cytotoxic T lymphocyte–associated antigen-4 expressions before and after neoadjuvant chemoradiation in rectal cancer. Transl Res. 2015;166(6):721–32.e1. doi: 10.1016/j.trsl.2015.06.019.
    1. Roxburgh CS, Weiser MR. Selective use of radiation for locally advanced rectal cancer: one size does not fit all. Minerva Chir. 2018;73(6):592–600. doi: 10.23736/S0026-4733.18.07791-X.
    1. Chalabi M, Fanchi LF, Dijkstra KK, Van den Berg JG, Aalbers AG, Sikorska K, et al. Neoadjuvant immunotherapy leads to pathological responses in MMR-proficient and MMR-deficient early-stage colon cancers. Nat Med. 2020;26(4):566–576. doi: 10.1038/s41591-020-0805-8.
    1. Reynders K, Illidge T, Siva S, Chang JY, De Ruysscher D. The abscopal effect of local radiotherapy: using immunotherapy to make a rare event clinically relevant. Cancer Treat Rev. 2015;41(6):503–510. doi: 10.1016/j.ctrv.2015.03.011.
    1. Sebag-Montefiore D, Adams R, Gollins S, Samuel LM, Glynne-Jones R, Harte R, et al. ARISTOTLE: a phase III trial comparing concurrent capecitabine with capecitabine and irinotecan (Ir) chemoradiation as preoperative treatment for MRI-defined locally advanced rectal cancer (LARC) J Clin Oncol. 2020;38(15):4101. doi: 10.1200/JCO.2020.38.15_suppl.4101.
    1. Appelt AL, Pløen J, Vogelius IR, Bentzen SM, Jakobsen A. Radiation dose-response model for locally advanced rectal cancer after preoperative chemoradiation therapy. Int J Radiat Oncol Biol Phys. 2013;85(1):74–80. doi: 10.1016/j.ijrobp.2012.05.017.
    1. Slevin, F. et al. Launch of the national rectal cancer intensity-modulated radiotherapy guidance. Clin Oncol. 33(4):209-13.
    1. Hanna CR, Slevin F, Appelt A, Beavon M, Adams R, Arthur C, et al. Intensity-modulated Radiotherapy for Rectal Cancer in the UK in 2020. Clin Oncol. 2021;33(4):214–223. doi: 10.1016/j.clon.2020.12.011.
    1. Beets-Tan RGH, Lambregts DMJ, Maas M, Bipat S, Barbaro B, Curvo-Semedo L, et al. Magnetic resonance imaging for clinical management of rectal cancer: updated recommendations from the 2016 European Society of Gastrointestinal and Abdominal Radiology (ESGAR) consensus meeting. Eur Radiol. 2018;28(4):1465–1475. doi: 10.1007/s00330-017-5026-2.
    1. Vayrynen JP, Vornanen JO, Sajanti S, Bohm JP, Tuomisto A, Makinen MJ. An improved image analysis method for cell counting lends credibility to the prognostic significance of T cells in colorectal cancer. Virchows Archiv Int J Pathol. 2012;460(5):455–465. doi: 10.1007/s00428-012-1232-0.
    1. Wirta EV, Seppala T, Friman M, Vayrynen J, Ahtiainen M, Kautiainen H, et al. Immunoscore in mismatch repair-proficient and -deficient colon cancer. J Pathol Clin Res. 2017;3(3):203–213. doi: 10.1002/cjp2.71.
    1. Park JH, van Wyk H, McMillan DC, Edwards J, Orange C, Horgan PG, Roxburgh CS. Preoperative, biopsy-based assessment of the tumour microenvironment in patients with primary operable colorectal cancer. J Pathol Clin Res. 2020;6(1):30–39. doi: 10.1002/cjp2.143.
    1. A'Hern RP. Sample size tables for exact single-stage phase II designs. Stat Med. 2001;20(6):859–866. doi: 10.1002/sim.721.
    1. Clopper CJ, Pearson ES. The use of confidence or fiducial limits illustrated in the case of the binomial. Biometrika. 1934;26(4):404–413. doi: 10.1093/biomet/26.4.404.
    1. Conroy T, Lamfichekh N, Etienne P-L, Rio E, Francois E, Mesgouez-Nebout N, et al. Total neoadjuvant therapy with mFOLFIRINOX versus preoperative chemoradiation in patients with locally advanced rectal cancer: Final results of PRODIGE 23 phase III trial, a UNICANCER GI trial. J Clin Oncol. 2020;38(15_suppl):4007. doi: 10.1200/JCO.2020.38.15_suppl.4007.
    1. Garcia-Aguilar J, Patil S, Kim JK, Yuval JB, Thompson H, Verheij F, et al. Preliminary results of the organ preservation of rectal adenocarcinoma (OPRA) trial. J Clin Oncol. 2020;38(15_suppl):4008. doi: 10.1200/JCO.2020.38.15_suppl.4008.
    1. Gani C, Gani N, Zschaeck S, Eberle F, Schaeffeler N, Hehr T, et al. Organ preservation in rectal cancer: the patients' perspective. Front Oncol. 2019;9:318. doi: 10.3389/fonc.2019.00318.
    1. Sharma RA, Plummer R, Stock JK, Greenhalgh TA, Ataman O, Kelly S, et al. Clinical development of new drug–radiotherapy combinations. Nat Rev Clin Oncol. 2016;13(10):627–642. doi: 10.1038/nrclinonc.2016.79.
    1. Ahmad SS, Crittenden MR, Tran PT, Kluetz PG, Blumenthal GM, Bulbeck H, et al. Clinical development of novel drug-radiotherapy combinations. Clin Cancer Res. 2019;25(5):1455. doi: 10.1158/1078-0432.CCR-18-2466.
    1. Fokas E, Glynne-Jones R, Appelt A, Beets-Tan R, Beets G, Haustermans K, et al. Outcome measures in multimodal rectal cancer trials. Lancet Oncol. 2020;21(5):e252–e264. doi: 10.1016/S1470-2045(20)30024-3.
    1. Fokas E, Fietkau R, Hartmann A, Hohenberger W, Grutzmann R, Ghadimi M, et al. Neoadjuvant rectal score as individual-level surrogate for disease-free survival in rectal cancer in the CAO/ARO/AIO-04 randomized phase III trial. Ann Oncol Off J Eur Soc Med Oncol. 2018;29(7):1521–1527. doi: 10.1093/annonc/mdy143.
    1. Galon J, Pagès F, Marincola FM, Thurin M, Trinchieri G, Fox BA, et al. The immune score as a new possible approach for the classification of cancer. J Transl Med. 2012;10:1. doi: 10.1186/1479-5876-10-1.
    1. Pagès F, Mlecnik B, Marliot F, Bindea G, Ou F-S, Bifulco C, et al. International validation of the consensus Immunoscore for the classification of colon cancer: a prognostic and accuracy study. The Lancet. 2018;391(10135):2128–2139. doi: 10.1016/S0140-6736(18)30789-X.
    1. Roxburgh CSD, McMillan DC. The role of the in situ local inflammatory response in predicting recurrence and survival in patients with primary operable colorectal cancer. Cancer Treat Rev. 2012;38(5):451–466. doi: 10.1016/j.ctrv.2011.09.001.
    1. Chau I, Brown G, Cunningham D, Tait D, Wotherspoon A, Norman AR, et al. Neoadjuvant capecitabine and oxaliplatin followed by synchronous chemoradiation and total mesorectal excision in magnetic resonance imaging-defined poor-risk rectal cancer. J Clin Oncol Off J Am Soc Clin Oncol. 2006;24(4):668–674. doi: 10.1200/JCO.2005.04.4875.
    1. Fokas E, Allgäuer M, Polat B, Klautke G, Grabenbauer GG, Fietkau R, et al. Randomized phase II trial of chemoradiotherapy plus induction or consolidation chemotherapy as total neoadjuvant therapy for locally advanced rectal cancer: CAO/ARO/AIO-12. J Clin Oncol Off J Am Soc Clin Oncol. 2019;37(34):3212–3222. doi: 10.1200/JCO.19.00308.
    1. Rahma OE, Yothers G, Hong TS, McGory Russell M, Nancy You, William Parker, et al., editors. NRG-GI002: A phase II clinical trial platform using total neoadjuvant therapy (TNT) in locally-advanced rectal cancer (LARC)—Pembrolizumab experimental arm (EA) primary results. ASCO GI; 2021; Virtual.
    1. van der Valk MJM, Hilling DE, Bastiaannet E, Kranenbarg EMK, Beets GL, Figueiredo NL, et al. Long-term outcomes of clinical complete responders after neoadjuvant treatment for rectal cancer in the International Watch & Wait Database (IWWD): an international multicentre registry study. Lancet. 2018;391(10139):2537–2545. doi: 10.1016/S0140-6736(18)31078-X.
    1. van der Valk MJM, Marijnen CAM, van Etten B, Dijkstra EA, Hilling DE, Kranenbarg EM-K, et al. Compliance and tolerability of short-course radiotherapy followed by preoperative chemotherapy and surgery for high-risk rectal cancer – Results of the international randomized RAPIDO-trial. Radiother Oncol. 2020;147:75–83.
    1. Bujko K, for the Polish Colorectal Study G, Wyrwicz L, for the Polish Colorectal Study G, Rutkowski A, for the Polish Colorectal Study G, et al. Long-course oxaliplatin-based preoperative chemoradiation versus 5 × 5 Gy and consolidation chemotherapy for cT4 or fixed cT3 rectal cancer: results of a randomized phase III study. Ann Oncol. 2016;27(5):834–42.

Source: PubMed

Sponsorit ja yhteistyökumppanit

Sairaudet

Huumeiden interventiot

3
Tilaa