The WIRE study a phase II, multi-arm, multi-centre, non-randomised window-of-opportunity clinical trial platform using a Bayesian adaptive design for proof-of-mechanism of novel treatment strategies in operable renal cell cancer - a study protocol

Stephan Ursprung, Helen Mossop, Ferdia A Gallagher, Evis Sala, Richard Skells, Jamal A N Sipple, Thomas J Mitchell, Anita Chhabra, Kate Fife, Athena Matakidou, Gemma Young, Amanda Walker, Martin G Thomas, Mireia Crispin Ortuzar, Mark Sullivan, Andrew Protheroe, Grenville Oades, Balaji Venugopal, Anne Y Warren, John Stone, Tim Eisen, James Wason, Sarah J Welsh, Grant D Stewart, Stephan Ursprung, Helen Mossop, Ferdia A Gallagher, Evis Sala, Richard Skells, Jamal A N Sipple, Thomas J Mitchell, Anita Chhabra, Kate Fife, Athena Matakidou, Gemma Young, Amanda Walker, Martin G Thomas, Mireia Crispin Ortuzar, Mark Sullivan, Andrew Protheroe, Grenville Oades, Balaji Venugopal, Anne Y Warren, John Stone, Tim Eisen, James Wason, Sarah J Welsh, Grant D Stewart

Abstract

Background: Window-of-opportunity trials, evaluating the engagement of drugs with their biological target in the time period between diagnosis and standard-of-care treatment, can help prioritise promising new systemic treatments for later-phase clinical trials. Renal cell carcinoma (RCC), the 7th commonest solid cancer in the UK, exhibits targets for multiple new systemic anti-cancer agents including DNA damage response inhibitors, agents targeting vascular pathways and immune checkpoint inhibitors. Here we present the trial protocol for the WIndow-of-opportunity clinical trial platform for evaluation of novel treatment strategies in REnal cell cancer (WIRE).

Methods: WIRE is a Phase II, multi-arm, multi-centre, non-randomised, proof-of-mechanism (single and combination investigational medicinal product [IMP]), platform trial using a Bayesian adaptive design. The Bayesian adaptive design leverages outcome information from initial participants during pre-specified interim analyses to determine and minimise the number of participants required to demonstrate efficacy or futility. Patients with biopsy-proven, surgically resectable, cT1b+, cN0-1, cM0-1 clear cell RCC and no contraindications to the IMPs are eligible to participate. Participants undergo diagnostic staging CT and renal mass biopsy followed by treatment in one of the treatment arms for at least 14 days. Initially, the trial includes five treatment arms with cediranib, cediranib + olaparib, olaparib, durvalumab and durvalumab + olaparib. Participants undergo a multiparametric MRI before and after treatment. Vascularised and de-vascularised tissue is collected at surgery. A ≥ 30% increase in CD8+ T-cells on immunohistochemistry between the screening and nephrectomy is the primary endpoint for durvalumab-containing arms. Meanwhile, a reduction in tumour vascular permeability measured by Ktrans on dynamic contrast-enhanced MRI by ≥30% is the primary endpoint for other arms. Secondary outcomes include adverse events and tumour size change. Exploratory outcomes include biomarkers of drug mechanism and treatment effects in blood, urine, tissue and imaging.

Discussion: WIRE is the first trial using a window-of-opportunity design to demonstrate pharmacological activity of novel single and combination treatments in RCC in the pre-surgical space. It will provide rationale for prioritising promising treatments for later phase trials and support the development of new biomarkers of treatment effect with its extensive translational agenda.

Trial registration: ClinicalTrials.gov: NCT03741426 / EudraCT: 2018-003056-21 .

Keywords: Bayesian adaptive trial; Cediranib [MeSH]; Clear cell renal cell carcinoma [MeSH]; Clinical trial protocol [MeSH]; Durvalumab [MeSH]; Neoadjuvant therapy [MeSH]; Olaparib [MeSH]; Phase II clinical trial [MeSH]; Window-of-opportunity.

Conflict of interest statement

This trial received funding from AstraZeneca, Cambridge, UK. G.D.S. declares educational grants from Pfizer, AstraZeneca, and Intuitive Surgical; consultancy fees from Pfizer, Merck, EUSA Pharma, and CMR Surgical; travel expenses from Pfizer; and speaker fees from Pfizer. S.J.W. has received travel support from Ipsen. E.S. declares being a co-founder and shareholder of Lucida Medical, consultancy fees from Amazon and speaker fees from GSK. S.U., M.G.T, R.S., G.Y. and J.A.N.S. declare no competing interests. T.E. was employed by and has stock in AstraZeneca, is employed by and has stock in Roche, has received research support from AstaZeneca, Bayer and Pfizer. K.F. has received advisory, consultancy or speaker fees from ESAI, Ipsen, Roche, Novartis, Merck, Pfizer, Eusa, BMS, conference support from Novartis, Ipsen and EUSA and institutional research funding from Roche, Merck, Exelixis. B.V. has received advisory, consultancy or speaker fees from Bristol Myers Squibb (BMS), Eisai, EUSA pharma, Ipsen, Merck Sorono, Merck Sharp & Dohme (MSD), Pfizer; conference support from Ipsen and Institutional research funding from Exelixis, Ipsen, MSD, Pfizer. A.P. has received advisory, consultancy or speaker fees from Eisai, BMS, Ipsen, MSD, Novartis, Roche, Astellas, Bayer, and Pfizer. Conference support from Pfizer, Ipsen, MSD, Roche, Astellas. Research funding from MSD. F.A.G. has research grants from GSK, research support from GE Healthcare and has consulted for AstraZeneca. M.C.O. has received research funding from Lilly. JS is an employee and stockholder in AstraZeneca, Cambridge, UK and a stockholder in GSK.

© 2021. The Author(s).

Figures

Fig. 1
Fig. 1
Bayesian adaptive trial design with interim analyses and decision boundaries for single-agent and combination-therapy arms. Green arrows denote efficacy, orange arrows denote futility
Fig. 2
Fig. 2
Timeline of interventions and assessments for the WIRE trial. *Optional, **Only in patients with cM1 disease. US: ultrasound

References

    1. Ferlay J, Ervik M, Lam F, Colombet M, Mery L, Piñeros M, et al. Global Cancer Observatory: Cancer Today. Int Agency Res Cancer. 2018; [cited 2020 Mar 23]. Available from: .
    1. Cheville JC, Lohse CM, Zincke H, Weaver AL, Blute ML. Comparisons of outcome and prognostic features among histologic subtypes of renal cell carcinoma. Am J Surg Pathol. 2003;27(5):612–624. doi: 10.1097/00000478-200305000-00005.
    1. Howlader N, Noone A, Krapcho M, Miller D, Brest A, Yu M, et al. SEER Cancer Statistics Review, 1975–2017: Kidney and Renal Pelvis Cancer — Cancer Stat Facts. Bethesda: National Cancer Institute; 2020.
    1. Campbell S, Uzzo RG, Allaf ME, Bass EB, Cadeddu JA, Chang A, Clark PE, Davis BJ, Derweesh IH, Giambarresi L, Gervais DA, Hu SL, Lane BR, Leibovich BC, Pierorazio PM. Renal mass and localized renal Cancer: AUA guideline. J Urol. 2017;198(3):520–529. doi: 10.1016/j.juro.2017.04.100.
    1. National Cancer Registration and Analysis Service Public Health England . Chemotherapy, Radiotherapy and Surgical Tumour Resections in England 2013–2016. 2020.
    1. Ljungberg B, Albiges L, Abu-Ghanem Y, Bensalah K, Dabestani S, Montes SFP, et al. European Association of Urology Guidelines on Renal Cell Carcinoma: The 2019 Update. Eur Urol. 2019;75(5):799–810. doi: 10.1016/j.eururo.2019.02.011.
    1. Rini BI, Campbell SC, Escudier B. Renal cell carcinoma. Lancet. 2009;373(9669):1119–1132. doi: 10.1016/S0140-6736(09)60229-4.
    1. Motzer RJ, Penkov K, Haanen J, Rini B, Albiges L, Campbell MT, Venugopal B, Kollmannsberger C, Negrier S, Uemura M, Lee JL, Vasiliev A, Miller WH, Jr, Gurney H, Schmidinger M, Larkin J, Atkins MB, Bedke J, Alekseev B, Wang J, Mariani M, Robbins PB, Chudnovsky A, Fowst C, Hariharan S, Huang B, di Pietro A, Choueiri TK. Avelumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2019;380(12):1103–1115. doi: 10.1056/NEJMoa1816047.
    1. ESMO Guidelines Committee. eUpdate – Renal Cell Carcinoma Treatment Recommendations | ESMO. [cited 2018 Jun 13]. Available from:
    1. Glimelius B, Lahn M. Window-of-opportunity trials to evaluate clinical activity of new molecular entities in oncology. Ann Oncol. 2011;22(8):1717–1725. doi: 10.1093/annonc/mdq622.
    1. Subramonian KR, Puranik S, Mufti GR. How will the two-weeks-wait rule affect delays in management of urological cancers? J R Soc Med. 2003;96(8):398–399. doi: 10.1177/014107680309600809.
    1. Stec AA, Coons BJ, Chang SS, Cookson MS, Herrell SD, Smith JA, Clark PE. Waiting time from initial urological consultation to nephrectomy for renal cell carcinoma-does it affect survival? J Urol. 2008;179(6):2152–2157. doi: 10.1016/j.juro.2008.01.111.
    1. Shiff B, Breau R, Patel P, Kapoor A, Pouliot F, So A, et al. Impact of time-to-surgery and surgical delay on oncologic outcomes for renal cell carcinoma. J Urol. 2019;201(1):78-85. 10.1097/JU.0000000000001230.
    1. Chen Y, Jungsuwadee P, Vore M, Butterfield DA, St. Clair DK. Collateral damage in cancer chemotherapy: oxidative stress in nontargeted tissues. Mol Interv. 2007;7(3):147–156. doi: 10.1124/mi.7.3.6.
    1. Golan T, Hammel P, Reni M, Van Cutsem E, Macarulla T, Hall MJ, et al. Maintenance olaparib for germline BRCA-mutated metastatic pancreatic cancer. N Engl J Med. 2019;381(4):317–327. doi: 10.1056/NEJMoa1903387.
    1. Robson M, Im S-A, Senkus E, Xu B, Domchek SM, Masuda N, Delaloge S, Li W, Tung N, Armstrong A, Wu W, Goessl C, Runswick S, Conte P. Olaparib for metastatic breast Cancer in patients with a germline BRCA mutation. N Engl J Med. 2017;377(6):523–533. doi: 10.1056/NEJMoa1706450.
    1. Ledermann J, Harter P, Gourley C, Friedlander M, Vergote I, Rustin G, Scott C, Meier W, Shapira-Frommer R, Safra T, Matei D, Macpherson E, Watkins C, Carmichael J, Matulonis U. Olaparib maintenance therapy in platinum-sensitive relapsed ovarian Cancer. N Engl J Med. 2012;366(15):1382–1392. doi: 10.1056/NEJMoa1105535.
    1. Lord CJ, Ashworth A. PARP inhibitors: Synthetic lethality in the clinic. Science (80- ) 2017;355(6330):1152–1158. doi: 10.1126/science.aam7344.
    1. Nowsheen S, Cooper T, Stanley JA, Yang ES. Synthetic Lethal Interactions between EGFR and PARP Inhibition in Human Triple Negative Breast Cancer Cells. PLoS One. 2012;7(10):e46614. doi: 10.1371/journal.pone.0046614.
    1. Espana-Agusti J, Warren A, Chew SK, Adams DJ, Matakidou A. Loss of PBRM1 rescues VHL dependent replication stress to promote renal carcinogenesis. Nat Commun. 2017;8(1):1–11. doi: 10.1038/s41467-017-02245-1.
    1. Kanu N, Grönroos E, Martinez P, Burrell RA, Yi Goh X, Bartkova J, Maya-Mendoza A, Mistrík M, Rowan AJ, Patel H, Rabinowitz A, East P, Wilson G, Santos CR, McGranahan N, Gulati S, Gerlinger M, Birkbak NJ, Joshi T, Alexandrov LB, Stratton MR, Powles T, Matthews N, Bates PA, Stewart A, Szallasi Z, Larkin J, Bartek J, Swanton C. SETD2 loss-of-function promotes renal cancer branched evolution through replication stress and impaired DNA repair. Oncogene. 2015;34(46):5699–5708. doi: 10.1038/onc.2015.24.
    1. Helleday T. The underlying mechanism for the PARP and BRCA synthetic lethality: clearing up the misunderstandings. Mol Oncol. 2011;5(4):387–393. doi: 10.1016/j.molonc.2011.07.001.
    1. Moore K, Colombo N, Scambia G, Kim B-G, Oaknin A, Friedlander M, Lisyanskaya A, Floquet A, Leary A, Sonke GS, Gourley C, Banerjee S, Oza A, González-Martín A, Aghajanian C, Bradley W, Mathews C, Liu J, Lowe ES, Bloomfield R, DiSilvestro P. Maintenance Olaparib in patients with newly diagnosed advanced ovarian Cancer. N Engl J Med. 2018;379(26):2495–2505. doi: 10.1056/NEJMoa1810858.
    1. Pujade-Lauraine E, Ledermann JA, Selle F, Gebski V, Penson RT, Oza AM, Korach J, Huzarski T, Poveda A, Pignata S, Friedlander M, Colombo N, Harter P, Fujiwara K, Ray-Coquard I, Banerjee S, Liu J, Lowe ES, Bloomfield R, Pautier P, Korach J, Huzarski T, Byrski T, Pautier P, Friedlander M, Harter P, Colombo N, Pignata S, Scambia G, Nicoletto M, Nussey F, Clamp A, Penson R, Oza A, Poveda Velasco A, Rodrigues M, Lotz JP, Selle F, Ray-Coquard I, Provencher D, Prat Aparicio A, Vidal Boixader L, Scott C, Tamura K, Yunokawa M, Lisyanskaya A, Medioni J, Pécuchet N, Dubot C, de la Motte Rouge T, Kaminsky MC, Weber B, Lortholary A, Parkinson C, Ledermann J, Williams S, Banerjee S, Cosin J, Hoffman J, Penson R, Plante M, Covens A, Sonke G, Joly F, Floquet A, Banerjee S, Hirte H, Amit A, Park-Simon TW, Matsumoto K, Tjulandin S, Kim JH, Gladieff L, Sabbatini R, O'Malley D, Timmins P, Kredentser D, Laínez Milagro N, Barretina Ginesta MP, Tibau Martorell A, Gómez de Liaño Lista A, Ojeda González B, Mileshkin L, Mandai M, Boere I, Ottevanger P, Nam JH, Filho E, Hamizi S, Cognetti F, Warshal D, Dickson-Michelson E, Kamelle S, McKenzie N, Rodriguez G, Armstrong D, Chalas E, Celano P, Behbakht K, Davidson S, Welch S, Helpman L, Fishman A, Bruchim I, Sikorska M, Słowińska A, Rogowski W, Bidziński M, Śpiewankiewicz B, Casado Herraez A, Mendiola Fernández C, Gropp-Meier M, Saito T, Takehara K, Enomoto T, Watari H, Choi CH, Kim BG, Kim JW, Hegg R, Vergote I. Olaparib tablets as maintenance therapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 2017;18(9):1274–1284. doi: 10.1016/S1470-2045(17)30469-2.
    1. Hussain M, Mateo J, Fizazi K, Saad F, Shore N, Sandhu S, Chi KN, Sartor O, Agarwal N, Olmos D, Thiery-Vuillemin A, Twardowski P, Roubaud G, Özgüroğlu M, Kang J, Burgents J, Gresty C, Corcoran C, Adelman CA, de Bono J. Survival with Olaparib in metastatic castration-resistant prostate Cancer. N Engl J Med. 2020;383(24):2345–2357. doi: 10.1056/NEJMoa2022485.
    1. Messiou C, Orton M, Ang JE, Collins DJ, Morgan VA, Mears D, Castellano I, Papadatos-Pastos D, Brunetto A, Tunariu N, Mann H, Tessier J, Young H, Ghiorghiu D, Marley S, Kaye SB, deBono JS, Leach MO, deSouza NM. Advanced solid tumors treated with Cediranib: comparison of dynamic contrast-enhanced MR imaging and CT as markers of vascular activity. Radiology. 2012;265(2):426–436. doi: 10.1148/radiol.12112565.
    1. Mulders P, Hawkins R, Nathan P, De Jong I, Osanto S, Porfiri E, et al. Cediranib monotherapy in patients with advanced renal cell carcinoma: results of a randomised phase II study. Eur J Cancer. 2012;48(4):527–537. doi: 10.1016/j.ejca.2011.12.022.
    1. Powles T, Brown J, Larkin J, Jones R, Ralph C, Hawkins R, Chowdhury S, Boleti E, Bhal A, Fife K, Webb A, Crabb S, Geldart T, Hill R, Dunlop J, Hall PE, McLaren D, Ackerman C, Beltran L, Nathan P. A randomized, double-blind phase II study evaluating cediranib versus cediranib and saracatinib in patients with relapsed metastatic clear-cell renal cancer (COSAK) Ann Oncol. 2016;27(5):880–886. doi: 10.1093/annonc/mdw014.
    1. Liu JF, Barry WT, Birrer M, Lee JM, Buckanovich RJ, Fleming GF, Rimel BJ, Buss MK, Nattam S, Hurteau J, Luo W, Quy P, Whalen C, Obermayer L, Lee H, Winer EP, Kohn EC, Ivy SP, Matulonis UA. Combination cediranib and olaparib versus olaparib alone for women with recurrent platinum-sensitive ovarian cancer: a randomised phase 2 study. Lancet Oncol. 2014;15(11):1207–1214. doi: 10.1016/S1470-2045(14)70391-2.
    1. Antonia SJ, Villegas A, Daniel D, Vicente D, Murakami S, Hui R, Kurata T, Chiappori A, Lee KH, de Wit M, Cho BC, Bourhaba M, Quantin X, Tokito T, Mekhail T, Planchard D, Kim YC, Karapetis CS, Hiret S, Ostoros G, Kubota K, Gray JE, Paz-Ares L, de Castro Carpeño J, Faivre-Finn C, Reck M, Vansteenkiste J, Spigel DR, Wadsworth C, Melillo G, Taboada M, Dennis PA, Özgüroğlu M. Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC. N Engl J Med. 2018;379(24):2342–2350. doi: 10.1056/NEJMoa1809697.
    1. Motzer RJ, Tannir NM, McDermott DF, Arén Frontera O, Melichar B, Choueiri TK, Plimack ER, Barthélémy P, Porta C, George S, Powles T, Donskov F, Neiman V, Kollmannsberger CK, Salman P, Gurney H, Hawkins R, Ravaud A, Grimm MO, Bracarda S, Barrios CH, Tomita Y, Castellano D, Rini BI, Chen AC, Mekan S, McHenry M, Wind-Rotolo M, Doan J, Sharma P, Hammers HJ, Escudier B, CheckMate 214 Investigators Nivolumab plus Ipilimumab versus Sunitinib in advanced renal-cell carcinoma. N Engl J Med. 2018;378(14):1277–1290. doi: 10.1056/NEJMoa1712126.
    1. Motzer RJ, Escudier B, McDermott DF, George S, Hammers HJ, Srinivas S, Tykodi SS, Sosman JA, Procopio G, Plimack ER, Castellano D, Choueiri TK, Gurney H, Donskov F, Bono P, Wagstaff J, Gauler TC, Ueda T, Tomita Y, Schutz FA, Kollmannsberger C, Larkin J, Ravaud A, Simon JS, Xu LA, Waxman IM, Sharma P, CheckMate 025 Investigators Nivolumab versus Everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015;373(19):1803–1813. doi: 10.1056/NEJMoa1510665.
    1. Shen J, Zhao W, Ju Z, Wang L, Peng Y, Labrie M, Yap TA, Mills GB, Peng G. PARPI triggers the STING-dependent immune response and enhances the therapeutic efficacy of immune checkpoint blockade independent of BRCANEss. Cancer Res. 2019;79(2):311–319. doi: 10.1158/0008-5472.CAN-18-1003.
    1. Jiao S, Xia W, Yamaguchi H, Wei Y, Chen MK, Hsu JM, Hsu JL, Yu WH, du Y, Lee HH, Li CW, Chou CK, Lim SO, Chang SS, Litton J, Arun B, Hortobagyi GN, Hung MC. PARP inhibitor upregulates PD-L1 expression and enhances cancer-associated immunosuppression. Clin Cancer Res. 2017;23(14):3711–3720. doi: 10.1158/1078-0432.CCR-16-3215.
    1. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1) Eur J Cancer. 2009;45(2):228–247. doi: 10.1016/j.ejca.2008.10.026.
    1. ICH GCP - ICH harmonised guideline integrated addendum to ICH E6(R1): Guideline for Good Clinical Practice ICH E6(R2) ICH Consensus Guideline - ICH GCP [Internet]. 2016 [cited 2021 Feb 15]. Available from:
    1. Welsh S, Fife K, Matakidou A, Mullin J, Machin A, Qian W, Ingleson V, Dalchau KM, Whittaker P, Warren A, Priest AN, Zaccagna F, Barrett T, Gallagher FA, Riddick A, Armitage JN, Eisen TGQ. A phase II clinical study evaluating the efficacy and safety of neoadjuvant and adjuvant sunitinib in previously untreated patients with metastatic renal cell carcinoma. J Clin Oncol. 2017;35(15):16087. doi: 10.1200/JCO.2017.35.15_suppl.e16087.
    1. Lee JM, Trepel JB, Choyke P, Cao L, Sissung T, Houston N, et al. CECs and IL-8 have prognostic and predictive utility in patients with recurrent platinum-sensitive ovarian cancer: biomarker correlates from the randomized phase-2 trial of olaparib and cediranib compared with olaparib in recurrent platinum-sensitive Ovar. Front Oncol. 2015;5. 10.3389/fonc.2015.00123.
    1. Tentori L, Lacal PM, Muzi A, Dorio AS, Leonetti C, Scarsella M, Ruffini F, Xu W, Min W, Stoppacciaro A, Colarossi C, Wang ZQ, Zhang J, Graziani G. Poly (ADP-ribose) polymerase (PARP) inhibition or PARP-1 gene deletion reduces angiogenesis. Eur J Cancer. 2007;43(14):2124–2133. doi: 10.1016/j.ejca.2007.07.010.
    1. Tumeh PC, Harview CL, Yearley JH, Shintaku IP, Taylor EJM, Robert L, Chmielowski B, Spasic M, Henry G, Ciobanu V, West AN, Carmona M, Kivork C, Seja E, Cherry G, Gutierrez AJ, Grogan TR, Mateus C, Tomasic G, Glaspy JA, Emerson RO, Robins H, Pierce RH, Elashoff DA, Robert C, Ribas A. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature. 2014;515(7528):568–571. doi: 10.1038/nature13954.
    1. Huang AC, Postow MA, Orlowski RJ, Mick R, Bengsch B, Manne S, Xu W, Harmon S, Giles JR, Wenz B, Adamow M, Kuk D, Panageas KS, Carrera C, Wong P, Quagliarello F, Wubbenhorst B, D’Andrea K, Pauken KE, Herati RS, Staupe RP, Schenkel JM, McGettigan S, Kothari S, George SM, Vonderheide RH, Amaravadi RK, Karakousis GC, Schuchter LM, Xu X, Nathanson KL, Wolchok JD, Gangadhar TC, Wherry EJ. T-cell invigoration to tumour burden ratio associated with anti-PD-1 response. Nature. 2017;545(7652):60–65. doi: 10.1038/nature22079.
    1. Tofts PS, Brix G, Buckley DL, Evelhoch JL, Henderson E, Knopp MV, Larsson HBW, Lee TY, Mayr NA, Parker GJM, Port RE, Taylor J, Weisskoff RM. Estimating kinetic parameters from dynamic contrast-enhanced T1- weighted MRI of a diffusable tracer: standardized quantities and symbols. J Magn Reson Imaging. 1999;10(3):223–232. doi: 10.1002/(SICI)1522-2586(199909)10:3<223::AID-JMRI2>;2-S.
    1. Fritz-Hansen T, Rostrup E, Larsson HBW, Søndergaard L, Ring P, Henriksen O. Measurement of the arterial concentration of Gd-DTPA using MRI: a step toward quantitative perfusion imaging. Magn Reson Med. 1996;36(2):225–231. doi: 10.1002/mrm.1910360209.
    1. Lubbock ALR, Stewart GD, O’Mahony FC, Laird A, Mullen P, O’Donnell M, Powles T, Harrison DJ, Overton IM. Overcoming intratumoural heterogeneity for reproducible molecular risk stratification: a case study in advanced kidney cancer. BMC Med. 2017;15(1):118. doi: 10.1186/s12916-017-0874-9.
    1. Berry SM, Carlin BP, Lee JJ, Muller P. Bayesian adaptive methods for clinical trials. CRC press; 2010.
    1. Gerety EL, Lawrence EM, Wason J, Yan H, Hilborne S, Buscombe J, Cheow HK, Shaw AS, Bird N, Fife K, Heard S, Lomas DJ, Matakidou A, Soloviev D, Eisen T, Gallagher FA. Prospective study evaluating the relative sensitivity of 18F-NaF PET/CT for detecting skeletal metastases from renal cell carcinoma in comparison to multidetector CT and 99mTc-MDP bone scintigraphy, using an adaptive trial design. Ann Oncol. 2015;26(10):2113–2118. doi: 10.1093/annonc/mdv289.

Source: PubMed

Спонсоры и соавторы

Заболевания

Медикаментозные вмешательства

Подписаться