REACTION (Radiation Enhanced Assessment of Combination Therapies in Immuno-ONcology) - Nivolumab or Nivolumab in Combination With Other Immuno-oncology (IO) Agents After Targeted Systemic Radiation in Patients With Advanced Esophagogastric Cancer

Summary

This is a Phase 1B study assessing the safety of immune checkpoint inhibition after SBRT in patients with recurrent or metastatic gastroesophageal cancer (limited metastatic disease).

Timeline

Start

2019-03-06

Primary completion

2026-12

Completion

2027-12

Publications

• Background Kang YK, Boku N, Satoh T, Ryu MH, Chao Y, Kato K, Chung HC, Chen JS, Muro K, Kang WK, Yeh KH, Yoshikawa T, Oh SC, Bai LY, Tamura T, Lee KW, Hamamoto Y, Kim JG, Chin K, Oh DY, Minashi K, Cho JY, Tsuda M, Chen LT. Nivolumab in patients with advanced gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens (ONO-4538-12, ATTRACTION-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017 Dec 2;390(10111):2461-2471. doi: 10.1016/S0140-6736(17)31827-5. Epub 2017 Oct 6.
• Background Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H, Eyring AD, Skora AD, Luber BS, Azad NS, Laheru D, Biedrzycki B, Donehower RC, Zaheer A, Fisher GA, Crocenzi TS, Lee JJ, Duffy SM, Goldberg RM, de la Chapelle A, Koshiji M, Bhaijee F, Huebner T, Hruban RH, Wood LD, Cuka N, Pardoll DM, Papadopoulos N, Kinzler KW, Zhou S, Cornish TC, Taube JM, Anders RA, Eshleman JR, Vogelstein B, Diaz LA Jr. PD-1 Blockade in Tumors with Mismatch-Repair Deficiency. N Engl J Med. 2015 Jun 25;372(26):2509-20. doi: 10.1056/NEJMoa1500596. Epub 2015 May 30.
• Background Cancer Genome Atlas Research Network. Comprehensive molecular characterization of gastric adenocarcinoma. Nature. 2014 Sep 11;513(7517):202-9. doi: 10.1038/nature13480. Epub 2014 Jul 23.
• Background Spranger S, Spaapen RM, Zha Y, Williams J, Meng Y, Ha TT, Gajewski TF. Up-regulation of PD-L1, IDO, and T(regs) in the melanoma tumor microenvironment is driven by CD8(+) T cells. Sci Transl Med. 2013 Aug 28;5(200):200ra116. doi: 10.1126/scitranslmed.3006504.
• Background Thompson ED, Zahurak M, Murphy A, Cornish T, Cuka N, Abdelfatah E, Yang S, Duncan M, Ahuja N, Taube JM, Anders RA, Kelly RJ. Patterns of PD-L1 expression and CD8 T cell infiltration in gastric adenocarcinomas and associated immune stroma. Gut. 2017 May;66(5):794-801. doi: 10.1136/gutjnl-2015-310839. Epub 2016 Jan 22.
• Background Derks S, Nason KS, Liao X, Stachler MD, Liu KX, Liu JB, Sicinska E, Goldberg MS, Freeman GJ, Rodig SJ, Davison JM, Bass AJ. Epithelial PD-L2 Expression Marks Barrett's Esophagus and Esophageal Adenocarcinoma. Cancer Immunol Res. 2015 Oct;3(10):1123-1129. doi: 10.1158/2326-6066.CIR-15-0046. Epub 2015 Jun 16.
• Background Muro K, Chung HC, Shankaran V, Geva R, Catenacci D, Gupta S, Eder JP, Golan T, Le DT, Burtness B, McRee AJ, Lin CC, Pathiraja K, Lunceford J, Emancipator K, Juco J, Koshiji M, Bang YJ. Pembrolizumab for patients with PD-L1-positive advanced gastric cancer (KEYNOTE-012): a multicentre, open-label, phase 1b trial. Lancet Oncol. 2016 Jun;17(6):717-726. doi: 10.1016/S1470-2045(16)00175-3. Epub 2016 May 3.
• Background Derks S, Liao X, Chiaravalli AM, Xu X, Camargo MC, Solcia E, Sessa F, Fleitas T, Freeman GJ, Rodig SJ, Rabkin CS, Bass AJ. Abundant PD-L1 expression in Epstein-Barr Virus-infected gastric cancers. Oncotarget. 2016 May 31;7(22):32925-32. doi: 10.18632/oncotarget.9076.
• Background McGranahan N, Furness AJ, Rosenthal R, Ramskov S, Lyngaa R, Saini SK, Jamal-Hanjani M, Wilson GA, Birkbak NJ, Hiley CT, Watkins TB, Shafi S, Murugaesu N, Mitter R, Akarca AU, Linares J, Marafioti T, Henry JY, Van Allen EM, Miao D, Schilling B, Schadendorf D, Garraway LA, Makarov V, Rizvi NA, Snyder A, Hellmann MD, Merghoub T, Wolchok JD, Shukla SA, Wu CJ, Peggs KS, Chan TA, Hadrup SR, Quezada SA, Swanton C. Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade. Science. 2016 Mar 25;351(6280):1463-9. doi: 10.1126/science.aaf1490. Epub 2016 Mar 3.
• Background Attwood SE, Smyrk TC, DeMeester TR, Mirvish SS, Stein HJ, Hinder RA. Duodenoesophageal reflux and the development of esophageal adenocarcinoma in rats. Surgery. 1992 May;111(5):503-10.
• Background Llosa NJ, Cruise M, Tam A, Wicks EC, Hechenbleikner EM, Taube JM, Blosser RL, Fan H, Wang H, Luber BS, Zhang M, Papadopoulos N, Kinzler KW, Vogelstein B, Sears CL, Anders RA, Pardoll DM, Housseau F. The vigorous immune microenvironment of microsatellite instable colon cancer is balanced by multiple counter-inhibitory checkpoints. Cancer Discov. 2015 Jan;5(1):43-51. doi: 10.1158/2159-8290.CD-14-0863. Epub 2014 Oct 30.
• Background Pera M, Brito MJ, Poulsom R, Riera E, Grande L, Hanby A, Wright NA. Duodenal-content reflux esophagitis induces the development of glandular metaplasia and adenosquamous carcinoma in rats. Carcinogenesis. 2000 Aug;21(8):1587-91.
• Background Zaidi AH, Saldin LT, Kelly LA, Bergal L, Londono R, Kosovec JE, Komatsu Y, Kasi PM, Shetty AA, Keane TJ, Thakkar SJ, Huleihel L, Landreneau RJ, Badylak SF, Jobe BA. MicroRNA signature characterizes primary tumors that metastasize in an esophageal adenocarcinoma rat model. PLoS One. 2015 Mar 31;10(3):e0122375. doi: 10.1371/journal.pone.0122375. eCollection 2015.
• Background Bonde P, Sui G, Dhara S, Wang J, Broor A, Kim IF, Wiley JE, Marti G, Duncan M, Jaffee E, Montgomery E, Maitra A, Harmon JW. Cytogenetic characterization and gene expression profiling in the rat reflux-induced esophageal tumor model. J Thorac Cardiovasc Surg. 2007 Mar;133(3):763-9. doi: 10.1016/j.jtcvs.2006.07.044.
• Background Gibson MK, Zaidi AH, Davison JM, Sanz AF, Hough B, Komatsu Y, Kosovec JE, Bhatt A, Malhotra U, Foxwell T, Rotoloni CL, Hoppo T, Jobe BA. Prevention of Barrett esophagus and esophageal adenocarcinoma by smoothened inhibitor in a rat model of gastroesophageal reflux disease. Ann Surg. 2013 Jul;258(1):82-8. doi: 10.1097/SLA.0b013e318270500d.
• Background Kosovec JE, Zaidi AH, Kelly LA, Rotoloni CL, Vytlacil C, DiCarlo C, Matsui D, Komatsu Y, Boyd NH, Omstead A, Kolano EL, Biederman RW, Finley G, Silverman JF, Landreneau RJ, Jobe BA. Preclinical Study of AUY922, a Novel Hsp90 Inhibitor, in the Treatment of Esophageal Adenocarcinoma. Ann Surg. 2016 Aug;264(2):297-304. doi: 10.1097/SLA.0000000000001467.
• Background Zaidi AH, Kosovec JE, Matsui D, Omstead AN, Raj M, Rao RR, Biederman RWW, Finley GG, Landreneau RJ, Kelly RJ, Jobe BA. PI3K/mTOR Dual Inhibitor, LY3023414, Demonstrates Potent Antitumor Efficacy Against Esophageal Adenocarcinoma in a Rat Model. Ann Surg. 2017 Jul;266(1):91-98. doi: 10.1097/SLA.0000000000001908.
• Background Miyashita T, Shah FA, Marti G, Wang J, Armstrong T, Bonde P, Gibson MK, Yoshimura K, Montgomery EA, Duncan MD, Jaffee EM, Harmon JW. Vaccine impedes the development of reflux-induced esophageal cancer in a surgical rat model: efficacy of the vaccine in a Pre-Barrett's esophagus setting. J Gastrointest Surg. 2008 Jan;12(1):2-7; discussion 7-9. doi: 10.1007/s11605-007-0337-2. Epub 2007 Oct 24.
• Background Kelly RJ, Zaidi AH, Smith MA, Omstead AN, Kosovec JE, Matsui D, Martin SA, DiCarlo C, Werts ED, Silverman JF, Wang DH, Jobe BA. The Dynamic and Transient Immune Microenvironment in Locally Advanced Esophageal Adenocarcinoma Post Chemoradiation. Ann Surg. 2018 Dec;268(6):992-999. doi: 10.1097/SLA.0000000000002410.
• Background Brahmer J, Reckamp KL, Baas P, Crino L, Eberhardt WE, Poddubskaya E, Antonia S, Pluzanski A, Vokes EE, Holgado E, Waterhouse D, Ready N, Gainor J, Aren Frontera O, Havel L, Steins M, Garassino MC, Aerts JG, Domine M, Paz-Ares L, Reck M, Baudelet C, Harbison CT, Lestini B, Spigel DR. Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer. N Engl J Med. 2015 Jul 9;373(2):123-35. doi: 10.1056/NEJMoa1504627. Epub 2015 May 31.
• Background Herbst RS, Baas P, Kim DW, Felip E, Perez-Gracia JL, Han JY, Molina J, Kim JH, Arvis CD, Ahn MJ, Majem M, Fidler MJ, de Castro G Jr, Garrido M, Lubiniecki GM, Shentu Y, Im E, Dolled-Filhart M, Garon EB. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet. 2016 Apr 9;387(10027):1540-1550. doi: 10.1016/S0140-6736(15)01281-7. Epub 2015 Dec 19.
• Background Rittmeyer A, Barlesi F, Waterkamp D, Park K, Ciardiello F, von Pawel J, Gadgeel SM, Hida T, Kowalski DM, Dols MC, Cortinovis DL, Leach J, Polikoff J, Barrios C, Kabbinavar F, Frontera OA, De Marinis F, Turna H, Lee JS, Ballinger M, Kowanetz M, He P, Chen DS, Sandler A, Gandara DR; OAK Study Group. Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial. Lancet. 2017 Jan 21;389(10066):255-265. doi: 10.1016/S0140-6736(16)32517-X. Epub 2016 Dec 13.
• Background Finkelstein SE, Timmerman R, McBride WH, Schaue D, Hoffe SE, Mantz CA, Wilson GD. The confluence of stereotactic ablative radiotherapy and tumor immunology. Clin Dev Immunol. 2011;2011:439752. doi: 10.1155/2011/439752. Epub 2011 Nov 15.
• Background Wang X, Schoenhals JE, Li A, Valdecanas DR, Ye H, Zang F, Tang C, Tang M, Liu CG, Liu X, Krishnan S, Allison JP, Sharma P, Hwu P, Komaki R, Overwijk WW, Gomez DR, Chang JY, Hahn SM, Cortez MA, Welsh JW. Suppression of Type I IFN Signaling in Tumors Mediates Resistance to Anti-PD-1 Treatment That Can Be Overcome by Radiotherapy. Cancer Res. 2017 Feb 15;77(4):839-850. doi: 10.1158/0008-5472.CAN-15-3142. Epub 2016 Nov 7.
• Background Gomez DR, Blumenschein GR Jr, Lee JJ, Hernandez M, Ye R, Camidge DR, Doebele RC, Skoulidis F, Gaspar LE, Gibbons DL, Karam JA, Kavanagh BD, Tang C, Komaki R, Louie AV, Palma DA, Tsao AS, Sepesi B, William WN, Zhang J, Shi Q, Wang XS, Swisher SG, Heymach JV. Local consolidative therapy versus maintenance therapy or observation for patients with oligometastatic non-small-cell lung cancer without progression after first-line systemic therapy: a multicentre, randomised, controlled, phase 2 study. Lancet Oncol. 2016 Dec;17(12):1672-1682. doi: 10.1016/S1470-2045(16)30532-0. Epub 2016 Oct 24.
• Background Wong J, Armour E, Kazanzides P, Iordachita I, Tryggestad E, Deng H, Matinfar M, Kennedy C, Liu Z, Chan T, Gray O, Verhaegen F, McNutt T, Ford E, DeWeese TL. High-resolution, small animal radiation research platform with x-ray tomographic guidance capabilities. Int J Radiat Oncol Biol Phys. 2008 Aug 1;71(5):1591-9. doi: 10.1016/j.ijrobp.2008.04.025.
• Background Demaria S, Golden EB, Formenti SC. Role of Local Radiation Therapy in Cancer Immunotherapy. JAMA Oncol. 2015 Dec;1(9):1325-32. doi: 10.1001/jamaoncol.2015.2756.
• Background Golden EB, Chhabra A, Chachoua A, Adams S, Donach M, Fenton-Kerimian M, Friedman K, Ponzo F, Babb JS, Goldberg J, Demaria S, Formenti SC. Local radiotherapy and granulocyte-macrophage colony-stimulating factor to generate abscopal responses in patients with metastatic solid tumours: a proof-of-principle trial. Lancet Oncol. 2015 Jul;16(7):795-803. doi: 10.1016/S1470-2045(15)00054-6. Epub 2015 Jun 18.
• Background Twyman-Saint Victor C, Rech AJ, Maity A, Rengan R, Pauken KE, Stelekati E, Benci JL, Xu B, Dada H, Odorizzi PM, Herati RS, Mansfield KD, Patsch D, Amaravadi RK, Schuchter LM, Ishwaran H, Mick R, Pryma DA, Xu X, Feldman MD, Gangadhar TC, Hahn SM, Wherry EJ, Vonderheide RH, Minn AJ. Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer. Nature. 2015 Apr 16;520(7547):373-7. doi: 10.1038/nature14292. Epub 2015 Mar 9.
• Background Sun J, Dirden-Kramer B, Ito K, Ernst PB, Van Houten N. Antigen-specific T cell activation and proliferation during oral tolerance induction. J Immunol. 1999 May 15;162(10):5868-75.
• Background Carlson CS, Emerson RO, Sherwood AM, Desmarais C, Chung MW, Parsons JM, Steen MS, LaMadrid-Herrmannsfeldt MA, Williamson DW, Livingston RJ, Wu D, Wood BL, Rieder MJ, Robins H. Using synthetic templates to design an unbiased multiplex PCR assay. Nat Commun. 2013;4:2680. doi: 10.1038/ncomms3680.
• Background Robins HS, Campregher PV, Srivastava SK, Wacher A, Turtle CJ, Kahsai O, Riddell SR, Warren EH, Carlson CS. Comprehensive assessment of T-cell receptor beta-chain diversity in alphabeta T cells. Blood. 2009 Nov 5;114(19):4099-107. doi: 10.1182/blood-2009-04-217604. Epub 2009 Aug 25.
• Background Anagnostou V, Smith KN, Forde PM, Niknafs N, Bhattacharya R, White J, Zhang T, Adleff V, Phallen J, Wali N, Hruban C, Guthrie VB, Rodgers K, Naidoo J, Kang H, Sharfman W, Georgiades C, Verde F, Illei P, Li QK, Gabrielson E, Brock MV, Zahnow CA, Baylin SB, Scharpf RB, Brahmer JR, Karchin R, Pardoll DM, Velculescu VE. Evolution of Neoantigen Landscape during Immune Checkpoint Blockade in Non-Small Cell Lung Cancer. Cancer Discov. 2017 Mar;7(3):264-276. doi: 10.1158/2159-8290.CD-16-0828. Epub 2016 Dec 28.

Drugs

Indications