Single Agent and Combined Inhibition After Allogeneic Stem Cell Transplant

Summary

The purpose of the study is to determine the safety and benefit of nivolumab, ipilimumab or the combination of nivolumab with ipilimumab given after bone marrow transplant for patients with acute myelogenous leukemia and myelodysplastic syndrome.

Timeline

Start

2019-03-08

Primary completion

2023-12-21

Completion

2023-12-21

Outcome

Outcome not reported

Stopped (Enrollment): “Lack of Enrollment”

Publications

• Background Martin S, Baldock SC, Ghoneim AT, Child JA. Defective neutrophil function and microbicidal mechanisms in the myelodysplastic disorders. J Clin Pathol. 1983 Oct;36(10):1120-8. doi: 10.1136/jcp.36.10.1120.
• Background Martino R, Iacobelli S, Brand R, Jansen T, van Biezen A, Finke J, Bacigalupo A, Beelen D, Reiffers J, Devergie A, Alessandrino E, Mufti GJ, Barge R, Sierra J, Ruutu T, Boogaerts M, Falda M, Jouet JP, Niederwieser D, de Witte T; Myelodysplastic Syndrome subcommittee of the Chronic Leukemia Working Party of the European Blood and Marrow Transplantation Group. Retrospective comparison of reduced-intensity conditioning and conventional high-dose conditioning for allogeneic hematopoietic stem cell transplantation using HLA-identical sibling donors in myelodysplastic syndromes. Blood. 2006 Aug 1;108(3):836-46. doi: 10.1182/blood-2005-11-4503. Epub 2006 Apr 4.
• Background Fukuda T, Hackman RC, Guthrie KA, Sandmaier BM, Boeckh M, Maris MB, Maloney DG, Deeg HJ, Martin PJ, Storb RF, Madtes DK. Risks and outcomes of idiopathic pneumonia syndrome after nonmyeloablative and conventional conditioning regimens for allogeneic hematopoietic stem cell transplantation. Blood. 2003 Oct 15;102(8):2777-85. doi: 10.1182/blood-2003-05-1597. Epub 2003 Jul 10.
• Background Diaconescu R, Flowers CR, Storer B, Sorror ML, Maris MB, Maloney DG, Sandmaier BM, Storb R. Morbidity and mortality with nonmyeloablative compared with myeloablative conditioning before hematopoietic cell transplantation from HLA-matched related donors. Blood. 2004 Sep 1;104(5):1550-8. doi: 10.1182/blood-2004-03-0804. Epub 2004 May 18.
• Background de Lima M, Anagnostopoulos A, Munsell M, Shahjahan M, Ueno N, Ippoliti C, Andersson BS, Gajewski J, Couriel D, Cortes J, Donato M, Neumann J, Champlin R, Giralt S. Nonablative versus reduced-intensity conditioning regimens in the treatment of acute myeloid leukemia and high-risk myelodysplastic syndrome: dose is relevant for long-term disease control after allogeneic hematopoietic stem cell transplantation. Blood. 2004 Aug 1;104(3):865-72. doi: 10.1182/blood-2003-11-3750. Epub 2004 Apr 15.
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• Background Ansell SM, Lesokhin AM, Borrello I, Halwani A, Scott EC, Gutierrez M, Schuster SJ, Millenson MM, Cattry D, Freeman GJ, Rodig SJ, Chapuy B, Ligon AH, Zhu L, Grosso JF, Kim SY, Timmerman JM, Shipp MA, Armand P. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin's lymphoma. N Engl J Med. 2015 Jan 22;372(4):311-9. doi: 10.1056/NEJMoa1411087. Epub 2014 Dec 6.
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• Background Fong L, Small EJ. Anti-cytotoxic T-lymphocyte antigen-4 antibody: the first in an emerging class of immunomodulatory antibodies for cancer treatment. J Clin Oncol. 2008 Nov 10;26(32):5275-83. doi: 10.1200/JCO.2008.17.8954. Epub 2008 Oct 6.
• Background Postow MA, Chesney J, Pavlick AC, Robert C, Grossmann K, McDermott D, Linette GP, Meyer N, Giguere JK, Agarwala SS, Shaheen M, Ernstoff MS, Minor D, Salama AK, Taylor M, Ott PA, Rollin LM, Horak C, Gagnier P, Wolchok JD, Hodi FS. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med. 2015 May 21;372(21):2006-17. doi: 10.1056/NEJMoa1414428. Epub 2015 Apr 20.
• Background Sledzinska A, Menger L, Bergerhoff K, Peggs KS, Quezada SA. Negative immune checkpoints on T lymphocytes and their relevance to cancer immunotherapy. Mol Oncol. 2015 Dec;9(10):1936-65. doi: 10.1016/j.molonc.2015.10.008. Epub 2015 Oct 26.
• Background 14. Antonia SJ, Bendell JC, Taylor MH. Phase I/II study of nivolumab with or without ipilimumab for treatment of recurrent small cell lung cancer (SCLC): CA209-032. ASCO Annual Meeting. 2015.
• Background Taur Y, Jenq RR, Ubeda C, van den Brink M, Pamer EG. Role of intestinal microbiota in transplantation outcomes. Best Pract Res Clin Haematol. 2015 Jun-Sep;28(2-3):155-61. doi: 10.1016/j.beha.2015.10.013. Epub 2015 Oct 22.
• Background Iida N, Dzutsev A, Stewart CA, Smith L, Bouladoux N, Weingarten RA, Molina DA, Salcedo R, Back T, Cramer S, Dai RM, Kiu H, Cardone M, Naik S, Patri AK, Wang E, Marincola FM, Frank KM, Belkaid Y, Trinchieri G, Goldszmid RS. Commensal bacteria control cancer response to therapy by modulating the tumor microenvironment. Science. 2013 Nov 22;342(6161):967-70. doi: 10.1126/science.1240527.
• Background Viaud S, Saccheri F, Mignot G, Yamazaki T, Daillere R, Hannani D, Enot DP, Pfirschke C, Engblom C, Pittet MJ, Schlitzer A, Ginhoux F, Apetoh L, Chachaty E, Woerther PL, Eberl G, Berard M, Ecobichon C, Clermont D, Bizet C, Gaboriau-Routhiau V, Cerf-Bensussan N, Opolon P, Yessaad N, Vivier E, Ryffel B, Elson CO, Dore J, Kroemer G, Lepage P, Boneca IG, Ghiringhelli F, Zitvogel L. The intestinal microbiota modulates the anticancer immune effects of cyclophosphamide. Science. 2013 Nov 22;342(6161):971-6. doi: 10.1126/science.1240537.
• Background Vetizou M, Pitt JM, Daillere R, Lepage P, Waldschmitt N, Flament C, Rusakiewicz S, Routy B, Roberti MP, Duong CP, Poirier-Colame V, Roux A, Becharef S, Formenti S, Golden E, Cording S, Eberl G, Schlitzer A, Ginhoux F, Mani S, Yamazaki T, Jacquelot N, Enot DP, Berard M, Nigou J, Opolon P, Eggermont A, Woerther PL, Chachaty E, Chaput N, Robert C, Mateus C, Kroemer G, Raoult D, Boneca IG, Carbonnel F, Chamaillard M, Zitvogel L. Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science. 2015 Nov 27;350(6264):1079-84. doi: 10.1126/science.aad1329. Epub 2015 Nov 5.
• Background Sivan A, Corrales L, Hubert N, Williams JB, Aquino-Michaels K, Earley ZM, Benyamin FW, Lei YM, Jabri B, Alegre ML, Chang EB, Gajewski TF. Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy. Science. 2015 Nov 27;350(6264):1084-9. doi: 10.1126/science.aac4255. Epub 2015 Nov 5.
• Background Xia Y, Medeiros LJ, Young KH. Immune checkpoint blockade: Releasing the brake towards hematological malignancies. Blood Rev. 2016 May;30(3):189-200. doi: 10.1016/j.blre.2015.11.003. Epub 2015 Nov 25.
• Background Chinai JM, Janakiram M, Chen F, Chen W, Kaplan M, Zang X. New immunotherapies targeting the PD-1 pathway. Trends Pharmacol Sci. 2015 Sep;36(9):587-95. doi: 10.1016/j.tips.2015.06.005. Epub 2015 Jul 7.
• Background Keir ME, Butte MJ, Freeman GJ, Sharpe AH. PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol. 2008;26:677-704. doi: 10.1146/annurev.immunol.26.021607.090331.
• Background Nishimura H, Nose M, Hiai H, Minato N, Honjo T. Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor. Immunity. 1999 Aug;11(2):141-51. doi: 10.1016/s1074-7613(00)80089-8.
• Background Iwai Y, Ishida M, Tanaka Y, Okazaki T, Honjo T, Minato N. Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade. Proc Natl Acad Sci U S A. 2002 Sep 17;99(19):12293-7. doi: 10.1073/pnas.192461099. Epub 2002 Sep 6.
• Background Xu F, Xu L, Wang Q, An G, Feng G, Liu F. Clinicopathological and prognostic value of programmed death ligand-1 (PD-L1) in renal cell carcinoma: a meta-analysis. Int J Clin Exp Med. 2015 Sep 15;8(9):14595-603. eCollection 2015.
• Background Massi D, Brusa D, Merelli B, Falcone C, Xue G, Carobbio A, Nassini R, Baroni G, Tamborini E, Cattaneo L, Audrito V, Deaglio S, Mandala M. The status of PD-L1 and tumor-infiltrating immune cells predict resistance and poor prognosis in BRAFi-treated melanoma patients harboring mutant BRAFV600. Ann Oncol. 2015 Sep;26(9):1980-1987. doi: 10.1093/annonc/mdv255. Epub 2015 Jun 2.
• Background Brahmer JR, Drake CG, Wollner I, Powderly JD, Picus J, Sharfman WH, Stankevich E, Pons A, Salay TM, McMiller TL, Gilson MM, Wang C, Selby M, Taube JM, Anders R, Chen L, Korman AJ, Pardoll DM, Lowy I, Topalian SL. Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. J Clin Oncol. 2010 Jul 1;28(19):3167-75. doi: 10.1200/JCO.2009.26.7609. Epub 2010 Jun 1.
• Background Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, Chow LQ, Vokes EE, Felip E, Holgado E, Barlesi F, Kohlhaufl M, Arrieta O, Burgio MA, Fayette J, Lena H, Poddubskaya E, Gerber DE, Gettinger SN, Rudin CM, Rizvi N, Crino L, Blumenschein GR Jr, Antonia SJ, Dorange C, Harbison CT, Graf Finckenstein F, Brahmer JR. Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer. N Engl J Med. 2015 Oct 22;373(17):1627-39. doi: 10.1056/NEJMoa1507643. Epub 2015 Sep 27.
• Background 29. Hodi FS, Sznol M, Kluger HM, McDermott DF, Carvajal RD, Lawrence DP. Long-term survival of ipilimumab-naive patients (pts) with advanced melanoma (MEL) treated with nivolumab (anti-PD-1, BMS-936558, ONO-4538) in a phase I trial. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2014;32(Supplement):9002.
• Background McKinstry KK, Strutt TM, Swain SL. Regulation of CD4+ T-cell contraction during pathogen challenge. Immunol Rev. 2010 Jul;236:110-24. doi: 10.1111/j.1600-065X.2010.00921.x.
• Background Ansell SM, Hurvitz SA, Koenig PA, LaPlant BR, Kabat BF, Fernando D, Habermann TM, Inwards DJ, Verma M, Yamada R, Erlichman C, Lowy I, Timmerman JM. Phase I study of ipilimumab, an anti-CTLA-4 monoclonal antibody, in patients with relapsed and refractory B-cell non-Hodgkin lymphoma. Clin Cancer Res. 2009 Oct 15;15(20):6446-53. doi: 10.1158/1078-0432.CCR-09-1339. Epub 2009 Oct 6.
• Background Bashey A, Medina B, Corringham S, Pasek M, Carrier E, Vrooman L, Lowy I, Solomon SR, Morris LE, Holland HK, Mason JR, Alyea EP, Soiffer RJ, Ball ED. CTLA4 blockade with ipilimumab to treat relapse of malignancy after allogeneic hematopoietic cell transplantation. Blood. 2009 Feb 12;113(7):1581-8. doi: 10.1182/blood-2008-07-168468. Epub 2008 Oct 30.
• Background Yu P, Steel JC, Zhang M, Morris JC, Waldmann TA. Simultaneous blockade of multiple immune system inhibitory checkpoints enhances antitumor activity mediated by interleukin-15 in a murine metastatic colon carcinoma model. Clin Cancer Res. 2010 Dec 15;16(24):6019-28. doi: 10.1158/1078-0432.CCR-10-1966. Epub 2010 Oct 5.
• Background Wolchok JD, Kluger H, Callahan MK, Postow MA, Rizvi NA, Lesokhin AM, Segal NH, Ariyan CE, Gordon RA, Reed K, Burke MM, Caldwell A, Kronenberg SA, Agunwamba BU, Zhang X, Lowy I, Inzunza HD, Feely W, Horak CE, Hong Q, Korman AJ, Wigginton JM, Gupta A, Sznol M. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med. 2013 Jul 11;369(2):122-33. doi: 10.1056/NEJMoa1302369. Epub 2013 Jun 2.
• Background 35. Blazer BR, O'Connor RS, Milone MC, et al. Role of PD-1/PD-l1 in Acute and Chronic Graft Versus Host Disease. Blood: 126: (23).
• Background 36. Davids MS, Haesook TK, Costello CL, et al. A Multicenter Phase I/Ib Study of Ipilimumab for Relapsed Hematologic Malignancies after Allogeneic Hematopoietic Stem Cell Transplantation. Blood: 126 (23).
• Background 37. Herbaux C, Gauthier J, Brice P. Nivolumab Is Effective and Reasonably Safe in Relapsed or Refractory Hodgkin's Lymphoma after Allogeneic Hematopoietic Cell Transplantation: A Study from the Lysa and SFGM-TC.

Drugs

Indications