untitled h1
14.4 t-dm1

Please see package insert for T-DM1 (also known as Kadcyla and Ado-Trastuzumab Emtansine) available at the FDA website: www.accessdata.fda.gov 14.4.1 Source / Acquisition and Accountability Ado-trastuzumab emtansine (also known as T-DM1 or Kadcyla) will be purchased by the site pharmacy from commercial sources. T-DM1 will be purchased from commercial sources by the site pharmacy and stored according to product labeling and standard site procedures. T-DM1 will be dispensed at the discretion of an investigator for administration to a study participant enrolled on the clinical trial. Disposal of expired product will be according to standard site procedures. 14.4.2 Administration Procedures Administration of T-DM1 is described in Section 3.2.3.
untitled h1
15 references

1. Ryerson AB, Eheman CR, Altekruse SF, Ward JW, Jemal A, Sherman RL, et al. Annual Report to the Nation on the Status of Cancer, 1975-2012, featuring the increasing incidence of liver cancer. Cancer. 2016;122(9):1312-37. 2. Kummar S, Gutierrez M, Gardner ER, Donovan E, Hwang K, Chung EJ, et al. Phase I trial of MS-275, a histone deacetylase inhibitor, administered weekly in refractory solid tumors and lymphoid malignancies. Clin Cancer Res. 2007;13(18 Pt 1):5411-7. 3. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin. 2018;68(1):730. 4. Howlader N, Altekruse SF, Li CI, Chen VW, Clarke CA, Ries LA, et al. US incidence of breast cancer subtypes defined by joint hormone receptor and HER2 status. J Natl Cancer Inst. 2014;106(5).  
5. Brenton JD, Carey LA, Ahmed AA, Caldas C. Molecular classification and molecular forecasting of breast cancer: Ready for clinical application? Journal of Clinical Oncology. 2005;23(29):7350-60. 6. Bauer KR, Brown M, Cress RD, Parise CA, Caggiano V. Descriptive analysis of estrogen receptor (ER)negative, progesterone receptor (PR)-negative, and HER2-negative invasive breast cancer, the so-called triple-negative phenotype - A population-based study from the California Cancer Registry. Cancer. 2007;109(9):1721-8. 7. Tutt A, Ellis P, Kilburn L, Gilett C, Pinder S, Abraham J, et al. The TNT trial: A randomized phase III trial of carboplatin (C) compared with docetaxel (D) for patients with metastatic or recurrent locally advanced triple negative or BRCA1/2 breast cancer (CRUK/07/012). Cancer Research. 2015;75(9):2. 8. Iwamoto T, Booser D, Valero V, Murray JL, Koenig K, Esteva FJ, et al. Estrogen receptor (ER) mRNA and ER-related gene expression in breast cancers that are 1% to 10% ERpositive by immunohistochemistry. J Clin Oncol. 2012;30(7):729-34.  
9. Landmann A, Farrugia DJ, Zhu L, Diego EJ, Johnson RR, Soran A, et al. Low Estrogen Receptor (ER)-Positive Breast Cancer and Neoadjuvant Systemic Chemotherapy: Is Response Similar to Typical ER-Positive or ER-Negative Disease? Am J Clin Pathol. 2018;150(1):34-42. 10. Allred DC, Carlson RW, Berry DA, Burstein HJ, Edge SB, Goldstein LJ, et al. NCCN Task Force Report: Estrogen Receptor and Progesterone Receptor Testing in Breast Cancer by Immunohistochemistry. J Natl Compr Canc Netw. 2009;7 Suppl 6:S1-S21; quiz S2-3. 11. Singh K, Tantravahi U, Lomme MM, Pasquariello T, Steinhoff M, Sung CJ. Updated 2013 College of American Pathologists/American Society of Clinical Oncology (CAP/ASCO) guideline recommendations for human epidermal growth factor receptor 2 (HER2) fluorescent in situ hybridization (FISH) testing increase HER2 positive and HER2 equivocal breast cancer cases; retrospective study of HER2 FISH results of 836 invasive breast cancers. Breast Cancer Res Treat. 2016;157(3):405-11. 12. Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science. 1987;235(4785):177-82. 13. Swain SM, Baselga J, Kim SB, Ro J, Semiglazov V, Campone M, et al. Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. N Engl J Med. 2015;372(8):724-34. 14. Geyer CE, Forster J, Lindquist D, Chan S, Romieu CG, Pienkowski T, et al. Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med. 2006;355(26):273343. 15. Cetin B, Benekli M, Dane F, Boruban C, Gumus M, Oksuzoglu B, et al. Lapatinib plus Capecitabine for HER2-Positive Advanced-Stage Breast Cancer in Elderly Women: Review of the Anatolian Society of Medical Oncology (ASMO) Experience. Breast Care (Basel). 2013;8(1):67-70. 16. Verma S, Miles D, Gianni L, Krop IE, Welslau M, Baselga J, et al. Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med. 2012;367(19):1783-91. 17. Bartsch R, Wenzel C, Altorjai G, Pluschnig U, Rudas M, Mader RM, et al. Capecitabine and trastuzumab in heavily pretreated metastatic breast cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2007;25(25):3853-8. 18. von Minckwitz G, du Bois A, Schmidt M, Maass N, Cufer T, de Jongh FE, et al. Trastuzumab beyond progression in human epidermal growth factor receptor 2-positive advanced breast cancer: a german breast group 26/breast international group 03-05 study. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2009;27(12):1999-2006. 19. Di Lauro V, Torrisi E, Bidoli E, Quitadamo D, Cecco S, Veronesi A. Trastuzumab and Gemcitabine in Pretreated HER2 Overexpressing Metastatic Breast Cancer Patients: Retrospective Analysis of Our Series. J Oncol. 2012;2012:198412. 20. Diéras V, Miles D, Verma S, Pegram M, Welslau M, Baselga J, et al. Trastuzumab emtansine versus capecitabine plus lapatinib in patients with previously treated HER2-positive advanced breast cancer (EMILIA): a descriptive analysis of final overall survival results from a randomised, open-label, phase 3 trial. Lancet Oncol. 2017;18(6):732-42.  
21. Katz D, Feldhamer I, Greenberg-Dotan S, Hammerman A. Duration of second-line TDM1 therapy: Is it associated with duration of first-line anti-Her2 therapy in metastatic HER2 +
breast cancer? Journal of Clinical Oncology. 2017;35(15_suppl):e12512-e.  
22. Dzimitrowicz H, Berger M, Vargo C, Hood A, Abdelghany O, Raghavendra AS, et al. TDM1 Activity in Metastatic Human Epidermal Growth Factor Receptor 2-Positive Breast Cancers That Received Prior Therapy With Trastuzumab and Pertuzumab. J Clin Oncol. 2016;34(29):3511-7. 23. Cho HS, Mason K, Ramyar KX, Stanley AM, Gabelli SB, Denney DW, et al. Structure of the extracellular region of HER2 alone and in complex with the Herceptin Fab. Nature. 2003;421(6924):756-60. 24. Bianchini G, Gianni L. The immune system and response to HER2-targeted treatment in breast cancer. Lancet Oncol. 2014;15(2):e58-68. 25. Clynes RA, Towers TL, Presta LG, Ravetch JV. Inhibitory Fc receptors modulate in vivo cytotoxicity against tumor targets. Nat Med. 2000;6(4):443-6. 26. Krop I, Winer EP. Trastuzumab emtansine: a novel antibody-drug conjugate for HER2positive breast cancer. Clin Cancer Res. 2014;20(1):15-20. 27. Junttila TT, Li G, Parsons K, Phillips GL, Sliwkowski MX. Trastuzumab-DM1 (T-DM1) retains all the mechanisms of action of trastuzumab and efficiently inhibits growth of lapatinib insensitive breast cancer. Breast Cancer Res Treat. 2011;128(2):347-56. 28. Müller P, Kreuzaler M, Khan T, Thommen DS, Martin K, Glatz K, et al. Trastuzumab emtansine (T-DM1) renders HER2+ breast cancer highly susceptible to CTLA-4/PD-1 blockade. Sci Transl Med. 2015;7(315):315ra188. 29. Bolden JE, Peart MJ, Johnstone RW. Anticancer activities of histone deacetylase inhibitors. Nat Rev Drug Discov. 2006;5(9):769-84. 30. Gameiro SR, Malamas AS, Tsang KY, Ferrone S, Hodge JW. Inhibitors of histone deacetylase 1 reverse the immune evasion phenotype to enhance T-cell mediated lysis of prostate and breast carcinoma cells. Oncotarget. 2016;7(7):7390-402. 31. Huang X, Gao L, Wang S, Lee CK, Ordentlich P, Liu B. HDAC inhibitor SNDX-275 induces apoptosis in erbB2-overexpressing breast cancer cells via down-regulation of erbB3 expression. Cancer Res. 2009;69(21):8403-11. 32. Yardley DA, Ismail-Khan RR, Melichar B, Lichinitser M, Munster PN, Klein PM, et al. Randomized phase II, double-blind, placebo-controlled study of exemestane with or without entinostat in postmenopausal women with locally recurrent or metastatic estrogen receptorpositive breast cancer progressing on treatment with a nonsteroidal aromatase inhibitor. J Clin Oncol. 2013;31(17):2128-35. 33. Huang X, Wang S, Lee CK, Yang X, Liu B. HDAC inhibitor SNDX-275 enhances efficacy of trastuzumab in erbB2-overexpressing breast cancer cells and exhibits potential to overcome trastuzumab resistance. Cancer Lett. 2011;307(1):72-9. 34. Lim B, Murthy R, Jackson S, Willey J, Lee J, Alvarez R, et al. Open-label phase Ib study of entinostat (E), and lapatinib (L) alone, and in combination with trastuzumab (T) in patients (pts) with HER2+ metastatic (mHER2+) breast cancer after progression on trastuzumab.: J Clin Onc; 2011. p. 609. 35. Trapani D, Esposito A, Criscitiello C, Mazzarella L, Locatelli M, Minchella I, et al. Entinostat for the treatment of breast cancer. Expert Opin Investig Drugs. 2017;26(8):965-71. 36. Orillion A, Hashimoto A, Damayanti N, Shen L, Adelaiye-Ogala R, Arisa S, et al. Entinostat Neutralizes Myeloid-Derived Suppressor Cells and Enhances the Antitumor Effect of PD-1 Inhibition in Murine Models of Lung and Renal Cell Carcinoma. Clin Cancer Res. 2017;23(17):5187-201. 37. Gameiro SR, Hodge JW, Jochems C. Potential of HDAC Inhibitors for Combination Therapy with Immunotherapy Platforms. 2016. 38. Tomita Y, Lee MJ, Lee S, Tomita S, Chumsri S, Cruickshank S, et al. The interplay of epigenetic therapy and immunity in locally recurrent or metastatic estrogen receptor-positive breast cancer: Correlative analysis of ENCORE 301, a randomized, placebo-controlled phase II trial of exemestane with or without entinostat. Oncoimmunology. 2016;5(11):e1219008. 39. Johnson M, Adjei A, Ramalingam S, Janne P, Dominguez G, Gabrilovich D, et al. Preliminary results of ENCORE 601, a phase 1b/2, open-label study of entinostat (ENT) in combination with pembrolizumab (PEMBRO) in patients with non-small cell lung cancer (NSCLC). JCO; 2016. 40. Christiansen AJ, West A, Banks KM, Haynes NM, Teng MW, Smyth MJ, et al.  
Eradication of solid tumors using histone deacetylase inhibitors combined with immunestimulating antibodies. Proc Natl Acad Sci U S A. 2011;108(10):4141-6.  
41. Hellman M, Janne P, M O, Hafez N, Raez L, Gabrilovich D, et al., editors.  
Efficacy/safety of entinostat and pembrolizymab in NSCLC patients previously treated with antiPD-(L)1 therapy. IASLC; 2018; Toronto, Canada.  
42. Agarwala S, Moschos S, Johnson M, Opyrchal M, Gabrilovich D, Danaher P, et al., editors. Efficacy and safety of entinostat and pembrolizumab in patients with melanoma progressing on or after PD-1/L1 blocking activity. ASCO; 2018; Chicago, IL. 43. Dirix LY, Takacs I, Jerusalem G, Nikolinakos P, Arkenau HT, Forero-Torres A, et al. Avelumab, an anti-PD-L1 antibody, in patients with locally advanced or metastatic breast cancer: a phase 1b JAVELIN Solid Tumor study. Breast Cancer Res Treat. 2017. 44. Nanda R, Chow LQ, Dees EC, Berger R, Gupta S, Geva R, et al. Pembrolizumab in Patients With Advanced Triple-Negative Breast Cancer: Phase Ib KEYNOTE-012 Study. J Clin Oncol. 2016;34(21):2460-7. 45. Rugo HS, Delord JP, Im SA, Ott PA, Piha-Paul SA, Bedard PL, et al. Safety and Antitumor Activity of Pembrolizumab in Patients with Estrogen Receptor-Positive/Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer. Clin Cancer Res. 2018;24(12):2804-11. 46. Loi S, Giobbie-Hurder A, Gombos A, Bachelot T, Hui R, Cuigliano G, et al., editors. Phase Ib/II Study Evaluating Safety and Efficacy of Pembrolizumab and Trastuzumab in Patients with Trastuzumab-Resistant HER2-positive Advanced Breast Cancer: Results from the PANACEA Study (IBCSG 45-13/BIG 4-13/KEYNOTE-014). San Antonio Breast Cancer Symposium; 2017; San Antonio, TX. 47. Emens L, Esteva F, Beresford M, Saura C, De Laurentiis M, Kim S-B, et al. Results from KATE2, a randomized phase 2 study of atezolizumab (atezo)+trastuzumab emtansine (T-DM1) vs placebo (pbo)+T-DM1 in previously treated HER2+ advanced breast cancer (BC) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium: Cancer Res; 2018. p. Abstract nr PD3-01. 48. Jakowlew SB. Transforming growth factor-beta in cancer and metastasis. Cancer Metastasis Rev. 2006;25(3):435-57. 49. Derynck R, Akhurst RJ, Balmain A. TGF-beta signaling in tumor suppression and cancer progression. Nat Genet. 2001;29(2):117-29. 50. Zarzynska JM. Two faces of TGF-beta1 in breast cancer. Mediators Inflamm. 2014;2014:141747. 51. Tan AR, Alexe G, Reiss M. Transforming growth factor-beta signaling: emerging stem cell target in metastatic breast cancer? Breast Cancer Res Treat. 2009;115(3):453-95.  
52. Tian M, Schiemann WP. TGF-β Stimulation of EMT Programs Elicits Non-genomic ERα Activity and Anti-estrogen Resistance in Breast Cancer Cells. J Cancer Metastasis Treat.  
2017;3:150-60. 53. Wang SE. The Functional Crosstalk between HER2 Tyrosine Kinase and TGF-β Signaling in Breast Cancer Malignancy. J Signal Transduct. 2011;2011:804236. 54. Chow A, Arteaga CL, Wang SE. When tumor suppressor TGFβ meets the HER2 (ERBB2) oncogene. J Mammary Gland Biol Neoplasia. 2011;16(2):81-8. 55. Massagué J. TGFbeta in Cancer. Cell. 2008;134(2):215-30. 56. Teicher BA. Transforming growth factor-beta and the immune response to malignant disease. Clin Cancer Res. 2007;13(21):6247-51.  
57. Reis ST, Pontes-Junior J, Antunes AA, Sousa-Canavez JM, Abe DK, Cruz JA, et al. Tgfbeta1 expression as a biomarker of poor prognosis in prostate cancer. Clinics (Sao Paulo, Brazil).  
2011;66(7):1143-7. 58. Bruna A, Darken RS, Rojo F, Ocana A, Penuelas S, Arias A, et al. High TGFbeta-Smad activity confers poor prognosis in glioma patients and promotes cell proliferation depending on the methylation of the PDGF-B gene. Cancer Cell. 2007;11(2):147-60. 59. Gao N, Zhai Q, Li Y, Huang K, Bian D, Wang X, et al. Clinical Implications of TbetaRII Expression in Breast Cancer. PLoS One. 2015;10(11):e0141412. 60. Colak S, Ten Dijke P. Targeting TGF-beta Signaling in Cancer. Trends Cancer. 2017;3(1):56-71. 61. Formenti SC, Lee P, Adams S, Goldberg JD, Li X, Xie M, et al. Focal Irradiation And Systemic Transforming Growth Factor β Blockade in Metastatic Breast Cancer. Clin Cancer Res. 2018. 62. Phan K, Tsai YC, Niranjan N, Bouchard D, Carrel TP, Dapunt OE, et al. Sutureless aortic valve replacement: a systematic review and meta-analysis. Ann Cardiothorac Surg. 2015;4(2):100-11.  
63. Pyo JS, Kang G, Kim JY. Prognostic role of PD-L1 in malignant solid tumors: a metaanalysis. Int J Biol Markers. 2017;32(1):e68-e74.  
64. Hu YG, Shen YF, Li Y. Effect of Pin1 inhibitor juglone on proliferation, migration and angiogenic ability of breast cancer cell line MCF7Adr. J Huazhong Univ Sci Technolog Med Sci. 2015;35(4):531-4.  
65. Wu P, Wu D, Li L, Chai Y, Huang J. PD-L1 and Survival in Solid Tumors: A MetaAnalysis. PLoS One. 2015;10(6):e0131403.  
66. Weber JS, D'Angelo SP, Minor D, Hodi FS, Gutzmer R, Neyns B, et al. Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2015;16(4):375-84. 67. Postow MA, Chesney J, Pavlick AC, Robert C, Grossmann K, McDermott D, et al. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med. 2015;372(21):2006-17. 68. Robert C, Schachter J, Long GV, Arance A, Grob JJ, Mortier L, et al. Pembrolizumab versus Ipilimumab in Advanced Melanoma. N Engl J Med. 2015;372(26):2521-32. 69. Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, et al. Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer. N Engl J Med. 2015;373(17):1627-39. 70. Herbst RS, Baas P, Kim DW, Felip E, Perez-Gracia JL, Han JY, et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet. 2016;387(10027):1540-50. 71. Motzer RJ, Escudier B, McDermott DF, George S, Hammers HJ, Srinivas S, et al. Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma. N Engl J Med. 2015;373(19):1803-13. 72. Seiwert TY, Burtness B, Mehra R, Weiss J, Berger R, Eder JP, et al. Safety and clinical activity of pembrolizumab for treatment of recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-012): an open-label, multicentre, phase 1b trial. Lancet Oncol. 2016;17(7):956-65. 73. Chow LQ, Haddad R, Gupta S, Mahipal A, Mehra R, Tahara M, et al. Antitumor Activity of Pembrolizumab in Biomarker-Unselected Patients With Recurrent and/or Metastatic Head and Neck Squamous Cell Carcinoma: Results From the Phase Ib KEYNOTE-012 Expansion Cohort. J Clin Oncol. 2016. 74. Ferris RL, Blumenschein G, Jr., Fayette J, Guigay J, Colevas AD, Licitra L, et al. Nivolumab for Recurrent Squamous-Cell Carcinoma of the Head and Neck. N Engl J Med. 2016;375(19):1856-67. 75. Kaufman HL, Russell J, Hamid O, Bhatia S, Terheyden P, D'Angelo SP, et al. Avelumab in patients with chemotherapy-refractory metastatic Merkel cell carcinoma: a multicentre, singlegroup, open-label, phase 2 trial. Lancet Oncol. 2016;17(10):1374-85.  
76. Massard C, Gordon MS, Sharma S, Rafii S, Wainberg ZA, Luke J, et al. Safety and Efficacy of Durvalumab (MEDI4736), an Anti-Programmed Cell Death Ligand-1 Immune Checkpoint Inhibitor, in Patients With Advanced Urothelial Bladder Cancer. J Clin Oncol. 2016;34(26):3119-25. 77. Strauss J, Madan RA, Gulley JL. Considerations for the combination of anticancer vaccines and immune checkpoint inhibitors. Expert Opin Biol Ther. 2016;16(7):895-901. 78. Melero I, Berman DM, Aznar MA, Korman AJ, Perez Gracia JL, Haanen J. Evolving synergistic combinations of targeted immunotherapies to combat cancer. Nat Rev Cancer. 2015;15(8):457-72.  
79. Knudson K, Hicks K, Luo X, Chen J, J S, Gameiro S. M7824, a novel bifunctional antiPD-L1/TGFb TRAP fusion protein, promotes anti-tumor efficacy as monotherapy and in combination with vaccine. OncoImmunology. 2018(Epub ahead of print).  
80. Grenga I, Donahue RN, Gargulak ML, Lepone LM, Roselli M, Bilusic M, et al. Anti-PDL1/TGFβR2 (M7824) fusion protein induces immunogenic modulation of human urothelial carcinoma cell lines, rendering them more susceptible to immune-mediated recognition and lysis. Urol Oncol. 2018;36(3):93.e1-.e11. 81. Jochems C, Tritsch SR, Pellom ST, Su Z, Soon-Shiong P, Wong HC, et al. Analyses of functions of an anti-PD-L1/TGFβR2 bispecific fusion protein (M7824). Oncotarget. 2017;8(43):75217-31. 82. Lacouture ME, Morris JC, Lawrence DP, Tan AR, Olencki TE, Shapiro GI, et al. Cutaneous keratoacanthomas/squamous cell carcinomas associated with neutralization of transforming growth factor beta by the monoclonal antibody fresolimumab (GC1008). Cancer Immunol Immunother. 2015;64(4):437-46. 83. Strauss J, Heery C, Schlom J, Madan RA, Cao L, Kang Z, et al. Phase 1 trial of M7824 (MSB0011359C), a bifunctional fusion protein targeting PD-L1 and TGF-β, in advanced solid tumors. Clin Cancer Res. 2018. 84. Strauss J, Heery CR, Schlom J, Madan RA, Cao L, Kang Z, et al. Phase I Trial of M7824 (MSB0011359C), a Bifunctional Fusion Protein Targeting PD-L1 and TGFβ, in Advanced Solid Tumors. Clin Cancer Res. 2018;24(6):1287-95. 85. Palena C, Roselli M, Litzinger MT, Ferroni P, Costarelli L, Spila A, et al. Overexpression of the EMT driver brachyury in breast carcinomas: association with poor prognosis. J Natl Cancer Inst. 2014;106(5). 86. Palena C, Hamilton DH. Immune Targeting of Tumor Epithelial-Mesenchymal Transition via Brachyury-Based Vaccines. Adv Cancer Res. 2015;128:69-93. 87. Hamilton DH, Roselli M, Ferroni P, Costarelli L, Cavaliere F, Taffuri M, et al. Brachyury, a vaccine target, is overexpressed in triple-negative breast cancer. Endocr Relat Cancer. 2016;23(10):783-96. 88. Palena C, Polev DE, Tsang KY, Fernando RI, Litzinger M, Krukovskaya LL, et al. The human T-box mesodermal transcription factor Brachyury is a candidate target for T-cellmediated cancer immunotherapy. Clin Cancer Res. 2007;13(8):2471-8.  
89. Heery CR, Palena C, McMahon S, Donahue RN, Lepone LM, Grenga I, et al. Phase I Study of a Poxviral TRICOM-Based Vaccine Directed Against the Transcription Factor Brachyury. Clin Cancer Res. 2017. 90. Hamilton DH, Litzinger MT, Jales A, Huang B, Fernando RI, Hodge JW, et al. Immunological targeting of tumor cells undergoing an epithelial-mesenchymal transition via a recombinant brachyury-yeast vaccine. Oncotarget. 2013;4(10):1777-90. 91. Heery CR, Singh BH, Rauckhorst M, Marte JL, Donahue RN, Grenga I, et al. Phase I Trial of a Yeast-Based Therapeutic Cancer Vaccine (GI-6301) Targeting the Transcription Factor Brachyury. Cancer Immunol Res. 2015;3(11):1248-56. 92. Madan RA, Mohebtash M, Arlen PM, Vergati M, Rauckhorst M, Steinberg SM, et al.  
Ipilimumab and a poxviral vaccine targeting prostate-specific antigen in metastatic castrationresistant prostate cancer: a phase 1 dose-escalation trial. Lancet Oncol. 2012;13(5):501-8.  
93. Vollmar J, Arndtz N, Eckl KM, Thomsen T, Petzold B, Mateo L, et al. Safety and immunogenicity of IMVAMUNE, a promising candidate as a third generation smallpox vaccine. Vaccine. 2006;24(12):2065-70. 94. Frey SE, Newman FK, Kennedy JS, Sobek V, Ennis FA, Hill H, et al. Clinical and immunologic responses to multiple doses of IMVAMUNE (Modified Vaccinia Ankara) followed by Dryvax challenge. Vaccine. 2007;25(51):8562-73. 95. von Krempelhuber A, Vollmar J, Pokorny R, Rapp P, Wulff N, Petzold B, et al. A randomized, double-blind, dose-finding Phase II study to evaluate immunogenicity and safety of the third generation smallpox vaccine candidate IMVAMUNE. Vaccine. 2010;28(5):1209-16. 96. Beukema EL, Brown MP, Hayball JD. The potential role of fowlpox virus in rational vaccine design. Expert Rev Vaccines. 2006;5(4):565-77. 97. Salgado R, Denkert C, Demaria S, Sirtaine N, Klauschen F, Pruneri G, et al. The evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer: recommendations by an International TILs Working Group 2014. Ann Oncol. 2015;26(2):259-71.  
98. Stanton SE, Adams S, Disis ML. Variation in the Incidence and Magnitude of TumorInfiltrating Lymphocytes in Breast Cancer Subtypes: A Systematic Review. JAMA Oncol. 2016.  
99. Loi S, Sirtaine N, Piette F, Salgado R, Viale G, Van Eenoo F, et al. Prognostic and predictive value of tumor-infiltrating lymphocytes in a phase III randomized adjuvant breast cancer trial in node-positive breast cancer comparing the addition of docetaxel to doxorubicin with doxorubicin-based chemotherapy: BIG 02-98. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2013;31(7):860-7. 100. Dieci MV, Mathieu MC, Guarneri V, Conte P, Delaloge S, Andre F, et al. Prognostic and predictive value of tumor-infiltrating lymphocytes in two phase III randomized adjuvant breast cancer trials. Ann Oncol. 2015;26(8):1698-704. 101. Loi S, Michiels S, Salgado R, Sirtaine N, Jose V, Fumagalli D, et al. Tumor infiltrating lymphocytes are prognostic in triple negative breast cancer and predictive for trastuzumab benefit in early breast cancer: results from the FinHER trial. Ann Oncol. 2014;25(8):1544-50. 102. Adams S, Gray RJ, Demaria S, Goldstein L, Perez EA, Shulman LN, et al. Prognostic value of tumor-infiltrating lymphocytes in triple-negative breast cancers from two phase III randomized adjuvant breast cancer trials: ECOG 2197 and ECOG 1199. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2014;32(27):2959-66. 103. Ibrahim EM, Al-Foheidi ME, Al-Mansour MM, Kazkaz GA. The prognostic value of tumor-infiltrating lymphocytes in triple-negative breast cancer: a meta-analysis. Breast Cancer Res Treat. 2014;148(3):467-76.  
104. Mao Y, Qu Q, Chen X, Huang O, Wu J, Shen K. The Prognostic Value of TumorInfiltrating Lymphocytes in Breast Cancer: A Systematic Review and Meta-Analysis. PLoS One.  
2016;11(4):e0152500. 105. García-Teijido P, Cabal ML, Fernández IP, Pérez YF. Tumor-Infiltrating Lymphocytes in Triple Negative Breast Cancer: The Future of Immune Targeting. Clin Med Insights Oncol. 2016;10(Suppl 1):31-9. 106. Luen SJ, Salgado R, Fox S, Savas P, Eng-Wong J, Clark E, et al. Tumour-infiltrating lymphocytes in advanced HER2-positive breast cancer treated with pertuzumab or placebo in addition to trastuzumab and docetaxel: a retrospective analysis of the CLEOPATRA study. Lancet Oncol. 2017;18(1):52-62.  
107. Roulois D, Loo Yau H, Singhania R, Wang Y, Danesh A, Shen SY, et al. DNADemethylating Agents Target Colorectal Cancer Cells by Inducing Viral Mimicry by Endogenous Transcripts. Cell. 2015;162(5):961-73. 108. Zaretsky JM, Garcia-Diaz A, Shin DS, Escuin-Ordinas H, Hugo W, Hu-Lieskovan S, et al. Mutations Associated with Acquired Resistance to PD-1 Blockade in Melanoma. N Engl J Med. 2016;375(9):819-29. 109. Le DT, Durham JN, Smith KN, Wang H, Bartlett BR, Aulakh LK, et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science. 2017;357(6349):409-13. 110. Li X, Gruosso T, Zuo D, Omeroglu A, Meterissian S, Guiot MC, et al. Infiltration of CD8. Proc Natl Acad Sci U S A. 2019;116(9):3678-87.  
111. Heery CR, Donahue R, Lepone L, Grenga I, Richards J, Metenou S, et al. Phase I, doseescalation, clinical trial of MVA-Brachyury-TRICOM vaccine demonstrating safety and brachyury-specific T cell responses.: J ImmunoTherapy of Cancer; 2015. p. P132. 112. 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):2509-20. 113. Strauss J, Heery C, Schlom J, Madan RA, Cao L, Kang Z, et al. Phase 1 trial of M7824 (MSB0011359C), a bifunctional fusion protein targeting PD-L1 and TGF-beta, in advanced solid tumors. Clin Cancer Res. 2018. 114. Hicks KC, Fantini M, Donahue RN, Schwab A, Knudson KM, Tritsch SR, et al. Epigenetic priming of both tumor and NK cells augments antibody-dependent cellular cytotoxicity elicited by the anti-PD-L1 antibody avelumab against multiple carcinoma cell types. Oncoimmunology. 2018;7(11):e1466018. 115. Christmas BJ, Rafie CI, Hopkins AC, Scott BA, Ma HS, Cruz KA, et al. Entinostat Converts Immune-Resistant Breast and Pancreatic Cancers into Checkpoint-Responsive Tumors by Reprogramming Tumor-Infiltrating MDSCs. Cancer Immunol Res. 2018;6(12):1561-77. 116. Bauzon M, Drake P, Barfield R, Cornali B, Rupniewski I, Rabuka D. Maytansine-bearing antibody-drug conjugates induce in vitro hallmarks of immunogenic cell death selectively in antigen-positive target cells. OncoImmunology; 2019. 117. Wolff AC, Hammond ME, Hicks DG, Dowsett M, McShane LM, Allison KH, et al. Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update. Arch Pathol Lab Med. 2014;138(2):241-56. 118. Ryan QC, Headlee D, Acharya M, Sparreboom A, Trepel JB, Ye J, et al. Phase I and pharmacokinetic study of MS-275, a histone deacetylase inhibitor, in patients with advanced and refractory solid tumors or lymphoma. J Clin Oncol. 2005;23(17):3912-22.  
119. Heery CR, Donahue R, Lepone L, Grenga I, Richards J, Metenou S, et al. Phase I, doseescalation, clinical trial of MVA-Brachyury-TRICOM vaccine demonstrating safety and brachyury-specific T cell responses. J Immunother Cancer. 2015;3(Supp 2):P132. 120. Lepone LM, Donahue RN, Grenga I, Metenou S, Richards J, Heery CR, et al. Analysis of 123 peripheral human immune cell subsets: defining differences with age and between healthy donors and cancer patients not detected in analysis of standard immune cell types. J Circ Biomark. In press. 121. Chung EJ, Lee S, Sausville EA, Ryan Q, Karp JE, Gojo I, et al. Histone deacetylase inhibitor pharmacodynamic analysis by multiparameter flow cytometry. Ann Clin Lab Sci. 2005;35(4):397-406. 122. Wolff AC, Hammond ME, Hicks DG, Dowsett M, McShane LM, Allison KH, et al. Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update. J Clin Oncol. 2013;31(31):3997-4013. 123. Hamilton DH, Fernando RI, Schlom J, Palena C. Aberrant expression of the embryonic transcription factor brachyury in human tumors detected with a novel rabbit monoclonal antibody. Oncotarget. 2015;6(7):4853-62. 124. Miettinen M, Wang Z, Lasota J, Heery C, Schlom J, Palena C. Nuclear Brachyury Expression Is Consistent in Chordoma, Common in Germ Cell Tumors and Small Cell Carcinomas, and Rare in Other Carcinomas and Sarcomas: An Immunohistochemical Study of 5229 Cases. Am J Surg Pathol. 2015;39(10):1305-12. 125. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228-47. 126. Simon R. Controlled Clinical Trials. 1989. p. 1-10. 127. Connolly RM, Rudek MA, Piekarz R. Entinostat: a promising treatment option for patients with advanced breast cancer. Future Oncol. 2017;13(13):1137-48. 128. Vugmeyster Y, Wilkins J, Harrison-Moench E, Geng W, Koenig A, Cao L, et al., editors. Selection of the recommended phase 2 dose (RP2D) for M7824 (MSB0011359C), a bifunctional fusion protein targeting TGF-βand PD-L1. . ASCO; 2018; Chicago, IL: J Clin Onc 36: 15_Suppl: Abstr 2566. 129. Goudie DR, D'Alessandro M, Merriman B, Lee H, Szeverenyi I, Avery S, et al. Multiple self-healing squamous epithelioma is caused by a disease-specific spectrum of mutations in TGFBR1. Nat Genet. 2011;43(4):365-9. 130. Morris JC, Tan AR, Olencki TE, Shapiro GI, Dezube BJ, Reiss M, et al. Phase I study of GC1008 (fresolimumab): a human anti-transforming growth factor-beta (TGFβ) monoclonal antibody in patients with advanced malignant melanoma or renal cell carcinoma. PLoS One. 2014;9(3):e90353.
untitled h1
16 appendicies

| 16.1                                                                                                                                                                                       | APPENDIX A: PERFORMANCE STATUS CRITERIA ECOG Performance Status Scale   | Karnofsky Performance Scale                                |             |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------|------------------------------------------------------------|-------------|
| Grade                                                                                                                                                                                      | Descriptions                                                            | Percent                                                    | Description |
| 100                                                                                                                                                                                        | Normal, no complaints, no  evidence of disease.                         |                                                            |             |
| Normal activity. Fully active,                                                                                                                                                             |                                                                         |                                                            |             |
| 0                                                                                                                                                                                          | able to carry on all pre-disease  performance without restriction.      | Able to carry on normal activity;                          |             |
| 90                                                                                                                                                                                         | minor signs or symptoms of  disease.                                    |                                                            |             |
| Symptoms, but ambulatory.  Restricted in physically strenuous  activity, but ambulatory and able  to carry out work of a light or  sedentary nature (e.g., light  housework, office work). | Normal activity with effort;                                            |                                                            |             |
| 80                                                                                                                                                                                         | some signs or symptoms of  disease.                                     |                                                            |             |
| 1                                                                                                                                                                                          | Cares for self, unable to carry on                                      |                                                            |             |
| 70                                                                                                                                                                                         | normal activity or to do active  work.                                  |                                                            |             |
| In bed <50% of the time.  Ambulatory and capable of all  self-care, but unable to carry out  any work activities. Up and  about more than 50% of waking  hours.                            | Requires occasional assistance,                                         |                                                            |             |
| 60                                                                                                                                                                                         | but is able to care for most of  his/her needs.                         |                                                            |             |
| 2                                                                                                                                                                                          | Requires considerable assistance                                        |                                                            |             |
| 50                                                                                                                                                                                         | and frequent medical care.                                              |                                                            |             |
| 40                                                                                                                                                                                         | Disabled, requires special care  and assistance.                        |                                                            |             |
| In bed >50% of the time.  Capable of only limited self-care,  confined to bed or chair more  than 50% of waking hours.                                                                     |                                                                         |                                                            |             |
| 3                                                                                                                                                                                          | Severely disabled,                                                      |                                                            |             |
| 30                                                                                                                                                                                         | hospitalization indicated. Death  not imminent.                         |                                                            |             |
| 100% bedridden. Completely  disabled. Cannot carry on any  self-care. Totally confined to bed  or chair.                                                                                   | 20                                                                      | Very sick, hospitalization  indicated. Death not imminent. |             |
| 4                                                                                                                                                                                          | 10                                                                      | Moribund, fatal processes  progressing rapidly.            |             |
| 5                                                                                                                                                                                          | Dead.                                                                   | 0                                                          | Dead.       |
16.2 appendix b oral medication
oral medication diary for entinostat

| Patient's Name: __________________________________   | Date: __________________   |
|------------------------------------------------------|----------------------------|
| Patient Study ID: _________________________________  | Cycle #: ________________  |
16.2 appendix b oral medication
instructions to the patient

1. Complete one form for each cycle (21 days). 2. You will take Entinostat by mouth each Tuesday (white spaces). You may take the capsules one hour before or two hours after eating, as you prefer. If you forget to take the pills on your assigned day, you can take the missed dose up to 1 day after (light gray space). Do not take the weekly dose if more than 1 day late after scheduled dose (dark gray spaces). 3. Record the date, the number of pills you took, and when you took them. 4. If you have any comments or notice any side effects, please record them in the Comments column. 5. Please bring your pill bottle and this form to your physician when you go for your next appointment.  
General Comments: ______________________________________________________________________________ ______________________________________________________________________________  
| # pills and when taken:   | # pills and when taken:   |            |            |            |      |          |
|---------------------------|---------------------------|------------|------------|------------|------|----------|
| Day                       | Entinostat                | Day        | Entinostat |            |      |          |
| Comments                  |                           |            |            |            |      |          |
| Date                      | # Capsules                | Time       | Date       | # Capsules | Time | Comments |
| 1                         | 15                        |            |            |            |      |          |
| 2                         | 16                        |            |            |            |      |          |
| 3                         | 17                        |            |            |            |      |          |
| 4                         | 18                        |            |            |            |      |          |
| 5                         | 19                        |            |            |            |      |          |
| 6                         | 20                        |            |            |            |      |          |
| 7                         | 21                        |            |            |            |      |          |
| 8                         | 22                        |            |            |            |      |          |
| 9                         | 23                        |            |            |            |      |          |
| 10                        | 24                        |            |            |            |      |          |
| 11                        | 25                        |            |            |            |      |          |
| 12                        | 26                        |            |            |            |      |          |
| 13                        | 27                        |            |            |            |      |          |
| 14                        | 28                        | Next Cycle |            |            |      |          |  
Patient's Signature: ___________________________________Date: ____________________ Study Team will complete this section:  
| 1.   | Date patient started protocol treatment_____________________   |
|------|----------------------------------------------------------------|
| 2.   | Date patient was removed from study _____________________      |
| 3.   | Patient's planned daily dose______________________________     |
| 4.   | Total number of pills taken this cycle ______________________  |  
Physician/Nurse's Signature ____________________________________________________________________
16.2 appendix b oral medication
16.3 appendix c ltib sop

1. Using sterile forceps and blade, process the tissue immediately after being collected by Interventional Radiology by cutting it in different pieces, as needed. Your time frame prior to freezing is maximum of 20 min.  
2. Immediately embed each tissue piece in a labeled & dated plastic capsule containing OCT medium (TissueTek \#4583), free of air bubbles. Cover the entire tissue with extra OCT.  
3. Transfer the OCT/core samples to a liquid nitrogen bath and cover with a lid. After 10-15 min, transfer the frozen specimens to the vapor phase of a liquid nitrogen tank.
16.2 appendix b oral medication
16.4 appendix d clinical and

To date, 19 clinical trials (13 sponsored by Bavarian Nordic [BN] and 6 sponsored by the Division of Microbiology and Infectious Diseases [DMID], National Institute of Allergy and Infectious Diseases [NIAID], the National Institutes of Health [NIH]) evaluating the safety and immunogenicity of MVA-BN have been completed. Currently 2 BN sponsored clinical trials are ongoing. In total, for MVA-BN and MVA-BN-based recombinant vaccines, the exposure sums up to more than 9,600 subjects (more than 7,700 with MVA-BN, more than 400 with recombinant vaccines other than MVA-BN Filo, and more than 1,500 with MVA-BN-Filo), having received more than 15,000 single doses of vaccine. For more details, refer to the current IB of MVA-BNBRACHYURY vaccine.  
16.4.1 Safety Overview of MVA-BN and Recombinant MVA-based Vaccines In all completed and ongoing clinical trials, vaccinations with MVA-BN have shown to be generally safe and well tolerated. No cases of death, assessed as being even possibly related, have been reported for a subject in a clinical trial using MVA-BN. Results obtained from completed Phase 1 and 2 trials and ongoing trials with several recombinant MVA-BN based vaccines in healthy adults and children, HIV infected, and cancer subjects demonstrate a similar safety profile as MVA-BN alone. Additional information on the safety profile of MVA-BN and recombinant MVA-based vaccines is provided in the Investigator's Brochure.
16.2 appendix b oral medication
adverse drug reactions

The following **Table 18** summarizes the pooled Adverse Drug Reaction (ADR) data of all completed MVA-BN trials. The safety profile of each of the trials with recombinant MVA-BNbased vaccines is comparable to the safety profile observed with MVA-BN trials as displayed in Table 19 as the occurrence of the ADRs is considered to be a reaction to the vector rather than the insert, based on previous experience with recombinant MVA-BN vaccine candidates.  
| Preferred Term (PT)                     | No. of reports by subjects   | Frequency (%)   |
|-----------------------------------------|------------------------------|-----------------|
| Injection site pain                     | 6,201                        | 82.3            |
| Injection site erythema                 | 4,920                        | 65.3            |
| Injection site swelling                 | 3,401                        | 45.1            |
| Injection site induration               | 3,253                        | 43.2            |
| Injection site induration (solicited)   | 3,248 out of 7,013           | 46.3            |
| Injection site induration (unsolicited) | 5 out of 521                 | 1.0.            |
| Injection site pruritus                 | 2,856                        | 37.9            |
| Injection site pruritus (solicited)     | 2,645 out of 6,339           | 41.7            |  
| Preferred Term (PT)                   | No. of reports by subjects   | Frequency (%)   |
|---------------------------------------|------------------------------|-----------------|
| Injection site pruritus (unsolicited) | 211 out of 1,213             | 17.4            |
| Fatigue                               | 2,121                        | 28.1            |
| Fatigue (solicited) +                 | 2,121 out of 6,339           | 33.5            |
| Myalgia                               | 2,444                        | 32.4            |
| Myalgia (solicited)                   | 2,443 out of 7,448           | 32.8            |
| Myalgia (unsolicited)                 | 1 out of 86                  | 1.2             |
| Headache                              | 2207                         | 29.3            |
| Headache (solicited)                  | 2,176 out of 7,013           | 31.0            |
| Headache (unsolicited)                | 31 out of 521                | 6.0             |
| Nausea                                | 1,073                        | 14.2            |
| Nausea (solicited)                    | 1,072 out of 7,448           | 14.4            |
| Nausea (unsolicited)                  | 1 out of 86                  | 1.2             |
| Rigors/chills                         | 664                          | 8.8             |
| Rigors/chills (solicited)             | 663 out of 6,732             | 9.8             |
| Rigors/chills (unsolicited)           | 1 out of 802                 | 0.1             |
| Body temperature increased            | 269                          | 3.6             |
| Injection site discoloration          | 190                          | 2.5             |
| Appetite disorder                     | 218                          | 2.9             |
| Appetite disorder (solicited)++       | 218 out of 1,801             | 12.1            |
| Injection site nodule                 | 149                          | 2.0             |
| Pain in extremity                     | 147                          | 2.0             |
| Pain in extremity (solicited)         | 139 out of 1,346             | 10.3            |
| Pain in extremity (unsolicited)       | 8 out of 6,188               | 0.1             |
| Arthralgia                            | 206                          | 2.7             |
| Injection site hematoma               | 107                          | 1.4             |
| Pyrexia                               | 94                           | 1.2             |
| Axillary pain                         | 91                           | 1.2             |  
* POX-MVA-001, -002, -004, -005, -007, -008, -009, -010, -011, -013, -023, -024, -027, -028, -029, -030, -036, HIV-NEF-004 and HIV- POL002; 7 subjects in POX-MVA-009 received Dryvax® either on the same day or within 7 days after MVA-BN administration and were therefore not included to avoid a potential bias in the adverse event reporting. + not in POX-MVA-001; ++ only in NIH trials Looking only at the events that were reported by at least 1% of subjects, the majority of ADRs represented local vaccination site reactions as well as common systemic reactions typical for modern injectable vaccines and were classified as being mild to moderate in intensity and resolved completely without intervention within the first 7 days following vaccination. To date, no trends have been identified suggesting the occurrence of any particular unexpected adverse reactions or classes of adverse reactions following vaccinations with MVA-BN.
16.2 appendix b oral medication
cardiac signs and symptoms

Based on observations with replicating smallpox vaccines particular attention has been placed on monitoring for cardiac signs and symptoms in all clinical trials using MVA-BN. Despite close cardiac monitoring, no confirmed event indicating a case of myo-/pericarditis has been observed in any completed MVA-BN trial. Serious Suspected Adverse Drug Reactions As of 31 July 2016, a total of 7 (7 out of 7,758 vaccinated subjects = 0.09%) serious suspected ADRs have been reported for MVA-BN smallpox vaccine in completed and ongoing trials
(**Table 18**).  
All of them have been thoroughly reviewed by BN and the trial specific Data Safety Monitoring Board who concluded that the continued use of MVA-BN in a clinical setting presented no special risks to the subjects. No pattern regarding Serious Adverse Drug Reactions (SADRs) could be detected.  
| Possibly Related to MVA-BN)                                                                                                                                                                                                                        | PI                                                                                                                                | BN                                   |                                      |                    |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------|--------------------------------------|--------------------------------------|--------------------|
| Assessment                                                                                                                                                                                                                                                    | Opinion                                                                                                                           |                                      |                                      |                    |
| Trial  Age/                                                                                                                                                                                                                                        | Days After  Vaccination Event                                                                                                     | Outcome Underlying Diseases/         |                                      |                    |
| Code  Gender                                                                                                                                                                                                                                       | Circumstances                                                                                                                     |                                      |                                      |                    |
| POXMVA  30/  Male  -005                                                                                                                                                                                                                                                    | 70 days after                                                                                                                     | Stable and                           |                                      |                    |
| second                                                                                                                                                                                                                                             | Sarcoidosis                                                                                                                       | asymptomatic                                      |                                      |                    |
| vaccination                                                                                                                                                                                                                                        | Urinary tract infection with  Chlamydia trachomatis at time of  first symptoms (arthralgia)  Possibly  Possibly  related  related |                                      |                                      |                    |
| Stable and  asymptomatic  under  therapy  Abnormal lab results (elevated  alkaline phosphatase, absolute  neutrophils and platelet counts) at  screening for 2-year follow-up  POX-MVA-023 (excluded)                                                                                                                                                                                                                                                    |                                                                                                                                   |                                      |                                      |                    |
| POXMVA                                                                                                                                                                                                                                                    | 26 months                                                                                                                         |                                      |                                      |                    |
| 31/                                                                                                                                                                                                                                                | after second  Crohn's disease                                                                                                     |                                      |                                      |                    |
| Female                                                                                                                                                                                                                                             |                                                                                                                                   |                                      |                                      |                    |
| -005                                                                                                                                                                                                                                               | vaccination                                                                                                                       | Possibly  Possibly  related  related |                                      |                    |
| POXMVA                                                                                                                                                                                                                                                    | 8 days after                                                                                                                      |                                      |                                      |                    |
| 28/                                                                                                                                                                                                                                                | second                                                                                                                            |                                      |                                      |                    |
| Female                                                                                                                                                                                                                                             |                                                                                                                                   |                                      |                                      |                    |
| -008                                                                                                                                                                                                                                               | vaccination                                                                                                                       | Resolved                             | No relevant medical history          | Probably  Possibly |
| without                                                                                                                                                                                                                                            | related                                                                                                                           | related                              |                                      |                    |
| sequelae                                                                                                                                                                                                                                           |                                                                                                                                   |                                      |                                      |                    |
| Transitory ocular  muscle paresis                                                                                                                                                                                                                  | Surgery for ventricular septal  defect as child. HIV infection.  Concomitant (denied, therefore  previously unknown to BN)  participation in a GrowthHormone Releasing Hormone  (GH- RH) trial; event also  assessed as possibly related to  GH-RH                                                                                                                                   |                                      |                                      |                    |
| Stable                                                                                                                                                                                                                                             |                                                                                                                                   |                                      |                                      |                    |
| Congestive heart                                                                                                                                                                                                                                   | under                                                                                                                             |                                      |                                      |                    |
| failure due to cardiomyopathy  cardiac  medications                                                                                                                                                                                                                                                    |                                                                                                                                   |                                      |                                      |                    |
| POXMVA                                                                                                                                                                                                                                                    | 133 days                                                                                                                          |                                      |                                      |                    |
| 30/                                                                                                                                                                                                                                                | after second                                                                                                                      |                                      |                                      |                    |
| Female                                                                                                                                                                                                                                             |                                                                                                                                   |                                      |                                      |                    |
| -010                                                                                                                                                                                                                                               | vaccination                                                                                                                       | Possibly  Unlikely  related  related |                                      |                    |
| HIV infection (CD4 count 4  weeks prior to second vaccination  was 299 cells/μL). History of  chronic obstructive pulmonary  disease. Acute sinusitis and nasal  congestion due to swimmer's ear  which triggered hospital  admittance.            |                                                                                                                                   |                                      |                                      |                    |
| POXMVA                                                                                                                                                                                                                                                    | 1 day after                                                                                                                       |                                      |                                      |                    |
| 39/-                                                                                                                                                                                                                                               | second                                                                                                                            |                                      |                                      |                    |
| Female                                                                                                                                                                                                                                             |                                                                                                                                   |                                      |                                      |                    |
| -011                                                                                                                                                                                                                                               | vaccination                                                                                                                       | Resolved  without  sequelae          |                                      |                    |
| Simple pneumonia  and pleurisy                                                                                                                                                                                                                     | Possibly  Unlikely  related  related                                                                                              |                                      |                                      |                    |
| The subject received her second  dose of MVA-BN 21 days after  the first dose and after 2 hours  developed symptoms such as skin  reactions and throat tightness  which was responsive to  epinephrine treatment. She had  no wheezing and was not |                                                                                                                                   |                                      |                                      |                    |
| Throat tightness and  other  hypersensitivity  symptoms such as  hives, pruritus,  tender vaccination  site, swollen axilla,                                                                                                                       |                                                                                                                                   |                                      |                                      |                    |
| POXMVA                                                                                                                                                                                                                                                    | 0 days after                                                                                                                      |                                      |                                      |                    |
| 27/                                                                                                                                                                                                                                                | second                                                                                                                            |                                      |                                      |                    |
| Female                                                                                                                                                                                                                                             |                                                                                                                                   |                                      |                                      |                    |
| -036                                                                                                                                                                                                                                               | vaccination                                                                                                                       | Resolved  without  sequelae          | Possibly  Possibly  related  related |                    |  
| PI                                                                                 | BN                             |                                                                               |                                      |
|------------------------------------------------------------------------------------|--------------------------------|-------------------------------------------------------------------------------|--------------------------------------|
| Assessment                                                                                    | Opinion                        |                                                                               |                                      |
| Trial  Age/                                                                        | Days After  Vaccination Event  | Outcome Underlying Diseases/                                                  |                                      |
| Code  Gender                                                                       | Circumstances                  |                                                                               |                                      |
| angioedema of                                                                      | hypotensive. Symptoms subsided |                                                                               |                                      |
| forearms                                                                           | after several days under  prednisone and diphenhydramine  treatment. She has a family  history of allergies and a medical  history of shingles. She has  received multiple vaccines before  but never had previous hives or  other problems with vaccines. Positive family history for  cardiovascular diseases (both  grandfathers had myocardial  infarctions in their 50ies, father  had blood clots), as well as  overweight with a BMI above 33.  A few days before event onset,  subject returned from a trip to  India with diarrhea and was  started on ciprofloxacin treatment  (which per US prescribing  information is associated with  angina pectoris and myocardial  infarction). He showed chest pain  and increased troponin I, but no  ST segment changes in the ECG  and no coronary artery disease in  cardiac catheterization. A postinfectious myocarditis (published  case reports exist for  campylobacter, shigella, and  salmonella) was considered as  alternative etiology for the  reported event.                                |                                                                               |                                      |
| POXMVA                                                                                    | 117 days                       |                                                                               |                                      |
| 30/Male  after first                                                               |                                |                                                                               |                                      |
| -036                                                                               | vaccination                    | Non-ST-segment  elevation myocardial  infarction  Resolved  without  sequelae | Possibly  Unlikely  related  related |
| 16.4.2 Safety Profile of MVA-BN Smallpox Vaccine in Healthy Population Compared to |                                |                                                                               |                                      |  
BN has evaluated the safety and immunogenicity of MVA-BN-based recombinant vaccines for several indications such as cancer, HIV and measles in more than 1,900 subjects including healthy and HIV infected populations. In recombinant MVA vaccine trials, doses up to 5 x 10e8 TCID50 were administered applying varying schedules of repeated vaccinations, e.g. a 3-dose schedule was used for recombinant HIV vaccines and multiple vaccinations have also been performed in subjects receiving a recombinant therapeutic breast cancer vaccine (MVA-BNHER2). Results obtained from these Phase 1 and 2 trials demonstrate a similar safety profile and vector immunogenicity as compared to MVA-BN alone. Two of the recombinant vaccine trials allowed for a direct comparison with MVA-BN as an active control. These trials (HIV-POL-002 and HIV-NEF-004) were performed to evaluate 2 different recombinant MVA-based HIV vaccine candidates in HIV-infected subjects. In both trials, a total of 3 vaccinations with either the recombinant HIV vaccine or MVA-BN were performed according to a 0, 8 and 16 week regimen. 16.4.3 Immunogenicity Overview of MVA-BN MVA-BN was tested for safety and immunogenicity among healthy volunteers in 3 Phase 1 and 2 dose finding trials. (93-95) Across these trials a linear dose relationship was observed between the vaccine doses and both vaccinia ELISA and Plaque Reduction Neutralization Test (PRNT) titers. Maximum ELISA seroconversion rates and peak titers were reached 2 weeks after the second vaccination, with 100% seroconversion after the second dose for all dose groups receiving at least 2 x 107 TCID50 per 0.5 mL dose of MVA- BN. Statistical analysis indicated lower doses to be inferior to the standard dose tested throughout all dose ranging trials, whereas the standard dose achieved ELISA seroconversion rates between 81% and 100% already after the first dose. For the PRNT, the same trend was observed with about 77% seroconversion rates 2 weeks after the second MVA-BN administration in all groups receiving the highest dose. The early onset of seroconversion and the higher titers of total and neutralizing antibodies combined with an excellent safety profile qualified the dose of at least 5 x 107 TCID50 as the most suitable human dose. The final optimal (standard) dose and schedule for the general population was decided to be 2 doses of at least 5 x 107 TCID50 MVA-BN administered subcutaneously
(s.c.) 2-4 weeks apart.
16.2 appendix b oral medication
16.5 appendix e ccr reportable

NCI Protocol \#: Click or tap here to enter text.  
Protocol Title: Click or tap here to enter text.  
Report version: *(select one)*
☐ Initial Report
☐ Follow-up Site Principal Investigator: Click or tap here to enter text.  
Date site PI was notified of the problem: Click or tap to enter a date.  
Date of problem: Click or tap to enter a date.  
If delay in reporting to the coordinating center, please explain: Click or tap here to enter text.  
Location of problem: *(e.g., patient's home, doctor's office )*
Click or tap here to enter text.
16.2 appendix b oral medication
description of subject

Does this problem apply to a subject?  
☐ yes
☐ not applicable (more than one subject is involved)
If yes, enter details below:
Subject ID: Click or tap here to enter text. (*do not use medical record number)*
Sex: ☐Male ☐ Female Age: Click or tap here to enter text.  
Diagnosis: Click or tap here to enter text.  
Name the problem: *(select all that apply)*
☐ Specimen collection issue
☐ Informed consent issue
☐ Ineligible for enrollment ☐ Breach of PII
☐ Other, briefly state the nature of the problem: Click or tap here to enter text.  
Detailed Description of the problem: (*Include any relevant treatment, outcomes or* pertinent history): Click or tap here to enter text.  
What are you reporting?  
☐ **unanticipated problem**
☐ **death**
☐ **non-compliance (other than a protocol deviation)**
☐ **protocol deviation**
☐ **new information that might affect the willingness of subjects to enroll or**
continue participation in this study If interventional or expanded access study, please answer the following questions about your site: How many participants are still receiving the study intervention? Click or tap here to enter text. How many participants completed study interventions but remain in follow up? Click or tap here to enter text. How many participants are enrolled but not yet receiving study interventions? Click or tap here to enter text. Have similar problems occurred on this protocol at your site?  
☐ **Yes** ☐ No Describe what steps you have already taken or will be taking **as a result of this** problem: Click or tap here to enter text. INVESTIGATOR'S SIGNATURE: DATE: