4.0 background & rationale
appendix b

ECOG Performance Status  
| Grade                                                                                                                                                                                                                                          | Description                                                                                                                                                                                                                        |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| 0                                                                                                                                                                                                                                              | Normal activity. Fully active, able to carry on all pre-disease  performance without restriction.  Symptoms, but ambulatory. Restricted in physically strenuous  activity, but ambulatory and able to carry out work of a light or |
| 1                                                                                                                                                                                                                                              | sedentary nature (e.g., light housework, office work).  In bed <50% of the time. Ambulatory and capable of all self-care,                                                                                                          |
| 2                                                                                                                                                                                                                                              | but unable to carry out any work activities. Up and about more than  50% of waking hours.                                                                                                                                          |
| 3                                                                                                                                                                                                                                              | In bed >50% of the time. Capable of only limited self-care, confined  to bed or chair more than 50% of waking hours.                                                                                                               |
| 4                                                                                                                                                                                                                                              | 100% bedridden. Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair.                                                                                                                                                                                                                                    |
| 5                                                                                                                                                                                                                                              | Dead.                                                                                                                                                                                                                              |
| *As published in Am. J. Clin. Oncol.:                                                                                                                                                                                                          | Oken, M.M., Creech, R.H., Tormey, D.C.,                                                                                                                                                                                            |
| Horton, J., Davis, T.E., McFadden, E. 7'., Carbone, P.P.: Toxicity And Response  Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649-655,  1982. The Eastern Cooperative Oncology Group, Robert Comis M.D., Group Chair. |                                                                                                                                                                                                                                    |  
Appendix C: Literature Cited Brahmer, J. R., C. G. Drake, I. Wollner, J. D. Powderly, J. Picus, W. H. Sharfman, E.  
Stankevich, A. Pons, T. M. Salay, T. L. McMiller, M. M. Gilson, C. Wang, M. Selby, J. M.  
Taube, R. Anders, L. Chen, A. J. Korman, D. M. Pardo11, I. Lowy and S. L. Topalian (2010).  
"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 28(19): 3167-3175.  
Gelderblom, H., J. Y. Blay, B. M. Seddon, M. Leahy, I. Ray-Coquard, S. Sleijfer, J. M.  
Kerst, P. Rutkowski, S. Bauer, M. Ouali, S. Marreaud, R. J. van der Straaten, H. J.  
Guchelaar, S. D. Weitman, P. C. Hogendoom and P. Hohenberger (2014). "Brostallicin versus doxorubicin as first-line chemotherapy in patients with advanced or metastatic soft tissue sarcoma: An European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group randomised phase II and pharmacogenetic study." Eur J Cancer 50(2): 388-396.  
Hamid, 0., C. Robert, A. Daud, F. S. Hodi, W. J. Hwu, R. Kefford, J. D. Wolchok, P.  
Hersey, R. W. Joseph, J. S. Weber, R. Dronca, T. C. Gangadhar, A. Patnaik, H. Zarour, A.  
M. Joshua, K. Gergich, J. Elassaiss-Schaap, A. Algazi, C. Mateus, P. Boasberg, P. C. Tumeh, B. Chmielowski, S. W. Ebbinghaus, X. N. Li, S. P. Kang and A. Ribas (2013). "Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma." N Engl J Med 369(2): 134144.  
Hirschhorn-Cymerman, D., G. A. Rizzuto, T. Merghoub, A. D. Cohen, F. Avogadri, A. M.  
Lesokhin, A. D. Weinberg, J. D. Wolchok and A. N. Houghton (2009). "0X40 engagement and chemotherapy combination provides potent antitumor immunity with concomitant regulatory T cell apoptosis." J Exp Med 206(5): 1103-1116.  
Judson, I., J. Verweij, H. Gelderblom, J. T. Hartmann, P. Schoffski, J. Y. Blay, J. M. Kerst, J.  
Sufliarsky, J. Whelan, P. Hohenberger, A. Krarup-Hansen, T. Alcindor, S. Marreaud, S.  
Litiere, C. Hermans, C. Fisher, P. C. Hogendoorn, A. P. dei Tos, W. T. van der Graaf, 0.  
European, T. Treatment of Cancer Soft and G. Bone Sarcoma (2014). "Doxorubicin alone versus intensified doxorubicin plus ifosfamide for first-line treatment of advanced or metastatic soft-tissue sarcoma: a randomised controlled phase 3 trial." Lancet Oncol 15(4):
415-423.  
Judson, I. R., Verjeij J, Gelderblom H, Hartman J, Schoffski P, Blay J, Paolo dei Tos A,
Marreud S, Litiere S, van der Grraaf W (2013). "Result of a Randomised phase III trial
(EORTC 62012) of single agent doxorubicin versus plus ifosfamide as first line chemotherapy for patients with advanced, soft tissue sarcoma: a suvival study by the EORTC
Soft Tissue and Bone Sarcoma Group." Oral Presentation 2013 Connective Tissue Oncology Society Meeing.  
Kim, J. R., Y. J. Moon, K. S. Kwon, J. S. Bae, S. Wagle, K. M. Kim, H. S. Park, H. Lee, W.  
S. Moon, M. J. Chung, M. J. Kang and K. Y. Jang (2013). "Tumor Infiltrating PD1-Positive Lymphocytes and the Expression of PD-Li Predict Poor Prognosis of Soft Tissue Sarcomas."
PLoS One 8(12): e82870.  
Ko, H. J., Y. J. Kim, Y. S. Kim, W. S. Chang, S. Y. Ko, S. Y. Chang, S. Sakaguchi and C. Y.  
Kang (2007). "A combination of chemoimmunotherapies can efficiently break self-tolerance and induce antitumor immunity in a tolerogenic murine tumor model." Cancer Res 67(15):
7477-7486.  
O'Bryan, R. M., L. H. Baker, J. E. Gottlieb, S. E. Rivkin, S. P. Balcerzak, G. N. Grumet, S.  
E. Salmon, T. E. Moon and B. Hoogstraten (1977). "Dose response evaluation of adriamycin in human neoplasia." Cancer 39(5): 1940-1948.  
Rajendra, R., R. L. Jones and S. M. Pollack (2013). "Targeted treatment for advanced soft tissue sarcoma: profile of pazopanib." Onco Targets Ther 6: 217-222.  
Santoro, A., T. Tursz, H. Mouridsen, J. Verweij, W. Steward, R. Somers, J. Buesa, P. Casali, D. Spooner, E. Rankin and et al. (1995). "Doxorubicin versus CYVADIC versus doxorubicin plus ifosfamide in first-line treatment of advanced soft tissue sarcomas: a randomized study of the European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group." J Clin Oncol 13(7): 1537-1545.  
Sorbye, S. W., T. Kilvaer, A. Valkov, T. Donnem, E. Smeland, K. Al-Shibli, R. M. Bremnes and L. T. Busund (2011). "Prognostic impact of lymphocytes in soft tissue sarcomas." PLoS
One 6(1): e14611.  
Tesnicre, A., F. Schlemmer, V. Boige, 0. Kepp, I. Martins, F. Ghiringhelli, L. Aymeric, M.  
Michaud, L. Apetoh, L. Barault, J. Mendiboure, J. P. Pignon, V. Jooste, P. van Endert, M.  
Ducreux, L. Zitvogel, F. Piard and G. Kroemer (2010). "Immunogenic death of colon cancer cells treated with oxaliplatin." Oncogene 29(4): 482-491.  
Topalian, S. L., F. S. Hodi, J. R. Brahmer, S. N. Gettinger, D. C. Smith, D. F. McDermott, J.  
D. Powderly, R. D. Carvajal, J. A. Sosman, M. B. Atkins, P. D. Leming, D. R. Spigel, S. J.  
Antonia, L. Horn, C. G. Drake, D. M. Pardoll, L. Chen, W. H. Sharfman, R. A. Anders, J. M.  
Taube, T. L. McMiller, H. Xu, A. J. Korman, M. Jure-Kunkel, S. Agrawal, D. McDonald, G.  
D. Kollia, A. Gupta, J. M. Wigginton and M. Sznol (2012). "Safety, activity, and immune correlates of anti-PD-1 antibody in cancer." N Engl J Med 366(26): 2443-2454.  
van der Graaf, W. T., J. Y. Blay, S. P. Chawla, D. W. Kim, B. Bui-Nguyen, P. G. Casali, P.  
Schoffski, M. Aglietta, A. P. Staddon, Y. Beppu, A. Le Cesne, H. Gelderblom, I. R. Judson, N. Araki, M. Ouali, S. Marreaud, R. Hodge, M. R. Dewji, C. Coens, G. D. Demetri, C. D.  
Fletcher, A. P. Dei Tos, P. Hohenberger, E. S. Tissue, G. Bone Sarcoma and P. s. group
(2012). "Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomised, doubleblind, placebo-controlled phase 3 trial." Lancet 379(9829): 1879-1886.