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123. Gladwin MT, and Kato GJ. Hemolysis-associated hypercoagulability in sickle cell disease:
the plot (and blood) thickens! *Haematologica.* 2008;93(1):1-3.  
124. Ataga KI, Moore CG, Hillery CA, Jones S, Whinna HC, Strayhorn D, et al. Coagulation activation and inflammation in sickle cell disease-associated pulmonary hypertension. Haematologica. 2008;93(1):20-6.  
125. Goldenthal EI, Cookson KM, Geil RG, and Wazeter FX. Preclinical toxicologic evaluation of tetrahydrouridine (NSC-112907) in beagle dogs and rhesus monkeys. Cancer chemotherapy reports Part 3. 1974;5(1):15-6.  
126. Scanlan MJ, Simpson AJ, and Old LJ. The cancer/testis genes: review, standardization, and commentary. *Cancer Immun.* 2004;4:1.
untitled h1
15 appendices and supplementary tables

| (Partial List)   |                                                                                            |                |                 |
|------------------|--------------------------------------------------------------------------------------------|----------------|-----------------|
| Gene family      | Family members                                                                             | CT  identifier |                 |
| MAGEA            | MAGEA1, MAGEA2, MAGEA3, MAGEA4, MAGEA5, MAGEA6,  MAGEA8, MAGEA9, MAGEA10, MAGEA11, MAGEA12 | CT1            | Xq28            |
| BAGE             | BAGE                                                                                       | CT2            | 21p11.1         |
| MAGEB            | MAGEB1, MAGEB2, MAGEB3, MAGEB4, MAGEB5, MAGEB6                                             | CT3            | Xp21.3          |
| GAGE             | GAGE1, GAGE2, GAGE3, GAGE4, GAGE5, GAGE6, GAGE7,  GAGE8                                    | CT4            | Xp11.23         |
| SSX              | SSX1, SSX2, SSX3, SSX4                                                                     | CT5            | Xp11.23-p11.22. |
| NY-ESO-1         | CTAG1B, CTAG2                                                                              | CT6            | Xq28            |
| MAGEC1           | MAGEC1                                                                                     | CT7            | Xq26            |
| SYCP1            | SYCP1                                                                                      | CT8            | 1p12-p13        |
| BRDT             | BRDT                                                                                       | CT9            | 1p22.1          |
| MAGEC2           | MAGEC2                                                                                     | CT10           | Xq27            |
| SPANX            | SPANXA1, SPANXB1, SPANXC, SPANXD                                                           | CT11           | Xq27.1          |
| XAGE             | XAGE1                                                                                      | CT12           | Xp11.22         |
| HAGE             | DDX43                                                                                      | CT13           | 6q12-q13.       |
| SAGE             | SAGE1                                                                                      | CT14           | Xq26.           |
| ADAM2            | ADAM2                                                                                      | CT15           | 8p11.2.         |
| PAGE-5           | PAGE5                                                                                      | CT16.1         | Xp11.23         |
| LIPI             | LIPI                                                                                       | CT17           | 21q11.2         |
| NA88A pseudogene | VENTXP1                                                                                    | CT18           | Xp21.3.         |
| IL13RA           | IL13RA2                                                                                    | CT19           | Xq13.1-q28      |
| TSP50            | TSP50                                                                                      | CT20           | 3p12–14         |
| CTAGE-1          | CTAGE1                                                                                     | CT21.1         | 18p11.2         |
| SPA17            | SPA17                                                                                      | CT22           | 11q24.2         |
| ACRBP            | ACRBP                                                                                      | CT23           | 12p12-p13.      |
| CSAG             | CSAG1, CSAG2                                                                               | CT24           | Xq28.           |
| MMA1             | DSCR8                                                                                      | CT25           | 21q22.2.        |
| CAGE/DDX53       | DDX53                                                                                      | CT26           | Xp22.11         |
| BORIS            | CTCFL                                                                                      | CT27           | 20q13.31        |
| HOM-TES-85       | LUZP4                                                                                      | CT28           | Xq23            |
| AF15q14          | CASC5                                                                                      | CT29           | 15q14           |
| HCA661           | TFDP3                                                                                      | CT30           | Xq26.2          |
| JARID1B          | JARID1B                                                                                    | CT31           | 1q32.1.         |
| LDHC             | LDHC                                                                                       | CT32           | 11p15.3-p15.5   |  
15.1.1 Supplementary Table 1: Cancer/Testis Genes and Their Chromosomal Locations
(Partial List)  
| Version Date: 08/01/2022 Gene family Family members   | CT                                                                                                 | Chromosomal   |               |
|-------------------------------------------------------|----------------------------------------------------------------------------------------------------|---------------|---------------|
| identifier                                            | localization                                                                                       |               |               |
| MORC                                                  | MORC1                                                                                              | CT33          | 3q13          |
| SGY-1                                                 | DKKL1                                                                                              | CT34          | 19q13.33      |
| SPO11                                                 | SPO11                                                                                              | CT35          | 20q13.2-q13.3 |
| TPX1                                                  | CRISP2                                                                                             | CT36          | 6p21-qter     |
| NY-SAR-35                                             | FMR1NB                                                                                             | CT37          | Xq27.3-q28.   |
| FTHL17                                                | FTHL17                                                                                             | CT38          | Xp21          |
| NXF2                                                  | NXF2                                                                                               | CT39          | Xq22.1        |
| TAF7L                                                 | TAF7L                                                                                              | CT40          | Xq22.1        |
| TDRD1                                                 | TDRD1                                                                                              | CT41          | 10q25.3.      |
| TEX15                                                 | TEX15                                                                                              | CT42          | 8p12          |
| FATE                                                  | FATE1                                                                                              | CT43          | Xq28          |
| TPTE                                                  | TPTE                                                                                               | CT44          | 21p11         |
| CT45                                                  | CT45-1, CT45-2, CT45-3, CT45-4, CT45-5, CT45-6                                                     | CT45          | Xq26.3        |
| HORMAD1                                               | HORMAD1                                                                                            | CT46          | 1q21.2.       |
| CT47                                                  | CT47-1, CT47-2, CT47-3, CT47-4, CT47-5, CT47-6, CT47-7, CT47- 8, CT47-9, CT47-10, CT47-11, CT47-12 | CT47          | Xq24          |
| SLCO6A1                                               | SLCO6A1                                                                                            | CT48          | 5q21.1        |
| TAG                                                   | TAG                                                                                                | CT49          | Na            |
| LEMD1                                                 | LEMD1                                                                                              | CT50          | 1q32.1        |
| HSPB9                                                 | HSPB9                                                                                              | CT51          | 1p36.2-p35    |
| CCDC110                                               | CCDC110                                                                                            | CT52          | 4q35.1        |
| ZNF165                                                | ZNF165                                                                                             | CT53          | 6p21.3        |
| SPACA3                                                | SPACA3                                                                                             | CT54          | 17q11.2       |
| CXorf48                                               | CXorf48                                                                                            | CT55          | Xq26.3        |
| THEG                                                  | THEG                                                                                               | CT56          | 19pter-p13    |
| ACTL8                                                 | ACTL8                                                                                              | CT57          | 1p36.2-p35    |
| NLRP4                                                 | NLRP4                                                                                              | CT58          | 1p36.2-p35    |
| COX6B2                                                | COX6B2                                                                                             | CT59          | 19q13.42      |
| LOC348120                                             | LOC348120                                                                                          | CT60          | 15q11.2       |
| CCDC33                                                | CCDC33                                                                                             | CT61          | 15q24.1       |
| LOC196993                                             | LOC196993                                                                                          | CT62          | 15q23         |
| PASD1                                                 | PASD1                                                                                              | CT63          | Xq28          |
| CT64                                                  | CT64/BX103208                                                                                      | CT64          | 3q26.1.       |
| TULP2                                                 | TULP2                                                                                              | CT65          | 19q13.1.      |
| CT66                                                  | CT66/AA884595                                                                                      | CT66          | 7q11.22.      |
| KLKBL4                                                | KLKBL4                                                                                             | CT67          | 16q21         |
| RBM46                                                 | RBM46                                                                                              | CT68          | 4q32.1        |
| CT69                                                  | CT69/BC040308                                                                                      | CT69          | 6q23.2        |
| CT70                                                  | CT70/BI818097                                                                                      | CT70          | Na            |  
| Version Date: 08/01/2022 Gene family Family members   | CT                                                   | Chromosomal   |             |
|-------------------------------------------------------|------------------------------------------------------|---------------|-------------|
| identifier                                            | localization                                         |               |             |
| SPINLW1                                               | SPINLW1                                              | CT71          | 20q12-q13.2 |
| TSSK6                                                 | TSSK6                                                | CT72          | 19p13.11    |
| ADAM29                                                | ADAM29                                               | CT73          | 4q34.       |
| CCDC36                                                | CCDC36                                               | CT74          | 3p21.31     |
| LOC440934                                             | LOC440934                                            | CT75          | 2q36.1      |
| SYCE1                                                 | SYCE1                                                | CT76          | 10q26.3     |
| CPXCR1                                                | CPXCR1                                               | CT77          | Xq21.3      |
| TSPY1                                                 | TSPY1                                                | CT78          | Yp11.2      |
| TSGA10                                                | TSGA10                                               | CT79          | 2q11.2.     |
| PIWIL2                                                | PIWIL2                                               | CT80          | 8p21.3      |
| ARMC3                                                 | ARMC3                                                | CT81          | 10p12.31    |
| AKAP3                                                 | AKAP3                                                | CT82          | 12p13.3.    |
| CXorf61                                               | Cxorf61                                              | CT83          | Xq23        |
| PBK                                                   | PBK                                                  | CT84          | 8p21.2      |
| C21orf99                                              | C21orf99                                             | CT85          | 21q11.2     |
| OIP5                                                  | OIP5                                                 | CT86          | 15q15.1     |
| CEP290                                                | CEP290                                               | CT87          | 12q21.32    |
| CABYR                                                 | CABYR                                                | CT88          | 18q11.2     |
| SPAG9                                                 | SPAG9                                                | CT89          | 17q21.33.   |
| MPHOSPH1                                              | MPHOSPH1                                             | CT90          | 10q23.31    |
| ROPN1                                                 | ROPN1                                                | CT91          | 3q21.1.     |
| PLAC1                                                 | PLAC1                                                | CT92          | Xq26        |
| CALR3                                                 | CALR3                                                | CT93          | 19p13.1     |
| PRM                                                   | PRM1/PRM2                                            | CT94.1        | 16p13.2     |
| CAGE1                                                 | CAGE1                                                | CT95          | 6p24.3      |
| CT96                                                  | TTK                                                  | CT96          | 6q13-q21    |
| LY6K                                                  | LY6K                                                 | CT97          | 8q24.3      |
| IMP-3                                                 | IMP-3                                                | CT98          | 7p11.       |
| AKAP4                                                 | AKAP4                                                | CT99          | Xp11.2      |
| DPPA2                                                 | DPPA2                                                | CT100         | 3q13.13     |
| KIAA0100/MLAA-22                                      | KIAA0100                                             | CT 101        | 7q11.2      |
| TCC52                                                 | TCC52                                                | CT102         | 9p13.3      |
| SEMG1                                                 | SEMG1                                                | CT103         | 20q12-q13.2 |
| POTE                                                  | POTE21, POTE2, POTE8, POTE14, POTE15, POTE18, POTE22 | CT104         | 2q21.1      |
| FLJ36144/MAD-CT2                                      | MAD-CT2                                              | CT105         | 15q11.2.    |
| NUF2/CDCA1                                            | CDCA1                                                | CT106         | 1q23        |
| RHOXF2/PEPP2                                          | PEPP2                                                | CT107         | Xq24        |  
| Gene family       | Family members   | CT    | Chromosomal   |
|-------------------|------------------|-------|---------------|
| identifier        | localization     |       |               |
| OTOA              | OTOA             | CT108 | 16p12.2       |
| CCDC62            | CCDC62           | CT109 | 12q24.31      |
| GPATCH2           | GPATCH2          | CT110 | 1q41          |
| Na: not available |                  |       |               |  
| Cancers as Determined by Semi-Quantitative RT-PCR   |                                           |            |                 |     |     |     |     |      |      |    |    |    |    |    |    |    |
|-----------------------------------------------------|-------------------------------------------|------------|-----------------|-----|-----|-----|-----|------|------|----|----|----|----|----|----|----|
| CT                                                  | Frequency (%) of Expression in Tumor Type |            |                 |     |     |     |     |      |      |    |    |    |    |    |    |    |
| Family (Member)                                     | Bla                                       | Brn        | Brst            | Col | Eso | Gas | H/N | Live | Leu  |    |    |    |    |    |    |    |
| d                                                   | r                                         | k/ Ly mp h | Lun g (NS CL C) | Mel | Ov  | Pan | Pro | Ren  | Sarc |    |    |    |    |    |    |    |
| cr                                                  | s                                         | al         |                 |     |     |     |     |      |      |    |    |    |    |    |    |    |
| MAGEA1/                                             | 22                                        | -          | 18              | 2   | 53  | 29  | 28  | 80   | 0    | 49 | 48 | 28 | -  | 15 | 0  | 14 |
| CT1.1 BAGE1/C                                       | 15                                        | -          | 10              | 0   | -   | -   | 8   | -    | 0    | 4  | 26 | 15 | -  | 0  | 0  | 6  |
| T2.1 MAGEB1/                                        | 0                                         | 0          | 17              | 0   | -   | 0   | 0   | -    | 0    | 14 | 22 | -  | -  | 0  | 0  | 9  |
| CT3.1 GAGE/CT                                       | 12                                        | -          | 9               | 0   | -   | -   | 19  | 38b  | 1    | 19 | 28 | 31 | -  | 10 | 0  | 25 |
| 4.1 SSX2/CT5                                        | 44                                        | 6          | 7               | 12  | -   | -   | 35  | 9 b  | 36   | 16 | 35 | -  | -  | 40 | 5  | 50 |
| .2 NY-ESO1/CT6.1                                                     | 80                                        | 0          | 30              | 0   | -   | 0   | -   | 29   | 0    | 17 | 34 | 25 | 0  | 25 | 9  | 0  |
| MAGEC1/                                             | 44                                        | -          | 30              | 10  | -   | -   | 36  | -    | -    | 33 | 70 | -  | -  | -  | -  | 60 |
| CT7.1 SYCP1/C                                       | -                                         | 47         | 20              | 0   | -   | 7   | -   | 28b  | 0    | 7  | 14 | 0  | -  | 0  | 8  | 0  |
| T8 BRDT/CT                                          | 0                                         | -          | 0               | 0   | 8   | -   | 8   | -    | -    | 25 | 0  | -  | -  | -  | 0  | -  |
| 9 MAGEE1/                                           | 44                                        | -          | 38              | 0   | -   | -   | 36  | -    | -    | 24 | 50 | -  | -  | -  | -  | 0  |
| CT10 SPANXC/                                        | 9                                         | -          | 25              | 22  | 0   | -   | -   | -    | -    | 33 | 70 | -  | 0  | -  | -  | -  |
| CT11.3 XAGE1a/CT12.1 a                                                     | -                                         | -          | -               | -   | -   | -   | -   | -    | -    | -  | 8  | -  | -  | -  | -  | 22 |
| HAGE/CT                                             | 24                                        | 37         | 5               | 31  | 27  | -   | -   | 20   | 9    | 32 | 17 | -  | -  | 22 | 6  | 20 |
| 13 SAGE/CT                                          | 12                                        | 0          | 5               | 0   | 20  | -   | 17  | -    | 4    | 22 | 4  | -  | -  | 0  | 5  | 5  |
| 14 ADAM2/                                           | -                                         | -          | 0               | 0   | -   | -   | -   | -    | -    | 0  | 0  | 0  | -  | -  | 12 | -  |
| CT15 PAGE5/CT16                                                     | -                                         | -          | 5               | 11  | -   | -   | -   | -    | -    | 39 | 22 | 0  | -  | -  | 44 | -  |
| LIP1/CT1                                            | -                                         | -          | 5               | 0   | -   | -   | -   | -    | -    | 0  | 0  | 0  | -  | -  | 25 | -  |
| 7                                                   |                                           |            |                 |     |     |     |     |      |      |    |    |    |    |    |    |    |  
| CT               | Frequency (%) of Expression in Tumor Type   |            |                 |     |     |     |     |      |      |     |    |    |    |    |    |    |
|------------------|---------------------------------------------|------------|-----------------|-----|-----|-----|-----|------|------|-----|----|----|----|----|----|----|
| Family (Member)  | Bla                                         | Brn        | Brst            | Col | Eso | Gas | H/N | Live | Leu  |     |    |    |    |    |    |    |
| d                | r                                           | k/ Ly mp h | Lun g (NS CL C) | Mel | Ov  | Pan | Pro | Ren  | Sarc |     |    |    |    |    |    |    |
| cr               | s                                           | al         |                 |     |     |     |     |      |      |     |    |    |    |    |    |    |
| NA88/CT          | -                                           | -          | -               | -   | -   | -   | -   | -    | -    | -   | 11 | -  | -  | -  | -  | -  |
| 18 TSP50/CT      | -                                           | -          | 28              | -   | -   | -   | -   | -    | -    | -   | -  | -  | -  | -  | -  | -  |
| 20 CTAGE1/CT21.1                  | -                                           | -          | -               | -   | -   | -   | -   | -    | 35   | -   | -  | -  | -  | -  | -  | -  |
| SPA17/CT         | -                                           | -          | -               | -   | -   | -   | -   | -    | 26   | -   | -  | -  | -  | -  | -  | -  |
| 22 OYTES1/       | 28                                          | -          | 40              | 15  | -   | 0   | -   | 40   | -    | 20  | -  | -  | -  | -  | 0  | -  |
| CT23 MMA1a/C     | -                                           | -          | 0               | 0   | 0   | -   | -   | -    | -    | 40  | 26 | -  | 0  | -  | -  | 18 |
| T25.1a CAGE/CT   | -                                           | -          | -               | -   | -   | 89  | -   | -    | -    | 100 | -  | -  | -  | -  | -  | -  |
| 26 HOMTES        | -                                           | 35         | 0               | 10  | -   | -   | -   | 19   | -    | 28  | 36 | 32 | -  | 0  | -  | -  |
| 85/CT28 D40/CT29 | -                                           | 20         | -               | 13  | -   | 0   | -   | -    | -    | 41  | -  | 36 | 27 | -  | -  | -  |
| HCA661/          | 0                                           | -          | -               | -   | -   | 0   | 0   | 29   | -    | -   | 20 | -  | -  | -  | -  | -  |
| CT30 PLU1/CT31                  | -                                           | -          | 86              | -   | -   | -   | -   | -    | -    | -   | -  | -  | -  | -  | -  | -  |
| LDHC/CT          | -                                           | -          | 35              | 15  | -   | -   | -   | -    | -    | 47  | 44 | 42 | -  | 37 | 57 | -  |
| 32 MORC/C        | -                                           | -          | 0               | 0   | -   | -   | -   | -    | -    | 18  | 18 | 14 | -  | 0  | 0  | -  |
| T33 SGY1/CT34                  | -                                           | -          | 20              | 0   | -   | -   | -   | -    | -    | 12  | 25 | 57 | -  | 12 | 0  | -  |
| SPO11/CT         | -                                           | -          | 0               | 0   | -   | -   | -   | -    | -    | 0   | 6  | 0  | -  | 0  | 0  | -  |
| 35 TPX1/CT3      | -                                           | -          | 15              | 0   | -   | -   | -   | -    | -    | -   | 6  | 14 | -  | 37 | 14 | -  |
| 6 NYSAR35        | 42                                          | -          | 23              | 0   | 8   | -   | -   | -    | -    | 17  | 6  | 8  | -  | -  | 0  | 8  |
| /CT37 FTHL17/C   | 22                                          | -          | 14              | 0   | 0   | -   | 10  | -    | 0    | 25  | 0  | -  | -  | 0  | 0  | 0  |
| T38 NXF2/CT      | 19                                          | -          | 0               | 11  | 12  | -   | 5   | -    | 0    | 15  | 55 | -  | -  | 14 | 0  | 27 |
| 39               |                                             |            |                 |     |     |     |     |      |      |     |    |    |    |    |    |    |  
| CT              | Frequency (%) of Expression in Tumor Type   |            |                 |     |     |     |     |      |      |    |    |    |    |    |    |    |
|-----------------|---------------------------------------------|------------|-----------------|-----|-----|-----|-----|------|------|----|----|----|----|----|----|----|
| Family (Member) | Bla                                         | Brn        | Brst            | Col | Eso | Gas | H/N | Live | Leu  |    |    |    |    |    |    |    |
| d               | r                                           | k/ Ly mp h | Lun g (NS CL C) | Mel | Ov  | Pan | Pro | Ren  | Sarc |    |    |    |    |    |    |    |
| cr              | s                                           | al         |                 |     |     |     |     |      |      |    |    |    |    |    |    |    |
| TAF7L/C         | 10                                          | -          | 0               | 0   | 0   | -   | 10  | -    | 0    | 9  | 21 | -  | -  | 0  | 0  | 12 |
| T40 TDRD1/C     | 28                                          | -          | 37              | 0   | 10  | -   | 22  | -    | 5    | 5  | 0  | -  | -  | 38 | 0  | 0  |
| T41.1 TEX15/C   | 21                                          | -          | 0               | 0   | 20  | -   | 11  | -    | 0    | 21 | 27 | -  | -  | 12 | 33 | 28 |
| T42 FATE/CT     | -                                           | -          | -               | 21  | -   | 7   | -   | 66   | -    | 0  | -  | -  | -  | -  | -  | -  |
| 43 TPTE/CT4     | -                                           | -          | -               | 0   | -   | 0   | -   | 39   | -    | 36 | -  | -  | -  | -  | -  | -  |
| 4               |                                             |            |                 |     |     |     |     |      |      |    |    |    |    |    |    |    |  
aAbbreviations: Blad, bladder; Brn, brain; Brst, breast; Col, colon; Gas, gastric; H/N, head and neck; Leuk, leukemia; Lymph, lymphoma, NSCLC, non-small cell lung carcinoma; Mel, melanoma; Ov, ovarian; Pancr, pancreatic; Pros, prostate; Sarc, sarcoma.  
Reprinted from ref (126)
untitled h1
15.2 appendices

| 15.2.1 Appendix 1: 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, able                                                                    |                                                                                                                        |                                                 |                                                                    |           |                                 |                                   |
| 0                                                                                                      | to                                                                                                                     | carry                                           | on                                                                 | all       | pre-disease                     | Able to carry on normal activity; |
| performance without restriction.                                                                       | 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 | Cares for self, unable to carry on                                                                                     |                                                 |                                                                    |           |                                 |                                   |
| sedentary                                                                                              | nature                                                                                                                 | (e.g.,                                          | light                                                              | 70        | normal activity or to do active |                                   |
| housework, office work).                                                                               | work.                                                                                                                  |                                                 |                                                                    |           |                                 |                                   |
| 80                                                                                                     | Normal activity with effort; some  signs or symptoms of disease.                                                       |                                                 |                                                                    |           |                                 |                                   |
| 1                                                                                                      | Requires occasional assistance,                                                                                        |                                                 |                                                                    |           |                                 |                                   |
| In                                                                                                     | bed                                                                                                                    | <50%                                            | of                                                                 | the       | time.                           |                                   |
| Ambulatory and capable of all                                                                          | 60                                                                                                                     | but is able to care for most of  his/her needs. |                                                                    |           |                                 |                                   |
| 2                                                                                                      | self-care, but unable to carry out  any work activities. Up and about  more than 50% of waking hours.                  | 50                                              | Requires considerable assistance  and frequent medical care.       |           |                                 |                                   |
| 40                                                                                                     | Disabled, requires special care  and assistance.                                                                       |                                                 |                                                                    |           |                                 |                                   |
| 3                                                                                                      | In bed >50% of the time. Capable  of only limited self-care, confined  to bed or chair more than 50% of  waking hours. | 30                                              | Severely disabled, hospitalization  indicated. Death not imminent. |           |                                 |                                   |
| 20                                                                                                     | Very                                                                                                                   | sick,                                           | hospitalization                                                    |           |                                 |                                   |
| indicated. Death not imminent.                                                                         |                                                                                                                        |                                                 |                                                                    |           |                                 |                                   |
| 4                                                                                                      | 100%                                                                                                                   | bedridden.                                      | Completely                                                         |           |                                 |                                   |
| disabled.                                                                                              | Cannot carry on any                                                                                                    |                                                 |                                                                    |           |                                 |                                   |
| self-care. Totally confined to bed  or chair.                                                          | 10                                                                                                                     | Moribund,                                       | fatal                                                              | processes |                                 |                                   |
| progressing rapidly.                                                                                   |                                                                                                                        |                                                 |                                                                    |           |                                 |                                   |
| 5                                                                                                      | Dead.                                                                                                                  | 0                                               | Dead.                                                              |           |                                 |                                   |  
  
or 2 hours after a meal. DAC should be taken 1 hour after THU.  
| Treated in  doctor's                                                                                                                                                                                                   | Hospitalized   | Comments         |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------|------------------|
| office                                                                                                                                                                                                                 |                |                  |
| GI                                                                                                                                                                                                                     | Dates          | Treated at  Home |
| diarrhea nausea vomiting mouth sores neuropathy tingling hands and feet sensitivity to cold general Fever Infection swelling arms/legs fatigue Injection site redness/swelling pain shortness of breath bruising/bumps |                |                  |  
| swollen glands  near injection  site rash Respiratory sore throat runny nose cough Other:   |
|---------------------------------------------------------------------------------------------|
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15.2.3 appendix 3 study calendar

| Screening to Completion of DAC-THU/Pembrolizumab                | Courses 1 and Course N+1 [Course 2 Onwards]*   |                                   |                                   |    |    |
|-----------------------------------------------------------------|------------------------------------------------|-----------------------------------|-----------------------------------|----|----|
| * Note: Couse N+1 administered only for patients who exhibit stable disease  or disease regression  Within 3  days prior  to  completion  of DACTHU During Treatment Baseline  Within 10  days prior to  start of DACTHU At the end of course  completion                                                                 | End of  Treatment  Visit7                      |                                   |                                   |    |    |
| History and PE                                                  | X                                              | X                                 | X                                 | X  |    |
| Vital signs                                                     | X                                              | X                                 | X                                 | X  |    |
| Performance Score                                               | X                                              | X                                 | X                                 |    |    |
| NCI LP Confirmation of Dx1                                      | X                                              |                                   |                                   |    |    |
| CBC with differential; Acute                                    | Twice weekly during Course 1,                  |                                   |                                   |    |    |
| Care Panel, Hepatic Panel                                       | X                                              | X                                 | and then weekly unless clinically | X  | X  |
| (Sections 2.2 and 3.4.1)                                        | indicated                                      |                                   |                                   |    |    |
| Day 1  of  DACTHU                                                                 | Day 2  of  DACTHU                                                |                                   |                                   |    |    |
| Screening                                                       |                                                |                                   |                                   |    |    |
| Within 4 weeks  prior to enrollment                             |                                                |                                   |                                   |    |    |
| Procedure                                                       | Twice weekly during Course 1,                  |                                   |                                   |    |    |
| PT, PTT                                                         | X                                              | X                                 | and then weekly unless clinically | X  |    |
| indicated                                                       |                                                |                                   |                                   |    |    |
| Thyroid Function Tests                                          | X                                              |                                   |                                   |    |    |
| Albumin, Ca2+ total, Mg2+                                       | Twice weekly during Course 1,                  |                                   |                                   |    |    |
| total, Phosphorus, LD, Total                                    | X                                              | and then weekly unless clinically | X                                 | X  |    |
| Protein, Total CK, Uric Acid                                    | indicated                                      |                                   |                                   |    |    |
| Fetal Hemoglobin                                                | X                                              |                                   |                                   |    |    |
| Urinalysis                                                      | X4                                             | X4                                |                                   |    |    |
| Anti HIV, anti HCV,  HBsAg, anti-HAV IgM, and                   | X                                              |                                   |                                   |    |    |
| if needed, HCV RNA Urine or serum HCG in  women of childbearing | X3                                             | X3                                |                                   |    |    |
| potential T, B, NK cell subsets                                 | X9                                             | X                                 |                                   |    |    |  
| Courses 1 and Course N+1 [Course 2 Onwards]*            |                                                                                                                     |    |    |
|---------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------|----|----|
| * Note: Couse N+1 administered only for patients who exhibit stable disease  or disease regression  Within 3  days prior  to  completion  of DACTHU During Treatment Baseline  Within 10  days prior to  start of DACTHU At the end of course  completion                                                         | End of  Treatment  Visit7                                                                                           |    |    |
| HLA class I and class II  analysis of PBMC              | X1                                                                                                                  |    |    |
| EKG                                                     | X                                                                                                                   |    |    |
| Echocardiogram                                          | X                                                                                                                   |    |    |
| PFTs                                                    | X                                                                                                                   | X  |    |
| ABGs (to be drawn if pulse  oximetry <90% on room  air) | Day 1  of  DACTHU                                                                                                                     | Day 2  of  DACTHU    |    |
| Screening                                               |                                                                                                                     |    |    |
| Within 4 weeks  prior to enrollment                     |                                                                                                                     |    |    |
| Procedure                                               | X                                                                                                                   | X  |    |
| Lupus Anticoagulant and  ANA                            | X                                                                                                                   |    |    |
| Radiological Assessments                                | X2                                                                                                                  | X2 |    |
| DAC-THU                                                 | Once a day on days according to  dose level                                                                         |    |    |
| Tumor sample for research8                              | X                                                                                                                   | X  |    |
| Correlative Research Studies                            | X5                                                                                                                  | X5 | X5 |
| PK/PD                                                   | X6                                                                                                                  | X6 |    |
| Adverse Events10                                        | X                                                                                                                   |    |    |
| Concomitant Medications10                               | X                                                                                                                   |    |    |
| 1.                                                      | May be obtained any time prior to initiation of study therapy. Does not need to be repeated if already done at NCI. |    |    |  
DAC-THU Once a day on days according to  
dose level  
Tumor sample for research8 X X Correlative Research Studies X5 X5 X5  
PK/PD X6 X6  
Adverse Events10 X  
Concomitant Medications10 X  
1. May be obtained any time prior to initiation of study therapy. Does not need to be repeated if already done at NCI.  
2. Radiological Assessments: Pre-enrollment screening assessment: X-rays, contrast enhanced CT scans of chest, abdomen, pelvis, as  
well as brain MR (no gadolinium contrast), and fused PET-CT scans to evaluate the status of disease. (All imaging must be obtained within 4 weeks prior to treatment.) At the end of each course completion assessment: CT scan (C/A/P) (with standard oral/IV contrast), fused PET/CT scan and brain MR without gadolinium contrast (or CT scan if MR contraindicated).  
3. Must be completed within 3 days prior to enrollment or 48 hours prior to start of study drugs. 4. Urinalysis and culture if indicated.  
5. See **Appendix 4** for details of Research Labs timepoints and collection details. Note: Tubes/media may be adjusted at the time of collection based upon materials available if approved by the PI/laboratory investigator.  
6. See **Appendix 4** for PK sampling timepoints and collection details. **Note:** PK samples will only be drawn on Day 1 and Day 2 of Cycle 1.  
7. End of treatment visit will occur approximately 30 days after the last dose of study drug. If the patient cannot return to the Clinical Center for this visit, a request will be made to collect required clinical labs (specify as needed) from a local physician or laboratory. If this is not possible, patients may be assessed by telephone/or other NIH approved remote platforms for symptoms.  
8. Tumor biopsy will be performed at baseline if screening biopsy was not performed and after one course of therapy (Week 10 +/-
one week).  
9. Every three weeks during therapy.  
10. Adverse events and concomitant medications will be assessed weekly during the dose finding portion of the trial and every three weeks prior to the administration of pembrolizumab during the expansion portion of the trial.  
| 15.2.4.1 Course 1 Cycle 1 TEL Research  Sample # (2 red top tubes,  2 lavender top  tubes) Immune  Subset & CTC  Samples # (2 CPT tubes,  and 2 lavender  top tubes) PK Sample  # (1 6 mL  green top  tube) Hour   | Target Time   | Actual Time Initials   |                   |      |     |     |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------|------------------------|-------------------|------|-----|-----|
| (pre dose = within 1  hour prior to THU)                                                                                                                                                                           |               |                        |                   |      |     |     |
| Baseline (post - enrollment) R1                                                                                                                                                                                    | T1            | n/a                    | n/a               | n/a  | n/a | n/a |
| Day 1 DAC-THU R2 (within 1 hour  T2                                                                                                                                                                                | (within       | 1                      |                   |      |     |     |
| prior to THU)                                                                                                                                                                                                      | hour          | prior                  | to                |      |     |     |
| THU)                                                                                                                                                                                                               | PK 1          | pre dose               |                   |      |     |     |
| n/a                                                                                                                                                                                                                | n/a           | PK 2                   | 0.5h              | post |     |     |
| DAC dose                                                                                                                                                                                                           |               |                        |                   |      |     |     |
| n/a                                                                                                                                                                                                                | n/a           | PK 3                   | 1h post DAC  dose |      |     |     |
| n/a                                                                                                                                                                                                                | n/a           | PK 4                   | 1.5h              | post |     |     |
| DAC dose                                                                                                                                                                                                           |               |                        |                   |      |     |     |
| n/a                                                                                                                                                                                                                | n/a           | PK 5                   | 2h post DAC  dose |      |     |     |
| n/a                                                                                                                                                                                                                | n/a           | PK 6                   | 3h post DAC  dose |      |     |     |
| n/a                                                                                                                                                                                                                | n/a           | PK 7                   | 4h post DAC  dose |      |     |     |
| n/a                                                                                                                                                                                                                | n/a           | PK 8                   | 8h post DAC  dose |      |     |     |
| Day 2 DAC-THU n/a                                                                                                                                                                                                  | n/a           | PK 9                   | pre dose          |      |     |     |
| n/a                                                                                                                                                                                                                | n/a           | PK 10                  | 0.5h              | post |     |     |
| DAC dose                                                                                                                                                                                                           |               |                        |                   |      |     |     |
| n/a                                                                                                                                                                                                                | n/a           | PK 11                  | 1h post DAC  dose |      |     |     |
| n/a                                                                                                                                                                                                                | n/a           | PK 12                  | 1.5h              | post |     |     |
| DAC dose                                                                                                                                                                                                           |               |                        |                   |      |     |     |
| n/a                                                                                                                                                                                                                | n/a           | PK 13                  | 2h post DAC  dose |      |     |     |
| n/a                                                                                                                                                                                                                | n/a           | PK 14                  | 3h post DAC  dose |      |     |     |
| n/a                                                                                                                                                                                                                | n/a           | PK 15                  | 4h post DAC  dose |      |     |     |
| n/a                                                                                                                                                                                                                | n/a           | PK 16                  | 8h post DAC  dose |      |     |     |  
| After completion of  each course of DACTHU R3 T3   | n/a   | n/a   | n/a   | n/a   | n/a   |
|---|-------|-------|-------|-------|-------|  
| 15.2.4.2 Course N+1 (Course 2 Onwards)* TEL Research  Sample # (2 red top tubes,  2 lavender top  tubes) Immune  Subset & CTC  Samples # (2 CPT tubes,  and 2 lavender  top tubes) PK Sample  # (1 6 mL  green top  tube) Hour   | Target Time   | Actual Time Initials   |     |     |     |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------|------------------------|-----|-----|-----|
| (pre dose = within 1  hour prior to THU)                                                                                                                                                                                         |               |                        |     |     |     |
| Day 1 DAC-THU R4* (within 1 hour  T4* (within 1  prior to THU) hour prior to  THU) n/a                                                                                                                                           | pre dose      |                        |     |     |     |
| After completion of  each course of DACTHU R5* T5*                                                                                                                                                                                                                                  | n/a           | n/a                    | n/a | n/a | n/a |
| *Note: Labels should list the specific collection number as appropriate; indicated collection numbers are                                                                                                                        |               |                        |     |     |     |
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15.2.4.3 instructions pk studies (pk)

Collect 6 mL blood in 1 green top tube. Tubes should then be placed on crushed ice, and samples should be centrifuged for 15 minutes at approximately 1000 x g at 0-5 °C within 2 hours after collection. The plasma should be transferred to separate pre-labeled screw-capped polypropylene transfer tubes and stored at -80 °C in the Thoracic Epigenetics Lab (TEL) until batched and later sent to the Figg Lab on dry ice for analysis. Note: All samples are to be placed on wet ice and transported to the Thoracic Epigenetics Lab (TEL) within one hour of draw.
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research labs (r)

Samples will be collected in 2 red top (10 mL each) tubes, and 2 lavender top tubes (EDTA; 10 mL each) for focused methylation analysis and immune response to treatment (see Section **5.1.2**). Note: All samples are to be placed on wet ice and transported to the Thoracic Epigenetics Lab (TEL) within one hour of draw. Research Labs will be collected at the following timepoints (see also Appendix 3: Study Calendar):
Baseline (once), see Section **3.4.1**;
Each Course o Prior to DAC-THU initiation, and at
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immune subset and circulating tumor

Samples will be collected in 2 CPT citrate tubes (BD; 8 mL) for immune subset analysis (see Section **5.1.3**) and 2 lavender top tubes (10 mL) for CTCs analysis (Section **5.1.4**). The Trepel Lab will be notified to pick up the samples (as indicated in Section **5.2.4**) as soon as the blood is drawn for sample processing and analysis. Samples will be drawn at the following timepoints (see also **Appendix 3**):
Each course o Prior to DAC-THU initiation, and at o DAC-THU completion.
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labeling (pk and research labs)

Prior to the infusion, the PK /research lab sheet and labels will be placed in the patient's room and a separate set of labels will be given to the Thoracic Epigenetics Lab staff. The labels will list the patient identifiers as well as the Cycle and draw number as appropriate. As the RN (or designee) draws the bloods, the RN (or designee) will place a label on the tube and write the sample reference \# on the label on the tube. When the Thoracic Epigenetics Lab personnel or fellow processes the sample, the TEL personnel will label the storage tube with the label and will transcribe the corresponding sample reference \# on the label on the tube.
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tracking (pk and research labs)

Upon completion of the PK/Research sample draws, the research nurse will make 3 copies of the PK sheet. The original and one copy should be placed in the research binder. 2 copies should be given to the TEL personnel. TEL will retain one copy for their records and will send the other copy with the PK samples to the Figg Lab. Note: Prior to sending the PK sheets to the Figg Lab, the patient name should be crossed out.