untitled h1
15.3 appendix c modified immune-related

This new classification is based on the recent learning from clinical studies with cancer immunotherapies that even if some new lesions appear at the beginning of a treatment or if the total tumor burden does not increase substantially, tumor regressions or stabilizations might still occur later. The irRC were created using bi-dimensional measurements (as previously widely used in the World Health Organization criteria). For this trial, the concepts of the irRC are combined with RECIST 1.1 to come up with the modified irRC. For modified irRC, only target and measurable lesions are taken into account. In contrast to the RECIST 1.1 criteria, the modified irRC criteria (a) require confirmation of both progression and response by imaging at 6 weeks after initial imaging and (b) do not necessarily score the appearance of new lesions as progressive disease if the sum of lesion diameters of target lesions (minimum of 10 mm per lesion, maximum of 5 target lesions, maximum of 2 per organ) and measurable new lesions does not increase by ≥ 20%. The same method of assessment and the same technique should be used to characterize each identified and reported target lesion(s) at baseline, during the trial, and at the end of trial visit. All measurements should be recorded in metric notation. The modified irRC based on RECIST 1.1 are displayed below.
untitled h1
overall responses derived from changes

| Measurable Response                                                           | Non-Measurable Response                                                                                  | Overall Response   |       |
|-------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------|--------------------|-------|
| Using Modified irRC                                                           |                                                                                                          |                    |       |
| Index and New, Measurable                                                     | Non-Index Lesions                                                                                        | New, Non-          |       |
| Lesions (Tumor Burden)¹                                                       | Measurable Lesions                                                                                       |                    |       |
| Decrease 100%                                                                 | Absent                                                                                                   | Absent             | irCR² |
| Decrease 100%                                                                 | Stable                                                                                                   | irPR 2             |       |
| Any                                                                           |                                                                                                          |                    |       |
| Decrease 100%                                                                 | Unequivocal progression                                                                                  | irPR²              |       |
| Any                                                                           | irPR²                                                                                                    |                    |       |
| Decrease ≥ 30%                                                                | Absent / Stable                                                                                          | Any                |       |
| Decrease ≥ 30%                                                                | irPR²                                                                                                    |                    |       |
| Unequivocal progression                                                       | Any                                                                                                      |                    |       |
| Decrease < 30% to increase <                                                  | Absent / Stable                                                                                          | Any                | irSD  |
| 20%                                                                           |                                                                                                          |                    |       |
| Decrease < 30% to increase <                                                  | Unequivocal progression                                                                                  | irSD               |       |
| Any                                                                           |                                                                                                          |                    |       |
| 20%                                                                           |                                                                                                          |                    |       |
| Increase ≥ 20%                                                                | Any                                                                                                      | Any                | irPD  |
| Decreases assessed relative to baseline                                       |                                                                                                          |                    |       |
| 2                                                                             | Assuming that the response (irCR and irPR) and progression (irPD) are confirmed by a second, consecutive |                    |       |
| assessment at least 4 weeks apart (normally it should be done 6 weeks apart). |                                                                                                          |                    |       |  
| 15.4                | Appendix D: List of Adverse Events related to study treatment before amendment D  DL1 (N=3) DL2 (N=12)   |    |    |    |    |    |    |    |    |     |     |     |                 |    |    |
|---------------------|----------------------------------------------------------------------------------------------------------|----|----|----|----|----|----|----|----|-----|-----|-----|-----------------|----|----|
| Events              | #1                                                                                                       | #2 | #3 | #4 | #5 | #6 | #7 | #8 | #9 | #10 | #11 | #12 | #13 #14 #15 #16 |    |    |
| Fever               | 3                                                                                                        | 2  | 3  | 3  | 3  | 2  | 2  | 1  | 2  | 3   | 3   | 2   | 3               | 2  | 2  |
| Hypotension         | 1                                                                                                        | 2  | 2  | 1  | 2  | 1  | 2  | 1  | 2  | 1   | 2   | 2   |                 |    |    |
| Chills              | 1                                                                                                        | 1  | 1  | 2  | 1  | 2  | 2  | 2  | 2  | 1   | 1   | 2   |                 |    |    |
| Fatigue             | 1                                                                                                        | 1  | 1  | 1  | 2  | 1  | 1  | 1  |    |     |     |     |                 |    |    |
| Papulopustular Rash | 1                                                                                                        | 1  | 1  | 1  | 1  | 1  |    |    |    |     |     |     |                 |    |    |
| Sinus Tachycardia   | 1                                                                                                        | 2  | 1  | 1  | 1  | 1  | 1  |    |    |     |     |     |                 |    |    |
| Vomiting            | 1                                                                                                        | 1  | 1  | 1  |    |    |    |    |    |     |     |     |                 |    |    |
| Nausea              | 1                                                                                                        | 1  | 1  | 1  | 1  | 1  |    |    |    |     |     |     |                 |    |    |
| Flu Like Symptoms   | 1                                                                                                        | 1  | 2  | 1  |    |    |    |    |    |     |     |     |                 |    |    |
| Headache            | 1                                                                                                        | 1  | 2  |    |    |    |    |    |    |     |     |     |                 |    |    |
| Nasal Congestion    | 1                                                                                                        | 1  |    |    |    |    |    |    |    |     |     |     |                 |    |    |
| Pain                | 1                                                                                                        | 2  |    |    |    |    |    |    |    |     |     |     |                 |    |    |
| Constipation        | 1                                                                                                        |    |    |    |    |    |    |    |    |     |     |     |                 |    |    |
| Cough               | 1                                                                                                        |    |    |    |    |    |    |    |    |     |     |     |                 |    |    |
| Cramp               | 2                                                                                                        |    |    |    |    |    |    |    |    |     |     |     |                 |    |    |
| Hypertension        | 2                                                                                                        | 1  |    |    |    |    |    |    |    |     |     |     |                 |    |    |
| Elevated ALT        | 2                                                                                                        | 1  | 1  | 1  |    |    |    |    |    |     |     |     |                 |    |    |
| Elevated AST        | 2                                                                                                        | 1  | 1  | 1  |    |    |    |    |    |     |     |     |                 |    |    |
| Elevated ALP        | 2                                                                                                        | 1  | 1  |    |    |    |    |    |    |     |     |     |                 |    |    |
| Elevated Bilirubin  | 1                                                                                                        |    |    |    |    |    |    |    |    |     |     |     |                 |    |    |  
| Lymphopenia              | 1   | 1   | 4   | 1   | 2   | 3   | 2   |
|--------------------------|-----|-----|-----|-----|-----|-----|-----|
| Neutropenia              | 3   | 1   |     |     |     |     |     |
| Anemia                   | 2   | 2   | 1   | 1   | 2   | 3   | 1   |
| Hyperuricemia            | 1   | 1   |     |     |     |     |     |
| Decreased platelet count | 1   |     |     |     |     |     |     |
| Hyponatremia             | 1   | 1   | 1   | 1   |     |     |     |
| Hypophosphatemia         | 2   |     |     |     |     |     |     |
| Hypomagnesemia           | 1   |     |     |     |     |     |     |
| Hypercalcemia            | 1   |     |     |     |     |     |     |
| Hypoalbuminemia          | 2   | 1   |     |     |     |     |     |
| Elevated Lipase          | 1   | 1   |     |     |     |     |     |
| Elevated Amylase         | 1   |     |     |     |     |     |     |
| Increased Creatinine     | 2   |     |     |     |     |     |     |