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16 appendices

| 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                                                                         | 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  work.                           |                                                              |
| housework, office work).                                                                                                          | 80                                                                                                       | Normal activity with effort; some  signs or symptoms of disease. |                                                              |
| 1                                                                                                                                 | Requires occasional assistance,                                                                          |                                                                  |                                                              |
| In bed <50% of the time.                                                                                                          | 60                                                                                                       | but is able to care for most of                                  |                                                              |
| Ambulatory and capable of all                                                                                                     | 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.                                                         |                                                                  |                                                              |
| In bed >50% of the time. Capable  of only limited self-care, confined  to bed or chair more than 50% of                           | Severely disabled,                                                                                       |                                                                  |                                                              |
| waking hours.                                                                                                                     | 30                                                                                                       | hospitalization indicated. Death  not imminent.                  |                                                              |
| 3                                                                                                                                 | 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.                                                        |
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16.2 appendix b durvalumab dose

The durvalumab dosing should be done depending on subject weight (if subject is < 30kg)): 1. Cohort dose: X mg/kg 2. Subject weight: Y kg 3. Dose for subject: XY mg = X (mg/kg) × Y (kg) 4. Dose to be added into infusion bag: Dose (mL) = XY mg / 50 (mg/mL) where 50 mg/mL is durvalumab nominal concentration The corresponding volume of durvalumab should be rounded to the nearest tenth mL (0.1 mL). Dose adjustments for each cycle only needed for greater than 10% change in weight. 5. The theoretical number of vials required for dose preparation is the next greatest whole number of vials from the following formula: Number of vials = Dose (mL) / 10 (mL/vial)
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example

1. Cohort dose: 10 mg/kg 2. Subject weight: 30 kg 3. Dose for subject: 300 mg = 10 (mg/kg) × 30 (kg) 4. Dose to be added into infusion bag: Dose (mL) = 300 mg / 50 (mg/mL) = 6.0 mL 5. The theoretical number of vials required for dose preparation: Number of vials = 6.0 (mL) / 10.0 (mL/vial) = 1 vials
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16.3 appendix c durvalumab dosing

These guidelines are standardized for durvalumab trials. However, these guidelines are superseded and should be superceded by any protocol-specific DLTs as as specified in section 3.1.1. This is specifically the case for toxicities such as hyperbilirubinemia, encephalopathy, neurotoxicity, peripheral neuromotor syndromes, and transaminase elevation as well as others.
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general considerations regarding immune-mediated reactions

These guidelines are provided as a recommendation to support investigators in the management of potential immune-mediated adverse events (imAEs). Immune-mediated events can occur in nearly any organ or tissue, therefore, these guidelines may not include all the possible immune-mediated reactions. Investigators are advised to take into consideration the appropriate practice guidelines and other society guidelines (e.g., National Comprehensive Cancer Network (NCCN), European Society of Medical Oncology (ESMO)) in the management of these events. Refer to the section of the table titled "Other -Immune-Mediated Reactions" for general guidance on imAEs not noted in the "Specific Immune-Mediated Reactions" section. Early identification and management of imAEs is essential to ensure safe use of the study drug. Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying imAEs. Patients with suspected imAEs should be thoroughly evaluated to rule out any alternative etiologies (e.g., disease progression, concomitant medications, infections). In the absence of a clear alternative etiology, all such events should be managed as if they were immune-mediated. Institute medical management promptly, including specialty consultation as appropriate. In general, withhold study drug/study regimen for severe (Grade 3) imAEs. Permanently discontinue study drug/study regimen for life-threatening (Grade 4) imAEs, recurrent severe (Grade 3) imAEs that require systemic immunosuppressive treatment, or an inability to reduce corticosteroid dose to 10 mg or less of prednisone or equivalent per day within 12 weeks of initiating corticosteroids. Based on the severity of the imAE, durvalumab and/or tremelimumab should be withheld and corticosteroids administered. Upon improvement to Grade ≤ 1, corticosteroid should be tapered over ≥ 28 days. More potent immunosuppressive agents should be considered for events not responding to systemic steroids. Alternative immunosuppressive agents not listed in this guideline may be considered at the discretion of the investigator based on clinical practice and relevant guidelines. With longterm steroid and other immunosuppressive use, consider the need for glucose monitoring.  
Dose modifications of study drug/study regimen should be based on severity of treatment-emergent toxicities graded per NCI CTCAE version in the applicable study protocol. Considerations for Prophylaxis for Long Term use of Steroids for Patients Receiving Immune Checkpoint Inhibitor Immunotherapy Infection Prophylaxis: Pneumocystis jirovecii pneumonia (PJP), antifungal and Herpes Zoster reactivation Gastritis: Consider prophylaxis for patients at high risk of gastritis (e.g. NSAID use, anticoagulation) when the patient is taking steroid therapy Osteoporosis: Consider measures for prevention and mitigation of osteoporosis .  
| General Considerations Regarding Immune-Mediated Reactions Relevant Society Guidelines for Management of imAEs   |
|------------------------------------------------------------------------------------------------------------------|  
These society guidelines are provided as references to serve in support of best clinical practice and the TMGs. Please note, these were the current versions of these guidelines at the time of updating TMGs. Please refer to the most up to date version of these guidelines. 1. Brahmer JR, et al. Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immune checkpoint inhibitor-related adverse events. J Immunother Cancer 2021;9:e002435 2. Brahmer JR, et al. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol 2018;36(17):1714-1768.  
3. Haanen JBAG, et al. Management of toxicities for immunotherapy: European Society for Medical Oncology (ESMO) clinical practice guidelines for diagnosis, treatment, and follow-up. Annals Oncol 2017;28(Suppl4):i119-i1142.  
4. Sangro B, et al. Diagnosis and management of toxicities of immune checkpoint inhibitors in hepatocellular carcinoma. J Hepatol 2020;72(2):320-341.  
5. Thompson JA, et al. National Comprehensive Cancer Network Guidelines: Management of immunotherapy-related toxicities version1.2022. Published February 28, 2022.