untitled h1
general considerations regarding immune-mediated reactions

Drug
(MEDI4736) Study Number ESR-18-14261 Edition Number **V2.0** Date **9/21/2021**
Dosing Modification and Toxicity Management Guidelines for Immune-Mediated, Infusion-Related, and Non-Immune–Mediated Reactions (MEDI4736 Monotherapy or Combination Therapy with Tremelimumab or Tremelimumab Monotherapy) 17 October 2019 Version (CTCAE v5.0)  
| Dose Modifications                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 | Toxicity Management                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| immunosuppressive) should be considered for events not responding to systemic steroids. Progression to use of more potent immunosuppressives should proceed more rapidly in events with high likelihood for morbidity and/or mortality - e.g., myocarditis, or other similar events even if they are not currently noted in the guidelines - when these events are not responding to systemic steroids.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          |
| −                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  | With long-term steroid and other immunosuppressive use, consider need for Pneumocystis jirovecii pneumonia (PJP, formerly known as Pneumocystis carinii pneumonia) prophylaxis, gastrointestinal protection, and glucose monitoring. − Discontinuation of study drug/study regimen is not mandated for Grade 3/Grade 4 inflammatory reactions attributed to local tumor response (e.g., inflammatory reaction at sites of metastatic disease and lymph nodes). Continuation of study drug/study regimen in this situation should be based upon a benefit-risk analysis for that patient. |
| Grade 3                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            | Depending on the individual toxicity, study drug/study regimen may be permanently discontinued. Please refer to guidelines below.                                                                                                                                                                                                                                                                                                                                                                                                                                                        |
| Grade 4                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            | Permanently discontinue study drug/study regimen.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        |
| Note: For asymptomatic amylase or lipase levels of >2X ULN, hold study                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          |
| drug/study regimen, and if complete work up shows no evidence of pancreatitis, study drug/study regimen may be continued or resumed. Note: Study drug/study regimen should be permanently discontinued in Grade 3 events with high likelihood for morbidity and/or mortality - e.g., myocarditis, or other similar events even if they are not currently noted in the guidelines. Similarly, consider whether study drug/study regimen should be permanently discontinued in Grade 2 events with high likelihood for morbidity and/or mortality - e.g., myocarditis, or other similar events even if they are not currently noted in the guidelines - when they do not rapidly improve to Grade <1 upon treatment with systemic steroids and following full taper Note: There are some exceptions to permanent discontinuation of study drug for Grade 4 events (i.e., hyperthyroidism, hypothyroidism, Type 1 diabetes mellitus). |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          |  
General Considerations regarding Immune-Mediated Reactions AE Adverse event; CTC Common Toxicity Criteria; CTCAE Common Terminology Criteria for Adverse Events; imAE immune-mediated adverse event; IV intravenous; NCI
National Cancer Institute; PO By mouth.  
Drug
(MEDI4736) Study Number ESR-18-14261 Edition Number **V2.0**  
Date **9/21/2021**  
| Pediatric Considerations regarding Immune-Mediated Reactions                                                                                                                                                                                                                                                                                                                                               |                                                                                                                                                                                                              |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Dose Modifications                                                                                                                                                                                                                                                                                                                                                                                         | Toxicity Management                                                                                                                                                                                          |
| −                                                                                                                                                                                                                                                                                                                                                                                                          | All recommendations for specialist consultation should occur with a pediatric specialist in the specialty recommended.                                                                                       |
| −                                                                                                                                                                                                                                                                                                                                                                                                          | The recommendations for dosing of steroids (i.e., mg/kg/day) and for IV IG and plasmapheresis that are provided for adult patients should also be used for pediatric patients.                               |
| −                                                                                                                                                                                                                                                                                                                                                                                                          | The infliximab 5 mg/kg IV dose recommended for adults is the same as recommended for pediatric patients ≥ 6 years old. For dosing in children younger than 6 years old, consult with a pediatric specialist. |
| −                                                                                                                                                                                                                                                                                                                                                                                                          | For pediatric dosing of mycophenolate mofetil, consult with a pediatric specialist.                                                                                                                          |
| −                                                                                                                                                                                                                                                                                                                                                                                                          | With long-term steroid and other immunosuppressive use, consider need for PJP prophylaxis, gastrointestinal protection, and glucose monitoring.                                                              |
| The criteria for permanent discontinuation of study drug/study regimen based on CTC grade/severity is the same for pediatric patients as it is for adult patients, as well as to permanently discontinue study drug/study regimen if unable to reduce corticosteroid ≤ a dose equivalent to that required for corticosteroid replacement therapy within 12 weeks of the start of the immune-mediated event |                                                                                                                                                                                                              |  
Drug
(MEDI4736) Study Number ESR-18-14261 Edition Number **V2.0**  
| Date 9/21/2021                                                                               | Specific Immune-Mediated Reactions                                                                                                                                                                                                                                                                                              |                                                                                                                              |                     |
|----------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------|---------------------|
| Adverse Events                                                                               | Severity Grade of the Event (NCI CTCAE version 5.0)                                                                                                                                                                                                                                                                             | Dose Modifications                                                                                                           | Toxicity Management |
| Pneumonitis/Interstitial Lung Disease (ILD)                                                  | Any Grade                                                                                                                                                                                                                                                                                                                       | General Guidance                                                                                                             | For Any Grade:      |
| −                                                                                            | Monitor patients for signs and symptoms of pneumonitis or ILD (new onset or worsening shortness of breath or cough). Patients should be evaluated with imaging and pulmonary function tests, including other diagnostic procedures as described below.                                                                          |                                                                                                                              |                     |
| −                                                                                            | Initial work-up may include clinical evaluation, monitoring of oxygenation via pulse oximetry (resting and exertion), laboratory work-up, and high- resolution CT scan.                                                                                                                                                         |                                                                                                                              |                     |
| Grade 1                                                                                      | No dose modifications required. However, consider holding study drug/study regimen dose as clinically appropriate and during diagnostic workup for other etiologies.                                                                                                                                                                                                                                                                                                                                 | For Grade 1 (radiographic changes only):                                                                                     |                     |
| −                                                                                            | Monitor and closely follow up in 2 to 4 days for clinical symptoms, pulse oximetry (resting and exertion), and laboratory work-up and then as clinically indicated.                                                                                                                                                             |                                                                                                                              |                     |
| −                                                                                            | Consider Pulmonary and Infectious Disease consults.                                                                                                                                                                                                                                                                             |                                                                                                                              |                     |
| (asymptomatic, clinical or diagnostic observations only; intervention not indicated) Grade 2 | Hold study drug/study regimen dose until Grade 2 resolution to Grade ≤1.  If toxicity worsens, then treat as Grade 3 or Grade 4.  If toxicity improves to Grade ≤1, then the decision to reinitiate study drug/study regimen will be based upon treating physician's clinical judgment and after completion of steroid taper. | For Grade 2 (mild to moderate new symptoms): − Monitor symptoms daily and consider hospitalization.                          |                     |
| (symptomatic; medical intervention indicated; limiting instrumental ADL)                     | −                                                                                                                                                                                                                                                                                                                               | Promptly start systemic steroids (e.g., prednisone 1 to 2 mg/kg/day PO or IV equivalent). − Reimage as clinically indicated. |                     |
| −                                                                                            | If no improvement within 3 to 5 days, additional workup should be considered and prompt treatment with IV methylprednisolone 2 to 4 mg/kg/day started                                                                                                                                                                           |                                                                                                                              |                     |
| −                                                                                            | If still no improvement within 3 to 5 days despite IV methylprednisolone at 2 to 4 mg/kg/day, promptly start immunosuppressive therapy such as TNF inhibitors                                                                                                                                                                   |                                                                                                                              |                     |
| Page 74 of 102                                                                               |                                                                                                                                                                                                                                                                                                                                 |                                                                                                                              |                     |  
Drug  
| (MEDI4736) Study Number ESR-18-14261 Edition Number V2.0 Date 9/21/2021                                                                                                                                                  | (e.g., infliximab at 5 mg/kg every 2 weeks). Caution: It is important to rule out sepsis and refer to infliximab label for general guidance before using infliximab.                                                                                                                                                                            |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         |                |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------|
| −                                                                                                                                                                                                                        | Once the patient is improving, gradually taper steroids over ≥28 days and consider prophylactic antibiotics, antifungals, or anti-PJP treatment (refer to current NCCN guidelines for treatment of cancer-related infections)a − Consider Pulmonary and Infectious Disease consults. − Consider, as necessary, discussing with study physician. |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         |                |
| Grade 3 or 4                                                                                                                                                                                                             | Permanently discontinue study drug/study regimen.                                                                                                                                                                                                                                                                                               | For Grade 3 or 4 (severe or new symptoms, new/worsening hypoxia, life-threatening): − Promptly initiate empiric IV methylprednisolone 1 to 4 mg/kg/day or equivalent. − Obtain Pulmonary and Infectious Disease consults; consider, as necessary, discussing with study physician. − Hospitalize the patient. − Supportive care (e.g., oxygen). − If no improvement within 3 to 5 days, additional workup should be considered and prompt treatment with additional immunosuppressive therapy such as TNF inhibitors (e.g., infliximab at 5 mg/kg every 2 weeks' dose) started. Caution: rule out sepsis and refer to infliximab label for general guidance before using infliximab. − Once the patient is improving, gradually taper steroids over ≥28 days and consider prophylactic antibiotics, antifungals, and, in particular, anti-PJP treatment (refer to current NCCN guidelines for treatment of cancer-related infections).a |                |
| (Grade 3: severe symptoms; limiting self-care ADL; oxygen indicated) (Grade 4: lifethreatening respiratory compromise; urgent intervention indicated [e.g., tracheostomy or intubation])                                                                                                                                                                                                                          |                                                                                                                                                                                                                                                                                                                                                 |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         |                |
| Diarrhea/Colitis                                                                                                                                                                                                         | Any Grade                                                                                                                                                                                                                                                                                                                                       | General Guidance                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        | For Any Grade: |
| −                                                                                                                                                                                                                        | Monitor for symptoms that may be related to                                                                                                                                                                                                                                                                                                     |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         |                |
| diarrhea/enterocolitis (abdominal pain, cramping, or changes in bowel habits such as increased frequency over baseline or blood in stool) or related to bowel perforation (such as sepsis, peritoneal signs, and ileus). |                                                                                                                                                                                                                                                                                                                                                 |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         |                |
| Large intestine                                                                                                                                                                                                          |                                                                                                                                                                                                                                                                                                                                                 |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         |                |
| perforation/Intestine perforation                                                                                                                                                                                        |                                                                                                                                                                                                                                                                                                                                                 |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         |                |  
Page 75 of 102  
Drug
(MEDI4736) Study Number ESR-18-14261 Edition Number **V2.0**  
Date **9/21/2021**  
| -                                                                                                                                                                                                                                                                                                                                                                        | When symptoms or evaluation indicate a perforation is suspected, consult a surgeon experienced in abdominal surgery immediately without any delay.                                                                                      |              |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------|
| −                                                                                                                                                                                                                                                                                                                                                                        | Patients should be thoroughly evaluated to rule out any alternative etiology (e.g., disease progression, other                                                                                                                          |              |
| medications, or infections), including testing for clostridium difficile toxin, etc. − Steroids should be considered in the absence of clear alternative etiology, even for low-grade events, in order to prevent potential progression to higher grade event, including perforation. − Use analgesics carefully; they can mask symptoms of perforation and peritonitis. |                                                                                                                                                                                                                                         |              |
| Grade 1                                                                                                                                                                                                                                                                                                                                                                  | No dose modifications.                                                                                                                                                                                                                  | For Grade 1: |
| −                                                                                                                                                                                                                                                                                                                                                                        | Monitor closely for worsening symptoms.                                                                                                                                                                                                 |              |
| −                                                                                                                                                                                                                                                                                                                                                                        | Consider symptomatic treatment, including hydration, electrolyte replacement, dietary changes (e.g., American Dietetic Association colitis diet), and loperamide. Use probiotics as per treating physician's clinical judgment.         |              |
| (Diarrhea: stool                                                                                                                                                                                                                                                                                                                                                         |                                                                                                                                                                                                                                         |              |
| frequency of <4 over baseline per day) (Colitis: asymptomatic; clinical or diagnostic observations only; intervention not indicated) Grade 2                                                                                                                                                                                                                             | Hold study drug/study regimen until resolution to Grade ≤1  If toxicity worsens, then treat as Grade 3 or Grade 4.  If toxicity improves to Grade ≤1, then study drug/study regimen can be resumed after completion of steroid taper. | For Grade 2: |
| −                                                                                                                                                                                                                                                                                                                                                                        | Consider symptomatic treatment, including hydration, electrolyte replacement, dietary changes (e.g., American Dietetic Association colitis diet), and loperamide and/or budesonide.                                                     |              |
| −                                                                                                                                                                                                                                                                                                                                                                        | Promptly start prednisone 1 to 2 mg/kg/day PO or IV equivalent.                                                                                                                                                                         |              |
| −                                                                                                                                                                                                                                                                                                                                                                        | If event is not responsive within 3 to 5 days or worsens                                                                                                                                                                                |              |
| despite prednisone at 1 to 2 mg/kg/day PO or IV equivalent, GI consult should be obtained for consideration of further                                                                                                                                                                                                                                                   |                                                                                                                                                                                                                                         |              |
| (Diarrhea: stool frequency of 4 to 6 over baseline per day; limiting instrumental ADL) (Colitis: abdominal                                                                                                                                                                                                                                                               | Page 76 of 102                                                                                                                                                                                                                          |              |  
Drug
(MEDI4736) Study Number ESR-18-14261 Edition Number **V2.0**  
| Date 9/21/2021                                                                                                                                                                                   | pain; mucus or blood in                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              | workup, such as imaging and/or colonoscopy, to confirm                          |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------|
| colitis and rule out perforation, and prompt treatment with IV methylprednisolone 2 to 4 mg/kg/day started.                                                                                      |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      |                                                                                 |
| −                                                                                                                                                                                                | If still no improvement within 3 to 5 days despite 2 to 4 mg/kg IV methylprednisolone, promptly start immunosuppressives such as infliximab at 5 mg/kg once every 2 weeksa . Caution: it is important to rule out bowel perforation and refer to infliximab label for general guidance before using infliximab.                                                                                                                                                                                                                                                                      |                                                                                 |
| −                                                                                                                                                                                                | Consider, as necessary, discussing with study physician if no resolution to Grade ≤1 in 3 to 4 days.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 |                                                                                 |
| −                                                                                                                                                                                                | Once the patient is improving, gradually taper steroids over ≥28 days and consider prophylactic antibiotics, antifungals, and anti-PJP treatment (refer to current NCCN guidelines for treatment of cancer-related infections).a                                                                                                                                                                                                                                                                                                                                                     |                                                                                 |
| stool)                                                                                                                                                                                           |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      |                                                                                 |
| (Perforation: invasive intervention not indicated)                                                                                                                                               | For Grade 3 or 4:                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    |                                                                                 |
| Grade 3 or 4                                                                                                                                                                                     | Grade 3                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              |                                                                                 |
| Permanently discontinue study drug/study regimen for Grade 3 if toxicity does not improve to Grade ≤1 within 14 days; study drug/study regimen can be resumed after completion of steroid taper. | −                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    | Promptly initiate empiric IV methylprednisolone 2 to 4 mg/kg/day or equivalent. |
| −                                                                                                                                                                                                | Monitor stool frequency and volume and maintain hydration. − Urgent GI consult and imaging and/or colonoscopy as appropriate. − If still no improvement within 3 to 5 days of IV methylprednisolone 2 to 4 mg/kg/day or equivalent, promptly start further immunosuppressives (e.g., infliximab at 5 mg/kg once every 2 weeks). Caution: Ensure GI consult to rule out bowel perforation and refer to infliximab label for general guidance before using infliximab. If perforation is suspected, consult a surgeon experienced in abdominal surgery immediately without any delay . |                                                                                 |
| −                                                                                                                                                                                                | Once the patient is improving, gradually taper steroids over ≥28 days and consider prophylactic antibiotics, antifungals, and anti-PJP treatment (refer to current NCCN guidelines for treatment of cancer-related infections).a                                                                                                                                                                                                                                                                                                                                                     |                                                                                 |
| (Grade 3 Diarrhea: stool frequency of ≥7 over baseline per day; limiting self care ADL; Grade 4 Diarrhea: life threatening consequences) (Grade 3 Colitis: severe abdominal pain, fever; ileus; peritoneal signs; Grade 4 Colitis: lifethreatening consequences, urgent intervention indicated)                                                                                                                                                                                                  | Grade 4                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              |                                                                                 |
| Permanently discontinue study drug/study regimen.                                                                                                                                                |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      |                                                                                 |  
Drug
(MEDI4736) Study Number ESR-18-14261 Edition Number **V2.0**
(Grade 3 Perforation:
invasive intervention indicated; Grade 4 Perforation:
life-threatening consequences; urgent intervention indicated)  
Drug
(MEDI4736) Study Number ESR-18-14261 Edition Number **V2.0**  
| Date 9/21/2021 Hepatitis (elevated LFTs)                                                                                                                                       | Any Grade                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               | General Guidance       | For Any Grade                                                                                                                                                                                                       |              |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------|
| −                                                                                                                                                                              | Monitor and evaluate liver function test: AST, ALT, ALP, and TB.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        |                        |                                                                                                                                                                                                                     |              |
| −                                                                                                                                                                              | Evaluate for alternative etiologies (e.g., viral hepatitis, disease progression, concomitant medications).                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              |                        |                                                                                                                                                                                                                     |              |
| Infliximab should not be used for management of immune-related hepatitis.                                                                                                      | Grade 1                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 |                        |                                                                                                                                                                                                                     |              |
| (AST or ALT >ULN                                                                                                                                                               |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        | No dose modifications. |                                                                                                                                                                                                                     |              |
|                                                                                                                                                                               | If it worsens, then treat as Grade 2.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   | −                      | Continue LFT monitoring per protocol.                                                                                                                                                                               |              |
| PLEASE SEE shaded area                                                                                                                                                         |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         |                        |                                                                                                                                                                                                                     |              |
| immediately below this section to find guidance for management of "Hepatitis (elevated LFTS)" in HCC patients                                                                  | and ≤3.0×ULN if baseline normal, 1.5- 3.0×baseline if baseline abnormal; and/or TB >ULN and ≤1.5×ULN if baseline normal, >1.0-1.5×baseline if baseline abnormal)                                                                                                                                                                                                                                                                                                                                                                                                                                        |                       | Hold study drug/study regimen dose until resolution to Grade≤1.  If toxicity worsens, then treat as Grade 3.  If toxicity improves to Grade≤1, resume study drug/study regimen after completion of steroid taper. | For Grade 2: |
| −                                                                                                                                                                              | Regular and frequent checking of LFTs (e.g., every 1 to 2 days) until elevations of these are improving or resolved.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    |                        |                                                                                                                                                                                                                     |              |
| −                                                                                                                                                                              | If no resolution to ≤Grade 1 in 1 to 2 days, consider, as necessary, discussing with study physician.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   |                        |                                                                                                                                                                                                                     |              |
| −                                                                                                                                                                              | If event is persistent (>3 to 5 days) or worsens, promptly start prednisone 1 to 2 mg/kg/day PO or IV equivalent. − If still no improvement within 3 to 5 days despite 1 to 2 mg/kg/day of prednisone PO or IV equivalent, consider additional work up and start prompt treatment with IV methylprednisolone 2 to 4 mg/kg/day. − If still no improvement within 3 to 5 days despite 2 to 4 mg/kg/day of IV methylprednisolone, promptly start immunosuppressives (i.e., mycophenolate mofetil).a Discuss with study physician if mycophenolate mofetil is not available. Infliximab should NOT be used. |                        |                                                                                                                                                                                                                     |              |
| Grade 2 (AST or                                                                                                                                                                |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         |                        |                                                                                                                                                                                                                     |              |
| ALT >3.0×ULN and ≤5.0×ULN if baseline normal, >3-5×baseline if baseline abnormal; and/or TB >1.5×ULN and ≤3.0×ULN if baseline normal, >1.5- 3.0×baseline if baseline abnormal) |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         |                        |                                                                                                                                                                                                                     |              |  
Drug
(MEDI4736) Study Number ESR-18-14261  
| Edition Number V2.0 Date 9/21/2021                                                                                                                                                                                                     | −                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    | Once the patient is improving, gradually taper steroids over ≥28 days and consider prophylactic antibiotics, antifungals, and anti-PJP treatment (refer to current NCCN guidelines for treatment of cancer-related infections).a For Grade 3 or 4:   |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| −                                                                                                                                                                                                                                      | Promptly initiate empiric IV methylprednisolone at 1 to 4 mg/kg/day or equivalent.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   |                                                                                                                                                                                                                                                      |
| −                                                                                                                                                                                                                                      | If still no improvement within 3 to 5 days despite 1 to                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              |                                                                                                                                                                                                                                                      |
| 4 mg/kg/day methylprednisolone IV or equivalent, promptly start treatment with immunosuppressive therapy (i.e., mycophenolate mofetil). Discuss with study physician if mycophenolate is not available. Infliximab should NOT be used. |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      |                                                                                                                                                                                                                                                      |
| −                                                                                                                                                                                                                                      | Request Hepatology consult, and perform abdominal workup and imaging as appropriate.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 |                                                                                                                                                                                                                                                      |
| −                                                                                                                                                                                                                                      | Once the patient is improving, gradually taper steroids over ≥28 days and consider prophylactic antibiotics, antifungals, and anti-PJP treatment (refer to current NCCN guidelines for treatment of cancer-related infections).a                                                                                                                                                                                                                                                                                                                                                     |                                                                                                                                                                                                                                                      |
| Grade 3                                                                                                                                                                                                                                | For elevations in transaminases                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      |                                                                                                                                                                                                                                                      |
| (AST or                                                                                                                                                                                                                                |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      |                                                                                                                                                                                                                                                      |
| ALT >5.0×ULN and ≤20×ULN if baseline normal, >5-20× baseline if baseline abnormal; and/or TB >3.0×ULN and ≤10.0×ULN if baseline normal, >3.0-10.0× baseline if baseline abnormal)                                                      | ≤8×ULN, or elevations in TB ≤5×ULN:  Hold study drug/study regimen dose until resolution to Grade≤1  Resume study drug/study regimen if elevations downgrade to Grade≤1 within 14 days and after completion of steroid taper.  Permanently discontinue study drug/study regimen if the elevations do not downgrade to Grade≤1 within 14 days. For elevations in transaminases >8×ULN or elevations in bilirubin >5×ULN, permanently discontinue study drug/study regimen. Permanently discontinue study drug/study regimen for any case meeting Hy's law criteria (AST and/or ALT |                                                                                                                                                                                                                                                      |
| Grade 4                                                                                                                                                                                                                                |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      |                                                                                                                                                                                                                                                      |
| (AST or ALT                                                                                                                                                                                                                            |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      |                                                                                                                                                                                                                                                      |
| >20×ULN if baseline normal, >20×baseline if baseline abnormal; and/or TB >10×ULN if                                                                                                                                                    | >3×ULN + bilirubin >2×ULN without initial findings of cholestasis [i.e., elevated alkaline P04] and in the absence of any alternative cause).b                                                                                                                                                                                                                                                                                                                                                                                                                                       |                                                                                                                                                                                                                                                      |
| baseline normal, >10.0×baseline if baseline abnormal)                                                                                                                                                                                  |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      |                                                                                                                                                                                                                                                      |  
Drug
(MEDI4736) Study Number ESR-18-14261 Edition Number **V2.0**
Drug
(MEDI4736) Study Number ESR-18-14261 Edition Number **V2.0**  
| Date 9/21/2021 Hepatitis (elevated LFTs)                                                                                                                                                                                                                                                                                                                                                                                        | Any Elevations of AST, ALT, or TB as                                                                                                                                                                                     | General Guidance   | For Any Elevations Described:   |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------|---------------------------------|
| −                                                                                                                                                                                                                                                                                                                                                                                                                               | Monitor and evaluate liver function test: AST, ALT, ALP, and TB.                                                                                                                                                         |                    |                                 |
| −                                                                                                                                                                                                                                                                                                                                                                                                                               | Evaluate for alternative etiologies (e.g., viral hepatitis, disease progression, concomitant medications, worsening of liver cirrhosis [e.g., portal vein thrombosis]).                                                  |                    |                                 |
| −                                                                                                                                                                                                                                                                                                                                                                                                                               | For HBV+ patients: evaluate quantitative HBV viral load, quantitative HBsAg, or HBeAg                                                                                                                                    |                    |                                 |
| −                                                                                                                                                                                                                                                                                                                                                                                                                               | For HCV+ patients: evaluate quantitative HCV viral load                                                                                                                                                                  |                    |                                 |
| − Consider consulting hepatologist/Infectious Disease specialist regarding change/implementation in/of antiviral medications for any patient with an elevated HBV viral load >2000 IU/ml − Consider consulting hepatologist/Infectious Disease specialist regarding change/implementation in/of antiviral HCV medications if HCV viral load increased by ≥2-fold − For HCV+ with HBcAB+: Evaluate for both HBV and HCV as above |                                                                                                                                                                                                                          |                    |                                 |
| Described Below                                                                                                                                                                                                                                                                                                                                                                                                                 |                                                                                                                                                                                                                          |                    |                                 |
| Infliximab should not be used for management of immune-related hepatitis. THIS shaded area is guidance only for management of "Hepatitis (elevated LFTs)" in HCC patientsSee instructions at bottom of shaded area if transaminase rise is not isolated but (at any time) occurs in setting of either increasing                                                                                                                | Isolated AST or ALT >ULN and ≤5.0×ULN, whether normal or elevated at baseline                                                                                                                                            |                   | No dose modifications.          |
|                                                                                                                                                                                                                                                                                                                                                                                                                                | If ALT/AST elevations represents significant worsening based on investigator assessment, then treat as described for elevations in the row below.                                                                        |                    |                                 |
| bilirubin or signs of DILI/liver decompensation                                                                                                                                                                                                                                                                                                                                                                                 | For all transaminase elevations, see instructions at bottom of shaded area if transaminase rise is not isolated but (at any time) occurs in setting of either increasing bilirubin or signs of DILI/liver decompensation |                    |                                 |  
Drug
(MEDI4736) Study Number ESR-18-14261 Edition Number **V2.0**  
| Date 9/21/2021                                                                                                                     | −                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                | Regular and frequent checking of LFTs (e.g., every 1 to 3 days) until elevations of these are improving or resolved.   |
|------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------|
| −                                                                                                                                  | Recommend consult hepatologist; consider abdominal                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               |                                                                                                                        |
| ultrasound, including Doppler assessment of liver perfusion.                                                                       |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  |                                                                                                                        |
| −                                                                                                                                  | Consider, as necessary, discussing with study physician.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         |                                                                                                                        |
| −                                                                                                                                  | If event is persistent (>3 to 5 days) or worsens, and                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            |                                                                                                                        |
| investigator suspects toxicity to be immune-mediated AE, recommend to start prednisone 1 to 2 mg/kg/day PO or IV equivalent.       |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  |                                                                                                                        |
| −                                                                                                                                  | If still no improvement within 3 to 5 days despite 1 to 2 mg/kg/day of prednisone PO or IV equivalent, consider additional workup and treatment with IV methylprednisolone 2 to 4 mg/kg/day. − If still no improvement within 3 to 5 days despite 2 to 4 mg/kg/day of IV methylprednisolone, consider additional abdominal workup (including liver biopsy) and imaging (i.e., liver ultrasound), and consider starting immunosuppressives (i.e., mycophenolate mofetil).a Discuss with study physician if mycophenolate mofetil is not available. Infliximab should NOT be used. |                                                                                                                        |
| Isolated AST or ALT >5.0×ULN and ≤8.0×ULN, if normal at baseline                                                                   |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 | Hold study drug/study regimen dose until resolution to AST or ALT ≤5.0×ULN.                                            |
|  If toxicity worsens, then treat as described for elevations in the rows below.                                                   |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  |                                                                                                                        |
| Isolated AST or ALT >2.0×baseline and ≤12.5×ULN, if                                                                                | If toxicity improves to AST or ALT ≤5.0×ULN, resume study drug/study                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             |                                                                                                                        |
| regimen after completion of steroid taper.                                                                                         |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  |                                                                                                                        |
| elevated >ULN at baseline                                                                                                          | −                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                | Regular and frequent checking of LFTs (e.g., every 1-2 days) until elevations of these are improving or resolved.      |
| −                                                                                                                                  | Consult hepatologist (unless investigator is hepatologist); obtain abdominal ultrasound, including Doppler assessment of liver perfusion; and consider liver biopsy.                                                                                                                                                                                                                                                                                                                                                                                                             |                                                                                                                        |
| −                                                                                                                                  | Consider, as necessary, discussing with study physician.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         |                                                                                                                        |
| −                                                                                                                                  | If investigator suspects toxicity to be immune-mediated, promptly initiate empiric IV methylprednisolone at 1 to 4 mg/kg/day or equivalent. − If no improvement within 3 to 5 days despite 1 to 4 mg/kg/day methylprednisolone IV or equivalent, obtain liver biopsy (if it has not been done already) and promptly start treatment with immunosuppressive therapy (mycophenolate mofetil). Discuss with study physician if                                                                                                                                                      |                                                                                                                        |
|                                                                                                                                   | Hold study drug/study regimen dose until resolution to AST or ALT ≤5.0×ULN.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      |                                                                                                                        |
|                                                                                                                                   | Resume study drug/study regimen if elevations downgrade to AST or ALT ≤5.0×ULN within 14 days and after completion of steroid taper.  Permanently discontinue study drug/study regimen if the elevations do not downgrade to AST or ALT ≤5.0×ULN within 14 days                                                                                                                                                                                                                                                                                                                 |                                                                                                                        |
| Isolated AST or ALT >8.0×ULN and ≤20.0×ULN, if normal at baseline Isolated AST or ALT >12.5×ULN and ≤20.0×ULN, if elevated >ULN at | Permanently discontinue study                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    |                                                                                                                        |
| drug/study regimen for any case meeting                                                                                            |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  |                                                                                                                        |
| baseline                                                                                                                           |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  |                                                                                                                        |  
Drug
(MEDI4736) Study Number ESR-18-14261 Edition Number **V2.0**  
| Date 9/21/2021                                                | mycophenolate is not available. Infliximab should NOT be used.                                                                                                                                                                   |               |
|---------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------|
| −                                                             | Once the patient is improving, gradually taper steroids over ≥28 days and consider prophylactic antibiotics, antifungals, and anti-PCP treatment (refer to current NCCN guidelines for treatment of cancer-related infections).a |               |
| Hy's law criteria, in the absence of any alternative cause. b |                                                                                                                                                                                                                                  |               |
| Isolated AST or ALT                                           | Permanently discontinue study drug/study regimen.                                                                                                                                                                                | Same as above |
| (except would recommend obtaining liver biopsy early)         |                                                                                                                                                                                                                                  |               |
| >20×ULN, whether normal or elevated at baseline               |                                                                                                                                                                                                                                  |               |  
If transaminase rise is not isolated but (at any time) occurs in setting of either increasing total/direct bilirubin (≥1.5×ULN, if normal at baseline; or **2×baseline,** if
>ULN at baseline) or signs of DILI/liver decompensation (e.g., fever, elevated **INR):**
- Manage dosing for each level of transaminase rise as instructed for the next highest level of transaminase **rise**
- For example, manage dosing for second level of transaminase rise (i.e., AST or ALT >5.0×ULN and ≤8.0×ULN, if normal at baseline, or AST or ALT
>2.0×baseline and ≤12.5×ULN, if elevated >ULN at baseline) as instructed for the third level of transaminase rise (i.e., AST or ALT >8.0×ULN and
≤20.0×ULN, if normal at baseline, or AST or ALT >12.5×ULN and ≤20.0×ULN, if elevated >ULN at **baseline)**
- For the third and fourth levels of transaminase rises, permanently discontinue study drug/study **regimen**  
| Nephritis or renal dysfunction   | Any Grade                                                                                                                                                                                                                                       | General Guidance   | For Any Grade:   |
|----------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------|------------------|
| −                                | Consult with nephrologist.                                                                                                                                                                                                                      |                    |                  |
| −                                | Monitor for signs and symptoms that may be related to changes in renal function (e.g., routine urinalysis, elevated serum BUN and creatinine, decreased creatinine clearance, electrolyte imbalance, decrease in urine output, or proteinuria). |                    |                  |
| (elevated serum creatinine)      |                                                                                                                                                                                                                                                 |                    |                  |  
Drug
(MEDI4736) Study Number ESR-18-14261  
| Edition Number V2.0   |
|-----------------------|  
| − Patients should be thoroughly evaluated to rule out any alternative etiology (e.g., disease progression or infections). − Steroids should be considered in the absence of clear alternative etiology even for low-grade events (Grade 2), in order to prevent potential progression to higher grade event.   |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
Drug
(MEDI4736) Study Number ESR-18-14261  
| Edition Number V2.0 Date 9/21/2021                       | Grade 1                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       | No dose modifications.                                                                       | For Grade 1:   |
|----------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------|----------------|
| −                                                        | Monitor serum creatinine weekly and any accompanying symptoms.  If creatinine returns to baseline, resume its regular monitoring per study protocol.  If creatinine worsens, depending on the severity, treat as Grade 2, 3, or 4.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          |                                                                                              |                |
| −                                                        | Consider symptomatic treatment, including hydration, electrolyte replacement, and diuretics.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  |                                                                                              |                |
| −                                                        | If baseline serum creatinine is elevated above normal, and there is a rise to > 1 to 1.5 × baseline, consider following recommendations in this row.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          |                                                                                              |                |
| (serum creatinine >ULN to 1.5×ULN) Grade 2               | Hold study drug/study regimen until resolution to Grade ≤1 or baseline.  If toxicity worsens, then treat as Grade 3 or 4.  If toxicity improves to Grade ≤1 or baseline, then resume study drug/study regimen after completion of steroid taper.                                                                                                                                                                                                                                                                                                                                                                                                                                                                            | For Grade 2:                                                                                 |                |
| (serum creatinine >1.5 to 3.0×baseline; >1.5 to 3.0×ULN) | −                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             | Consider symptomatic treatment, including hydration, electrolyte replacement, and diuretics. |                |
| −                                                        | Carefully monitor serum creatinine every 2 to 3 days and as clinically warranted.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             |                                                                                              |                |
| −                                                        | Consult nephrologist and consider renal biopsy if clinically indicated.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       |                                                                                              |                |
| −                                                        | If event is persistent (>3 to 5 days) or worsens, promptly start prednisone 1 to 2 mg/kg/day PO or IV equivalent. − If event is not responsive within 3 to 5 days or worsens despite prednisone at 1 to 2 mg/kg/day PO or IV equivalent, additional workup should be considered and prompt treatment with IV methylprednisolone at 2 to 4 mg/kg/day started. − Once the patient is improving, gradually taper steroids over ≥28 days and consider prophylactic antibiotics, antifungals, and anti-PJP treatment (refer to current NCCN guidelines for treatment of cancer-related infections).a − When event returns to baseline, resume study drug/study regimen and routine serum creatinine monitoring per study protocol. |                                                                                              |                |  
Drug
(MEDI4736) Study Number ESR-18-14261  
| Edition Number V2.0 Date 9/21/2021                                                                                                                                           | Grade 3 or 4                                                                                                                                                                                                                     | Permanently discontinue study drug/study regimen.                       | For Grade 3 or 4:   |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------|---------------------|
| −                                                                                                                                                                            | Carefully monitor serum creatinine on daily basis.                                                                                                                                                                               |                                                                         |                     |
| (Grade 3: serum creatinine                                                                                                                                                   |                                                                                                                                                                                                                                  |                                                                         |                     |
| >3.0×baseline; >3.0 to                                                                                                                                                       | −                                                                                                                                                                                                                                | Consult nephrologist and consider renal biopsy if clinically indicated. |                     |
| −                                                                                                                                                                            | Promptly start prednisone 1 to 2 mg/kg/day PO or IV equivalent.                                                                                                                                                                  |                                                                         |                     |
| −                                                                                                                                                                            | If event is not responsive within 3 to 5 days or worsens                                                                                                                                                                         |                                                                         |                     |
| despite prednisone at 1 to 2 mg/kg/day PO or IV equivalent, additional workup should be considered and prompt treatment with IV methylprednisolone 2 to 4 mg/kg/day started. |                                                                                                                                                                                                                                  |                                                                         |                     |
| −                                                                                                                                                                            | Once the patient is improving, gradually taper steroids over ≥28 days and consider prophylactic antibiotics, antifungals, and anti-PJP treatment (refer to current NCCN guidelines for treatment of cancer-related infections).a |                                                                         |                     |
| 6.0×ULN)                                                                                                                                                                     |                                                                                                                                                                                                                                  |                                                                         |                     |
| (Grade 4: serum                                                                                                                                                              |                                                                                                                                                                                                                                  |                                                                         |                     |
| creatinine >6.0×ULN)                                                                                                                                                         |                                                                                                                                                                                                                                  |                                                                         |                     |
| Rash or Dermatitis                                                                                                                                                           | Any Grade                                                                                                                                                                                                                        | General Guidance                                                        | For Any Grade:      |
| −                                                                                                                                                                            | Monitor for signs and symptoms of dermatitis (rash and pruritus).                                                                                                                                                                |                                                                         |                     |
| −                                                                                                                                                                            | IF THERE IS ANY BULLOUS FORMATION, THE                                                                                                                                                                                           |                                                                         |                     |
| STUDY PHYSICIAN SHOULD BE CONTACTED AND STUDY DRUG DISCONTINUED IF SUSPECT STEVENS-JOHNSON SYNDROME OR TOXIC EPIDERMAL NECROLYSIS.                                           |                                                                                                                                                                                                                                  |                                                                         |                     |
| (including Pemphigoid)                                                                                                                                                       | (refer to NCI CTCAE v 5.0 for definition of severity/grade depending on type of skin rash) Grade 1                                                                                                                               | No dose modifications.                                                  | For Grade 1:        |
| −                                                                                                                                                                            | Consider symptomatic treatment, including oral antipruritics (e.g., diphenhydramine or hydroxyzine) and topical therapy (e.g., urea cream).                                                                                      |                                                                         |                     |
| Grade 2                                                                                                                                                                      | For persistent (>1 to 2 weeks) Grade 2 events, hold scheduled study drug/study regimen until resolution to Grade ≤1 or baseline.                                                                                                 | For Grade 2:                                                            |                     |
| −                                                                                                                                                                            | Obtain Dermatology consult.                                                                                                                                                                                                      |                                                                         |                     |
| −                                                                                                                                                                            | Consider symptomatic treatment, including oral antipruritics (e.g., diphenhydramine or hydroxyzine) and topical therapy (e.g., urea cream).                                                                                      |                                                                         |                     |  
Page 87 of 102  
Drug
(MEDI4736) Study Number ESR-18-14261  
| Edition Number V2.0 Date 9/21/2021                                                                                                                                                                                                                           | −                                                                                                                                                                                                                                | Consider moderate-strength topical steroid.                                                                                                           |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
|                                                                                                                                                                                                                                                             | If toxicity worsens, then treat as Grade 3.                                                                                                                                                                                      |                                                                                                                                                       |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 |
|                                                                                                                                                                                                                                                             | If toxicity improves to Grade ≤1 or baseline, then resume drug/study regimen after completion of steroid taper.                                                                                                                  | −                                                                                                                                                     | If no improvement of rash/skin lesions occurs within 3 to 5 days or is worsening despite symptomatic treatment and/or use of moderate strength topical steroid, consider, as necessary, discussing with study physician and promptly start systemic steroids such as prednisone 1 to 2 mg/kg/day PO or IV equivalent. If > 30% body surface area is involved, consider initiation of systemic steroids promptly. − Consider skin biopsy if the event is persistent for >1 to 2 weeks or recurs. |
| Grade 3 or 4                                                                                                                                                                                                                                                 | For Grade 3:                                                                                                                                                                                                                     | For Grade 3 or 4 (or life-threatening): − Consult Dermatology.                                                                                        |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 |
| Hold study drug/study regimen until resolution to Grade ≤1 or baseline.                                                                                                                                                                                      | −                                                                                                                                                                                                                                | Promptly initiate empiric IV methylprednisolone 1 to 4 mg/kg/day or equivalent. − Consider hospitalization. − Monitor extent of rash [Rule of Nines]. |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 |
| −                                                                                                                                                                                                                                                            | Consider skin biopsy (preferably more than 1) as clinically feasible.                                                                                                                                                            |                                                                                                                                                       |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 |
| −                                                                                                                                                                                                                                                            | Once the patient is improving, gradually taper steroids over ≥28 days and consider prophylactic antibiotics, antifungals, and anti-PJP treatment (refer to current NCCN guidelines for treatment of cancer-related infections).a |                                                                                                                                                       |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 |
| −                                                                                                                                                                                                                                                            | Consider, as necessary, discussing with study physician.                                                                                                                                                                         |                                                                                                                                                       |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 |
| If temporarily holding the study                                                                                                                                                                                                                             |                                                                                                                                                                                                                                  |                                                                                                                                                       |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 |
| drug/study regimen does not provide improvement of the Grade 3 skin rash to Grade ≤1 or baseline within 30 days, then permanently discontinue study drug/study regimen. For Grade 4 (or life-threatening): Permanently discontinue study drug/study regimen. |                                                                                                                                                                                                                                  |                                                                                                                                                       |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 |
| Endocrinopathy                                                                                                                                                                                                                                               | Any Grade                                                                                                                                                                                                                        | General Guidance                                                                                                                                      | For Any Grade:                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  |
| −                                                                                                                                                                                                                                                            | Consider consulting an endocrinologist for endocrine events.                                                                                                                                                                     |                                                                                                                                                       |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 |
| −                                                                                                                                                                                                                                                            | Consider, as necessary, discussing with study physician.                                                                                                                                                                         |                                                                                                                                                       |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 |
| −                                                                                                                                                                                                                                                            | Monitor patients for signs and symptoms of endocrinopathies. Non-specific symptoms include headache, fatigue, behavior changes, changed mental status, vertigo, abdominal pain,                                                  |                                                                                                                                                       |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 |
| (e.g., hyperthyroidism, thyroiditis, hypothyroidism, Type 1 diabetes mellitus,                                                                                                                                                                               | (depending on the type of endocrinopathy, refer to NCI CTCAE                                                                                                                                                                     | Page 88 of 102                                                                                                                                        |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 |  
Drug
(MEDI4736) Study Number ESR-18-14261  
| Edition Number V2.0 Date 9/21/2021 hypophysitis,                                                 | v5.0 for defining the                                                                                                                                                                                                                               |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         |
|--------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| hypopituitarism, and                                                                             | CTC grade/severity)                                                                                                                                                                                                                                 |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         |
| adrenal insufficiency; exocrine event of amylase/lipase increased also included in this section) | unusual bowel habits, polydipsia, polyuria, hypotension, and weakness.                                                                                                                                                                              |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         |
| −                                                                                                | Patients should be thoroughly evaluated to rule out any                                                                                                                                                                                             |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         |
| alternative etiology (e.g., disease progression including brain metastases, or infections).      |                                                                                                                                                                                                                                                     |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         |
| −                                                                                                | Depending on the suspected endocrinopathy, monitor and evaluate thyroid function tests: TSH, free T3 and free T4 and other relevant endocrine and related labs (e.g., blood glucose and ketone levels, HgA1c).                                      |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         |
| −                                                                                                | For asymptomatic elevations in serum amylase and lipase >ULN and <3×ULN, corticosteroid treatment is not indicated as long as there are no other signs or symptoms of pancreatic inflammation.                                                      |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         |
| −                                                                                                | If a patient experiences an AE that is thought to be possibly of autoimmune nature (e.g., thyroiditis, pancreatitis, hypophysitis, or diabetes insipidus), the investigator should send a blood sample for appropriate autoimmune antibody testing. |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         |
| Grade 1                                                                                          | No dose modifications.                                                                                                                                                                                                                              | For Grade 1 (including those with asymptomatic TSH elevation): − Monitor patient with appropriate endocrine function tests. − For suspected hypophysitis/hypopituitarism, consider consultation of an endocrinologist to guide assessment of early-morning ACTH, cortisol, TSH and free T4; also consider gonadotropins, sex hormones, and prolactin levels, as well as cosyntropin stimulation test (though it may not be useful in diagnosing early secondary adrenal insufficiency). − If TSH < 0.5 × LLN, or TSH >2 × ULN, or consistently out of range in 2 subsequent measurements, include free T4 at subsequent cycles as clinically indicated and consider consultation of an endocrinologist. |
| Grade 2                                                                                          | For Grade 2 endocrinopathy other than hypothyroidism and Type 1 diabetes mellitus, hold study drug/study regimen dose until patient is clinically stable.                                                                                           | For Grade 2 (including those with symptomatic endocrinopathy): − Consult endocrinologist to guide evaluation of endocrine function and, as indicated by suspected endocrinopathy and as clinically indicated, consider pituitary scan.                                                                                                                                                                                                                                                                                                                                                                                                                                                                  |
| Page 89 of 102                                                                                   |                                                                                                                                                                                                                                                     |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         |  
Drug
(MEDI4736) Study Number  
| ESR-18-14261 Edition Number V2.0 Date 9/21/2021                                                                                                                                                                                                                                                                                                                                                                                                                              | −                                                                                                                                                                          | For all patients with abnormal endocrine work up, except those with isolated hypothyroidism or Type 1 DM, and as guided by an endocrinologist, consider short-term corticosteroids (e.g., 1 to 2 mg/kg/day methylprednisolone or IV equivalent) and prompt initiation of treatment with relevant hormone replacement (e.g., hydrocortisone, sex hormones).   |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| −                                                                                                                                                                                                                                                                                                                                                                                                                                                                            | Isolated hypothyroidism may be treated with replacement therapy, without study drug/study regimen interruption, and without corticosteroids.                               |                                                                                                                                                                                                                                                                                                                                                              |
| −                                                                                                                                                                                                                                                                                                                                                                                                                                                                            | Isolated Type 1 diabetes mellitus (DM) may be treated with appropriate diabetic therapy, without study drug/study regimen interruption, and without corticosteroids.       |                                                                                                                                                                                                                                                                                                                                                              |
| −                                                                                                                                                                                                                                                                                                                                                                                                                                                                            | Once patients on steroids are improving, gradually taper immunosuppressive steroids (as appropriate and with guidance of endocrinologist) over ≥28 days and consider prophylactic antibiotics, antifungals, and anti-PJP treatment (refer to current NCCN guidelines for treatment of cancerrelated infections).a                                                                                                                                                                            |                                                                                                                                                                                                                                                                                                                                                              |
| −                                                                                                                                                                                                                                                                                                                                                                                                                                                                            | For patients with normal endocrine workup (laboratory                                                                                                                      |                                                                                                                                                                                                                                                                                                                                                              |
| assessment or MRI scans), repeat laboratory assessments/MRI as clinically indicated.                                                                                                                                                                                                                                                                                                                                                                                         |                                                                                                                                                                            |                                                                                                                                                                                                                                                                                                                                                              |
|                                                                                                                                                                                                                                                                                                                                                                                                                                                                             | If toxicity worsens, then treat as Grade 3 or Grade 4.                                                                                                                     |                                                                                                                                                                                                                                                                                                                                                              |
| Study drug/study regimen can be                                                                                                                                                                                                                                                                                                                                                                                                                                              |                                                                                                                                                                            |                                                                                                                                                                                                                                                                                                                                                              |
| resumed once event stabilizes and after completion of steroid taper. Patients with endocrinopathies who may require prolonged or continued steroid replacement (e.g., adrenal insufficiency) can be retreated with study drug/study regimen on the following conditions: 1. The event stabilizes and is controlled. 2. The patient is clinically stable as per investigator or treating physician's clinical judgement. 3. Doses of prednisone are ≤10 mg/day or equivalent. |                                                                                                                                                                            |                                                                                                                                                                                                                                                                                                                                                              |
| Grade 3 or 4                                                                                                                                                                                                                                                                                                                                                                                                                                                                 | For Grade 3 or 4 endocrinopathy other than hypothyroidism and Type 1 diabetes mellitus, hold study drug/study regimen dose until endocrinopathy symptom(s) are controlled. | For Grade 3 or 4:                                                                                                                                                                                                                                                                                                                                            |
| −                                                                                                                                                                                                                                                                                                                                                                                                                                                                            | Consult endocrinologist to guide evaluation of endocrine                                                                                                                   |                                                                                                                                                                                                                                                                                                                                                              |
| function and, as indicated by suspected endocrinopathy and as clinically indicated, consider pituitary scan. Hospitalization recommended.                                                                                                                                                                                                                                                                                                                                    |                                                                                                                                                                            |                                                                                                                                                                                                                                                                                                                                                              |
| − For all patients with abnormal endocrine work up, except those with isolated hypothyroidism or Type 1 DM, and as guided by an endocrinologist, promptly initiate empiric IV methylprednisolone 1 to 2 mg/kg/day or equivalent, as well as relevant hormone replacement (e.g., hydrocortisone, sex hormones). − For adrenal crisis, severe dehydration, hypotension, or shock, immediately initiate IV corticosteroids with mineralocorticoid activity.                     |                                                                                                                                                                            |                                                                                                                                                                                                                                                                                                                                                              |
| Study drug/study regimen can be                                                                                                                                                                                                                                                                                                                                                                                                                                              |                                                                                                                                                                            |                                                                                                                                                                                                                                                                                                                                                              |
| resumed once event stabilizes and after completion of steroid taper. Patients with endocrinopathies who may require prolonged or continued steroid replacement (e.g., adrenal insufficiency) Page 90 of 102                                                                                                                                                                                                                                                                  |                                                                                                                                                                            |                                                                                                                                                                                                                                                                                                                                                              |  
Drug
(MEDI4736) Study Number ESR-18-14261 Edition Number **V2.0**  
| Date 9/21/2021                                                                                                                                                                                                                                                                  | −                                                                                                                                               | Isolated hypothyroidism may be treated with replacement therapy, without study drug/study regimen interruption, and without corticosteroids. − Isolated Type 1 diabetes mellitus may be treated with appropriate diabetic therapy, without study drug/study regimen interruption, and without corticosteroids. − Once patients on steroids are improving, gradually taper immunosuppressive steroids (as appropriate and with guidance of endocrinologist) over ≥28 days and consider prophylactic antibiotics, antifungals, and anti-PJP treatment (refer to current NCCN guidelines for treatment of cancerrelated infections).a                  |                |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------|------------------|----------------|
| can be retreated with study drug/study regimen on the following conditions: 1. The event stabilizes and is controlled. 2. The patient is clinically stable as per investigator or treating physician's clinical judgement. 3. Doses of prednisone are ≤10 mg/day or equivalent. |                                                                                                                                                 |                  |                |
| Neurotoxicity                                                                                                                                                                                                                                                                   | Any Grade                                                                                                                                       | General Guidance | For Any Grade: |
| −                                                                                                                                                                                                                                                                               | Patients should be evaluated to rule out any alternative etiology (e.g., disease progression, infections, metabolic syndromes, or medications). |                  |                |
| −                                                                                                                                                                                                                                                                               | Monitor patient for general symptoms (headache, nausea, vertigo, behavior change, or weakness).                                                 |                  |                |
| −                                                                                                                                                                                                                                                                               | Consider appropriate diagnostic testing (e.g., electromyogram and nerve conduction investigations).                                             |                  |                |
| −                                                                                                                                                                                                                                                                               | Perform symptomatic treatment with Neurology consult as appropriate. −                                                                          |                  |                |
| (to include but not be limited to limbic encephalitis and autonomic neuropathy, excluding Myasthenia Gravis and GuillainBarre)                                                                                                                                                                                                                                                                                 | (depending on the type of neurotoxicity, refer to NCI CTCAE v5.0 for defining the CTC grade/severity)                                           |                  |                |  
Drug
(MEDI4736) Study Number ESR-18-14261  
| Edition Number V2.0 Date 9/21/2021                                                                                                                                                                                                                                                    | Grade 1                                                                                                                                                                                                                                                                                  | No dose modifications.                                                                                           | For Grade 1:   |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------|----------------|
| −                                                                                                                                                                                                                                                                                     | See "Any Grade" recommendations above.                                                                                                                                                                                                                                                   |                                                                                                                  |                |
| −                                                                                                                                                                                                                                                                                     | Treat mild signs/symptoms as Grade 1 (e.g. loss of deep tendon reflexes or paresthesia)                                                                                                                                                                                                  |                                                                                                                  |                |
| Grade 2                                                                                                                                                                                                                                                                               | For acute motor neuropathies or neurotoxicity, hold study drug/study regimen dose until resolution to Grade ≤1.                                                                                                                                                                          | For Grade 2:                                                                                                     |                |
| −                                                                                                                                                                                                                                                                                     | Consider, as necessary, discussing with the study physician. − Obtain Neurology consult.                                                                                                                                                                                                 |                                                                                                                  |                |
| −                                                                                                                                                                                                                                                                                     | Sensory neuropathy/neuropathic pain may be managed by appropriate medications (e.g., gabapentin or duloxetine).                                                                                                                                                                          |                                                                                                                  |                |
| −                                                                                                                                                                                                                                                                                     | Promptly start systemic steroids prednisone 1 to 2 mg/kg/day PO or IV equivalent. − If no improvement within 3 to 5 days despite 1 to 2 mg/kg/day prednisone PO or IV equivalent, consider additional workup and promptly treat with additional immunosuppressive therapy (e.g., IV IG). |                                                                                                                  |                |
| For sensory neuropathy/neuropathic pain, consider holding study drug/study regimen dose until resolution to Grade ≤1. If toxicity worsens, then treat as Grade 3 or 4. Study drug/study regimen can be resumed once event improves to Grade ≤1 and after completion of steroid taper. |                                                                                                                                                                                                                                                                                          |                                                                                                                  |                |
| Grade 3 or 4                                                                                                                                                                                                                                                                          | For Grade 3:                                                                                                                                                                                                                                                                             | For Grade 3 or 4:                                                                                                |                |
| Hold study drug/study regimen dose until resolution to Grade ≤1.                                                                                                                                                                                                                      | −                                                                                                                                                                                                                                                                                        | Consider, as necessary, discussing with study physician. − Obtain Neurology consult. − Consider hospitalization. |                |
| Permanently discontinue study                                                                                                                                                                                                                                                         |                                                                                                                                                                                                                                                                                          |                                                                                                                  |                |
| drug/study regimen if Grade 3 imAE does not resolve to Grade ≤1 within 30 days.                                                                                                                                                                                                       | −                                                                                                                                                                                                                                                                                        | Promptly initiate empiric IV methylprednisolone 1 to 2 mg/kg/day or equivalent.                                  |                |
| −                                                                                                                                                                                                                                                                                     | If no improvement within 3 to 5 days despite IV                                                                                                                                                                                                                                          |                                                                                                                  |                |
| corticosteroids, consider additional workup and promptly treat with additional immunosuppressants (e.g., IV IG). − Once stable, gradually taper steroids over ≥28 days.                                                                                                               |                                                                                                                                                                                                                                                                                          |                                                                                                                  |                |
| For Grade 4:                                                                                                                                                                                                                                                                          |                                                                                                                                                                                                                                                                                          |                                                                                                                  |                |  
Page 92 of 102  
Drug
(MEDI4736) Study Number ESR-18-14261 Edition Number **V2.0**  
| Date 9/21/2021                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 | Permanently discontinue study drug/study regimen.            |                        |                |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------|------------------------|----------------|
| Peripheral neuromotor syndromes                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                | Any Grade                                                    | General Guidance       | For Any Grade: |
| The prompt diagnosis of immune-mediated peripheral neuromotor syndromes is important, since certain patients may unpredictably experience acute decompensations that can result in substantial morbidity or in the worst case, death. Special care should be taken for certain sentinel symptoms that may predict a more severe outcome, such as prominent dysphagia, rapidly progressive weakness, and signs of respiratory insufficiency or autonomic instability. − Patients should be evaluated to rule out any alternative etiology (e.g., disease progression, infections, metabolic syndromes or medications). It should be noted that the diagnosis of immune-mediated peripheral neuromotor syndromes can be particularly challenging in patients with underlying cancer, due to the multiple potential confounding effects of cancer (and its treatments) throughout the neuraxis. Given the importance of prompt and accurate diagnosis, it is essential to have a low threshold to obtain a Neurology consult. − Neurophysiologic diagnostic testing (e.g., electromyogram and nerve conduction investigations, and "repetitive stimulation" if myasthenia is suspected) are routinely indicated upon suspicion of such conditions and may be best facilitated by means of a Neurology consultation. − It is important to consider that the use of steroids as the primary treatment of Guillain-Barre is not typically considered effective. Patients requiring treatment should be started with IV IG and followed by plasmapheresis if not responsive to IV IG. | −                                                            |                        |                |
| (such as Guillain-Barre and myasthenia gravis)                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 | Grade 1                                                      | No dose modifications. | For Grade 1:   |
| −                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              | Consider, as necessary, discussing with the study physician. |                        |                |
| (Guillain-Barre [GB]: mild symptoms)                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           | Page 93 of 102                                               |                        |                |  
Drug
(MEDI4736) Study Number ESR-18-14261  
| Edition Number V2.0 Date 9/21/2021                                                                                                                                                                                                                                                                                                                                                                                                                                                      | −                                                                                                                                                                                                             | Care should be taken to monitor patients for sentinel   |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------|
| symptoms of a potential decompensation as described above. − Obtain a Neurology consult.                                                                                                                                                                                                                                                                                                                                                                                                |                                                                                                                                                                                                               |                                                         |
| (Myasthenia gravis                                                                                                                                                                                                                                                                                                                                                                                                                                                                      |                                                                                                                                                                                                               |                                                         |
| [MG]: asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated) Grade 2 (GB: moderate symptoms; limiting instrumental ADL)                                                                                                                                                                                                                                                                                                                   | Hold study drug/study regimen dose until resolution to Grade ≤1.                                                                                                                                              | For Grade 2:                                            |
| −                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       | Consider, as necessary, discussing with the study physician. − Care should be taken to monitor patients for sentinel symptoms of a potential decompensation as described above. − Obtain a Neurology consult  |                                                         |
| −                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       | Sensory neuropathy/neuropathic pain may be managed by appropriate medications (e.g., gabapentin or duloxetine).                                                                                               |                                                         |
| Permanently discontinue study                                                                                                                                                                                                                                                                                                                                                                                                                                                           |                                                                                                                                                                                                               |                                                         |
| drug/study regimen if it does not resolve to Grade ≤1 within 30 days or if there are signs of respiratory insufficiency or autonomic instability.                                                                                                                                                                                                                                                                                                                                       |                                                                                                                                                                                                               |                                                         |
| (MG: moderate; minimal, local or noninvasive                                                                                                                                                                                                                                                                                                                                                                                                                                            |                                                                                                                                                                                                               |                                                         |
| intervention indicated; limiting ageappropriate instrumental ADL)                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         | MYASTHENIA GRAVIS:                                                                                                                                                                                            |                                                         |
| o                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       | Steroids may be successfully used to treat                                                                                                                                                                    |                                                         |
| myasthenia gravis. It is important to consider that steroid therapy (especially with high doses) may result in transient worsening of myasthenia and should typically be administered in a monitored setting under supervision of a consulting neurologist. o Patients unable to tolerate steroids may be candidates for treatment with plasmapheresis or IV IG. Such decisions are best made in consultation with a neurologist, taking into account the unique needs of each patient. |                                                                                                                                                                                                               |                                                         |
| o                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       | If myasthenia gravis-like neurotoxicity is present, consider starting AChE inhibitor therapy in addition to steroids. Such therapy, if successful, can also serve to reinforce the diagnosis. GUILLAIN-BARRE: |                                                         |  
Page 94 of 102  
Drug
(MEDI4736) Study Number ESR-18-14261 Edition Number **V2.0**  
| Date 9/21/2021                                                                                                                                                                                                                                             | o                                                                                                                                                                         | It is important to consider here that the use of                                                                                                                                               |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| steroids as the primary treatment of Guillain-Barre is not typically considered effective.                                                                                                                                                                 |                                                                                                                                                                           |                                                                                                                                                                                                |
| o                                                                                                                                                                                                                                                          | Patients requiring treatment should be started with IV IG and followed by plasmapheresis if not responsive to IV IG.                                                      |                                                                                                                                                                                                |
| Grade 3 or 4                                                                                                                                                                                                                                               |                                                                                                                                                                           |                                                                                                                                                                                                |
| (Grade 3 GB: severe symptoms; limiting self care ADL;                                                                                                                                                                                                      | For Grade 3:                                                                                                                                                              | For Grade 3 or 4 (severe or life-threatening events): − Consider, as necessary, discussing with study physician. − Recommend hospitalization. − Monitor symptoms and obtain Neurology consult. |
| Hold study drug/study regimen dose until resolution to Grade ≤1. Permanently discontinue study drug/study regimen if Grade 3 imAE does not resolve to Grade ≤1 within 30 days or if there are signs of respiratory insufficiency or autonomic instability. |                                                                                                                                                                           |                                                                                                                                                                                                |
| Grade 4 GB: lifethreatening consequences; urgent intervention indicated; intubation)                                                                                                                                                                                                                                                            | MYASTHENIA GRAVIS:                                                                                                                                                        |                                                                                                                                                                                                |
| o                                                                                                                                                                                                                                                          | Steroids may be successfully used to treat myasthenia gravis. They should typically be administered in a monitored setting under supervision of a consulting neurologist. |                                                                                                                                                                                                |
| o                                                                                                                                                                                                                                                          | Patients unable to tolerate steroids may be                                                                                                                               |                                                                                                                                                                                                |
| candidates for treatment with plasmapheresis or IV IG.                                                                                                                                                                                                     |                                                                                                                                                                           |                                                                                                                                                                                                |
| o                                                                                                                                                                                                                                                          | If myasthenia gravis-like neurotoxicity present,                                                                                                                          |                                                                                                                                                                                                |
| consider starting AChE inhibitor therapy in addition to steroids. Such therapy, if successful, can also serve to reinforce the diagnosis.                                                                                                                  |                                                                                                                                                                           |                                                                                                                                                                                                |
| (Grade 3 MG: severe or medically significant but not immediately life-threatening; hospitalization or prolongation of existing hospitalization indicated; limiting self care ADL; Grade 4 MG: lifethreatening consequences; urgent intervention indicated)                                                                                                                                                                                                                                                            | For Grade 4:                                                                                                                                                              |                                                                                                                                                                                                |
| Permanently discontinue study drug/study regimen.                                                                                                                                                                                                          | GUILLAIN-BARRE:                                                                                                                                                           |                                                                                                                                                                                                |
| o                                                                                                                                                                                                                                                          | It is important to consider here that the use of                                                                                                                          |                                                                                                                                                                                                |
| steroids as the primary treatment of Guillain-Barre is not typically considered effective.                                                                                                                                                                 |                                                                                                                                                                           |                                                                                                                                                                                                |
| o                                                                                                                                                                                                                                                          | Patients requiring treatment should be started with IV IG and followed by plasmapheresis if not responsive to IV IG.                                                      |                                                                                                                                                                                                |  
Drug
(MEDI4736) Study Number  
| ESR-18-14261 Edition Number V2.0 Date 9/21/2021 Myocarditis   | Any Grade                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   | General Guidance                                                                                                                                               | For Any Grade:   |
|---------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------|
| Discontinue drug permanently if biopsyproven immune-mediated myocarditis.                                                               | −                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           | The prompt diagnosis of immune-mediated myocarditis is important, particularly in patients with baseline cardiopulmonary disease and reduced cardiac function. |                  |
| −                                                             | Consider, as necessary, discussing with the study physician.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                |                                                                                                                                                                |                  |
| −                                                             | Monitor patients for signs and symptoms of myocarditis (new onset or worsening chest pain, arrhythmia, shortness of breath, peripheral edema). As some symptoms can overlap with lung toxicities, simultaneously evaluate for and rule out pulmonary toxicity as well as other causes (e.g., pulmonary embolism, congestive heart failure, malignant pericardial effusion). A Cardiology consultation should be obtained early, with prompt assessment of whether and when to complete a cardiac biopsy, including any other diagnostic procedures. − Initial work-up should include clinical evaluation, BNP, cardiac enzymes, ECG, echocardiogram (ECHO), monitoring of oxygenation via pulse oximetry (resting and exertion), and additional laboratory work-up as indicated. Spiral CT or cardiac MRI can complement ECHO to assess wall motion abnormalities when needed. − Patients should be thoroughly evaluated to rule out any alternative etiology (e.g., disease progression, other medications, or infections) |                                                                                                                                                                |                  |  
Drug
(MEDI4736) Study Number ESR-18-14261 Edition Number **V2.0**  
| Date 9/21/2021                                                                                         | Grade 1                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          | No dose modifications required unless clinical suspicion is high, in which case hold study drug/study regimen dose during diagnostic work-up for other etiologies. If study drug/study regimen is held, resume after complete resolution to Grade 0.   | For Grade 1 (no definitive findings):   |
|--------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------|
| (asymptomatic or mild symptoms*; clinical or diagnostic observations only; intervention not indicated) | -                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                | Monitor and closely follow up in 2 to 4 days for clinical symptoms, BNP, cardiac enzymes, ECG, ECHO, pulse oximetry (resting and exertion), and laboratory work-up as clinically indicated. - Consider using steroids if clinical suspicion is high.   |                                         |
| *Treat myocarditis with mild symptoms as Grade 2. Grade 2, 3 or 4                                      | - If Grade 2 -- Hold study drug/study regimen dose until resolution to Grade 0. If toxicity rapidly improves to Grade 0, then the decision to reinitiate study drug/study regimen will be based upon treating physician's clinical judgment and after completion of steroid taper. If toxicity does not rapidly improve, permanently. discontinue study drug/study regimen.                                                                                                                                                                                      | For Grade 2-4:                                                                                                                                                                                                                                         |                                         |
| −                                                                                                      | Monitor symptoms daily, hospitalize.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             |                                                                                                                                                                                                                                                        |                                         |
| −                                                                                                      | Promptly start IV methylprednisolone 2 to 4 mg/kg/day or equivalent after Cardiology consultation has determined whether and when to complete diagnostic procedures including a cardiac biopsy. − Supportive care (e.g., oxygen). − If no improvement within 3 to 5 days despite IV methylprednisolone at 2 to 4 mg/kg/day, promptly start immunosuppressive therapy such as TNF inhibitors (e.g., infliximab at 5 mg/kg every 2 weeks). Caution: It is important to rule out sepsis and refer to infliximab label for general guidance before using infliximab. |                                                                                                                                                                                                                                                        |                                         |
| −                                                                                                      | Once the patient is improving, gradually taper steroids over ≥28 days and consider prophylactic antibiotics, antifungals, or anti-PJP treatment (refer to current NCCN guidelines for treatment of cancer-related infections).a                                                                                                                                                                                                                                                                                                                                  |                                                                                                                                                                                                                                                        |                                         |
| (Grade 2: Symptoms with moderate activity or exertion) (Grade 3: Severe with symptoms at rest or with minimal activity or exertion; intervention indicated; new onset of symptoms*) (Grade 4: Lifethreatening conse                                                                                                        | If Grade 3-4, permanently discontinue                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            |                                                                                                                                                                                                                                                        |                                         |
| quences; urgent                                                                                        | study drug/study regimen.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        |                                                                                                                                                                                                                                                        |                                         |
| intervention indicated (e.g., continuous IV therapy or mechanical hemodynamic support))                |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  |                                                                                                                                                                                                                                                        |                                         |  
Drug
(MEDI4736) Study Number ESR-18-14261 Edition Number **V2.0**  
| Date 9/21/2021        | * Consider "new onset of symptoms" as referring to patients with prior episode of myocarditis.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   |                |
|-----------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------|
| Myositis/Polymyositis | Any Grade                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           | General Guidance                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  | For Any Grade: |
| ("Poly/myositis")     | −                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   | Monitor patients for signs and symptoms of poly/myositis. Typically, muscle weakness/pain occurs in proximal muscles including upper arms, thighs, shoulders, hips, neck and back, but rarely affects the extremities including hands and fingers; also difficulty breathing and/or trouble swallowing can occur and progress rapidly. Increased general feelings of tiredness and fatigue may occur, and there can be new-onset falling, difficulty getting up from a fall, and trouble climbing stairs, standing up from a seated position, and/or reaching up. |                |
| −                     | If poly/myositis is suspected, a Neurology consultation should be obtained early, with prompt guidance on diagnostic procedures. Myocarditis may co-occur with poly/myositis; refer to guidance under Myocarditis. Given breathing complications, refer to guidance under Pneumonitis/ILD. Given possibility of an existent (but previously unknown) autoimmune disorder, consider Rheumatology consultation.                                                                                                                                                                                                                       |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   |                |
| −                     | Consider, as necessary, discussing with the study physician.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   |                |
| −                     | Initial work-up should include clinical evaluation, creatine kinase, aldolase, LDH, BUN/creatinine, erythrocyte sedimentation rate or C-reactive protein level, urine myoglobin, and additional laboratory work-up as indicated, including a number of possible rheumatological/antibody tests (i.e., consider whether a rheumatologist consultation is indicated and could guide need for rheumatoid factor, antinuclear antibody, anti-smooth muscle, antisynthetase [such as anti-Jo-1], and/or signal-recognition particle antibodies). Confirmatory testing may include electromyography, nerve conduction studies, MRI of the |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   |                |  
Page 98 of 102  
Drug
(MEDI4736) Study Number ESR-18-14261 Edition Number **V2.0**  
| Date 9/21/2021                                                                                                                              | muscles, and/or a muscle biopsy. Consider Barium swallow for evaluation of dysphagia or dysphonia.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              |                                                                                                                                                   |
|---------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------|
| Patients should be thoroughly evaluated to rule out any alternative etiology (e.g., disease progression, other medications, or infections). |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 |                                                                                                                                                   |
| Grade 1                                                                                                                                     | - No dose modifications.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        | For Grade 1:                                                                                                                                      |
| (mild pain)                                                                                                                                 | −                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               | Monitor and closely follow up in 2 to 4 days for clinical symptoms and initiate evaluation as clinically indicated. − Consider Neurology consult. |
| −                                                                                                                                           | Consider, as necessary, discussing with the study physician.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    |                                                                                                                                                   |
| Grade 2                                                                                                                                     | Hold study drug/study regimen dose until resolution to Grade ≤1.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                | For Grade 2:                                                                                                                                      |
| −                                                                                                                                           | Monitor symptoms daily and consider hospitalization.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            |                                                                                                                                                   |
| −                                                                                                                                           | Obtain Neurology consult, and initiate evaluation.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              |                                                                                                                                                   |
| −                                                                                                                                           | Consider, as necessary, discussing with the study physician. − If clinical course is rapidly progressive (particularly if difficulty breathing and/or trouble swallowing), promptly start IV methylprednisolone 2 to 4 mg/kg/day systemic steroids along with receiving input from Neurology consultant − If clinical course is not rapidly progressive, start systemic steroids (e.g., prednisone 1 to 2 mg/kg/day PO or IV equivalent); if no improvement within 3 to 5 days, continue additional work up and start treatment with IV methylprednisolone 2 to 4 mg/kg/day − If after start of IV methylprednisolone at 2 to 4 mg/kg/day there is no improvement within 3 to 5 days, consider start of immunosuppressive therapy such as TNF inhibitors (e.g., infliximab at 5 mg/kg every 2 weeks). Caution: It is important to rule out sepsis and refer to infliximab label for general guidance before using infliximab. − Once the patient is improving, gradually taper steroids over ≥28 days and consider prophylactic antibiotics, antifungals, or anti-PJP treatment (refer to current NCCN guidelines for treatment of cancer-related infections).a |                                                                                                                                                   |
| (moderate pain associated with                                                                                                              |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 |                                                                                                                                                   |
| weakness; pain limiting instrumental activities of daily living [ADLs])                                                                     | - Permanently discontinue study drug/study regimen if it does not resolve to Grade ≤1 within 30 days or if there are signs of respiratory insufficiency.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        |                                                                                                                                                   |  
Page 99 of 102  
Drug
(MEDI4736) Study Number ESR-18-14261 Edition Number **V2.0**  
| Grade 3 or 4                                                                                                                       | For Grade 3:                                                                                                                                                                                                                                                                                                                                    | For Grade 3 or 4 (severe or life-threatening events):   |                                                      |
|------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------|------------------------------------------------------|
| (Grade 3: pain                                                                                                                     |                                                                                                                                                                                                                                                                                                                                                 |                                                         |                                                      |
| associated with severe weakness; limiting self-care ADLs                                                                           | Hold study drug/study regimen dose until resolution to Grade ≤1.                                                                                                                                                                                                                                                                                | −                                                       | Monitor symptoms closely; recommend hospitalization. |
| −                                                                                                                                  | Obtain Neurology consult, and complete full evaluation.                                                                                                                                                                                                                                                                                         |                                                         |                                                      |
| −                                                                                                                                  | Consider, as necessary, discussing with the study physician.                                                                                                                                                                                                                                                                                    |                                                         |                                                      |
| −                                                                                                                                  | Promptly start IV methylprednisolone 2 to 4 mg/kg/day                                                                                                                                                                                                                                                                                           |                                                         |                                                      |
| systemic steroids along with receiving input from Neurology consultant.                                                            |                                                                                                                                                                                                                                                                                                                                                 |                                                         |                                                      |
| −                                                                                                                                  | If after start of IV methylprednisolone at 2 to 4 mg/kg/day there is no improvement within 3 to 5 days, consider start of immunosuppressive therapy such as TNF inhibitors (e.g., infliximab at 5 mg/kg every 2 weeks). Caution: It is important to rule out sepsis and refer to infliximab label for general guidance before using infliximab. |                                                         |                                                      |
| −                                                                                                                                  | Consider whether patient may require IV IG, plasmapheresis.                                                                                                                                                                                                                                                                                     |                                                         |                                                      |
| −                                                                                                                                  | Once the patient is improving, gradually taper steroids over ≥28 days and consider prophylactic antibiotics, antifungals, or anti-PJP treatment (refer to current NCCN guidelines for treatment of cancer-related infections).a                                                                                                                 |                                                         |                                                      |
| Permanently discontinue study                                                                                                      |                                                                                                                                                                                                                                                                                                                                                 |                                                         |                                                      |
| drug/study regimen if Grade 3 imAE does not resolve to Grade ≤1 within 30 days or if there are signs of respiratory insufficiency. |                                                                                                                                                                                                                                                                                                                                                 |                                                         |                                                      |
| Grade 4: lifethreatening                                                                                                                                    |                                                                                                                                                                                                                                                                                                                                                 |                                                         |                                                      |
| consequences; urgent intervention indicated)                                                                                       | For Grade 4:                                                                                                                                                                                                                                                                                                                                    |                                                         |                                                      |
| - Permanently discontinue study drug/study regimen.                                                                                |                                                                                                                                                                                                                                                                                                                                                 |                                                         |                                                      |  
aASCO Educational Book 2015 "Managing Immune Checkpoint Blocking Antibody Side Effects" by Michael Postow MD.  
bFDA Liver Guidance Document 2009 Guidance for Industry: Drug Induced Liver Injury - Premarketing Clinical Evaluation.  
AChE Acetylcholine esterase; ADL Activities of daily living; AE Adverse event; ALP Alkaline phosphatase test; ALT Alanine aminotransferase; AST Aspartate aminotransferase; BUN Blood urea nitrogen; CT Computed tomography; CTCAE Common Terminology Criteria for Adverse Events; ILD Interstitial lung disease; imAE immune-mediated adverse event; IG Immunoglobulin; IV Intravenous; GI Gastrointestinal; LFT Liver function tests; LLN Lower limit of normal; MRI Magnetic resonance imaging; NCI National Cancer Institute; NCCN National Comprehensive Cancer Network; PJP Pneumocystis *jirovecii* pneumonia (formerly known as Pneumocystis *carinii* pneumonia); PO By mouth; T3 Triiodothyronine; T4 Thyroxine; TB Total bilirubin; TNF Tumor necrosis factor; TSH Thyroid-stimulating hormone; ULN Upper limit of normal.  
Drug
(MEDI4736) Study Number ESR-18-14261 Edition Number **V2.0**  
| Date 9/21/2021                                                                                                                                                                                                                                                                                                                                   | Infusion-Related Reactions                                                                                                                                                                               |                     |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------|
| Severity Grade of the Event (NCI CTCAE version 5.0)                                                                                                                                                                                                                                                                                              | Dose Modifications                                                                                                                                                                                       | Toxicity Management |
| Any Grade                                                                                                                                                                                                                                                                                                                                        | General Guidance                                                                                                                                                                                         | For Any Grade:      |
| −                                                                                                                                                                                                                                                                                                                                                | Manage per institutional standard at the discretion of investigator.                                                                                                                                     |                     |
| −                                                                                                                                                                                                                                                                                                                                                | Monitor patients for signs and symptoms of infusion-related                                                                                                                                              |                     |
| reactions (e.g., fever and/or shaking chills, flushing and/or itching, alterations in heart rate and blood pressure, dyspnea or chest discomfort, or skin rashes) and anaphylaxis (e.g., generalized urticaria, angioedema, wheezing, hypotension, or tachycardia).                                                                              |                                                                                                                                                                                                          |                     |
| Grade 1 or 2                                                                                                                                                                                                                                                                                                                                     | For Grade 1:                                                                                                                                                                                             | For Grade 1 or 2:   |
| −                                                                                                                                                                                                                                                                                                                                                | Acetaminophen and/or antihistamines may be administered per institutional standard at the discretion of the investigator. − Consider premedication per institutional standard prior to subsequent doses. |                     |
| −                                                                                                                                                                                                                                                                                                                                                | Steroids should not be used for routine premedication of Grade ≤2 infusion reactions.                                                                                                                    |                     |
| The infusion rate of study drug/study regimen may be decreased by 50% or temporarily interrupted until resolution of the event. For Grade 2: The infusion rate of study drug/study regimen may be decreased 50% or temporarily interrupted until resolution of the event. Subsequent infusions may be given at 50% of the initial infusion rate. |                                                                                                                                                                                                          |                     |
| Grade 3 or 4                                                                                                                                                                                                                                                                                                                                     | For Grade 3 or 4:                                                                                                                                                                                        | For Grade 3 or 4:   |
| −                                                                                                                                                                                                                                                                                                                                                | Manage severe infusion-related reactions per institutional                                                                                                                                               |                     |
| standards (e.g., IM epinephrine, followed by IV diphenhydramine and ranitidine, and IV glucocorticoid).                                                                                                                                                                                                                                          |                                                                                                                                                                                                          |                     |
| Permanently discontinue study drug/study regimen.                                                                                                                                                                                                                                                                                                |                                                                                                                                                                                                          |                     |
| CTCAE Common Terminology Criteria for Adverse Events; IM intramuscular; IV intravenous; NCI National Cancer Institute.                                                                                                                                                                                                                           |                                                                                                                                                                                                          |                     |  
Drug
(MEDI4736) Study Number ESR-18-14261 Edition Number **V2.0**  
| Non–Immune-Mediated Reactions                                                                                                                                         |                                                                                                                                                                                                                                                                              |                                                   |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------|
| Severity Grade of the Event (NCI CTCAE version 5.0)                                                                                                                   | Dose Modifications                                                                                                                                                                                                                                                           | Toxicity Management                               |
| Any Grade                                                                                                                                                             | Note: Dose modifications are not required for AEs not deemed to be related to study treatment (i.e., events due to underlying disease) or for laboratory abnormalities not deemed to be clinically significant.                                                              | Treat accordingly, as per institutional standard. |
| Grade 1                                                                                                                                                               | No dose modifications.                                                                                                                                                                                                                                                       | Treat accordingly, as per institutional standard. |
| Grade 2                                                                                                                                                               | Hold study drug/study regimen until resolution to ≤Grade 1 or                                                                                                                                                                                                                | Treat accordingly, as per institutional standard. |
| baseline.                                                                                                                                                             |                                                                                                                                                                                                                                                                              |                                                   |
| Grade 3                                                                                                                                                               | Hold study drug/study regimen until resolution to ≤Grade 1 or baseline. For AEs that downgrade to ≤Grade 2 within 7 days or resolve to ≤Grade 1 or baseline within 14 days, resume study drug/study regimen administration. Otherwise, discontinue study drug/study regimen. | Treat accordingly, as per institutional standard. |
| Grade 4                                                                                                                                                               | Discontinue study drug/study regimen (Note: For Grade 4 labs, decision to discontinue should be based on accompanying clinical signs/symptoms, the Investigator's clinical judgment, and consultation with the Sponsor.).                                                    | Treat accordingly, as per institutional standard. |
| Note: As applicable, for early phase studies, the following sentence may be added: "Any event greater than or equal to Grade 2, please discuss with Study Physician." |                                                                                                                                                                                                                                                                              |                                                   |  
Note: As applicable, for early phase studies, the following sentence may be added: "Any event greater than or equal to Grade 2, please discuss with Study Physician."  
AE Adverse event; CTCAE Common Terminology Criteria for Adverse Events; NCI National Cancer Institute.