untitled h1
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 steroid dosing (i.e., mg/kg/day) provided for adult  patients should also be used for pediatric patients.                                                                                             |
| −                                                                                                                                                                                                                                                                                                                                                                                                     | The recommendations for intravenous immunoglobulin (IVIG) and  plasmapheresis use provided for adult patients may be considered for  pediatric patients.                                                                      |
| −                                                                                                                                                                                                                                                                                                                                                                                                     | The infliximab 5 mg/kg IV one time dose recommended for adults is the  same as recommended for pediatric patients ≥ 6 years old. For subsequent  dosing and dosing in children < 6 years old, consult a pediatric specialist. |
| −                                                                                                                                                                                                                                                                                                                                                                                                     | For pediatric dosing of mycophenolate mofetil, consult 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  CTCAE 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 initiating corticosteroids. |                                                                                                                                                                                                                               |  
| Specific Immune-Mediated Reactions                                                                  |                                                                                                                                                                                                                                                                             |                                                                                                                                                           |                     |
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| Adverse Events                                                                                      | Severity Grade of the  Event                                                                                                                                                                                                                                                | Dose Modifications                                                                                                                                        | Toxicity Management |
| Pneumonitis/Interstitial  Lung Disease (ILD)                                                        | Any Grade                                                                                                                                                                                                                                                                   | General Guidance                                                                                                                                          | For Any Grade       |
| (Refer to NCI CTCAE  applicable version in  study protocol for  defining the CTCAE  grade/severity) | −                                                                                                                                                                                                                                                                           | Patients should be thoroughly evaluated to  rule out any alternative etiology with similar  clinical presentation (e.g. infection,  progressive disease). |                     |
| −                                                                                                   | Monitor patients for signs (e.g. tachypnoea)  and symptoms of pneumonitis or ILD (new  onset or worsening shortness of breath or  cough). Evaluate patients with imaging and  pulmonary function tests, including other  diagnostic procedures as described below.          |                                                                                                                                                           |                     |
| −                                                                                                   | Suspected pneumonitis should be confirmed  with radiographic imaging and other  infectious and disease-related etiologies  excluded, and managed as described below.                                                                                                        |                                                                                                                                                           |                     |
| −                                                                                                   | Initial work-up may include clinical  evaluation, monitoring of oxygenation via  pulse oximetry (resting and exertion),  laboratory work-up (including clinically  relevant culture specimens to rule out  infection), and high- resolution computed  tomography (CT) scan. |                                                                                                                                                           |                     |
| −                                                                                                   | Consider Pulmonary and Infectious Diseases  consults.                                                                                                                                                                                                                       |                                                                                                                                                           |                     |
| Grade 1                                                                                             | No dose modifications required. However, consider holding  study drug/study regimen dose as clinically appropriate and  during diagnostic work-up for other etiologies.                                                                                                     | For Grade 1                                                                                                                                               |                     |
| −                                                                                                   | Monitor and closely follow up in 2 to 4 days  for clinical symptoms, pulse oximetry  (resting and exertion), and laboratory workup, and then as clinically indicated.                                                                                                                                                                                                                                                                             |                                                                                                                                                           |                     |
| Grade 2                                                                                             | Hold study drug/study regimen dose until Grade 2 resolution to  Grade ≤1.  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                                | For Grade 2                                                                                                                                               |                     |
| −                                                                                                   | Monitor symptoms daily and consider  hospitalization as clinically indicated.                                                                                                                                                                                               |                                                                                                                                                           |                     |  
| completion of steroid taper (<10 mg prednisone or   | −                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         | Consider Pulmonary and Infectious Diseases   |
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| equivalent).                                        | Consults.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 |                                              |
| −                                                   | Promptly start systemic steroids (e.g.,  prednisone 1 to 2 mg/kg/day PO or IV  equivalent).                                                                                                                                                                                                                                                                                                                                                                                               |                                              |
| −                                                   | Consider HRCT or chest CT with contrast,  Repeat imaging as clinically indicated.                                                                                                                                                                                                                                                                                                                                                                                                         |                                              |
| −                                                   | If no improvement within 2 to 3 days,  additional workup should be considered and  prompt treatment with IV  methylprednisolone 2 to 4 mg/kg/day  started.                                                                                                                                                                                                                                                                                                                                |                                              |
| −                                                   | If no improvement within 2 to 3 days despite  IV methylprednisolone at 2 to 4 mg/kg/day,  promptly start immunosuppressive therapy.  such as tumor necrosis factor (TNF)  inhibitors (e.g., infliximab at 5 mg/kg IV  once, may be repeated at 2 and 6 weeks after  initial dose at the discretion of the treating  provider or relevant practice guidelines).  Caution: It is important to rule out sepsis and  refer to infliximab label for general guidance  before using infliximab. |                                              |
| −                                                   | Consider discussing with Clinical Study  Lead.                                                                                                                                                                                                                                                                                                                                                                                                                                            |                                              |
| Grade 3 or 4                                        | Permanently discontinue study drug/study regimen.                                                                                                                                                                                                                                                                                                                                                                                                                                         | For Grade 3 or 4                             |
| −                                                   | Hospitalize the patient                                                                                                                                                                                                                                                                                                                                                                                                                                                                   |                                              |
| −                                                   | Promptly initiate empiric IV  methylprednisolone 1 to 4 mg/kg/day or  equivalent.                                                                                                                                                                                                                                                                                                                                                                                                         |                                              |
| −                                                   | Obtain Pulmonary and Infectious Diseases  Consults; consider discussing with Clinical  Study Lead, as needed.                                                                                                                                                                                                                                                                                                                                                                             |                                              |
| −                                                   | Consider starting anti-infective therapy if  infection is still a consideration on the basis  of other diagnostic testing despite negative  culture results                                                                                                                                                                                                                                                                                                                               |                                              |
| −                                                   | Supportive care (e.g., oxygen).                                                                                                                                                                                                                                                                                                                                                                                                                                                           |                                              |  
| −                                                                                                   | If no improvement within 2 days, additional  workup should be considered and prompt  treatment with additional  immunosuppressive therapy such as TNF  inhibitors (e.g., infliximab at 5 mg/kg IV,  may be repeated at 2 and 6 weeks after  initial dose at the discretion of the treating  provider or relevant practice guidelines).  Caution: rule out sepsis and refer to  infliximab label for general guidance before  using infliximab.   |                                                                                                                                                                                                         |               |
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| Diarrhea/Colitis                                                                                    | Any Grade                                                                                                                                                                                                                                                                                                                                                                                                                                        | General Guidance                                                                                                                                                                                        | For Any Grade |
| (Refer to NCI CTCAE  applicable version in  study protocol for  defining the CTCAE  grade/severity) | −                                                                                                                                                                                                                                                                                                                                                                                                                                                | 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. |               |
| −                                                                                                   | 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).                                                                                                                                                                       |                                                                                                                                                                                                         |               |
| −                                                                                                   | Consider further evaluation with imaging  study with contrast.                                                                                                                                                                                                                                                                                                                                                                                   |                                                                                                                                                                                                         |               |
| −                                                                                                   | Consult a gastrointestinal (GI) specialist for  consideration of further workup                                                                                                                                                                                                                                                                                                                                                                  |                                                                                                                                                                                                         |               |
| −                                                                                                   | WHEN SYMPTOMS OR EVALUATION  INDICATE AN INTESTINAL  PERFORATION IS SUSPECTED,  CONSULT A SURGEON  EXPERIENCED IN ABDOMINAL  SURGERY IMMEDIATELY WITHOUT  ANY DELAY.                                                                                                                                                                                                                                                                             |                                                                                                                                                                                                         |               |
| −                                                                                                   | PERMANENTLY DISCONTINUE  STUDY DRUG FOR ANY GRADE OF  INTESTINAL PERFORATION.                                                                                                                                                                                                                                                                                                                                                                    |                                                                                                                                                                                                         |               |
| −                                                                                                   | Steroids should be considered in the absence  of clear alternative etiology, even for lowgrade events, in order to prevent potential                                                                                                                                                                                                                                                                                                                                                                                                                                                  |                                                                                                                                                                                                         |               |  
| progression to higher grade events, including  intestinal perforation.   |                                                                                                                                                                                                                                                                                                                                                                                                                                                    |             |
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| −                                                                        | 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), loperamide, and other  supportive care measures.                                                                                                                                                                                                                                              |             |
| −                                                                        | If symptoms persist, consider checking  lactoferrin; if positive, treat as Grade 2  below. If negative and no infection, continue  Grade 1 management.                                                                                                                                                                                                                                                                                             |             |
| Grade 2                                                                  | Hold study drug/study regimen until resolution to Grade ≤1  If toxicity improves to Grade ≤1, then study drug/study  regimen can be resumed after completion of steroid taper  (<10 mg prednisone, or equivalent).                                                                                                                                                                                                                                | For Grade 2 |
| −                                                                        | Consider symptomatic treatment, including  hydration, electrolyte replacement, dietary  changes (e.g., American Dietetic Association  colitis diet), and loperamide and/or  budesonide.                                                                                                                                                                                                                                                            |             |
| −                                                                        | Consider further evaluation with imaging  study with contrast.                                                                                                                                                                                                                                                                                                                                                                                     |             |
| −                                                                        | Consider consult of a gastrointestinal (GI)  specialist for consideration of further  workup.                                                                                                                                                                                                                                                                                                                                                      |             |
| −                                                                        | Promptly start prednisone 1 to 2 mg/kg/day  PO or IV equivalent.                                                                                                                                                                                                                                                                                                                                                                                   |             |
| −                                                                        | If no improvement within 3 days despite  therapy with 1 to 2 mg/kg IV prednisone  equivalent, reconsult GI specialist and, if  indicated, promptly start additional  immunosuppressant agent such as infliximab  at 5 mg/kg IV, may be repeated at 2 and 6  weeks after initial dose at the discretion of  the treating provider or relevant practice  guidelines. Caution: it is important to rule  out bowel perforation and refer to infliximab |             |  
| label for general guidance before using  infliximab.                                                |                                                                                                                                                                                                                                                                                                                                                                                                                       |                  |               |
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| −                                                                                                   | If perforation is suspected, consult a  surgeon experienced in abdominal  surgery immediately without any delay.                                                                                                                                                                                                                                                                                                      |                  |               |
| −                                                                                                   | Consider, as necessary, discussing with  Clinical Study Lead if no resolution to Grade  ≤1 in 3 to 4 days.                                                                                                                                                                                                                                                                                                            |                  |               |
| Grade 3 or 4                                                                                        | Grade 3                                                                                                                                                                                                                                                                                                                                                                                                               |                  |               |
|                                                                                                    | For patients treated with durvalumab monotherapy,  hold study drug/study regimen until resolution to  Grade ≤1; study drug/study regimen can be resumed  after completion of steroid taper (<10 mg prednisone  per day, or equivalent).                                                                                                                                                                               |                  |               |
|                                                                                                    | For patients treated with durvalumab in combination  with other products (not tremelimumab), decision to  be made at the discretion of the study investigator, in  discussion with AstraZeneca Clinical Study Lead.                                                                                                                                                                                                   |                  |               |
|                                                                                                    | For patients treated with durvalumab in  combination with tremelimumab or  tremelimumab monotherapy, permanently  discontinue both durvalumab and tremelimumab  for 1) Grade 3 diarrhea colitis or 2) Any grade of  intestinal perforation.                                                                                                                                                                           | For Grade 3 or 4 |               |
| −                                                                                                   | Urgent GI consult and imaging and/or  colonoscopy as appropriate.                                                                                                                                                                                                                                                                                                                                                     |                  |               |
| −                                                                                                   | Promptly initiate empiric IV  methylprednisolone 1 to 2 mg/kg/day or  equivalent.                                                                                                                                                                                                                                                                                                                                     |                  |               |
| −                                                                                                   | Monitor stool frequency and volume and  maintain hydration.                                                                                                                                                                                                                                                                                                                                                           |                  |               |
| −                                                                                                   | If still no improvement within 2 days,  continue steroids and promptly add further  immunosuppressants. (e.g., infliximab at 5  mg/kg IV, may be repeated at 2 and 6 weeks  after initial dose at the discretion of the  treating provider or relevant practice  guidelines). 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.                                                                                                                                                                                                                                                                                                      |                  |               |
| Grade 4                                                                                             |                                                                                                                                                                                                                                                                                                                                                                                                                       |                  |               |
| Permanently discontinue study drug/study regimen.                                                   |                                                                                                                                                                                                                                                                                                                                                                                                                       |                  |               |
| Hepatitis                                                                                           |                                                                                                                                                                                                                                                                                                                                                                                                                       |                  |               |
| Infliximab should not  be used for  management of  immune-related  hepatitis.                       | Any Grade                                                                                                                                                                                                                                                                                                                                                                                                             | General Guidance | For Any Grade |
| −                                                                                                   | Patients should be thoroughly evaluated to  rule out any alternative etiology (e.g., viral  hepatitis, disease progression, concomitant  medications).                                                                                                                                                                                                                                                                |                  |               |
| −                                                                                                   | Monitor and evaluate transaminases  (aspartate aminotransferase [AST], alanine  aminotransferase [ALT], alkaline  phosphatase [ALP], and total bilirubin.                                                                                                                                                                                                                                                             |                  |               |
| (Refer to NCI CTCAE  applicable version in  study protocol for  defining the CTCAE  grade/severity) |                                                                                                                                                                                                                                                                                                                                                                                                                       |                  |               |
| PLEASE SEE  shaded area                                                                             |                                                                                                                                                                                                                                                                                                                                                                                                                       |                  |               |  
PLEASE SEE shaded area immediately below this section to find guidance for management of "Hepatitis (elevated LFTS)" in hepatocellular carcinoma (HCC) patients (or secondary tumour involvement of the liver with abnormal baseline values [BLV])  
| ALT or AST ≤ 3 x  ULN or total  bilirubin ≤ 1.5 x  ULN         |                                                                                                                                                                                                                                                                                                                                                                                                                              | No dose modifications.                                                                                                                                                                                                  |                                                                                                                                          |
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|                                                               | If it worsens, then consider holding therapy.                                                                                                                                                                                                                                                                                                                                                                                 | −                                                                                                                                                                                                                       | Continue transaminase and total bilirubin  monitoring per protocol.                                                                      |
|                                                               | Hold study drug/study regimen dose until ALT or AST ≤ 3 x ULN or total bilirubin ≤ 1.5 x ULN. Resume study  drug/study regimen after completion of steroid taper (<10  mg prednisone or equivalent).                                                                                                                                                                                                                          |                                                                                                                                                                                                                         |                                                                                                                                          |
|                                                               | Permanently discontinue study drug/study regimen for any  case meeting Hy's law laboratory criteria (AST or ALT  >3 × ULN AND bilirubin >2 × ULN without initial  findings of cholestasis (i.e., elevated ALP) and in the  absence of any alternative cause.                                                                                                                                                                  | −                                                                                                                                                                                                                       | Regular and frequent checking of  transaminases and total bilirubin (e.g., every  1 to 2 days) until LFT elevations improve or  resolve. |
| −                                                              | If no resolution to ALT or AST ≤ 3 x ULN  or total bilirubin ≤ 1.5 x ULN in 1 to 2 days,  consider discussing with Clinical Study  Lead, as needed.                                                                                                                                                                                                                                                                           |                                                                                                                                                                                                                         |                                                                                                                                          |
| −                                                              | If event is persistent (>2 to 3 days) or  worsens, promptly start prednisone 1 to  2 mg/kg/day PO or IV equivalent.                                                                                                                                                                                                                                                                                                           |                                                                                                                                                                                                                         |                                                                                                                                          |
| ALT or AST > 3 ≤ 5  x ULN or total  bilirubin > 1.5 ≤ 3 x  ULN |                                                                                                                                                                                                                                                                                                                                                                                                                              | Hold study drug/study regimen . Resume study drug/study  regimen if elevations downgrade to ALT or AST ≤ 3 x  ULN or total bilirubin ≤ 1.5 x ULN after completion of  steroid taper (<10 mg prednisone, or equivalent). |                                                                                                                                          |
|                                                               | If in combination with tremelimumab, do not restart  tremelimumab.                                                                                                                                                                                                                                                                                                                                                            | −                                                                                                                                                                                                                       | Promptly initiate empiric IV  methylprednisolone at 1 to 2 mg/kg/day or  equivalent.                                                     |
| −                                                              | Perform Hepatology Consult, abdominal  workup, and imaging as appropriate                                                                                                                                                                                                                                                                                                                                                     |                                                                                                                                                                                                                         |                                                                                                                                          |
| −                                                              | If still no improvement within 2 to 3 days  despite 1 to 2 mg/kg/day methylprednisolone  IV or equivalent, promptly start treatment  with an additional immunosuppressant.(e.g.,  mycophenolate mofetil 0.5 - 1 g every 12  hours then taper in consultation with  hepatology consult or relevant practice  guidelines). Discuss with Clinical Study Lead  if mycophenolate is not available. Infliximab  should NOT be used. |                                                                                                                                                                                                                         |                                                                                                                                          |
| ALT or AST > 5-≤ 10 x ULN Concurrent ALT or                    | Permanently discontinue study drug/study regimen.                                                                                                                                                                                                                                                                                                                                                                             | −                                                                                                                                                                                                                       | Promptly initiate empiric IV  methylprednisolone at 1 to 2 mg/kg/day                                                                     |
| AST > 3 x ULN and                                              |                                                                                                                                                                                                                                                                                                                                                                                                                               |                                                                                                                                                                                                                         |                                                                                                                                          |  
| t o t a l b i l i r u b i n                                                                                                                                                                                                                                                            | or equivalent.                                                                                                                                                                                                       |                                                                                                                                                                                                                                                                                                                                                                                                                                |                              |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------|
| > 2 x U L N d                                                                                                                                                                                                                                                                          | −                                                                                                                                                                                                                    | If still no improvement within 2 to 3 days  despite 1 to 2 mg/kg/day  methylprednisolone IV or equivalent,  promptly start treatment with an  additional immunosuppressant.(e.g.,  mycophenolate mofetil 0.5 - 1 g every  12 hours then taper in consultation with  hepatology consult or relevant practice  guidelines). Discuss with Clinical Study  Lead if mycophenolate is not available.  Infliximab should NOT be used. |                              |
| −                                                                                                                                                                                                                                                                                      | Perform Hepatology Consult, abdominal  workup, and imaging as appropriate.                                                                                                                                           |                                                                                                                                                                                                                                                                                                                                                                                                                                |                              |
| A L T o r A S T                                                                                                                                                                                                                                                                        |                                                                                                                                                                                                                      |                                                                                                                                                                                                                                                                                                                                                                                                                                |                              |
| > 1 0 x U L N O R t o t a l b i l i r u b i n > 3 x U L N                                                                                                                                                                                                                              |                                                                                                                                                                                                                      |                                                                                                                                                                                                                                                                                                                                                                                                                                |                              |
| Hepatitis  (elevated  transaminases and total                                                                                                                                                                                                                                          | Any Elevations of  AST, ALT, or T. Bili  as Described Below                                                                                                                                                          | General Guidance                                                                                                                                                                                                                                                                                                                                                                                                               | For Any Elevations Described |
| −                                                                                                                                                                                                                                                                                      | Patients should be thoroughly evaluated to  rule out any alternative etiology (e.g., viral  hepatitis, disease progression, concomitant  medications, worsening of liver cirrhosis  [e.g., portal vein thrombosis]). |                                                                                                                                                                                                                                                                                                                                                                                                                                |                              |
| −                                                                                                                                                                                                                                                                                      | Monitor and evaluate liver function test:  AST, ALT, ALP, and T. Bili.                                                                                                                                               |                                                                                                                                                                                                                                                                                                                                                                                                                                |                              |
| −                                                                                                                                                                                                                                                                                      | For hepatitis B (HBV) + patients: evaluate  quantitative HBV viral load, quantitative  Hepatitis B surface antigen (HBsAg), or  Hepatitis B envelope antigen (HBeAg).                                                |                                                                                                                                                                                                                                                                                                                                                                                                                                |                              |
| −                                                                                                                                                                                                                                                                                      | For hepatitis C (HCV) + patients: evaluate  quantitative HCV viral load.                                                                                                                                             |                                                                                                                                                                                                                                                                                                                                                                                                                                |                              |
| −                                                                                                                                                                                                                                                                                      | Consider consulting Hepatology or  Infectious Diseases specialists regarding  changing or starting antiviral HBV  medications if HBV viral load is >2000  IU/ml.                                                     |                                                                                                                                                                                                                                                                                                                                                                                                                                |                              |
| −                                                                                                                                                                                                                                                                                      | Consider consulting Hepatology or  Infectious Diseases specialists regarding  changing or starting antiviral HCV  medications if HCV viral load has increased  by ≥2-fold.                                           |                                                                                                                                                                                                                                                                                                                                                                                                                                |                              |
| bilirubin) 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  patients (or  secondary tumour  involvement of the  liver with abnormal  baseline values  [BLV]) |                                                                                                                                                                                                                      |                                                                                                                                                                                                                                                                                                                                                                                                                                |                              |  
| −                                                                                                                                                                                               | For HCV+ with Hepatitis B core antibody  (HBcAb) +: Evaluate for both HBV and  HCV as above.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             |                                                                                                                                                     |                                                                                                                                                      |
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| 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 | Isolated AST or ALT                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     | No dose modifications.                                                                                                                              |                                                                                                                                                      |
| >ULN and ≤2.5 BLV                                                                                                                                                                               |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         | If ALT/AST elevations represents significant worsening  based on investigator assessment, then treat as described  for elevations in the row below. |                                                                                                                                                      |
|                                                                                                                                                                                                | 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                                                                                                                                                                                                                                                                                                                                                             |                                                                                                                                                     |                                                                                                                                                      |
| AST or ALT >2.5  BLV and ≤5×BLV and ≤ 20 ULN                                                                                                                                                    |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         | Hold study drug/study regimen dose until resolution to  AST or ALT ≤2.5×BLV.                                                                        |                                                                                                                                                      |
|                                                                                                                                                                                                | If toxicity worsens, then treat as described for elevations  in the rows below. If toxicity improves to AST or ALT  ≤2.5×BLV, resume study drug/study regimen after  completion of steroid taper (<10 mg prednisone, or  equivalent).                                                                                                                                                                                                                                                                                                                                                    | −                                                                                                                                                   | Regular and frequent checking of  Transaminases and total bilirubin (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  Clinical Study Lead.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            |                                                                                                                                                     |                                                                                                                                                      |
| −                                                                                                                                                                                               | If event is persistent (>2 to 3 days) or  worsens, and investigator suspects toxicity  to be an imAE, start prednisone 1 to  2 mg/kg/day PO or IV equivalent.                                                                                                                                                                                                                                                                                                                                                                                                                            |                                                                                                                                                     |                                                                                                                                                      |
| −                                                                                                                                                                                               | If still no improvement within 2 to 3 days  despite 1 to 2 mg/kg/day of prednisone PO  or IV equivalent, consider additional  workup. If still no improvement within 2 to  3 days despite 2mg/kg/day of IV  methylprednisolone, consider additional  abdominal workup (including liver biopsy)  and imaging (i.e., liver ultrasound), and  consider starting additional  immunosuppressants. (e.g., mycophenolate  mofetil 0.5 - 1 g every 12 hours then taper in  consultation with hepatology consult or  relevant practice guidelines). Discuss  Clinical Study Lead if mycophenolate |                                                                                                                                                     |                                                                                                                                                      |  
| mofetil is not available. Infliximab should  NOT be used.                                                          |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                |                                                               |                                                                                                                     |
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| ALT or AST                                                                                                         |                                                                                                                                                                                                                                                                                                                                                                                                                                                                               | Withhold durvalumab and permanently discontinue  tremelimumab |                                                                                                                     |
|                                                                                                                   | Resume study drug/study regimen if elevations  downgrade to AST or ALT ≤2.5×BLV and after  completion of steroid taper (<10 mg prednisone, or  equivalent).                                                                                                                                                                                                                                                                                                                    |                                                               |                                                                                                                     |
|                                                                                                                   | Permanently discontinue study drug/study regimen if the  elevations do not downgrade to AST or ALT ≤2.5×BLV within 14 days                                                                                                                                                                                                                                                                                                                                                     | −                                                             | 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 discussing with Clinical Study  Lead, as needed.                                                                                                                                                                                                                                                                                                                                                                                                                      |                                                               |                                                                                                                     |
| −                                                                                                                  | If investigator suspects toxicity to be  immune-mediated, promptly initiate empiric  IV methylprednisolone at 1 to 2 mg/kg/day  or equivalent.                                                                                                                                                                                                                                                                                                                                 |                                                               |                                                                                                                     |
| −                                                                                                                  | If no improvement within 2 to 3 days despite  1 to 2 mg/kg/day methylprednisolone IV or  equivalent, obtain liver biopsy (if it has not  been done already) and promptly start  treatment with an additional  immunosuppressant. (e.g. mycophenolate  mofetil 0.5 - 1 g every 12 hours then taper in  consultation with a hepatologist or relevant  practice guidelines). Discuss with Study  Clinical Lead if mycophenolate is not  available. Infliximab should NOT be used. |                                                               |                                                                                                                     |
| >5-7X BLV and ≤ 20X ULN OR  concurrent 2.5-5X  BLV and ≤20XULN and total bilirubin  > 1.5 - < 2 x ULN d ALT or AST | Permanently discontinue study drug/study regimen.                                                                                                                                                                                                                                                                                                                                                                                                                              | Same as above                                                 |                                                                                                                     |
| (except recommend obtaining liver biopsy early)                                                                    |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                |                                                               |                                                                                                                     |
| > 7 X BLV OR > 20 ULN whichever  occurs first OR bilirubin > 3ULN                                                  |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                |                                                               |                                                                                                                     |
| Nephritis and/or renal  dysfunction                                                                                | Any Grade                                                                                                                                                                                                                                                                                                                                                                                                                                                                      | General Guidance                                              | For Any Grade                                                                                                       |
| −                                                                                                                  | Patients should be thoroughly evaluated to  rule out any alternative etiology (e.g.,                                                                                                                                                                                                                                                                                                                                                                                           |                                                               |                                                                                                                     |
| (Refer to NCI CTCAE  applicable version in                                                                         |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                |                                                               |                                                                                                                     |  
| disease progression, infections, recent IV  contrast, medications, fluid status).   |                                                                                                                                                                                                                                                    |             |
|-------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------|
| −                                                                                   | Consider Consulting a nephrologist.                                                                                                                                                                                                                |             |
| −                                                                                   | Consider imaging studies to rule out any  alternative etiology.                                                                                                                                                                                    |             |
| −                                                                                   | 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, decreased urine  output, or proteinuria). |             |
| −                                                                                   | Follow urine protein/creatinine ratio every 3- 7 days.                                                                                                                                                                                             |             |
| study protocol for  defining the CTCAE  grade/severity) 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 hydration, electrolyte replacement,  and diuretics, as clinically indicated.                                                                                                                                                              |             |
| −                                                                                   | Consider nephrologist consult if not resolved  within 14 days, or earlier as clinically  indicated                                                                                                                                                 |             |
| Grade 2                                                                             | Hold study drug/study regimen until resolution to Grade ≤1 or  baseline.   If toxicity improves to Grade ≤1 or baseline, then resume  study drug/study regimen after completion of steroid taper  (<10 mg prednisone, or equivalent).             | For Grade 2 |
| −                                                                                   | Consider including hydration, electrolyte  replacement, and diuretics as clinically  indicated.                                                                                                                                                    |             |
| −                                                                                   | Follow urine protein/creatinine ratio every 3- 7 days.                                                                                                                                                                                             |             |
| −                                                                                   | Carefully monitor serum creatinine and as  clinically warranted.                                                                                                                                                                                   |             |
| −                                                                                   | Consult nephrologist and consider renal  biopsy if clinically indicated.                                                                                                                                                                           |             |  
| −                                                                                                                               | Start prednisone 0.5 - 1 mg/kg/day if other  causes are ruled out.                                                                                                                                                                                                            |                                                                                |               |
|---------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------|---------------|
| −                                                                                                                               | If event is persistent beyond 5 days or  worsens, increase to prednisone up to 2  mg/kg/day PO or IV equivalent.                                                                                                                                                              |                                                                                |               |
| −                                                                                                                               | If event is not responsive within 5 days or  worsens despite prednisone at 1 to 2  mg/kg/day PO or IV equivalent, consider  additional workup. When event returns to  baseline, resume study drug/study regimen  and routine serum creatinine monitoring per  study protocol. |                                                                                |               |
| Grade 3 or 4                                                                                                                    | Permanently discontinue study drug/study regimen.                                                                                                                                                                                                                             | For Grade 3 or 4                                                               |               |
| −                                                                                                                               | Carefully monitor serum creatinine daily.                                                                                                                                                                                                                                     |                                                                                |               |
| −                                                                                                                               | Follow urine protein/creatinine ratio every 3- 7 days.                                                                                                                                                                                                                        |                                                                                |               |
| −                                                                                                                               | 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  of steroids or worsens despite prednisone at  1 to 2 mg/kg/day PO or IV equivalent,  consider additional workup and prompt  treatment with an immunosuppressant.                                                               |                                                                                |               |
| Rash or Dermatitis                                                                                                              | Any Grade                                                                                                                                                                                                                                                                     | General Guidance                                                               | For Any Grade |
| (Refer to NCI CTCAE  applicable version in  study protocol for  definition of  severity/grade  depending on type of  skin rash) | −                                                                                                                                                                                                                                                                             | Patients should be thoroughly evaluated to  rule out any alternative etiology. |               |
| −                                                                                                                               | Monitor for signs and symptoms of  dermatitis (rash and pruritus).                                                                                                                                                                                                            |                                                                                |               |
| −                                                                                                                               | HOLD STUDY DRUG IF GRADE 3  PEMPHIGOID OR SEVERE  CUTANEOUS ADVERSE REACTION  (SCAR) IS SUSPECTED.                                                                                                                                                                            |                                                                                |               |
| −                                                                                                                               | PERMANENTLY DISCONTINUE  STUDY DRUG IF SCAR OR GRADE 3  PEMPHIGOID IS CONFIRMED.                                                                                                                                                                                              |                                                                                |               |
| (Including Pemphigoid)                                                                                                          |                                                                                                                                                                                                                                                                               |                                                                                |               |  
| Grade 1                                           | No dose modifications.                                                                                                                                                                                                                                                                                                   | For Grade 1                                                                                        |
|---------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------|
| −                                                 | Consider symptomatic treatment, including  oral antipruritics (e.g., diphenhydramine or  hydroxyzine) and topical therapy  (e.g., emolient, lotion, or institutional  standard).                                                                                                                                         |                                                                                                    |
| Grade 2                                           | For persistent (>1 week) Grade 2 events, hold scheduled study  drug/study regimen until resolution to Grade ≤1 or baseline.  If toxicity improves to Grade ≤1 or baseline, then resume  drug/study regimen after completion of steroid taper (<10  mg prednisone, or equivalent).                                       | For Grade 2                                                                                        |
| −                                                 | Consider dermatology consult and skin  biopsy, as indicated.                                                                                                                                                                                                                                                             |                                                                                                    |
| −                                                 | Consider symptomatic treatment, including  oral antipruritics (e.g., diphenhydramine or  hydroxyzine) and topical therapy                                                                                                                                                                                                |                                                                                                    |
| −                                                 | Consider moderate-strength topical steroid.                                                                                                                                                                                                                                                                              |                                                                                                    |
| −                                                 | If no improvement of rash/skin lesions  occurs within 1 week or is worsening despite  symptomatic treatment and/or use of  moderate strength topical steroid, consider  discussing with Clinical Study Lead, as  needed, and promptly start systemic steroids  such as prednisone 1 to 2 mg/kg/day PO or  IV equivalent. |                                                                                                    |
| Grade 3                                           | For Grade 3                                                                                                                                                                                                                                                                                                              | For Grade 3                                                                                        |
| −                                                 | Reconsult dermatologist. Consider skin  biopsy (preferably more than 1) as clinically  feasible.                                                                                                                                                                                                                         |                                                                                                    |
| −                                                 | Promptly initiate empiric IV  methylprednisolone 1 to 2 mg/kg/day or  equivalent.                                                                                                                                                                                                                                        |                                                                                                    |
| −                                                 | Consider hospitalization.                                                                                                                                                                                                                                                                                                |                                                                                                    |
| −                                                 | Monitor the extent of rash [Rule of Nines].                                                                                                                                                                                                                                                                              |                                                                                                    |
| −                                                 | Consider, as necessary, discussing with  Clinical Study Lead.                                                                                                                                                                                                                                                            |                                                                                                    |
|                                                  | Hold study drug/study regimen until resolution to Grade  ≤1 or baseline.                                                                                                                                                                                                                                                 |                                                                                                    |
|                                                  | If toxicity improves to Grade ≤1 or baseline, then resume  drug/study regimen after completion of steroid taper (<10  mg prednisone, or equivalent).                                                                                                                                                                     | For Grade 4                                                                                        |
| Grade 4                                           | For Grade 4                                                                                                                                                                                                                                                                                                              |                                                                                                    |
| Permanently discontinue study drug/study regimen. | −                                                                                                                                                                                                                                                                                                                        | Reconsult a dermatologist. Consider skin  biopsy (preferably more than 1) as clinically  feasible. |
| −                                                 | Promptly initiate empiric IV  methylprednisolone 1 to 2 mg/kg/day or  equivalent.                                                                                                                                                                                                                                        |                                                                                                    |
| −                                                 | Consider hospitalization.                                                                                                                                                                                                                                                                                                |                                                                                                    |
| −                                                 | Monitor the extent of rash [Rule of Nines].                                                                                                                                                                                                                                                                              |                                                                                                    |
| 115                                               |                                                                                                                                                                                                                                                                                                                          |                                                                                                    |  
| Endocrinopathy                                                                                                                                 | Any Grade                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    | General Guidance   | For Any Grade                                                                                                                                          |
|------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------|
| (e.g., hyperthyroidism,  thyroiditis,  hypothyroidism, type 1  diabetes mellitus,  hypophysitis,  hypopituitarism, and  adrenal insufficiency) | (Depending on the  type of  endocrinopathy, refer  to NCI CTCAE  applicable version in  study protocol for  defining the CTCAE  grade/severity)                                                                                                                                                                                                                                                                                                                                                                              | −                  | Patients should be thoroughly evaluated to  rule out any alternative etiology (e.g.,  disease progression including brain  metastases, or infections). |
| −                                                                                                                                              | Consider consulting an endocrinologist for  endocrine events.                                                                                                                                                                                                                                                                                                                                                                                                                                                                |                    |                                                                                                                                                        |
| −                                                                                                                                              | Consider discussing with Clinical Study  Lead, as needed.                                                                                                                                                                                                                                                                                                                                                                                                                                                                    |                    |                                                                                                                                                        |
| −                                                                                                                                              | Monitor patients for signs and symptoms of  endocrinopathies. (Non-specific symptoms  include headache, fatigue, behaviour  changes, mental status changes,  photophobia, visual field cuts, vertigo,  abdominal pain, unusual bowel habits,  polydipsia, polyuria, hypotension, and  weakness.)                                                                                                                                                                                                                             |                    |                                                                                                                                                        |
| −                                                                                                                                              | Depending on the suspected endocrinopathy,  monitor and evaluate thyroid function tests:  thyroid stimulating hormone (TSH), free T3  and free T4 and other relevant endocrine and  related labs (e.g., blood glucose and ketone  levels, hemoglobin A1c (HgA1c)). 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. |                    |                                                                                                                                                        |
| −                                                                                                                                              | Investigators should ask subjects with  endocrinopathies who may require  prolonged or continued hormonal  replacement, to consult their primary care  physicians or endocrinologists about further  monitoring and treatment after completion of  the study.                                                                                                                                                                                                                                                                |                    |                                                                                                                                                        |  
| Grade 1          | No dose modifications.                                                                                                                                                                                                                                                                                                                                                                     | For Grade 1                                                                                                                                                                   |
|------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| −                | Monitor patient with appropriate endocrine  function tests.                                                                                                                                                                                                                                                                                                                                |                                                                                                                                                                               |
| −                | For suspected hypophysitis/hypopituitarism,  consider consulting an endocrinologist to  guide assessment of early-morning  adrenocorticotropin hormone (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, 3, or 4 |                                                                                                                                                                                                                                                                                                                                                                                           | For Grade 2-4 endocrinopathies other than hypothyroidism  and type 1 diabetes mellitus (T1DM), consider holding  study drug/study regimen dose until acute symptoms  resolve. |
|                 | Study drug/study regimen can be resumed once patient  stabilizes and after completion of steroid taper (<10 mg  prednisone, or equivalent).                                                                                                                                                                                                                                                |                                                                                                                                                                               |
|                 | Patients with endocrinopathies who may require prolonged  or continued steroid replacement (e.g., adrenal  insufficiency) can be retreated with study drug/study  regimen if the patient is clinically stable as per investigator  or treating physician's clinical judgement.                                                                                                             | For Grade 2, 3, or 4                                                                                                                                                          |
| −                | Consult endocrinologist to guide evaluation  of endocrine function and, as indicated by  suspected endocrinopathy and as clinically  indicated, consider pituitary scan.                                                                                                                                                                                                                   |                                                                                                                                                                               |
| −                | For all patients with abnormal endocrine  work up, except those with isolated  hypothyroidism or T1DM, 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.                                                                    |                                                                                                                                                                               |
| −                | Isolated hypothyroidism may be treated  with replacement therapy, without study  drug/study regimen interruption, and  without corticosteroids.                                                                                                                                                                                                                                            |                                                                                                                                                                               |
| −                | Isolated T1DM may be treated with  appropriate diabetic therapy, and without  corticosteroids. Only hold study  drug/study regimen in setting of                                                                                                                                                                                                                                           |                                                                                                                                                                               |  
| hyperglycemia when diagnostic workup is  positive for diabetic ketoacidosis.                                                                                                                   |                                                                                                                                                                                           |                                                                                                                                                                        |               |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------|
| −                                                                                                                                                                                              | For patients with normal endocrine workup  (laboratory assessment or magnetic  resonance imaging (MRI) scans), repeat  laboratory assessments/MRI as clinically  indicated.               |                                                                                                                                                                        |               |
| Amylase/Lipase  increased                                                                                                                                                                      | Any Grade                                                                                                                                                                                 | General Guidance                                                                                                                                                       | For Any Grade |
| (Refer to NCI CTCAE  applicable version in  study protocol for  defining the CTCAE  grade/severity)                                                                                            | −                                                                                                                                                                                         | Patients should be thoroughly evaluated to  rule out any alternative etiology (e.g. disease  progression, viral infection, concomitant  medications, substance abuse). |               |
| −                                                                                                                                                                                              | For modest asymptomatic elevations in  serum amylase and lipase, corticosteroid  treatment is not indicated as long as there are  no other signs or symptoms of pancreatic  inflammation. |                                                                                                                                                                        |               |
| −                                                                                                                                                                                              | Assess for signs/symptoms of pancreatitis                                                                                                                                                 |                                                                                                                                                                        |               |
| −                                                                                                                                                                                              | Consider appropriate diagnostic testing (e.g.,  abdominal CT with contrast, MRCP if  clinical suspicion of pancreatitis and no  radiologic evidence on CT)                                |                                                                                                                                                                        |               |
| −                                                                                                                                                                                              | If isolated elevation of enzymes without  evidence of pancreatitis, continue  immunotherapy. Consider other causes of  elevated amylase/lipase                                            |                                                                                                                                                                        |               |
| −                                                                                                                                                                                              | If evidence of pancreatitis, manage  according to pancreatitis recommendations                                                                                                            |                                                                                                                                                                        |               |
| Grade 1                                                                                                                                                                                        | No dose modifications.                                                                                                                                                                    |                                                                                                                                                                        |               |
| Grade 2, 3, or 4                                                                                                                                                                               | For Grade 2, 3, or 4                                                                                                                                                                      |                                                                                                                                                                        |               |
| In consultation with relevant gastroenterology specialist,  consider continuing study drug/study regimen if no  clinical/radiologic evidence of pancreatitis ± improvement in  amylase/lipase. |                                                                                                                                                                                           |                                                                                                                                                                        |               |
| Acute Pancreatitis                                                                                                                                                                             | Any Grade                                                                                                                                                                                 |                                                                                                                                                                        |               |
| (Refer to NCI CTCAE  applicable version in  study protocol for  defining the CTCAE  grade/severity)                                                                                            | General Guidance                                                                                                                                                                          | For Any Grade                                                                                                                                                          |               |
| −                                                                                                                                                                                              | Patients should be thoroughly evaluated to  rule out any alternative etiology.                                                                                                            |                                                                                                                                                                        |               |
| −                                                                                                                                                                                              | Consider Gastroenterology referral                                                                                                                                                        |                                                                                                                                                                        |               |  
| Grade 2                                                                                                                                                                                                                                                                                                                             | Consider holding study drug/regimen.                                                                                            | Grade 2                    |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------|----------------------------|
| −                                                                                                                                                                                                                                                                                                                                   | Consider IV hydration                                                                                                           |                            |
| −                                                                                                                                                                                                                                                                                                                                   | Consider Gastroenterology referral                                                                                              |                            |
| Grade 3, or 4                                                                                                                                                                                                                                                                                                                       | For Grade 3                                                                                                                     | For Grade 3, or 4          |
| −                                                                                                                                                                                                                                                                                                                                   | Promptly start systemic steroids prednisone  1 to 2 mg/kg/day PO or IV equivalent.                                              |                            |
| −                                                                                                                                                                                                                                                                                                                                   | IV hydration                                                                                                                    |                            |
| Hold study drug/study regimen until resolution of elevated  enzymes and no radiologic findings. If no elevation in enzymes or return to baseline values, then  resume study drug/study regimen after completion of steroid  taper (<10 mg prednisone, or equivalent). For Grade 4 Permanently discontinue study drug/study regimen. |                                                                                                                                 |                            |
| Nervous System Disorders Aseptic Meningitis Any Grade                                                                                                                                                                                                                                                                               | General Guidance                                                                                                                | For Any Grade              |
| (Refer to NCI CTCAE  applicable version in  study protocol for  defining the CTCAE  grade/severity)                                                                                                                                                                                                                                 | −                                                                                                                               | Consider neurology consult |
| −                                                                                                                                                                                                                                                                                                                                   | Consider MRI brain with and without  contrast with pituitary protocol and a lumbar  puncture for diagnosis.                     |                            |
| −                                                                                                                                                                                                                                                                                                                                   | Exclude bacterial and viral infections. (ie  HSV)                                                                               |                            |
| −                                                                                                                                                                                                                                                                                                                                   | Consider IV acyclovir until polymerase  chain reactions are available                                                           |                            |
| −                                                                                                                                                                                                                                                                                                                                   | Symptoms may include headache, photophobia, and  neck stiffness, nausea/ vomiting which may resemble  an infectious meningitis. |                            |
| −                                                                                                                                                                                                                                                                                                                                   | Patients may be febrile.                                                                                                        |                            |
| −                                                                                                                                                                                                                                                                                                                                   | Mental status should be normal                                                                                                  |                            |
| Any Grade                                                                                                                                                                                                                                                                                                                           | Permanently discontinue study drug/study regimen                                                                                | For Any Grade              |
| −                                                                                                                                                                                                                                                                                                                                   | Consider neurology consult                                                                                                      |                            |
| −                                                                                                                                                                                                                                                                                                                                   | Consider MRI brain with and without  contrast with pituitary protocol and a lumbar  puncture for diagnosis.                     |                            |
| −                                                                                                                                                                                                                                                                                                                                   | Exclude bacterial and viral infections. (ie  HSV)                                                                               |                            |
| −                                                                                                                                                                                                                                                                                                                                   | Consider IV acyclovir until polymerase  chain reactions are available                                                           |                            |
| −                                                                                                                                                                                                                                                                                                                                   | Consider, as necessary, discussing with  Clinical Study Lead.( Last bullet)                                                     |                            |  
| −                                                                                                                                                                             | Consider hospitalization.                                                                                                                                                                                                                                                                                                                                                  |                            |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------|
| −                                                                                                                                                                             | Once infection has been ruled out promptly  initiate empiric IV methylprednisolone 1 to  2 mg/kg/day or equivalent.                                                                                                                                                                                                                                                        |                            |
| − Symptoms may include Confusion, altered behaviour,  headaches, seizures, short-term memory loss, depressed level  of consciousness, focal weakness, and speech abnormality. |                                                                                                                                                                                                                                                                                                                                                                            |                            |
| Encephalitis                                                                                                                                                                  | Any Grade                                                                                                                                                                                                                                                                                                                                                                  | For Any Grade              |
| (Refer to NCI CTCAE  applicable version in  study protocol for  defining the CTCAE  grade/severity)                                                                           | −                                                                                                                                                                                                                                                                                                                                                                          | Consider neurology consult |
| −                                                                                                                                                                             | Consider testing including MRI of the brain  with and without contrast, lumbar puncture,  electroencephalogram (EEG) to evaluate for  subclinical seizures, ESR, CRP,  antineutrophil cytoplasmic antibody  (ANCA) (if vasculitic process suspected),  thyroid panel including TPO and  thyroglobulin and additional autoantibodies  to rule out paraneoplastic disorders. |                            |
| −                                                                                                                                                                             | Exclude bacterial and viral infections. (i.e.                                                                                                                                                                                                                                                                                                                              |                            |
| −                                                                                                                                                                             | HSV) Consider IV acyclovir until  polymerase chain reactions are available.                                                                                                                                                                                                                                                                                                |                            |
| Grade 2                                                                                                                                                                       | For Grade 2                                                                                                                                                                                                                                                                                                                                                                | For Grade 2                |
| −                                                                                                                                                                             | Consider, as necessary, discussing with the  Clinical Study Lead.                                                                                                                                                                                                                                                                                                          |                            |
| −                                                                                                                                                                             | Once infection has been ruled out  methylprednisolone 1–2 mg/kg/day                                                                                                                                                                                                                                                                                                        |                            |
| −                                                                                                                                                                             | For progressive symptoms or if oligoclonal  bands are present consider  methylprednisolone 1 g IV daily for 3–5 days  plus IVIG or plasmapheresis                                                                                                                                                                                                                          |                            |
| Permanently discontinue study drug/study regimen.                                                                                                                             |                                                                                                                                                                                                                                                                                                                                                                            |                            |
| Grade 3 or 4                                                                                                                                                                  | For Grade 3 or 4                                                                                                                                                                                                                                                                                                                                                           | For Grade 3 or 4           |
| −                                                                                                                                                                             | Consider, as necessary, discussing with  Clinical Study Lead.                                                                                                                                                                                                                                                                                                              |                            |
| −                                                                                                                                                                             | Consider hospitalization.                                                                                                                                                                                                                                                                                                                                                  |                            |
| −                                                                                                                                                                             | Once infection is ruled out, start  methylprednisolone 1 g IV daily for 3–5  days for progressive symptoms consider  adding IVIG or plasmapheresis                                                                                                                                                                                                                         |                            |
| Permanently discontinue study drug/study regimen.                                                                                                                             |                                                                                                                                                                                                                                                                                                                                                                            |                            |  
| Transverse Myelitis                                                                                         | Any Grade                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          | General Guidance   |               |
|-------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------|---------------|
| −                                                                                                           | Permanently discontinue immunotherapy                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              |                    |               |
| −                                                                                                           | Consider MRI of the spine and brain                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                |                    |               |
| −                                                                                                           | Once imaging is complete, consider lumbar  puncture                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                |                    |               |
| Consider testing to rule out additional aetiologies: B12,  HIV, rapid plasma reagin (RPR), ANA, anti-Ro/La  antibodies, aquaporin-4 IgG, myelin oligodendrocyte  glycoprotein (MOG) IgG, paraneoplastic panel for antiHu and anti-CRMP5/CV2                                                                                                             | For Any Grade                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      |                    |               |
| −                                                                                                           | Consider neurology consult                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         |                    |               |
| −                                                                                                           | Inpatient care                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     |                    |               |
| −                                                                                                           | Consider prompt initiation of high  methylprednisolone pulse dosing                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                |                    |               |
| −                                                                                                           | Strongly consider IVIG or plasmapheresis                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           |                    |               |
| Peripheral neuropathy                                                                                       | Any Grade                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          | General Guidance   | For Any Grade |
| −                                                                                                           | Patients should be evaluated to rule out any  alternative etiology for neuropathy (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 neurological  consult. |                    |               |
| −                                                                                                           | Neurophysiologic diagnostic testing  (e.g., electromyogram and nerve conduction  investigations) are routinely indicated upon  suspicion of such conditions and may be best  facilitated by means of a neurology  consultation.                                                                                                                                                                                                                                                                                                                                                    |                    |               |
| (Refer to NCI CTCAE  applicable version in  study protocol for  defining the CTCAE  grade/severity) Grade 1 | No dose modifications.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             | For Grade 1        |               |
| −                                                                                                           | Consider discussing with the Clinical Study  Lead, as needed.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      |                    |               |
| −                                                                                                           | Monitor symptoms for interference with  ADLS, gait difficulties, imbalance, or  autonomic dysfunction                                                                                                                                                                                                                                                                                                                                                                                                                                                                              |                    |               |  
| Grade 2                                           | Hold study drug/study regimen dose until resolution to Grade  ≤1.                                                 | For Grade 2      |                           |
|---------------------------------------------------|-------------------------------------------------------------------------------------------------------------------|------------------|---------------------------|
| −                                                 | Consult a neurologist.                                                                                            |                  |                           |
| −                                                 | Consider EMG/NCS                                                                                                  |                  |                           |
| −                                                 | Consider discussing with the Clinical Study  Lead, as needed.                                                     |                  |                           |
| −                                                 | Observation for additional symptoms  decompensation or consider initiating  prednisone 0.5–1 mg/kg orally         |                  |                           |
| −                                                 | − If progression, initiate methylprednisolone  2–4 mg/kg/day and treat as GBS.                                    |                  |                           |
| −                                                 | Sensory neuropathy/neuropathic pain may  be managed by appropriate medications  (e.g., gabapentin or duloxetine). |                  |                           |
| Grade 3 or 4                                      | For Grade 3 or 4                                                                                                  | For Grade 3 or 4 |                           |
| −                                                 | Consider discussing with Clinical Study  Lead, as needed.                                                         |                  |                           |
| −                                                 | Recommend hospitalization.                                                                                        |                  |                           |
| −                                                 | Monitor symptoms and consult a  neurologist.                                                                      |                  |                           |
| −                                                 | Treat per Guillain-Barré Syndrome  recommendations                                                                |                  |                           |
| Permanently discontinue study drug/study regimen. |                                                                                                                   |                  |                           |
| Guillain-Barré  Syndrome (GBS)                    | General Guidance                                                                                                  | −                | Recommend hospitalization |
| −                                                 | Obtain neurology consult                                                                                          |                  |                           |
| −                                                 | Obtain MRI of spine to rule out compression  lesion                                                               |                  |                           |
| −                                                 | Obtain lumbar puncture                                                                                            |                  |                           |
| −                                                 | Antibody tests for GBS variants                                                                                   |                  |                           |
| −                                                 | Pulmonary function tests                                                                                          |                  |                           |
| −                                                 | Obtain electromyography (EMG)  and nerve conduction studies                                                       |                  |                           |
| −                                                 | Frequently monitor pulmonary function  tests and neurologic evaluations                                           |                  |                           |
| −                                                 | Monitor for concurrent autonomic dysfunction                                                                      |                  |                           |  
| −                       | Initiate medication as needed for neuropathic  pain                                                                            |                                                                                                                    |                                                                                                                              |
|-------------------------|--------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------|
| Grade 2-4               | Grade 2-4                                                                                                                      | Start IVIG or plasmapheresis in addition to  methylprednisolone 1 gram daily for 5 days, then  taper over 4 weeks. |                                                                                                                              |
| Permanently discontinue |                                                                                                                                |                                                                                                                    |                                                                                                                              |
| Myasthenia gravis       | General Guidance                                                                                                               | −                                                                                                                  | Obtain neurology consult                                                                                                     |
| −                       | Recommend hospitalization                                                                                                      |                                                                                                                    |                                                                                                                              |
| −                       | Obtain pulmonary function tests                                                                                                |                                                                                                                    |                                                                                                                              |
| −                       | Obtain labs: ESR, CRP, creatine  phosphokinase (CPK), aldolase and antistriational antibodies                                                                                                                                |                                                                                                                    |                                                                                                                              |
| −                       | Consider cardiac exam, ECG, troponin,  transthoracic echocardiogram for possible  concomitant myocarditis                      |                                                                                                                    |                                                                                                                              |
| −                       | Obtain electromyography (EMG) and nerve  conduction studies                                                                    |                                                                                                                    |                                                                                                                              |
| −                       | Consider MRI of brain/spine to rule out  CNS involvement by disease                                                            |                                                                                                                    |                                                                                                                              |
| −                       | Avoid medications that might exacerbate  MG (e.g. beta blockers, some antibiotics, IV  magnesium)                              |                                                                                                                    |                                                                                                                              |
| Grade 2                 | Permanently discontinue                                                                                                        | −                                                                                                                  | Consider pyridostigmine 30mg three times  daily and gradually increase based on  symptoms (max dose 120mg four times  daily) |
| −                       | Consider starting low dose prednisone 20mg  daily and increase every 3-5 days. (Target  dose 1mg/kg/day. Max dose 100mg daily) |                                                                                                                    |                                                                                                                              |
| Grade 3-4               | Permanently discontinue                                                                                                        | −                                                                                                                  | Start methylprednisolone 1- 2mg/kg/day. Taper steroids based on  symptom improvement                                         |
| −                       | Start plasmapheresis or IVIG                                                                                                   |                                                                                                                    |                                                                                                                              |
| −                       | Consider rituximab if refractory to  plasmapheresis or IVIG                                                                    |                                                                                                                    |                                                                                                                              |
| −                       | Frequent PFT assessments                                                                                                       |                                                                                                                    |                                                                                                                              |
| −                       | Daily neurologic evaluations                                                                                                   |                                                                                                                    |                                                                                                                              |  
| Myocarditis                                                                                         | Any Grade                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          | General Guidance   | For Any Grade                                                                                                                                                                                                                                                                                                                                                                     |
|-----------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| (Refer to NCI CTCAE  applicable version in  study protocol for  defining the CTCAE  grade/severity) | Discontinue drug permanently if biopsy-proven immunemediated myocarditis.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    | −                  | Initial work-up should include clinical  evaluation, B-type natriuretic peptide (BNP),  cardiac enzymes, electrocardiogram (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)                                                                                                                                                                                                                                                                                                                                                                                      |                    |                                                                                                                                                                                                                                                                                                                                                                                   |
| −                                                                                                   | The prompt diagnosis of immune-mediated  myocarditis is important, particularly in  patients with baseline cardiopulmonary  disease and reduced cardiac function.                                                                                                                                                                                                                                                                                                                                                                  |                    |                                                                                                                                                                                                                                                                                                                                                                                   |
| −                                                                                                   | Consider discussing with the Clinical Study  Lead, as needed.                                                                                                                                                                                                                                                                                                                                                                                                                                                                      |                    |                                                                                                                                                                                                                                                                                                                                                                                   |
| −                                                                                                   | 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). Consult a  cardiologist early, to promptly assess  whether and when to complete a cardiac  biopsy, including any other diagnostic  procedures. |                    |                                                                                                                                                                                                                                                                                                                                                                                   |
| −                                                                                                   | as indicated. Spiral CT or cardiac MRI can  complement ECHO to assess wall motion  abnormalities when needed.                                                                                                                                                                                                                                                                                                                                                                                                                      |                    |                                                                                                                                                                                                                                                                                                                                                                                   |  
| Grade 2, 3 or 4                                                                                     |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 | If Grade 2-4, permanently discontinue study                                                                                                    | For Grade 2-4   |
|-----------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------|-----------------|
| drug/study regimen.                                                                                 | −                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                | Monitor symptoms daily, hospitalize.                                                                                                           |                 |
| −                                                                                                   | Consider cardiology consultation and a  prompt start of high-dose/pulse  corticosteroid therapy                                                                                                                                                                                                                                                                                                                                                                                                                  |                                                                                                                                                |                 |
| −                                                                                                   | Supportive care (e.g., oxygen).                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  |                                                                                                                                                |                 |
| −                                                                                                   | If no improvement consider additional  immunosuppressive therapy such as TNF  inhibitors (e.g., infliximab), IVIG or  plasmapheresis or other therapies depending  on the clinical condition of the patient, based  on at the discretion of the treating specialist  consultant or relevant practice guidelines.  Caution: It is important to rule out sepsis  and refer to infliximab label for general  guidance before using infliximab.  Infliximab is contraindicated for patients  who have heart failure. |                                                                                                                                                |                 |
| Myositis/ Polymyositis                                                                              | Any Grade                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        | General Guidance                                                                                                                               | For Any Grade   |
| (Refer to NCI CTCAE  applicable version in  study protocol for  defining the CTCAE  grade/severity) | −                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                | Patients should be thoroughly evaluated to  rule out any alternative etiology (e.g.,  disease progression, other medications, or  infections). |                 |
| −                                                                                                   | 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, 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  Clinical Study Lead.                                                                                                                                                                                                                                                                                                                                                                                                                                                |                                                                                                                                                |                 |
| 125                                                                                                 |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  |                                                                                                                                                |                 |  
− Patients should be thoroughly evaluated to  
rule out any alternative etiology (e.g., disease progression, other medications, or infections).  
− 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, 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  
Clinical Study Lead.  
− Initial work-up should include clinical  
evaluation, creatine kinase, aldolase, lactate dehydrogenase (LDH), blood urea nitrogen (BUN)/creatinine, erythrocyte sedimentation rate or C-reactive protein (CRP) level, urine  
myoglobin, and additional laboratory workup 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 muscles, and/or a muscle biopsy. Consider Barium swallow for evaluation of dysphagia or dysphonia.  
| Grade 1   |                                                                                                                                                                                                                                                                                                                                                                                                                                                               | No dose modifications.                                            | For Grade 1   |
|-----------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------|---------------|
| −         | 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  Clinical Study Lead.                                                                                                                                                                                                                                                                                                                                                                                              |                                                                   |               |
| Grade 2   |                                                                                                                                                                                                                                                                                                                                                                                                                                                               | Hold study drug/study regimen dose until resolution to  Grade ≤1. |               |
|          | 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.                                                                                                                                                                                                                                                                                                       | For Grade 2                                                       |               |
| −         | Monitor symptoms daily and consider  hospitalization.                                                                                                                                                                                                                                                                                                                                                                                                          |                                                                   |               |
| −         | Consider Rheumatology or Neurology  consult, and initiate evaluation.                                                                                                                                                                                                                                                                                                                                                                                          |                                                                   |               |
| −         | Consider, as necessary, discussing with the  Clinical Study Lead.                                                                                                                                                                                                                                                                                                                                                                                              |                                                                   |               |
| −         | 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 2 to 3 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 days, consider additional  immunosuppressive therapy such as a TNF  inhibitor (e.g., infliximab ) IVIG or  plasmapheresis, or other therapies based on  the discretion of the specialist consultant or  relevant practice guideline. Caution: It is  important to rule out sepsis and refer to  infliximab label for general guidance  before using infliximab. |                                                                   |               |  
| Grade 3   | For Grade 3                                                                                                                                                                                                                                                                                                                                                                                                                                                                             |             |
|-----------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------|
|          | 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.                                                                                                                                                                                                                                                                                                                      | For Grade 3 |
| −         | Monitor symptoms closely; recommend  hospitalization.                                                                                                                                                                                                                                                                                                                                                                                                                                   |             |
| −         | Consider Rheumatology or Neurology  consult                                                                                                                                                                                                                                                                                                                                                                                                                                             |             |
| −         | Consider discussing with the Clinical Study  Lead, as needed.                                                                                                                                                                                                                                                                                                                                                                                                                           |             |
| −         | 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  2 to 3 days, consider starting another  immunosuppressive therapy such as a TNF  inhibitor (e.g., infliximab at 5 mg/kg IV,  may be repeated at 2 and 6 weeks after  initial dose at the discretion of the treating  provider or relevant practice guidelines).  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.                                                                                                                                                                                                                                                                                                                                                                                                                            |             |  
| Grade 4                                                                                                                                                               | For Grade 4                                                                                                                                                                                                                                                                                                                                                                                                                                                                   | Grade 4                                               |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------|
| Permanently discontinue study drug/study regimen.                                                                                                                     | −                                                                                                                                                                                                                                                                                                                                                                                                                                                                             | Monitor symptoms closely; recommend  hospitalization. |
| −                                                                                                                                                                     | Consider Rheumatology and/or Neurology  consult                                                                                                                                                                                                                                                                                                                                                                                                                               |                                                       |
| −                                                                                                                                                                     | Consider discussing with the Clinical Study  Lead, as needed.                                                                                                                                                                                                                                                                                                                                                                                                                 |                                                       |
| −                                                                                                                                                                     | 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 2 to 3 days, consider starting another immunosuppressive therapy such as a TNF inhibitor (e.g., infliximab at 5 mg/kg IV, may be repeated at 2 and 6 weeks after initial dose at the discretion of the treating provider or relevant practice guidelines). Caution: It is important to rule out sepsis and refer to infliximab label for general guidance before using infliximab. |                                                       |
| 1 SCAR terms include Stevens-Johnson Syndrome (SJS), Toxic Epidermal Necrolysis (TEN), Erythema Multiforme, Acute Generalized Exanthematous Pustulosis, Drug Reaction |                                                                                                                                                                                                                                                                                                                                                                                                                                                                               |                                                       |  
1 SCAR terms include Stevens-Johnson Syndrome (SJS), Toxic Epidermal Necrolysis (TEN), Erythema Multiforme, Acute Generalized Exanthematous Pustulosis, Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) and Drug-induced hypersensitivity syndrome.  
| Other–Immune-Mediated Reactions                                                                                                                                           |                                                                                                                                                                                                                                                                    |                                                                          |                                                                                                                                               |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------|
| Severity Grade of the Event                                                                                                                                               |                                                                                                                                                                                                                                                                    |                                                                          |                                                                                                                                               |
| (Refer to NCI CTCAE applicable  version in study protocol for  defining the CTCAE  grade/severity)                                                                        | Dose Modifications                                                                                                                                                                                                                                                 | Toxicity Management                                                      |                                                                                                                                               |
| Any Grade                                                                                                                                                                 | Note: It is possible that events with an inflammatory or  immune mediated mechanism could occur in nearly all  organs, some of them are not noted specifically in these  guidelines (e.g. immune thrombocytopenia, haemolytic  anaemia, uveitis, vasculitis).      | −                                                                        | Patients should be thoroughly evaluated to rule out any  alternative etiology (e.g., disease progression, other  medications, or infections). |
| −                                                                                                                                                                         | The Clinical Study Lead may be contacted for immunemediated reactions not listed in the "specific immunemediated reactions" section                                                                                                                                                                                                                                                                    |                                                                          |                                                                                                                                               |
| −                                                                                                                                                                         | Consultation with relevant specialist                                                                                                                                                                                                                              |                                                                          |                                                                                                                                               |
| −                                                                                                                                                                         | Treat accordingly, as per institutional standard.                                                                                                                                                                                                                  |                                                                          |                                                                                                                                               |
| Grade 1                                                                                                                                                                   | No dose modifications.                                                                                                                                                                                                                                             | Monitor as clinically indicated                                          |                                                                                                                                               |
| Grade 2                                                                                                                                                                   |                                                                                                                                                                                                                                                                   | Hold study drug/study regimen until resolution to  ≤Grade 1 or baseline. | For Grade 2, 3, or 4                                                                                                                          |
| Treat accordingly, as per institutional standard, appropriate  clinical practice guidelines, and society guidelines. (See  page 4).                                       |                                                                                                                                                                                                                                                                    |                                                                          |                                                                                                                                               |
|                                                                                                                                                                          | If toxicity worsens, then treat as Grade 3 or Grade 4.                                                                                                                                                                                                             |                                                                          |                                                                                                                                               |
|                                                                                                                                                                          | Study drug/study regimen can be resumed once event  stabilizes to Grade ≤1 after completion of steroid  taper.                                                                                                                                                     |                                                                          |                                                                                                                                               |
|                                                                                                                                                                          | Consider whether study drug/study regimen should be  permanently discontinued in Grade 2 events with high  likelihood for morbidity and/or mortality when they  do not rapidly improve to Grade <1 upon treatment  with systemic steroids and following full taper |                                                                          |                                                                                                                                               |
| Grade 3                                                                                                                                                                   | Hold study drug/study regimen                                                                                                                                                                                                                                      |                                                                          |                                                                                                                                               |
| Grade 4                                                                                                                                                                   | Permanently discontinue study drug/study regimen                                                                                                                                                                                                                   |                                                                          |                                                                                                                                               |
| 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 Clinical Study Lead." |                                                                                                                                                                                                                                                                    |                                                                          |                                                                                                                                               |  
| Infusion-Related Reactions                                                                                                        |                                                                                                                                                                                                                                                                                                                                     |                                                                                                                            |
|-----------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------|
| Severity Grade of the Event  (Refer to NCI CTCAE  applicable version in study  protocol for defining the  CTCAE grade/severity)   | 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                                                                                                           |
| The infusion rate of study drug/study regimen may be  decreased by 50% or temporarily interrupted until  resolution of the event. | −                                                                                                                                                                                                                                                                                                                                   | Acetaminophen and/or antihistamines may be administered per  institutional standard at the discretion of the investigator. |
| −                                                                                                                                 | Consider premedication per institutional standard or study protocol  prior to subsequent doses.                                                                                                                                                                                                                                     |                                                                                                                            |
| −                                                                                                                                 | Steroids should not be used for routine premedication of Grade ≤2 infusion reactions.                                                                                                                                                                                                                                               |                                                                                                                            |
| 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 standard,  appropriate clinical practice guidelines, and society guidelines.                                                                                                                                                                                             |                                                                                                                            |
| Permanently discontinue study drug/study regimen.                                                                                 |                                                                                                                                                                                                                                                                                                                                     |                                                                                                                            |  
| Non-Immune-Mediated Reactions                                                                                                                                             |                                                                                                                                                                                                                              |                                                   |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------|
| Severity Grade of the Event  (Refer to NCI CTCAE  applicable version in study  protocol for defining the  CTCAE grade/severity)                                           | 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 2-3                                                                                                                                                                 | Hold study drug/study regimen until resolution to ≤Grade 1 or                                                                                                                                                                | Treat accordingly, as per institutional standard. |
| baseline.                                                                                                                                                                 |                                                                                                                                                                                                                              |                                                   |
| 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 Clinical Study Lead." |                                                                                                                                                                                                                              |                                                   |