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| Toxicity                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     | Dose Interruptions                                                | Toxicity Management                                                                  |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------|--------------------------------------------------------------------------------------|
| > Grade 3                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    | Discontinue protocol  therapy and remove  from protocol  therapy. | severe (Grade ≥3) events promptly start prednisone PO 1- 2mg/kg/day or IV equivalent |
| - If symptoms recur or worsen during corticosteroid tapering  (> 28 days of taper), increase the corticosteroid dose  (prednisone dose [e.g. up to 2-4mg/kg/day PO or IV  equivalent]) until stabilization or improvement of symptoms,  then resume corticosteroid tapering (> 28 days) at a slower  rate  - More potent immunosuppressives such as TNF inhibitors  (e.g. infliximab, also refer to the individual sections of the  immune-related adverse event for specific type of  immunosuppressive) should be considered for events not  responding to systemic steroids.  - Discontinuation of study drug is not mandated for Grade 3 /  Grade 4 inflammatory reactions attributed to local tumor  response (e.g. inflammatory reaction at sites of metastatic  disease, lymph nodes etc.). Continuation of study drug in  this situation should be based upon a benefit/risk analysis  for that patient - Patients with endocrinopathies who may require prolonged  or continued steroid replacement can be retreated with  study drug/study regimen on the following conditions: 1) the  event stabilizes and is controlled, 2) the patient is clinically  stable as per Investigator or treating physician's clinical  judgement, and 3) doses of prednisone are at less than or  equal to 10mg/day or equivalent. |                                                                   |                                                                                      |  
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| Version Date 10/21/19                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              |                    |                     |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------|---------------------|
| Toxicity                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           | Dose Interruptions | Toxicity Management |
| Pneumonitis/ Interstitial Lung Disease (ILD) Any Grade - Monitor patients for signs and symptoms of pneumonitis or  ILD (new onset or worsening shortness of breath or cough).  Patients should be evaluated with imaging and pulmonary  function tests including other diagnostic procedures as  described below ‒ Initial work-up may include clinical evaluation, monitoring of  oxygenation via pulse oximetry (resting and exertion),  laboratory work-up and high-resolution CT scan. Grade 1 No dose  modifications  However, consider  holding study  drug/study regimen  dosing as clinically  appropriate and  during diagnostic  work-up for other  etiologies. (Radiographic Changes Only) - Monitor and closely follow up in 2-4 days for clinical  symptoms, pulse oximetry (resting and exertion) and  laboratory workup and then as clinically indicated - Consider Pulmonary and Infectious disease consult Grade 2 Hold protocol therapy until resolution to ≤  Grade 1 and after  completion of steroid  taper then resume  protocol therapy administration at next  scheduled dose. - Monitor symptoms daily and consider hospitalization - Promptly start systemic steroids (e.g., prednisone 1-2  mg/kg/day PO or IV equivalent) - Reimaging as clinically indicated - If no improvement within 3-5 days, additional workup should  be considered and prompt treatment with IV  methylprednisolone 2-4 mg/kg/day started  - If still no improvement within 3-5 days despite IV  methylprednisolone at 2-4 mg/kg/day, promptly start  immunosuppressive therapy such as TNF inhibitors (e.g.  infliximab at 5 mg/kg every 2 weeks). Caution: Important to  rule out sepsis and refer to infliximab label for general  guidance before using infliximab  - Once improving, gradually taper steroids over ≥28 days and  consider prophylactic antibiotics, antifungal or anti PCP  treatment (refer to current NCCN guidelines for treatment of  cancer-related infections)  - Consider pulmonary and infectious disease consult - Consider as necessary after discussing with Study Chair > Grade 3 Permanently  discontinue protocol  therapy and remove  from protocol  therapy. - If toxicity worsens  then treat as ≥  Grade 3  - Promptly initiate empiric IV methylprednisolone 1 to 4  mg/kg/day or equivalent  - Obtain Pulmonary and iInfectious disease consult; consider,  as necessary, discussing with study physician. - Hospitalize the patient - Supportive Care (oxygen, etc.) - If no improvement within 3-5 days, additional workup should  be considered and prompt treatment with additional  immunosuppressive therapy such as TNF inhibitors (e.g.  infliximab at 5 mg/kg every 2 weeks dose) started. Caution:  rule out sepsis and refer to infliximab label for general  guidance before using infliximab  - Once improving, gradually taper steroids over ≥ 28 days and  consider prophylactic antibiotics, antifungals and in  particular, anti PCP treatment (please refer to current NCCN  guidelines for treatment of cancer-related infections |                    |                     |  
| Toxicity                                                                           | Dose Interruptions                                                                                                                                                                                                                     | Toxicity Management                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           |
|------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Diarrhea/ Colitis Any Grade                                                        | -                                                                                                                                                                                                                                      | Monitor for symptoms that may be related to  diarrhea/enterocolitis (abdominal pain, cramping, or changes  in bowel habits such as increased frequency over baseline  or blood in stool) or related to bowel perforation (such as  sepsis, peritoneal signs and ileus)                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        |
| -                                                                                  | Patients should be thoroughly evaluated to rule out any  alternative etiology (e.g., disease progression, other  medications, infections including testing for clostridium  difficile toxin, etc.)                                     |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               |
| -                                                                                  | Steroids should be considered in the absence of clear  alternative etiology, even for low grade events, in order to  prevent potential progression to higher grade event                                                               |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               |
| - Use analgesics carefully; they can mask symptoms of  perforation and peritonitis |                                                                                                                                                                                                                                        |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               |
| Grade 1                                                                            | No dose                                                                                                                                                                                                                                | - Close monitoring for worsening symptoms                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     |
| modifications                                                                      | - Consider symptomatic treatment including hydration,  electrolyte replacement, dietary changes (e.g., American  Dietetic Association colitis diet), and loperamide. Use of  probiotics as per treating physician's clinical judgment. |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               |
| Grade 2                                                                            | Hold protocol therapy until resolution to ≤  Grade 1 and after  completion of steroid  taper then, resume  protocol therapy administration at next  scheduled dose.                                                                    | - Consider symptomatic treatment including hydration,  electrolyte replacement, dietary changes (e.g., American  Dietetic Association colitis diet), and loperamide and/or  budesonide - Promptly start prednisone 1 to 2 mg/kg/day PO or IV  equivalent  - If event is not responsive within 3-5 days or worsens despite  prednisone at 1-2 mg/kg/day PO or IV equivalent, GI consult  should be obtained for consideration of further workup such  as imaging and/or colonoscopy to confirm colitis and rule out  perforation, and prompt treatment with IV methylprednisolone  2-4mg/kg/day started.  - If still no improvement within 3-5 days despite 2-4 mg/kg IV  methylprednisolone, promptly start immunosuppressives  such as (infliximab at 5mg/kg once every 2 weeks). Caution:  Important to rule out bowel perforation and refer to infliximab  label for general guidance before using infliximab  - Consider consulting study physician if no resolution to ≤  Grade 1 in 3-4 days - Once improving, gradually taper steroids over ≥28 days and  consider prophylactic antibiotics, antifungals and anti PCP  treatment (please refer to current NCCN guidelines for  treatment of cancer-related infections) |
| Grade 3                                                                            | Hold protocol therapy  until resolution to ≤  Grade 1 and after  completion of steroid  taper then, resume  protocol therapy  administration at next  scheduled dose. If resolution to ≤  Grade 1 does not  occur within 14 days,      | - Promptly initiate empiric IV methylprednisolone 2 to 4  mg/kg/day or equivalent  - Monitor stool frequency and volume and maintain hydration  - Urgent GI consult and imaging and/or colonoscopy as  appropriate - If still no improvement within 3-5 days of IV  methylprednisolone 2 to 4 mg/kg/day or equivalent, promptly  start further immunosuppressives (e.g. infliximab at 5 mg/kg  once every 2 weeks).                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           |  
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| permanently  discontinue protocol  therapy.   | - Caution: Ensure GI consult to rule out bowel perforation and  refer to infliximab label for general guidance before using  infliximab.  - Once improving, gradually taper steroids over ≥28 day and  consider prophylactic antibiotics, antifungals and anti PCP  treatment (please refer to current NCCN guidelines for  treatment of cancer-related infections)   |
|-----------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| > Grade 4                                     | Permanently  discontinue protocol  therapy and remove  from protocol therapy.                                                                                                                                                                                                                                                                                         |  
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| Version Date 10/21/19                                                                                                                                                                                                                                                                                                                                                                                                                                                                       |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           |                                                                                                                   |                                                                                    |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------|
| Toxicity                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    | Dose Interruptions                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        | Toxicity Management                                                                                               |                                                                                    |
| Hepatitis (Elevated LFTs) Any Grade                                                                                                                                                                                                                                                                                                                                                                                                                                                         | -                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         | Monitor and evaluate liver function test: AST, ALT, ALP and  total bilirubin                                      |                                                                                    |
| -                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           | Evaluate for alternative etiologies (e.g., viral hepatitis,  disease progression, concomitant medications)                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                |                                                                                                                   |                                                                                    |
| Grade 1 (Based on  ULN  regardless of  baseline LFT)                                                                                                                                                                                                                                                                                                                                                                                                                                        | No dose                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   | -                                                                                                                 | Continue LFT monitoring per protocol                                               |
| modifications                                                                                                                                                                                                                                                                                                                                                                                                                                                                               |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           |                                                                                                                   |                                                                                    |
| Grade 2 (Based on  ULN  regardless of  baseline LFT)                                                                                                                                                                                                                                                                                                                                                                                                                                        | ‒                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         | Regular and frequent checking of LFTs (e.g. every 1-2  days) until elevations of these are improving or resolved. |                                                                                    |
| ‒                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           | If no resolution to ≤ Grade 1 in 1-2 days, consider  discussing with study physician.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     |                                                                                                                   |                                                                                    |
| ‒                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           | If event is persistent (> 3-5 days) or worsens, promptly start prednisone 1-2 mg/kg/day PO or IV equivalent.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              |                                                                                                                   |                                                                                    |
| ‒                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           | If still no improvement within 3-5 days despite 1-2  mg/kg/day of prednisone PO or IV equivalent, consider  additional workup and prompt treatment with IV  methylprednisolone at 2-4 mg/kg/day started.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  |                                                                                                                   |                                                                                    |
| ‒ If still no improvement within 3-5 days despite 2-4  mg/kg/day of IV methylprednisolone, promptly start  immunosuppressives (i.e.mycophenolate mofetil). Discuss  with Study Chair if mycophenolate mofetil is not available.  Infliximab should NOT be used.  ‒ Once improving, gradually taper steroids over ≥28 days and consider prophylactic antibiotics, antifungals and anti  PCP treatment (please refer to current NCCN guidelines  for treatment of cancer-related infections). |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           |                                                                                                                   |                                                                                    |
| Grade 3 (Based on  ULN  regardless of  baseline LFT)                                                                                                                                                                                                                                                                                                                                                                                                                                        | Hold protocol therapy until resolution to ≤  Grade 1 or baseline  and after completion  of steroid taper then  resume protocol  therapy administration at next  scheduled dose. For elevated  transaminases, ≤ 8x  ULN or bilirubin ≤5x  ULN, hold protocol  therapy until  resolution to ≤ Grade  1 or baseline and  after completion of  steroid taper.  Resume protocol  therapy administration at next  scheduled dose. If resolution to ≤  Grade 1 or baseline  does not occur within  14 days, permanently  discontinue protocol  therapy.  For elevated  transaminases > 8×  ULN or bilirubin >5x  ULN, permanently  discontinue protocol  therapy. Permanently  discontinue study | ‒                                                                                                                 | Promptly initiate empiric IV methylprednisolone at 1 to 4  mg/kg/day or equivalent |
| ‒                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           | If still no improvement within 3-5 days despite 1 to 4  mg/kg/day methylprednisolone IV or equivalent , promptly  start treatment with immunosuppressive therapy  (i.e.mycophenolate mofetil) Discuss with study physician if  mycophenolate is not available. Infliximab should NOT be  used.                                                                                                                                                                                                                                                                                                                                                                                            |                                                                                                                   |                                                                                    |
| ‒                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           | Hepatology consult, abdominal workup, and imaging as  appropriate.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        |                                                                                                                   |                                                                                    |
| ‒ Once improving, gradually taper steroids over ≥28 days  and consider prophylactic antibiotics, antifungals and anti  PCP treatment (please refer to current NCCN guidelines  for treatment of cancer-related infections.                                                                                                                                                                                                                                                                  |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           |                                                                                                                   |                                                                                    |  
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| Version Date 10/21/19                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          |                     |                     |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------|---------------------|
| Toxicity                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       | Dose Interruptions  | Toxicity Management |
| Hepatitis (Elevated LFTs) drug/study regimen  for any case meeting  Hy's law criteria (AST  and/or ALT > 3x ULN  + bilirubin > 2x ULN  without initial findings  of cholestasis (i.e.  elevated alkaline  P04) and in the  absence of any  alternative cause. Grade 4 (Based on  ULN  regardless of  baseline LFT)  Permanently  discontinue protocol  therapy.  Toxicity Dose Interruptions                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   | Toxicity Management |                     |
| Hepatitis (Elevated LFTs) -                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    | Infliximab should not be used for management of immunerelated hepatitis                     |                     |
| Hepatitis If transaminase rise is not isolated but (at any time) occurs in setting of either increasing  total/direct bilirubin (≥1.5×ULN, if normal at baseline; or 2×baseline, if >ULN at baseline) or signs  of DILI/liver decompensation (e.g., fever, elevated INR): - Manage dosing for Grade 1 transaminase rise as instructed for Grade 2 transaminase rise - Manage dosing for Grade 2 transaminase rise as instructed for Grade 3 transaminase rise - Grade 3-4: Permanently discontinue study drug/study regimen Any  - Monitor and evaluate liver function test: AST, ALT, ALP, and  Grade TB.  - Evaluate for alternative etiologies (e.g., viral hepatitis,  disease progression, concomitant medications, worsening of  liver cirrhosis [e.g., portal vein thrombosis]). - For HBV+ patients: evaluate quantitative HBV viral load,  quantitative HBsAg, or HBeAg - For HCV+ patients: evaluate quantitative HCV viral load - Consider consulting hepatologist/Infectious disease specialist  regarding change/implementation in/of antiviral medications  for any patient with an elevated HBV viral load >2000 IU/ml - Consider consulting hepatologist/Infectious disease specialist  regarding change/implementation in/of antiviral HCV  medications if HCV viral load increased by ≥2-fold For HCV+ with HBcAB+: Evaluate for both HBV and HCV as  above Grade 2 Hold protocol therapy  until resolution to ≤ Grade  1 or baseline and after  completion of steroid  taper then resume  protocol therapy  administration at next  scheduled dose. - Regular and frequent checking of LFTs (e.g., every 1 to 3  days) until elevations of these are improving or resolved. - Recommend consult hepatologist; consider abdominal  ultrasound, including Doppler assessment of liver perfusion. - Consider, as necessary, discussing with study physician. - If event is persistent (>3 to 5 days) or worsens, and  investigator suspects toxicity to be immune-mediated AE, |                     |                     |  
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|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Toxicity                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 | Dose Interruptions                                                                                                                                                                                                                                                                                                                                                                                                | Toxicity Management                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             |
| Hepatitis (Elevated LFTs) -                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              | Infliximab should not be used for management of immunerelated hepatitis                                                                                                                                                                                                                                                                                                                                                                                                                   |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 |
| Hepatitis                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                | recommend to start prednisone 1 to 2 mg/kg/day PO or IV  equivalent.                                                                                                                                                                                                                                                                                                                                              |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 |
| - If still no improvement within 3 to 5 days despite 1 to  2 mg/kg/day of prednisone PO or IV equivalent, consider  additional workup and treatment with IV methylprednisolone  2 to 4 mg/kg/day. If still no improvement within 3 to 5 days despite 2 to  4 mg/kg/day of IV methylprednisolone, consider additional  abdominal workup (including liver biopsy) and imaging (i.e., liver  ultrasound), and consider starting immunosuppressives (i.e.,  mycophenolate mofetil). Discuss with study physician if  mycophenolate mofetil is not available. Infliximab should NOT  be used. |                                                                                                                                                                                                                                                                                                                                                                                                                   |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 |
| Grade 3                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  | Hold protocol therapy  until resolution to ≤ Grade  1 and after completion of  steroid taper then,  resume protocol therapy  administration at next  scheduled dose. If resolution to ≤ Grade 1  does not occur within 14  days, permanently  discontinue protocol  therapy Permanently discontinue  study drug/study regimen  for any case meeting Hy's  law criteria, in the  absence of any  alternative cause | - Regular and frequent checking of LFTs (e.g., every 1-2 days)  until elevations of these are improving or resolved. - Consult hepatologist (unless investigator is hepatologist);  obtain abdominal ultrasound, including Doppler assessment  of liver perfusion; and consider liver biopsy. - Consider, as necessary, discussing with study physician. - If investigator suspects toxicity to be immune-mediated,  promptly initiate empiric IV methylprednisolone at 1 to  4 mg/kg/day or equivalent. - If no improvement within 3 to 5 days despite 1 to 4 mg/kg/day  methylprednisolone IV or equivalent, obtain liver biopsy (if it  has not been done already) and promptly start treatment with  immunosuppressive therapy (mycophenolate mofetil).  Discuss with study physician if mycophenolate is not  available. Infliximab should NOT be used. - Once the patient is improving, gradually taper steroids over  ≥28 days and consider prophylactic antibiotics, antifungals,  and anti-PCP treatment (refer to current NCCN guidelines for  treatment of cancer-related infections |
| Grade 4                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  | Permanently discontinue  protocol therapy.                                                                                                                                                                                                                                                                                                                                                                        |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 |  
| Toxicity                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              | Dose Interruptions   | Toxicity Management   |
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| Nephritis or Renal Dysfunction (Elevated Serum Creatinine) Any Grade - Consult with Nephrologist - Monitor for signs and symptoms that may be related to  changes in renal function (e.g. routine urinalysis, elevated  serum BUN and creatinine, decreased creatinine  clearance, electrolyte imbalance, decrease in urine output,  proteinuria, etc.)  - Thoroughly evaluate to rule out any alternative etiology  (e.g., disease progression, infections etc.) ‒ Steroids should be considered in the absence of clear  alternative etiology even for low grade events (Grade 2), in  order to prevent potential progression to higher grade  event Grade 1 No dose  ‒ Monitor serum creatinine weekly and any accompanying  modifications  symptom - If creatinine returns to baseline, resume its regular  monitoring per study protocol. - If it worsens, depending on the severity , treat as Grade  2 or Grade 3 or 4  ‒ Consider symptomatic treatment including hydration,  electrolyte replacement, diuretics, etc. Grade 2 Hold protocol therapy until resolution to ≤  Grade 1 or baseline and after completion  of steroid taper then resume protocol  therapy administration at next  scheduled dose.  ‒ Consider symptomatic treatment including hydration,  electrolyte replacement, diuretics, etc.  ‒ Carefully monitor serum creatinine every 2-3 days and as  clinically warranted ‒ Consult Nephrologist and consider renal biopsy if clinically  indicated ‒ If event is persistent (> 3-5 days) or worsens, promptly  start prednisone 1 to 2 mg/kg/day PO or IV equivalent  ‒ If event is not responsive within 3-5 days or worsens  despite prednisone at 1-2 mg/kg/day or PO IV equivalent,  additional workup should be considered and prompt  treatment with IV methylprednisolone at 2-4 mg/kg/day  started.  ‒ Once improving gradually taper steroids over ≥ 28 days and consider prophylactic antibiotics, antifungals and anti  PCP treatment (please refer to current NCCN guidelines  for treatment of cancer-related infections. ‒ When event returns to baseline, resume study drug/study  regimen and routine serum creatinine monitoring per study  protocol. |                      |                       |  
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| > Grade 3                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   | Permanently  discontinue protocol  therapy and remove  from protocol therapy.   | - Carefully monitor serum creatinine on daily basis - 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 3-5 days or worsens  despite prednisone at 1-2 mg/kg/day PO or IV equivalent,  additional workup should be considered and prompt  treatment with IV methylprednisolone 2-4 mg/kg/day  started.  - Once improving, gradually taper steroids over ≥ 28 days  and consider prophylactic antibiotics, antifungals and anti  PCP treatment (please refer to current NCCN guidelines  for treatment of cancer-related infections).   |
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| Toxicity                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    | Dose Interruptions                                                              | Toxicity Management                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 |
| Rash (excluding Bullous skin formations) Any Grade Monitor for signs and symptoms of dermatitis (rash and  pruritus)  **IF THERE IS ANY BULLOUS FORMATION, THE STUDY  CHAIR SHOULD BE CONTACTED AND STUDY DRUG  DISCONTINUED** Grade 1 No dose  Consider symptomatic treatment including oral antipruritics  modifications  (e.g., diphenhydramine or hydroxyzine) and topical therapy  (e.g., urea cream) Grade 2 For persistent (> 1- 2  weeks) Grade 2  events, hold protocol  therapy until  resolution to ≤ Grade  1 or baseline and  after completion of  steroid taper, resume  protocol therapy administration at next  scheduled dose.  ‒ Obtain dermatology consult  ‒ Consider symptomatic treatment including oral antipruritics  (e.g., diphenhydramine or hydroxyzine) and topical therapy  (e.g., urea cream) ‒ Consider moderate-strength topical steroid  ‒ If no improvement of rash/skin lesions occurs within 3-5  days or is worsening despite symptomatic treatment and/or  use of moderate strength topical steroid, consider  discussing with study physician and promptly start systemic  steroids prednisone 1-2 mg/kg/day PO or IV equivalent  ‒ Consider skin biopsy if persistent for >1-2 weeks or recurs Grade 3 Hold protocol therapy until resolution to ≤  Grade 1 or baseline; resume protocol  therapy  administration at next  scheduled dose.  ‒ Consult dermatology  ‒ Promptly initiate empiric IV methylprednisolone 1 to 4  mg/kg/day or equivalent  ‒ Consider hospitalization ‒ Monitor extent of rash [Rule of Nines] ‒ Consider skin biopsy (preferably more than 1) as clinically  feasible. ‒ Once improving, gradually taper steroids over ≥28 days and consider prophylactic antibiotics, antifungals and anti  PCP treatment (please refer to current NCCN guidelines  for treatment of cancer-related infections) Grade 4 Permanently  discontinue protocol  therapy and remove  from protocol therapy. |                                                                                 |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     |  
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| Toxicity                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    | Dose Interruptions | Toxicity Management |
| Endocrinopathy (e.g., hyper-thyroidism, hypo-thyroidism, hypo-pituitarism, Type 1 diabetes  mellitus hypophysitis, adrenal insufficiency, etc.)  Any Grade ‒ Consider consult an Endocrinologist for endocrine events ‒ Consider discussing with study physician  ‒ Monitor patients for signs and symptoms of  endocrinopathies. Non-specific symptoms include  headache, fatigue, behavior changes, changed mental  status, vertigo, abdominal pain, unusual bowel habits,  polydipsia, polyuria, hypotension and weakness. ‒ Patients should be thoroughly evaluated to rule out any  alternative etiology (e.g., disease progression including  brain metastases, infections, etc.) ‒ Depending on the suspected endocrinopathy, monitor and  evaluate thyroid function tests: TSH, free T3 and free T4  and other relevant endocrine and related labs (e.g., blood  glucose and ketone levels, HgA1c). ‒ For 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. ‒ If a patient experiences an AE that is thought to be  possibly of autoimmune nature (e.g., thyroiditis,  pancreatitis, hypophysitis, diabetes insipidus), the  investigator should send a blood sample for appropriate  autoimmune antibody testing Grade 1 No dose (including those with asymptomatic TSH elevation) modifications  - Monitor patient with appropriate endocrine function tests - For suspected hypophysitis/hypopituitarism, consider  consultation of an endocrinologist to guide assessment of  early-morning ACTH, cortisol, TSH and free T4; also  consider gonadotropins, sex hormones, and prolactin  levels, as well as cosyntropin stimulation test (though it  may not be useful in diagnosing early secondary adrenal  insufficiency). - If TSH < 0.5X LLN, or TSH >2X ULN or consistently out of  range in 2 subsequent measurements, include FT4 at  subsequent cycles as clinically indicated and consider  endocrinology consult. Grade 2 For Grade 2  endocinopathy other  than hypothyroidism  and Type 1 diabetes  mellitus, hold protocol  therapy until patient is  clinically stable, and  after completion of  steroid taper, resume protocol therapy  administration at next  scheduled dose. (including those with symptomatic endocrinopathy) - EvaluateConsult 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  for those with isolated hypothyroidism or Type 1 DM, and  as guided by an endocrinologist, consider short term  corticosteroids (e.g., 1 to 2 mg/kg/day methylprednisolone  or IV equivalent) and prompt initiation of treatment with  relevant hormone replacement (e.g., levothyroxine,  hydrocortisone, or sex hormones). -  - Isolated hypothyroidism may be treated with replacement  therapy, without study drug/study regimen interruption, and  without corticosteroids. - Isolated Type 1 diabetes mellitus (DM) may be treated with  appropriate diabetic therapy, without study drug/study  regimen interruption, and without corticosteroids.Patients with  endocrinopathies who  may require  prolonged or  continued steroid |                    |                     |  
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| Toxicity                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      | Dose Interruptions | Toxicity Management |
| Endocrinopathy (e.g., hyper-thyroidism, hypo-thyroidism, hypo-pituitarism, Type 1 diabetes  mellitus hypophysitis, adrenal insufficiency, etc.)  replacement can be  retreated with  protocol therapy on  the following  conditions: 1) the  event stabilizes and is  controlled, 2) the  patient is clinically  stable as per  Investigator or  treating physician's  clinical judgement,  and 3) doses of  prednisone are at  less than or equal to  10mg/day or  equivalent. - Once the patient ispatients on steroids are improving,  gradually taper steroids immunosuppressive steroids (as  appropriate and with guidance of endocrinologist) over ≥28  days and consider prophylactic antibiotics, antifungals, and  anti-PJP treatment (refer to current NCCN guidelines for  treatment of cancer-related infections [Category 2B  recommendation]). For patients with normal endocrine workup (laboratory  assessment or MRI scans), repeat laboratory  assessments/MRI as clinically indicated. > Grade 3 For Grade 3/4 endocrinopathy other  than hypothyroidism and Type 1 diabetes  mellitus, hold protocol  patient is clinically  stable and after  completion of steroid  taper, resume  protocol therapy  administration at next  scheduled dose.  Patients with  endocrinopathies  who may require  prolonged or  continued steroid  replacement (e.g.,  adrenal insufficiency)  can be retreated with  study drug/study  regimen on the  following conditions: 1. The event  stabilizes and is  controlled. 2. The patient is  clinically stable as  per investigator or  treating physician's  clinical judgement. - Consult endocrinologist to guide evaluation of endocrine  function and, as indicated by suspected endocrinopathy  and as clinically indicated, consider pituitary scan.  Hospitalization recommended. - For all patients with abnormal endocrine work up, except  those with isolated hypothyroidism or Type 1 DM, and as  guided by an endocrinologist, promptly initiate empiric IV  methylprednisolone 1 to 2 mg/kg/day or equivalent, as well  as relevant hormone replacement (e.g., hydrocortisone,  sex hormones). - For adrenal crisis, severe dehydration, hypotension, or  shock, immediately initiate IV corticosteroids with  mineralocorticoid activity. - Isolated hypothyroidism may be treated with replacement  therapy, without study drug/study regimen interruption, and  without corticosteroids. - Isolated Type 1 diabetes mellitus may be treated with  appropriate diabetic therapy, without study drug/study  regimen interruption, and without corticosteroids. - Once patients on steroids are improving, gradually taper  immunosuppressive steroids (as appropriate and with  guidance of endocrinologist) over ≥28 days and consider  prophylactic antibiotics, antifungals, and anti-PJP  treatment (refer to current NCCN guidelines for treatment  of cancer-related infections). |                    |                     |  
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| Version Date 10/21/19                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              |                    |                     |
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| Toxicity                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           | Dose Interruptions | Toxicity Management |
| Immune Mediated Neurotoxicity (except Myasthenia Gravis and Guillain-Barre) Any Grade - Patients should be evaluated to rule out any alternative  etiology (e.g., disease progression, infections, metabolic  syndromes and medications, etc.)  - Monitor patient for general symptoms (headache, nausea,  vertigo, behavior change, or weakness) - Consider appropriate diagnostic testing (e.g.  electromyogram and nerve conduction investigations) - Symptomatic treatment with neurological consult as  appropriate Grade 1 No dose  modifications Grade 2 Hold protocol therapy  until resolution to ≤  Grade 1 and after  completion of steroid  taper then resume  protocol therapy  administration at next  scheduled dose. - Consider discussing with the study chair  - Consider Neurology Consult  - Sensory neuropathy/neuropathic pain may be managed by  appropriate medications (e.g., gabapentin, duloxetine, etc.) - Promptly start systemic prednisone 1-2 mg/kg/day PO or IV  equivalent  - If no improvement within 3-5 days despite 1-2 mg/kg/day  prednisone PO or IV equivalent consider additional workup  and promptly treat with additional immunosuppressive  therapy (e.g. IVIG)  Grade 3 Hold protocol therapy  until resolution to ≤  Grade 1 and after  completion of steroid  taper then resume  protocol therapy  administration at next  scheduled dose. - Consider, as necessary, discussing with study physician. - Obtain neurology consult. - Consider hospitalization. - Promptly initiate empiric IV methylprednisolone 1 to  2 mg/kg/day or equivalent. - If no improvement within 3 to 5 days despite IV  corticosteroids, consider additional workup and promptly  treat with additional immunosuppressants (e.g., IV IG). Grade 4 Permanently - Once stable, gradually taper steroids over ≥28 days. discontinue protocol  therapy and remove  from protocol therapy. |                    |                     |  
| Toxicity                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                | Dose Interruptions   | Toxicity Management   |
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| Immune Mediated Peripheral Neuromotor Syndromes, such as Guillain-Barre and Myasthenia  Gravis Any Grade ‒ The prompt diagnosis of immune-mediated peripheral  neuromotor syndromes is important, since certain subjects  may unpredictably experience acute decompensations  which can result in substantial morbidity or in the worst  case, death. Special care should be taken for certain  sentinel symptoms which may predict a more severe  outcome, such as prominent dysphagia, rapidly  progressive weakness, and signs of respiratory  insufficiency or autonomic instability ‒ Evaluate patients to rule out any alternative etiology (e.g.,  disease progression, infections, metabolic syndromes and  medications, etc.). It should be noted that the diagnosis of  immune-mediated peripheral neuromotor syndromes can  be particularly challenging in subjects 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, and "repetitive  stimulation" if myasthenia is suspected)are routinely  indicated upon suspicion of such conditions and may be  best facilitated by means of a neurology consultation  ‒ Important to consider that the use of steroids as the  primary treatment of Guillain-Barre is not typically  considered effective. Patients requiring treatment should  be started with IVIG and followed by plasmapheresis if not  responsive to IVIG Grade 1 No dose  - Consider discussing with the study chair modifications  - Care should be taken to monitor patients for sentinel  symptoms of a potential decompensation as described  above - Obtain neurology consult  Grade 2 Hold protocol  therapy until  resolution to ≤  Grade 1; resume  protocol therapy  administration at  next scheduled  dose. ‒ Consider discussing with the study chair ‒ Monitor patients for sentinel symptoms of a potential  decompensation as described above ‒ Obtain a Neurology Consult ‒ Manage sensory neuropathy/neuropathic pain with  appropriate medications (e.g., gabapentin, duloxetine, etc.) MYASTHENIA GRAVIS o Steroids may be successfully used to treat Myasthenia  Gravis. Important to consider that steroid therapy  (especially with high doses) may result in transient  worsening of myasthenia and should typically be  administered in a monitored setting under supervision of  a consulting neurologist. o Patients unable to tolerate steroids may be candidates for  treatment with plasmapheresis or IVIG. Such decisions  are best made in consultation with a neurologist, taking  into account the unique needs of each patient. o If Myasthenia Gravis-like neurotoxicity present, consider If there are signs of  respiratory  insufficiency or  autonomic instability permanently  discontinue protocol  therapy and remove  from protocol  therapy. |                      |                       |  
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| Toxicity                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       | Dose Interruptions   | Toxicity Management   |
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| Immune Mediated Peripheral Neuromotor Syndromes, such as Guillain-Barre and Myasthenia  Gravis starting acetylcholine esterase (AChE) inhibitor therapy  in addition to steroids. Such therapy, if successful, can  also serve to reinforce the diagnosis. GUILLAIN-BARRE:  o Importantly the use of steroids as the primary treatment  of Guillain-Barre is not typically considered effective.  Patients requiring treatment should be started with IVIG  and followed by plasmapheresis if not responsive to  IVIG. Grade 3 Hold protocol  therapy until  resolution to ≤  Grade 1; resume  protocol therapy  administration at  next scheduled  dose. - Consider discussing with study chair - Recommend hospitalization - Monitor symptoms and obtain neurological consult MYASTHENIA GRAVIS o Steroids may be successfully used to treat Myasthenia  Gravis. It should typically be administered in a  monitored setting under supervision of a consulting  neurologist. o Patients unable to tolerate steroids may be candidates  for treatment with plasmapharesis or IVIG.  o If Myasthenia Gravis-like neurotoxicity present, consider  starting acetylcholine esterase (AChE) inhibitor therapy  in addition to steroids. Such therapy, if successful, can  also serve to reinforce the diagnosis. GUILLAIN-BARRE:  o Important to consider here that the use of steroids as the  primary treatment of Guillain-Barre is not typically  considered effective. Patients requiring treatment should  be started with IVIG and followed by plasmapheresis if  not responsive to IVIG. Grade 4 Permanently  discontinue protocol  therapy and remove  from protocol  therapy.If there are signs of  respiratory  insufficiency or  autonomic instability permanently  discontinue protocol  therapy and remove  from protocol  therapy. |                      |                       |  
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| Toxicity                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   | Dose Modification   | Toxicity Management   |
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| Cardiac toxicities (including arrhythmia, conduction disorder heart failure, IV dysfunction, Myocarditis) Any Grade General Guidance for Any Grade: − The prompt diagnosis of immune-mediated myocarditis is important, particularly in patients  with baseline cardiopulmonary disease and reduced cardiac function.  − Consider, as necessary, discussing with the study physician. − Monitor patients for signs and symptoms of myocarditis (new onset or worsening chest pain,  arrhythmia, shortness of breath, peripheral edema). As some symptoms can overlap with  lung toxicities, simultaneously evaluate for and rule out pulmonary toxicity as well as other  causes (e.g., pulmonary embolism, congestive heart failure, malignant pericardial effusion).  A Cardiology consultation should be obtained early, with prompt assessment of whether and  when to complete a cardiac biopsy, including any other diagnostic procedures. − Initial workup should include clinical evaluation, BNP, cardiac enzymes, ECG,  echocardiogram (ECHO), monitoring of oxygenation via pulse oximetry (resting and  exertion), and additional laboratory workup 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) − Discontinue protocol therapy permanently upon diagnosis of myocarditis, regardless  of grade Grade 1  (asymptoma tic with  laboratory  (e.g., BNP,  EKG,  Troponin)  and etiology  is unclear) No dose modifications  required unless  clinical suspicion for  myocarditis is high in  which case  suspected, hold  protocol therapy during workup.  For Grade 1 (no definitive findings): − Monitor and closely follow up in 2 to 4 days for clinical symptoms,  BNP, cardiac enzymes, ECG, ECHO, pulse oximetry (resting and  exertion), and laboratory workup as clinically indicated. − Consider using steroids if clinical suspicion is high.− If myocarditis is  excluded, resume  after complete  resolution to  Grade 0. − If myocarditis is  diagnosed,  permanently  discontinue  protocol therapy. |                     |                       |  
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| Toxicity                | Dose Modification | Toxicity Management |
| Cardiac toxicities (including arrhythmia, conduction disorder heart failure, IV dysfunction, Myocarditis) ≥ Grade 2 (Grade 2:  Symptoms  with mild to  moderate  activity or  exertion)  If Grade 2 - Hold  protocol therapy.  − If toxicity rapidly  improves to Grade  0 AND myocarditis  is excluded, then  the decision to  reinitiate protocol  therapy will be  based upon  treating  physician's clinical  judgment and after  completion of  steroid taper. − If toxicity does not  rapidly improve.  permanently  discontinue  protocol therapy − If myocarditis is  diagnosed,  permanently  discontinue protocol therapy For Grade 2-4: − Monitor symptoms daily, hospitalize. − Promptly start IV methylprednisolone 2 to 4 mg/kg/day or  equivalent after Cardiology consultation has determined whether  and when to complete diagnostic procedures including a cardiac  biopsy. − Supportive care (e.g., oxygen). − If no improvement within 3 to 5 days despite IV  methylprednisolone at 2 to 4 mg/kg/day, promptly start  immunosuppressive therapy such as TNF inhibitors  (e.g., infliximab at 5 mg/kg every 2 weeks). Caution: It is  important to rule out sepsis and refer to infliximab label for  general guidance before using infliximab. − Once the patient is improving, gradually taper steroids over ≥28  days and consider prophylactic antibiotics, antifungals, or antiPJP treatment (refer to current NCCN guidelines for treatment of  cancer-related infections [Category 2B recommendation]).a (Grade 3:  Severe with  symptoms at  rest or with  minimal  activity or  exertion;  intervention  indicated)  (Grade 4:  Lifethreatening  consequenc es; urgent intervention  indicated  (e.g.,  continuous  IV therapy or  mechanical  hemodynami c support) If Grade 3-4,  permanently  discontinue protocol  therapy.  Toxicity Dose Interruptions Toxicity Management Myositis/Polymyositis ("Poly/myositis") Any Grade - Monitor patients for signs and symptoms of  poly/myositis. Typically, muscle weakness/pain occurs  in proximal muscles including upper arms, thighs,  shoulders, hips, neck and back, but rarely affects the  extremities including hands and fingers; also difficulty  breathing and/or trouble swallowing can occur and  progress rapidly. Increased general feelings of  tiredness and fatigue may occur, and there can be  new-onset falling, difficulty getting up from a fall, and  trouble climbing stairs, standing up from a seated  position, and/or reaching up. - If poly/myositis is suspected, a Neurology consultation  should be obtained early, with prompt guidance on  diagnostic procedures. Myocarditis may co-occur with  poly/myositis; refer to guidance under Myocarditis.  Given breathing complications, refer to guidance  under Pneumonitis/ILD.  Given possibility of an existent (but previously  unknown) autoimmune disorder, consider  Rheumatology consultation.                         |                   |                     |  
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| Toxicity                                | Dose Interruptions                                                                                                     | Toxicity Management                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            |
| Myositis/Polymyositis ("Poly/myositis") | - Consider, as necessary, discussing with the study  physician. - Initial work-up should include clinical evaluation,  creatine kinase, aldolase, LDH, BUN/creatinine,  erythrocyte sedimentation rate or C-reactive protein  level, urine myoglobin, and additional laboratory 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. - Patients should be thoroughly evaluated to rule out  any alternative etiology (e.g., disease progression,  other medications, or infections). - Monitor and closely follow up in 2 to 4 days for clinical  symptoms and initiate evaluation as clinically  indicated. - Consider Neurology consult. - Consider, as necessary, discussing with the study  physician.                                                                                                                        |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                |
| Grade 2                                 | Hold protocol therapy until resolution  to ≤ Grade 1; resume protocol  therapy administration at next  scheduled dose. |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                |
| Grade 1                                 | No dose modifications                                                                                                  | - Monitor symptoms daily and consider hospitalization. - Obtain Neurology consult, and initiate evaluation. - Consider, as necessary, discussing with the study  physician. - If clinical course is rapidly progressive (particularly if  difficulty breathing and/or trouble swallowing),  promptly start IV methylprednisolone 2 to 4 mg/kg/day  systemic steroids along with receiving input from  Neurology consultant  - If clinical course is not rapidly progressive, start  systemic steroids (e.g., prednisone 1 to 2 mg/kg/day  PO or IV equivalent); if no improvement within 3 to 5  days, continue additional work up and start treatment  with IV methylprednisolone 2 to 4 mg/kg/day - If after start of IV methylprednisolone at 2 to  4 mg/kg/day there is no improvement within 3 to 5  days, consider start of immunosuppressive therapy  such as TNF inhibitors (e.g., infliximab at 5 mg/kg  every 2 weeks). Caution: It is important to rule out  sepsis and refer to infliximab label for general  guidance before using infliximab. - Once the patient is improving, gradually taper steroids  over ≥28 days and consider prophylactic antibiotics,  antifungals, or anti-PJP treatment (refer to current  NCCN guidelines for treatment of cancer-related  infections |  
| Toxicity                                                                                                                                                               | Dose Interruptions                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             | Toxicity Management   |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------|
| Myositis/Polymyositis ("Poly/myositis") Grade 3 Hold protocol therapy until resolution  to ≤ Grade 1; resume protocol  therapy administration at next  scheduled dose. | - Monitor symptoms closely; recommend  hospitalization. - Obtain Neurology consult, and complete full  evaluation. - Consider, as necessary, discussing with the study  physician. - Promptly start IV methylprednisolone 2 to 4 mg/kg/day  systemic steroids along with receiving input from  Neurology consultant. - If after start of IV methylprednisolone at 2 to  4 mg/kg/day there is no improvement within 3 to 5  days, consider start of immunosuppressive therapy  such as TNF inhibitors (e.g., infliximab at 5 mg/kg  every 2 weeks). Caution: It is important to rule out  sepsis and refer to infliximab label for general  guidance before using infliximab. - Consider whether patient may require IV IG,  plasmapheresis. - Once the patient is improving, gradually taper steroids  over ≥28 days and consider prophylactic antibiotics,  antifungals, or anti-PJP treatment (refer to current  NCCN guidelines for treatment of cancer-related  infections |                       |
| Grade 4                                                                                                                                                                | Permanently discontinue protocol  therapy and remove from protocol  therapy.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   |                       |  
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For treatment or dose modification questions, please contact Drs. Natasha Leighl and Naiyer Rizvi at S1400FMedicalQuery@swog.org. For dosing principles or questions, please consult the SWOG Policy \#38 "Dosing Principles for Patients on Clinical Trials" at https://www.swog.org/sites/default/files/docs/2017-11/Policy38.
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8.5 adverse event reporting

Toxicities (including suspected reactions) that meet the expedited reporting criteria as outlined in Section 16.0 of the protocol must be reported to the Operations Office, Study Coordinator and NCI via CTEP-AERS, and to the IRB per local IRB requirements.
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9.0 study calendar

| Cycle  1                                                   | Cycle 2   | Cycle                       | Cycle  4   | Cycle 5   | Cycle   | Cycle   |    |    |    |              |    |    |
|------------------------------------------------------------|-----------|-----------------------------|------------|-----------|---------|---------|----|----|----|--------------|----|----|
| 3                                                          | 6         | 7                           | Subsequent | At Off    |         |         |    |    |    |              |    |    |
| Cycles β                                                   | TX        | Off Tx  FU Prior  to Prog ∆ | Off Tx FU  |           |         |         |    |    |    |              |    |    |
| PRESTUDY                                                            | Wk        | Wk                          | Wk         | Wk        | Wk      | Wk      | Wk | Wk | Wk | After Prog √ |    |    |
| REQUIRED STUDIES                                           | 1         | 5                           | 7          | 9         | 13      | 17      | 19 | 21 | 25 |              |    |    |
| PHYSICAL                                                   |           |                             |            |           |         |         |    |    |    |              |    |    |
| History & Physical Exam                                    | X         | X                           | X          | X         | X       | X       | X  | X  | X  | X            |    |    |
| Weight & Performance Status                                | X         | X                           | X          | X         | X       | X       | X  | X  | X  | X            |    |    |
| Vital Signs £                                              | X£        | X£                          | X£         | X£        | X£      | X£      | X£ | X£ | X£ |              |    |    |
| Disease Assessment Ω                                       | X         | XΩ                          | XΩ         | XΩ        | XΩ      | XΩ      | XΩ |    |    |              |    |    |
| Toxicity Notation                                          | X         | X                           | X          | X         | X       | X       | X  | X  | X  | Xȸ           | Xȸ |    |
| Smoking Status Assessment                                  | X         | X                           |            |           |         |         |    |    |    |              |    |    |
| LABORATORY                                                 |           |                             |            |           |         |         |    |    |    |              |    |    |
| CBC/Diff/Platelets/Hgb                                     | X         | X€                          | X          | X         | X       | X       | X  | X  | X  | X            | Xȸ | Xȸ |
| Serum Bilirubin                                            | X         | X€                          | X          | X         | X       | X       | X  | X  | X  | X            | Xȸ | Xȸ |
| ALT or AST                                                 | X         | X€                          | X          | X         | X       | X       | X  | X  | X  | X            | Xȸ | Xȸ |
| Serum Creatinine/Calc CrCl                                 | X         | X€                          | X          | X         | X       | X       | X  | X  | X  | X            | Xȸ | Xȸ |
| Lipase π                                                   | X         | X€                          | X          | X         | X       | X       | X  | X  | Xπ | X            | Xπ | Xȸ |
| Amylase π                                                  | X         | X€                          | X          | X         | X       | X       | X  | X  | Xπ | X            | Xπ | Xȸ |
| TSH w/ reflex Free T3/Free T4 π                            | X         | X€                          | X          | X         | X       | X       | X  | X  | Xπ | X            | Xπ | Xȸ |
| Albumin ¥                                                  | X         |                             |            |           |         |         |    |    |    |              |    |    |
| X-RAYS AND SCANS                                           |           |                             |            |           |         |         |    |    |    |              |    |    |
| CT or MRI for Disease  Assessment Ω                        | X         | XΩ                          | XΩ         | XΩ        | XΩ      | XΩ      | XΩ |    |    |              |    |    |
| Brain CT/MRI                                               | X         | X♦                          | X♦         | X♦        | X♦      |         |    |    |    |              |    |    |
| EKG ©                                                      | X         |                             |            |           |         |         |    |    |    |              |    |    |
| Image Submission Σ                                         | X         | X                           | X          | X         | X       | X       | X  |    |    |              |    |    |
| SPECIMEN SUBMISSION                                        |           |                             |            |           |         |         |    |    |    |              |    |    |
| Tissue for Banking                                         | Xǂ        | X§                          |            |           |         |         |    |    |    |              |    |    |
| Blood for Banking ƒ                                        | X         | X                           | X          | X         | Xð      |         |    |    |    |              |    |    |
| Calendar continued on next page. Click here for footnotes. |           |                             |            |           |         |         |    |    |    |              |    |    |  
9.1 MEDI4736 (Durvalumab) plus Tremelimumab  
| Cycle  1                    | Cycle 2   | Cycle                       | Cycle  4   | Cycle 5   | Cycle   | Cycle   |    |    |     |              |
|-----------------------------|-----------|-----------------------------|------------|-----------|---------|---------|----|----|-----|--------------|
| 3                           | 6         | 7                           | Subsequent | At Off    |         |         |    |    |     |              |
| Cycles β                    | TX        | Off Tx  FU Prior  to Prog ∆ | Off Tx FU  |           |         |         |    |    |     |              |
| PRESTUDY                             | Wk        | Wk                          | Wk         | Wk        | Wk      | Wk      | Wk | Wk | Wlk | After Prog √ |
| REQUIRED STUDIES            | 1         | 5                           | 7          | 9         | 13      | 17      | 19 | 21 | 25  |              |
| TREATMENT                   |           |                             |            |           |         |         |    |    |     |              |
| 28 day cycle Tremelimumab * | X         | X                           | X          | X         |         |         |    |    |     |              |
| MEDI4736 (Durvalumab) *     | X         | X                           | X          | X         | X       | X       | X  | X  |     |              |  
NOTE: Forms are found on the protocol abstract page of the SWOG website (www.swog.org). Forms submission guidelines are found in Section 14.0.  
NOTE: Unless indicated otherwise in the protocol, scheduled procedures and assessments (treatment administration, toxicity assessment for continuous treatment, disease assessment, specimen collection and follow-up activities) must follow the established SWOG guidelines as outlined in https://www.swog.org/sites/default/files/docs/2017-10/Best%20Practices%20upddate.pdf. Click here for footnotes.  
Footnotes for Calendar (Durvalumab [MEDI4736] plus Tremelimumab):
Ω CT or MRI (the same method used at prestudy to meet the eligibility criteria in Section 5.3 of **S1400F**) must be repeated every 6 weeks (±
7 day window) until disease progression, regardless of treatment delays. The 6 weeks should start from Cycle 1 Day 1. If the patient remains on treatment following RECIST 1.1 progression, irRC disease progression is to be confirmed by a second consecutive determination of progression at least 28 days from the date of initial documentation of progression (see Section 10.0).  
♦ Only if patient has brain metastases at baseline. Scans must use the same modality as baseline and be repeated every 12 weeks (+/- 7 days)
until disease progression.  
Σ Submit scans as outlined in Section 14.0 and Section 15.0 of **S1400F**.  
£ Vital signs (Temperature, Blood Pressure, Pulse, and Respiratory Rate) are to be performed pre-study and at three timepoints at every cycle: pre-infusion, between tremelimumab and MEDI4736 (Durvalumab) dosing, and post-infusion. Vital signs are to be reported on the S1400F Onstudy and **S1400F** Treatment forms.  
© EKG to be performed at pre-study within 7 days prior to sub-study registration, then as clinically required throughout treatment.  
β During continued treatment, items marked under physical and laboratory should be performed at the beginning of every subsequent cycle unless otherwise noted. Disease assessments and image submission are to take place every 6 weeks (± 7 days).  
∆ After off treatment prior to progression, patients should be followed by repeating indicated studies every 3 months or more often as clinically indicated for the first year, then every 6 months for up to 3 years from date of sub-study registration. Disease assessment should continue every 6 weeks until progression.  
√ After off treatment after progression, follow-up will occur (with lab tests and scans performed at the discretion of the treating physician) every 6 months for 2 years then at end of year 3 from date of sub-study registration.  
ǂ With patient's consent, an additional research biopsy prior to treatment must be collected. Patients who provided fresh biopsy during screening may use that leftover tissue if they received no intervening treatment (see Section 15.0 of **S1400F**).  
§ With patient's consent, an additional research biopsy within 1 month after the time of first progression (irRC-Progression defined in Section 10 of **S1400F**) among patients who had a response to treatment (in the opinion of the treating physician) must be collected (see Section 15.0 of **S1400F**).  
ƒ With patient's consent, additional research blood draws will be collected (see Section 15.0 of **S1400F**).  
π Lipase, Amylase, and TSH/Reflex T3/T4 are required at pre-study within 7 days prior to sub-study registration. TSH/Reflex T3/T4 must be repeated every 4 weeks throughout treatment, then as clinically required until disease progression, as defined in Section 10.0 of **S1400F**.  
Lipase and Amylase must be repeated every 4 weeks throughout treatment, if clinically indicated, then as clinically required until disease progression, as defined in Section 10.0 of **S1400F**.  
¥ Results of these tests do not determine eligibility but are recommended prior to sub-study registration. € If the pre-study tests are obtained within 14 days prior to treatment, tests need not be repeated on Cycle 1 Day 1. * MEDI4736 (Durvalumab) and Tremelimumab will be administered on Day 1 of Cycles 1-4. Note that tremelimumab must be administered first.  
MEDI4736 (Durvalumab) only will be administered on Day 1 of Cycle 5 and subsequent cycles until one of the criterion from Section 7.3 is met.  
ȸ Assessments should continue until resolution of all acute adverse events.  
ð Blood for Banking specimen must be collected at first progression (irRC-Progression defined in Section 10.0 of **S1400F**) after study treatment
(see Section 15.0 of **S1400F**).
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