untitled h1
15 appendices 15.1 appendix a-performance

| ECOG Performance Status Scale       |                                                                                                                                                                                                                                                          |
|-------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Grade                               | Descriptions                                                                                                                                                                                                                                             |
| Normal activity. Fully active, able |                                                                                                                                                                                                                                                          |
| 0                                   | to carry on all pre-disease  performance without restriction. Symptoms, but ambulatory.  Restricted in physically strenuous  activity, but ambulatory and able  to carry out work of a light or  sedentary nature (e.g., light  housework, office work). |
| 1                                   | In bed <50% of the time. Ambulatory and capable of all  self-care, but unable to carry out  any work activities. Up and about  more than 50% of waking hours.                                                                                            |
| 2                                   | In bed >50% of the time. Capable  of only limited self-care, confined  to bed or chair more than 50% of  waking hours.                                                                                                                                   |
| 3                                   | 100% bedridden. Completely  disabled. Cannot carry on any  self-care. Totally confined to bed  or chair.                                                                                                                                                 |
| 4  5                                | Dead.                                                                                                                                                                                                                                                    |  
15.2 Appendix B - Tremelimumab and Durvalumab Dosing Modifications Dosing Modification and Toxicity Management Guidelines for Immune-Mediated, Infusion-Related, and Non-Immune–Mediated Reactions (MEDI4736 Monotherapy or Combination Therapy With Tremelimumab or Tremelimumab Monotherapy) 17 October 2019 Version (CTCAE v4.03)
General Considerations **regarding Immune-Mediated Reactions**  
Dose Modifications **Toxicity Management**  
It is recommended that management of immune-mediated adverse events (imAEs)  
follows the guidelines presented in this table:  
− It is possible that events with an inflammatory or immune mediated  
mechanism could occur in nearly all organs, some of them not noted  
specifically in these guidelines.  
− Whether specific immune-mediated events (and/or laboratory indicators of  
such events) are noted in these guidelines or not, patients should be  
thoroughly evaluated to rule out any alternative etiology (e.g., disease  
progression, concomitant medications, and infections) to a possible immunemediated event. In the absence of a clear alternative etiology, all such events  
should be managed as if they were immune related. General  
recommendations follow.  
− Symptomatic and topical therapy should be considered for low-grade (Grade  
1 or 2, unless otherwise specified) events.  
− For persistent (>3 to 5 days) low-grade (Grade 2) or severe (Grade ≥3)  
events, promptly start prednisone 1 to 2 mg/kg/day PO or IV equivalent.  
− Some events with high likelihood for morbidity and/or mortality - e.g.,  
myocarditis, or other similar events even if they are not currently noted in  
the guidelines - should progress rapidly to high dose IV corticosteroids  
(methylprednisolone at 2 to 4 mg/kg/day) even if the event is Grade 2, and if  
clinical suspicion is high and/or there has been clinical confirmation.  
Consider, as necessary, discussing with the study physician, and promptly  
pursue specialist consultation.  
− If symptoms recur or worsen during corticosteroid tapering (28 days of  
taper), increase the corticosteroid dose (prednisone dose [e.g., up to 2 to  
4 mg/kg/day PO or IV equivalent]) until stabilization or improvement of  
symptoms, then resume corticosteroid tapering at a slower rate (>28 days of  
taper).  
− More potent immunosuppressives such as TNF inhibitors (e.g., infliximab;  
also refer to the individual sections of the imAEs for specific type of  
immunosuppressive) should be considered for events not responding to  
systemic steroids. Progression to use of more potent immunosuppressives  
should proceed more rapidly in events with high likelihood for morbidity  
and/or mortality - e.g., myocarditis, or other similar events even if they are  
| It is recommended that management of immune-mediated adverse events (imAEs)  follows the guidelines presented in this table: − It is possible that events with an inflammatory or immune mediated  mechanism could occur in nearly all organs, some of them not noted  specifically in these guidelines. − Whether specific immune-mediated events (and/or laboratory indicators of  such events) are noted in these guidelines or not, patients should be  thoroughly evaluated to rule out any alternative etiology (e.g., disease  progression, concomitant medications, and infections) to a possible immunemediated event. In the absence of a clear alternative etiology, all such events  should be managed as if they were immune related. General  recommendations follow. − Symptomatic and topical therapy should be considered for low-grade (Grade  1 or 2, unless otherwise specified) events.  − For persistent (>3 to 5 days) low-grade (Grade 2) or severe (Grade ≥3)                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Drug administration modifications of study drug/study regimen will be made to  manage potential immune-related AEs based on severity of treatment-emergent  toxicities graded per NCI CTCAE v4.03 (unless indicated otherwise).  In addition to the criteria for permanent discontinuation of study drug/study  regimen based on CTC grade/severity (table below), permanently discontinue  study drug/study regimen for the following conditions: - Inability to reduce corticosteroid to a dose of ≤10 mg of prednisone per  day (or equivalent) within 12 weeks of the start of the immune-mediated  adverse event (imAE) - Grade 3 recurrence of a previously experienced treatment-related imAE  following resumption of dosing |  
Grade 1 No dose modification Grade 2 Hold study drug/study regimen dose until Grade 2 resolution to Grade ≤1.  
If toxicity worsens, then treat as Grade 3 or Grade 4.  
Study drug/study regimen can be resumed once event stabilizes to Grade ≤1 after completion of steroid taper.  
| taper).                                                                                    |                                                                                                                                                                                                                                                                                                                                                                                                                                                            |
|--------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| −                                                                                          | More potent immunosuppressives such as TNF inhibitors (e.g., infliximab;  also refer to the individual sections of the imAEs for specific type of  immunosuppressive) should be considered for events not responding to  systemic steroids. Progression to use of more potent immunosuppressives  should proceed more rapidly in events with high likelihood for morbidity  and/or mortality - e.g., myocarditis, or other similar events even if they are |
| drug/study regimen on the following conditions: 1. The event stabilizes and is controlled. |                                                                                                                                                                                                                                                                                                                                                                                                                                                            |
| 2.                                                                                         | The patient is clinically stable as per Investigator or treating  physician's clinical judgement. 3. Doses of prednisone are at ≤10 mg/day or equivalent.                                                                                                                                                                                                                                                                                                  |  
Dosing Modification and Toxicity Management Guidelines for Immune-Mediated, Infusion-Related, and Non-Immune–Mediated Reactions (MEDI4736 Monotherapy or Combination Therapy With Tremelimumab or Tremelimumab Monotherapy) 17 October 2019 Version (CTCAE v4.03)  
| Dose Modifications                                                                                                                                                                                                 | Toxicity Management                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| not currently noted in the guidelines - when these events are not responding  to systemic steroids.                                                                                                                |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 |
| −                                                                                                                                                                                                                  | With long-term steroid and other immunosuppressive use, consider need for  Pneumocystis jirovecii pneumonia (PJP, formerly known as Pneumocystis  carinii pneumonia) prophylaxis, gastrointestinal protection, and glucose  monitoring. − Discontinuation of study drug/study regimen is not mandated for  Grade 3/Grade 4 inflammatory reactions attributed to local tumor response  (e.g., inflammatory reaction at sites of metastatic disease and lymph nodes).  Continuation of study drug/study regimen in this situation should be based  upon a benefit-risk analysis for that patient. |
| Grade 3                                                                                                                                                                                                            | Depending on the individual toxicity, study drug/study regimen  may be permanently discontinued. Please refer to guidelines below.                                                                                                                                                                                                                                                                                                                                                                                                                                                              |
| Grade 4                                                                                                                                                                                                            | Permanently discontinue study drug/study regimen.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               |
| Note: For asymptomatic amylase or lipase levels of >2.0×ULN, hold study                                                                                                                                            |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 |
| drug/study regimen, and if complete work up shows no evidence of pancreatitis,  study drug/study regimen may be continued or resumed. Note: Study drug/study regimen should be permanently discontinued in Grade 3 |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 |  
General Considerations **regarding Immune-Mediated Reactions**
Note: Study drug/study regimen should be permanently discontinued in Grade 3 events with high likelihood for morbidity and/or mortality - e.g., myocarditis, or other similar events even if they are not currently noted in the guidelines.  
Similarly, consider whether study drug/study regimen should be permanently discontinued in Grade 2 events with high likelihood for morbidity and/or mortality
- e.g., myocarditis, or other similar events even if they are not currently noted in the guidelines - when they do not rapidly improve to Grade <1 upon treatment with systemic steroids and following full taper Note: There are some exceptions to permanent discontinuation of study drug for Grade 4 events (i.e., hyperthyroidism, hypothyroidism, Type 1 diabetes mellitus).  
| Specific Immune-Mediated Reactions                                                               |                                                                                                                                                                                                                                                                                                                                         |                                                                                                                               |                     |
|--------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------|---------------------|
| Adverse Events                                                                                   | Severity Grade of the  Event (NCI CTCAE  version 4.03)                                                                                                                                                                                                                                                                                  | Dose Modifications                                                                                                            | Toxicity Management |
| Pneumonitis/Interstitial  Lung Disease (ILD)                                                     | Any Grade                                                                                                                                                                                                                                                                                                                               | General Guidance                                                                                                              | For Any Grade:      |
| −                                                                                                | Monitor patients for signs and symptoms of pneumonitis or  ILD (new onset or worsening shortness of breath or cough).  Patients should be evaluated with imaging and pulmonary  function tests, including other diagnostic procedures as  described below.                                                                              |                                                                                                                               |                     |
| −                                                                                                | Initial work-up may include clinical evaluation, monitoring of  oxygenation via pulse oximetry (resting and exertion),  laboratory work-up, and high- resolution CT scan.                                                                                                                                                               |                                                                                                                               |                     |
| Grade 1                                                                                          | No dose modifications required. However,  consider holding study drug/study  regimen dose as clinically appropriate and  during diagnostic work-up for other  etiologies.                                                                                                                                                               | For Grade 1 (radiographic changes only):                                                                                      |                     |
| −                                                                                                | Monitor and closely follow up in 2 to 4 days for clinical  symptoms, pulse oximetry (resting and exertion), and  laboratory work-up and then as clinically indicated.                                                                                                                                                                   |                                                                                                                               |                     |
| −                                                                                                | Consider Pulmonary and Infectious Disease consults.                                                                                                                                                                                                                                                                                     |                                                                                                                               |                     |
| (asymptomatic, clinical  or diagnostic  observations only;  intervention not  indicated) Grade 2 | Hold study drug/study regimen dose until  Grade 2 resolution to Grade ≤1. - If toxicity worsens, then treat as  Grade 3 or Grade 4. - If toxicity improves to Grade ≤1,  then the decision to reinitiate study  drug/study regimen will be based  upon treating physician's clinical  judgment and after completion of  steroid taper.  | For Grade 2 (mild to moderate new symptoms): − Monitor symptoms daily and consider hospitalization.                           |                     |
| (symptomatic; medical  intervention indicated;  limiting instrumental  ADL)                      | −                                                                                                                                                                                                                                                                                                                                       | Promptly start systemic steroids (e.g., prednisone 1 to  2 mg/kg/day PO or IV equivalent). − Reimage as clinically indicated. |                     |
| −                                                                                                | If no improvement within 3 to 5 days, additional workup  should be considered and prompt treatment with IV  methylprednisolone 2 to 4 mg/kg/day started                                                                                                                                                                                 |                                                                                                                               |                     |
| −                                                                                                | If still no improvement within 3 to 5 days despite IV  methylprednisolone at 2 to 4 mg/kg/day, promptly start  immunosuppressive therapy such as TNF inhibitors  (e.g., infliximab at 5 mg/kg every 2 weeks). Caution: It is  important to rule out sepsis and refer to infliximab label for  general guidance before using infliximab. |                                                                                                                               |                     |
| −                                                                                                | Once the patient is improving, gradually taper steroids over  ≥28 days and consider prophylactic antibiotics, antifungals, or                                                                                                                                                                                                           |                                                                                                                               |                     |  
| anti-PJP treatment (refer to current NCCN guidelines for  treatment of cancer-related infections)a                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                |                                                          |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    |                |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------|
| −                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 | Consider Pulmonary and Infectious Disease consults.      |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    |                |
| −                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 | Consider, as necessary, discussing with study physician. |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    |                |
| Grade 3 or 4                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      | Permanently discontinue study drug/study  regimen.       | For Grade 3 or 4 (severe or new symptoms, new/worsening hypoxia,  life-threatening): − Promptly initiate empiric IV methylprednisolone 1 to  4 mg/kg/day or equivalent. − Obtain Pulmonary and Infectious Disease consults; consider, as  necessary, discussing with study physician. − Hospitalize the patient. − Supportive care (e.g., oxygen). − If no improvement within 3 to 5 days, additional workup  should be considered and prompt treatment with additional  immunosuppressive therapy such as TNF inhibitors  (e.g., infliximab at 5 mg/kg every 2 weeks' dose) started.  Caution: rule out sepsis and refer to infliximab label for general  guidance before using infliximab. − Once the patient is improving, gradually taper steroids over  ≥28 days and consider prophylactic antibiotics, antifungals,  and, in particular, anti-PJP treatment (refer to current NCCN  guidelines for treatment of cancer-related infections).a |                |
| (Grade 3: severe  symptoms; limiting  self-care ADL; oxygen  indicated) (Grade 4: lifethreatening respiratory  compromise; urgent  intervention indicated  [e.g., tracheostomy or  intubation])                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   |                                                          |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    |                |
| Diarrhea/Colitis                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  | Any Grade                                                | General Guidance                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   | For Any Grade: |
| Large intestine                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   |                                                          |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    |                |
| perforation/Intestine  perforation                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                | −                                                        | 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). − When symptoms or evaluation indicate a perforation is  suspected, consult a surgeon experienced in abdominal surgery  immediately without any delay. − Patients should be thoroughly evaluated to rule out any  alternative etiology (e.g., disease progression, other  medications, or infections), including testing for clostridium  difficile toxin, etc. − Steroids should be considered in the absence of clear  alternative etiology, even for low-grade events, in order to |                                                          |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    |                |  
| prevent potential progression to higher grade event, including  perforation.  − Use analgesics carefully; they can mask symptoms of  perforation and peritonitis.                                          |                                                                                                                                                                                                                                                                                                                                                         |                                                                                                                                                                                                                                    |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Grade 1                                                                                                                                                                                                    | No dose modifications.                                                                                                                                                                                                                                                                                                                                  | For Grade 1:                                                                                                                                                                                                                       |
| −                                                                                                                                                                                                          | Monitor closely for worsening symptoms.                                                                                                                                                                                                                                                                                                                 |                                                                                                                                                                                                                                    |
| (Diarrhea: stool                                                                                                                                                                                           |                                                                                                                                                                                                                                                                                                                                                         |                                                                                                                                                                                                                                    |
| frequency of <4 over  baseline per day) (Colitis: asymptomatic;  clinical or diagnostic  observations only)                                                                                                | −                                                                                                                                                                                                                                                                                                                                                       | Consider symptomatic treatment, including hydration,  electrolyte replacement, dietary changes (e.g., American  Dietetic Association colitis diet), and loperamide. Use  probiotics as per treating physician's clinical judgment. |
| Grade 2                                                                                                                                                                                                    | Hold study drug/study regimen until  resolution to Grade ≤1 - If toxicity worsens, then treat as  Grade 3 or Grade 4. - If toxicity improves to Grade ≤1,  then study drug/study regimen can be  resumed after completion of steroid  taper.                                                                                                            | For Grade 2:                                                                                                                                                                                                                       |
| −                                                                                                                                                                                                          | Consider symptomatic treatment, including hydration,  electrolyte replacement, dietary changes (e.g., American  Dietetic Association colitis diet), and loperamide and/or  budesonide.                                                                                                                                                                  |                                                                                                                                                                                                                                    |
| −                                                                                                                                                                                                          | Promptly start prednisone 1 to 2 mg/kg/day PO or IV  equivalent.                                                                                                                                                                                                                                                                                        |                                                                                                                                                                                                                                    |
| −                                                                                                                                                                                                          | If event is not responsive within 3 to 5 days or worsens despite  prednisone at 1 to 2 mg/kg/day PO or IV equivalent, GI consult  should be obtained for consideration of further workup, such as  imaging and/or colonoscopy, to confirm colitis and rule out  perforation, and prompt treatment with IV methylprednisolone  2 to 4 mg/kg/day started. |                                                                                                                                                                                                                                    |
| −                                                                                                                                                                                                          | If still no improvement within 3 to 5 days despite 2 to 4 mg/kg  IV methylprednisolone, promptly start immunosuppressives  such as infliximab at 5 mg/kg once every 2 weeksa . Caution: it  is important to rule out bowel perforation and refer to  infliximab label for general guidance before using infliximab.                                     |                                                                                                                                                                                                                                    |
| −                                                                                                                                                                                                          | Consider, as necessary, discussing with study physician if no  resolution to Grade ≤1 in 3 to 4 days.                                                                                                                                                                                                                                                   |                                                                                                                                                                                                                                    |
| −                                                                                                                                                                                                          | Once the patient is improving, gradually taper steroids over  ≥28 days and consider prophylactic antibiotics, antifungals, and  anti-PJP treatment (refer to current NCCN guidelines for  treatment of cancer-related infections).a                                                                                                                     |                                                                                                                                                                                                                                    |
| (Diarrhea: stool                                                                                                                                                                                           |                                                                                                                                                                                                                                                                                                                                                         |                                                                                                                                                                                                                                    |
| frequency of 4 to 6 over  baseline per day)  (Colitis: abdominal  pain; mucus or blood in  stool) (Perforation:  symptomatic; medical  intervention indicated*) * "medical  intervention" is not  invasive |                                                                                                                                                                                                                                                                                                                                                         |                                                                                                                                                                                                                                    |  
| Grade 3 or 4                                                                                                                                                                                                                                                                               | Grade 3                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Permanently discontinue study drug/study  regimen for Grade 3 if toxicity does not  improve to Grade ≤1 within 14 days;  study drug/study regimen can be resumed  after completion of steroid taper.                                                                                       | For Grade 3 or 4:                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           |
| −                                                                                                                                                                                                                                                                                          | Promptly initiate empiric IV methylprednisolone 2 to  4 mg/kg/day or equivalent.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            |
| −                                                                                                                                                                                                                                                                                          | Monitor stool frequency and volume and maintain hydration. − Urgent GI consult and imaging and/or colonoscopy as  appropriate. − If still no improvement within 3 to 5 days of IV  methylprednisolone 2 to 4 mg/kg/day or equivalent, promptly  start further immunosuppressives (e.g., infliximab at 5 mg/kg  once every 2 weeks). Caution: Ensure GI consult to rule out  bowel perforation and refer to infliximab label for general  guidance before using infliximab. If perforation is suspected,  consult a surgeon experienced in abdominal surgery  immediately without any delay. |
| −                                                                                                                                                                                                                                                                                          | Once the patient is improving, gradually taper steroids over  ≥28 days and consider prophylactic antibiotics, antifungals, and  anti-PJP treatment (refer to current NCCN guidelines for  treatment of cancer-related infections).a                                                                                                                                                                                                                                                                                                                                                         |
| (Grade 3 Diarrhea:  stool frequency of ≥7  over baseline per day; Grade 4 Diarrhea: life  threatening  consequences) (Grade 3 Colitis: severe  abdominal pain, change  in bowel habits, medical intervention indicated, peritoneal signs; Grade 4 Colitis: lifethreatening  consequences, urgent  intervention indicated)                                                                                                                                                                                                                                                                                            | Grade 4                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     |
| Permanently discontinue  study drug/study regimen.                                                                                                                                                                                                                                         |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             |
| (Grade 3 Perforation:  severe symptoms,  elective* operative  intervention indicated;  Grade 4 Perforation:  life-threatening  consequences, urgent  intervention indicated)  *This guidance  anticipates that Grade 3  operative interventions  of perforations are  usually not elective |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             |  
| Hepatitis                                                                                                                                                                                |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 |                                                                                                                                                                                                                                                                                                                                                                 |                               |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------|
| (elevated LFTs)                                                                                                                                                                          | Any Elevations in  AST, ALT or TB as  Described Below                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           | General Guidance                                                                                                                                                                                                                                                                                                                                                | For Any Elevations Described: |
| −                                                                                                                                                                                        | Monitor and evaluate liver function test: AST, ALT, ALP, and  TB.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               |                                                                                                                                                                                                                                                                                                                                                                 |                               |
| −                                                                                                                                                                                        | Evaluate for alternative etiologies (e.g., viral hepatitis, disease  progression, concomitant medications).                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     |                                                                                                                                                                                                                                                                                                                                                                 |                               |
| Infliximab should not be  used for management of  immune-related hepatitis.                                                                                                              | −                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               | Continue LFT monitoring per protocol.                                                                                                                                                                                                                                                                                                                           |                               |
| AST or ALT >ULN  and ≤3.0×ULN if  baseline normal, 1.5- 3.0×baseline if  baseline abnormal;  and/or TB > ULN and  ≤1.5×ULN if baseline  normal, >1.0- 1.5×baseline if  baseline abnormal | -                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               | No dose modifications.                                                                                                                                                                                                                                                                                                                                          |                               |
| -                                                                                                                                                                                        | If it worsens, then treat as described  for elevations in the row below.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        |                                                                                                                                                                                                                                                                                                                                                                 |                               |
| PLEASE SEE  shaded area  immediately below this section to find guidance for  management of "Hepatitis (elevated  LFTS)" in HCC  patients                                                | −                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               | Regular and frequent checking of LFTs (e.g., every 1 to 2 days)  until elevations of these are improving or resolved. − If no resolution to AST or ALT ≤3.0×ULN and/or TB  ≤1.5×ULN if baseline normal, or to AST or ALT ≤3.0×baseline  and/or TB ≤1.5×baseline if baseline abnormal, in 1 to 2 days,  consider, as necessary, discussing with study physician. |                               |
| −                                                                                                                                                                                        | If event is persistent (>3 to 5 days) or worsens, promptly start  prednisone 1 to 2 mg/kg/day PO or IV equivalent. − If still no improvement within 3 to 5 days despite 1 to  2 mg/kg/day of prednisone PO or IV equivalent, consider  additional work up and start prompt treatment with IV  methylprednisolone 2 to 4 mg/kg/day. − If still no improvement within 3 to 5 days despite 2 to  4 mg/kg/day of IV methylprednisolone, promptly start  immunosuppressives (i.e., mycophenolate mofetil).a Discuss  with study physician if mycophenolate mofetil is not available.  Infliximab should NOT be used. |                                                                                                                                                                                                                                                                                                                                                                 |                               |
| −                                                                                                                                                                                        | Once the patient is improving, gradually taper steroids over  ≥28 days and consider prophylactic antibiotics, antifungals, and  anti-PJP treatment (refer to current NCCN guidelines for  treatment of cancer-related infections).a                                                                                                                                                                                                                                                                                                                                                                             |                                                                                                                                                                                                                                                                                                                                                                 |                               |
| -                                                                                                                                                                                        | Hold study drug/study regimen dose  until resolution to AST or ALT  ≤3.0×ULN and/or TB ≤1.5×ULN if  baseline normal, or to AST or ALT  ≤3.0×baseline and/or TB ≤1.5×baseline if baseline abnormal.  - If toxicity worsens, then treat as  described for elevation in the row  below.  - If toxicity improves to AST or ALT  ≤3.0×ULN and/or TB ≤1.5×ULN if  baseline normal, or to AST or ALT  ≤3.0×baseline and/or TB ≤1.5×baseline if baseline abnormal,  resume study drug/study regimen  after completion of steroid taper.                                                                                 |                                                                                                                                                                                                                                                                                                                                                                 |                               |
| AST or                                                                                                                                                                                   |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 |                                                                                                                                                                                                                                                                                                                                                                 |                               |
| ALT >3.0×ULN and  ≤5.0×ULN if baseline  normal, >3-5×baseline  if baseline abnormal;  and/or  TB >1.5×ULN and  ≤3.0×ULN if baseline  normal, >1.5-  3.0×baseline if  baseline abnormal   |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 |                                                                                                                                                                                                                                                                                                                                                                 |                               |  
| −                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        | Promptly initiate empiric IV methylprednisolone at 1 to  4 mg/kg/day or equivalent.                                                                                                                                                                                                                                                                                                                                                                                                                     |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| −                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        | If still no improvement within 3 to 5 days despite 1 to                                                                                                                                                                                                                                                                                                                                                                                                                                                 |
| 4 mg/kg/day methylprednisolone IV or equivalent, promptly  start treatment with immunosuppressive therapy (i.e.,  mycophenolate mofetil). Discuss with study physician if  mycophenolate is not available. Infliximab should NOT be  used.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         |
| −                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        | Request Hepatology consult, and perform abdominal workup  and imaging as appropriate.                                                                                                                                                                                                                                                                                                                                                                                                                   |
| −                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        | Once the patient is improving, gradually taper steroids over  ≥28 days and consider prophylactic antibiotics, antifungals, and  anti-PJP treatment (refer to current NCCN guidelines for  treatment of cancer-related infections).a                                                                                                                                                                                                                                                                     |
| For elevations in transaminases ≤8×ULN  and/or in TB ≤5×ULN if baseline normal,  or for elevations in transaminases  ≤8×baseline and/or TB ≤5×baseline if  baseline abnormal:  - Hold study drug/study regimen dose  until resolution to AST or ALT  ≤3.0×ULN and/or TB ≤1.5×ULN if  baseline normal, or to AST or ALT  ≤3.0×baseline and/or TB ≤1.5×baseline if baseline abnormal - Resume study drug/study regimen if  elevations downgrade to AST or ALT  ≤3.0×ULN and/or TB ≤1.5×ULN if  baseline normal, or to AST or ALT  ≤3.0×baseline and/or TB ≤1.5×baseline if baseline abnormal,  within 14 days and after completion  of steroid taper. - Permanently discontinue study  drug/study regimen if the elevations  do not downgrade as described in  bullet above within 14 days |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         |
| AST or                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         |
| ALT >5.0×ULN if  baseline normal,                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         |
| >5×baseline if baseline  abnormal; and/or  TB >3.0×ULN if  baseline normal;  >3.0×baseline if  baseline abnormal                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         | For elevations in transaminases >8×ULN  or elevations in TB >5×ULN if baseline  normal, or for elevations in transaminases  >8×baseline and/or TB >5×baseline if  baseline abnormal, permanently  discontinue study drug/study regimen. Permanently discontinue study drug/study  regimen for any case meeting Hy's law  criteria (AST and/or ALT >3 × ULN +  bilirubin >2 × ULN without initial  findings of cholestasis (i.e., elevated  alkaline P04) and in the absence of any  alternative cause.b |  
| Hepatitis                                                                                                                                                                                                                                                                                                                                                                       |                                                                                                                                                                                                                               |                        |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| (elevated LFTs)                                                                                                                                                                                                                                                                                                                                                                 | Any Elevations in  AST, ALT or TB as  Described Below                                                                                                                                                                         | General Guidance       | For Any Elevations Described:  − Monitor and evaluate liver function test: AST, ALT, ALP, and  TB.  − Evaluate for alternative etiologies (e.g., viral hepatitis, disease  progression, concomitant medications, worsening of liver  cirrhosis [e.g., portal vein thrombosis]). − For HBV+ patients: evaluate quantitative HBV viral load,  quantitative HBsAg, or HBeAg − For HCV+ patients: evaluate quantitative HCV viral load − Consider consulting hepatologist/Infectious Disease specialist  regarding change/implementation in/of antiviral medications  for any patient with an elevated HBV viral load >2000 IU/ml − Consider consulting hepatologist/Infectious Disease specialist  regarding change/implementation in/of antiviral HCV  medications if HCV viral load increased by ≥2-fold − For HCV+ with HBcAB+: Evaluate for both HBV and HCV as above |
| Infliximab should not be  used for management of  immune-related hepatitis. THIS shaded area  is guidance only for  management of  "Hepatitis (elevated  LFTs)" in HCC  patientsSee instructions at  bottom of shaded area  if transaminase rise is  not isolated but (at any  time) occurs in setting  of either increasing  bilirubin or signs of  DILI/liver  decompensation | -                                                                                                                                                                                                                             | No dose modifications. |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        |
| -                                                                                                                                                                                                                                                                                                                                                                               | If ALT/AST elevations represents  significant worsening based on  investigator assessment, then treat as  described for elevations in the row  below.                                                                         |                        |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        |
| Isolated AST or ALT  >ULN and ≤5.0×ULN,  whether normal or  elevated at baseline                                                                                                                                                                                                                                                                                                | For all transaminase elevations, see  instructions at bottom of shaded area if  transaminase rise is not isolated but (at  any time) occurs in setting of either  increasing bilirubin or signs of  DILI/liver decompensation |                        |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        |  
| −                                                                                                                                                                                                                                                                                                                    | Regular and frequent checking of LFTs (e.g., every 1 to 3 days)  until elevations of these are improving or resolved. − Recommend consult hepatologist; consider abdominal  ultrasound, including Doppler assessment of liver perfusion.  − Consider, as necessary, discussing with study physician.                                                                                                                                                                                                                                                                                                                                                                                                                                                                             |                                                                                                                    |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------|
| −                                                                                                                                                                                                                                                                                                                    | If event is persistent (>3 to 5 days) or worsens, and investigator  suspects toxicity to be immune-mediated AE, recommend to  start prednisone 1 to 2 mg/kg/day PO or IV equivalent. − If still no improvement within 3 to 5 days despite 1 to  2 mg/kg/day of prednisone PO or IV equivalent, consider  additional workup and treatment with IV methylprednisolone 2  to 4 mg/kg/day. − If still no improvement within 3 to 5 days despite 2 to  4 mg/kg/day of IV methylprednisolone, consider additional  abdominal workup (including liver biopsy) and imaging (i.e.,  liver ultrasound), and consider starting immunosuppressives  (i.e., mycophenolate mofetil).a Discuss with study physician if  mycophenolate mofetil is not available. Infliximab should  NOT be used. |                                                                                                                    |
| Isolated AST or ALT  >5.0×ULN and  ≤8.0×ULN, if normal  at baseline                                                                                                                                                                                                                                                  | -                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                | Hold study drug/study regimen dose  untilresolution to AST or ALT  ≤5.0×ULN.                                       |
| -                                                                                                                                                                                                                                                                                                                    | If toxicity worsens, then treat as  described for elevations in the rows  below.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 |                                                                                                                    |
| Isolated AST or ALT  >2.0×baseline and  ≤12.5×ULN, if  elevated >ULN at  baseline                                                                                                                                                                                                                                    | If toxicity improves to AST or ALT  ≤5.0×ULN, resume study drug/study                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            |                                                                                                                    |
| regimen after completion of steroid taper.                                                                                                                                                                                                                                                                           | −                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                | 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).a                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              |                                                                                                                    |
| -                                                                                                                                                                                                                                                                                                                    | Hold study drug/study regimen dose  until resolution to AST or ALT  ≤5.0×ULN                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     |                                                                                                                    |
| -                                                                                                                                                                                                                                                                                                                    | Resume study drug/study regimen if  elevations downgrade to AST or ALT  ≤5.0×ULN within 14 days and after  completion of steroid taper. - Permanently discontinue study  drug/study regimen if the elevations  do not downgrade to AST or ALT  ≤5.0×ULN within 14 days                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           |                                                                                                                    |
| Isolated AST or ALT  >8.0×ULN and  ≤20.0×ULN, if normal  at baseline Isolated AST or ALT  >12.5×ULN and  ≤20.0×ULN, if  elevated >ULN at  baseline                                                                                                                                                                   | Permanently discontinue study drug/study  regimen for any case meeting Hy's law  criteria, in the absence of any alternative  cause.b                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            |                                                                                                                    |  
| Same as above                                                          |                                                    |
|------------------------------------------------------------------------|----------------------------------------------------|
| (except would recommend obtaining liver biopsy early)                  |                                                    |
| Isolated AST or ALT  >20×ULN, whether  normal or elevated at  baseline | Permanently discontinue study drug/study  regimen. |  
If transaminase rise is not isolated but (at any time) occurs in setting of either increasing **total/direct bilirubin (≥1.5×ULN, if normal at baseline; or 2×baseline, if**
>ULN at baseline) or signs of DILI/liver decompensation (e.g., fever, elevated INR):
- Manage dosing for each level of transaminase rise as instructed for the next highest level of transaminase riseFor example, manage dosing for second level of transaminase rise (i.e., **AST or ALT >5.0×ULN and ≤8.0×ULN, if normal at baseline, or AST or ALT >2.0×baseline and ≤12.5×ULN, if elevated >ULN at**
baseline) as instructed for the third level of transaminase rise (i.e., AST or ALT >8.0×ULN and ≤20.0×ULN, if normal at baseline, or AS**T or ALT**
>12.5×ULN and ≤20.0×ULN, if elevated >ULN at baseline)  
| -                               | For the third and fourth levels of transaminase rises, permanently discontinue study drug/study regimen                                                                                                                                                                                                                                                                                                                                                                                                                                                            |                  |                |
|---------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------|----------------|
| Nephritis or renal  dysfunction | Any Grade                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          | General Guidance | For Any Grade: |
| −                               | Consult with nephrologist.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         |                  |                |
| −                               | Monitor for signs and symptoms that may be related to changes  in renal function (e.g., routine urinalysis, elevated serum BUN  and creatinine, decreased creatinine clearance, electrolyte  imbalance, decrease in urine output, or proteinuria). − Patients should be thoroughly evaluated to rule out any  alternative etiology (e.g., disease progression or infections). − Steroids should be considered in the absence of clear  alternative etiology even for low-grade events (Grade 2), in  order to prevent potential progression to higher grade event. |                  |                |
| (elevated serum  creatinine)    |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    |                  |                |  
- For the third and fourth levels of transaminase rises, permanently discontinue study drug/study regimen  
| Grade 1                                                                 | No dose modifications.                                                                                                                                                                                                                                                                                                                                              | For Grade 1:                                                                                                                                |
|-------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------|
| −                                                                       | Monitor serum creatinine weekly and any accompanying  symptoms. - If creatinine returns to baseline, resume its regular  monitoring per study protocol. - If creatinine worsens, depending on the severity, treat  as Grade 2, 3, or 4.                                                                                                                             |                                                                                                                                             |
| −                                                                       | Consider symptomatic treatment, including hydration,  electrolyte replacement, and diuretics.                                                                                                                                                                                                                                                                       |                                                                                                                                             |
| (Serum creatinine > 1  to 1.5×baseline;  > ULN to 1.5×ULN) Grade 2      | Hold study drug/study regimen until  resolution to Grade ≤1 or baseline.  - If toxicity worsens, then treat as  Grade 3 or 4. - If toxicity improves to Grade ≤1 or  baseline, then resume study  drug/study regimen after completion  of steroid taper.                                                                                                            | For Grade 2:                                                                                                                                |
| −                                                                       | Consider symptomatic treatment, including hydration,  electrolyte replacement, and diuretics.                                                                                                                                                                                                                                                                       |                                                                                                                                             |
| −                                                                       | Carefully monitor serum creatinine every 2 to 3 days and as  clinically warranted.                                                                                                                                                                                                                                                                                  |                                                                                                                                             |
| −                                                                       | Consult nephrologist and consider renal biopsy if clinically  indicated.                                                                                                                                                                                                                                                                                            |                                                                                                                                             |
| −                                                                       | If event is persistent (>3 to 5 days) or worsens, promptly start  prednisone 1 to 2 mg/kg/day PO or IV equivalent.                                                                                                                                                                                                                                                  |                                                                                                                                             |
| −                                                                       | If event is not responsive within 3 to 5 days or worsens despite  prednisone at 1 to 2 mg/kg/day PO or IV equivalent, additional  workup should be considered and prompt treatment with IV  methylprednisolone at 2 to 4 mg/kg/day started.                                                                                                                         |                                                                                                                                             |
| −                                                                       | Once the patient is improving, gradually taper steroids over  ≥28 days and consider prophylactic antibiotics, antifungals, and  anti-PJP treatment (refer to current NCCN guidelines for  treatment of cancer-related infections).a − When event returns to baseline, resume study drug/study  regimen and routine serum creatinine monitoring per study  protocol. |                                                                                                                                             |
| (serum creatinine >1.5  to 3.0×baseline; >1.5 to  3.0×ULN) Grade 3 or 4 | Permanently discontinue study drug/study  regimen.                                                                                                                                                                                                                                                                                                                  | For Grade 3 or 4:                                                                                                                           |
| −                                                                       | Carefully monitor serum creatinine on daily basis.                                                                                                                                                                                                                                                                                                                  |                                                                                                                                             |
| (Grade 3: serum  creatinine                                             |                                                                                                                                                                                                                                                                                                                                                                     |                                                                                                                                             |
| >3.0×baseline; >3.0 to  6.0×ULN)                                        | −                                                                                                                                                                                                                                                                                                                                                                   | Consult nephrologist and consider renal biopsy if clinically  indicated. − Promptly start prednisone 1 to 2 mg/kg/day PO or IV  equivalent. |
| −                                                                       | If event is not responsive within 3 to 5 days or worsens despite  prednisone at 1 to 2 mg/kg/day PO or IV equivalent, additional                                                                                                                                                                                                                                    |                                                                                                                                             |  
| workup should be considered and prompt treatment with IV  methylprednisolone 2 to 4 mg/kg/day started.   |                                                                                                                                                                                                                                                                                                                            |                        |                |
|----------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------|----------------|
| −                                                                                                        | Once the patient is improving, gradually taper steroids over  ≥28 days and consider prophylactic antibiotics, antifungals, and  anti-PJP treatment (refer to current NCCN guidelines for  treatment of cancer-related infections).a                                                                                        |                        |                |
| (Grade 4: serum                                                                                          |                                                                                                                                                                                                                                                                                                                            |                        |                |
| creatinine >6.0×ULN)                                                                                     |                                                                                                                                                                                                                                                                                                                            |                        |                |
| Rash or Dermatitis                                                                                       | Any Grade                                                                                                                                                                                                                                                                                                                  | General Guidance       | For Any Grade: |
| −                                                                                                        | Monitor for signs and symptoms of dermatitis (rash and  pruritus).                                                                                                                                                                                                                                                         |                        |                |
| −                                                                                                        | IF THERE IS ANY BULLOUS FORMATION, THE STUDY  PHYSICIAN SHOULD BE CONTACTED AND STUDY  DRUG DISCONTINUED IF SUSPECT STEVENSJOHNSON SYNDROME OR TOXIC EPIDERMAL  NECROLYSIS.                                                                                                                                                                                                                                                                                                                            |                        |                |
| (including Pemphigoid)                                                                                   | (refer to NCI CTCAE  v 4.03 for definition of  severity/grade  depending on type of  skin rash) Grade 1                                                                                                                                                                                                                    | No dose modifications. | For Grade 1:   |
| −                                                                                                        | Consider symptomatic treatment, including oral antipruritics  (e.g., diphenhydramine or hydroxyzine) and topical therapy  (e.g., urea cream).                                                                                                                                                                              |                        |                |
| Grade 2                                                                                                  | For persistent (>1 to 2 weeks) Grade 2  events, hold scheduled study drug/study  regimen until resolution to Grade ≤1 or  baseline. - If toxicity worsens, then treat as  Grade 3. - If toxicity improves to Grade ≤1 or  baseline, then resume drug/study  regimen after completion of steroid  taper.                    | For Grade 2:           |                |
| −                                                                                                        | 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 to  5 days or is worsening despite symptomatic treatment and/or  use of moderate strength topical steroid, consider, as necessary,  discussing with study physician and promptly start systemic  steroids such as prednisone 1 to 2 mg/kg/day PO or IV  equivalent. |                        |                |
| −                                                                                                        | Consider skin biopsy if the event is persistent for >1 to 2 weeks  or recurs.                                                                                                                                                                                                                                              |                        |                |  
| Grade 3 or 4                                                                                                                                                                                                                                | For Grade 3:                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             | For Grade 3 or 4: − Consult Dermatology.                                                                                                               |                                                          |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------|
| Hold study drug/study regimen until  resolution to Grade ≤1 or baseline.                                                                                                                                                                    | −                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        | Promptly initiate empiric IV methylprednisolone 1 to  4 mg/kg/day or equivalent. − Consider hospitalization. − Monitor extent of rash [Rule of Nines]. |                                                          |
| −                                                                                                                                                                                                                                           | Consider skin biopsy (preferably more than 1) as clinically  feasible.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   |                                                                                                                                                        |                                                          |
| −                                                                                                                                                                                                                                           | Once the patient is improving, gradually taper steroids over  ≥28 days and consider prophylactic antibiotics, antifungals, and  anti-PJP treatment (refer to current NCCN guidelines for  treatment of cancer-related infections).a − Consider, as necessary, discussing with study physician.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           |                                                                                                                                                        |                                                          |
| If temporarily holding the study                                                                                                                                                                                                            |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          |                                                                                                                                                        |                                                          |
| drug/study regimen does not provide  improvement of the Grade 3 skin rash to  Grade ≤1 or baseline within 30 days, then  permanently discontinue study drug/study  regimen. For Grade 4: Permanently discontinue study drug/study  regimen. |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          |                                                                                                                                                        |                                                          |
| Endocrinopathy                                                                                                                                                                                                                              | Any Grade                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                | General Guidance                                                                                                                                       | For Any Grade:                                           |
| −                                                                                                                                                                                                                                           | Consider consulting an endocrinologist for endocrine events.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             |                                                                                                                                                        |                                                          |
| (e.g., hyperthyroidism,  thyroiditis,  hypothyroidism, Type 1  diabetes mellitus,  hypophysitis,  hypopituitarism, and  adrenal insufficiency;  exocrine event of  amylase/lipase increased  also included in this  section)                | (depending on the type  of endocrinopathy,  refer to NCI CTCAE  v4.03 for defining the  CTC grade/severity)                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              | −                                                                                                                                                      | Consider, as necessary, discussing with study physician. |
| −                                                                                                                                                                                                                                           | Monitor patients for signs and symptoms of endocrinopathies.  Non-specific symptoms include headache, fatigue, behavior  changes, changed mental status, vertigo, abdominal pain,  unusual bowel habits, polydipsia, polyuria, hypotension, and  weakness. − Patients should be thoroughly evaluated to rule out any  alternative etiology (e.g., disease progression including brain  metastases, or infections). − Depending on the suspected endocrinopathy, monitor and  evaluate thyroid function tests: TSH, free T3 and free T4 and  other relevant endocrine and related labs (e.g., blood glucose  and ketone levels, HgA1c). − For asymptomatic elevations in serum amylase and lipase >ULN and <3×ULN, corticosteroid treatment is not indicated  as long as there are no other signs or symptoms of pancreatic inflammation. |                                                                                                                                                        |                                                          |
| −                                                                                                                                                                                                                                           | If a patient experiences an AE that is thought to be possibly of  autoimmune nature (e.g., thyroiditis, pancreatitis, hypophysitis,                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      |                                                                                                                                                        |                                                          |  
| or diabetes insipidus), the investigator should send a blood  sample for appropriate autoimmune antibody testing.                                                                                                                                                                                                                                                                                                                                                                                                      |                                                                                                                                                                                                                        |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Grade 1                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                | No dose modifications.                                                                                                                                                                                                 | For Grade 1 (including those with asymptomatic TSH elevation): − Monitor patient with appropriate endocrine function tests. − For suspected hypophysitis/hypopituitarism, consider  consultation of an endocrinologist to guide assessment of earlymorning ACTH, cortisol, TSH and free T4; also consider  gonadotropins, sex hormones, and prolactin levels, as well as  cosyntropin stimulation test (though it may not be useful in  diagnosing early secondary adrenal insufficiency). − If TSH < 0.5 × LLN, or TSH >2 × ULN, or consistently out of  range in 2 subsequent measurements, include free T4 at  subsequent cycles as clinically indicated and consider  consultation of an endocrinologist.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              |
| Grade 2                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                | For Grade 2 endocrinopathy other than  hypothyroidism and Type 1 diabetes  mellitus, hold study drug/study regimen  dose until patient is clinically stable. - If toxicity worsens, then treat as  Grade 3 or Grade 4. | For Grade 2 (including those with symptomatic endocrinopathy): − Consult endocrinologist to guide evaluation of endocrine  function and, as indicated by suspected endocrinopathy and as  clinically indicated, consider pituitary scan. − For all patients with abnormal endocrine work up, except those  with isolated hypothyroidism or Type 1 DM, and as guided by  an endocrinologist, consider short-term corticosteroids (e.g., 1  to 2 mg/kg/day methylprednisolone or IV equivalent) and  prompt initiation of treatment with relevant hormone  replacement (e.g., hydrocortisone, sex hormones). − Isolated hypothyroidism may be treated with replacement  therapy, without study drug/study regimen interruption, and  without corticosteroids. − Isolated Type 1 diabetes mellitus (DM) may be treated with  appropriate diabetic therapy, without study drug/study regimen  interruption, and without corticosteroids. − Once patients on steroids are improving, gradually taper  immunosuppressive steroids (as appropriate and with guidance  of endocrinologist) over ≥28 days and consider prophylactic  antibiotics, antifungals, and anti-PJP treatment (refer to current  NCCN guidelines for treatment of cancer-related infections).a − For patients with normal endocrine workup (laboratory  assessment or MRI scans), repeat laboratory assessments/MRI  as clinically indicated. |
| Study drug/study regimen can be resumed  once event stabilizes and after completion  of steroid taper. Patients with endocrinopathies who may  require prolonged or continued steroid  replacement (e.g., adrenal insufficiency)  can be retreated with study drug/study  regimen on the following conditions: 1. The event stabilizes and is  controlled. 2. The patient is clinically stable as per  investigator or treating physician's  clinical judgement. 3. Doses of prednisone are ≤10 mg/day  or equivalent. |                                                                                                                                                                                                                        |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              |  
| Grade 3 or 4                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           | For Grade 3 or 4 endocrinopathy other  than hypothyroidism and Type 1 diabetes  mellitus, hold study drug/study regimen  dose until endocrinopathy symptom(s) are  controlled.                                                                                                                                                                                                                                                                                                                                                                                                                                                             | For Grade 3 or 4:   |                |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------|----------------|
| −                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      | Consult endocrinologist to guide evaluation of endocrine                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   |                     |                |
| function and, as indicated by suspected endocrinopathy and as  clinically indicated, consider pituitary scan. Hospitalization  recommended.                                                                                                                                                                                                                                                                                                                                                                            |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            |                     |                |
| −                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      | For all patients with abnormal endocrine work up, except those  with isolated hypothyroidism or Type 1 DM, and as guided by  an endocrinologist, promptly initiate empiric IV  methylprednisolone 1 to 2 mg/kg/day or equivalent, as well as  relevant hormone replacement (e.g., hydrocortisone, sex  hormones).                                                                                                                                                                                                                                                                                                                          |                     |                |
| −                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      | For adrenal crisis, severe dehydration, hypotension, or shock,  immediately initiate IV corticosteroids with mineralocorticoid  activity.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  |                     |                |
| −                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      | 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).a |                     |                |
| Study drug/study regimen can be resumed  once event stabilizes and after completion  of steroid taper. Patients with endocrinopathies who may  require prolonged or continued steroid  replacement (e.g., adrenal insufficiency)  can be retreated with study drug/study  regimen on the following conditions: 1. The event stabilizes and is  controlled. 2. The patient is clinically stable as per  investigator or treating physician's  clinical judgement. 3. Doses of prednisone are ≤10 mg/day  or equivalent. |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            |                     |                |
| Neurotoxicity                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          | Any Grade                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  | General Guidance    | For Any Grade: |
| −                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      | Patients should be evaluated to rule out any alternative etiology  (e.g., disease progression, infections, metabolic syndromes, or  medications). − Monitor patient for general symptoms (headache, nausea,  vertigo, behavior change, or weakness).                                                                                                                                                                                                                                                                                                                                                                                       |                     |                |
| −                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      | Consider appropriate diagnostic testing (e.g., electromyogram  and nerve conduction investigations).                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       |                     |                |
| −                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      | Perform symptomatic treatment with Neurology consult as  appropriate. −                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    |                     |                |
| (to include but not be  limited to limbic  encephalitis and  autonomic neuropathy,  excluding Myasthenia  Gravis and GuillainBarre)                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        | (depending on the type  of neurotoxicity, refer  to NCI CTCAE v4.03  for defining the CTC  grade/severity)                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 |                     |                |  
| Grade 1                                                                                                                                                                                                                                                                                                                        | No dose modifications.                                                                                                                                                                                  | For Grade 1:                                                                                                     |                |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------|----------------|
| −                                                                                                                                                                                                                                                                                                                              | See "Any Grade" recommendations above.                                                                                                                                                                  |                                                                                                                  |                |
| Grade 2                                                                                                                                                                                                                                                                                                                        | For acute motor neuropathies or  neurotoxicity, hold study drug/study                                                                                                                                   |                                                                                                                  |                |
| regimen dose until resolution to Grade ≤1.                                                                                                                                                                                                                                                                                     | For Grade 2:                                                                                                                                                                                            |                                                                                                                  |                |
| −                                                                                                                                                                                                                                                                                                                              | Consider, as necessary, discussing with the study physician. − Obtain Neurology consult.                                                                                                                |                                                                                                                  |                |
| −                                                                                                                                                                                                                                                                                                                              | Sensory neuropathy/neuropathic pain may be managed by  appropriate medications (e.g., gabapentin or duloxetine).                                                                                        |                                                                                                                  |                |
| −                                                                                                                                                                                                                                                                                                                              | Promptly start systemic steroids prednisone 1 to 2 mg/kg/day  PO or IV equivalent.                                                                                                                      |                                                                                                                  |                |
| −                                                                                                                                                                                                                                                                                                                              | If no improvement within 3 to 5 days despite 1 to 2 mg/kg/day  prednisone PO or IV equivalent, consider additional workup  and promptly treat with additional immunosuppressive therapy  (e.g., IV IG). |                                                                                                                  |                |
| For sensory neuropathy/neuropathic pain,  consider holding study drug/study  regimen dose until resolution to Grade ≤1. If toxicity worsens, then treat as  Grade 3 or 4. Study drug/study regimen can be resumed  once event improves to Grade ≤1 and  after completion of steroid taper.                                     |                                                                                                                                                                                                         |                                                                                                                  |                |
| Grade 3 or 4                                                                                                                                                                                                                                                                                                                   | For Grade 3:                                                                                                                                                                                            | For Grade 3 or 4:                                                                                                |                |
| Hold study drug/study regimen dose until  resolution to Grade ≤1.                                                                                                                                                                                                                                                              | −                                                                                                                                                                                                       | Consider, as necessary, discussing with study physician. − Obtain Neurology consult. − Consider hospitalization. |                |
| Permanently discontinue study drug/study  regimen if Grade 3 imAE does not resolve  to Grade ≤1 within 30 days.                                                                                                                                                                                                                | −                                                                                                                                                                                                       | Promptly initiate empiric IV methylprednisolone 1 to  2 mg/kg/day or equivalent.                                 |                |
| −                                                                                                                                                                                                                                                                                                                              | If no improvement within 3 to 5 days despite IV                                                                                                                                                         |                                                                                                                  |                |
| corticosteroids, consider additional workup and promptly treat  with additional immunosuppressants (e.g., IV IG). − Once stable, gradually taper steroids over ≥28 days.                                                                                                                                                       |                                                                                                                                                                                                         |                                                                                                                  |                |
| For Grade 4:                                                                                                                                                                                                                                                                                                                   |                                                                                                                                                                                                         |                                                                                                                  |                |
| Permanently discontinue study drug/study  regimen.                                                                                                                                                                                                                                                                             |                                                                                                                                                                                                         |                                                                                                                  |                |
| Peripheral neuromotor  syndromes                                                                                                                                                                                                                                                                                               | Any Grade                                                                                                                                                                                               | General Guidance                                                                                                 | For Any Grade: |
| −                                                                                                                                                                                                                                                                                                                              | The prompt diagnosis of immune-mediated peripheral                                                                                                                                                      |                                                                                                                  |                |
| neuromotor syndromes is important, since certain patients may  unpredictably experience acute decompensations that can result  in substantial morbidity or in the worst case, death. Special care  should be taken for certain sentinel symptoms that may predict  a more severe outcome, such as prominent dysphagia, rapidly |                                                                                                                                                                                                         |                                                                                                                  |                |
| (such as Guillain-Barre  and myasthenia gravis)                                                                                                                                                                                                                                                                                |                                                                                                                                                                                                         |                                                                                                                  |                |  
| progressive weakness, and signs of respiratory insufficiency or  autonomic instability.                                                                                             |                                                                                                                                                                                                                                                                                         |              |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------|
| −                                                                                                                                                                                   | Patients should be evaluated to rule out any alternative etiology  (e.g., disease progression, infections, metabolic syndromes or  medications). It should be noted that the diagnosis of immunemediated peripheral neuromotor syndromes can be particularly  challenging in patients with underlying cancer, due to the  multiple potential confounding effects of cancer (and its  treatments) throughout the neuraxis. Given the importance of  prompt and accurate diagnosis, it is essential to have a low  threshold to obtain a Neurology consult.                                                                                                                                                                                                                                                                                         |              |
| −                                                                                                                                                                                   | Neurophysiologic diagnostic testing (e.g., electromyogram and  nerve conduction investigations, and "repetitive stimulation" if  myasthenia is suspected) are routinely indicated upon suspicion  of such conditions and may be best facilitated by means of a  Neurology consultation. |              |
| −                                                                                                                                                                                   | It is important to consider that the use of steroids as the primary  treatment of Guillain-Barre is not typically considered  effective. Patients requiring treatment should be started with IV  IG and followed by plasmapheresis if not responsive to IV IG.                          |              |
| Grade 1                                                                                                                                                                             | No dose modifications.                                                                                                                                                                                                                                                                  | For Grade 1: |
| −                                                                                                                                                                                   | Consider, as necessary, discussing with the study physician.                                                                                                                                                                                                                            |              |
| −                                                                                                                                                                                   | Care should be taken to monitor patients for sentinel symptoms  of a potential decompensation as described above. − Obtain a Neurology consult.                                                                                                                                         |              |
| Grade 2                                                                                                                                                                             | Hold study drug/study regimen dose until  resolution to Grade ≤1.                                                                                                                                                                                                                       | For Grade 2: |
| −                                                                                                                                                                                   | Consider, as necessary, discussing with the study physician.                                                                                                                                                                                                                            |              |
| −                                                                                                                                                                                   | Care should be taken to monitor patients for sentinel symptoms  of a potential decompensation as described above. − Obtain a Neurology consult                                                                                                                                          |              |
| −                                                                                                                                                                                   | Sensory neuropathy/neuropathic pain may be managed by  appropriate medications (e.g., gabapentin or duloxetine).                                                                                                                                                                        |              |
| Permanently discontinue study drug/study  regimen if it does not resolve to Grade ≤1  within 30 days or if there are signs of  respiratory insufficiency or autonomic  instability. | MYASTHENIA GRAVIS:                                                                                                                                                                                                                                                                      |              |
| o                                                                                                                                                                                   | Steroids may be successfully used to treat myasthenia  gravis. It is important to consider that steroid therapy  (especially with high doses) may result in transient  worsening of myasthenia and should typically be                                                                  |              |  
| administered in a monitored setting under supervision  of a consulting neurologist.                                                                                                           |                                                                                                                                                                                                                               |                                                                                                                  |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------|
| o                                                                                                                                                                                             | Patients unable to tolerate steroids may be candidates  for treatment with plasmapheresis or IV IG. Such  decisions are best made in consultation with a  neurologist, taking into account the unique needs of  each patient. |                                                                                                                  |
| o                                                                                                                                                                                             | If myasthenia gravis-like neurotoxicity is present,  consider starting AChE inhibitor therapy in addition  to steroids. Such therapy, if successful, can also serve  to reinforce the diagnosis. GUILLAIN-BARRE:              |                                                                                                                  |
| o                                                                                                                                                                                             | It is important to consider here that the use of steroids  as the primary treatment of Guillain-Barre is not  typically considered effective.                                                                                 |                                                                                                                  |
| o                                                                                                                                                                                             | Patients requiring treatment should be started with IV  IG and followed by plasmapheresis if not responsive  to IV IG.                                                                                                        |                                                                                                                  |
| Grade 3 or 4                                                                                                                                                                                  | For Grade 3:                                                                                                                                                                                                                  | For Grade 3 or 4 (severe or life-threatening events): − Consider, as necessary, discussing with study physician. |
| Hold study drug/study regimen dose until  resolution to Grade ≤1.                                                                                                                             | −                                                                                                                                                                                                                             | Recommend hospitalization.                                                                                       |
| −                                                                                                                                                                                             | Monitor symptoms and obtain Neurology consult.                                                                                                                                                                                |                                                                                                                  |
| Permanently discontinue study drug/study  regimen if Grade 3 imAE does not resolve  to Grade ≤1 within 30 days or if there are  signs of respiratory insufficiency or  autonomic instability. | MYASTHENIA GRAVIS:                                                                                                                                                                                                            |                                                                                                                  |
| o                                                                                                                                                                                             | Steroids may be successfully used to treat myasthenia  gravis. They should typically be administered in a  monitored setting under supervision of a consulting  neurologist.                                                  |                                                                                                                  |
| o                                                                                                                                                                                             | Patients unable to tolerate steroids may be candidates  for treatment with plasmapheresis or IV IG.                                                                                                                           |                                                                                                                  |
| For Grade 4:                                                                                                                                                                                  | o                                                                                                                                                                                                                             | If myasthenia gravis-like neurotoxicity present,                                                                 |
| consider starting AChE inhibitor therapy in addition  to steroids. Such therapy, if successful, can also serve  to reinforce the diagnosis.                                                   |                                                                                                                                                                                                                               |                                                                                                                  |
| Permanently discontinue study drug/study  regimen.                                                                                                                                            | GUILLAIN-BARRE:                                                                                                                                                                                                               |                                                                                                                  |
| o                                                                                                                                                                                             | It is important to consider here that the use of steroids  as the primary treatment of Guillain-Barre is not  typically considered effective.                                                                                 |                                                                                                                  |  
o Patients requiring treatment should be started with IV
IG and followed by plasmapheresis if not responsive to IV IG.  
| 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 work-up should include clinical evaluation, BNP,  cardiac enzymes, ECG, echocardiogram (ECHO), monitoring  of oxygenation via pulse oximetry (resting and exertion), and  additional laboratory work-up as indicated. Spiral CT or  cardiac MRI can complement ECHO to assess wall motion  abnormalities when needed. − Patients should be thoroughly evaluated to rule out any  alternative etiology (e.g., disease progression, other  medications, or infections) |                    |                  |
| Discontinue drug permanently if biopsyproven immune-mediated myocarditis. No dose modifications required unless  clinical suspicion is high, in which case  hold study drug/study regimen dose  during diagnostic work-up for other  etiologies. If study drug/study regimen is  held, resume after complete resolution to  Grade 0.                                                                                |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            |                    |                  |
| Grade 1                                                                        | 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 work-up as clinically  indicated.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             |                    |                  |
| -                                                                              | Consider using steroids if clinical suspicion is high.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     |                    |                  |
| (asymptomatic with  laboratory [e.g., BNP]  or cardiac imaging  abnormalities) |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            |                    |                  |  
| Grade 2, 3 or 4                                                                                                                                                                                                                                                                                                                                                                                                                                       | - If Grade 2 -- Hold study drug/study  regimen dose until resolution to  Grade 0. If toxicity rapidly improves to  Grade 0, then the decision to reinitiate  study drug/study regimen will be based  upon treating physician's clinical  judgment and after completion of  steroid taper. If toxicity does not  rapidly improve, permanently.  discontinue study drug/study regimen.                                                                                                                                                                                      | For Grade 2-4:                                                                                                    |                |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------|----------------|
| −                                                                                                                                                                                                                                                                                                                                                                                                                                                     | Monitor symptoms daily, hospitalize.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      |                                                                                                                   |                |
| (Grade 2: Symptoms  with mild to moderate  activity or exertion)                                                                                                                                                                                                                                                                                                                                                                                      | −                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         | Promptly start IV methylprednisolone 2 to 4 mg/kg/day or  equivalent after Cardiology consultation has determined |                |
| whether and when to complete diagnostic procedures including  a cardiac biopsy. − Supportive care (e.g., oxygen). − If no improvement within 3 to 5 days despite IV  methylprednisolone at 2 to 4 mg/kg/day, promptly start  immunosuppressive therapy such as TNF inhibitors  (e.g., infliximab at 5 mg/kg every 2 weeks). Caution: It is  important to rule out sepsis and refer to infliximab label for  general guidance before using infliximab. |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           |                                                                                                                   |                |
| −                                                                                                                                                                                                                                                                                                                                                                                                                                                     | Once the patient is improving, gradually taper steroids over  ≥28 days and consider prophylactic antibiotics, antifungals, or  anti-PJP treatment (refer to current NCCN guidelines for  treatment of cancer-related infections).a                                                                                                                                                                                                                                                                                                                                        |                                                                                                                   |                |
| (Grade 3: Severe with  symptoms at rest or  with minimal activity  or exertion;  intervention indicated)                                                                                                                                                                                                                                                                                                                                              | If Grade 3-4, permanently discontinue  study drug/study regimen.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          |                                                                                                                   |                |
| (Grade 4: Lifethreatening                                                                                                                                                                                                                                                                                                                                                                                                                                                       |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           |                                                                                                                   |                |
| consequences; urgent intervention indicated  (e.g., continuous IV  therapy or mechanical  hemodynamic support))                                                                                                                                                                                                                                                                                                                                       |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           |                                                                                                                   |                |
| Myositis/Polymyositis  ("Poly/myositis")                                                                                                                                                                                                                                                                                                                                                                                                              | Any Grade                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 | General Guidance                                                                                                  | For 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.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             |                                                                                                                                                    |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| −                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               | Consider, as necessary, discussing with the study physician.                                                                                       |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    |
| −                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               | Initial work-up should include clinical evaluation, creatine  kinase, aldolase, LDH, BUN/creatinine, erythrocyte                                   |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    |
| sedimentation rate or C-reactive protein level, urine myoglobin,  and additional laboratory work-up as indicated, including a  number of possible rheumatological/antibody tests (i.e.,  consider whether a rheumatologist consultation is indicated and  could guide need for rheumatoid factor, antinuclear antibody,  anti-smooth muscle, antisynthetase [such as anti-Jo-1], and/or  signal-recognition particle antibodies). Confirmatory testing  may include electromyography, nerve conduction studies, MRI  of the muscles, and/or a muscle biopsy. Consider Barium  swallow for evaluation of dysphagia or dysphonia. |                                                                                                                                                    |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    |
| Patients should be thoroughly evaluated to rule out any alternative  etiology (e.g., disease progression, other medications, or infections).                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    |                                                                                                                                                    |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    |
| Grade 1                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         | - No dose modifications.                                                                                                                           | For Grade 1:                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       |
| −                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               | 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.                                                                                       |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    |
| (mild pain) Grade 2                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             | Hold study drug/study regimen dose until  resolution to Grade ≤1.                                                                                  | For Grade 2:                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       |
| −                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               | Monitor symptoms daily and consider hospitalization.                                                                                               |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    |
| (moderate pain  associated with                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 |                                                                                                                                                    |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    |
| weakness; pain limiting  instrumental activities  of daily living [ADLs])                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       | −                                                                                                                                                  | Obtain Neurology consult, and initiate evaluation.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 |
| - Permanently discontinue study  drug/study regimen if it does not  resolve to Grade ≤1 within 30 days or  if there are signs of respiratory  insufficiency.                                                                                                                                                                                                                                                                                                                                                                                                                                                                    | −                                                                                                                                                  | Consider, as necessary, discussing with the study physician. − If clinical course is rapidly progressive (particularly if  difficulty breathing and/or trouble swallowing), promptly start  IV methylprednisolone 2 to 4 mg/kg/day systemic steroids  along with receiving input from Neurology consultant  − If clinical course is not rapidly progressive, start systemic  steroids (e.g., prednisone 1 to 2 mg/kg/day PO or IV  equivalent); if no improvement within 3 to 5 days, continue  additional work up and start treatment with IV  methylprednisolone 2 to 4 mg/kg/day − If after start of IV methylprednisolone at 2 to 4 mg/kg/day  there is no improvement within 3 to 5 days, consider start of  immunosuppressive therapy such as TNF inhibitors |  
| (e.g., infliximab at 5 mg/kg every 2 weeks). Caution: It is  important to rule out sepsis and refer to infliximab label for  general guidance before using infliximab.   |                                                                                                                                                                                                                                                                                                                                                      |                                                       |                                                      |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------|------------------------------------------------------|
| −                                                                                                                                                                        | Once the patient is improving, gradually taper steroids over  ≥28 days and consider prophylactic antibiotics, antifungals, or  anti-PJP treatment (refer to current NCCN guidelines for  treatment of cancer-related infections).a                                                                                                                   |                                                       |                                                      |
| Grade 3 or 4                                                                                                                                                             | For Grade 3:                                                                                                                                                                                                                                                                                                                                         | For Grade 3 or 4 (severe or life-threatening events): |                                                      |
| (pain associated with  severe weakness;  limiting self-care  ADLs)                                                                                                       | Hold study drug/study regimen dose until  resolution to Grade ≤1.                                                                                                                                                                                                                                                                                    | −                                                     | Monitor symptoms closely; recommend hospitalization. |
| −                                                                                                                                                                        | Obtain Neurology consult, and complete full evaluation.                                                                                                                                                                                                                                                                                              |                                                       |                                                      |
| −                                                                                                                                                                        | Consider, as necessary, discussing with the study physician.                                                                                                                                                                                                                                                                                         |                                                       |                                                      |
| Permanently discontinue study drug/study  regimen if Grade 3 imAE does not resolve  to Grade ≤1 within 30 days or if there are  signs of respiratory insufficiency.      | −                                                                                                                                                                                                                                                                                                                                                    | Promptly start IV methylprednisolone 2 to 4 mg/kg/day |                                                      |
| systemic steroids along with receiving input from Neurology  consultant.                                                                                                 |                                                                                                                                                                                                                                                                                                                                                      |                                                       |                                                      |
| −                                                                                                                                                                        | If after start of IV methylprednisolone at 2 to 4 mg/kg/day  there is no improvement within 3 to 5 days, consider start of  immunosuppressive therapy such as TNF inhibitors  (e.g., infliximab at 5 mg/kg every 2 weeks). Caution: It is  important to rule out sepsis and refer to infliximab label for  general guidance before using infliximab. |                                                       |                                                      |
| −                                                                                                                                                                        | Consider whether patient may require IV IG, plasmapheresis.                                                                                                                                                                                                                                                                                          |                                                       |                                                      |
| −                                                                                                                                                                        | Once the patient is improving, gradually taper steroids over  ≥28 days and consider prophylactic antibiotics, antifungals, or  anti-PJP treatment (refer to current NCCN guidelines for  treatment of cancer-related infections).a                                                                                                                   |                                                       |                                                      |
| For Grade 4:                                                                                                                                                             |                                                                                                                                                                                                                                                                                                                                                      |                                                       |                                                      |
| - Permanently discontinue study  drug/study regimen.                                                                                                                     |                                                                                                                                                                                                                                                                                                                                                      |                                                       |                                                      |
| a ASCO Educational Book 2015 "Managing Immune Checkpoint Blocking Antibody Side Effects" by Michael Postow MD.                                                           |                                                                                                                                                                                                                                                                                                                                                      |                                                       |                                                      |  
bFDA Liver Guidance Document 2009 Guidance for Industry: Drug Induced Liver Injury - Premarketing Clinical Evaluation.  
AChE Acetylcholine esterase; ADL Activities of daily living; AE Adverse event; ALP Alkaline phosphatase test; ALT Alanine aminotransferase; AST Aspartate aminotransferase; BUN Blood urea nitrogen; CT Computed tomography; CTCAE Common Terminology Criteria for Adverse Events; ILD Interstitial lung disease; imAE immune-mediated adverse event; IG Immunoglobulin; IV Intravenous; GI Gastrointestinal; LFT Liver function tests; LLN Lower limit of normal; MRI Magnetic resonance imaging; NCI National Cancer Institute; NCCN National Comprehensive Cancer Network; PJP *Pneumocystis jirovecii* pneumonia (formerly known as *Pneumocystis carinii* pneumonia); PO By mouth; T3 Triiodothyronine; T4 Thyroxine; TB Total bilirubin; TNF Tumor necrosis factor; TSH Thyroid-stimulating hormone; ULN Upper limit of normal.  
| Infusion-Related Reactions                                                                                                                                                                                                                                                                                                                          |                                                                                                                                                                                                                                                                                                                                                                                                           |                                                            |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------|
| Severity Grade of the  Event (NCI CTCAE  version 4.03)                                                                                                                                                                                                                                                                                              | Dose Modifications                                                                                                                                                                                                                                                                                                                                                                                        | Toxicity Management                                        |
| Any Grade                                                                                                                                                                                                                                                                                                                                           | General Guidance                                                                                                                                                                                                                                                                                                                                                                                          | For Any Grade:                                             |
| −                                                                                                                                                                                                                                                                                                                                                   | Manage per institutional standard at the discretion of investigator. − Monitor patients for signs and symptoms of infusion-related  reactions (e.g., fever and/or shaking chills, flushing and/or itching,  alterations in heart rate and blood pressure, dyspnea or chest  discomfort, or skin rashes) and anaphylaxis (e.g., generalized urticaria, angioedema, wheezing, hypotension, or tachycardia). |                                                            |
| Grade 1 or 2                                                                                                                                                                                                                                                                                                                                        | For Grade 1:                                                                                                                                                                                                                                                                                                                                                                                              | For Grade 1 or 2:                                          |
| −                                                                                                                                                                                                                                                                                                                                                   | Acetaminophen and/or antihistamines may be administered per  institutional standard at the discretion of the investigator. − Consider premedication per institutional standard prior to  subsequent doses.                                                                                                                                                                                                |                                                            |
| −                                                                                                                                                                                                                                                                                                                                                   | Steroids should not be used for routine premedication of Grade ≤2  infusion reactions.                                                                                                                                                                                                                                                                                                                    |                                                            |
| The infusion rate of study drug/study regimen may be decreased  by 50% or temporarily interrupted until resolution of the event. For Grade 2: The infusion rate of study drug/study regimen may be decreased  50% or temporarily interrupted until resolution of the event. Subsequent infusions may be given at 50% of the initial  infusion rate. |                                                                                                                                                                                                                                                                                                                                                                                                           |                                                            |
| Grade 3 or 4                                                                                                                                                                                                                                                                                                                                        | For Grade 3 or 4:                                                                                                                                                                                                                                                                                                                                                                                         | For Grade 3 or 4:                                          |
| Permanently discontinue study drug/study regimen.                                                                                                                                                                                                                                                                                                   | −                                                                                                                                                                                                                                                                                                                                                                                                         | Manage severe infusion-related reactions per institutional |
| standards (e.g., IM epinephrine, followed by IV diphenhydramine  and ranitidine, and IV glucocorticoid).                                                                                                                                                                                                                                            |                                                                                                                                                                                                                                                                                                                                                                                                           |                                                            |
| CTCAE Common Terminology Criteria for Adverse Events; IM intramuscular; IV intravenous; NCI National Cancer Institute.                                                                                                                                                                                                                              |                                                                                                                                                                                                                                                                                                                                                                                                           |                                                            |  
| Non–Immune-Mediated Reactions                                                                                                                                         |                                                                                                                                                                                                                                                                                  |                                                   |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------|
| Severity Grade of the Event  (NCI CTCAE version 4.03)                                                                                                                 | Dose Modifications                                                                                                                                                                                                                                                               | Toxicity Management                               |
| Any Grade                                                                                                                                                             | Note: Dose modifications are not required for AEs not deemed to  be related to study treatment (i.e., events due to underlying  disease) or for laboratory abnormalities not deemed to be  clinically significant.                                                               | Treat accordingly, as per institutional standard. |
| Grade 1                                                                                                                                                               | No dose modifications.                                                                                                                                                                                                                                                           | Treat accordingly, as per institutional standard. |
| Grade 2                                                                                                                                                               | Hold study drug/study regimen until resolution to ≤Grade 1 or  baseline.                                                                                                                                                                                                         | Treat accordingly, as per institutional standard. |
| Grade 3                                                                                                                                                               | Hold study drug/study regimen until resolution to ≤Grade 1 or  baseline. For AEs that downgrade to ≤Grade 2 within 7 days or resolve to  ≤Grade 1 or baseline within 14 days, resume study drug/study  regimen administration. Otherwise, discontinue study drug/study  regimen. | Treat accordingly, as per institutional standard. |
| Grade 4                                                                                                                                                               | Discontinue study drug/study regimen (Note: For Grade 4 labs,  decision to discontinue should be based on accompanying  clinical signs/symptoms, the Investigator's clinical judgment, and  consultation with the Sponsor.).                                                     | Treat accordingly, as per institutional standard. |
| Note: As applicable, for early phase studies, the following sentence may be added: "Any event greater than or equal to Grade 2, please discuss with Study Physician." |                                                                                                                                                                                                                                                                                  |                                                   |  
AE Adverse event; CTCAE Common Terminology Criteria for Adverse Events; NCI National Cancer Institute.