4.11. diet/activity/other considerations
6.2. dose modifications of pembrolizumab

AEs (both non-serious and serious) associated with pembrolizumab and epacadostat exposure may represent an immunologic etiology. These adverse events may occur shortly after the first dose or several months after the last dose of treatment. Based on existing clinical trial data, most irAEs were reversible and could be managed with interruptions of pembrolizumab and epacadostat, administration of corticosteroids and/or other supportive care. For suspected irAEs,  
  
 ensure adequate evaluation to confirm etiology or exclude other causes. Based on the severity of irAEs, withhold or permanently discontinue pembrolizumab and epacadostat and administer corticosteroids. Dose modification and toxicity management guidelines for irAEs associated with pembrolizumab are provided in **Table 4**. See Sections 4.10.4 for additional supportive care guidelines, including use of corticosteroids if necessary. Patients requiring treatment with corticosteroids for irAEs should be held through completion of taper, unless otherwise discussed and approved by Merck and Incyte.  
In case toxicity does not resolve to Grade 1 within 12 weeks after last dose of study treatment should be discontinued only after consultation with Merck and Incyte. With investigator and Merck and Incyte agreement, subjects with a laboratory AE still at Grade 2 after 12 weeks may continue treatment in the study only if asymptomatic and controlled. General Instructions for management of irAE
1. Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over at least 4 weeks.  
2. For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has been reduced to Grade 1 or 0 and corticosteroid has been tapered. For subjects with Grade 3 or 4 immune-related endocrinopathy, pembrolizumab may be resumed when AE improves to Grade 2 or lower and is controlled with hormonal replacement therapy.  
3. For situation where pembrolizumab is withheld initially, pembrolizumab should be permanently discontinued if AE does not resolve within 12 weeks of last dose or corticosteroids cannot be reduced to ≤ 10 mg prednisone or equivalent per day within 12 weeks. However, subjects with asymptomatic 4. For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. Other immunosuppressive treatment should be initiated if irAEs cannot be controlled by corticosteroids Table 4: Dose Modification Guidelines for Drug Immune-Related AEs associated with epacadostat  
  
  
  
and pembrolizumab General instructions for AEs associated with Pembrolizumab:
1. Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over at least 4 weeks.  
2. For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has been reduced to Grade 1 or 0 and corticosteroid has been tapered. Pembrolizumab should be permanently discontinued if AE does not resolve within 12 weeks of last dose or corticosteroids cannot be reduced to ≤10 mg prednisone or equivalent per day within 12 weeks.  
3. For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. Other immunosuppressive treatment should be initiated if irAEs cannot be controlled by corticosteroids.  
The below table represents guidelines and are not required management for immune-related AEs and can be implemented at the discretion of the investigator. Specialist referral (Endocrinology, Pulmonary, GI, etc) is encouraged if questions arise about appropriate management. Note: Unless listed below, Grade 1 for all disease groups: continue therapy, treat symptoms, close monitoring for worsening symptoms, educate patient to report worsening  
  
 immediately, if worsens: Treat as Grade (G) 2 or 3/4.  
| Toxicity                                                                                                                                                                                                                                                                                         | Hold Treatment                                                                                                                                                | Management + Timing for Restarting  Treatment                                                                                                                         | Follow-up   | Treatment Discontinuation   |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------|-----------------------------|
| For Grade                                                                                                                                                                                                                                                                                        | - Delay therapy for new onset Type 1  diabetes mellitus or Grade 3-4  hyperglycemia associated with evidence of  beta cell failure.                           |                                                                                                                                                                       |             |                             |
| Type 1 diabetes  mellitus (if new  onset, including  diabetic  ketoacidosis  [DKA]) or ≥ Grade  3 Hyperglycemia, if  associated with  ketosis (ketonuria)  or metabolic  acidosis (DKA)                                                                                                          | - Insulin replacement therapy is  recommended for Type I diabetes mellitus  and for Grade 3-4 hyperglycemia associated  with metabolic acidosis or ketonuria. |                                                                                                                                                                       |             |                             |
| Type 1 diabetes  mellitus (if new  onset) or  Hyperglycemia1                                                                                                                                                                                                                                     | Discontinue Pembrolizumab and  Epacadostat if not clinically and  metabolically stable                                                                        |                                                                                                                                                                       |             |                             |
| ________                                                                                                                                                                                                                                                                                         |                                                                                                                                                               |                                                                                                                                                                       |             |                             |
| - Evaluate patients with serum glucose and a  metabolic panel, urine ketones, glycosylated  hemoglobin, and C-peptide.  - Resume therapy when patients are  clinically and metabolically stable  - Continue therapy.                                                                             |                                                                                                                                                               |                                                                                                                                                                       |             |                             |
| Grade 2                                                                                                                                                                                                                                                                                          | ________                                                                                                                                                      | ________                                                                                                                                                              |             |                             |
| - Non-selective beta blockers (e.g.  propranolol) are suggested as initial therapy. - Delay therapy - Resume therapy with one dose reduction  when toxicity resolves to Grade 0-1                                                                                                                |                                                                                                                                                               |                                                                                                                                                                       |             |                             |
| Hyperthyroidism1                                                                                                                                                                                                                                                                                 | -Treat with non-selective beta-blockers or  thionamides as appropriate                                                                                        | Toxicity does not resolve within 12  weeks of last dose or inability to  reduce corticosteroid to 10 mg or less  of prednisone or equivalent per day  within 12 weeks |             |                             |
| Grade 3                                                                                                                                                                                                                                                                                          | ________                                                                                                                                                      |                                                                                                                                                                       |             |                             |
| - Treat with an initial dose of IV  corticosteroid followed by oral  corticosteroids. When symptoms improve to  Grade 1 or less, steroid taper should be  started and continued over no less than 4  weeks. Replacement of appropriate hormones may  be required as the steroid dose is tapered. |                                                                                                                                                               |                                                                                                                                                                       |             |                             |  
  
  
| -Consider endocrine consult - Discontinue therapy permanently.  - Treat with an initial dose of IV  corticosteroid followed by oral  corticosteroids. When symptoms improve to  Grade 1 or less, steroid taper should be  started and continued over no less than 4  weeks.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           |                                                         |                                           |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------|-------------------------------------------|
| Grade 4                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               | _________                                               | Permanently discontinue                   |
| - Consider endocrine consult - Continue therapy at same doses. - Thyroid hormone replacement therapy,  with levothyroxine or liothyroinine, is  indicated per standard of care.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       | Discontinue Pembrolizumab and                           |                                           |
| ________                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              | Epacadostat if not clinically and  metabolically stable |                                           |
| Hypothyroidism1                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       | Grade 2-4                                               | -Consider endocrine consult for Grade 3-4 |
| Thyroid disorders can occur at any time during treatment. Monitor patients for changes in thyroid function (at the start of treatment, periodically during treatment, and as indicated based on  clinical evaluation) and for clinical signs and symptoms of thyroid disorders - Delay therapy - 1.0 to 2.0 mg/kg/day methylprednisolone  IV or IV equivalent and initiate hormonal  replacement as clinically indicated Toxicity does not resolve within 12  weeks of last dose or inability to  reduce corticosteroid to 10 mg or less  of prednisone or equivalent per day  within 12 weeks ________ - Can resume once metabolically and  clinically stable and on doses of steroids <  10mg/day prednisone equivalent. Grade 2 Hypophysitis - Consult endocrinology for all grades Grades 3-4 - Discontinue therapy permanently. ________ Permanently discontinue |                                                         |                                           |  
  
  
| - Delay therapy - Rule out sepsis - Stress dose of IV steroids with  mineralocorticoid activity                                                                                                                                   |                                                                                                                                                                       |                                                                                                                                                                                                                                                              |          |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------|
| Suspicion of adrenal  crisis (e.g. severe  dehydration,  hypotension, shock  out of proportion to  current illness1                                                                                                               | - IV fluids                                                                                                                                                           | ________                                                                                                                                                                                                                                                     | ________ |
| - Consult endocrinologist - If adrenal crisis ruled out, then treat as  above for symptomatic endocrinopathy.  - Can resume once metabolically and  clinically stable and on doses of steroids <  10mg/day prednisone equivalent. | If improves for to grade 1: - Resume therapy with same dose                                                                                                           |                                                                                                                                                                                                                                                              |          |
| Grade 2                                                                                                                                                                                                                           |                                                                                                                                                                       |                                                                                                                                                                                                                                                              |          |
| Diarrhea: 4-6  stools/day over  baseline; IV fluids  indicated < 24 hours  (hrs); not interfering  with ADL.  Colitis: abdominal  pain; blood in stool                                                                            | -Delay therapy for 5-7 days and reevaluate.                                                                                                                           | If persists > 5-7 days or recur: - 1.0-2.0 mg/kg/day methylprednisolone or oral  equivalent - When symptoms improve to grade 1, taper  steroids over at least 4 weeks, consider  prophylactic antibiotics for opportunistic  infections, and resume therapy. |          |
| -Resume therapy with same dose when  toxicity resolves to Grade 0-1                                                                                                                                                               | Toxicity does not resolve within 12  weeks of last dose or inability to  reduce corticosteroid to 10 mg or less  of prednisone or equivalent per day  within 12 weeks |                                                                                                                                                                                                                                                              |          |
| Diarrhea/Colitis1                                                                                                                                                                                                                 | -Symptomatic treatment  -Drink liberal liquids if not feasible  administer fluids via IV infusion                                                                     | If worsens or persists >3-5 days with oral  steroids: - Treat as Grade 3/4                                                                                                                                                                                   |          |  
  
  
| - Delay therapy for 3-5 days and reevaluate.                                                                                                                                    |                                                                                                                                                                                 |                                                                                 |                                                         |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------|---------------------------------------------------------|
| Grade 3                                                                                                                                                                         |                                                                                                                                                                                 |                                                                                 |                                                         |
| Diarrhea: >7  stools/day over  baseline; IV fluids  ≥24 hrs; interfering  with ADL.  Colitis: severe  abdominal pain,  medical intervention  indicated, peritoneal  signs       | If improves: - Continue steroids until grade 1, then taper over  at least 4 weeks.                                                                                              |                                                                                 |                                                         |
| -Resume therapy with one dose reduction  when toxicity resolves to Grade 0-1. - 1.0 to 2.0 mg/kg/day methylprednisolone  IV or IV equivalent.                                   | Toxicity does not resolve within 12  weeks of last dose or inability to  reduce corticosteroid to 10 mg or less  of prednisone or equivalent per day  within 12 weeks           |                                                                                 |                                                         |
| If persists > 3-5 days, or recurs after  improvement: - GI referral, and consideration of Infliximab 5  mg/kg under supervision by gastroenterologist (if  no contraindication) |                                                                                                                                                                                 |                                                                                 |                                                         |
| - Add prophylactic antibiotics for  opportunistic infections - Consider lower endoscopy                                                                                         | Note: Infliximab should not be used in cases of  perforation or sepsis                                                                                                          |                                                                                 |                                                         |
| -Drink liberal liquids if not feasible  administer fluids via IV infusion - Discontinue therapy permanently.                                                                    | If improves: - Continue steroids until grade 1, then taper over  at least 4 Weeks.                                                                                              |                                                                                 |                                                         |
| - 1.0 to 2.0 mg/kg/day methylprednisolone  IV or IV equivalent.                                                                                                                 | If persists > 3-5 days, or recurs after  improvement: - GI referral, and consideration of Infliximab 5  mg/kg under supervision by gastroenterologist (if  no contraindication) |                                                                                 |                                                         |
| Grade 4                                                                                                                                                                         |                                                                                                                                                                                 |                                                                                 |                                                         |
| life-threatening,  perforation                                                                                                                                                  | - Add prophylactic antibiotics for  opportunistic infections                                                                                                                    | Permanently discontinue                                                         |                                                         |
| - Consider lower endoscopy -Drink liberal liquids if not feasible  administer fluids via IV infusion                                                                            | Note: Infliximab should not be used in cases of  perforation or sepsis                                                                                                          |                                                                                 |                                                         |
| Grade 1                                                                                                                                                                         |                                                                                                                                                                                 |                                                                                 |                                                         |
| AST or ALT > ULN  TO 3.0 x ULN  and/or T. bili > ULN  - 1.5 x ULN                                                                                                               | - Continue liver function tests (LFT) monitoring                                                                                                                                |                                                                                 |                                                         |
| - Continue therapy                                                                                                                                                              | per protocol                                                                                                                                                                    |                                                                                 |                                                         |
| AST, ALT, or                                                                                                                                                                    |                                                                                                                                                                                 |                                                                                 |                                                         |
| Increased Bilirubin1                                                                                                                                                            | Grade 2                                                                                                                                                                         |                                                                                 |                                                         |
| AST or ALT > 3.0  to ≤ 5 x ULN and/or  T. bili > 1.5 to 3 x  ULN                                                                                                                | - Delay therapy for 5-7 days and reevaluate.                                                                                                                                    | If returns to baseline: - Resume routine monitoring, resume therapy  same dose. | Toxicity does not resolve within 12  weeks of last dose |
| - Resume therapy with same dose when  toxicity resolves to Grade 0-1                                                                                                            | If elevation persist > 5-7 days or worsen:                                                                                                                                      |                                                                                 |                                                         |  
  
  
| - Increase frequency of monitoring to every                                                                                                                                      | - 0.5-1.0 mg/kg/day methylprednisolone or oral                                                                                                                                                                                            |                                                                                                                                                                       |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| 3 days.                                                                                                                                                                          | equivalent and when LFT returns to grade 1 or  baseline, a steroid taper should be started and  continued over no less than 4 weeks, consider  prophylactic antibiotics for opportunistic  infections, and resume therapy with same dose. |                                                                                                                                                                       |
| - Discontinue therapy permanently (see  exception below)a (Therapy may be delayed rather  discontinued if AST/ALT ≤ 8 x ULN and  T.bili ≤ 5 x ULN)                               | If returns to grade 2: - Taper steroids over at least 4 weeks                                                                                                                                                                             |                                                                                                                                                                       |
| - Increase frequency of monitoring to every  1-2 days                                                                                                                            |                                                                                                                                                                                                                                           |                                                                                                                                                                       |
| Grade 3-4                                                                                                                                                                        |                                                                                                                                                                                                                                           |                                                                                                                                                                       |
| AST or ALT > 5 x  ULN and/or T. bili >  3 x ULN                                                                                                                                  | If does not improve in > 3-5 days, or worsens  or rebounds: - Add mycophenolate mofetil 1g twice daily  (BID) - If no response within an additional 3-5 days,  consider other immunosuppressants per local  guidelines.                   |                                                                                                                                                                       |
| - 1.0 to 2.0 mg/kg/day methylprednisolone  IV or IV equivalent (The recommended starting dose for grade 4  hepatitis is 2 mg/kg/day methylprednisolone  IV)                      | Permanently discontinue                                                                                                                                                                                                                   |                                                                                                                                                                       |
| - Add prophylactic antibiotics for  opportunistic infections - Consult gastroenterologist - Delay therapy.  - Resume therapy with same dose when  toxicity resolves to Grade 0-1 | If improves to baseline: - Resume therapy with same dose when toxicity  resolves to Grade 0-1                                                                                                                                             | Toxicity does not resolve within 12  weeks of last dose or inability to  reduce corticosteroid to 10 mg or less  of prednisone or equivalent per day  within 12 weeks |
| Grade 2 Moderate                                                                                                                                                                 |                                                                                                                                                                                                                                           |                                                                                                                                                                       |
| symptoms; Limiting  instrumental ADL                                                                                                                                             | - Treat symptoms per local guidelines                                                                                                                                                                                                     |                                                                                                                                                                       |
| Neurological1                                                                                                                                                                    | - Consider 0.5 to 1.0 mg/kg/day  methylprednisolone IV or PO equivalent.                                                                                                                                                                  | If worsens: - Treat as Grade 3-4                                                                                                                                      |
| -If ≥ Grade 2 Neurologic AE consider  Neurology consult and brain imaging - Discontinue therapy                                                                                  | If improves to grade 2:                                                                                                                                                                                                                   | Permanently discontinue                                                                                                                                               |  
  
  
| Grade 3-4                                                                                                                                                                                  |                                                                                                                                                                            |                                                                   |           |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------|-----------|
| Severe symptoms;  Limiting self-care  ADL; Lifethreatening                                                                                                                                                                                            | - Taper steroids over at least 4 weeks                                                                                                                                     |                                                                   |           |
| - If ≥ Grade 2 Neurologic AE consider  Neurology consult and brain imaging                                                                                                                 | If worsens or atypical presentation: - Consider IVIG or other immunosuppressive  therapies per local guidelines.                                                           |                                                                   |           |
| - Treat symptoms per local guidelines - 1.0-2.0 mg/kg/day IV methylprednisolone  or IV equivalent - Add prophylactic antibiotics for  opportunistic infections - Consider delay of therapy |                                                                                                                                                                            |                                                                   |           |
| Grade 1                                                                                                                                                                                    |                                                                                                                                                                            |                                                                   |           |
| Radiographic  changes only                                                                                                                                                                 | - Monitor for symptoms every 2-3 days                                                                                                                                      | - Re-image at least every 3 weeks                                 | _________ |
| - Consider Pulmonary and Infectious  Disease (ID) consults - Delay therapy -Resume therapy with same dose when  toxicity resolves to Grade 0-1                                             | - Re-image every 1-3 days                                                                                                                                                  |                                                                   |           |
| - For recurrent Grade 2 Pneumonitis  discontinue therapy                                                                                                                                   | If improves: - When symptoms return to near baseline, taper  steroids over at least 4 weeks and then resume  therapy with same dose and consider prophylactic  antibiotics |                                                                   |           |
| Pneumonitis1                                                                                                                                                                               | Toxicity does not resolve within 12  weeks of last dose or inability to  reduce corticosteroid to 10 mg or less  of prednisone or equivalent per day  within 12 weeks      |                                                                   |           |
| Grade 2                                                                                                                                                                                    |                                                                                                                                                                            |                                                                   |           |
| Mild to moderate  new symptoms                                                                                                                                                             | - Pulmonary and ID consults - Monitor symptoms daily, consider  hospitalization                                                                                            | If not improving after 2 weeks or worsening: - Treat as Grade 3-4 |           |
| - 1.0-2.0 mg/kg/day methylprednisolone IV  or oral equivalent, followed by taper - Add prophylactic antibiotics for  opportunistic infections - Consider bronchoscopy, lung biopsy         | If improves to baseline:                                                                                                                                                   |                                                                   |           |
| - Discontinue therapy                                                                                                                                                                      | - Taper steroids over at least 6 weeks                                                                                                                                     | Permanently discontinue                                           |           |
| Grade 3-4                                                                                                                                                                                  |                                                                                                                                                                            |                                                                   |           |  
  
  
| Severe new  symptoms;  New/worsening hypoxia; Lifethreatening                                                                                                                                                                                       | - Hospitalize                                                                                                                                                                                          | If not improving after 48 hours or worsening: - Add additional immunosuppression (e.g.  infliximab, cyclophosphamide, intravenous  immunoglobulin (IVIG), or mycophenolate  mofetil).   |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| - Pulmonary and ID consults - 2-4 mg/kg/day methylprednisolone IV or  IV equivalent - Add prophylactic antibiotics for  opportunistic infections - Consider bronchoscopy, lung biopsy |                                                                                                                                                                                                        |                                                                                                                                                                                         |
| Grade 1                                                                                                                                                                               |                                                                                                                                                                                                        |                                                                                                                                                                                         |
| Creatinine > ULN  and > than baseline  but ≤ 1.5 x baseline                                                                                                                           | If returns to baseline: - Resumes routine creatinine monitoring per                                                                                                                                    | ________                                                                                                                                                                                |
| protocol                                                                                                                                                                              |                                                                                                                                                                                                        |                                                                                                                                                                                         |
| - Continue therapy  - Monitor creatinine weekly - Delay therapy                                                                                                                       | If returns to Grade 1: - Taper steroids over at least 4 weeks, consider  prophylactic antibiotics for opportunistic  infections, and resume therapy with same dose  and routine creatinine monitoring. |                                                                                                                                                                                         |
| -Resume therapy with same dose when  toxicity resolves to Grade 0-1                                                                                                                   | Toxicity does not resolve within 12  weeks of last dose or inability to  reduce corticosteroid to 10 mg or less  of prednisone or equivalent per day  within 12 weeks                                  |                                                                                                                                                                                         |
| Grade 2                                                                                                                                                                               |                                                                                                                                                                                                        |                                                                                                                                                                                         |
| Creatinine > 1.5 x  baseline to 3.0 x  ULN                                                                                                                                            | - Monitor Creatinine every 2-3 days - 1.0 -2.0 mg/kg/day methylpredniolone IV  or oral equivalent.                                                                                                     |                                                                                                                                                                                         |
| Renal Failure or  Nephritis1                                                                                                                                                          | If elevations persist > 7 days or worsen: - Treat as Grade 4                                                                                                                                           |                                                                                                                                                                                         |
| - Consider renal biopsy - Discontinue therapy permanently - Monitor Creatinine daily                                                                                                  | If returns to grade 1: - Taper steroids over at least 4 weeks and add  prophylactic antibiotics for opportunistic                                                                                      | Permanently discontinue                                                                                                                                                                 |
| infections.                                                                                                                                                                           |                                                                                                                                                                                                        |                                                                                                                                                                                         |
| Grade 3-4                                                                                                                                                                             |                                                                                                                                                                                                        |                                                                                                                                                                                         |
| Creatinine > 3 x  baseline to > 6 x  ULN                                                                                                                                              | - 1.0-2.0 mg/kg/day methylpredniolone IV  or IV equivalent - Consult nephrologist - Consider renal biopsy                                                                                              |                                                                                                                                                                                         |  
  
  
| If persists > 1-2 weeks or recurs: - Continue therapy - Consider skin biopsy  - Consider 0.5-1.0 mg/kg/day methylprednisolone  IV or oral equivalent. Once improving, taper  steroids over at least 4 weeks, consider  prophylactic antibiotics for opportunistic  infections.   |                                                                                                                                                                                                                                                                                                               |                                  |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------|
| Grade 1                                                                                                                                                                                                                                                                          |                                                                                                                                                                                                                                                                                                               |                                  |
| Covering < 10%  body surface area  (BSA)*                                                                                                                                                                                                                                        | - Continue therapy                                                                                                                                                                                                                                                                                            | ________                         |
| - Symptomatic therapy (e.g. antihistamines,  topical steroids)                                                                                                                                                                                                                   | If persists > 1-2 weeks or recurs: - Consider skin biopsy  - Delay therapy - Consider 0.5-1.0 mg/kg/day methylprednisolone  IV or oral equivalent. Once improving, taper  steroids over at least 4 weeks, consider  prophylactic antibiotics for opportunistic  infections, and resume therapy with same dose |                                  |
| - Symptomatic therapy (e.g. antihistamines,  topical steroids) -Delay therapy for 1-2 weeks and  reevaluate.                                                                                                                                                                     | Toxicity does not resolve within 12  weeks of last dose or inability to  reduce corticosteroid to 10 mg or less  of prednisone or equivalent per day  within 12 weeks                                                                                                                                         |                                  |
| Grade 2                                                                                                                                                                                                                                                                          |                                                                                                                                                                                                                                                                                                               |                                  |
| Covering 10-30%  BSA*                                                                                                                                                                                                                                                            |                                                                                                                                                                                                                                                                                                               |                                  |
| Skin1                                                                                                                                                                                                                                                                            | -Resume therapy with same dose when  toxicity resolves to Grade 0-1                                                                                                                                                                                                                                           | If worsens: - Treat as Grade 3-4 |
| - Delay treatment and consider oral steroids  if necessary.                                                                                                                                                                                                                      | If improves to grade 1: - Taper steroids over at least 4 weeks and add  prophylactic antibiotics for opportunistic  infections - Resume therapy with one dose reduction when  toxicity resolves to Grade 0-1                                                                                                  |                                  |
| - Resume therapy with one dose reduction  when toxicity resolves to Grade 0-1                                                                                                                                                                                                    | Toxicity does not resolve within 12  weeks of last dose or inability to  reduce corticosteroid to 10 mg or less  of prednisone or equivalent per day  within 12 weeks                                                                                                                                         |                                  |
| Grade 3                                                                                                                                                                                                                                                                          |                                                                                                                                                                                                                                                                                                               |                                  |
| Covering > 30%  BSA                                                                                                                                                                                                                                                              | - If the rash is grade 3 only based on BSA,  and is otherwise mild and responds to dose  interruption and topical steroids, can  consider resuming at the same dose. - Consider skin biopsy                                                                                                                   |                                  |  
  
  
| - Dermatology consult - 1.0-2.0 mg/kg/day IV methylprednisolone  or IV equivalent - Discontinue therapy permanently   |                                                                                                                                                                       |                         |                         |
|-----------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------|-------------------------|
| Grade 4                                                                                                               |                                                                                                                                                                       |                         |                         |
| Any % BSA; Life-threatening  consequences (Refer to NCI CTCAE  v5 for term-specific  grading criteria)                | - Consider skin biopsy                                                                                                                                                | Permanently discontinue | Permanently discontinue |
| - Dermatology consult - 1.0-2.0 mg/kg/day IV methylprednisolone  or IV equivalent                                     | Toxicity does not resolve within 12  weeks of last dose or inability to  reduce corticosteroid to 10 mg or less  of prednisone or equivalent per day  within 12 weeks |                         |                         |
| - Delay therapy                                                                                                       |                                                                                                                                                                       |                         |                         |
| Grade 1 or 2                                                                                                          | ________                                                                                                                                                              |                         |                         |
| - Administer corticosteroids                                                                                          |                                                                                                                                                                       |                         |                         |
| Myocarditis                                                                                                           | - Discontinue therapy permanently                                                                                                                                     |                         |                         |
| Grade 3 or 4                                                                                                          | Permanently Discontinue                                                                                                                                               | Permanently Discontinue |                         |
| - Administer corticosteroids - Delay therapy -Resume therapy with same dose when  toxicity resolves to Grade 0-1      |                                                                                                                                                                       |                         |                         |
| Grade 3 or Severe  (meeting SAE  criteria) or intolerable/  persistent Grade 2                                        | Toxicity does not resolve within 12  weeks of last dose or inability to  reduce corticosteroid to 10 mg or less  of prednisone or equivalent per day  within 12 weeks |                         |                         |
| - Based on severity of AE administer  corticosteroids                                                                 | ________                                                                                                                                                              |                         |                         |
| All Other DrugRelated Toxicityc                                                                                                                       | - If an SAE, consider dose reduction. - Ensure adequate evaluation to confirm  etiology or exclude other causes - Permanently discontinue                             |                         |                         |
| Grade 4                                                                                                               |                                                                                                                                                                       |                         |                         |
| or recurrent Grade  3                                                                                                 | ________                                                                                                                                                              | Permanently discontinue |                         |
| - Based on severity of AE administer  corticosteroids                                                                 |                                                                                                                                                                       |                         |                         |  
  
  
| - Ensure adequate evaluation to confirm  etiology or exclude other causes   |
|-----------------------------------------------------------------------------|  
Note: Permanently discontinue for any severe (meeting SAE criteria) or Grade 3 drug-related AE that recurs or any life-threatening event.
4.11. diet/activity/other considerations
1. in general for disease

- Rule out non-inflammatory causes. If non-inflammatory causes are identified, treat accordingly and continue I-O therapy. - Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids (e.g. prednisone) at start of tapering or earlier, once sustained clinical improvement is observed. Lower bioavailability of oral corticosteroids should be taken into account when switching to the equivalent dose of oral corticosteroids. For the below disease groups, also:
- For Endocrinopathy AE management:
Consider visual field testing, endocrinology consultation, and imaging.  
- For GI AE management:
Opiates/narcotics may mask symptoms of perforation. Infliximab should not be used in cases of perforation or sepsis.  
- For Hepatic AE management:
Consider imaging for obstruction.  
- For Pulmonary AE management:
Evaluate with imaging and pulmonary consultation.  
- For Renal AE management:
Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids (e.g. prednisone) at start of tapering or earlier, once sustained clinical improvement is observed. Lower bioavailability of oral corticosteroids should be taken into account when switching to the equivalent dose of oral corticosteroids.  
a For patients with liver metastasis who begin treatment with Grade 2 AST or ALT, if AST or ALT increases by greater than or equal to 50% relative to baseline and lasts for at least 1 week then patients should be discontinued.  
bIf symptoms resolve within one hour of stopping drug infusion, the infusion may be restarted at 50% of the original infusion rate (e.g., from 100 mL/hr to 50 mL/hr). Otherwise dosing will be held until symptoms resolve and the subject should be pre-medicated for the next scheduled dose.  
c Patients with intolerable or persistent Grade 2 drug-related AE may delay study medication at physician discretion. Permanently discontinue study drug for persistent Grade 2 AEs for which treatment with study drug has been held, that do not recover to Grade 0-1 within 12 weeks of the last dose.
4.11. diet/activity/other considerations
table 5 dose modification guidelines

| Dose/Schedule for Treatment Restart             | Discontinue Subject                                    |                            |                                          |                           |                              |                           |
|-------------------------------------------------|--------------------------------------------------------|----------------------------|------------------------------------------|---------------------------|------------------------------|---------------------------|
| Hold                                            | Timing for                                             | Pembrolizumab              |                                          |                           |                              |                           |
| Treatment                                       | Treatment                                              | Epacadostat                | with Merck & Incyte) (After Consultation |                           |                              |                           |
| Toxicity                                        | Grade                                                  | (Y/N)                      | Restart                                  | (INCB024360)              | (MK-3475)                    |                           |
| Hematologic toxicity                            | 1, 2                                                   | No                         | N/A                                      | N/A                       | N/A                          | N/A                       |
| First occurrence, restart at  same dose.        |                                                        |                            |                                          |                           |                              |                           |
| 3                                               | Yes                                                    | Toxicity resolves          | Restart at same dose and                 | Toxicity does not resolve |                              |                           |
| to ≤ Grade 1 or                                 | schedule. See Sections                                 | within 12 weeks of last    |                                          |                           |                              |                           |
| baseline                                        | Second occurrence or more,  reduce dose when resuming. | 4.10.4. and 6.3. for       | infusion.                                |                           |                              |                           |
| recommendations regarding  immune-mediated AEs. |                                                        |                            |                                          |                           |                              |                           |
| 4                                               | Yes                                                    | N/A                        | N/A                                      | N/A                       | Permanently discontinue      |                           |
| Non-hematologic toxicity,                       | 1                                                      | No                         | N/A                                      | N/A                       | N/A                          | N/A                       |
| excluding immune related                        | 2                                                      | Consider                   | Toxicity resolves                        | Restart at same dose and  | Toxicity does not resolve    |                           |
| AEs in Table 4                                  | holding for                                            | to ≤ Grade 1 or            | schedule. See Sections                   | within 12 weeks of last   |                              |                           |
| Reduce 1 dose level                             |                                                        |                            |                                          |                           |                              |                           |
| Note: Exception to be treated                   | persistent                                             | baseline                   | 4.10.4. and 6.3. for                     | infusion                  |                              |                           |
| to similar Grade 1 toxicity:                    | symptoms                                               | recommendations regarding  |                                          |                           |                              |                           |
| -                                               | Grade 2 alopecia                                       | immune-mediated AEs.       |                                          |                           |                              |                           |
| -                                               | Grade 2 fatigue                                        | 3                          | Yes                                      | Toxicity resolves         | Restart at same dose and     | Toxicity does not resolve |
| -                                               | Grade 3 rash in the                                    | to ≤ Grade 1 or            | Reduce 1 dose level                      | schedule. See Sections    | within 12 weeks of last dose |                           |
| absence of                                      | baseline                                               | 4.10.4. and 6.3. for       | or inability to reduce                   |                           |                              |                           |
| desquamation, no                                | recommendations regarding                              | corticosteroid to 10 mg or |                                          |                           |                              |                           |
| mucosal                                         | immune-mediated AEs.                                   | less of prednisone or      |                                          |                           |                              |                           |
| involvement, does                               | equivalent per day within 12                           |                            |                                          |                           |                              |                           |
| not require                                     | weeks                                                  |                            |                                          |                           |                              |                           |  
  
| Dose/Schedule for Treatment Restart                                                                     | Discontinue Subject   |             |                      |              |           |                         |
|---------------------------------------------------------------------------------------------------------|-----------------------|-------------|----------------------|--------------|-----------|-------------------------|
| Hold                                                                                                    | Timing for            |             |                      |              |           |                         |
| Treatment                                                                                               | Treatment             | Epacadostat | with Merck & Incyte) |              |           |                         |
| Pembrolizumab                                                                                           | (After Consultation   |             |                      |              |           |                         |
| Toxicity                                                                                                | Grade                 | (Y/N)       | Restart              | (INCB024360) | (MK-3475) |                         |
| systemic steroids,                                                                                      | 4                     | Yes         | N/A                  | N/A          | N/A       | Permanently discontinue |
| and resolves to  Grade 1 within  14 days                                                                |                       |             |                      |              |           |                         |
| For additional information  regarding AE with potential  immune etiology, see  Sections 4.10.4 and 6.3. |                       |             |                      |              |           |                         |  
  
  
Note: Subjects who experience a recurrence of the same severe or life-threatening AE at the same grade or greater with re-challenge of the combination should be discontinued from study treatment immediately and not re-challenged.
4.11. diet/activity/other considerations
6.3. management of immune-related adverse

Events of clinical interest of a potential immunologic etiology or irAEs may be defined as an AE of unknown etiology, associated with drug exposure and consistent with an immune phenomenon. irAEs may be predicted based on the nature of the pembrolizumab or epacadostat compounds, their mechanism of action, and reported experience with immunotherapies that have a similar mechanism of action. Special attention should be paid to AEs that may be suggestive of potential irAEs. An irAE can occur shortly after the first dose or several months after the last dose of treatment. If an irAE is suspected, efforts should be made to rule out neoplastic, infectious, metabolic, toxin or other etiologic causes before labeling an AE as an irAE. Subjects who develop a ≥ Grade 2 irAE should be discussed immediately with the sponsor. Please refer to Table 4 in Section 6.2.
4.11. diet/activity/other considerations
6.4. procedures for subjects exhibiting

There is a theoretical chance that epacadostat could cause an increase in serotonin levels in the brain that might trigger SS when administered in combination with other serotonergic agents. This syndrome has been most closely associated with use of MAOIs, Demerol®,
linezolid, or methylene blue; all of these agents are prohibited during the study. Serotonin reuptake inhibitors (SSRIs) and serotonin/norepinephrine reuptake inhibitors (SNRIs) are permitted in the study. The following procedures will be implemented if subjects exhibit the signs/symptoms of SS including tremor; hyperreflexia; spontaneous, ocular, or inducible clonus; together with agitation, fever, diaphoresis, or muscle rigidity:
- Immediately interrupt epacadostat administration. Administration of pembrolizumab may continue.  
- Immediately interrupt any SSRI or SNRI administration. - Provide appropriate medical management of the subject until all signs/symptoms are resolved (eg, IV fluids and/or sympathomimetic amines for hypotension, benzodiazepines for agitation, administration of 5-hydroxytryptamine antagonists such as cyproheptadine).  
- If subject chooses to remain in the study, restart treatment with epacadostat after  
  
  
  
the SSRI or SNRI has been discontinued, no sooner than 5 half-lives have elapsed for the specific SSRI or SNRI in question, and after resolution of signs/symptoms of SS. The SSRI or SNRI dosing MAY NOT be restarted.  
- If subject chooses to withdraw from the study, or must restart treatment with SSRI
or SNRI, the subject should be scheduled for a follow-up visit. Treatment with SSRI or SNRI may be initiated 2 weeks after resolution of signs and symptoms of SS.
4.11. diet/activity/other considerations
7. adverse events and reporting

An AE is defined as any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition that is temporally associated with the use of the Merck's product, is also an AE. AEs can be spontaneously reported or elicited during open-ended questioning, examination, or evaluation of a subject. In order to prevent reporting bias, subjects should not be questioned regarding the specific occurrence of one or more AEs. AEs will be graded according to NCI CTCAE v5. Both serious and non-serious AEs will be clearly noted in source documentation and listed on study specific eCRFs. The investigator or designee will assess each AE to determine whether it is unexpected according to the informed consent document, protocol document, or IBs, and related to the investigation. After the end of treatment, each subject will be followed up to 30 days or until new anticancer treatment is initiated, whichever occurs first for adverse event monitoring, including SAEs grade 3 and above, and all subsequent follow-up reports will be reported to the Stanford Cancer Institute Data and Safety Monitoring Committee (DSMC) using the study  
  
 specific eCRF regardless of the event's relatedness to the investigation. Events meeting the IRB definition of 'Unanticipated Problem' will be reported to the IRB within 10 working days of investigator determination expedited reporting is required, or within 5 working days for deaths or life-threatening experiences. Changes resulting from normal growth and development that do not vary significantly in frequency or severity from expected levels are not to be considered AEs. Examples of this may include, but are not limited to, teething, typical crying in infants and children and onset of menses or menopause occurring at a physiologically appropriate time. Merck product includes any pharmaceutical product, biological product, device, diagnostic agent or protocol-specified procedure, whether investigational (including placebo or active comparator medication) or marketed, manufactured by, licensed by, provided by or distributed by Merck for human use. Adverse events may occur during the course of the use of Merck product in clinical trials, or as prescribed in clinical practice, from overdose (whether accidental or intentional), from abuse and from withdrawal. Progression of the cancer under study is not considered an AE. All AEs/SAEs that occur after the consent form has been signed but before treatment allocation/randomization must be reported by the investigator if they cause the subject to be excluded from the study, or are the result of a protocol-specified intervention, including but not limited to washout or discontinuation of usual therapy, diet, placebo treatment or a procedure. From the time of treatment allocation/randomization through initiation of a new anticancer therapy, all AEs must be reported by the investigator. Such events will be recorded at each examination on the AE eCRF. The reporting timeframe for AEs meeting any serious criteria is described in section 7.1. The investigator will make every attempt to follow all subjects with non-serious AEs for outcome. Adverse events will not be collected for subjects during the pre-screening period (for determination of archival tissue status); subjects will begin AE collection after signing consent. Epacadostat Adverse Event reporting:  
  
 1. Initial Serious Adverse events (SAEs) and/or subsequent follow-up reports should be reported via email to: *IncytePhVOpsIST@incyte.com*. SAE reports should be for a single subject with any additional documents (i.e. discharge summary, relevant test results) included for the same subject as individual attachments to the email. One email can have multiple attachments as long as each attachment contains relevant information for the same subject.  
2. Please email your SAE form with a cover sheet and any additional attachments to the IST email address: *IncytePhVOpsIST@incyte.com.*
3. Telerx C3i is the PhV Clinical Research Organization (CRO) for Incyte. They will be contacting you for SAE follow-up requests and data clarifications by sending you a data clarification form (DCF). See follow-up section for details on this process. The following is general contact information for Telerx C3i.  
TELERX C3I (Incyte PhV CRO) US SAE fax number 1-866-726-9234
4.11. diet/activity/other considerations
- initial reports

Incyte needs to be notified within 24 hrs of learning of an event as well as providing a completed SAE form emailed to *IncytePhVOpsIST@incyte.com.* 1. SAE reporting for each subject begins the day patient start treatment and up to 30 days after subject has completed or discontinued from the study or until new anticancer treatment is initiated, whichever occurs first.  
2. All SAE notices are sent from the site to Incyte via a central email address:
IncytePhVOpsIST@incyte.com established for IST sites for this process.  
3. SAEs, occurring using Incyte Study drug, are reported in accordance with the effective protocol. SAEs occurring with any another commercial drug are reported to manufacturer of that drug in accordance with regulations and protocol.  
4. SAEs related to concomitant medications/drug delivery systems are reported  
  
  
  
directly to the manufacturers of those drugs/devices in accordance with the package insert. Meaning, follow the SAE manufacturer reporting requirements for all medication other than Epacadostat.  
5. All SAE details are recorded on the SAE Report form, regardless of causality to the investigational product and sent via email in accordance with the protocol. If a non-serious Adverse Event (AE) becomes serious, the process for SAE reporting is followed.  
6. Additional information requested upon internal Incyte review will be asked by Telerx C3i in the form of a Data Clarification Form (DCF).
4.11. diet/activity/other considerations
- follow-up reports

1. Follow-up SAE reports are sent via email to *IncytePhVOpsIST@incyte.com* from the Investigator site.  
2. Telerx C3i tracks any critical outstanding follow-up items and questions and contacts the investigational site via a faxed DCF for the additional requested information until all outstanding queries are resolved. A sample of this form is included in Appendix III. This includes requests for hospital discharge summaries, autopsy reports, and death certificates (if applicable), results of relevant laboratory, and diagnostic tests. The investigational site faxes the additional information to Telerx C3i, using the Telerx C3i SAE fax number. The site personnel will update all relevant data on the appropriate SAE Report Form or equivalent to include any new or changed information. The Incyte Safety Representative (IC SR) will monitor outstanding queries and take appropriate action needed for resolution.  
3. Any serious SAE upgraded to death or life-threatening requires that the follow up report be emailed to: *IncytePhVOpsIST@incyte.com* email address within 24 hours.  
- **Regulatory Reporting**  
  
  
The Investigator Sponsor (George A. Fisher, Jr., MD, PhD) of the IST trial is responsible for meeting expedited reporting requirements to Health Authorities and all participating investigators under their institution's IND. Incyte is responsible for meeting expedited reporting requirements to Health Authorities (HAs) in their respective territory and for cross reporting any Serious Unexpected Suspected Adverse Reaction (SUSAR) originating from IST sponsored studies to Incyte's IND, NDA, and Incyte investigators from Incyte sponsored trials as required.
4.11. diet/activity/other considerations
- reporting of pregnancy

An "Initial Pregnancy Report" or equivalent must be completed in full and emailed to IncytePhVOpsIST@incyte.com within 24 hrs of discovery of a pregnancy of a subject who has taken the Incyte product or the pregnancy of a partner for a subject who has taken the Incyte product. The "Follow-up Pregnancy Report Form" or equivalent must be completed and emailed to *IncytePhVOpsIST@incyte.com* within 30 days after delivery, so that Incyte is provided with information regarding the outcome of the pregnancy. If the pregnancy results in any events which meet the serious criteria (i.e., miscarriage or termination), the SAE reporting process needs to be followed and the timelines associated with an SAE should be followed.
4.11. diet/activity/other considerations
7.2. definition of an overdose

For purposes of this study, an overdose of pembrolizumab will be defined as any dose of 1,000 mg or greater (≥5 times the indicated dose). No specific information is available on the treatment of overdose of pembrolizumab. Appropriate supportive treatment should be provided if clinically indicated. In the event of overdose, the subject should be observed closely for signs of toxicity. Appropriate supportive treatment should be provided if clinically indicated. If an adverse event(s) is associated with ("results from") the overdose of a Merck product, the adverse event(s) is reported as a serious adverse event, even if no other seriousness criteria are met. If a dose of Merck's product meeting the protocol definition of overdose is taken without any associated clinical symptoms or abnormal laboratory results, the overdose is reported as a  
  
 non-serious Event of Clinical Interest (ECI), using the terminology "accidental or intentional overdose without adverse effect."
All reports of overdose with and without an adverse event must be reported within 24 hours to Merck Global Safety Attn: Worldwide Product Safety; FAX 215 993-1220)
4.11. diet/activity/other considerations
7.3. definition of an overdose

There has been no clinical experience with overdose of Epacadostat. Treatment of overdose should consist of general supportive measures.
4.11. diet/activity/other considerations
7.4. reporting of pregnancy and

Although pregnancy and lactation are not considered AEs, it is the responsibility of investigators or their designees to report any pregnancy or lactation in a subject (spontaneously reported to them) that occurs during the study. Pregnancies and lactations that occur after the consent form is signed but before treatment allocation/randomization must be reported by the investigator if they cause the subject to be excluded from the study, or are the result of a protocol-specified intervention, including but not limited to washout or discontinuation of usual therapy, diet, placebo treatment or a procedure. Pregnancies and lactations that occur from the time of treatment allocation/randomization through 120 days following cessation of study product, or 30 days following cessation of treatment if the subject initiates new anticancer therapy, whichever is earlier, must be reported by the investigator. All reported pregnancies must be followed to the completion/termination of the pregnancy. Pregnancy outcomes of spontaneous abortion, missed abortion, benign hydatidiform mole, blighted ovum, fetal death, intrauterine death, miscarriage and stillbirth must be reported as serious events (Important Medical Events). If the pregnancy continues to term, the outcome (health of infant) must also be reported. Such events must be reported within 24 hours to Merck Global Safety (Attn: Worldwide Product Safety; FAX 215 993-1220) AND Incyte (IncytePhVOpsIST@incyte.com)
4.11. diet/activity/other considerations
7.5. reporting of adverse events

7.5.1. Serious Adverse Events  
A serious adverse event is any adverse event occurring at any dose or during any use of investigational product that:
- Results in death; - Is life threatening (defined as an event in which the subject was at risk of death at the time of the event; it does not refer to an event which hypothetically must have caused death if it were more severe);
- Results in persistent or significant disability/incapacity;
- Results in or prolongs an existing inpatient hospitalization;
- Is a congenital anomaly/birth defect; - Is another important medical event - *Note:* The following hospitalizations are not considered SAEs:
o A visit to the emergency room or other hospital department lasting less than 24 hours that does not result in admission (unless considered an "important medical event" or a life-threatening event).  
o Elective surgery planned before signing consent o Admission per protocol for planned medical/surgical procedure (e.g.,
mediport placement)
o Routine health assessment requiring admission for baseline/trending of health status (e.g., routine colonoscopy)
o Medical/surgical admission for purpose other than remedying ill health state that was planned before study entry. Appropriate documentation is required in these cases.  
o Admission encountered for another life circumstance that carries no bearing on health status and requires no medical/surgical intervention (e.g., lack of housing, economic inadequacy, caregiver respite, family circumstances, administrative)
- *Note:* In addition to the above criteria, AEs meeting either of the below criteria, although not serious per ICH definition, are reportable to the Merck in the same timeframe as SAEs to meet certain local requirements. Therefore, these events are  
  
 considered serious by Merck for collection purposes.  
o Is a new cancer (that is not a condition of the study);
o Is associated with an overdose.  
For the time period beginning when the consent form has been signed until treatment allocation/randomization, any serious adverse event, or follow up to a serious adverse event, including death due to any cause other than progression of the cancer under study that occurs to any subject must be reported to the FDA through appropriate channels and within 10 working days to Merck Global Safety and Incyte Global Safety if it causes the subject to be excluded from the study, or is the result of a protocol-specified intervention, including but not limited to washout or discontinuation of usual therapy, diet, placebo treatment or a procedure. For the time period beginning at treatment allocation/randomization through 30 days following the final dose, any SAE or follow-up to a SAE, including death due to any cause other than progression of the cancer under study, whether or not related to the study products, must be reported to the FDA as appropriate and within 10 working days to Merck Global Safety and Incyte team. Additionally, any SAE, considered by an investigator to be related to Merck product at any time after signing consent through the end of the specified safety follow-up period specified in the paragraph above, or at any time outside of the time period specified in the previous paragraph also must be reported immediately to Merck Global Safety.
4.11. diet/activity/other considerations
incyte serious adverse event specifics

1. Initial Serious Adverse events (SAEs) and/or subsequent follow-up reports should be reported via email to: *IncytePhVOpsIST@incyte.com*. SAE reports should be for a single subject with any additional documents (i.e. discharge summary, relevant test results) included for the same subject as individual attachments to the email. One email can have multiple attachments as long as each attachment contains relevant information for the same subject.  
2. Please email your SAE form with a cover sheet and any additional attachments to the IST  
  
  
email address: *IncytePhVOpsIST@incyte.com.*
3. Telerx C3i is the PhV Clinical Research Organization (CRO) for Incyte. They will be contacting you for SAE follow-up requests and data clarifications by sending you a data clarification form (DCF). See follow-up section for details on this process. The following is general contact information for Telerx C3i.  
TELERX C3I (Incyte PhV CRO) US SAE fax number 1-866-726-9234
4.11. diet/activity/other considerations
- initial reports

Incyte needs to be notified within 24 hrs of learning of an event as well as providing a completed SAE form emailed to *IncytePhVOpsIST@incyte.com.* 1. SAE reporting for each subject begins the day patient start treatment and up to 30 days after subject has completed or discontinued from the study or until new anti-cancer treatment is initiated, whichever occurs first.  
2. All SAE notices are sent from the site to Incyte via a central email address:
IncytePhVOpsIST@incyte.com established for IST sites for this process.  
3. SAEs, occurring using Incyte Study drug, are reported in accordance with the effective protocol. SAEs occurring with any another commercial drug are reported to manufacturer of that drug in accordance with regulations and protocol.  
4. SAEs related to concomitant medications/drug delivery systems are reported directly to the manufacturers of those drugs/devices in accordance with the package insert. Meaning, follow the SAE manufacturer reporting requirements for all medication other than Epacadostat.  
5. All SAE details are recorded on the SAE Report form, regardless of causality to the  
  
  
investigational product and sent via email in accordance with the protocol. If a nonserious Adverse Event (AE) becomes serious, the process for SAE reporting is followed.  
6. Additional information requested upon internal Incyte review will be asked by Telerx C3i in the form of a Data Clarification Form (DCF).
4.11. diet/activity/other considerations
- follow-up reports

1. Follow-up SAE reports are sent via email to *IncytePhVOpsIST@incyte.com* from the Investigator site.  
2. Telerx C3i tracks any critical outstanding follow-up items and questions and contacts the investigational site via a faxed DCF for the additional requested information until all outstanding queries are resolved. A sample of this form is included in Appendix III. This includes requests for hospital discharge summaries, autopsy reports, and death certificates (if applicable), results of relevant laboratory, and diagnostic tests. The investigational site faxes the additional information to Telerx C3i, using the Telerx C3i SAE fax number. The site personnel will update all relevant data on the appropriate SAE Report Form or equivalent to include any new or changed information. The Incyte Safety Representative (IC SR) will monitor outstanding queries and take appropriate action needed for resolution.  
3. Any serious SAE upgraded to death or life-threatening requires that the follow up report be emailed to: *IncytePhVOpsIST@incyte.com* email address within 24 hours.
4.11. diet/activity/other considerations
- regulatory reporting

The Investigator Sponsor (George A. Fisher, Jr., MD, PhD) of the IST trial is responsible for meeting expedited reporting requirements to Health Authorities and all participating investigators under their institution's IND. Incyte is responsible for meeting expedited reporting requirements to Health Authorities (HAs) in their respective territory and for cross reporting any Serious Unexpected Suspected Adverse Reaction (SUSAR) originating from IST sponsored studies to Incyte's IND, NDA, and Incyte investigators from Incyte sponsored trials as required.
4.11. diet/activity/other considerations
- reporting of pregnancy

An "Initial Pregnancy Report" or equivalent must be completed in full and emailed to  
 IncytePhVOpsIST@incyte.com within 24 hrs of discovery of a pregnancy of a subject who has taken the Incyte product or the pregnancy of a partner for a subject who has taken the Incyte product. The "Follow-up Pregnancy Report Form" or equivalent must be completed and emailed to *IncytePhVOpsIST@incyte.com* within 30 days after delivery, so that Incyte is provided with information regarding the outcome of the pregnancy. If the pregnancy results in any events which meet the serious criteria (i.e., miscarriage or termination), the SAE reporting process needs to be followed and the timelines associated with an SAE should be followed. All subjects with SAEs must be followed up for outcome. A copy of all 15 Day Reports and Annual Progress Reports is submitted as required by FDA, European Union (EU), Pharmaceutical and Medical Devices agency (PMDA) or other local regulators. Investigators will cross reference this submission according to local regulations to the Merck Investigational Compound Number (IND, CSA, etc.) at the time of submission. Additionally, investigators will submit a copy of these reports to Merck & Co., Inc. (Attn: Worldwide Product Safety; FAX 215 993-1220) and Incyte (*IncytePhVOpsIST@incyte.com*) at the time of submission to FDA.
4.11. diet/activity/other considerations
7.5.2. events of clinical interest

Selected non-serious and SAEs are also known as ECIs, must be reported within 10 working days to Merck Global Safety. (Attn: Worldwide Product Safety; FAX 215 993-1220). For the time period after the consent has been signed through 30 days following the safety follow-up, any ECI, or follow up to an ECI, whether or not related to study products, must be reported within 10 working days to Merck Global Safety. ECIs for this study include:
1. An overdose of drug; 2. An elevated AST or ALT lab value that is ≥ 3 x ULN and an elevated total bilirubin lab value that is ≥ 2 x ULN and, at the same time, an alkaline phosphatase lab value that is < 2 x ULN, as determined by way of protocol-specified laboratory testing or  
  
 unscheduled laboratory testing* *Note: These criteria are based upon available regulatory guidance documents. The purpose of the criteria is to specify a threshold of abnormal hepatic tests that may require an additional evaluation for an underlying etiology.
4.11. diet/activity/other considerations
7.6. assignment of intensity and

Causal relationship to investigational product as determined by the investigator(s) should be defined based on the definitions below:
- **Related:** There is a reasonable causal relationship to investigational product administration and the adverse event.  
- **Not Related:** There is not a reasonable causal relationship to investigational product administration and the adverse event.  
The expression "reasonable causal relationship" is meant to convey in general that there are facts (e.g., evidence such as de-challenge/re-challenge) or other arguments to suggest a positive causal relationship.
4.11. diet/activity/other considerations
7.7. responsibility for reporting aes

All AEs will be reported to regulatory authorities, IRB/IECs and investigators in accordance with all applicable global laws and regulations.
4.11. diet/activity/other considerations
7.8. evaluating adverse events

All investigators who are qualified physicians and delegated, can evaluate for AEs. All AEs will be graded based on the NCI CTCAE v.5. Any AE which changes in grade over the course of a given episode will have each change of grade recorded independently in the appropriate eCRF. All adverse events regardless of grade must be evaluated for seriousness and causality to the investigational agents. See Table 6 for further guidance on evaluating an AE by grade, seriousness, and causality.
4.11. diet/activity/other considerations
table 6evaluating adverse events

| An investigator who is a qualified physician, will evaluate all AEs for the following:   |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 |                                                                                                           |
|------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------|
| V4.03                                                                                    | Grade 1                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         | Mild; asymptomatic or mid symptoms; clinical or diagnostic observations only; intervention not indicated. |
| Grade 2                                                                                  | Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      |                                                                                                           |
| Grade 3                                                                                  | Severe or medically significant but not immediately life-threatening; hospitalization or prolongation or  hospitalization indicated; disabling; limiting self-care ADL.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         |                                                                                                           |
| Grade 4                                                                                  | Life threatening consequences; urgent intervention indicated.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   |                                                                                                           |
| Grade 5                                                                                  | Death                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           |                                                                                                           |
| Seriousness                                                                              | A SAE is any AE occurring at any dose or during any use of an investigational drug that: †Results in death; or †Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from the event as it occurred (Note:  This does not include an AE that, had it occurred in a more severe form, might have caused death.); or †Results in a persistent or significant disability/incapacity (substantial disruption of one's ability to conduct normal life functions); or †Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient admission, regardless of length of  stay, even if the hospitalization is a precautionary measure for continued observation. (Note: Hospitalization for an elective procedure to  treat a pre-existing condition that has not worsened is not a SAE. A pre-existing condition is a clinical condition that is diagnosed prior to  the use of the agent and is documented in the patient's medical history.); or †Is a congenital anomaly/birth defect (in offspring of subject taking the product regardless of time to diagnosis);or Is a new cancer (that is not a condition of the study) (although not serious per ICH definition, is reportable to Merck and Incyte within 2  working days to meet certain local requirements); or Is an overdose (whether accidental or intentional). Any AE associated with an overdose is considered a SAE for collection purposes. An  overdose that is not associated with an AE is considered a non-serious ECI and must be reported within 24 hours to Merck and Incyte. Other important medical events that may not result in death, not be life threatening, or not require hospitalization may be considered a  SAE when, based upon appropriate medical judgment, the event may jeopardize the subject and may require medical or surgical intervention  to prevent one of the outcomes listed previously (designated above by a †). |                                                                                                           |
| Duration                                                                                 | Record the start and stop dates of the AE. If less than 1 day, indicate the appropriate length of time.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         |                                                                                                           |
| Action taken                                                                             | Did the AE cause drug to be discontinued?                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       |                                                                                                           |
| Relationship  to Study  Drug                                                             | Did study drug cause the AE? The determination of the likelihood that the investigational agent caused the AE will be provided by an  investigator who is a qualified physician. The investigator's signed/dated initials on the source document or worksheet that supports the  causality noted on the AE form, ensures that a medically qualified assessment of causality was done. This initialed document must be  retained for the required regulatory time frame. The criteria below are intended as reference guidelines to assist the investigator in assessing  the likelihood of a relationship between the test drug and the AE based upon the available information. The following components are to be used to assess the relationship between the investigational agents and the AE; the greater the  correlation with the components and their respective elements (in number and/or intensity), the more likely product caused the AE: Exposure Is there evidence that the subject was actually exposed to the investigational drug such as: reliable history, acceptable  compliance assessment (pill count, diary, etc.), expected pharmacologic effect, or measurement of drug/metabolite in                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 |                                                                                                           |  
| bodily specimen?                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              |                                                                                                                                                                                                                   |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Time Course                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   | Did the AE follow in a reasonable temporal sequence from administration of drug?  Is the time of onset of the AE compatible with a drug-induced effect (applies to studies with investigational medicinal  drug)? |
| Likely Cause                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  | Is the AE not reasonably explained by another etiology such as underlying disease, other drug(s)/vaccine(s), or other  host or environmental factors?                                                             |
| The following components are to be used to assess the relationship between the test drug and the AE: (continued) Dechallenge Was drug discontinued or dose/exposure/frequency reduced? If yes, did the AE resolve or improve? If yes, this is a positive dechallenge. If no, this is a negative dechallenge. (Note: This criterion is not applicable if: (1) the AE resulted in death or permanent disability; (2) the AE  resolved/improved despite continuation of the product; or (3) the study is a single-dose drug study); or (4) drug(s) is/are  only used one time.) Rechallenge Was the subject re-exposed to drug on this study? If yes, did the AE recur or worsen? If yes, this is a positive rechallenge. If no, this is a negative rechallenge. (Note: This criterion is not applicable if: (1) the initial AE resulted in death or permanent disability, or (2) the study is a  single-dose drug study); or (3) product(s) is/are used only one time). NOTE: IF A RECHALLENGE IS PLANNED FOR AN AE WHICH WAS SERIOUS AND WHICH MAY HAVE  BEEN CAUSED BY DRUG, OR IF REEXPOSURE TO DRUG POSES ADDITIONAL POTENTIAL SIGNIFICANT  RISK TO THE SUBJECT, THEN THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE MERCK  AND INCYTE AS PER DOSE MODIFICATION GUIDELINES IN THE PROTOCOL. Consistency  with  StudyTreatment  Profile Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding drug or drug class  pharmacology or toxicology? |                                                                                                                                                                                                                   |
| The assessment of relationship will be reported on the CRFs by an investigator who is a qualified physician according to his/her best clinical judgment,  including consideration of the above elements. Record one of the following Use the following scale of criteria as guidance (not all criteria must be present to be indicative of product  relationship). Yes, there is a reasonable  possibility of product  relationship. There is evidence of exposure to drug. The temporal sequence of the AE onset relative to the administration of drug is  reasonable. The AE is more likely explained by drug than by another cause. No, there is not a reasonable  possibility of product  relationship Subject did not receive the investigational drugs OR temporal sequence of the AE onset relative to administration of  drug is not reasonable OR the AE is more likely explained by another cause than the drug. (Also entered for a subject  with overdose without an associated AE.)                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             |                                                                                                                                                                                                                   |
4.11. diet/activity/other considerations
7.9. laboratory test abnormalities definition

Laboratory abnormalities that constitute an AE in their own right (are considered clinically meaningful, induce clinical signs or symptoms, require concomitant therapy, or require changes in study drug), should be recorded on the AE page of the eCRF. Whenever possible, a diagnosis rather than a symptom should be provided (e.g., anemia instead of low hemoglobin). Laboratory abnormalities that meet the criteria for AEs (all grades) should be followed until they have returned to normal or an adequate explanation of the abnormality is found. When an abnormal laboratory test result corresponds to a sign or symptom of a previously reported AE, it is not necessary to separately record the laboratory test result as an additional event. A Grade 3 or 4 (severe) AE, as per CTCAE v5, does not automatically indicate an SAE unless it meets the definition of serious, as defined in Section 7.5.1, and/or per the investigator's discretion. A dose interruption or adjustment for the laboratory abnormality may be required and should not contribute to the designation of a laboratory test abnormality as an SAE.
4.11. diet/activity/other considerations
7.10. handling of expedited safety

In accordance with local regulations, Merck and Incyte will notify investigators of all SAEs that are suspected (related to the investigational products) and unexpected (i.e., not previously described in the IBs) regarding the drugs under study at other sites in other investigations. In the European Union (EU), an event meeting these criteria is termed a Suspected, Unexpected Serious Adverse Reaction (SUSAR). Investigator notification of these events will be in the form of an expedited safety report (ESR). Other important findings which may be reported by the sponsor as an ESR include: increased frequency of a clinically significant expected SAE, an SAE considered associated with study procedures that could modify the conduct of the study, lack of efficacy that poses significant hazard to study subjects, clinically significant safety finding from a nonclinical (e.g., animal) study, important safety recommendations from a study data monitoring committee, or sponsor decision to end or temporarily halt a clinical study for safety reasons. Upon receiving an ESR from Merck and/or Incyte, the investigator must review and retain the ESR with the IBs. Where required by local regulations or when there is a central IRB/IEC for the study, the sponsor will submit the ESR to the appropriate IRB/IEC. The investigator and IRB/IEC will determine if the informed consent requires revision. The investigator should also  
  
  
 comply with the IRB/IEC procedures for reporting any other safety information. In addition, suspected serious adverse reactions (whether expected or unexpected) shall be reported by Merck and Incyte to the relevant competent health authorities in all concerned countries according to local regulations (either as expedited and/or in aggregate reports).
4.11. diet/activity/other considerations
7.11. warnings and precautions

No evidence available at the time of the approval of this study protocol indicated that special warnings or precautions were appropriate, other than those noted in the provided IB. Additional safety information collected between IB updates will be communicated in the form of Investigator Notifications (INs). Any important new safety information should be discussed with the subject during the study as needed. If new, significant risks are identified, they will be added to the ICF.
4.11. diet/activity/other considerations
7.12. data safety monitoring committee

There will be no formal external data monitoring committee for this open-label study. This study will be monitored per standard Stanford's data and safety monitoring schedule.
4.11. diet/activity/other considerations
8. correlative/special studies

Blood and tissue will be collected during the context of the study for future correlative studies including organoids (tissue) and immune markers (blood). Section 9 outlines the frequency of the testing being done and then being stored with the intent to analyze in the future. For the context of this particular protocol, we will only be collecting and storing blood, serum, plasma, and tissue that could be used for the indicated testing in the future.
4.11. diet/activity/other considerations
8.1. blood samples 8.1.1. required

Blood will be collected in green and purple top tubes. One 10 mL purple top EDTA tube for whole blood collection and three 10 mL green top tubes for plasma will be collected every 3 weeks prior to pembrolizumab infusion for storage for future research. All these samples will be processed and stored frozen at -80°C.
4.11. diet/activity/other considerations
8.2. tissue samples

Pre-treatment and on-treatment biopsies are to be collected on patients when safe and feasible. Details and methods for obtaining, processing, and shipping the fresh tumor biopsy are as follows:
- 6-15 (average 10) core biopsies measuring at least 4mm, if possible 10mm will be obtained from an accessible and safe primary or metastatic tumor site
- When feasible, all core samples should be obtained from the same lesion/location at the appropriate time point
- When feasible, 16-18 gauge needles should be used to obtain core samples. FNA samples are acceptable
- Samples should contain at minimum 20% tumor viability as measured by adequate number of living cells based on H&E slide
- Specimens will be collected/stored in FFPE or as a single cell suspension via the Correlatives Sciences Unit SOP.
4.11. diet/activity/other considerations
9. study calendars

Schedule Of Events  
| Treatment Phase1                    | EOT             | Post-Treatment   |           |                      |                |    |    |
|-------------------------------------|-----------------|------------------|-----------|----------------------|----------------|----|----|
| Day 1 All  Subsequent               | Discontinuation | Survival         |           |                      |                |    |    |
| Cycles                              | Visit           | Follow-Up Visits | Follow-Up |                      |                |    |    |
| Screening                           | C1D1            | C2D1             | C3D1      | Every 9 Weeks  After | Every 12 Weeks |    |    |
| Discontinuation (± 7 Days)          | (± 7 Days)      |                  |           |                      |                |    |    |
| ADMINISTRATIVE PROCEDURES           |                 |                  |           |                      |                |    |    |
| Evaluation/Window                   | Day -28         | ± 3              | ± 3       |                      |                |    |    |
| to Day -1                           | Day 1           | Days             | Days      | ± 3 Days             | + 5 Days       |    |    |
| Informed consent                    | X               |                  |           |                      |                |    |    |
| Inclusion/exclusion criteria        | X               | X                |           |                      |                |    |    |
| Prior medical and cancer history    | X               |                  |           |                      |                |    |    |
| Concomitant medications review      | X               | X                | X         | X                    | X              | X  |    |
| Administer Pembrolizumab2           | X               | X                | X         | X                    |                |    |    |
| Administer Epacadostat3             | X               | X                | X         | X                    |                |    |    |
| Survival follow-up                  | X               |                  |           |                      |                |    |    |
| CLINICAL PROCEDURES AND ASSESSMENTS |                 |                  |           |                      |                |    |    |
| Comprehensive physical exam         | X               | X                |           |                      |                |    |    |
| Targeted physical exam              | X               | X                | X         | X                    | X              |    |    |
| ECOG performance status             | X               | X                | X         | X                    | X              | X  | X  |  
1 Treatment cycles are every 3 weeks (~ 21 days ± 3 days).  
2 Fixed dose at 200 mg per IV every 3 weeks.  
3 Fixed dose at 300 mg orally twice daily every day, all 21 days of each cycle.  
| Treatment Phase1               | EOT             | Post-Treatment   |           |                                       |                |    |    |
|--------------------------------|-----------------|------------------|-----------|---------------------------------------|----------------|----|----|
| Day 1 All  Subsequent          | Discontinuation | Survival         |           |                                       |                |    |    |
| Cycles                         | Visit           | Follow-Up Visits | Follow-Up |                                       |                |    |    |
| Screening                      | C1D1            | C2D1             | C3D1      | Every 9 Weeks  After  Discontinuation | Every 12 Weeks |    |    |
| (± 7 Days)                     | (± 7 Days)      |                  |           |                                       |                |    |    |
| Vital signs and weight         | X               | X4               | X         | X                                     | X              | X  | X  |
| Evaluation/Window              | Day -28         | ± 3              | ± 3       |                                       |                |    |    |
| to Day -1                      | Day 1           | Days             | Days      | ± 3 Days                              | + 5 Days       |    |    |
| 12-lead ECG                    | X               | X                |           |                                       |                |    |    |
| AE assessment                  | X               | X                | X         | X                                     | X              | X  | X  |
| EFFICACY MEASUREMENTS          |                 |                  |           |                                       |                |    |    |
| Radiologic tumor assessment    | X5              | X6,7             | X8,9      | X6                                    |                |    |    |
| LABORATORY ASSESSMENTS10,11,12 |                 |                  |           |                                       |                |    |    |
| Comprehensive serum chemistry  | X               | X                | X         | X                                     | X              | X  | X  |
| Tumor molecular profiling13    | X               |                  |           |                                       |                |    |    |  
  
  
4 Height only required to be collected at Cycle 1 Day 1. 5 Initial tumor imaging will be performed within 28 days before the first dose of study treatment. A CT chest/abdomen/pelvis with IV contrast is preferred. MRI abdomen with gadolinium is acceptable for patients with contrast allergies. 6 Imaging on-study will be performed every 9 weeks (± 5 days) after the first dose of study treatment for the first 18 months then every 12 weeks thereafter. On-study imaging should follow calendar days and not be adjusted for delays in cycle starts or extension of treatment cycles due to toxicity. The same imaging technique should be used in a subject throughout the study. 7 Per the RECIST v1.1 and irRC, if imaging shows progressive disease, the imaging assessment should be performed at a minimum of 4 weeks later to confirm progression as described. 8 For patients that discontinue treatment for reasons other than disease progression, every effort should be made to continue monitoring their disease status by radiographic imaging at the imaging interval that was used at the time they came off study until 1) start of new anti-cancer therapy, 2) documented disease progression, 3) death, or 4) end of study, whichever occurs first. 9 If a prior scan was obtained within 4 weeks before the date of discontinuation, then a scan at the discontinuation visit is not required. In subjects who discontinue study drug without confirmed disease progression, a radiological evaluation should be repeated at the time of treatment discontinuation (i.e., date of discontinuation ± 4 week window). 10 If labs at screening are collected within 7 days of Cycle 1 Day 1, these do not need to be repeated at this visit.  
11 Pre-dose laboratory results need to be within 2 days of dosing at all cycles.  
12 See Table 2 for complete listing of all required laboratory tests required.  
| Treatment Phase1                        | EOT             | Post-Treatment   |           |                                       |                |    |    |
|-----------------------------------------|-----------------|------------------|-----------|---------------------------------------|----------------|----|----|
| Day 1 All  Subsequent                   | Discontinuation | Survival         |           |                                       |                |    |    |
| Cycles                                  | Visit           | Follow-Up Visits | Follow-Up |                                       |                |    |    |
| Screening                               | C1D1            | C2D1             | C3D1      | Every 9 Weeks  After  Discontinuation | Every 12 Weeks |    |    |
| (± 7 Days)                              | (± 7 Days)      |                  |           |                                       |                |    |    |
| Hematology with differential            | X               | X                | X         | X                                     | X              | X  | X  |
| Evaluation/Window                       | Day -28         | ± 3              | ± 3       |                                       |                |    |    |
| to Day -1                               | Day 1           | Days             | Days      | ± 3 Days                              | + 5 Days       |    |    |
| Lipid panel                             | X               | X                | X         | X                                     | X              | X  |    |
| Coagulation panel (PT, aPTT,            | X               |                  |           |                                       |                |    |    |
| INR14 Endocrine function testing15      | X               | X                | X         | X                                     | X              | X  |    |
| Serum pregnancy test or urine16         | X               |                  |           |                                       |                |    |    |
| Tumor Markers17                         | X               | X                | X         | X                                     | X              |    |    |
| Urinalysis                              | X               | X                | X         | X                                     | X              | X  |    |
| Required research samples (blood)       | X18             | X                | X         | X                                     |                |    |    |
| TUMOR BIOPSY/ARCHIVAL TISSUE COLLECTION |                 |                  |           |                                       |                |    |    |
| Fresh tissue collection for             | X               | X                |           |                                       |                |    |    |
| Correlative studies (tissue) 19         |                 |                  |           |                                       |                |    |    |  
  
  
13 Tumor molecular profilingcan be performed on archived tissue or newly obtained during the study participation 14 If a coumadin-based anticoagulant is given, INR should be monitored weekly for the first 4 weeks after initiation of therapy and again upon discontinuing epacadostat. 15 TSH required at all day 1 visits, T3 and fT4 only required if TSH is abnormal or patient is symptomatic. 16 For women of childbearing potential, a serum pregnancy test is required at screening but must be within 3 days before first dose of study treatment. Pregnancy tests (serum or urine) should be repeated as needed if required by institutional regulations. 17 CEA and CA19-9 will be checked at baseline on C1D1 prior to Pembrolizumab and Epacadostat and, if elevated, followed every 9 weeks during therapy.  
18 Before pembrolizumab dose every 3 weeks 19 Fresh tumor biopsy will be collected pre-treatment (between day -14 to day 0) and on treatment (day 42 ± 5 days). For additional reference go to section 4.9.3 and 8.2
4.11. diet/activity/other considerations
schedule of events - second

| Treatment Phase21                     | EOT             | Post-Treatment   |           |                                       |                |    |
|---------------------------------------|-----------------|------------------|-----------|---------------------------------------|----------------|----|
| Day 1 All  Subsequent                 | Discontinuation | Survival         |           |                                       |                |    |
| Cycles                                | Visit           | Follow-Up Visits | Follow-Up |                                       |                |    |
| Progression                           | C1D1            | C2D1             | C3D1      | Every 9 Weeks  After  Discontinuation | Every 12 Weeks |    |
| (± 7 Days)                            | (± 7 Days)      |                  |           |                                       |                |    |
| ADMINISTRATIVE PROCEDURES             |                 |                  |           |                                       |                |    |
| Evaluation/Window                     | Day -14 to      | ± 3              | ± 3       |                                       |                |    |
| Day -1                                | Day 1           | Days             | Days      | ± 3 Days                              | + 5 Days       |    |
| Re-check inclusion/exclusion          | X               | X                |           |                                       |                |    |
| criteria22 Updated medical and cancer | X               |                  |           |                                       |                |    |
| history Concomitant medications       | X               | X                | X         | X                                     | X              | X  |
| review Administer Pembrolizumab23     | X               | X                | X         | X                                     |                |    |
| Administer Epacadostat24              | X               | X                | X         | X                                     |                |    |
| Survival follow-up                    | X               |                  |           |                                       |                |    |
| CLINICAL PROCEDURES AND ASSESSMENTS   |                 |                  |           |                                       |                |    |
| Comprehensive physical exam           | X               | X                |           |                                       |                |    |
| Targeted physical exam                | X               | X                | X         | X                                     |                |    |
| ECOG performance status               | X               | X                | X         | X                                     | X              | X  |  
20 Fresh tissue collection not required during the second course phase. 21 Treatment given every 3 weeks (~ 21 days ± 3 days). 22 Patient must meet required re-start criteria as defined in Section 4.8.  
23 Fixed dose at 200 mg per IV every 3 weeks. 24 Fixed dose, resume with the same dose level of first course, orally twice daily every day, all 21 days of each cycle.  
| Treatment Phase21                      | EOT             | Post-Treatment   |           |                                       |                |    |    |    |
|----------------------------------------|-----------------|------------------|-----------|---------------------------------------|----------------|----|----|----|
| Day 1 All  Subsequent                  | Discontinuation | Survival         |           |                                       |                |    |    |    |
| Cycles                                 | Visit           | Follow-Up Visits | Follow-Up |                                       |                |    |    |    |
| Progression                            | C1D1            | C2D1             | C3D1      | Every 9 Weeks  After  Discontinuation | Every 12 Weeks |    |    |    |
| (± 7 Days)                             | (± 7 Days)      |                  |           |                                       |                |    |    |    |
| Vital signs and weight                 | X               | X25              | X         | X                                     | X              | X  |    |    |
| Evaluation/Window                      | Day -14 to      | ± 3              | ± 3       |                                       |                |    |    |    |
| Day -1                                 | Day 1           | Days             | Days      | ± 3 Days                              | + 5 Days       |    |    |    |
| 12-lead ECG                            | X               |                  |           |                                       |                |    |    |    |
| AE assessment                          | X26             | X                | X         | X                                     | X              | X  | X  | X  |
| EFFICACY MEASUREMENTS                  |                 |                  |           |                                       |                |    |    |    |
| Radiologic tumor assessment            | X27             | X28,29           | X         | X                                     |                |    |    |    |
| LABORATORY ASSESSMENTS                 |                 |                  |           |                                       |                |    |    |    |
| Comprehensive serum                    | X               | X                | X         | X                                     | X              | X  | X  |    |
| chemistry Hematology with differential | X               | X                | X         | X                                     | X              | X  | X  |    |
| Lipid panel                            | X               | X                | X         | X                                     | X              | X  |    |    |
| Coagulation panel (PT, aPTT,           | X               |                  |           |                                       |                |    |    |    |
| INR) Endocrine function testing        | X               | X                | X         | X                                     | X              | X  |    |    |  
  
  
25 Height required to be collected at Cycle 1 Day 1 only. 26 All AEs from previous treatment with pembrolizumab and epacadostat must be ≤ grade 1 and stable. 27 For subjects that have had a scan within 14 days of restarting therapy due to progression, scan does not need to be repeated pre-dosing.  
28 Imaging in the second course phase will be performed every 9 weeks (± 5 days) after the first dose of study treatment for the first 18 months then every 12 weeks thereafter. Onstudy imaging should follow calendar days and not be adjusted for delays in cycle starts or extension of treatment cycles due to toxicity. The same imaging technique should be used in a subject throughout the study.  
29 Per the RECIST v1.1 and irRC, if imaging shows progressive disease, the imaging assessment should be performed at a minimum of 4 weeks later to confirm progression as described.  
| Treatment Phase21             | EOT             | Post-Treatment   |           |                                       |                |    |
|-------------------------------|-----------------|------------------|-----------|---------------------------------------|----------------|----|
| Day 1 All  Subsequent         | Discontinuation | Survival         |           |                                       |                |    |
| Cycles                        | Visit           | Follow-Up Visits | Follow-Up |                                       |                |    |
| Progression                   | C1D1            | C2D1             | C3D1      | Every 9 Weeks  After  Discontinuation | Every 12 Weeks |    |
| (± 7 Days)                    | (± 7 Days)      |                  |           |                                       |                |    |
| Serum pregnancy test or urine | X30             |                  |           |                                       |                |    |
| Evaluation/Window             | Day -14 to      | ± 3              | ± 3       |                                       |                |    |
| Day -1                        | Day 1           | Days             | Days      | ± 3 Days                              | + 5 Days       |    |
| Tumor Markers                 | X               | X                | X         | X                                     | X              | X  |
| Urinalysis                    | X               | X                | X         | X                                     | X              | X  |
| Required research samples     | X31             | X                | X         | X                                     |                |    |
4.11. diet/activity/other considerations
10. measurements

10.1. Tumor Imaging Evaluations  
Imaging of the chest, abdomen and pelvis is required at screening/baseline, every 9 weeks (± 5 days) for the first 18 months, then every 12 weeks thereafter regardless of the location of known metastases. Similar methods of tumor assessment and similar techniques must be used to characterize each identified and reported lesion at screening/baseline and during subsequent tumor assessments. Imaging-based evaluation is preferred to clinical examination. All measurements should be taken and recorded in metric notation using a ruler or calipers. Conventional CT and MRI: This guideline has defined measurability of lesions on CT scan based on the assumption that CT slice thickness is 5 mm or less. If CT scans have slice thickness greater than 5 mm, the minimum size for a measurable lesion should be twice the slice thickness. MRI is also acceptable in certain situations (e.g. for body scans), but NOT for the chest. RECIST v1.1 will be applied by the site as the primary measure for assessment of tumor response and as a basis for protocol guidelines related to disease status (e.g., discontinuation of study therapy). RECIST v1.1 will be adapted for defining progressive disease (PD) as follows to account for the unique tumor response seen in this class of therapeutics.
4.11. diet/activity/other considerations
10.2. definition of measurable/non-measurable or

Measurable lesions are lesions that can be accurately measured in two perpendicular diameters, with at least one diameter ≥ 10 mm and the other dimension ≥ 10 mm (10 mm x 10 mm for spiral CT). The area will be defined as the product of the largest diameter with its perpendicular. Skin lesions can be considered measurable. Non-measurable (evaluable) lesions are all other lesions, including unidimensionally measurable disease and small lesions (lesions without at least one diameter ≥ 20 mm), and any of the following:
- Lesions occurring in a previously irradiated area (unless they are documented as new lesions since the completion of radiation therapy), bone lesions, leptomeningeal disease, ascites, pleural or pericardial effusion, lymphangitis cutis/pulmonitis, abdominal masses that are not pathologically/cytologically confirmed and followed by imaging techniques  
  
  
 and cystic lesions.  
All measurable and non-measurable lesions should be measured at screening/baseline and at the defined tumor assessment time points (~ every 9 weeks ± 5 days for the first 18 months then every 12 weeks thereafter). Extra assessments may be performed, as clinically indicated, if there is a suspicion of progression.
4.11. diet/activity/other considerations
10.2.2. index and non-index lesions

All measurable lesions, up to a maximum of five lesions per organ and ten lesions in total, should be identified as index lesions to be measured and recorded in the medical record at Screening. The index lesions should be representative of all involved organs. In addition, index lesions should be selected based on their size (lesions with the longest diameters), their suitability for accurate repeat assessment by imaging techniques, and how representative they are of the patient's tumor burden. At screening, a sum of the products of diameters (SPD) for all index lesions will be calculated and considered the baseline sum of the products of diameters. Response criteria to be followed are listed below. The baseline sum will be used as the reference point to determine the objective tumor response of the index lesions at tumor assessment. Measurable lesions, other than index lesions, and all sites of non-measurable disease, will be identified as non-index lesions. Non-index lesions will be recorded in the medical record and should be evaluated at the same assessment time points as the index lesions. In subsequent assessments, non-index lesions will be recorded as "stable or decreased disease," "absent," or "progression."
4.11. diet/activity/other considerations
10.2.3. evaluation of target lesions

Complete Response: Complete disappearance of all target lesions. Partial Response: Decrease, relative to baseline, of 30% or greater in the sum of the diameters of the two largest perpendicular diameters. Stable Disease: Does not meet criteria for complete or partial response, in the absence of  
  
  
 progressive disease. Subject with PR or CR that is not confirmed after at least 6 weeks are scored as SD unless they have new primary lesions. Progressive Disease: At least 20% increase in the sum of the products of all target lesions (taking as reference the smallest sum recorded at or following baseline) and/or the appearance of any new lesion(s). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.
4.11. diet/activity/other considerations
10.2.4. evaluation of non-target lesions

Complete Response: Complete disappearance of all non-target lesions and normalization of tumor marker level. All lymph nodes must be non-pathological in size (< 10 mm in short axis). Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level above the normal limits. Progressive Disease: Appearance of one or more new lesions and/or *unequivocal progression* of existing non-target lesions.
4.11. diet/activity/other considerations
10.3. assessment of disease according

If imaging shows PD, tumor assessment should be repeated ≥ 4 weeks later to confirm PD with the option of continuing treatment for clinically stable subjects. Clinically stable is defined by the following criteria:
- Absence of signs and symptoms indicating disease progression
- No decline in ECOG performance status - Absence of rapid progression of disease Absence of progressive tumor at critical anatomical sites (e.g., cord compression) requiring urgent alternative medical intervention.  
| Clinically Stable   | Clinically Unstable                                                    |                                                                                                     |                                                                   |                                                                                                                    |
|---------------------|------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------|-------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------|
| Imaging             | Treatment                                                              | Imaging                                                                                             | Treatment                                                         |                                                                                                                    |
| First radiologic    | Repeat imaging at                                                      |                                                                                                     |                                                                   |                                                                                                                    |
| evidence of PD      | ≥ 4 weeks to  confirm PD                                               | May continue study  treatment at the  investigator's  discretion while  awaiting  confirmatory scan | Repeat imaging at  ≥ 4 weeks to  confirm PD if  possible          | Discontinue  treatment                                                                                             |
| Repeat scan         | No additional                                                          | Discontinue                                                                                         | No additional                                                     | N/A                                                                                                                |
| confirms PD         | imaging required                                                       | treatment                                                                                           | imaging required                                                  |                                                                                                                    |
| Repeat scan shows   | Continue regularly                                                     |                                                                                                     |                                                                   |                                                                                                                    |
| SD, PR, or CR       | scheduled imaging  assessments every  9 weeks                          | Continue study  treatment at the  investigator's  discretion                                        | Continue regularly  scheduled imaging  assessments every  9 weeks | May restart study  treatment if  condition has  improved and/or  clinically stable  per investigator's  discretion |
| Table 7:            | Imaging and Treatment after First Radiographic Evidence of Progression |                                                                                                     |                                                                   |                                                                                                                    |  
  
  
In determining whether the tumor burden has increased or decreased, investigators should consider all target lesions as well as non-target lesions. Subjects who are deemed clinically unstable are not required to have repeat imaging for confirmation. If radiologic progression is confirmed, then the subject will be discontinued from study treatment as specified in the protocol, and the first radiographic evidence of PD should be the date of progression. If radiologic progression is not confirmed, then the subject should resume/continue study treatment and have their next scan according to the Protocol-specified schedule. If progression is not confirmed and the subject continues on treatment, the next scan that documents disease progression (and is confirmed by a second scan at least 4 weeks later), will be considered the date of disease progression. Note: If a subject with confirmed radiographic progression (i.e., 2 scans at least 28 days apart demonstrating progressive disease) is clinically stable or clinically improved, and there is no further increase in the tumor dimensions at the confirmatory scan, an exception may be considered to continue treatment if in the best interest of the patient clinically. Meaning, the investigator can continue if the risk-benefit is acceptable to continue the patient on study. Clinically stable subjects should also have at the confirmatory scan no further increase in the target lesions, no unequivocal increase in non-target lesions, and no additional new lesions  
  
 develop (non-worsening PD) to continue study treatment. Imaging during the follow-up period is to be repeated every 9 weeks (63 ± 5 days) for subjects who discontinue study treatment for reasons other than disease progression until the subject experiences confirmed disease progression or starts a new antineoplastic therapy.
4.11. diet/activity/other considerations
10.4. response endpoints

Pembrolizumab and epacadostat are expected to trigger immune-mediated responses, which require activation of the immune system prior to the observation of clinical response. Such immune activation may take weeks to months to be evident.  
| Progression Free         | Response Rate                                                                                             | Overall Survival                                                                                                                                                      | Safety                |                                                          |
|--------------------------|-----------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------|----------------------------------------------------------|
| Survival (PFS)           | (RR)                                                                                                      | (OS)                                                                                                                                                                  |                       |                                                          |
| Primary or               | Primary                                                                                                   | Secondary                                                                                                                                                             | Secondary             | Secondary                                                |
| Secondary Definition and | Time from first                                                                                           |                                                                                                                                                                       |                       |                                                          |
| Time Frame               | treatment to  documented disease  progression or death  due to any cause                                  | Assessed on the  basis of adverse  events (AEs; graded  according to the  National Cancer  Institute Common  Terminology  Criteria for Adverse  Events, version 4.03) |                       |                                                          |
| Safety Issue             | No                                                                                                        | No                                                                                                                                                                    | No                    | Yes                                                      |
| (Yes/No)                 | Defined as  proportion of  patients with  RECIST v1.1 response (sum of  partial and complete  responses). | Time from first  treatment until the  day of death due to  any cause                                                                                                  |                       |                                                          |
| Relevant Subset          | Patients who receive  baseline imaging  and at least first  follow-up imaging at  9 weeks.                | Patients who receive  baseline imaging  and at least first  follow-up imaging at  9 weeks.                                                                            | All enrolled patients | Patients who receive  at least 1 dose of  pembrolizumab. |
| Measurement              | CT or MRI every 9                                                                                         | CT or MRI every 9                                                                                                                                                     | CT or MRI every 9     | CTCAE v5                                                 |
| Method                   | weeks                                                                                                     | weeks                                                                                                                                                                 | weeks                 |                                                          |
| Measurement Time         | Every 9 weeks                                                                                             | Every 9 weeks                                                                                                                                                         | Every 9 weeks         | Day 1 of each cycle                                      |
| Points                   |                                                                                                           |                                                                                                                                                                       |                       |                                                          |
4.11. diet/activity/other considerations
table 8 response evaluations based

The protocol, the proposed informed consent and all forms of participant information related to the study (e.g. advertisements used to recruit participants) will be reviewed and approved by the Stanford IRB and Stanford Cancer Institute Scientific Review Committee (SRC). Any changes  
  
  
 made to the protocol will be submitted as a modification and will be approved by the IRB prior to implementation. The Protocol Director will disseminate the protocol amendment information to all participating investigators.
4.11. diet/activity/other considerations
11.2. data and safety monitoring

The Stanford Cancer Institute Data and Safety Monitoring Committee (DSMC) will be the monitoring entity for this study. The DSMC will audit study-related activities to determine whether the study has been conducted in accordance with the protocol, local standard operating procedures, FDA regulations, and Good Clinical Practice (GCP). This may include review of the following types of documents participating in the study: regulatory binders, case report forms, eligibility checklists, and source documents. In addition, the DSMC will regularly review serious adverse events and protocol deviations associated with the research to ensure the protection of human subjects. Results of the DSMC audit will be communicated to the IRB and the appropriate regulatory authorities at the time of continuing review, or in an expedited fashion, as needed.
4.11. diet/activity/other considerations
11.3. data management plan

The Protocol Director, or his/her designee, will prepare and maintain adequate and accurate participant case histories with observations and data pertinent to the study. Study specific CRFs will document treatment outcomes for data analysis. CRFs will be developed using the OnCore database system and will be maintained by the study team. CRFs will be electronic and only accessible to the research team via password, dual-authentication database. All research charts will be kept in a locked office.
4.11. diet/activity/other considerations
11.4. study monitoring

The study will be monitored by Stanford's internal Data Safety Monitoring Committee (DSMC) on an annual basis per institutional guidelines.
4.11. diet/activity/other considerations
11.5. good clinical practice

This study will be conducted in accordance with Good Clinical Practice (GCP), as defined by the International Conference on Harmonisation (ICH) and in accordance with the ethical principles underlying European Union Directive 2001/20/EC and the United States Code of Federal  
  
 Regulations, Title 21, Part 50 (21CFR50). The study will be conducted in compliance with the protocol. The protocol and any amendments and the subject informed consent will receive IRB/IEC approval/favorable opinion prior to initiation of the study. All potential serious breaches must be reported to Genentech immediately. A serious breach is a breach of the conditions and principles of GCP in connection with the study or the protocol, which is likely to affect, to a significant degree, the safety or physical or mental integrity of the subjects of the study or the scientific value of the study. Study personnel involved in conducting this study will be qualified by education, training, and experience to perform their respective task(s). This study will not use the services of study personnel where sanctions have been invoked or where there has been scientific misconduct or fraud (e.g., loss of medical licensure, debarment). Systems with procedures that ensure the quality of every aspect of the study will be implemented.
4.11. diet/activity/other considerations
11.6. protocol adherence

The principal investigator must obtain IRB or IEC approval for the investigation. Initial IRB or IEC approval and all materials approved by the IRB or IEC for this study including the subject ICF and recruitment materials must be maintained by the investigator and made available for inspection. Each investigator must adhere to the Protocol as described in this document and agree that changes to the Protocol, with the exception of medical emergencies, must be discussed and approved, firstly, by the sponsor or its designee and, secondly, by the IRB or IEC. Each investigator is responsible for enrolling subjects who have met the Protocol inclusion and exclusion criteria. The IRB that granted original approval, or the IRB currently responsible for overseeing the conduct of the study, must be notified of all changes in and deviations from the Protocol that may increase risk to the subject, and/or that may adversely affect the rights of the subject or validity of the investigation. The investigator must send a copy of the approval letter  
  
  
 from the IRB to the sponsor or its designee and retain the original in the site study regulatory file. Major eligibility deviations must be reported to the IRB in accordance with the IRB requirements. During the course of the study, the monitor must notify the sponsor or its designee of subjects found not to have met eligibility criteria. The medical monitor, in collaboration with the investigator, will determine if the subject should be withdrawn from the study.
4.11. diet/activity/other considerations
11.7. financial disclosure

All clinical investigators participating in clinical studies subject to FDA Regulation Title 21 Code of Federal Regulations (CFR) Part 54 - Financial Disclosure by Clinical Investigators, are required before study initiation to submit a completed Clinical Investigator Financial Disclosure Request Form that sufficiently details any financial interests and arrangements that apply. For the purpose of this regulation, clinical investigator is defined as any investigator or subinvestigator who is directly involved in the treatment or evaluation of research subjects, including the spouse and each dependent child of the clinical investigator. These requirements apply to both US and foreign clinical investigators conducting covered clinical studies. Any new investigators or sub-investigators added to the covered clinical study during its conduct must also submit a completed Clinical Investigator Financial Disclosure Request Form. During a covered clinical study, any changes to the financial information previously reported by a clinical investigator must be reported to the sponsor or its designee. At the conclusion of the covered clinical study, the clinical investigators will be reminded of their obligation to report to the sponsor or its designee any changes to the financial information previously reported. The clinical investigators will also be reminded that they must report any changes in their financial information for a period of 1 year after completion of the covered clinical study.
4.11. diet/activity/other considerations
11.8. compliance with study registration

Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the Food and Drug Administration Amendments Act (FDAAA), the Sponsor of the study is solely responsible for determining whether the study and its results are subject to the requirements for submission to the Clinical Trials Data Bank, http://www.clinicaltrials.gov. Information posted will allow subjects to identify potentially appropriate studies for their disease conditions and  
  
 pursue participation by calling a central contact number for further information on appropriate study locations and study site contact information.
4.11. diet/activity/other considerations
11.9. quality control and quality

At some point during the study, individuals from the Merck and/or Incyte Quality Assurance department and/or their authorized representative may visit the investigator's site to conduct an audit of the study. The purpose of this visit will be to determine the investigator's adherence to the protocol, applicable regulations, and outlined procedures, in addition to assessing the accuracy of the study data. Before initiating this audit, the investigator will be contacted by the company(ies) to arrange a convenient time for this visit. The investigator and staff are expected to cooperate with the auditors and allow access to all subject records supporting the CRFs and other study-related documents.
4.11. diet/activity/other considerations
11.9.2. inspection by regulatory authorities

At some point during the investigational product's development program, a regulatory authority may visit the investigator to conduct an inspection of the study and the site. The investigator and staff are expected to cooperate with the inspectors and allow access to all source documents supporting the CRFs and other study-related documents. The investigator must immediately notify the sponsor when contacted by any regulatory authority for purposes of conducting an inspection.
4.11. diet/activity/other considerations
11.10. ethics 11.10.1. ethical conduct

This study will be performed in accordance with ethical principles that have their origin in the Declaration of Helsinki and conducted in adherence to the study Protocol, GCPs as defined in Title 21 of the US CFR Parts 50, 54 56, 312, and Part 11, as well as ICH GCP consolidated guidelines (E6) and applicable regulatory requirements.
4.11. diet/activity/other considerations
11.10.2. ethics review

It is the responsibility of the investigator to assure that all aspects of the ethics review are  
 conducted in accordance with the Declaration of Helsinki as described in the ICH E6: Guideline for GCP, and/or local laws, whichever provides the greatest level of protection for the study participants. The Protocol and any information supplied to the subject to obtain informed consent, including written ICFs, subject recruitment procedures (e.g., advertisements), and written information to be provided to subjects (information leaflets), must be reviewed and approved by a qualified IRB/IEC before enrollment of participants in the study. Before initiation of the study, the sponsor or its designee must receive documentation of the IRB or IEC approval, which specifically identifies the study/Protocol, and a list of the committee members. The principal investigator is responsible for informing the IRB or IEC of any amendment to the Protocol in accordance with local requirements. Protocol amendments and revisions to the ICF must be submitted to and approved by the IRB or IEC. Investigators must submit progress reports to the IRB or IEC in accordance with the IRB or IEC requirements and local regulations. Annual re-approval of the study must be obtained. Copies of progress reports and annual re-approvals must be sent to the sponsor or its designee. The principal investigator is also responsible for providing the IRB or IEC with reports of any reportable serious adverse drug reactions from any other study conducted with the investigational product. The sponsor or its designee will provide this information to the principal investigator. When the sponsor or its designee provides the investigator with a safety report, the investigator is responsible for ensuring that the safety report is reviewed and processed in accordance with regulatory requirements and with the policies and procedures established by their respective IRBs. After completion or termination of the study, the investigator must submit a final report to the IRB or IEC and to the sponsor or its designee. The investigator, as part of the records retention requirements for the study, must maintain documentation of all submissions, correspondence, and approvals to and from the IRB or IEC. Each clinical investigator is responsible to conduct the study in accordance with the Protocol, all  
  
  
 applicable laws, regulations, and GCP according to ICH guidelines.
4.11. diet/activity/other considerations
11.11. data privacy

The investigator and the sponsor or its designee must adhere to applicable data privacy laws and regulations. The investigator and the sponsor (or its designee) are responsible for ensuring that sensitive information is handled in accordance with local requirements (eg, HIPAA). Appropriate consent and authorizations for use and disclosure and/or transfer (if applicable) of protected information must be obtained.
4.11. diet/activity/other considerations
11.12. data handling and record

The investigator must ensure that all records pertaining to the conduct of the clinical study (as listed above) are adequately maintained for a period of 2 years after the last approval of a marketing application in an ICH region and until there are no pending or contemplated marketing applications in an ICH region, or at least 2 years have elapsed since the formal termination of clinical development of the investigational product.
4.11. diet/activity/other considerations
11.12.2. retention of records

The principal investigator must maintain all documentation relating to the study for a period of 2 years after the last marketing application approval, or if not approved, 2 years following the termination of the test article for investigation. If it becomes necessary for the sponsor or the regulatory authority to review any documentation relating to the study, the investigator must permit access to such records. The investigator must not destroy any records associated with the study without receiving approval from Incyte and/or Merck. The investigator must notify the sponsor or its designee in the event of accidental loss or destruction of any study records. If the investigator leaves the institution where the study was conducted, the sponsor or its designee must be contacted to arrange alternative record storage options. Whenever possible, an original recording of an observation must be retained as the source  
  
  
 document. However, a photocopy of a record is acceptable, provided it is legible and is a verified copy of the original document. All CRF data entered by the site (including audit trail), as well as computer hardware and software (for accessing the data), will be maintained or made available at the site in compliance with applicable record retention regulations.