Yarchoan. Grade 3 Abdominal pain, fever, change in bowel habits with ileus; peritoneal signs Endoscopy is indicated to confirm the etiology of the patient’s symptoms. Hold therapy, start lomotil and budesonide 9mg daily and start systemic steroids. Continue steroids until symptoms improve to grade 1, then taper. Therapy may be resumed only when patient returns to ≤ grade 1. If symptoms are not controlled within 7 days of initiating steroids, contact Dr. Azad or Dr. Yarchoan. Patients should be taken off study if symptoms are not controlled within 14 days. Grade 4 Life-threatening consequences (perforation, bleeding, ischemia, necrosis, toxic megacolon) Permanently discontinue therapy Hepatitis Grade 1 ALT/AST > ULN – 2.5 x ULN; Bilirubin > ULN – 1.5 x ULN Maintain treatment, but increase frequency of liver function testing Grade 2 ALT/AST > 2.5 – 5.0 x ULN; Bilirubin > 1/5 – 3.0 x ULN Maintain treatment, increase frequency of liver function testing, consider systemic steroids until liver function tests return to ≤ grade 1. Grade 3 ALT/AST > 5.0 – 20.0 x ULN; Bilirubin > 3.0 – 10.0 x ULN Permanently discontinue therapy. Hepatology consultation is indicated to confirm the etiology of the patient’s symptoms. Start system ic steroids. Rule out infectious causes of hepatitis. Grade 4 AST/ALT 20.0 x ULN; Bilirubin > 10.0 x ULN Permanently discontinue therapy. Phase 2 Study of GVAX (with CY) and pembrolizum ab in MMR-p advanced colorectal cancer J16154/Version 5 / January 17, 2018 28For patients with liver metastasis who begi n treatment with Grade 2 AST or ALT, if AST or ALT increases by greater than or equal to 50% rela tive to baseline and lasts for at least 1 week then patients should be discontinued. Pneumonitis Grade 1 Asymptoma tic; clinical or diagnostic observations only; intervention not needed Hold MK-3475 but may continue Cy/GVAX. Monitor symptoms every 2-3 days. Consider pulmonary consult and/or systemic steroids. May resume MK-3475 when symptoms near baseline. Grade 2 Symptomatic; medical intervention indicated limited instrumental ADLs Hold MK-3475 but may continue Cy/GVAX. Monitor symptoms every 2-3 days. Obtain pulmonary consult and initiate systemic steroids (1/2 mg/kg/day prednisone or equivalent). Consider hospitalization and bronchoscopy. Hold MK-3475 and continue systemic steroids until symptoms near baseline. If symptoms persist for 3 weeks or re-develop upon re-challenge, permanently discontinue MK-3475. Grade 3 Severe symptoms; limiting self-care ADL; oxygen indicated Permanently discontinue therapy and admit to the hospital. Obtain pulmonary and ID consults, and treat with systemic steroids (1/2 mg/kg/ day prednisone or equivalent) and prophylactic antibiotics. Recommend bronchoscopy and consideration of lung biopsy. Consider addition of additional immunosuppressant (eg anti- tumour necrosis factor alpha, IVIG, etc.) Grade 4 Life-threatening respiratory compromise; urgent intervention indicated (e.g. tracheostomy or intubation). Toxicity Hold Treatment For Grade Timing for Restarting Treatment Treatment Discontinuation Type 1 diabetes mellitus (if new onset) or Hyperglycemia T1DM or 3-4 Hold therapy for new onset Type 1 diabetes mellitus or Grade 3-4 hyperglycemia associated with evidence of beta cell failure. May resume therapy when patients are clinically and metabolically stable. Phase 2 Study of GVAX (with CY) and pembrolizum ab in MMR-p advanced colorectal cancer J16154/Version 5 / January 17, 2018 29Toxicity Hold Treatment For Grade Timing for Restarting Treatment Treatment Discontinuation Hypophysitis 2-4 Toxicity resolves to Grade 0-1. Therapy can be continued while endocrine replacement therapy is instituted 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. Hyperthyroidism 3 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. 4 Permanently discontinue Permanently discontinue Hypothyroidi sm Therapy can be continued while thyroid replacement therapy is instituted Therapy can be continued while thyroid replacement therapy is instituted. Infusion Reaction 3-4 Permanently discontinue Permanently discontinue Renal Failure or Nephritis 2 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. 3-4 Permanently discontinue Permanently discontinue All Other Drug-Related Toxicity2 3 or Severe 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. 4 Permanently discontinue Permanently discontinue The proportion of unacceptable toxicities will be monitored. If the toxicity levels are unacceptable (high probability that it is >4 5% of subjects), then enrollment will be suspended until further review and consid eration by the IND Sponsor and MEC. 4.8 Duration of Therapy In the absence of treatment delays due to adverse event(s), treatment may continue indefinitely until one of the following criteria applies: Phase 2 Study of GVAX (with CY) and pembrolizum ab in MMR-p advanced colorectal cancer J16154/Version 5 / January 17, 2018 30 Continued radiographic evidence of di sease progression on two subsequent imaging scans 6 weeks apart,  Clinical progression or deterioration per Section 4.10 ,  Intercurrent illness that prevents further administration of treatment,  Unacceptable adverse event(s) as described in Section 4.7 ,  Patient decides to withdraw from the study, or  General or specific changes in the patient's condition render the patient unacceptable for further treatment in th e judgment of the investigator, or  Achieved a complete response to therapy, and received 6 weeks of therapy beyond the date when the initial comp lete response was declared without evidence of disease recurrence, or  Completed 24 months of study medi cation or 35 administrations of Cy/GVAX/pembrolizumab, whichever is later. Note: 24 months of study medication is calculated from the date of first dose. Subjec ts who stop therapy after 24 months may be eligible for up to one year of additional study treatment if they progress after st opping study treatment provide d they meet the initial study requirements. See Section 4.9 below. 4.9 Off Treatment Evaluation and Retreatment Criteria If a patient is disc ontinued from study medication afte r completion of 24 months of treatment, a mandatory Off Treatment Evalua tion should be performed 30 days (+/- 7 days) after the last treatment as described in the Study Calendar ( Section 9 ). Patients should continue to be monitored for dise ase status by radiologic imaging and tumor marker(s) every 12 weeks (+/- 2 weeks). In addition, we will also continue to collect peripheral blood, serum, and plasma samp les every 12 weeks (+/- 2 weeks) as described in the Study Calendar ( Section 9 ). Patients will also be monitored for AEs up to the Off Treatment Evaluation or to resolution of drug-related AEs to ≤ Grade 1, whichever occurs later. SAEs that occur with in 90 days of the last treatment or before initiation of a new antineoplastic treatment should also be followed and recorded. Retreatment Criteria Patients who stop therapy with SD or better may be eligible for up to one year of additional therapy with Cy/GVAX/pembroliz umab if they progr ess after stopping therapy and they meet the following criteria: EITHER:  Stopped initial treatment with Cy/GVAX/pembrolizumab after attaining an investigator determined confir med CR according to RECIST 1.1 o Was treated for at least 24 weeks with Cy/GVAX/pembrolizumab before Phase 2 Study of GVAX (with CY) and pembrolizum ab in MMR-p advanced colorectal cancer J16154/Version 5 / January 17, 2018 31discontinuing therapy o Received at least two treatments with Cy/GVAX/pembrolizumab beyond the date when the initial CR was declared OR:  Subject had SD, PR or CR and stopped Cy /GVAX/pembrolizumab treatment after 24 months of study therapy for reasons other th an disease progression or intolerability AND:  Experienced an investigator-determined confirmed radiographic disease progression after stopping their initial treatment with Cy/GVAX/pembrolizumab  Did not receive any anti-cancer tr eatment since the last dose of Cy/GVAX/pembrolizumab  Meets the initial study requirements as detailed in Section 3.1  Female subject of childbearing potential should have a negative urine or serum pregnancy test within 72 hours prior to re ceiving retreatment with study medication. Subjects who restart treatment should resume at the same dose and cycle interval which they were receiving prior to di scontinuation.