Severe local inflammation or significant clinical autoimmunity will be managed on a case-by-case basis. 5.2.3 CRS -207 Guidance on treatment of the common infusion reactions related to CRS -207 dosing is as follows: • Fevers: Despite the acetaminophen premedication, subjects can spike fevers up to 40°C starting at the end of the CRS -207 infusion generally through the next 24 hours. Oral ibuprofen (400 to 800 mg) and acetaminophen (650 to 1000 mg) may be used in alternate sequen ce every 4 hours. • Rigors : Rigors (generally once or twice per infusion) have been observed to start during or at the end of a CRS -207 infusion through 24 hours. IV narcotics such as morphine or meperidine may be administered per institutional policy. Oral morphine or non -steroidal anti -inflammatory drugs (NSAIDs) (e.g., aspirin, ibuprofen, naproxen) may be used as home treatment. • Blood pressure : Decreases in blood pressure have been observed necessitating additional IV fluids during the 4 hour observation period (up to 1 or 2 liters). Reasons for this include the development of fever, compartmental shifts of fluid resulting from the CRS -207 infusion and the use of narcotics. Some subjects have also been slightly hypotensive at 24 hours upon arrival to the clinic after CRS -207 administration . Subjects are encouraged to hydrate themselves liberally at home with oral fluids. • Nausea and vomiting : Nausea and vomiting have been reported and observed within 24 hours after CRS -207 infusion. Subjects may be given a nti-emetics as needed. Blood draws for clinical hematology and serum chemistry will be done the day after the CRS -207 infusion . Any unexpected grade 3 or greater laboratory abnormalities should be repeated within 24 -72 hours. Grade 3 or greater creatinine , AST, ALT, and bilirubin should be repeated within 24 -72 hours as well. 5.2.4 Nivolumab and Ipilimumab J1790 / Version 7.0/ December 10, 2020 21 Nivolumab and ipilimumab are fully human monoclonal immunoglobulin (Ig) G4 antibod ies. Subjects should be closely monitored for potential AEs during antibody infusion and potential AEs throughout the study. 5.2.4.1 Infusion Reactions Since nivolumab and ipilimumab contain only human immunoglobulin protein sequences, it is unlikely to be immunogenic and induce an infusion or hypersensitivity r eaction. However, if such a reaction were to occur, it might manifest with fever, chills, rigors, headache, rash, pruritis, arthralgias, hypo - or hypertension, bronchospasm, or other symptoms. All grade 3 or 4 infusion reactions should be reported within 2 4 hours to the Protocol Chair and BMS and reported as an SAE if criteria are met. Infusion reactions should be graded according to CTCAE (version 4.03) guidelines. Treatment recommendations are provided below and may be modified based on local treatment standards and guidelines as appropriate: For grade 1 symptoms ( mild reaction; infusion interruption not indicated; intervention not indicated): Remain at bedside and monitor subject until recovery from symptoms. The following prophylactic premedications are recommended for future infusions: diphenhydramine 50 mg (or equivalent) and/or acetaminophen 325 to 1000 mg at least 30 minutes before additional nivolumab or ipilimumab administrations. For grade 2 symptoms ( moderate reaction requires therapy or infu sion interruption but responds promptly to symptomatic treatment [e .g., antihistamines, non -steroidal anti-inflammatory drugs, narcotics, corticosteroids, bronchodilators, IV fluids]; prophylactic medications indicated for 24 hours): Stop the nivolumab or ipilimumab infusion, begin an IV infusion of normal saline, and treat the subject with diphenhydramine 50 mg IV (or equivalent) and/or acetaminophen 325 to 1000 mg; remain at bedside and monitor subject until resolution of symptoms. Corticosteroid or bron chodilator therapy may also be administered as appropriate. If the infusion is interrupted, restart the infusion at 50% of the original infusion rate when symptoms resolve; if no further complications ensue after 30 minutes, the rate may be increased to 10 0% of the original infusion rate. Monitor subject closely. If symptoms recur then no further nivolumab or ipilimumab will be administered at that visit. Administer diphenhydramine 50 mg IV, and remain at bedside and monitor the subject until resolution of symptoms. The amount of study drug infused must be recorded on the case report form (CRF). The following prophylactic premedications are recommended for future infusions: diphenhydramine 50 mg (or equivalent) and/or acetaminophen 325 to 1000 mg should be a dministered at least 30 minutes before additional nivolumab or ipilimumab administrations. For grade 3 or grade 4 symptoms ( severe reaction, grade 3: prolonged [i .e., not rapidly responsive to symptomatic medication and/or brief interruption of infusion] ; recurrence of symptoms following initial improvement; hospitalization indicated for J1790 / Version 7.0/ December 10, 2020 22 other clinical sequelae [e .g., renal impairment, pulmonary infiltrates]; grade 4: (life threatening; pressor or ventilator support indicated): Immediately di scontinue infusion of nivolumab or ipilimumab . Begin an IV infusion of normal saline, and treat the subject as follows. Recommend bronchodilators, epinephrine 0.2 to 1 mg of a 1:1,000 solution for subcutaneous administration or 0.1 to 0.25 mg of a 1:10,000 solution injected slowly for IV administration, and/or diphenhydramine 50 mg IV with methylprednisolone 100 mg IV (or equivalent), as needed. Subject should be monitored until the investigator is comfortable that the symptoms will not recur. Nivolumab and ipilimuma b will be permanently discontinued. Investigators should follow their institutional guidelines for the treatment of anaphylaxis. Remain at bedside and monitor subject until recovery from symptoms. In the case of late -occurring hypersensitivity symptoms (e .g., appearance of a localized or generalized pruritis within 1 week after treatment), symptomatic treatment may be given (e .g., oral antihistamine, or corticosteroids). Please refer to Section 6.2 for guidelines regarding ipilimumab, GVAX and CRS - 207 treatment delays following a nivolumab or ipilimumab infusion -related reaction. 5.2.4.2 Nivolumab and Ipilimumab -Related Adverse Events Blocking PD-1 or CTLA -4 function may permit the emergence of auto -reactive T cells and resultant clinical autoimmunity. Rash /pruritus , diarrhea/colitis, pneumonitis, hepatitis , and hypothyroidism were drug -related, presumptive autoimmune events noted in previous nivolumab and ipilimumab studies. For the purposes of this study, a nivolumab or ipilimumab -related AE is defin ed as an AE of unknown etiology, associated with drug exposure and is consistent with an immune phenomenon. Efforts should be made to rule out neoplastic, infectious, metabolic, toxin or other etiologic causes. Serological, immunological, and histological (biopsy) data should be used to support the diagnosis of an immune - mediated toxicity. Suspected nivolumab or ipilimumab -related AEs must be documented on an AE or SAE CRF. Identification and treatment of nivolumab and ipilimumab -related AEs can be found in Appendix B . Additional guidance can be found in the nivolumab and ipilimumab Investigator ’s Brochure s (IB). Antibiotics will also be administered to subjects who have not yet received antibiotics for CRS - 207 and the subject requires steroids for a suspected nivolumab or ipilimumab -related AE (Section 5. 5). Subjects who experience a grade 2 or higher nivolumab or ipilimumab -related AE should be discussed with the Protocol Chair and IND sponsor immediately. 5.3 Prohibited and/or Restricted Medications and Devices The following therapies or devices are not permitted during the treatment period (if administered, the subject may be removed from the study): J1790 / Version 7.0/ December 10, 2020 23 • Any non -study anticancer chemotherapy or immunotherapy (approved or investigational) • Any major surgery or surgical procedure; if required must be discussed with the Protocol Chair to determine if it is appropriate for the subject to continue study treatment • TNF pathway inhibitors or PI3 kinase inhibitors • Another investigational agent • Filgrastim (Neupogen® or G -CSF) or sargramostim (Leukine® or GM -CSF) • Live vaccines (examples of live vaccines include, but are not limited to: measles, mumps, rubella, chicken pox, yellow fever, rabies, BCG, and typhoid [oral] vac cine). Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed. However, intranasal influenza vaccines (e.g. Flu -Mist®) are live attenuated vaccines, and are not allowed. • The use of anticoagulants is known to increas e the risk of gastrointestinal hemorrhage. Since gastrointestinal hemorrhage is an adverse reaction with nivolumab, subjects who require concomitant anticoagulant therapy should be monitored closely. • Implanted medical devices that pose high risks for colonization and cannot be easily removed (e.g., artificial heart valves, pacemakers, prosthetic joints, orthopedic screw(s), metal plate(s)) if infection occurs are prohibited. Other common devices such as venous access devices (e.g., Port -a-Cath or Medip ort), arterial and venous stents, and dental and breast implants may be permitted if approved by the Protocol Chair. • Palliative (limited -field) radiation therapy is permitted, but only for pain control and with approval by the Protocol Chair or IND Spons or. • Systemically active steroids can be used but should be reported to the Protocol Chair and/or IND Sponsor. Steroid treatment should be completed at least 14 days prior to resuming study -related treatments. Patients requiring adrenal replacement steroid doses < 10 mg daily prednisone equivalent (in the absence of active autoimmune disease) may resume treatment if approved by the Protocol Chair or the IND Sponsor . Patients requiring replacement doses of steroids are required to discontinue treatment with C RS- 207. • If steroids or immunosuppressive agents are required during treatment, prophylactic antibiotics will be administered as outlined in Section 5.5. In addition, the following therapies should not be administered during the treatment period unless medically necessary and approval must be obtained from the Protocol Chair for a subject to continue dosing if therapy is given concurrently with study participation: • General anesthesia • Aspirin >325 mg/day (chronic daily use of aspirin ≤325 mg/day and heparin flushes for central lines are allowed except during CRS -207 infusions through 4 days after each CRS -207 infusion. ) • More than 3 g/day of acetaminophen • Systemic antibiotics 5.4 Other Restrictions and Precautions Palliative (limited -field) rad iation therapy is permitted, but only for pain control to sites present at baseline and with approval by the Protocol Chair or IND Sponsor . J1790 / Version 7.0 / December 10, 2020 24 If subjects receive immunosuppressive medications on or after study, prophylactic antibiotics to prevent CRS - 207 in fection are strongly recommended for the duration of the treatment with the immunosuppressant 5. 5 Antibiotic Administration - J1790 / Version 7.0 / December 10, 2020 25 - Subjects with clinical or laboratory signs or symptoms of persistent infection who require initiation of antibiotics other than specified by protocol should have a clinically - relevant evaluation, including appropriate bacterial cultures. Culture of cerebrospinal fluid should be obtained for subjects with suspected central nervous system infection. In such instances, analysis of cerebrospinal fluid should also include cell count, protein, glucose and Gram stain. IV ampicillin (or trimethoprim/sulfamethoxazole in penicillin - allergic subjects) plus gentamicin should be initiated for possible infectious complications of CRS - 207 for subjects who are suspected of having persistent CRS - 207 infection and meet the criteria listed below: • Flu - like symptoms Grade 3 or greater lasting for ≥12 hours • Fever Grade 4 or higher (>40.0ºC for >24 hours) • Persistent fever >39ºC lasting for ≥48 hours • Infection Grade 3 or higher (infection with interventional radiology or operative intervention indicated) • Evidence of abscess • Clinical signs or symptoms (e.g., neurologic signs or symptoms), which, in the judgment of the investigator, necessitate starting antibiotics - Suspected or confirmed infection with CRS - 207 and/or Listeria is considered an adverse event of special interest (AESI) and should be reported following SAE rep orting procedures (Section 7.1.3) irrespective of temporal relationship to study drug administration. This includes scheduled blood cultures during surveillance monitoring that are positive for CRS - 207 or if a subject presents with symptoms suspicious for a Listeria - like infection and/or is tested positive for Listeria at a local hospital/clinic. 5 . 6 Definition of an Overdose for t his Protocol J1790 / Version 7.0/ December 10, 2020 26 Overdose of nivolumab or ipilimumab are defined as: An overdose is defined as the accidental or intentional admi nistration of any dose of a product that is considered both excessive and medically important. All occurrences of overdose must be reported as SAEs (see Section 7.5.1 for reporting details). Appropriate supportive treatment should be provided if clinically indicated. All reports of overdose with and without an AE must be reported within 24 hours to the Protocol Chair, IND Sponsor ( Dr. Elizabeth Jaffee), and Bristol -Myers Squibb ( BMS ). IND Sponsor , and BMS contact information can be found in Section 7.5.1 . 5.7 Unacceptable T oxicity Unacceptable toxicities are defined as : 1. Any treatment -related > grade 3 AEs . Exceptions include: • Asymptomatic laboratory abnormalities • Grade 3 fatigue • Grade 3 dermatologic AEs that are considered mild in severity but only considered grade 3 because of >30% body surface involvement • Fever, chills, rigors, hypertension, hypotension, syncope, or hypoxia occurring within 12 hours of CRS -207 administration • Diarrhea, nausea, or vomiting that resolves to < grade 3 within 24 hours of intervention • Grade 3 -4 hyperglycemia or grade 3 endocrinopathies where symptoms are controlled on hormone replacement therapy 2. Any of the following toxicities related to CRS -207: • A fever of >40°C that lasts for greater than 24 hours and does not respond to antipyretics . • Clinically significant hypotension unresponsive to IV fluids ( e.g., systolic blood pressure [BP] <90 mm Hg or mean arterial pressure <55 mm Hg as measured on two separate occasions at least 10 minutes apart) . • Initiation of antibiotic therapy, coincident with simultaneous isolation of CRS -207 from a normally sterile body site, other than blood (e.g., cerebrospinal fluid, joint fluid) . 3. Treatment related b lood bilirubin > 5 x ULN or concurrent blood bilirubin > 2 x ULN and AST or ALT > 3 x ULN 4. Treatment related e ye pain ≥ grade 2 or reduction of visual acuity that does not respond to topical therapy an d does not improve to ≤ grade 1 severity within 2 weeks of starting therapy, or requires systemic therapy is an unacceptable toxicity. Unexpected Grade 3 or greater laboratory abnormalities should be repeated within 24 -72 hours if clinically indicated and monitored as necessary to determine if event meets toxicity criteria. Grade 3 or greater creatinine, AST, ALT, and bilirubin should be repeated within 24 -72 hours as well. The proportion of unacceptable toxicities will be monitored separately in each arm . If the toxicity levels in either treatment arm (A or B) are unacceptable , then enrollment will be suspended until J1790 / Version 7.0/ December 10, 2020 27 further review and consideration by the Protocol Chair , IND Sponsor , and the Medical Expert Committee (MEC) . If treatment in one arm is permanently discontinued due to toxicity, the other arm may continue as long as the toxicity level remains acceptable . There will be no dose reductions for CY, nivolumab , ipilimumab, CRS -207, or GVAX pancreas vaccine . The propor tion of treated subjects with unacceptable toxicity will be monitored using a Bayesian stopping guideline. A Beta (1.5, 5.5) prior, representing a toxicity rate of 21%, a slightly conservative estimate, was used in the development of our guidelines. The therapy will be re - evaluated if the posterior probability that the toxicity rate exceeds the 33% boundary is greater than 50%. Toxicity will be monitored continuously. Table 3 summarizes the stopping bo undaries for unacceptable toxicities. Table 3. The number of toxicities needed to trigger stopping guidelines throughout the course of the study. Number of Subjects Per Treatment Arm Number of toxicities needed to trigger re-evaluation 6 3 7-9 4 10-12 5 13-15 6 16-18 7 19-21 8 22-24 9 25-27 10 28-30 11 The probability of triggering the stopping guidelines was assessed for a range of possible true toxicity rates using simulations with 10,000 replicates ( Table 4). The probability of stopping to re-evaluate was 7.3% if the true proportion with an unacceptable toxicity was 15%. In comparison, the prob ability of stopping early is 72.6% if the true proportion with an unacceptable toxicity was 33%. Table 4. Prob ability of triggering a re -evaluation based upon the proportion with an unacceptable toxicity for a range of true toxicity probabilities. True probability of unacceptable toxicity Probability of triggering stopping guidelines 1% <0.1% 5% 0.2% 10% 2.0% 15% 6.9% 20% 17.5% 25% 33.0% 30% 52.4% 35% 71.2% J1790 / Version 7.0/ December 10, 2020 28 5.8 WOCBP, Contraception, Use in Pregnancy, Use in Nursing A WOCBP is defined as any female who has experienced menarche and who has not undergone surgical sterilization (hysterectomy or bilateral oophorectomy) and is not postmenopausal. Menopause is defined clinically as 12 months of amenorrhea in a woman over age 45 years in the absence of other biological or physiological causes. In addition, women under the age of 62 years must have a documented serum follicle stimulating hormone (FSH) level > 40mIU/mL to confirm menopause. Women treated with hormone replacement therapy (HRT) are likely to have artificially suppressed FSH levels and may require a washout period in order to obtain a physiologic F SH level. The duration of the washout period is a function of the type of HRT used. The duration of the washout period below are suggested guidelines and the investigators should use their judgment in checking serum FSH levels. If the serum FSH level is >4 0 mIU/ml at any time during the washout period, the woman can be considered postmenopausal: • 1 week minimum for vaginal hormonal products (rings, creams, gels) • 4 week minimum for transdermal products • 8 week minimum for oral products 5.8.1 Contraception The investigational agents used in this protocol may have adverse effects on a fetus in utero . Furthermore, it is not known if the investigational agents have transient adverse effects on the composition of sperm. Non-pregnant, non -breast -feeding women may be enrolled if they are considered highly unlikely to conceive. Highly unlikely to conceive is defined as 1) surgically sterilized, or 2) postmenopausal ( defined as a woman who is > 45 years of age and has not had menses for greater than 12 months and women under the age of 62 must have a documented serum follicle stimulating hormone (FSH) level less than 40mlU/mL will be considered postmenopausal ). or 3) amenorrheaic for < 2 years without a hysterectomy and oophorectomy and with a documented FSH va lue in the postmenopausal range, or ) not heterosexually active for the duration of the study, or 5) heterosexually active and willing to use 2 methods of birth control (which is also required for the female partners of male subjects ). The 2 birth control methods can be 2 barrier methods or a barrier method plus a hormonal method to prevent pregnancy, used throughout the study starting with Visit 1 through 5 months after the last dose of study drug. Male subjects enrolled in this study must also agree to use an adequate method of contraception starting with Visit 1 through 7 months after the last dose of study drug . Investigators shall counsel WOCBP and male subjects who are sexually active with WOCBP on the impo rtance of pregnancy prevention and the implications of an unexpected pregnancy Investigators shall advise WOCBP and male subjects who are sexually active with WOCBP on the use of highly effective methods of contraception. Highly effective methods of contra ception have a failure rate of < 1% per year when used consistently and correctly. J1790 / Version 7.0/ December 10, 2020 29 HIGHLY EFFECTIVE METHODS OF CONTRACEPTION • Male condoms with spermicide • Hormonal methods of contraception including combined oral contraceptive pills, vaginal ring, injectables, implants, and intrauterine devices (IUDs) such as Mirena by WOCBP subject or male subject’s WOCBP partner. • Nonhormonal IUDs, such as ParaGard • Tubal ligation • Vasectomy • Complete abstinence * *Complete abstinence is defined as complete avoidance of heterosexual intercourse and is an acceptable form of contraception for all study drugs. Abstinence is only acceptable when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, symptother mal, profession of abstinence for entry into a clinical trial, post-ovulation methods) and withdrawal are not acceptable methods of contraception. Subjects who choose complete abstinence are not required to use a second method of contraception, but female subjects must continue to have pregnancy tests. Acceptable alternate methods of highly effective contraception must be discussed in the event that the subject chooses to forego complete abstinence. LESS EFFECTIVE METHODS OF CONTRACEPTION • Diaphragm with spermicide • Cervical cap with spermicide • Vaginal sponge • Male condom without spermicide* • Progestin only pills by WOCBP subject or male subject’s WOCBP partner • Female condom * *A male and female condom must not be used together Subjects should be informed tha t taking the study drug may involve unknown risks to the fetus (unborn baby) if pregnancy were to occur during the study. In order to participate in the study they must adhere to the contraception requirement (described above) for the duration of the study. If there is any question that a subject will not reliably comply with the requirements for contraception, that subject should not be entered into the study. 5.8.2 Use in Pregnancy The investigational agents used in this protocol may have adve rse effects on a fetus; therefore, women with a positive pregnancy test at screening will not be eligible for enrollment. If a subject inadvertently becomes pregnant while on treatment, the subject will immediately be removed from the study. The site wil l contact the subject at least monthly and document the subject ’s status until the pregnancy has been completed or terminated. Pregnancy in female subjects throughout the study or within 5 months of completing treatment as well as any pregnancy in partn ers of male subjects throughout the study or within 7 months of completing the study should be reported initially as a serious adverse J1790 / Version 7.0/ December 10, 2020 30 event (see SAE reporting procedures in section 7.5.1 and 7.5.5 ) by the investigator within 24 hours of learning of its occurrence. Pregnancy information must be reported on the Pregnancy Form . Protocol required procedures for study discontinuation and follow -up must be performed on the subject unless contraindicated b y pregnancy (e .g., x-ray studies). Other appropriate pregnancy follow -up procedures should be considered if indicated. Follow -up information regarding the course of the pregnancy, including any voluntary or spontaneous termination, perinatal and neonatal outcome and where applicable, offspring information must be reported on the Pregnancy Follow -up Form. Pregnancy outcomes must also be collected for the female partners of any males in this trial. Consent to report information regardi ng these pregnancy outcomes should be obtained from the female partner. 5.8.3 Use in Nursing Women Since many drugs are excreted in human milk, and because of the potential for serious adverse reactions in the nursing infant, subjects who are breast -feeding are not eligible for enrollment. 5.8.4 All Subjects (Male and Female) All sexually active patients must use at least a barrier method (i.e., condom) to prevent transmission of body fluids. 5.9 Duration of Therapy Subjects on both arms will receive treatment every 3 weeks for 6 cycles of treatment within a course (18 weeks total). At the investigator’s discretion, subjects who are clinically stable and meet dosing requirements (per Section 6.2) at the end of the fir st course may receive additional courses of their assigned treatment for up to a maximum of 2 years . Subjects that begin a new course prior to the 2 year cut -off may complete that course prior to coming off study. The additional course(s) may start as early as 3 weeks (+7 days) from last dose of previous course and all assessments will be followed per the study schedule in Section 10 , with the first dose of the additional course corresponding to Day 1, Cycle 1 of the study schedule. The following assess ments are not required during additional courses: • HLA -typing • Tumor biopsies 5.10 Criteria for Removal from Treatment The reason for study removal and the date the subject was removed will be documented in the CRF . A subject will be discontinued from the trial for any of the following reasons: • The subject or legal representative (such as a parent or legal guardian) withdraws consent for participation in the study . J1790 / Version 7.0/ December 10, 2020 31 A subject must be discontinued from treatment (but may continue to be monitored in the post- treatment follow -up portion of the trial) for any of the following reasons: • The subject or legal representative (such as a parent or legal guardian) withdraws consent for treatment • Intercurrent illness that prevents further administration of treatme nt • Unacceptable toxicity (see Section 5.7). Exceptions for treatment discontinuation are listed in Section 5.10.2 . If the study treatment has provided clinical benefit (as defined in Section 5.10.1 ), the IND sponsor may approve trial continuation for patients experiencing toxicities that are not life threatening or of major clinical concern (such as pruritis or transient hypotension). • Disease progression as defined in Section 5.10.1 • Severe or life -threatening nivolumab or ipilimumab -related AE(s) (see Section 5.10.2) • Need for >2 dose delays due to the same drug-related toxicity as per the dose delay guidelines (see Section 6.2) • If, in the opinion of the Investigator, a change or temporal or permanent discontinuation of therapy would be in the best interest of the subject , • Noncompliance with trial treatment or procedure requirements, • Subject is lost to follow -up • Subject becomes pr egnant 5.10.1 Disease Progression GVAX Pancreas vaccine , CRS -207, nivolumab , and ipilimumab are expected to trigger immune -mediated responses, which require activation of the immune system prior to the observation of clinical responses. Such immune activ ation may take weeks to months to be evident. Some subjects may have objective volume increase of tumor lesions or other disease parameters within weeks following the start of immunotherapy . Such subjects may not have had sufficient time to develop the required immune activation or, in some subjects , tumor volume or other disease parameter increases may represent infiltration of lymphocytes into the original tumor. In conventional studies, such tumor volum e or relevant laboratory parameter increases during the first 2 -4 months of the study would constitute disease progression and lead to discontinuation of imaging to detect response, thus disregarding the potential for subsequent immune -mediated clinical re sponse. This phenomenon was observed in approximately 10% of subjects in the Phase 1 study of nivolumab and has also been reported for ipilimumab monotherapy16. Subjects will be permitted to continue with treatment beyond RECIST 1.1 defined PD as long as they meet the following criteria: • Investigator -assessed clinical benefit , and • Subject is tolerating study drug. J1790 / Version 7.0/ December 10, 2020 32 The assessment of clinical benefit should take into account whether the subject is clinically deteriorating and unlikely to receive further benefit from continued treatment. The following criteria need to be taken into consideration: • No decline in ECOG performance status. • Absence of rapid progression of disease or of progressive tumor at critical anatomical sites (e.g., cord compression) requiring urgent alternative medical inter vention. All decisions to continue treatment beyond PD must be discussed with the Protocol Chair and documented in the study records. Tumor assessments will be made using RECIST 1.1 (Appendix C ) and irRC (Appendix D). 5.10.2 Nivolumab and Ipilimumab -Related Adverse Events Permanent discontinuation of study treatment should be considered for any of the following: 1. Severe or life -threatening related AEs, including, but not limited to, any of the following ( the IND Sponsor , and BMS must be notified in the event of these AEs): • Any grade 2 treatment -related uveitis, eye pain, or blurred vision that does not respond to topical therapy and does not improve to Grade 1 severity within 2 weeks of starting therapy OR requires systemic treat ment • Any grade 3 non -skin, drug -related AE lasting > 7 days, with the following exceptions: ▪ Grade 3 treatment -related uveitis, pneumonitis, bronchospasm, diarrhea, colitis, neurologic toxicity, hypersensitivity reaction, or infusion reaction (applies to nivolumab and ipilimumab only) of any duration requires discontinuation ▪ Grade 3 treatment -related endocrinopathies adequately controlled with only physiologic hormone replacement do not require discontinuation ▪ Grade 3 treatment -related laboratory abnormali ties do not require treatment discontinuation except: o Grade 3 treatment -related thrombocytopenia > 7 days OR that is associated with bleeding requires discontinuation o Any treatment -related liver function test (LFT) abnormality that meets the following criteria require discontinuation: − Total bilirubin > 3 × ULN − Concurrent AST or ALT > 3 × ULN and total bilirubin > 2 × ULN • Any grade 4 treatment -related AE or laboratory abnormality, except for the following events which do not require discontinuation: J1790 / Version 7.0/ December 10, 2020 33 ▪ Grade 4 amylase or lipase abnormalities that are not associated with symptoms or clinical manifestations, or radiographic signs of pancreatitis. It is recommended to consult with the Protocol Chair for grade 4 amylase or lipase abnormalities.