Testing an Immunotherapy Anti-cancer Drug, Nivolumab, for Advanced Cancers in Patients With Autoimmune Disorders, AIM-NIVO

Inclusion Criteria:

• Patients can have either histologically confirmed malignancy that is radiologicallyevaluable and metastatic or unresectable, or have a malignancy for which aPD-1/PD-L1 inhibitor has been approved in the adjuvant setting, as well as theneoadjuvant or perioperative setting in which such treatment is considered standardof care or has been approved. Eligible tumor types include solid tumors andmalignancies in which there is known evidence of clinical activity for single agentPD-1 or PD-L1 antibodies. Nivolumab or other PD1/PD-L1 inhibitors are FDA-approvedfor the treatment of melanoma, non-small cell lung cancer (NSCLC), Merkel cellcancer, bladder cancer, renal cell carcinoma (RCC), gastric cancer, hepatocellularcarcinoma (HCC), cervical cancer, head and neck cancer, Hodgkin lymphoma (HL),metastatic small cell lung cancer (SCLC), and any solid tumor with microsatelliteinstability (MSI)-high status confirmed. Patients with HL are eligible but mustfollow standard response criteria. Additional tumor types may be eligible on a caseby case basis upon discussion with principal investigator (PI)

• Patients enrolling on the trial for adjuvant use will be restricted to thosewith histology for which a PD-1/PD-L1 inhibitor has been approved in theadjuvant setting including but not limited to NSCLC, melanoma, RCC, cervicalcancer, and bladder cancer

• Patients enrolled on the study can receive Nivolumab with other FDA-approvedcombinations according to the FDA package insert, including, but not limited toipilimumab, cabozantinib or chemotherapy

• Patients who have previously received other forms of immunotherapy (high-dose [HD]IL-2, IFN, CTLA-4) are allowed. Patients must not have received cytokineimmunotherapy for at least 4 weeks before nivolumab administration. Patients whohave received prior anti-CTLA4 will be allowed and the washout period is 6 weeks

• Age >= 18 years; children are excluded from this study but may be eligible forfuture pediatric phase 1 combination trials

• Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 (Karnofsky >=

• Life expectancy of greater than 12 weeks

• Leukocytes >= 1,000/mcL

• Absolute neutrophil count >= 500/mcL

• Platelets >= 50,000/mcL

• Total bilirubin =< 2 x institutional upper limit of normal (ULN)

• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 5 x institutional ULN or =< 8 x institutional ULN for patients with livermetastases or an autoimmune disease that is contributing to the elevation of thesevalues

• Creatinine ULN OR glomerular filtration rate (GFR) >= 30 mL/min (if using theCockcroft-Gault formula)

• Human immunodeficiency virus (HIV)-infected patients on effective antiretroviraltherapy with undetectable viral load within 6 months are eligible for this trial

• If evidence of chronic hepatitis B virus (HBV) infection, HBV viral load must beundetectable on suppressive therapy if indicated

• If history of hepatitis C virus (HCV) infection, must be treated with undetectableHCV viral load

• Patients with new or progressive brain metastases (active brain metastases) orleptomeningeal disease are eligible if the treating physician determines thatimmediate central nervous system (CNS) specific treatment is not required and isunlikely to be required for at least 4 weeks (or scheduled assessment after thefirst cycle of treatment), and a risk-benefit analysis (discussion) by the patientand the investigator favors participation in the clinical trial

• The effects of nivolumab on the developing human fetus are unknown. For this reason,women of child-bearing potential (WOCBP) and men must agree to use adequatecontraception (hormonal or barrier method of birth control; abstinence) prior tostudy entry and for the duration of study participation. WOCBP receiving nivolumabwill be instructed to adhere to contraception for a period of 5 months after thelast dose of investigational product. Men receiving nivolumab and who are sexuallyactive with WOCBP will be instructed to adhere to contraception for a period of 7months after the last dose of investigational product

• Women of childbearing potential must have a negative serum or urine pregnancytest (minimum sensitivity 25 IU/L or equivalent units of human chorionicgonadotropin [HCG]) within 24 hours prior to the start of nivolumab. Women mustnot be breastfeeding. Women who are not of childbearing potential (i.e., whoare postmenopausal or surgically sterile as well as azoospermic men) do notrequire contraception

• WOCBP is defined as any female who has experienced menarche and who has notundergone surgical sterilization (hysterectomy or bilateral oophorectomy),tubal ligation, or who is not postmenopausal. Menopause is defined clinicallyas 12 months of amenorrhea in a woman over 45 in the absence of otherbiological or physiological causes. In addition, women under the age of 55 musthave a documented serum follicle stimulating hormone (FSH) level less than 40mIU/mL

• These durations have been calculated using the upper limit of the half-life fornivolumab (25 days) and are based on the protocol requirement that WOCBP usecontraception for 5 half-lives plus 30 days, and men who are sexually activewith WOCBP use contraception for 5 half-lives plus 90 days

• Should a woman become pregnant or suspect she is pregnant while she or herpartner is participating in this study, she (or the participating partner)should inform the treating physician immediately. Patients can resume treatmentupon termination of a pregnancy or the completion of a successful pregnancy

• Ability to understand and the willingness to sign a written informed consentdocument

• Patients with more than one autoimmune disease are eligible. The treating physicianwould determine which autoimmune disease is dominant and the patient would betreated under that specific cohort (Please note: Patients with more than oneautoimmune disease should receive assessments for all previously diagnosedautoimmune diseases. For example, a patient with psoriasis and IBD might be enrolledin the IBD cohort. Disease assessments for both psoriasis and IBD should beobtained, as per protocol. Case report forms [CRFs] for all relevant autoimmunediseases should be utilized. However, all additional cohort requirements will beconsidered optional and only the assessments from the assigned cohort will beconsidered mandatory)

• DM/SSc-SPECIFIC INCLUSION: Patients with known SSc or DM according to updatedclassification criteria (Van den Hoogan et al., Arthritis Rheum 2013;65(11):2737-47;Lundberg et al., A&R in press). Overlap features are permitted, but patients mustmeet criteria for a "primary diagnosis" of DM or SSc

• DM/SSc-SPECIFIC INCLUSION: Patients may be on any concurrent therapy for DM or SScunless specifically excluded

• DM/SSc-SPECIFIC INCLUSION: Patients must have a baseline computed tomography (CT) ofthe chest (within 6 months of study entry)

• RA-SPECIFIC INCLUSION: Rheumatologist-diagnosed RA requiring prior treatment withdisease-modifying antirheumatic drugs (DMARDs) before patient was diagnosed withcurrent malignancy. We recommend, but do not require, documentation for meeting 2010American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR)classification criteria for RA

• RA-SPECIFIC INCLUSION: Prednisone up to 10 mg/day will be allowed. Intraarticularsteroids will be allowed for the treatment of new symptomatic joints

• RA-SPECIFIC INCLUSION: Nonsteroidal anti-inflammatory drugs (NSAIDs) will be allowed

• SLE-SPECIFIC INCLUSION: SLE diagnosed by a rheumatologist. The patient should meetthe revised 1997 American College of Rheumatology (ACR) classification criteria forSLE, but this is not mandatory

• ULCERATIVE COLITIS (UC)-SPECIFIC INCLUSION: Diagnosis of UC must be made byendoscopy with biopsies

• UC-SPECIFIC INCLUSION: Complete colonoscopy with biopsies during study screening,within 8 weeks before initial nivolumab administration, or within 4 weeks afterinitial nivolumab administration

• UC-SPECIFIC INCLUSION: Patients must test negative for hepatitis B (antigen [Ag]negative, antibody [core (c)Ab] negative, antibody [surface (s)Ab] positive ornegative) and Mycobacterium tuberculosis (purified-protein- derivative [PPD] orenzyme-linked immunospot assay [ELISpot or T-spot]) or be on appropriateanti-microbial treatment for these infections

• UC-SPECIFIC INCLUSION: Mild Disease Cohort: Patients must be in clinical remission,defined as a Mayo Clinic score (MCS) of 2 or lower and no subscore higher than 1,and an endoscopic subscore of 0 or 1 either without medications, or treated with 5-ASA derivative, probiotic, or prior fecal transplant

• UC-SPECIFIC INCLUSION: Moderate Disease Cohort: Patients must be in clinicalremission, defined as a MCS of 2 or lower and no subscore higher than 1, and anendoscopic subscore of 0 or 1 on 6-mercaptopurine, azathioprine, methotrexate, orrectal hydrocortisone, budesonide, or one of these medications in combination withany of the medications listed in the Mild cohort

• UC-SPECIFIC INCLUSION: Severe Disease Cohort (A or B): Patients must either be A) inclinical remission, defined as a MCS of 2 or lower and no subscore higher than 1,and an endoscopic subscore of 0 or 1 on a biologic therapy targeting tumor necrosisalpha (TNF-α) (infliximab, adalimumab, golimumab), α4β7 integrin (vedolizumab), orone of these biologic therapies in combination with any of the medications listed inthe Mild or Moderate cohort, or B) have mild active disease defined as a MCS of 3-5and no subscore higher than 2, and an endoscopic subscore of < 2 on one of themedications or combination of medications defined for the Moderate or Mild cohort

• CROHN'S DISEASE (CD)-SPECIFIC INCLUSION: Complete colonoscopy with biopsies duringstudy screening, within 8 weeks before initial nivolumab administration, or within 4weeks after initial nivolumab administration

• CD-SPECIFIC INCLUSION: If patients have prior known disease in the stomach or smallintestines, appropriate endoscopic evaluation (esophagogastroduodenoscopy/videocapsule endoscopy) and/or imaging (computed tomography or magnetic resonanceenterography) must also be current within 4 weeks prior to nivolumab administration

• CD-SPECIFIC INCLUSION: Deep enteroscopy techniques, such as double balloonenteroscopy, will not be required

• CD-SPECIFIC INCLUSION: Patients must test negative for hepatitis B (sAg negative,cAb negative, sAb positive or negative) and M. tuberculosis (PPD or ELISpot orT-spot) or be on appropriate anti-microbial treatment for these infections

• CD-SPECIFIC INCLUSION: Mild Disease Cohort: Patients must be in clinical remissionas defined by a Crohn's Disease Activity Index (CDAI) < 150 either without treatmentor on a 5-ASA derivative, probiotic, antibiotics, or following fecal transplant

• CD-SPECIFIC INCLUSION: Moderate Disease Cohort: Patients must be in clinicalremission as defined by a CDAI < 150 on 6-mercaptopurine, azathioprine,methotrexate, rectal hydrocortisone, budesonide, or one of these medications incombination with any of the medications listed in the Mild cohort

• CD-SPECIFIC INCLUSION: Severe Disease Cohort (A or B): Patients must either A) be inclinical remission as defined by a CDAI < 150 on biologic therapy targeting TNF-α (infliximab, adalimumab, certolizumab pegol), IL-12/23p40 (ustekinumab), α4β7integrin (vedolizumab), or one of these biologic therapies in combination with anyof the medications listed in the Mild or Moderate cohort, or B) have mild activedisease as defined by a CDAI of 150 to 220 on one of medications or combination ofmedications defined for the Moderate or Mild cohort

• OTHER AUTOIMMUNE DISEASES- NS-SPECIFIC INCLUSION: For other autoimmune diseases thatcannot be classified, the eligibility criteria will be determined by the managingrheumatologist or other autoimmune disease specialist, based on the clinicaljudgement and current American College of Radiology (ACR) classification guidelinesor other relevant guidelines, as per the disease category in question

• OTHER AUTOIMMUNE DISEASES- NS-SPECIFIC INCLUSION: For giant cell arteritis (GCA),patients must have had positive temporal artery biopsy for GCA and abnormalerythrocyte sedimentation rate (ESR) at time of diagnosis

• OTHER AUTOIMMUNE DISEASES- NS-SPECIFIC INCLUSION: For polymyalgia rheumatica (PMR),patients must have clinical diagnosis in addition to elevated inflammatory markersincluding (ESR, C reactive protein [CRP])

• OTHER AUTOIMMUNE DISEASES- NS-SPECIFIC INCLUSION: Patients can be in remission (withno glucocorticoids or immunosuppressive medications) or have low-moderate activity,which is defined as being on prednisone ≤ 10 mg or equivalent

• MS-SPECIFIC INCLUSION: Patients must meet 2017 McDonald criteria for the diagnosisof MS (Thompson AJ, et al. Diagnosis of multiple sclerosis: 2017 revision of theMcDonald criteria. Lancet Neurol. 17(2):162-173.)

• MS-SPECIFIC INCLUSION: Patients with MS can be in remission and can have a historyof being on immunomodulatory agents, but at the time of entry into the clinicaltrial, patients should be off any concurrent MS therapy for at least 2 weeks.Patients receiving concomitant interferon gamma (IFN-γ treatment) will be permittedin the study

• SJS-SPECIFIC INCLUSION: SjS diagnosed by a rheumatologist or oral medicine provider.The patient should meet the American-European Consensus Criteria for Sjögren'sSyndrome (Vitali, et al., 2002). If on treatment, the patient may only be onhydroxychloroquine and prednisone ≤ 10 mg or equivalent

• PSO/PSA-SPECIFIC INCLUSION: Patients with known PsO as diagnosed by a dermatologistor PsA by a rheumatologist and/or by Classification for Psoriatic Arthritis (CASPAR)criteria (Tillett et al., 2012)

• PSO/PSA-SPECIFIC INCLUSION: Patients must have stable disease as determined by theinvestigator with no change in systemic therapy and/or biologic therapy for at least 3 months, except for those on tumor necrosis factor (TNF) inhibitors. In the case ofTNF inhibition, patients may have transitioned to an alternative biologic therapywith stable disease for at least 4 weeks. For PsA, no change in corticosteroidtherapy for at least 1 month prior to baseline and dose must be 10 mg or less

• PSO/PSA-SPECIFIC INCLUSION: Patients may be on any concurrent therapy for PsO or PsAunless specifically excluded

Exclusion Criteria:

• Patients who have had chemotherapy or radiotherapy within 2 weeks (6 weeks fornitrosoureas or mitomycin C) prior to entering the study or those who have notrecovered from adverse events (AEs) due to agents administered more than 4 weeksearlier have not resolved or stabilized. Palliative (limited-field) radiationtherapy (RT) is permitted (2 week washout from start of treatment), if all of thefollowing criteria are met:

• Repeat imaging demonstrates no new sites of bone metastases

• The lesion being considered for palliative radiation is not a target lesion

• Patients with prior therapy with an anti-PD-1 or anti-PD-L1

• Patients with prior allogeneic hematologic transplant

• Patients who are receiving any other anticancer investigational agents

• Uncontrolled intercurrent illness including, but not limited to, ongoing or activeinfection, symptomatic congestive heart failure, unstable angina pectoris, cardiacarrhythmia, or psychiatric illness/social situations that would limit compliancewith study requirements

• UC-SPECIFIC EXCLUSION: Patients who have received ipilimumab treatment

• UC-SPECIFIC EXCLUSION: Prior colectomy

• UC-SPECIFIC EXCLUSION: Concurrent primary sclerosing cholangitis (PSC). Patientswith PSC can be enrolled on the Other Autoimmune Diseases Cohorts

• UC-SPECIFIC EXCLUSION: Patients on empiric immunosuppressive treatment without anyclinical workup

• CD-SPECIFIC EXCLUSION: Known untreated abscesses, untreated and symptomaticstrictures, short gut physiology, or isolated jejunal disease

• CD-SPECIFIC EXCLUSION: Patients who have received ipilimumab treatment

• CD-SPECIFIC EXCLUSION: Patients on empiric immunosuppressive treatment without anyclinical workup

• MS-SPECIFIC EXCLUSION: Patients with MS cannot have medical contraindications togadolinium-enhanced magnetic resonance imaging (MRI)