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

PRIMARY OBJECTIVES:

I. To assess the overall safety, and toxicities associated with the use of the anti-programmed death 1 (PD-1) antibody nivolumab in patients with varying severity of dermatomyositis (DM)/systemic sclerosis (SSc), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), inflammatory bowel disease (IBD) (ulcerative colitis [UC] and Crohn's disease [CD]), multiple sclerosis (MS), Sjogren's syndrome [SjS], psoriasis (PsO)/psoriatic arthritis (PsA), and other autoimmune diseases.

II. To assess the overall safety, and toxicities associated with the use of the anti-programmed death 1 (PD-1) antibody nivolumab and other Food and Drug Administration (FDA)-approved combinations for given oncologic indications in patients with varying severity of DM/SSc, RA, SLE, IBD (ulcerative colitis [UC] and Crohn's disease [CD]), MS, Sjogren's syndrome [SjS], psoriasis (PsO)/psoriatic arthritis (PsA), and other autoimmune diseases.

SECONDARY OBJECTIVES:

I. To evaluate the efficacy of nivolumab in terms of objective response rates (ORRs), progression-free survival (PFS), and overall survival (OS) in patients with cancer and DM/SSc, RA, SLE, IBD (UC and CD), MS, SjS, PsO/PsA, and other autoimmune diseases.

II. To observe and record anti-tumor activity. III. To propose dosing recommendations for anti-PD-1 antibodies based on the severity of the autoimmune disorder.

IV. To evaluate the impact of nivolumab on the disease severity indices for: DM/SSc, RA, SLE, IBD: UC and CD, not specified (NS), MS, SjS, PsO/PsA.

V. To identify biomarkers of response and toxicity.

OUTLINE: Patients are assigned to 1 of 11 arms.

ARM I (MONOTHERAPY): Patients may receive single agent nivolumab intravenously (IV) over 30 minutes every 4 weeks for up to 2 years for patients with metastatic indications, for up to 1 year for adjuvant indications or for up to 3 months after surgery for neoadjuvant indications in the absence of disease progression or unacceptable toxicity.

ARM II (UNRESECTABLE OR METASTATIC MELANOMA): Patients receive nivolumab IV over 30 minutes every 2 or 4 weeks in combination with ipilimumab IV every 3 weeks for up to 4 doses of combination therapy in the absence of disease progression or unacceptable toxicity. Treatment with nivolumab may continue every 4 weeks in the absence of disease progression or unacceptable toxicity.

ARM III (NEOADJUVANT TREATMENT OF RESECTABLE NON-SMALL CELL LUNG CANCER [NSCLC]): Patients receive nivolumab IV over 30 minutes in combination with platinum doublet therapy every 3 weeks for up to 3 cycles in the absence of disease progression or unacceptable toxicity.

ARM IV (METASTATIC PD-L1 POSITIVE NSCLC): Patients receive nivolumab IV over 30 minutes every 3 weeks and ipilimumab IV every 6 weeks for up to 2 years in the absence of disease progression or unacceptable toxicity.

ARM V (METASTATIC OR RECURRENT NSCLC): Patients receive nivolumab IV over 30 minutes every 3 weeks, ipilimumab IV every 6 weeks and platinum doublet therapy every 3 weeks for up to 2 cycles of combination therapy. Treatment with nivolumab and ipilimumab repeats for up to 2 years in the absence of disease progression or unacceptable toxicity.

ARM VI (MALIGNANT PLEURAL MESOTHELIOMA): Patients receive nivolumab IV over 30 minutes every 3 weeks and ipilimumab IV every 6 weeks for up to 2 years in the absence of disease progression or unacceptable toxicity.

ARM VII (ADVANCED RENAL CELL CARCINOMA [RCC]): Patients receive nivolumab IV over 30 minutes in combination with ipilimumab IV every 3 weeks for up to 4 doses of combination therapy in the absence of disease progression or unacceptable toxicity. Patients may continue to receive single agent nivolumab every 2 or 4 weeks in the absence of disease progression or unacceptable toxicity. Patients may optionally receive nivolumab IV every 2 or 4 weeks in combination with cabozantinib orally (PO) once daily (QD) for up to 2 years of combination therapy in the absence of disease progression or unacceptable toxicity. Treatment with single agent cabozantinib may continue in the absence of disease progression or unacceptable toxicity.

ARM VIII (MICROSATELLITE INSTABILITY-HIGH [MSI-H] OR MISMATCH REPAIR DEFICIENT [dMMR] METASTATIC COLORECTAL CANCER): Patient receive nivolumab IV over 30 minutes every 2 or 4 weeks in combination with ipilimumab IV every 3 weeks for up to 4 doses of combination therapy in the absence of disease progression or unacceptable toxicity. Patients may continue to receive single agent nivolumab every 2 or 4 weeks in the absence of disease progression or unacceptable toxicity.

ARM IX (HEPATOCELLULAR CARCINOMA [HCC]): Patients receive nivolumab IV over 30 minutes in combination with ipilimumab IV every 3 weeks for up to 4 doses of combination therapy. Patients may continue to receive single agent nivolumab every 2 or 4 weeks in the absence of disease progression or unacceptable toxicity.

ARM X (ESOPHAGEAL SQUAMOUS CELL CARCINOMA): Patients receive nivolumab IV over 30 minutes every 2 or 4 weeks in combination with fluoropyrimidine and platinum-containing chemotherapy for up to 2 years in the absence of disease progression or unacceptable toxicity OR receive nivolumab IV every 2 or 3 weeks in combination with ipilimumab IV every 6 weeks for up to 2 years in the absence of disease progression or unacceptable toxicity. Patients may then continue receiving fluoropyrimidine and platinum-containing chemotherapy in the absence of disease progression or unacceptable toxicity.

ARM XI (GASTRIC CANCER, GASTROESOPHAGEAL JUNCTION CANCER, AND ESOPHAGEAL ADENOCARCINOMA): Patients receive nivolumab IV over 30 minutes in combination with fluoropyrimidine and platinum-containing chemotherapy every 2 or 3 weeks for up to 2 years in the absence of disease progression or unacceptable toxicity.

Patients also undergo collection of blood, cerebrospinal fluid (CSF), tissue, stool, and urine samples throughout the trial.

After completion of study treatment, patients without disease progression are followed for 100 days, and patients with disease progression are followed every 12 weeks for up to 5 years.

Inclusion criteria

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

• Patients enrolling on the trial for adjuvant use will be restricted to those with histology for which a PD-1/PD-L1 inhibitor has been approved in the adjuvant setting including but not limited to NSCLC, melanoma, RCC, cervical cancer, and bladder cancer
• Patients enrolled on the study can receive Nivolumab with other FDA-approved combinations according to the FDA package insert, including, but not limited to ipilimumab, 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 cytokine immunotherapy for at least 4 weeks before nivolumab administration. Patients who have 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 for future pediatric phase 1 combination trials
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 (Karnofsky >= 60)
• 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 liver metastases or an autoimmune disease that is contributing to the elevation of these values
• Creatinine ULN OR glomerular filtration rate (GFR) >= 30 mL/min (if using the Cockcroft-Gault formula)
• Human immunodeficiency virus (HIV)-infected patients on effective antiretroviral therapy 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 be undetectable on suppressive therapy if indicated
• If history of hepatitis C virus (HCV) infection, must be treated with undetectable HCV viral load
• Patients with new or progressive brain metastases (active brain metastases) or leptomeningeal disease are eligible if the treating physician determines that immediate central nervous system (CNS) specific treatment is not required and is unlikely to be required for at least 4 weeks (or scheduled assessment after the first cycle of treatment), and a risk-benefit analysis (discussion) by the patient and 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 adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. WOCBP receiving nivolumab will be instructed to adhere to contraception for a period of 5 months after the last dose of investigational product. Men receiving nivolumab and who are sexually active with WOCBP will be instructed to adhere to contraception for a period of 7 months after the last dose of investigational product

• Women of childbearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin [HCG]) within 24 hours prior to the start of nivolumab. Women must not be breastfeeding. Women who are not of childbearing potential (i.e., who are postmenopausal or surgically sterile as well as azoospermic men) do not require contraception
• WOCBP is defined as any female who has experienced menarche and who has not undergone surgical sterilization (hysterectomy or bilateral oophorectomy), tubal ligation, or who is not postmenopausal. Menopause is defined clinically as 12 months of amenorrhea in a woman over 45 in the absence of other biological or physiological causes. In addition, women under the age of 55 must have a documented serum follicle stimulating hormone (FSH) level less than 40 mIU/mL
• These durations have been calculated using the upper limit of the half-life for nivolumab (25 days) and are based on the protocol requirement that WOCBP use contraception for 5 half-lives plus 30 days, and men who are sexually active with WOCBP use contraception for 5 half-lives plus 90 days
• Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she (or the participating partner) should inform the treating physician immediately. Patients can resume treatment upon termination of a pregnancy or the completion of a successful pregnancy
• Ability to understand and the willingness to sign a written informed consent document
• Patients with more than one autoimmune disease are eligible. The treating physician would determine which autoimmune disease is dominant and the patient would be treated under that specific cohort (Please note: Patients with more than one autoimmune disease should receive assessments for all previously diagnosed autoimmune diseases. For example, a patient with psoriasis and IBD might be enrolled in the IBD cohort. Disease assessments for both psoriasis and IBD should be obtained, as per protocol. Case report forms [CRFs] for all relevant autoimmune diseases should be utilized. However, all additional cohort requirements will be considered optional and only the assessments from the assigned cohort will be considered mandatory)
• DM/SSc-SPECIFIC INCLUSION: Patients with known SSc or DM according to updated classification 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 must meet criteria for a "primary diagnosis" of DM or SSc
• DM/SSc-SPECIFIC INCLUSION: Patients may be on any concurrent therapy for DM or SSc unless specifically excluded
• DM/SSc-SPECIFIC INCLUSION: Patients must have a baseline computed tomography (CT) of the chest (within 6 months of study entry)
• RA-SPECIFIC INCLUSION: Rheumatologist-diagnosed RA requiring prior treatment with disease-modifying antirheumatic drugs (DMARDs) before patient was diagnosed with current malignancy. We recommend, but do not require, documentation for meeting 2010 American 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. Intraarticular steroids 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 meet the revised 1997 American College of Rheumatology (ACR) classification criteria for SLE, but this is not mandatory
• ULCERATIVE COLITIS (UC)-SPECIFIC INCLUSION: Diagnosis of UC must be made by endoscopy with biopsies
• UC-SPECIFIC INCLUSION: Complete colonoscopy with biopsies during study screening, within 8 weeks before initial nivolumab administration, or within 4 weeks after initial 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 or negative) and Mycobacterium tuberculosis (purified-protein- derivative [PPD] or enzyme-linked immunospot assay [ELISpot or T-spot]) or be on appropriate anti-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 clinical remission, defined as a MCS of 2 or lower and no subscore higher than 1, and an endoscopic subscore of 0 or 1 on 6-mercaptopurine, azathioprine, methotrexate, or rectal hydrocortisone, budesonide, or one of these medications in combination with any of the medications listed in the Mild cohort
• UC-SPECIFIC INCLUSION: Severe Disease Cohort (A or B): Patients must either be A) in clinical 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 necrosis alpha (TNF-α) (infliximab, adalimumab, golimumab), α4β7 integrin (vedolizumab), or one of these biologic therapies in combination with any of the medications listed in the Mild or Moderate cohort, or B) have mild active disease defined as a MCS of 3-5 and no subscore higher than 2, and an endoscopic subscore of < 2 on one of the medications or combination of medications defined for the Moderate or Mild cohort
• CROHN'S DISEASE (CD)-SPECIFIC INCLUSION: Complete colonoscopy with biopsies during study screening, within 8 weeks before initial nivolumab administration, or within 4 weeks after initial nivolumab administration
• CD-SPECIFIC INCLUSION: If patients have prior known disease in the stomach or small intestines, appropriate endoscopic evaluation (esophagogastroduodenoscopy/video capsule endoscopy) and/or imaging (computed tomography or magnetic resonance enterography) must also be current within 4 weeks prior to nivolumab administration
• CD-SPECIFIC INCLUSION: Deep enteroscopy techniques, such as double balloon enteroscopy, 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 or T-spot) or be on appropriate anti-microbial treatment for these infections
• CD-SPECIFIC INCLUSION: Mild Disease Cohort: Patients must be in clinical remission as defined by a Crohn's Disease Activity Index (CDAI) < 150 either without treatment or on a 5-ASA derivative, probiotic, antibiotics, or following fecal transplant
• CD-SPECIFIC INCLUSION: Moderate Disease Cohort: Patients must be in clinical remission as defined by a CDAI < 150 on 6-mercaptopurine, azathioprine, methotrexate, rectal hydrocortisone, budesonide, or one of these medications in combination with any of the medications listed in the Mild cohort
• CD-SPECIFIC INCLUSION: Severe Disease Cohort (A or B): Patients must either A) be in clinical remission as defined by a CDAI < 150 on biologic therapy targeting TNF-α (infliximab, adalimumab, certolizumab pegol), IL-12/23p40 (ustekinumab), α4β7 integrin (vedolizumab), or one of these biologic therapies in combination with any of the medications listed in the Mild or Moderate cohort, or B) have mild active disease as defined by a CDAI of 150 to 220 on one of medications or combination of medications defined for the Moderate or Mild cohort
• OTHER AUTOIMMUNE DISEASES- NS-SPECIFIC INCLUSION: For other autoimmune diseases that cannot be classified, the eligibility criteria will be determined by the managing rheumatologist or other autoimmune disease specialist, based on the clinical judgement and current American College of Radiology (ACR) classification guidelines or 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 abnormal erythrocyte 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 markers including (ESR, C reactive protein [CRP])
• OTHER AUTOIMMUNE DISEASES- NS-SPECIFIC INCLUSION: Patients can be in remission (with no 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 diagnosis of MS (Thompson AJ, et al. Diagnosis of multiple sclerosis: 2017 revision of the McDonald criteria. Lancet Neurol. 17(2):162-173.)
• MS-SPECIFIC INCLUSION: Patients with MS can be in remission and can have a history of being on immunomodulatory agents, but at the time of entry into the clinical trial, patients should be off any concurrent MS therapy for at least 2 weeks. Patients receiving concomitant interferon gamma (IFN-γ treatment) will be permitted in 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's Syndrome (Vitali, et al., 2002). If on treatment, the patient may only be on hydroxychloroquine and prednisone ≤ 10 mg or equivalent
• PSO/PSA-SPECIFIC INCLUSION: Patients with known PsO as diagnosed by a dermatologist or 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 the investigator 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 of TNF inhibition, patients may have transitioned to an alternative biologic therapy with stable disease for at least 4 weeks. For PsA, no change in corticosteroid therapy 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 PsA unless specifically excluded

Exclusion criteria

• Patients who have had chemotherapy or radiotherapy within 2 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events (AEs) due to agents administered more than 4 weeks earlier have not resolved or stabilized. Palliative (limited-field) radiation therapy (RT) is permitted (2 week washout from start of treatment), if all of the following 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 active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
• UC-SPECIFIC EXCLUSION: Patients who have received ipilimumab treatment
• UC-SPECIFIC EXCLUSION: Prior colectomy
• UC-SPECIFIC EXCLUSION: Concurrent primary sclerosing cholangitis (PSC). Patients with PSC can be enrolled on the Other Autoimmune Diseases Cohorts
• UC-SPECIFIC EXCLUSION: Patients on empiric immunosuppressive treatment without any clinical workup
• CD-SPECIFIC EXCLUSION: Known untreated abscesses, untreated and symptomatic strictures, 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 any clinical workup
• MS-SPECIFIC EXCLUSION: Patients with MS cannot have medical contraindications to gadolinium-enhanced magnetic resonance imaging (MRI)