Nivolumab Combined With Ipilimumab for Patients With Advanced Rare Genitourinary Tumors

This research study is a Phase II clinical trial. Phase II clinical trials test the safety
and effectiveness of an investigational drug to learn whether the combination of drugs works
in treating a specific disease. "Investigational" means that the drugs are being studied.

The FDA (the U.S. Food and Drug Administration) has not approved nivolumab in combination
with ipilimumab for this specific disease but the combination is approved for use in melanoma
patients.

In this research study, the investigators are...

- Investigating the response of the participant's cancer to treatment with nivolumab plus
ipilimumab,

- Assessing the safety of treatment with nivolumab and ipilimumab and

- Evaluating response and resistance to treatment by looking at the participant's tumor
tissue and blood for markers to predict response and resistance to therapy.

Inclusion Criteria:

- Age ≥ 18 years at the time of consent.

- Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤ 2 within 28 days
prior to registration (Appendix A).

- Unresectable advanced or metastatic ACC, non-urothelial bladder/upper tract cancer,
non-adenocarcinoma prostate cancer, penile cancer or treatment refractory germ-cell
tumor. Pure is defined as >90% and those with a portion of urothelial carcinoma or
prostate adenocarcinoma may be included at discretion of the principal investigator.
With variant histology in the primary, if metastatic biopsy shows pure variant
histology, patient is eligible

- Availability of Formalin-fixed, Paraffin-embedded (FFPE) archival tumor specimens,
when available, and willingness of the subject to undergo mandatory fresh tumor biopsy
prior to treatment initiation unless determined medically unsafe or not feasible.

- The archival specimen, when available, must contain adequate viable tumor tissue.

- The specimen may consist of a tissue block (preferred and should contain the
highest grade of tumor) or at least 20 unstained serial sections. Fine-needle
aspiration, brushings, cell pellet from pleural effusion, bone marrow
aspirate/biopsy are not acceptable.

- A mandatory biopsy at the time of radiographic progression will be requested from
patients who have an initial response to treatment and then subsequently progress
as determined by RECIST version 1.1.

- Measurable disease as defined by RECIST 1.1 within 28 days prior to registration.

- Demonstrate adequate organ function. All screening labs to be obtained within 28 days
prior to first study treatment.

- Hematological

- White blood cell (WBC) ≥ 2000 cells/µL

- Absolute Neutrophil Count (ANC) ≥ 1000 cells/µL

- Platelet count (plt) ≥ 75,000/ µL

- Hemoglobin (Hgb) ≥ 9 g/dL

- Absolute lymphocyte count ≥ 500 cells/µL

- Renal

- Serum creatinine OR

- Calculated creatinine clearance1 ≤ 1.5 x ULN ≥ 40 mL/min

- Hepatic and Other

- Bilirubin ≤ 1.5 × upper limit of normal (ULN)

- AST2 ≤ 2.5 × ULN

- ALT2 ≤ 2.5 × ULN

- Alkaline Phosphatase2 ≤ 2.5 × ULN

- Albumin > 2.5 g/dL

- Coagulation

- International Normalized Ratio (INR) or Prothrombin Time (PT)

- Activated Partial Thromboplastin Time (aPTT) ≤ 1.5 × ULN (unless on
prophylactic or therapeutic dosing with low molecular weight heparin or
warfarin)

- Females of childbearing potential must have a negative urine or serum pregnancy test
within 28 days prior to registration. NOTE: Females are considered of child bearing
potential unless they are surgically sterile (have undergone a hysterectomy, bilateral
tubal ligation, or bilateral oophorectomy) or they are naturally postmenopausal for at
least 12 consecutive months

- Females of childbearing potential and males must be willing to abstain from
heterosexual activity or to use 2 forms of effective methods of contraception from the
time of informed consent until 120 days after treatment discontinuation. The two
contraception methods can be comprised of two barrier methods, or a barrier method
plus a hormonal method.

- As determined by the enrolling physician or protocol designee, ability of the subject
to understand and comply with study procedures for the entire length of the study

Exclusion Criteria:

- Prior use of systemic checkpoint inhibitors (including PD-1, PD-L1, and CTLA-4
targeting agents) for the management of ACC, non-urothelial bladder cancer/upper
tract, non-adenocarcinoma prostate cancer, penile cancer or treatment refractory
germ-cell tumor is excluded

- Treatment with systemic immunosuppressive medications including but not limited to:
prednisone, dexamethasone, cyclosporine, azathioprine, methotrexate, thalidomide,
anti-tumor necrosis factor (TNF) agents within 2 weeks of first study dose.

- Subjects who have received acute, low-dose systemic immunosuppressant medications
may be enrolled (such as steroids for acute nausea or cancer-related pain ≤ 10 mg
prednisone) maybe enrolled sooner than 2 weeks of first study dose.

- Subjects with adrenal insufficiency on physiologic replacement doses of steroids
may be enrolled (≤ 10 mg prednisone).

- The use of inhaled, topical, ocular or intra-articular corticosteroids and
mineralocorticoids are allowed.

- Treatment with chemotherapy, hormone therapy, or other investigational therapy within
3 weeks of first study doses. Patients with non-adenocarcinoma of the prostate who may
be on luteinizing hormone-releasing hormone agonist/antagonist therapy may continue
use. For ACC patients, hormonal agents (e.g mitotane) are allowed for the purpose to
control endocrine-related symptoms when needed.

- Radiotherapy within 14 days of first study treatment with the exception of a single
fraction of radiation administered for palliation of symptoms.

- Known active metastases to the brain, spinal cord or leptomeninges. Patients who are
treated with radiotherapy, radiosurgery, or surgery and clinically stable for at least
2 weeks of first study treatment are eligible. Repeat imaging is not required to
document treatment response.

- Malignancies other than ACC, non-urothelial bladder/upper tract cancer,
non-adenocarcinoma prostate cancer, penile cancer or treatment refractory germ-cell
tumor within 5 years of first study treatment with the exception of those with
negligible risk of metastases or death and/or treated with expected curative outcome
(included but not limited to carcinoma in situ of the cervix, basal or squamous cell
skin cancer, localized prostate cancer for patients with malignancies other than
non-adenocarcinoma of the prostate, ductal carcinoma in situ of the breast, non-muscle
invasive urothelial carcinoma of the bladder for patients with malignancies other than
non-urothelial bladder cancer).

- History of severe allergic, anaphylactic, or other hypersensitivity reactions to
chimeric or humanized antibodies or fusion protein.

- Known hypersensitivity to any component of the nivolumab or ipilimumab product.

- Any active or recent history (within 6 months of first study dose) of autoimmune
disease or syndrome that requires systemic corticosteroids (>10 mg daily prednisone
equivalent) or immunosuppressive medications including but not limited to: myasthenia
gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid
arthritis, inflammatory bowel disease, vascular thrombosis associated with
anti-phospholipid syndrome, Wegner's granulomatosis, Sjogren's syndrome,
Guillain-Barre syndrome, multiple sclerosis, vasculitis, or glomerulonephritis.
Subjects with vitiligo, controlled type I diabetes mellitus, residual hypothyroidism
due to autoimmune thyroiditis only requiring hormone replacement therapy are permitted
to enroll.

- Any condition requiring treatment with corticosteroids (>10 mg daily prednisone
equivalent) or other immunosuppressive medication within 14 days of the first dose of
study drug. Inhaled, topical, ocular or intra-articular corticosteroids and adrenal
replacement steroid doses ≤ 10 mg daily prednisone equivalents are permitted in the
absence of active autoimmune disease.

- Uncontrolled adrenal insufficiency.

- History of idiopathic pulmonary fibrosis, organized pneumonia, drug-induced
pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening
imaging CT of the chest. History of radiation pneumonitis in the radiation field is
permitted.

- Known history of testing positive for human immunodeficiency virus (HIV) or known
acquired immunodeficiency syndrome.

- Active or chronic hepatitis B infection (defined as having a positive hepatitis B
surface antigen (HBsAg) test at screening). Subject with past or resolved hepatitis B
infection (defined as having a negative HBsAg test and positive antibody to hepatitis
B core antigen test) are eligible. Hepatitis B viral DNA must be obtained in Subjects
with positive hepatitis B core antibody prior to first treatment start.

- Active hepatitis C infection. Subjects positive hepatitis C antibody test are eligible
if PCR is negative for hepatitis C viral DNA.

- Receipt of therapeutic oral or IV antibiotics within 2 weeks of first study treatment.
Subjects receiving routine antibiotic prophylaxis (for dental extractions/procedures)
are eligible.

- Significant cardiovascular disease such New York Heart Association (NYHA) class III or
greater, myocardial infarction within the previous 3 months, unstable arrhythmias,
unstable angina, need for cardiac angioplasty or stenting, coronary artery by-pass
graft surgery, symptomatic peripheral vascular disease. Subjects with known coronary
artery disease treated with stenting or coronary artery by-pass graft, congestive
heart failure not meeting the above criteria, or left ventricular ejection fraction <
50% must be on a stable regimen that is optimized in the opinion of the treating
physician, in consultation with a cardiologist when appropriate.

- Prolongation of the QTcF interval defined as > 450 msec for males and > 470 msec for
females.

- Inadequately controlled hypertension (defined as systolic blood pressure > 160 mmHg
and/or diastolic blood pressure > 100 mmHg). Anti-hypertensive therapy to achieve
these parameters is allowed.

- History of cerebrovascular accident or transient ischemic attack within 3 months of
first study dose.

- Significant vascular disease (such as aortic aneurysm requiring surgical repair or
recent peripheral arterial thrombosis) within 3 months of first study dose.

- Evidence of bleeding diathesis or significant coagulopathy (in the absence of
therapeutic anticoagulation) within 4 weeks of first study dose.

- History of symptomatic deep vein thrombosis or pulmonary embolism within 4 weeks of
first study dose.

- History of abdominal or tracheoesophageal fistula or GI perforation within 6 months of
first study treatment.

- Clinical signs or symptoms of GI obstruction or requirement of routine parenteral
nutrition or tube feedings.

- Evidence of abdominal free air not explained by paracentesis or recent surgical
procedure.

- Serious, non-healing or dehiscing wound or active ulcer.

- Major surgical procedure within 4 weeks of first study treatment.

- Presence of any toxicities attributed to prior anti-cancer therapy that are not
resolved to grade 2 (CTCAE version 4.0) or baseline that could impose risk for serious
complications before administration of study drug,

- Prior allogenic stem cell or solid organ transplant.