A Phase II Study of Nivolumab Combined With Ipilimumab for Patients With Advanced Rare Genitourinary Tumors

• 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, treatment refractory germ-cell tumor or a high grade neuroendocrine carcinoma/small cell carcinoma of any genitourinary site. 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.

• at this time only the bladder and neuroendocrine cohorts are open

• 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