Summary

This phase II trial studies how well nivolumab and ipilimumab work in treating patients with rare genitourinary tumors that have spread to other anatomic sites or is no longer responding to treatment. Immunotherapy with monoclonal antibodies, such as nivolumab and ipilimumab, may help the body’s immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread.

Objectives

PRIMARY OBJECTIVE:
I. To assess the objective response rate (ORR) by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 by tumor cohort.

SECONDARY OBJECTIVES:
I. To assess ORR across all rare genitourinary (GU) tumor types.
II. To assess ORR across all tumors with high grade neuroendocrine carcinoma or small cell phenotype.
III. To assess ORR across all tumors with squamous histology.
IV. To assess duration of response (DOR) by RECIST version 1.1.
V. To assess the ORR by Immune Related Response Criteria (irRC).
VI. To assess progression-free survival (PFS) for the total cohort and by tumor type (adrenocortical carcinoma [ACC], non-urothelial bladder/upper tract cancer, non-adenocarcinoma prostate cancer, penile cancer or treatment refractory germ-cell tumor).
VII. To assess overall survival (OS) for the total cohort and by tumor type (ACC, non-urothelial bladder/upper tract cancer, non-adenocarcinoma prostate cancer, penile cancer or treatment refractory germ-cell tumor).
VIII. To assess safety and toxicity by Common Terminology Criteria for Adverse Events (CTCAE) version 4.
IX. To assess the objective response rate by histology independent of site of origin (adenocarcinoma, squamous cell carcinoma, small cell carcinoma, other).

CORRELATIVE OBJECTIVES:
I. To correlate ORR by RECIST version 1.1 with programmed death ligand-1 (PD-L1) tumor expression status in baseline pre-treatment biopsy.
II. To correlate ORR by RECIST version 1.1 with total exonic mutation burden as determined by whole-exome sequencing of baseline pre-treatment biopsy.
III. To correlate ORR by RECIST version 1.1 with neoantigen load as determined by whole-exome sequencing of baseline pre-treatment biopsy.
IV. To correlate ORR by RECIST version 1.1 with blood-based predictive biomarkers of response and resistance to therapy via collection of baseline, on-treatment, and progression blood specimens.
V. To assess molecular mechanisms of acquired resistance in progression biopsies in responders.
VI. To assess molecular mechanisms of response and resistance to treatment via circulating free deoxyribonucleic acid (DNA) (cfDNA) assessment and to correlate cfDNA molecular profile with metastasis biopsy molecular profile.
VII. Correlate single cell molecular profile with metastasis biopsy molecular profile.

OUTLINE:
Patients receive nivolumab intravenously (IV) over 30 minutes and ipilimumab IV over 30 minutes on days 1 and 22. Treatment repeats every 6 weeks for 2 cycles in the absence of disease progression or unacceptable toxicity. Beginning on cycle 3, patients then receive nivolumab IV over 30 minutes on day 1. Cycles repeat every 4 weeks in the absence of disease progression or unaccepted toxicity.

After completion of study treatment, patients are followed up at 30 and 100 days and then every 24 weeks for up to 2 years.

Eligibility

1. Age >= 18 years at the time of consent
2. Eastern Cooperative Oncology Group (ECOG) performance status of =< 2 within 28 days prior to registration
3. 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/small cell carcinoma; 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
4. 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
5. Measurable disease as defined by RECIST 1.1 within 28 days prior to registration
6. White blood cell (WBC) >= 2000 cells/uL (obtained within 28 days prior to registration)
7. Absolute neutrophil count (ANC) >= 1000 cells/uL (obtained within 28 days prior to registration)
8. Platelet count (plt) >= 75,000/uL (obtained within 28 days prior to registration)
9. Hemoglobin (Hgb) >= 9 g/dL (obtained within 28 days prior to registration)
10. Absolute lymphocyte count >= 500 cells/uL (obtained within 28 days prior to registration)
11. Serum creatinine =< 1.5 x upper limit of normal (ULN) OR calculated creatinine clearance >= 40 mL/min (Cockcroft-Gault formula will be used to calculate creatinine clearance) (obtained within 28 days prior to registration)
12. Bilirubin =< 1.5 x upper limit of normal (ULN) (subjects with known Gilbert’s disease should have a serum bilirubin =< 3 x ULN) (obtained within 28 days prior to registration)
13. Aspartate aminotransferase (AST) =< 2.5 x ULN (subjects with documented liver metastases should have AST =< 5 x ULN) (obtained within 28 days prior to registration)
14. Alanine aminotransferase (ALT) =< 2.5 x ULN (subjects with documented liver metastases should have ALT =< 5 x ULN) (obtained within 28 days prior to registration)
15. Alkaline phosphatase =< 2.5 x ULN (subjects with documented liver or bone metastases should have alkaline phosphatase =< 5 x ULN) (obtained within 28 days prior to registration)
16. Albumin > 2.5 g/dL (obtained within 28 days prior to registration)
17. International normalized ratio (INR) or prothrombin time (PT) =< 1.5 x ULN (unless on prophylactic or therapeutic dosing with low molecular weight heparin) (obtained within 28 days prior to registration)
18. Activated partial thromboplastin time (aPTT) =< 1.5 x ULN (unless on prophylactic or therapeutic dosing with low molecular weight heparin) (obtained within 28 days prior to registration)
19. 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
20. 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
21. 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

Treatment Sites in Georgia