Nivolumab and Ipilimumab in Treating Patients with Advanced Rare Genitourinary Tumors
- Eastern Cooperative Oncology Group (ECOG) performance status of =< 2 within 28 days prior to registration
- 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
- 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
- White blood cell (WBC) >= 2000 cells/uL (obtained within 28 days prior to registration)
- Absolute neutrophil count (ANC) >= 1000 cells/uL (obtained within 28 days prior to registration)
- Platelet count (plt) >= 75,000/uL (obtained within 28 days prior to registration)
- Hemoglobin (Hgb) >= 9 g/dL (obtained within 28 days prior to registration)
- Absolute lymphocyte count >= 500 cells/uL (obtained within 28 days prior to registration)
- 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)
- 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)
- 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)
- 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)
- 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)
- Albumin > 2.5 g/dL (obtained within 28 days prior to registration)
- 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)
- 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)
- 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
- 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, antitumor 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, treatment refractory germ-cell tumor or genitourinary high grade neuroendocrine carcinoma/small cell carcinoma 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; if the patient has successfully completed desensitization and has shown to take a drug with similar components safely the patient is eligible provided they are given appropriate premedications
- 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, Wegener’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 computed tomography (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 polymerase chain reaction (PCR) is negative for hepatitis C viral DNA
- Active infection requiring systemic treatment
- 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 or 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 corrected QT interval by Fridericia's formula (QTcF) interval defined as > 455 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 gastrointestinal (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 (Common Terminology Criteria for Adverse Events [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
I. To assess the objective response rate (ORR) by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 by tumor cohort.
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).
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.
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.
Trial Phase Phase II
Trial Type Treatment
Dana-Farber Harvard Cancer Center
Bradley A. McGregor
- Primary ID 17-423
- Secondary IDs NCI-2018-00182
- Clinicaltrials.gov ID NCT03333616