Nivolumab Combined With Ipilimumab for Patients With Advanced Rare Genitourinary Tumors

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Brief Title

Nivolumab Combined With Ipilimumab for Patients With Advanced Rare Genitourinary Tumors

Official Title

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

Brief Summary

      This research study is studying a combination of drugs as a possible treatment for rare
      genitourinary malignancies among four cohorts, bladder or upper tract carcinoma with variant
      histology, adrenocortical carcinoma, other rare genitourinary carcinomas and any
      genitourinary carcinoma with neuroendocrine differentiation. Given preliminary results, the
      study is being tested in additional patients with bladder or upper tract carcinoma with
      variant histology at this time while the adrenocortical carcinoma, other rare genitourinary
      malignancies arms have closed to accrual

      -The names of the study drugs involved in this study are:

        -  Nivolumab

        -  Ipilimumab

Detailed Description

      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

      In this research study, the investigators are...

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

        -  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.

Study Phase

Phase 2

Study Type


Primary Outcome

Objective Response Rate

Secondary Outcome

 Objective Response Rate for all rare GU tumor types


Genitourinary Cancer



Study Arms / Comparison Groups

Description:  Nivolumab and Ipilimumab are administered intravenously every 3 weeks for a total of 4 maximum doses. After combination therapy, nivolumab will be administered as monotherapy every 4 weeks.
Doses are determined per protocol.


* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information

Recruitment Status


Estimated Enrollment


Start Date

December 28, 2017

Completion Date

May 31, 2025

Primary Completion Date

December 31, 2023

Eligibility Criteria

        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, 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

          -  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, 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.

          -  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

          -  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.

          -  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, 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

          -  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

          -  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.




18 Years - N/A

Accepts Healthy Volunteers



Bradley A McGregor, MD, 617-632-6328, [email protected]

Location Countries

United States

Location Countries

United States

Administrative Informations



Organization ID


Responsible Party

Principal Investigator

Study Sponsor

Dana-Farber Cancer Institute


 Bristol-Myers Squibb

Study Sponsor

Bradley A McGregor, MD, Principal Investigator, Dana-Farber Cancer Institute

Verification Date

July 2022