Nivolumab With or Without Bevacizumab or Ipilimumab Before Surgery in Treating Patients With Metastatic Kidney Cancer That Can Be Removed by Surgery
Nivolumab With or Without Bevacizumab or Ipilimumab Before Surgery in Treating Patients With Metastatic Kidney Cancer That Can Be Removed by Surgery
This randomized pilot early phase I trial studies the side effects and how well nivolumab
 alone works compared to nivolumab with bevacizumab or ipilimumab before surgery in treating
 patients with kidney cancer, also referred to as renal cell cancer, that has spread to
 another place in body and can be removed by surgery. Immunotherapy with monoclonal
 antibodies, such as nivolumab, bevacizumab, 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.
PRIMARY OBJECTIVES:

 I. Safety and tolerability of therapy with nivolumab or nivolumab + bevacizumab or nivolumab
 + ipilimumab in metastatic renal cell carcinoma (mRCC) in the context of presurgical or
 prebiopsy therapy.

 SECONDARY OBJECTIVES:

 I. To study immunological changes in tumor tissues and peripheral blood in response to
 nivolumab versus (vs.) nivolumab + bevacizumab vs nivolumab + ipilimumab in renal cell
 carcinoma (RCC) therapy.

 II. To assess the efficacy of presurgical nivolumab or nivolumab + bevacizumab or nivolumab +
 ipilimumab therapy in RCC by evaluating objective response rate, duration of response, and
 progression free survival, and overall survival.

 OUTLINE: Patients are randomized to 1 of 3 treatment arms.

 ARM A: Patients receive nivolumab intravenously (IV) over 60 minutes on day 1 every 2 weeks
 for 6 weeks. Approximately 4 weeks later, patients undergo nephrectomy, metastasectomy or
 biopsy.

 ARM B: Patients receive nivolumab IV over 60 minutes and bevacizumab IV over 90 minutes on
 day 1 every 2 weeks for 6 weeks. Patients also undergo nephrectomy, metastasectomy or biopsy
 as in Arm A.

 ARM C: Patients receive nivolumab IV over 60 minutes and ipilimumab IV over 90 minutes on day
 1 every 3 weeks for 6 weeks. Patients also undergo nephrectomy, metastasectomy or biopsy as
 in Arm A.

 Beginning 4-6 weeks after surgery, patients in all arms who have clinical response, stable
 disease, or even slight progression of disease to therapy preoperatively, receive maintenance
 nivolumab IV over 60 minutes on day 1. Cycles repeat every 4 weeks for 2 years in the absence
 of disease progression or unacceptable toxicity.

 After completion of study treatment, patients are followed up at 30 days and 86 days, every 3
 months for 2 years, every 6 months for 1 year, and then annually thereafter.
Inclusion Criteria:

 -  Patients must give written informed consent prior to initiation of therapy, in keeping
 with the policies of the institution; patients with a history of major psychiatric
 illness must be judged able to fully understand the investigational nature of the
 study and the risks associated with the therapy

 -  Patients with histologically or cytologically confirmed metastatic clear cell RCC who
 are eligible for cytoreductive nephrectomy, metastasectomy or post-treatment biopsy;
 diagnosis must be confirmed by pathologist review of screening biopsy; the
 determination of resectability will ultimately lie in the clinical judgment of the
 urologist and medical oncologist involved in the care of the patient

 -  Patients must have measurable disease and is defined as a lesion that can be
 accurately measured on the long axis with a minimum size of 10 mm or a lymph node that
 can be accurately measured along the short axis of a minimum size of 15 mm (computed
 tomography [CT] scan slice thickness can be no greater than 5 mm)

 -  Patients can have had prior treatment for RCC including prior surgery, radiation
 therapy, immunotherapy with interleukin (IL)-2 or interferon (but not anti-programmed
 cell death [PD]1 or anti-cytotoxic T-lymphocyte-associated protein 4 [CTLA-4]), target
 therapy with receptor tyrosine kinase (RTK) inhibitors/mammalian target of rapamycin
 (mTOR) inhibitors, such as sunitinib, sorafenib, pazopanib, axitinib, everolimus, and
 temsirolimus (but not bevacizumab) or chemotherapy

 -  Eastern Cooperative Oncology Group (ECOG) performance status =< 2

 -  Absolute neutrophil count >= 1,500/uL within 14 days of the first dose of study drug

 -  Platelets >= 100,000/uL within 14 days of the first dose of study drug

 -  Hemoglobin (Hgb) > 9.0 g/dL (may be transfused or receive epoetin alfa [e.g., Epogen]
 to maintain or exceed this level) within 14 days of the first dose of study drug

 -  Total bilirubin =< 1.5 mg/dl within 14 days of the first dose of study drug

 -  Serum creatinine =< 1.5 times the upper limit of normal or estimated creatinine
 clearance (CrCl) > 40 mL/min within 14 days of the first dose of study drug

 -  Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])
 and/or alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
 =< 2.5 x institutional upper limit of normal for patients without evidence of liver
 metastases, AST (SGOT) and/or ALT (SGPT) =< 5 x institutional upper limit of normal
 for patients with documented liver metastases within 14 days of the first dose of
 study drug

 -  Mild autoimmune conditions (such as localized psoriasis) requiring minimal treatment
 or systemic autoimmune conditions well controlled by target agents such as an
 anti-IL-17 that do not affect overall immune system

 -  Patients with a history of Hashimoto's thyroiditis only requiring hormone replacement,
 type I diabetes, or conditions not expected to recur in the absence of an external
 trigger are allowed to participate

 -  Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy
 test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin
 [HCG]) within 24 hours prior to the start of study drug

 -  Women must not be breastfeeding

 -  WOCBP must agree to follow instructions for method(s) of contraception from the time
 of enrollment for the duration of treatment with study drug (s) plus 5 half-lives of
 study drug (s) plus 30 days (duration of ovulatory cycle) for a total of 23 weeks post
 treatment completion

 -  Men who are sexually active with WOCBP must agree to follow instructions for method(s)
 of contraception for the duration of treatment with study drug (s) plus 5 half-lives
 of study drug (s) plus 90 days duration of sperm turnover for a total of 31 weeks
 post-treatment completion

 -  Azoospermic males and WOCBP who are continuously not heterosexually active are exempt
 from contraceptive requirements; however WOCBP must still undergo pregnancy testing as
 described; investigators shall counsel WOCBP and male subjects who are sexually active
 with WOCBP on the importance of pregnancy prevention and the implications of an
 unexpected pregnancy; investigators shall advise WOCBP and male subjects who are
 sexually active with WOCBP on the use of highly effective methods of contraception;
 highly effective methods of contraception have a failure rate of < 1% per year when
 used consistently and correctly; at a minimum, subjects must agree to the use of two
 methods of contraception, with one method being highly effective and the other method
 being either highly effective or less effective as listed below: HIGHLY EFFECTIVE
 METHODS OF CONTRACEPTION:

 -  Male condoms with spermicide

 -  Hormonal methods of contraception including combined oral contraceptive pills,
 vaginal ring, injectables, implants, and intrauterine devices (IUDs) such as
 Mirena by WOCBP subject or male subject's WOCBP partner

 -  Nonhormonal IUDs, such as ParaGard

 -  Tubal ligation

 -  Vasectomy

 -  Complete abstinence

 -  Complete abstinence is defined as complete avoidance of heterosexual
 intercourse and is an acceptable form of contraception for all study drugs;
 abstinence is only acceptable when this is in line with the preferred and
 usual lifestyle of the subject; periodic abstinence (e.g., calendar,
 ovulation, symptothermal, profession of abstinence for entry into a clinical
 trial, post-ovulation methods) and withdrawal are not acceptable methods of
 contraception

 -  Subjects who choose complete abstinence are not required to use a second method of
 contraception, but female subjects must continue to have pregnancy tests; acceptable
 alternate methods of highly effective contraception must be discussed in the event
 that the subject chooses to forego complete abstinence; LESS EFFECTIVE METHODS OF
 CONTRACEPTION:

 -  Diaphragm with spermicide

 -  Cervical cap with spermicide

 -  Vaginal sponge

 -  Male condom without spermicide

 -  A male and female condom must not be used together

 -  Progestin only pills by WOCBP subject or male subject's WOCBP partner

 -  Female condom

 -  A male and female condom must not be used together

 Exclusion Criteria:

 -  Any other malignancy from which the patient has been disease-free for less than 2
 years, except for non-melanoma skin cancer, in situ carcinoma of any site

 -  Patients who have organ allografts

 -  Patients who have had a major surgical procedure, open biopsy, or significant
 traumatic injury with poorly healed wound within 6 weeks prior to first dose of study
 drug; or anticipation of need for major surgical procedure during the course of the
 study (other than defined by protocol); or fine needle aspirations or core biopsies
 within 7 days prior to first dose of study drug

 -  Known or suspected autoimmune disease; patients with a history of inflammatory bowel
 disease (including Crohn's disease and ulcerative colitis) are excluded from this
 study as are patients with a history of autoimmune disease (e.g., rheumatoid
 arthritis, systemic progressive sclerosis [scleroderma], systemic lupus erythematosus,
 autoimmune vasculitis [e.g., Wegener's granulomatosis]) are excluded from this study;
 any condition requiring systemic treatment with corticosteroids (> 10 mg daily
 prednisone equivalents) or other immunosuppressive medications within 14 days prior to
 first dose of study drug; inhaled steroids and adrenal replacement steroids doses > 10
 mg daily prednisone equivalents are permitted in the absence of active autoimmune
 disease

 -  Known history of testing positive for human immunodeficiency virus (HIV) or known
 acquired immunodeficiency syndrome (AIDS); positive test for hepatitis B virus (HBV)
 using HBV surface antigen (HBV sAg) test or positive test for hepatitis C virus (HCV)
 using HCV ribonucleic acid (RNA) or HCV antibody test indicating acute or chronic
 infection

 -  Any underlying medical condition, which in the opinion of the investigator, will make
 the administration of study drug hazardous or obscure the interpretation of adverse
 events, such as a condition associated with frequent diarrhea

 -  Patients who have had a history of acute diverticulitis, abdominal fistula,
 gastrointestinal perforation, intra-abdominal abscess, gastrointestinal (GI)
 obstruction, abdominal carcinomatosis which are known risks factors for bowel
 perforation, should be excluded from the study

 -  Patients who have a primary brain tumor (excluding meningiomas and other benign
 lesions), any brain metastases, leptomeningeal disease, seizure disorders not
 controlled with standard medical therapy, history of stroke within the past year

 -  History of serious systemic disease, including myocardial infarction or unstable
 angina within the last 12 months, history of hypertensive crisis or hypertensive
 encephalopathy, uncontrolled hypertension (blood pressure of > 140/90 mmHg) at the
 time of enrollment, New York Heart Association (NYHA) grade II or greater congestive
 heart failure, unstable symptomatic arrhythmia requiring medication (patients with
 chronic atrial arrhythmia, i.e., atrial fibrillation or paroxysmal supraventricular
 tachycardia are eligible), significant vascular disease or symptomatic peripheral
 vascular disease

 -  Patients who have history of other diseases, metabolic dysfunction, physical
 examination finding, or clinical laboratory finding giving reasonable suspicion of a
 disease or condition that contraindicates the use of an investigational drug or that
 might affect the interpretation of the results of the study or render the subject at
 high risk from treatment complications

 -  Patients who have proteinuria at baseline; patients who are unexpectedly discovered to
 have >= grade 2 proteinuria at baseline routine urinalysis should undergo a 24-hour
 urine collection, which must be an adequate collection and must demonstrate =< 1 g of
 protein/24 hour (hr) to allow participation in the study

 -  Patients who have uncontrolled hypertension (systolic > 140 mmHg and/or diastolic > 90
 mmHg); it is permissible to start treatment for hypertension prior to randomization

 -  Patients who are on high dose steroid (e.g. > 10 mg prednisone daily or equivalent) or
 other more potent immune suppression medications (e.g. infliximab)

 -  Patients who have had flu, hepatitis, or other vaccines within a month prior to
 initiation of study drugs

 -  Patients who have clinical history of coagulopathy, bleeding diathesis or thrombosis
 within the past year

 -  Patients who have serious, non-healing wound, ulcer, or bone fracture

 -  Pregnancy (positive pregnancy test) or lactation

 -  Patients must not have received prior anticancer therapy with bevacizumab,
 anti-CLTA-4, or anti-PD1 for renal cell carcinoma; patients receiving any concomitant
 systemic therapy for renal cell cancer are excluded

 -  Patients must not be scheduled to receive another experimental drug while on this
 study

 -  Patients who require ongoing anticoagulation will be excluded; only aspirin will be
 permitted; pre and post-surgical prophylactic anti-coagulation treatment is permitted

 -  Patients must not require total parenteral nutrition with lipids

 -  Any patients who cannot be compliant with the appointments required in this protocol
 must not be enrolled in this study