Testing the Effectiveness of Two Immunotherapy Drugs (Nivolumab and Ipilimumab) With One Anti-cancer Targeted Drug (Cabozantinib) for Rare Genitourinary Tumors
Testing the Effectiveness of Two Immunotherapy Drugs (Nivolumab and Ipilimumab) With One Anti-cancer Targeted Drug (Cabozantinib) for Rare Genitourinary Tumors
This phase II trial studies how well cabozantinib works in combination with nivolumab and
 ipilimumab in treating patients with rare genitourinary (GU) tumors that have spread to other
 places in the body. Cabozantinib may stop the growth of tumor cells by blocking some of the
 enzymes needed for cell growth. 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. Giving cabozantinib, nivolumab, and ipilimumab
 may work better in treating patients with genitourinary tumors that have no treatment options
 compared to giving cabozantinib, nivolumab, or ipilimumab alone.
PRIMARY OBJECTIVE:

 I. To evaluate the efficacy of cabozantinib s-malate (cabozantinib) combined with nivolumab
 and ipilimumab in the first or second-line (and beyond) setting for patients within each of
 the rare genitourinary (GU) variant histology group of interest, as measured by objective
 response rate (ORR).

 SECONDARY OBJECTIVES:

 I. To estimate the progression-free survival (PFS) for patients treated with cabozantinib
 combined with nivolumab and ipilimumab within each rare variant histology.

 II. To estimate the overall survival (OS) for patients treated with cabozantinib combined
 with nivolumab and ipilimumab within each rare variant histology.

 III. To estimate the clinical benefit rate (defined as complete response [CR] or partial
 response [PR] or stable disease [SD]) for patients treated with cabozantinib combined with
 nivolumab and ipilimumab within each rare variant histology.

 IV. To assess the safety of treating patients with rare variant histologies with cabozantinib
 combined with nivolumab and ipilimumab.

 V. To support tissue banking and collection of clinical follow-up data for GU tract rare
 histological variants.

 EXPLORATORY OBJECTIVES:

 I. To assess effects of treatment in patients with bone-only disease by bone scan.

 OUTLINE:

 Patients receive cabozantinib orally (PO) once daily (QD) on days 1-21 of cycles 1-4 and on
 days 1-28 of subsequent cycles. Patients also receive nivolumab intravenously (IV) over 30
 minutes on day 1 and ipilimumab IV over 90 minutes on day 1 of cycles 1-4. Patients then
 receive nivolumab IV over 30 minutes on day 1 of subsequent cycles. Treatment repeats every
 21 days for cycles 1-4 and every 28 days for subsequent cycles for 2 years in the absence of
 disease progression or unacceptable toxicity.

 After completion of study treatment, patients are followed up every 2 months for 5 years.
Inclusion Criteria:

 -  Metastatic disease defined as new or progressive lesions on cross-sectional imaging or
 bone scan. Patients must have at least:

 -  One measurable site of disease as per Response Evaluation Criteria in Solid
 Tumors (RECIST) version (v) 1.1

 -  One bone lesion on bone scan (tec99 or sodium fluoride [NaF] positron emission
 tomography [PET]/computed tomography [CT], CT, or magnetic resonance imaging
 [MRI]) for the bone-only cohort

 -  Histologically confirmed diagnosis of one of the following metastatic cohorts:

 -  Small cell/ neuroendocrine carcinoma of the bladder - All urothelial
 carcinomas with any amount of neuroendocrine differentiation (including
 small cell differentiation) will be included. If the tumor is purely
 neuroendocrine, metastasis from another site of origin should be clinically
 excluded.

 -  Adenocarcinoma of the bladder, or urachal adenocarcinoma, or bladder/urethra
 clear cell adenocarcinoma - must be pure (per World Health Organization
 [WHO] definition), (i.e. urothelial carcinoma with glandular differentiation
 is not considered a pure adenocarcinoma.

 -  Squamous cell carcinoma of the bladder - must be pure (i.e. urothelial
 carcinoma with squamous differentiation is not considered a pure squamous
 cell carcinoma).

 -  Plasmacytoid urothelial carcinoma - Tumor should show predominantly > or
 equal ~50% plasmacytoid histology (including all types of discohesive
 growth, such as tumors with signet-ring and/or rhabdoid features as well).

 -  Any penile cancer

 -  Sarcomatoid renal cell carcinoma - Tumor should be predominantly sarcomatoid
 ~50% (including rhabdoid differentiation) is also unclassified renal cell
 carcinomas (RCCs): all (assuming they are high grade with metastasis)
 malignant angiomyolipomas are allowed.

 -  Sarcomatoid urothelial carcinoma - Tumor should show predominantly ~ 50%
 sarcomatoid differentiation.

 -  Renal medullary carcinoma - Per WHO definition, ideally confirmed with
 immunostains.

 -  Renal collecting duct carcinoma - Per WHO definition (medullary involvement,
 predominant tubular morphology, desmoplastic stromal reaction, high grade
 cytology, infiltrative growth pattern, and absence of other renal cell
 carcinoma subtype or urothelial carcinoma).

 -  Bone only urothelial carcinoma or other non-prostate GU tumor

 -  Urethra carcinoma - May be of any histology but if urothelial carcinoma then
 must be isolated to the urethra and not have metachronous or synchronous
 urothelial carcinoma of the bladder.

 -  Other miscellaneous histologic variants of the urothelial carcinoma, such
 as, but not limited to: micropapillary (Tumor should show predominantly > or
 equal 50% micropapillary architecture), giant cell, lipid-rich, clear cell
 and nested variants (Tumor should predominantly > or equal 50% show these
 features), large cell neuroendocrine carcinoma, lymphoepithelioma-like
 carcinoma and mixed patterns will be considered, as well as small cell
 neuroendocrine prostate cancer (Only treatment-naïve primary small cell of
 prostate with any amount of small cell component allowed. Post-treatment
 small cell prostatic carcinomas are not allowed), Malignant testicular
 Sertoli or Leydig cell tumors, and papillary and chromophobe RCC.

 -  Note: Translocation positive renal cell carcinoma patients are
 eligible. However, AREN1721 should be considered before this trial.

 -  Hematoxylin and eosin (H&E) slides from diagnostic tumor tissue for retrospective
 central pathology review

 -  Patients may have received up to 2 systemic anti-cancer treatments or be treatment
 naive. Patients with small cell carcinoma should have received a platinum-based
 combination regimen either as neoadjuvant, adjuvant or first-line treatment). Patients
 in the bone-only cohort may be urothelial carcinoma histology but must receive
 standard cisplatin-based chemotherapy (if cisplatin-eligible).

 -  Patients must be able to swallow oral formulation of the tablets

 -  Karnofsky performance status >= 80%

 -  Absolute neutrophil count (ANC) >= 1,000/mcL

 -  Platelet count >= 75,000/mcL

 -  Total bilirubin =< 1.5 x upper limit of normal (ULN). For subjects with known
 Gilbert's disease or similar syndrome with slow conjugation of bilirubin, total
 bilirubin =< 3.0 mg/dL

 -  Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 3.0 x institutional
 upper limit of normal (ULN) (or =< 5 x ULN for patients with liver metastases or
 Gilbert's disease)

 -  Creatinine =< 1.5 x upper limit of normal (ULN) OR creatinine clearance >= 40
 mL/min/1.73 m^2 (calculated using the Chronic Kidney Disease Epidemiology [CKD-EPI]
 equation or Cockcroft-Gault formula) for patients with creatinine levels above
 institutional normal

 -  Hemoglobin >= 9 g/dL (transfusion of packed red blood cells [PRBCs] allowed)

 -  Serum albumin >= 3.2 g/dL

 -  Lipase and amylase =< 2.0 x ULN and no radiologic (on baseline anatomical imaging) or
 clinical evidence of pancreatitis

 -  Prior treatment with MET or VEGFR inhibitors is allowed. However, prior cabozantinib
 will not be allowed. Also, patients that have received both prior MET or VEGF and
 prior PD-1/PD-L1/CTLA-4 (sequentially or in combination) are also not allowed

 -  Prior treatment with any therapy on the PD-1/PD-L1 axis or anti- CTLA-4/CTLA-4
 inhibitors is allowed, either in the perioperative or in the metastatic setting.
 However, patients that have received both prior MET or VEGF and prior
 PD-1/PD-L1/CTLA-4 (sequentially or in combination) are not allowed

 -  Human immunodeficiency virus (HIV)-positive patients are eligible if on stable dose of
 highly active antiretroviral therapy (HAART), no clinically significant drug-drug
 interactions are anticipated with the current HAART regimen, CD4 counts are greater
 than 350 and viral load is undetectable

 -  Patients with rheumatoid arthritis and other rheumatologic arthropathies, Sjogren's
 syndrome and psoriasis controlled with topical medication only and patients with
 positive serology, such as antinuclear antibodies (ANA), anti-thyroid antibodies etc.
 are eligible but should be considered for rheumatologic evaluation for the presence of
 target organ involvement and potential need for systemic treatment

 -  Patients with vitiligo, endocrine deficiencies including thyroiditis managed with
 replacement hormones or medications (e.g. thyroiditis managed with propylthiouracil
 [PTU] or methimazole) including physiologic oral corticosteroids are eligible

 -  Patients who have evidence of active or acute diverticulitis, intra-abdominal abscess,
 and gastrointestinal (GI) obstruction, within 12 months are not eligible

 -  Women of childbearing potential must have a negative pregnancy test =< 7 days prior to
 registration

 -  Women of childbearing potential include women who have experienced menarche and
 who have not undergone successful surgical sterilization (hysterectomy, bilateral
 tubal ligation, or bilateral oophorectomy) or are not postmenopausal. Post
 menopause is defined as amenorrhea >= 12 consecutive months. Note: women who have
 been amenorrheic for 12 or more months are still considered to be of childbearing
 potential if the amenorrhea is possibly due to prior chemotherapy, antiestrogens,
 ovarian suppression or any other reversible reason

 -  Pregnant women may not participate in this study because with cabozantinib, nivolumab,
 and ipilimumab have potential for teratogenic or abortifacient effects. Because there
 is an unknown but potential risk for adverse events in nursing infants secondary to
 treatment of the mother with cabozantinib, nivolumab, and ipilimumab, breastfeeding
 should be discontinued if the mother is treated with these agents

 -  The patient has received no cytotoxic chemotherapy (including investigational
 cytotoxic chemotherapy) or biologic agents (e.g., cytokines or antibodies) within 2
 weeks before the first dose of study treatment

 -  The patient has received no radiation therapy:

 -  To the lungs and mediastinum or abdomen within 4 weeks before the first dose of
 study treatment, or has ongoing complications, or is healing from prior radiation
 therapy

 -  To brain metastasis within 3 weeks for whole-brain radiotherapy (WBXRT), and 2
 weeks for stereotactic body radiation therapy (SBRT) before the first dose of
 study treatment

 -  To the abdomen within 4 weeks before the first dose of study treatment, or has
 ongoing complications, or is healing from prior radiation therapy

 -  To any other site(s) within 2 weeks before the first dose of study treatment

 -  The patient has received no radionuclide treatment within 6 weeks of the first dose of
 study treatment

 -  The patient has received no prior treatment with a small molecule kinase inhibitor
 within 14 days or five half-lives of the compound or active metabolites, whichever is
 longer, before the first dose of study treatment

 -  The patient has received no prior treatment with hormonal therapy within 14 days or
 five half-lives of the compound or active metabolites, whichever is longer, before the
 first dose of study treatment. Subjects receiving gonadotropin-releasing hormone
 (GnRH) agonists and antagonists are allowed to participate

 -  The patient has not received any other type of investigational agent within 14 days
 before the first dose of study treatment

 -  The patient must have recovered to baseline or Common Terminology Criteria for Adverse
 Events (CTCAE) =< grade 1 from toxicity due to all prior therapies except alopecia,
 neuropathy and other non-clinically significant adverse events (AEs) defined as lab
 elevation with no associated symptoms or sequelae

 -  The patient may not have active brain metastases or epidural disease. Patients with
 brain metastases previously treated with whole brain radiation or radiosurgery who are
 asymptomatic and do not require steroid treatment for at least 2 weeks before starting
 study treatment are eligible. Neurosurgical resection of brain metastases or brain
 biopsy is permitted if completed at least 3 months before starting study treatment.
 Baseline brain imaging with contrast-enhanced computed tomography (CT) or magnetic
 resonance imaging (MRI) scans for subjects with known brain metastases is required to
 confirm eligibility

 -  No concomitant treatment with warfarin. Aspirin (up to 325 mg/day), thrombin or factor
 Xa inhibitors, low-dose warfarin (=< 1 mg/day), prophylactic and therapeutic low
 molecular weight heparin (LMWH) are permitted

 -  No chronic concomitant treatment with strong CYP3A4 inducers (e.g., dexamethasone,
 phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital, and St.
 John's wort) or strong CYP3A4 inhibitors

 -  Because the lists of these agents are constantly changing, it is important to
 regularly consult medical reference texts such as the Physicians' Desk Reference
 may also provide this information. As part of the enrollment/informed consent
 procedures, the patient will be counseled on the risk of interactions with other
 agents, and what to do if new medications need to be prescribed or if the patient
 is considering a new over-the-counter medicine or herbal product

 -  The patient has not experienced any of the following:

 -  Clinically-significant gastrointestinal bleeding within 6 months before the first
 dose of study treatment

 -  Hemoptysis of >= 0.5 teaspoon (2.5 mL) of red blood per day within 1 months
 before the first dose of study treatment

 -  Any other signs indicative of pulmonary hemorrhage within 3 months before the
 first dose of study treatment

 -  The patient has no tumor invading any major blood vessels

 -  The patient has no evidence of tumor invading the GI tract (esophagus, stomach, small
 or large bowel, rectum or anus), or any evidence of endotracheal or endobronchial
 tumor within 28 days before the first dose of cabozantinib. Patients with rectal tumor
 masses are not eligible.

 -  The patient has no uncontrolled, significant intercurrent or recent illness including,
 but not limited to, the following conditions:

 -  Cardiovascular disorders including:

 -  Congestive heart failure (CHF): New York Heart Association (NYHA) class III
 (moderate) or class IV (severe) at the time of screening.

 -  Concurrent uncontrolled hypertension defined as sustained blood pressure
 (BP) > 150 mm Hg systolic, or > 90 mm Hg diastolic despite optimal
 antihypertensive treatment within 7 days of the first dose of study
 treatment

 -  The subject has a corrected QT interval calculated by the Fridericia formula
 (QTcF) > 500 ms within 28 days before randomization. Note: if initial QTcF
 is found to be > 500 ms, two additional electrocardiograms (EKGs) separated
 by at least 3 minutes should be performed. If the average of these three
 consecutive results for QTcF is =< 500 ms, the subject meets eligibility in
 this regard

 -  Any history of congenital long QT syndrome

 -  Any of the following within 6 months before registration of study treatment:

 -  Unstable angina pectoris

 -  Clinically-significant cardiac arrhythmias (patients with atrial
 fibrillation are eligible)

 -  Stroke (including transient ischemic attack [TIA], or other ischemic
 event)

 -  Myocardial infarction

 -  Cardiomyopathy

 -  No significant gastrointestinal disorders particularly those associated with a
 high risk of perforation or fistula formation including:

 -  Any of the following that have not resolved within 28 days before the first
 dose of study treatment:

 -  Active peptic ulcer disease

 -  Acute diverticulitis, cholecystitis, symptomatic cholangitis or
 appendicitis, or malabsorption syndrome

 -  None of the following within 2 years before the first dose of study
 treatment:

 -  Abdominal fistula or genitourinary fistula

 -  Gastrointestinal perforation

 -  Bowel obstruction or gastric outlet obstruction

 -  Intra-abdominal abscess. Note: Complete resolution of an
 intra-abdominal abscess must be confirmed prior to initiating treatment
 with cabozantinib even if the abscess occurred more than 2 years before
 the first dose of study treatment

 -  Disorders associated with a high risk of fistula formation including percutaneous
 endoscopic gastrostomy (PEG) tube placement are not eligible

 -  No other clinically significant disorders such as:

 -  Severe active infection requiring IV systemic treatment within 14 days
 before the first dose of study treatment

 -  Serious non-healing wound/ulcer/bone fracture within 28 days before the
 first dose of study treatment

 -  History of organ or allogeneic stem cell transplant

 -  Concurrent uncompensated hypothyroidism or thyroid dysfunction within 7 days
 before the first dose of study treatment (for asymptomatic patients with an
 elevated thyroid-stimulating hormone [TSH], thyroid replacement may be
 initiated if clinically indicated without delaying the start of study
 treatment)

 -  No history of major surgery as follows:

 -  Major surgery within 3 months of the first dose of ca