Testing the Effectiveness of Two Immunotherapy Drugs (Nivolumab and Ipilimumab) With One Anti-cancer Targeted Drug (Cabozantinib) for Rare Genitourinary Tumors

  • End date
    Feb 28, 2023
  • participants needed
  • sponsor
    National Cancer Institute (NCI)
Updated on 25 November 2020
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ct scan
platelet count
tubal ligation
monoclonal antibodies
growth factor
karnofsky performance status
squamous cell carcinoma
kinase inhibitor
major surgery
neutrophil count
hormone therapy
liver metastasis
pet scan
tumor cells
brain metastases
programmed cell death 1 ligand 1
ovarian suppression
transitional cell carcinoma


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.



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).


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.


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


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.

Treatment Ipilimumab, Nivolumab, Cabozantinib, Cabozantinib S-malate
Clinical Study IdentifierNCT03866382
SponsorNational Cancer Institute (NCI)
Last Modified on25 November 2020

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Inclusion Criteria

Is your age greater than or equal to 18 yrs?
Gender: Male or Female
Do you have any of these conditions: Malignant neoplasm of kidney or Metastatic Prostate Small Cell Carcinoma or Bone Lesion or Metastatic Penile Carcinoma or Metastatic Bladder Small Cel...?
Do you have any of these conditions: Testicular Sertoli Cell Tumor or Kidney Medullary Carcinoma or Metastatic Bladder Large Cell Neuroendocrine Carcinoma or Kidney Cancer or Metastatic B...?
Do you have any of these conditions: Bladder Squamous Cell Carcinoma or Metastatic Bladder Small Cell Carcinoma or Bladder Mixed Adenocarcinoma or Metastatic Infiltrating Bladder Urotheli...?
Do you have any of these conditions: Adenocarcinoma or Stage IV Renal Cell Cancer AJCC v8 or Infiltrating Bladder Urothelial Carcinoma, Plasmacytoid Variant or Stage IVA Bladder Cancer AJ...?
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 metastatic: small cell carcinoma of the bladder; adenocarcinoma of the bladder; squamous cell carcinoma of the bladder; plasmacytoid urothelial carcinoma; any penile cancer; sarcomatoid renal cell carcinoma; sarcomatoid urothelial carcinoma; renal medullary carcinoma or other miscellaneous histologic variants of the urothelial carcinoma, such as, but not limited to micropapillary, giant cell, lipid-rich, clear cell and nested variants, large cell neuroendocrine carcinoma, lymphoepithelioma-like carcinoma and mixed patterns will be considered, as well as small cell neuroendocrine prostate cancer, testicular Sertoli or Leydig cell tumors, and papillary and chromophobe renal cell carcinoma (RCC)
Hematoxylin and eosin (H&E) slides from diagnostic tumor tissue for retrospective central pathology review
Patients may have received any number of prior anti-cancer treatments or be treatment naive (with the exception of patients with small cell carcinoma of the bladder, whom should have received a platinum-based combination regimen either as neoadjuvant, adjuvant or first-line treatment)
Patients must be able to swallow oral formulation of the tablets
Karnofsky performance status >= 70%
Absolute neutrophil count (ANC) >= 1,200/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 >= 2.8 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 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 or subjects with epidural disease previously treated with radiation or surgery 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
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
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
Intra-abdominal tumor/metastases invading GI mucosa
Active peptic ulcer disease
Diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis, or malabsorption syndrome
None of the following within 1 year before the first dose of study
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 12 months 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 cabozantinib; however, if there were no wound healing complications, patients with rapidly growing aggressive cancers, may start as soon as 6 weeks if wound has completely healed post-surgery
Minor surgery within 1 month of the first dose of cabozantinib if there were no wound healing complications or within 3 months of the first dose of cabozantinib if there were wound complications excluding core biopsies and mediport placement
Complete wound healing from prior surgery must be confirmed before the first dose of cabozantinib irrespective of the time from surgery
No history of severe hypersensitivity reaction to any monoclonal antibody
No evidence of active malignancy, requiring systemic treatment within 2 years of registration
No history of allergic reactions attributed to compounds of similar chemical or biologic composition to cabozantinib, nivolumab, ipilimumab or other agents used in study
No positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection
No patients with active autoimmune disease or history of autoimmune disease that might recur, which may affect vital organ function or require immune suppressive treatment including systemic corticosteroids. These include, but are not limited to patients with a history of immune related neurologic disease, multiple sclerosis, autoimmune (demyelinating) neuropathy, Guillain-Barre syndrome, myasthenia gravis; systemic autoimmune disease such as systemic lupus erythematosus (SLE), connective tissue diseases, scleroderma, inflammatory bowel disease (IBD), Crohn's, ulcerative colitis, hepatitis; and patients with a history of toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome, or phospholipid syndrome should be excluded because of the risk of recurrence or exacerbation of disease
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