Cabozantinib-s-malate and Nivolumab With or Without Ipilimumab in Treating Patients With Metastatic Genitourinary Tumors

• Incidence of adverse events evaluated according National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 (Phase I) [ Time Frame: Up to 3 years ]
  The safety and tolerability of a novel dose of cabozantinib, nivolumab and ipilimumab in patients with genitourinary cancer will be assessed.
• Recommended phase II dose defined as the highest dose for which no more than 1/6 patients experience a dose limiting toxicity evaluated according to National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 (Phase I) [ Time Frame: Up to 4-6 weeks ]
  The safe dose level of cabozantinib and nivolumab, as well as of cabozantinib, nivolumab, and ipilimumab will be established.

• Clinical response rate assessed by Response Evaluation Criteria in Solid Tumors 1.1 and Immune-Related Response Criteria [ Time Frame: Up to 3 years ]
  The response rate may be used to guide the further development of the combinations.
• Fraction of patients who have been identified as being alive and progression free at two months [ Time Frame: At 2 months ]
  May be determined as well and reported on both arms. This fraction will be considered as a secondary endpoint for the expansion cohorts as well, and this information may be used to guide the further development of the combinations. A Kaplan-Meier curve for progression free survival will also be presented as a secondary endpoint, in addition to reporting the fraction without progression at two months.
• PDL-1 and MET expression [ Time Frame: Up to day 1 of final course ]
  PDL-1 and MET expression data will be obtained in patients with urothelial carcinoma checkpoint inhibition naive, clear cell renal cell carcinoma, adenocarcinoma of the bladder, squamous cell carcinoma of the bladder, urothelial carcinoma with prior checkpoint inhibition therapy, and penile cancer. Data will be obtained in pre- and post-treatment biopsies and analyze, in at least an exploratory fashion, their association to response or clinical benefit.

• Overall response rate in patients receiving ipilimumab challenge/re-challenge [ Time Frame: Up to 3 years ]
  The overall response rates determined at this time point will be combined and reported along with 95% confidence intervals.
• Progression free survival in bone-only urothelial carcinoma [ Time Frame: Up to 3 years ]
  Patients with bone-only disease will be enrolled and evaluated using progression free survival for a descriptive analysis of the effect of treatment. In addition, if PDL-1 or MET data are obtained in this small cohort, exploratory and descriptive analyses may be done as appropriate.

PRIMARY OBJECTIVES:

I. Determine the dose limiting toxicity (DLT) and recommended phase II dose (RP2D) of the combination of cabozantinib (cabozantinib-s-malate) and nivolumab (cabo-nivo) and separately the combination of cabozantinib, nivolumab and ipilimumab (cabo-nivo-ipi) in patients with genitourinary tumors. (Phase I) II. Assess safety and tolerability of cabozantinib, nivolumab and ipilimumab (cabo-nivo-ipi) in patients with genitourinary tumors at this novel dose. (Dose Level 8 Cohort)

SECONDARY OBJECTIVES:

I. Preliminarily evaluate the activity, as determined by objective response rate using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and the modified Immune-Related Response Criteria (irRC), derived from RECIST1.1, of cabo-nivo and cabo-nivo-ipi in patients with advanced/refractory metastatic urothelial carcinoma (checkpoint inhibition therapy naive) and with renal cell carcinoma in the second-line and beyond setting.

II. Preliminarily evaluate the activity, as determined by objective response rate using RECIST 1.1 and the modified irRC, derived from RECIST 1.1, of cabo-nivo in patients with adenocarcinoma and with squamous cell carcinoma of the bladder in the first line or beyond setting.

III. Preliminarily evaluate the activity, as determined by objective response rate using RECIST 1.1 and the modified irRC, derived from RECIST 1.1, of cabo-nivo in patients with urothelial carcinoma previously treated with checkpoint inhibition therapy in the second line or beyond setting.

IV. Preliminarily evaluate the activity, as determined by objective response rate using RECIST 1.1 and the modified irRC, derived from RECIST 1.1, of cabo-nivo-ipi in patients with squamous cell carcinoma of the penis.

V. To evaluate the activity as determined by progression free survival (PFS) and overall survival (OS) of: cabo-nivo and cabo-nivo-ipi in patients with advanced/refractory metastatic urothelial carcinoma (checkpoint inhibition therapy naive) or with renal cell carcinoma in the second-line and beyond setting.

VI. To evaluate the activity as determined by PFS and OS of: cabo-nivo in patients with advanced adenocarcinoma or squamous cell carcinoma of the bladder in the first-line and beyond setting.

VII. To evaluate the activity as determined by PFS and OS of: cabo-nivo in patients with urothelial carcinoma previously treated with checkpoint inhibition therapy in the second line or beyond setting.

To evaluate the activity as determined by PFS and OS of: cabo-nivo-ipi in patients with squamous cell carcinoma of the penis.

VIII. To obtain additional data to evaluate the safety of both combinations in patients with clear cell renal cell carcinoma (ccRCC).

IX. To assess the number of malignant soft tissue and bone lesions on fludeoxyglucose F-18 (18F-FDG) positron emission tomography (PET)/computed tomography (CT) (scan 1) versus combined fluorine F 18 sodium fluoride (18F-NaF) and 18F-FDG PET/CT (scan 2).

X. To assess response assessment by RECIST 1.1 using CT of the chest, abdomen, and pelvis with intravenous (IV) contrast versus assessment by combined 18F-NaF and 18F-FDG PET/CT (scan 2) using number of malignant and change (modified PET RECIST [PERCIST]) of soft tissue and bone lesions.

XI. To test the feasibility of automated density and volume application (ADaVA) as a means of assessing tumor response.

XII. To assess PDL-1 and MET expression data and in exploratory fashion analyze their association to response or clinical benefit.

TERTIARY OBJECTIVES:

I. To assess overall response rates (ORR) on patients who have been challenged or re-challenged with ipilimumab therapy post disease progression.

II. To assess effects of treatment in patients with bone-only disease.

OUTLINE: This is a dose-escalation study. Patients are assigned to 1 of 2 treatment arms.

PART I: Patients receive cabozantinib-s-malate orally (PO) once daily (QD) on days 1-28 and nivolumab intravenously (IV) over 60 minutes on days 1 and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. After 21 courses, patients receive nivolumab IV over 60 minutes every 4 weeks in the absence of disease progression or unacceptable toxicity. After progression, patients may receive cabozantinib-s-malate PO, nivolumab IV, and ipilimumab IV at the part II RP2D for 4 courses followed by cabozantinib-s-malate PO QD and nivolumab IV every 2 weeks or 4 weeks if post-course 21 in the absence of disease progression or unacceptable toxicity.

PART II: Patients receive cabozantinib-s-malate PO QD on days 1-21, nivolumab IV over 60 minutes on day 1, and ipilimumab IV over 90 minutes on day 1. Treatment repeats every 21 days for up to 4 courses in the absence of disease progression or unacceptable toxicity. After completion of 4 courses with ipilimumab, patients continue receiving cabozantinib-s-malate PO QD on days 1-28 and nivolumab IV over 60 minutes on days 1 and 15. Treatment repeats every 28 days for up to 42 courses in the absence of disease progression or unacceptable toxicity. After 21 courses, patients receive nivolumab IV over 60 minutes every 4 weeks in the absence of disease progression or unacceptable toxicity. After progression, patients may receive cabozantinib-s-malate PO, nivolumab IV, and ipilimumab IV at the part II RP2D for 4 courses followed by cabozantinib-s-malate PO QD and nivolumab IV every 2 weeks or 4 weeks if post-course 21 in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 16 weeks or 100 days and then every 2 months thereafter.

• Clear Cell Renal Cell Carcinoma
• Metastatic Malignant Neoplasm in the Bone
• Metastatic Penile Carcinoma
• Renal Pelvis Urothelial Carcinoma
• Squamous Cell Carcinoma of the Penis
• Stage III Bladder Adenocarcinoma
• Stage III Bladder Squamous Cell Carcinoma
• Stage III Bladder Urothelial Carcinoma
• Stage III Penile Cancer
• Stage III Renal Cell Cancer
• Stage III Renal Pelvis Carcinoma
• Stage III Ureter Cancer
• Stage III Urethral Cancer
• Stage IIIa Penile Cancer
• Stage IIIb Penile Cancer
• Stage IV Bladder Adenocarcinoma
• Stage IV Bladder Squamous Cell Carcinoma
• Stage IV Bladder Urothelial Carcinoma
• Stage IV Penile Cancer
• Stage IV Renal Cell Cancer
• Stage IV Renal Pelvis Carcinoma
• Stage IV Ureter Cancer
• Stage IV Urethral Cancer
• Ureter Urothelial Carcinoma
• Urethral Urothelial Carcinoma

• Drug: Cabozantinib S-malate
  Given PO
  Other Names:

  • BMS-907351
  • Cabometyx
  • Cometriq
  • XL184
• Biological: Ipilimumab
  Given IV
  Other Names:

  • Anti-Cytotoxic T-Lymphocyte-Associated Antigen-4 Monoclonal Antibody
  • BMS-734016
  • MDX-010
  • MDX-CTLA4
  • Yervoy
• Other: Laboratory Biomarker Analysis
  Correlative studies
• Biological: Nivolumab
  Given IV
  Other Names:

  • BMS-936558
  • MDX-1106
  • NIVO
  • ONO-4538
  • Opdivo

• Experimental: Part I (cabozantinib-s-malate, nivolumab)
  Patients receive cabozantinib-s-malate PO QD on days 1-28 and nivolumab IV over 60 minutes on days 1 and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. After 21 courses, patients receive nivolumab IV over 60 minutes every 4 weeks in the absence of disease progression or unacceptable toxicity. After progression, patients may receive cabozantinib-s-malate PO QD, nivolumab IV, and ipilimumab IV at the part II RP2D for 4 courses followed by cabozantinib-s-malate PO QD and nivolumab IV every 2 weeks or 4 weeks if post-course 21 in the absence of disease progression or unacceptable toxicity.
  Interventions:

  • Drug: Cabozantinib S-malate
  • Other: Laboratory Biomarker Analysis
  • Biological: Nivolumab
• Experimental: Part II (cabozantinib-s-malate, nivolumab, ipilimumab)
  Patients receive cabozantinib-s-malate PO QD on days 1-21, nivolumab IV over 60 minutes on day 1, and ipilimumab IV over 90 minutes on day 1. Treatment repeats every 21 days for up to 4 courses in the absence of disease progression or unacceptable toxicity. After completion of 4 courses with ipilimumab, patients continue receiving cabozantinib-s-malate PO QD on days 1-28 and nivolumab IV over 60 minutes on days 1 and 15. Treatment repeats every 28 days for up to 42 courses in the absence of disease progression or unacceptable toxicity. After 21 courses, patients receive nivolumab IV over 60 minutes every 4 weeks in the absence of disease progression or unacceptable toxicity. After progression, patients may receive cabozantinib-s-malate PO, nivolumab IV, and ipilimumab IV at the part II RP2D for 4 courses followed by cabozantinib-s-malate PO QD and nivolumab IV every 2 weeks or 4 weeks if post-course 21 in the absence of disease progression or unacceptable toxicity.
  Interventions:

  • Drug: Cabozantinib S-malate
  • Biological: Ipilimumab
  • Other: Laboratory Biomarker Analysis
  • Biological: Nivolumab

Inclusion Criteria:

• Patients in the phase I portion must have:

  • Histologically confirmed diagnosis of metastatic, genitourinary solid tumor

  • Metastatic disease defined as new or progressive lesions on cross-sectional imaging; patients must have at least:

    • One evaluable site of disease
    • Or, appearance of one new bone lesion

• Patients in the expansion portion must have:

  • Histologically confirmed diagnosis of metastatic:

    • Urothelial carcinoma of the bladder, urethra, ureter, renal pelvis, OR
    • Clear cell renal cell carcinoma OR
    • Adenocarcinoma of the bladder OR
    • Non-resectable squamous cell carcinoma of the penis OR
    • Squamous cell carcinoma of the bladder AND

  • Patients with urothelial cancer or renal cell carcinoma must have progressive metastatic disease defined as new or progressive lesions on cross-sectional imaging; patients must have at least:

    • One measurable site of disease (according to RECIST criteria) or bone disease by NaF PET/CT
• Patients must have failed at least one standard therapy or no standard treatment exists that has been shown to prolong survival; patients may have received any number of prior cytotoxic agents
• Karnofsky performance status >= 70%
• Leukocytes >= 3,000/mcL
• Absolute neutrophil count >= 1,200/mcL
• Platelets >= 75,000/mcL
• Total bilirubin =< 1.5 x upper limit of normal (ULN)
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.0 x institutional upper limit of normal (ULN) or < 5.0 x ULN in patients with Gilbert's syndrome
• Creatinine =< 1.5 x ULN OR creatinine clearance >= 40 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal
• Hemoglobin >= 9 g/dL
• Serum albumin >= 2.8 g/dL
• Lipase and amylase < 2.0 x ULN and no radiologic or clinical evidence of pancreatitis
• Urine protein/creatinine ratio (UPCR) =< 2
• Serum phosphorus >= lower limit of normal (LLN)
• Serum calcium >= LLN
• Serum magnesium >= LLN
• Serum potassium >= LLN
• Women of childbearing potential must have a negative pregnancy test at screening; 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; postmenopause 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
• Women of child-bearing potential and men must agree to use adequate contraception, as defined below, prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while she is participating in this study, she should inform her treating physician immediately; men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 31 weeks after completion of all study medications; women treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and for 23 weeks after completion of all study medications
• Sexually active subjects (men and women) must agree to use medically accepted barrier methods of contraception (e.g., male or female condom) during the course of the study and for 23 or 31 weeks for women or men respectively, after the last dose of study drugs, even if oral contraceptives are also used; all subjects of reproductive potential must agree to use both a barrier method and a second method of birth control during the course of the study and for 23 or 31 weeks for women and men respectively after the last dose of study drugs
• Tissue availability for programmed cell death ligand 1 (PD-L1) expression is mandatory for enrollment; however if archived tissue is unavailable the patient will be given the option to consent to pre and post treatment tissue biopsies; tissue biopsies will be collected pretreatment (prior to the first dose of therapy) and post treatment (after at least 1 dose, preferably 2 doses of nivolumab)
• Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

• The subject has received cytotoxic chemotherapy (including investigational cytotoxic chemotherapy) or biologic agents (e.g., cytokines or antibodies) within 3 weeks, or nitrosoureas/mitomycin C within 6 weeks before the first dose of study treatment
• Patients who have been previously treated with met MET or vascular endothelial growth factor receptor (VEGFR) inhibitors (except for patients on renal cell cancer [RCC] cohort) are not eligible for the expansion cohorts but can enroll in the phase I portion
• Prior treatment with any therapy on the programmed cell death 1 (PD-1)/PD-L1 axis or anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors unless enrolling the urothelial carcinoma with previous checkpoint inhibition therapy expansion cohort

• The subject has received radiation therapy:

  • To the thoracic cavity or abdomen within 3 months before the first dose of study treatment, or has ongoing complications, or is without complete recovery and healing from prior radiation therapy
  • To bone or brain metastasis within 3 weeks before the first dose of study treatment
  • To any other site(s) within 28 days before the first dose of study treatment
• The subject has received radionuclide treatment within 6 weeks of the first dose of study treatment
• The subject has received 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 subject has received any other type of investigational agent within 28 days before the first dose of study treatment
• The subject has not recovered to baseline or Common Terminology Criteria for Adverse Events (CTCAE) =< grade 1 from toxicity due to all prior therapies except alopecia and other non-clinically significant adverse events (AEs) defined as lab elevation with no associated symptoms or sequelae
• The subject has active brain metastases or epidural disease; subjects 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 CT or magnetic resonance imaging (MRI) scans for subjects with known brain metastases is required to confirm eligibility
• The subject has prothrombin time (PT)/international normalized ratio (INR) or partial thromboplastin time (PTT) test >= 1.5 x the laboratory ULN within 7 days before the first dose of study treatment
• The subject requires concomitant treatment, in therapeutic doses, with anticoagulants such as warfarin or warfarin-related agents, thrombin or factor Xa inhibitors; aspirin (up to 325 mg/day), low-dose warfarin (=< 1 mg/day), prophylactic and therapeutic low molecular weight heparin (LMWH) are permitted
• The subject requires chronic concomitant treatment of strong cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) inducers (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital, and St. John's wort)

• The subject has 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 within 3 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 subject has tumor invading any major blood vessels
• The subject has evidence of tumor invading the gastrointestinal (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 subject has 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) > 140 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 the first dose of study treatment:

    • Unstable angina pectoris
    • Clinically-significant cardiac arrhythmias
    • Stroke (including transient ischemic attack [TIA], or other ischemic event)
    • Myocardial infarction
    • Cardiomyopathy

• 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
    • Malabsorption syndrome

  • Any of the following within 6 months before the first dose of study treatment:

    • Abdominal 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 6 months before the first dose of study treatment
• Other disorders associated with a high risk of fistula formation including percutaneous endoscopic gastrostomy (PEG) tube placement within 3 months before the first dose of study therapy

• Other clinically significant disorders such as:

  • Severe active infection requiring systemic treatment within 28 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 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)

  • 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
  • In addition, complete wound healing from prior surgery must be confirmed at least 28 days before the first dose of cabozantinib irrespective of the time from surgery
• The subject is unable to swallow tablets
• History of severe hypersensitivity reaction to any monoclonal antibody
• The subject is unable or unwilling to abide by the study protocol or cooperate fully with the investigator or designee
• For disease specific studies: the subject has had evidence within 2 years of the start of study treatment of another malignancy which required systemic treatment
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to cabozantinib, nivolumab, ipilimumab or other agents used in study
• Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with cabozantinib
• Human immunodeficiency virus (HIV)-positive patients are eligible if on stable dose of highly active antiretroviral therapy (HAART), cluster of differentiation (CD)4 counts are greater than 350 and viral load is undetectable
• Patients are excluded if they have a positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection
• 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, should be excluded; 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; patients with vitiligo, endocrine deficiencies including thyroiditis managed with replacement hormones including physiologic corticosteroids are eligible; patients with rheumatoid arthritis and other arthropathies, Sjogren's syndrome and psoriasis controlled with topical medication and patients with positive serology, such as antinuclear antibodies (ANA), anti-thyroid antibodies should be evaluated for the presence of target organ involvement and potential need for systemic treatment but should otherwise be eligible
• Patients are permitted to enroll if they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger (precipitating event)
• Pat