| Eligibility |
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 or small cell carcinoma of the bladder, renal medullary carcinoma
(RMC), sarcomatoid bladder and renal cell carcinomas, plasmacytoid carcinoma
of the bladder or other rare bladder/kidney cancer histology 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 either progressed on at least one standard therapy or there must be
no standard treatment that has been shown to prolong survival for the patient's
disease (patients with urothelial carcinoma who are cisplatin-ineligible may receive
protocol therapy as a first line therapy); patients may have received any number of
prior cytotoxic agents
- Age >= 18 years on day of consent. Because no dosing or adverse event data are
currently available on the use of cabozantinib in combination with nivolumab and
ipilimumab in patients < 18 years of age, children are excluded from this study, but
will be eligible for future pediatric trials
- 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); for subjects with known
Gilbert's disease or similar syndrome with slow conjugation of bilirubin, total
bilirubin =< 3.0 mg/dL
- 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)
- Creatinine =< 1.5 x ULN OR creatinine clearance >= 40 mL/min/1.73 m^2 (calculated
using the Chronic Kidney Disease-Epidemiology Collaboration [CKD-EPI] equation or
Cockcroft-Gault formula) 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) (if below LLN, for asymptomatic
patients replacement may be initiated if clinically indicated without delaying the
start of study treatment)
- Serum calcium >= LLN (if below LLN, for asymptomatic patients replacement may be
initiated if clinically indicated without delaying the start of study treatment)
- Serum magnesium >= LLN (if below LLN, for asymptomatic patients replacement may be
initiated if clinically indicated without delaying the start of study treatment)
- Serum potassium >= LLN (if below LLN, for asymptomatic patients replacement may be
initiated if clinically indicated without delaying the start of study treatment)
- 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
- The effects of the drugs used in this trial on the developing human fetus are unknown;
however, cabozantinib was embryolethal in rats at exposures below the 140 mg dose in
the label, with increased incidences of skeletal variations in rats and visceral
variations and malformations in rabbits; for this reason and because tyrosine kinase
inhibitors agents as well as other therapeutic agents used in this trial are known to
be teratogenic, 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 for 7 months 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 5 months 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 5 or 7 months 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 5 or 7 months for women and men respectively
after the last dose of study drugs
- Tissue availability for 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 or 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 PD-1/PD-L1 axis or 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 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 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
- No concomitant treatment with warfarin is permitted. 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
- The subject requires chronic concomitant treatment of strong CYP3A4 inducers (e.g.,
dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine,
phenobarbital, and St. John's wort); 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 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 mmHg systolic, or > 90 mmHg 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 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 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 because cabozantinib is a tyrosine kinase
inhibitor with the 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, breastfeeding should be discontinued if the
mother is treated with cabozantinib; these potential risks may also apply to other
agents used in this study
- Human immunodeficiency virus (HIV)-positive patients are eligible if on stable dose of
highly active antiretroviral therapy (HAART), CD4 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 because of the risk of recurrence or exacerbation of disease; 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)
- Patients are excluded if they have a condition requiring systemic treatment with
either corticosteroids (> 10 mg daily prednisone equivalents) or other
immunosuppressive medications within 14 days of study drug administration; inhaled or
topical steroids and adrenal replacement doses < 10 mg daily prednisone equivalents
are permitted in the absence of active autoimmune disease; patients are permitted to
use topical, ocular, intra-articular, intranasal, and inhalational corticosteroids
(with minimal systemic absorption); physiologic replacement doses of systemic
corticosteroids are permitted, even if < 10 mg/day prednisone equivalents; a brief
course of corticosteroids for prophylaxis (e.g., contrast dye allergy) or for
treatment of non-autoimmune conditions (e.g., delayed-type hypersensitivity reaction
caused by contact allergen) is permitted
- Patients who have had evidence of active or acute diverticulitis, intra-abdominal
abscess, GI obstruction and abdominal carcinomatosis which are known risk factors for
bowel perforation should be evaluated for the potential need for additional treatment
before coming on study
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