| Eligibility |
Inclusion Criteria:
- Histological confirmation of renal cell carcinoma (RCC) with a clear-cell, papillary
or sarcomatoid component
- Advanced (not amenable to curative surgery or radiation therapy) or metastatic
(American Joint Committee on Cancer [AJCC] stage IV) RCC
- No prior systemic therapy for RCC with the following exception:
- One prior adjuvant or neoadjuvant therapy for completely resectable RCC if
recurrence occurred at least 6 months after the last dose of adjuvant or
neoadjuvant therapy
- Measurable disease as per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
- Recovery to baseline or =< grade 1 CTCAE v5 from toxicities related to any prior
treatments unless adverse events (AE[s]) are clinically nonsignificant and/or stable
on supportive therapy
- Karnofsky performance status >= 70%
- Males and females, ages >= 18
- Any ethnicity or race
- Absolute neutrophil count (ANC) >= 1500/uL without granulocyte colony-stimulating
factor support (within 14 days before first dose of study treatment)
- White blood cell count >= 2500/uL (within 14 days before first dose of study
treatment)
- Platelets >= 100,000/uL without transfusion (within 14 days before first dose of study
treatment)
- Hemoglobin >= 9 g/dL (>= 90 g/L) (within 14 days before first dose of study treatment)
- Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline
phosphatase (ALP) =< 3 x upper limit of normal (ULN). ALP =< 5 x ULN with documented
bone metastases (within 14 days before first dose of study treatment)
- Total bilirubin =< 1.5 x ULN (for subjects with Gilbert's disease =< 3 x ULN) (within
14 days before first dose of study treatment)
- Serum albumin >= 2.8 g/dl (within 14 days before first dose of study treatment)
- Prothrombin time (PT)/international normalized ratio (INR) or partial thromboplastin
time (PTT) test < 1.3 x the laboratory ULN (within 14 days before first dose of study
treatment)
- Serum creatinine =< 1.5 x ULN or calculated creatinine clearance >= 40mL/min (>= 0.675
mL/sec) using the Cockcroft-Gault equation (within 14 days before first dose of study
treatment)
- Urine protein/creatinine ratio (UPCR) =< 1 mg/mg (=< 113.2 mg/mmol), or 24-hour (h)
urine protein =< 1 g (within 14 days before first dose of study treatment)
- Capable of understanding and complying with the protocol requirements and must have
signed the informed consent document
- Sexually active fertile subjects and their partners must agree to use medically
accepted methods of contraception (e.g., barrier methods, including male condom,
female condom, or diaphragm with spermicidal gel) during the course of the study and
for 4 months after the last dose of cabozantinib, 5 months after the last dose of
nivolumab for women with childbearing potential, and 7 months after the last dose of
nivolumab for men
- Female subjects of childbearing potential must not be pregnant at screening. Female
subjects are considered to be of childbearing potential unless one of the following
criteria is met: documented permanent sterilization (hysterectomy, bilateral
salpingectomy, or bilateral oophorectomy) or documented postmenopausal status (defined
as 12 months of amenorrhea in a woman > 45 years-of-age in the absence of other
biological or physiological causes. In addition, females < 55 years-of-age must have a
serum follicle stimulating [FSH] level > 40 mIU/mL to confirm menopause). Note:
Documentation may include review of medical records, medical examinations, or medical
history interview by study site
Exclusion Criteria:
- Prior treatment with cabozantinib
- Current use, or intent to use, probiotics, yogurt, or bacterial fortified foods during
the period of treatment
- Active interstitial lung disease (ILD)/pneumonitis or history of ILD/pneumonitis
requiring treatment with systemic steroids
- Known medical condition (e.g., a condition associated with diarrhea or acute
diverticulitis) that, in the investigator's opinion, would increase the risk
associated with study participation or study drug administration or interfere with the
interpretation of safety results
- Receipt of any type of small molecule kinase inhibitor (including investigational
kinase inhibitor) within 2 weeks before first dose of study treatment
- Receipt of any type of cytotoxic, biologic, or other systemic anticancer therapy
(including investigational) within 4 weeks before first dose of study treatment
- Radiation therapy for bone metastasis within 2 weeks or any other radiation therapy
within 4 weeks before first dose of study treatment. Systemic treatment with
radionuclides within 6 weeks before first dose of study treatment. Subjects with
clinically relevant ongoing complications from prior radiation therapy are not
eligible
- Known brain metastases or cranial epidural disease unless adequately treated with
radiotherapy and/or surgery (including radiosurgery) and stable for at least 4 weeks
prior to first dose of study treatment after radiotherapy or at least 4 weeks prior to
first dose of study treatment after major surgery (e.g., removal or biopsy of brain
metastasis). Subjects must have complete wound healing from major surgery or minor
surgery before first dose of study treatment. Eligible subjects must be neurologically
asymptomatic and without corticosteroid treatment at the time of first dose of study
treatment
- Concomitant anticoagulation with coumarin agents (e.g., warfarin), direct thrombin
inhibitors (e.g., dabigatran), direct factor Xa inhibitor betrixaban, or platelet
inhibitors (e.g., clopidogrel). Allowed anticoagulants are the following:
- Prophylactic use of low-dose aspirin for cardio-protection (per local applicable
guidelines) and low-dose low molecular weight heparins (LMWH)
- Therapeutic doses of LMWH or anticoagulation with direct factor Xa inhibitors
rivaroxaban, edoxaban, or apixaban in subjects without known brain metastases who
are on a stable dose of the anticoagulant for at least 1 week before first dose
of study treatment without clinically significant hemorrhagic complications from
the anticoagulation regimen or the tumor
- Administration of a live, attenuated vaccine within 30 days before first dose of study
treatment
- The subject has uncontrolled, significant intercurrent or recent illness including,
but not limited to, the following conditions:
- Cardiovascular disorders:
- Congestive heart failure New York Heart Association class 3 or 4, unstable
angina pectoris, serious cardiac arrhythmias
- Uncontrolled hypertension defined as sustained blood pressure (BP) > 140 mm
Hg systolic or > 90 mm Hg diastolic despite optimal antihypertensive
treatment
- Stroke (including transient ischemic attack [TIA]), myocardial infarction
(MI), or other ischemic event, or thromboembolic event (e.g., deep venous
thrombosis, pulmonary embolism) within 6 months before first dose of study
treatment
- Subjects with a diagnosis of incidental, subsegmental pulmonary
embolism (PE) or deep vein thrombosis (DVT) within 6 months are allowed
if stable, asymptomatic, and treated with a stable dose of permitted
anticoagulation for at least 1 week before first dose of study
treatment
- Gastrointestinal (GI) disorders including those associated with a high risk of
perforation or fistula formation:
- The subject has evidence of tumor invading the GI tract, active peptic ulcer
disease, inflammatory bowel disease (e.g., Crohn's disease), diverticulitis,
cholecystitis, symptomatic cholangitis or appendicitis, acute pancreatitis,
acute obstruction of the pancreatic duct or common bile duct, or gastric
outlet obstruction.
- Abdominal fistula, GI perforation, bowel obstruction, or intra-abdominal
abscess within 6 months before first dose of study treatment. Note: Complete
healing of an intra-abdominal abscess must be confirmed before first dose of
study treatment
- Clinically significant hematuria, hematemesis, or hemoptysis of > 0.5 teaspoon (2.5
ml) of red blood, or other history of significant bleeding (e.g., pulmonary
hemorrhage) within 12 weeks before first dose of study treatment
- Cavitating pulmonary lesion(s) or known endotracheal or endobronchial disease
manifestation
- Lesions invading or encasing any major blood vessels
- Other clinically significant disorders that would preclude safe study participation:
- Any active, known, or suspected autoimmune disease will be excluded, with the
following exceptions:
- Type 1 diabetes mellitus.
- Hypothyroidism only requiring hormone replacement.
- Skin disorders (e.g., vitiligo, psoriasis, or alopecia) not requiring
systemic treatment.
- Conditions not expected to recur in the absence of an external trigger.
- Any condition requiring systemic treatment with either corticosteroids (> 10 mg
daily prednisone equivalent) or other immunosuppressive medications within 14
days before first dose of study treatment.
- Note: Inhaled, intranasal, intra-articular, or topical steroids are
permitted. Adrenal replacement steroid doses > 10 mg daily prednisone
equivalent are permitted. Transient short-term use of systemic
corticosteroids for allergic conditions (e.g., contrast allergy) is also
allowed.
- Active infection requiring systemic treatment. Acute or chronic hepatitis B or C
infection, known human immunodeficiency virus (HIV) or acquired immunodeficiency
syndrome (AIDS)-related illness, or known positive test for tuberculosis
infection where there is clinical or radiographic evidence of active
mycobacterial infection.
- History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced
pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on
screening chest CT scan.
- Serious non-healing wound/ulcer/bone fracture.
- Malabsorption syndrome.
- Uncompensated/symptomatic hypothyroidism.
- Moderate to severe hepatic impairment (Child-Pugh B or C).
- Requirement for hemodialysis or peritoneal dialysis.
- History of solid organ or allogenic stem cell transplant.
- Major surgery (e.g., laparoscopic nephrectomy, GI surgery, removal, or biopsy of brain
metastasis) within 2 weeks before first dose of study treatment. Minor surgeries
within 10 days before first dose of study treatment. Subjects must have complete wound
healing from major surgery or minor surgery before first dose of study treatment.
Subjects with clinically relevant ongoing complications from prior surgery are not
eligible.
- Corrected QT interval calculated by the Fridericia formula (QTcF) > 500 ms per
electrocardiogram (ECG) within 14 days before first dose of study treatment.
Furthermore, subjects with a history of additional risk factors for torsades de
pointes (e.g., long QT syndrome) are also excluded.
- Note: If a single ECG shows a QTcF with an absolute value > 500 ms, two
additional ECGs at intervals of approximately 3 min must be performed within 30
min after the initial ECG, and the average of these three consecutive results for
QTcF will be used to determine eligibility.
- Pregnant or lactating females
- Inability to swallow tablets or unwillingness or inability to receive IV
administration
- Previously identified allergy or hypersensitivity to components of the study treatment
formulations or history of severe infusion-related reactions to monoclonal antibodies.
Subjects with rare hereditary problems of galactose intolerance, the Lapp lactase
deficiency or glucose-galactose malabsorption are also excluded.
- Any other active malignancy at time of first dose of study treatment or diagnosis of
another malignancy within 3 years prior to first dose of study treatment that requires
active treatment, except for locally curable cancers that have been apparently cured,
such as basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma
in situ of the prostate, cervix, or breast.
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