A Randomized, Double-Blind, Controlled Phase 3 Study of Cabozantinib in Combination with Nivolumab and Ipilimumab versus Nivolumab and Ipilimumab in Subjects with Previously Untreated Advanced or Metastatic Renal Cell Carcinoma of Intermediate or Poor Risk

1. Histologically confirmed advanced (not amenable to curative surgery or
radiation therapy) or metastatic (AJCC Stage IV) renal cell carcinoma with a
clear-cell component, including subjects who also have a sarcomatoid feature.
2. Intermediate- or poor-risk RCC as defined by IMDC criteria.
3. Measurable disease per RECIST 1.1 as determined by the Investigator.
Measurable disease must be outside the radiation field if radiation therapy was
previously administered.
4. Shipment of archival tumor tissue (unstained slides or paraffin block to the
study central laboratory prior to randomization. The tumor tissue can be
obtained from any organ except brain or bone and must have been biopsied no
more than 2 years prior to the date of informed consent. Alternatively, a fresh
tumor sample must be obtained and shipped to the study central laboratory prior
to randomization if archival tumor tissue is unavailable or inadequate.
5. Recovery to baseline or <= Grade 1 CTCAE v5 from toxicities related to any
prior treatments, unless AE(s) are clinically nonsignificant and/or stable on
supportive therapy. Examples of exceptions are subjects with Grade 2 neuropathy
or alopecia who are allowed for trial participation.
6. Age eighteen years or meeting country definition of adult, whichever is
older, on the day of consent.
7. Karnofsky Performance Status (KPS) >= 70%.
8. Adequate organ and marrow function, based upon meeting all of the following
laboratory criteria within 14 days prior to randomization:
a. Absolute neutrophil count (ANC) >= 1500/µL (>= 1.5 GI/L) without granulocyte
colony stimulating factor support within 2 weeks before screening laboratory
sample collection.
b. Criterion intentionally left blank.
c. Platelets >= 100,000/µL (>= 100 GI/L) without transfusion within 2 weeks
before screening laboratory sample collection.
d. Hemoglobin >= 8 g/dL (>= 80 g/L) without transfusion within 1 week before
screening laboratory sample collection and no clinical evidence of bleeding.
e. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) <= 3 x
ULN.
f. Total bilirubin <= 1.5 x ULN (with the exception that total bilirubin for
subjects with Gilbert*s disease <= 3 x ULN).
g. Serum creatinine <= 1.5 x ULN or calculated creatinine clearance >= 40 mL/min
(>= 0.67 mL/sec) using the Cockcroft-Gault equation.
h. Urine protein-to-creatinine ratio (UPCR) <= 1 mg/mg (<= 113.2 mg/mmol), or
24-h urine protein <= 1
9. Capable of understanding and complying with the protocol requirements and
must have signed the informed consent document prior to any screening
assessments except those procedures performed as standard of care within the
screening window.
10. Sexually active fertile subjects and their partners must agree to use
highly effective methods of contraception during the course of the study and
for 5 months for women, and 7 months for men, after the last dose of study
treatment. A barrier contraceptive method (eg, condom) is also required.
11. 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 are 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 hormone (FSH) level > 40 mIU/mL to confirm menopause).
Note: Documentation may include review of medical records, medical examination,
or medical history interview by study site staff.

1. Prior systemic anticancer therapy for unresectable locally advanced or
metastatic RCC including investigational agents.
Note: One prior systemic adjuvant therapy is allowed for completely resected
RCC and if recurrence occurred at least 6 months after the last dose of
adjuvant therapy.
Note: Adjuvant therapy with a PD1 or PD-L1 inhibitor in combination with a
CTLA-4 inhibitor is not permitted.
2. Radiation therapy for bone metastasis within 2 weeks, any other radiation
therapy within 4 weeks prior to randomization. Subjects with clinically
relevant ongoing complications from prior radiation therapy are not eligible.
3. Known brain metastases or cranial epidural disease unless adequately treated
with radiotherapy and/or radiosurgery and stable for at least 4 weeks prior to
randomization after radiotherapy, or at least 4 weeks prior to randomization
after major surgery (eg, removal or biopsy of brain metastasis). Subjects who
are neurologically symptomatic as a result of their CNS disease or are
receiving systemic corticosteroid treatment (prednisone equivalent > 10 mg/day)
at the planned time of randomization are not eligible.
4. Concomitant anticoagulation with oral anticoagulants (eg, warfarin, direct
thrombin and Factor Xa inhibitors) or platelet inhibitors (eg, clopidogrel).
a. Allowed anticoagulants are:
i. Low-dose aspirin for cardioprotection (per local applicable guidelines) and
low-dose low molecular weight heparins (LMWH)
ii. Therapeutic doses of LMWH in subjects without known brain metastases who
are on a stable dose of LMWH for at least 1 week before randomization without
clinically significant hemorrhagic complications from the anticoagulation
regimen or the tumor
Note: Subjects who switch from an oral anticoagulant to LMWH are allowed if the
oral anticoagulant was stopped >= 5 half-lives of the oral anticoagulant prior
to planned randomization date.
5. Administration of a live, attenuated vaccine within 30 days prior to
randomization. The use of inactivated (killed) vaccines for the prevention of
infectious disease is permitted.
6. The subject has uncontrolled, significant intercurrent or recent illness
including, but not limited to, the following conditions:
a. Cardiovascular disorders:
i. Congestive heart failure (CHF) class III or IV as defined by the New York
Heart Association, unstable angina pectoris, serious cardiac arrhythmias (eg,
ventricular flutter, ventricular fibrillation, Torsades de pointes).
ii. Uncontrolled hypertension defined as sustained blood pressure (BP) > 150 mm
Hg systolic or > 90 mm Hg diastolic despite optimal antihypertensive treatment.
iii. Stroke transient ischemic attack (TIA), myocardial infarction, or other
symptomatic ischemic event or thromboembolic event (eg, deep venous thrombosis,
pulmonary embolism [DVT/PE]) within 6 months before randomization.
Note: Subjects with a diagnosis of DVT within 6 months are allowed if
asymptomatic and stable at screening and treated with LMWH for at least 1 week
before randomization.
Note: Non-symptomatic white matter disease in the brain is acceptable.
b. Gastrointestinal (GI) disorders including those associated with a high risk
of perforation or fistula formation:
i. Tumors invading the GI tract, active peptic ulcer disease, inflammatory
bowel disease, diverticulitis, cholecystitis, symptomatic cholangitis or
appendicitis, acute pancreatitis or acute obstruction of the pancreatic or
biliary duct, or gastric outlet obstruction.
ii. Abdominal fistula, GI perforation, bowel obstruction, or intra-abdominal
abscess within 6 months prior to randomization. Complete healing of an intra
abdominal abscess must be confirmed prior to randomization.
c. Clinically significant hematuria, hematemesis, or hemoptysis of > 0.5
teaspoon (2.5 mL) of red blood, or other history of significant bleeding (eg,
pulmonary hemorrhage) within 3 months before randomization.
d. Cavitating pulmonary lesion(s) or known endobronchial disease manifestation.
e. Lesions invading major pulmonary blood vessels.
f. Other clinically significant disorders such as:
i. Autoimmune disease that has been symptomatic or required treatment within
the past two years from the date of randomization.
Note: Patients with a history of Crohn*s disease or ulcerative colitis are
always excluded.
Note: Subjects with type I diabetes mellitus, hypothyroidism only requiring
hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia)
not requiring systemic treatment, or conditions not expected to recur in the
absence of an external trigger are permitted to enroll.
ii. Any condition requiring systemic treatment with either corticosteroids (>
10 mg daily prednisone equivalent) or other immunosuppressive medications
within 14 days of randomization.
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 (eg, contrast allergy) is also allowed.
iii. 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.
iv. History of idiopathic pulmonary fibrosis, organizing pneumonia,
drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active
pneumonitis on screening chest CT scan
v. Serious non-healing wound/ulcer/bone fracture.
vi. Malabsorption syndrome.
vii. Uncompensated/symptomatic hypothyroidism.
viii. Moderate to severe hepatic impairment (Child-Pugh B or C).
ix. Requirement for hemodialysis or peritoneal dialysis.
x. History of solid organ or allogeneic stem cell transplant.
xi. Known history of COVID-19 unless the subject has clinically recovered from
the disease at least 30 days prior to randomization.
7. Major surgery (eg, nephrectomy, GI surgery, removal or biopsy of brain
metastasis) within 4 weeks prior to randomization. Minor surgeries within 10
days prior to randomization. Subjects must have complete wound healing from
major or minor surgery before randomization. Subjects with clinically relevant
ongoing complications from prior surgery are not eligible.
8. Corrected QT interval calculated by the Fridericia formula (QTcF) > 500 ms
per electrocardiogram (ECG) within 14 days before randomization. Furthermore,
subjects with a history of additional risk factors for torsades de pointes (eg,
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
9. History of neuropsychiatric disorder likely to interfere with ability to
comply with protocol requirements or give informed consent.
10. Pregnant or breastfeeding females.
11. Inability to swallow tablets or unwillingness or inability to receive IV
administration.
12. 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.
13. Any other active malignancy at time of randomization or diagnosis of
another malignancy within 3 years prior to randomization 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.