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
- Conditions
- 10038364HypernephromaRenal Cell Cancer
- Registration Number
- NL-OMON49041
- Lead Sponsor
- Exelixis Inc.
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Completed
- Sex
- Not specified
- Target Recruitment
- 15
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 statu
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, divertic
Study & Design
- Study Type
- Interventional
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method <p>Duration of PFS, per Response Evaluation Criteria in Solid Tumors version 1.1<br /><br>(RECIST 1.1), by Blinded Independent Radiology Committee (BIRC) </p><br>
- Secondary Outcome Measures
Name Time Method <p>Secondary efficacy endpoint:<br /><br>• Duration of OS<br /><br>Additional endpoints:<br /><br>• ORR per RECIST 1.1 by BIRC<br /><br>• PFS and ORR per RECIST 1.1 by BIRC according to PD-L1 status<br /><br>• PFS and ORR per RECIST 1.1 as assessed by the Investigator<br /><br>• Duration of radiographic response as assessed by the Investigator and by<br /><br>BIRC<br /><br>• Safety through the evaluation of AEs, including immune-related AEs (irAEs),<br /><br>and other safety assessments.<br /><br>• Pharmacokinetics (PK) of cabozantinib given in combination with nivolumab and<br /><br>ipilimumab<br /><br>• Immunogenicity of nivolumab and ipilimumab given in combination with<br /><br>cabozantinib<br /><br>• Correlation of biomarker analyses with clinical outcomes<br /><br>• Health-related quality of life (HRQoL) as assessed by the EuroQol Health<br /><br>questionnaire instruments (EQ 5D 5L)<br /><br>• Health care resource utilization</p><br>