Research Hypothesis: Molecular groups of ccrcc will define patients who will respond to
nivolumab alone, nivolumab combined with ipilimumab, or VEGFR-TKI (sunitinib or pazopanib) in
subjects with previously untreated metastatic renal cell carcinoma (mRCC).
Conditions:
- Advanced or metastatic RCC: previously untreated in metastatic setting.
- Frozen tumor samples available for molecular group determination.
- Determination of molecular subgroup prior to randomization.
Product(s):
- Nivolumab administered IV over 60 minutes at 3 mg/kg combined with ipilimumab
administered IV over 30 minutes at 1 mg/kg every 3 weeks for 4 doses followed by
nivolumab administered IV over 60 minutes at 3 mg/kg every 2 weeks or nivolumab a l o n
e administered IV over 60 minutes at 3 mg/kg every 2 weeks (molecular group 1 and 4), or
TKI (molecular group 2 and 3), pazopanib or sunitinib according to investigator's choice
until disease progression, unacceptable toxicity or other reasons specified in the
protocol.
Biological assessments:
Molecular groups (1 to 4) will be determined for all patients from frozen tumor tissue
samples or from fresh tumor samples immediately stored in "RNA later" medium.
Further exploratory biological assessments will be performed in order to define predictive
biomarkers of response to N+I, N alone or TKI (sunitinib or pazopanib) by analyzing tumor
specimens and blood samples:
- To assess gene expression of immune population markers in the primary tumor as well as
in the metastases before beginning treatment, and at progression if safely achievable.
- Gene expression analysis will be performed from frozen and FFPE tumor tissue in order to
compare the two methods.
- To assess the density and phenotype of selected immune populations (CD8, CD3/CD20, PD-1,
TIM-3, LAG3, FoxP3) as well as the phenotype of tumor cells (PD-L1, PD-L2) by
immunohistochemistry (IHC) in the primary tumor and metastases, before treatment
initiation and at progression if safely achievable.
- To assess the functional status of peripheral blood lymphocytes (PBL) by flow cytometry,
before treatment initiation, during treatment, and at progression.
- To quantify plasmatic angiogenesis-related (i.e. VEGF-A, VEGF-C its soluble receptors
VEGFR-1 and 2 and co-receptors neuropilin 1 and 2, angiopoietins, SDF-1, PDGFs…)) and
endothelial cell-derived molecules (i.e. endoglin, VE-cadherin) before treatment
initiation, during treatment, and at progression.
- To correlate plasmatic angiogenesis-related molecules with tumor vascularization studied
by immunofluorescence (IF) and a multi-spectral analyzer (Vectra technology) on tumor
tissue.
- To investigate a predictive role of the response of CXCL7 and sCD146 to TKI, nivolumab
and/or nivolumab+ipilimumab.
Statistical Considerations:
An adaptative design will be used to ensure that conclusions can be made with a limited
number of patients in each molecular group, which is the major constraint of the study.
Sample Size: Approximately 150 patients are planned to be treated. Given an expected failure
rate of molecular grouping of less than 20%, 180 patients must be included.
Key Inclusion Criteria:
- Histological confirmation of RCC with a clear-cell component. Patients with TFE3 or
TFEB translocation proven by cytogenetic analysis or by fluorescence in situ
hybridization (FISH) are eligible.
- Metastatic (American Joint Committee on Cancer [AJCC] Stage IV) RCC
- No prior systemic therapy for mRCC
- Eastern Cooperative Oncology Group (ECOG) performance status (PS) of ≤2
- Measurable disease as per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
- Frozen tumor samples (primary tumor and/or metastasis biopsies) must be available and
received by the central laboratory (Cordelier Research Center) to determine molecular
groups. (Note: fine needle aspiration [FNA] and bone metastases samples are not
acceptable for submission).
- Molecular group has to be determined prior to randomization.
- Formalin-fixed, paraffin-embedded (FFPE) tumor tissue available for biomarker (gene
expression and immunohistochemistry (IHC)) analysis.
Key Exclusion Criteria:
- Any untreated CNS metastases. Patients with CNS metastases will be eligible if they
are: asymptomatic, without significant oedema, not on corticosteroids, not eligible
for radiation therapy/surgery or have already received radiation therapy.
- Prior systemic treatment with vascular endothelial growth factor (VEGF) or VEGF
receptor-targeted therapy (including, but not limited to, sunitinib, pazopanib,
axitinib, tivozanib, and bevacizumab) except in an adjuvant setting with a free
interval of more than 1 year.
- Prior treatment with an anti-programmed cell death protein 1 (PD-1), anti-programmed
death-ligand 1 (PD-L1), anti-PD-L2, anti-CD137, or anti-cytotoxic
T-lymphocyte-associated protein 4 (CTLA-4) antibody, or any other antibody or drug
specifically targeting T-cell co-stimulation or checkpoint pathways.
- Any active or recent history of a known or suspected autoimmune disease or recent
history of a syndrome that required systemic corticosteroids (>10 mg daily prednisone
equivalent) or immunosuppressive medications except for syndromes which would not be
expected to recur in the absence of an external trigger. Subjects with vitiligo or
type 1 diabetes mellitus or residual hypothyroidism due to autoimmune thyroiditis only
requiring hormone replacement are permitted to enroll.
- Any condition requiring systemic treatment with corticosteroids (>10 mg daily
prednisone equivalents) or other immunosuppressive medications within 14 days prior to
first dose of study drug. Inhaled steroids and adrenal replacement steroid doses >10
mg daily prednisone equivalents are permitted in the absence of active autoimmune
disease.
- Uncontrolled adrenal insufficiency.
- Ongoing symptomatic cardiac dysrhythmias, uncontrolled atrial fibrillation, or
prolongation of the Fridericia corrected QT (QTcF) interval defined as >450 msec for
males and >470 msec for females, where QTcF = QT / 3√RR.
- Poorly controlled hypertension (defined as systolic blood pressure (SBP) of >150 mmHg
or diastolic blood pressure (DBP) of >90 mmHg), despite antihypertensive therapy.
- History of any of the following cardiovascular conditions within 12 months of
enrollment: cardiac angioplasty or stenting, myocardial infarction, unstable angina,
coronary artery by-pass graft surgery, symptomatic peripheral vascular disease, class
III or IV congestive heart failure, as defined by the New York Heart Association.
- History of cerebrovascular accident including transient ischemic attack within the
past 12 months.
- History of deep vein thrombosis (DVT) unless adequately treated with low molecular
weight heparin.
- History of pulmonary embolism within the past 6 months unless stable, asymptomatic,
and treated with low molecular weight heparin for at least 6 weeks.
- Known history of COPD (of any stage).
- Known history of uveitis or complaint of double vision.
- History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess
within the past 6 months.
- Serious, non-healing wound or ulcer.
- Evidence of active bleeding or bleeding susceptibility; or medically significant
hemorrhage within prior 30 days.
- Any requirement for anti-coagulation, except for low molecular weight heparin.
- Prior malignancy active within the previous 3 years 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.
- Known history of testing positive for human immunodeficiency virus (HIV) or known
acquired immunodeficiency syndrome (AIDS).
- Any positive test for hepatitis B or hepatitis C virus indicating acute or chronic
infection.
- 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.
- Known history of hyperesthesia, hypoesthesia, paresthesia, dysesthesia, peripheral
motor neuropathy, peripheral sensory, neuropathy, and polyneuropathy.
- Major surgery (e.g., nephrectomy) less than 35 days prior to the first dose of study
drug.
- Focal radiation therapy less than 14 days prior to the first dose of study drug.
- Receiving concomitant CYP3A4 inducers or strong CYP3A4 inhibitors
- Impairment of gastrointestinal function or gastrointestinal disease that may
significantly alter the absorption of cabozantinib (e.g., malabsorptive disorder,
ulcerative disease, uncontrolled nausea, vomiting, diarrhea, or small bowel
resection).
- Any of the following laboratory test findings:
1. WBC <2,000/mm3
2. Hemoglobin ≤9.0 g/dL
3. Neutrophils <1,500/mm3
4. Platelets <100,000/mm3
5. AST or ALT >3 x ULN (>5 x ULN if liver metastases are present)
6. Lipase and amylase > 1.5 ULN
7. Total Bilirubin >1.5 x ULN (except subjects with Gilbert Syndrome, who can have
total bilirubin <3.0 mg/dL)
8. Serum creatinine >1.5 x ULN or creatinine clearance <40 mL/min (measured or
calculated by Cockroft-Gault formula)
9. Proteinuria: patients with ≥2+ protein on urine dipstick at baseline must undergo
a 24-hour urine collection for protein then if > 1.0 g of protein patient will
not be included.
