Naïve metastatic Kidney cancer(mRCC)
Conditions
Interventions
Trade Name: Yervoy
Product Name: Ipilimumab-40 ml vial
Product Code: BMS-734016
Pharmaceutical Form: Concentrate for solution for infusion
Trade Name: Opdivo
Product Name: Nivolumab-10 ml vial
Produc
Sponsors
A.R.T.I.C (Association pour la Recherche de Thérapeutiques Innovantes en Cancérologie)
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: •Histological confirmation of RCC with a clear-cell component •Metastatic (American Joint Committee on Cancer [AJCC] Stage IV) RCC •No prior systemic therapy for mRCC (patients with relapse >1 year after adjuvant treatment discontinuation are eligible) •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 or fresh tumor samples immediately stored in “RNA later” medium (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. •Recent (=65 years) yes F.1.3.1 Number of subjects for this age range 100
Exclusion criteria
Exclusion criteria: •Any untreated CNS metastases. Patients with CNS metastases will be eligible if they are: asymptomatic, without significant edema, 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 / 3vRR. •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. •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 he
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To evaluate the ORR according to molecular subgroups (ccRCC1 to 4) and assigned treatment (nivolumab monotherapy, nivolumab combined with ipilimumab, or TKI: sunitinib or pazopanib), based on Investigator assessments.;Secondary Objective: •To evaluate PFS •To evaluate OS •To evaluate ORR at 22 weeks •To evaluate DOT and DOR •To estimate the incidence of AEs associated with nivolumab combined with ipilimumab or nivolumab alone or TKI •To evaluate the association between exploratory biomarkers and outcomes (ORR and PFS) •Exploratory biomarkers include: gene and protein expression of immune populations and regulatory markers within the primary tumor, and metastases whenever possible, using frozen and FFPE tumor tissue •To assess gene expression of immune population markers (T-cell chemotaxis, T-cell activation, inhibition, inflammation) in the primary tumor as well as in the metastases before beginning treatment, and at progression if safely achievable •Gene expression levels obtained from FFPE tumor tissue (exploratory method) will be compared to those obtained with frozen tumor tissue (standard method) •To assess the functional status of PBL by flow cytometry, at baseline,at cycle2 and at progression;Primary end point(s): Investigator-assessed ORR is defined as the proportion of randomized subjects who achieve a best overall response (BOR) of complete response (CR) or partial response (PR) using RECIST 1.1 criteria based on Investigator assessments.;Timepoint(s) of evaluation of this end point: Subjects will be assessed for response by computed tomography (CT) or magnetic resonance imaging (MRI) beginning at 10 weeks (±1 week) after randomization and continuing every 12 weeks (±1 week) until progression or treatment discontinuation, whichever occurs first. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Progression-free Survival The primary definition of PFS is specified as the time between randomization to the first date of documented progression, based on Investigator radiological assessments (as per RECIST 1.1 criteria), or death due to any cause, whichever occurs first. Subjects who die without a reported progression will be considered to have progressed on the date of their death. Overall Survival OS is defined as the time from randomization to the date of death from any cause. For subjects that are alive, their survival time will be censored at the date of last contact (“last known alive date”). Objective response rate at 22 weeks ORR at 22 weeks as defined as percentage of patients with an objective response (decrease of SLD by at least 30%) at second CT or MRI after treatment initiation. Duration of treatment Duration of treatment (DOT) is defined as the time between treatment initiation and discontinuation for any reason or End of study. Duration of response Duration of response (DOR) is defined as the time between response to treatment and discontinuation for any reason or End of study. AE Incidence Rate The AE incident rate is defined as the proportion of subjects with any-grade AEs among subjects in each treatment arm. Events reported from the first dose, up to and including 100 days following the last dose of study treatment will be included in calculating this incidence rate. Exploratory biomarkers will be correlated with outcome endpoints ;Timepoint(s) of evaluation of this end point: Biomarkers will be assessed at pre-treatement, at cycle 2 and at progression AEs assessement continuously | — |
Countries
France
Contacts
Public ContactSponsor
A.R.T.I.C (Association pour la Recherche de Thérapeutiques Innovantes en Cancérologie)
Outcome results
None listed