A Phase 2 BIOmarker Driven Trial With Nivolumab and Ipilimumab or VEGFR tKi in Naïve Metastatic Kidney Cancer
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- 入组人数
- 200
- 试验地点
- 16
- 主要终点
- ORR evaluation according to molecular groups (ccRCC1 to 4) and assigned treatment
研究概览
简要总结
Disease and Stage: naïve metastatic kidney cancer.
A multicenter, randomized, a Phase 2 BIOmarker driven trial with Nivolumab and Ipilimumab or VEGFR tKi in naïve metastatic Kidney cancer
详细描述
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):
- ARM A: nivolumab alone administered IV over 60 minutes at 240 mg every 2 weeks (molecular group 1 and 4).
- ARM B : 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 240 mg every 2 weeks
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
排除标准
- •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:
- •WBC <2,000/mm3
- •Hemoglobin ≤9.0 g/dL
- •Neutrophils <1,500/mm3
- •Platelets <100,000/mm3
- •AST or ALT >3 x ULN (>5 x ULN if liver metastases are present)
- •Lipase and amylase > 1.5 ULN
- •Total Bilirubin >1.5 x ULN (except subjects with Gilbert Syndrome, who can have total bilirubin <3.0 mg/dL)
- •Serum creatinine >1.5 x ULN or creatinine clearance <40 mL/min (measured or calculated by Cockroft-Gault formula)
- •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.
研究组 & 干预措施
ccRCC molecular subgroup 1: 1A
ccRCC molecular subgroup 1 -> randomisation: subjects with ccRCC1 treated with nivolumab 240mg IV every 2 weeks until disease progression, unacceptable toxicity or other reasons specified in the protocol.
Starting from the Cycle 7 possibility to switch from nivolumab 240 mg every 2 weeks to 480 mg every 4 weeks according to the Investigator's preference.
干预措施: Nivolumab (Drug)
ccRCC molecular subgroup 1: 1B
ccRCC molecular subgroup 1 -> randomisation: subjects with ccRCC1 treated with nivolumab 3 mg/kg IV combined with ipilimumab 1 mg/kg IV every 3 weeks for 4 doses then nivolumab 240mg IV every 2 weeks until disease progression, unacceptable toxicity or other reasons specified in the protocol.
Starting from the Cycle 7 possibility to switch from nivolumab 240 mg every 2 weeks to 480 mg every 4 weeks according to the Investigator's preference.
干预措施: Nivolumab (Drug)
ccRCC molecular subgroup 1: 1B
ccRCC molecular subgroup 1 -> randomisation: subjects with ccRCC1 treated with nivolumab 3 mg/kg IV combined with ipilimumab 1 mg/kg IV every 3 weeks for 4 doses then nivolumab 240mg IV every 2 weeks until disease progression, unacceptable toxicity or other reasons specified in the protocol.
Starting from the Cycle 7 possibility to switch from nivolumab 240 mg every 2 weeks to 480 mg every 4 weeks according to the Investigator's preference.
干预措施: Ipilimumab (Drug)
ccRCC molecular subgroup 4: 4A
ccRCC molecular subgroup 4 -> randomisation: subjects with ccRCC1 treated with nivolumab 240mg IV every 2 weeks until disease progression, unacceptable toxicity or other reasons specified in the protocol.
Starting from the Cycle 7 possibility to switch from nivolumab 240 mg every 2 weeks to 480 mg every 4 weeks according to the Investigator's preference.
干预措施: Nivolumab (Drug)
ccRCC molecular subgroup 4: 4B
ccRCC molecular subgroup 4 -> randomisation: subjects with ccRCC1 treated with nivolumab 3 mg/kg IV combined with ipilimumab 1 mg/kg IV every 3 weeks for 4 doses then nivolumab 240mg IV every 2 weeks until disease progression, unacceptable toxicity or other reasons specified in the protocol.
Starting from the Cycle 7 possibility to switch from nivolumab 240 mg every 2 weeks to 480 mg every 4 weeks according to the Investigator's preference.
干预措施: Nivolumab (Drug)
ccRCC molecular subgroup 4: 4B
ccRCC molecular subgroup 4 -> randomisation: subjects with ccRCC1 treated with nivolumab 3 mg/kg IV combined with ipilimumab 1 mg/kg IV every 3 weeks for 4 doses then nivolumab 240mg IV every 2 weeks until disease progression, unacceptable toxicity or other reasons specified in the protocol.
Starting from the Cycle 7 possibility to switch from nivolumab 240 mg every 2 weeks to 480 mg every 4 weeks according to the Investigator's preference.
干预措施: Ipilimumab (Drug)
ccRCC molecular subgroup 2: 2C
ccRCC molecular subgroup 2 -> randomisation: TKI (sunitinib 50mg daily or Pazopanib 800mg daily) according to investigator's choice until disease progression, unacceptable toxicity or other reasons specified in the protocol.
干预措施: Pazopanib (Drug)
ccRCC molecular subgroup 2: 2C
ccRCC molecular subgroup 2 -> randomisation: TKI (sunitinib 50mg daily or Pazopanib 800mg daily) according to investigator's choice until disease progression, unacceptable toxicity or other reasons specified in the protocol.
干预措施: Sunitinib (Drug)
ccRCC molecular subgroup 2: 2B
ccRCC molecular subgroup 2 -> randomisation: subjects with ccRCC1 treated with nivolumab 3 mg/kg IV combined with ipilimumab 1 mg/kg IV every 3 weeks for 4 doses then nivolumab 240mg IV every 2 weeks until disease progression, unacceptable toxicity or other reasons specified in the protocol.
Starting from the Cycle 7 possibility to switch from nivolumab 240 mg every 2 weeks to 480 mg every 4 weeks according to the Investigator's preference.
干预措施: Nivolumab (Drug)
ccRCC molecular subgroup 2: 2B
ccRCC molecular subgroup 2 -> randomisation: subjects with ccRCC1 treated with nivolumab 3 mg/kg IV combined with ipilimumab 1 mg/kg IV every 3 weeks for 4 doses then nivolumab 240mg IV every 2 weeks until disease progression, unacceptable toxicity or other reasons specified in the protocol.
Starting from the Cycle 7 possibility to switch from nivolumab 240 mg every 2 weeks to 480 mg every 4 weeks according to the Investigator's preference.
干预措施: Ipilimumab (Drug)
ccRCC molecular subgroup 3: 3B
ccRCC molecular subgroup 3 -> randomisation: subjects with ccRCC1 treated with nivolumab 3 mg/kg IV combined with ipilimumab 1 mg/kg IV every 3 weeks for 4 doses then nivolumab 240mg IV every 2 weeks until disease progression, unacceptable toxicity or other reasons specified in the protocol.
Starting from the Cycle 7 possibility to switch from nivolumab 240 mg every 2 weeks to 480 mg every 4 weeks according to the Investigator's preference.
干预措施: Nivolumab (Drug)
ccRCC molecular subgroup 3: 3B
ccRCC molecular subgroup 3 -> randomisation: subjects with ccRCC1 treated with nivolumab 3 mg/kg IV combined with ipilimumab 1 mg/kg IV every 3 weeks for 4 doses then nivolumab 240mg IV every 2 weeks until disease progression, unacceptable toxicity or other reasons specified in the protocol.
Starting from the Cycle 7 possibility to switch from nivolumab 240 mg every 2 weeks to 480 mg every 4 weeks according to the Investigator's preference.
干预措施: Ipilimumab (Drug)
ccRCC molecular subgroup 3: 3C
ccRCC molecular subgroup 3 -> randomisation: TKI (sunitinib 50mg daily or Pazopanib 800mg daily) according to investigator's choice until disease progression, unacceptable toxicity or other reasons specified in the protocol.
干预措施: Pazopanib (Drug)
ccRCC molecular subgroup 3: 3C
ccRCC molecular subgroup 3 -> randomisation: TKI (sunitinib 50mg daily or Pazopanib 800mg daily) according to investigator's choice until disease progression, unacceptable toxicity or other reasons specified in the protocol.
干预措施: Sunitinib (Drug)
结局指标
主要结局
ORR evaluation according to molecular groups (ccRCC1 to 4) and assigned treatment
时间窗: 54 months
ORR evaluation according to molecular groups (ccRCC1 to 4) and assigned treatment (nivolumab monotherapy, nivolumab combined with ipilimumab, or TKI: sunitinib or pazopanib), based on Investigator assessments.
次要结局
- Progression-free survival (PFS)(54 months)
- Functional status of peripheral blood lymphocytes (PBL)(at baseline, at cycle 2 and at progression (36 months maximum))
- Duration of response (DOR)(54 months)
- Number of Participants With Treatment-Related Adverse Events(54 months)
- Gene expression levels obtained from FFPE(at the end of the study (36 months))
- Gene expression of immune population markers(at baseline at progression (36 months maximum))
- Association between non-immune tissue and circulating biomarkers and outcomes(36 months maximum)
- Overall Survival(54 months)
- Objective response rate at 22 weeks(at 22 weeks)
- Duration of treatment (DOT)(54 months)
- Mutation and methylation analysis of circulating tumor DNA(36 months maximum)
- Genetic and epigenetic alterations(36 months maximum)
- association between immune cells composing tumor microenvironment and response and/or resistance(36 months maximum)
- additional genetic and epigenetic tumor alterations(36 months maximum)