Short TeRm Intensified Pembrolizumab (KEytruda) and Tivozanib for High-Risk Renal Cell Carcinoma - STRIKE
试验速览
- 阶段
- 3 期
- 状态
- 招募中
- 入组人数
- 1,040
- 试验地点
- 782
- 主要终点
- Disease-free survival (DFS)
研究概览
简要总结
This phase III trial compares the effect of adding tivozanib to standard therapy pembrolizumab versus pembrolizumab alone for the treatment of patients with high-risk renal cell carcinoma (RCC). Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Tivozanib is in a class of medications called kinase inhibitors. It works by blocking the action of the abnormal protein that signals tumor cells to multiply. This helps stop the spread of tumor cells. Giving pembrolizumab and tivozanib together may work better than pembrolizumab alone in treating patients with RCC.
详细描述
PRIMARY OBJECTIVE:
I. To compare disease free survival (DFS) as assessed by the investigator for high-risk renal cell carcinoma patients treated with adjuvant pembrolizumab and tivozanib versus those receiving pembrolizumab alone.
SECONDARY OBJECTIVES:
I. To compare overall survival (OS) for patients treated with adjuvant pembrolizumab and tivozanib versus those receiving pembrolizumab alone.
II. To assess adverse events in each study arm by Common Terminology Criteria for Adverse Events (CTCAE) 5.0.
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
- •• Histologically confirmed diagnosis of RCC with clear cell component with or without sarcomatoid features following complete resection of the primary tumor (radical or partial nephrectomy)
- •Note: Patients with microscopically positive soft tissue or vascular margins without gross residual disease are permitted
- •Intermediate-high risk RCC:
- •pT2 grade 4 or sarcomatoid features, N0M0
- •pT3 any grade N0, M0
- •High-risk RCC
- •pT4, any grade, N0, M0
- •pT, any stage., any grade, N+, M0
- •cM1 no evidence of disease (NED) RCC
- •Participants who have had resection of primary tumor (radical or partial nephrectomy) and resection or definitive radiation or ablation of solid, isolated, soft tissue metastases (excluding brain and bone lesions) at the time of primary tumor removal (synchronous) or ≤1 year from primary tumor removal (metachronous)
- •Surgery (radical or partial nephrectomy or metastasectomy or ablation) > 4 weeks but =< 16 weeks prior to study registration with no ongoing complications from surgery
- •No evidence of disease at time of randomization as assessed by investigator by either CT or MRI scan of the brain and chest, abdomen and pelvis
- •No prior systemic treatment for RCC
- •Age >= 18 years
- •Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (or Karnofsky >= 60%)
- •Absolute neutrophil count (ANC) >= 1,000/mm^3
- •Platelet count >= 100,000/mm^3
- •Hemoglobin >= 8 g/dL
- •Total bilirubin =< 3 x upper limit of normal (ULN)
- •Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 x upper limit of normal (ULN)
- •Calculated (calc.) creatinine clearance >= 30 mL/min (using Cockcroft Gault equation or the estimated glomerular filtration rate from the modification of diet in renal disease trial)
- •Urine protein =< 1+ on urine analysis (UA) or urine protein creatinine ration (UPCR) < 2mg/mg
- •Not pregnant and not nursing, because this study involves an agent that has known genotoxic, mutagenic and teratogenic effects. Therefore, for women of childbearing potential only, a negative pregnancy test is required =< 14 days prior to registration
- •HIV status: HIV-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial
- •Hepatitis
- •Hepatitis B: For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated. Patients with resolved HBV infection, defined as positive hepatitis B core antibody (anti-HBc) and negative hepatitis B surface antigen (HbsAg), are eligible
- •Hepatitis C: Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load
- •Cardiac Disease: Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class IIB or better
- •No history of myocarditis
- •No history of clinically significant pneumonitis
- •No uncontrolled hypertension (systolic blood pressure [BP] > 150 mm Hg or diastolic BP > 90 mm Hg) documented on 2 consecutive measurements taken at least 2 hours apart
- •No serious non-healing wound, ulcer or bone fracture within 28 days prior to registration
- •No serious/active infection requiring parenteral antibiotics
- •No moderate or severe hepatic impairment (child-Pugh B or C)
- •No significant bleeding disorders within 1 month prior to registration, for example:
- •Hematemesis, hematochezia or other gastrointestinal bleeding grade 3 or higher
- •Hemoptysis of pulmonary bleeding grade 3 or higher
- •Hematuria or other genitourinary bleeding grade 3 or higher
- •No history of allogeneic organ transplantation
- •No history of allergy of hypersensitivity to study drugs or components
- •No condition requiring systemic treatment with either corticosteroid (> 10 mg daily or prednisone equivalent) within 14 days of treatment initiation or other immunosuppressive medications within 30 days of randomization. Inhaled or topical steroids and adrenal replacement doses ≤10 mg daily prednisone equivalent are permitted in absence of active autoimmune disease
- •No active peptic ulcer disease, inflammatory bowel disease, ulcerative colitis or other gastrointestinal condition associated with increased risk of perforation; history of abdominal fistula, gastrointestinal perforation or intra-abdominal abscess within 4 weeks prior to registration
- •Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial
- •No patients with a history of autoimmune disease that has required systemic treatment in the past 2 years (i.e., with use of disease modifying agents, corticosteroids > 10 mg/day, or immunosuppressive drugs) with the following exceptions:
- •Replacement therapy (e.g., thyroxine, insulin, physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is allowed
- •Brief (<7 days) use of systemic corticosteroids is allowed when use is considered standard of care
- •Patients with vitiligo, psoriasis, type 1 diabetes mellitus, hypothyroidism, or resolved childhood asthma/atopy will not be excluded
- •Patients requiring intermittent use of bronchodilators, inhaled steroids, or local steroid injections will not be excluded
- •Patients with hypothyroidism that is stable with hormone replacement or Sjögren's syndrome will not be excluded • Chronic concomitant treatment with strong CYP3A4 inducers is not allowed. Patients must discontinue the drug 14 days prior to the start of study treatment
排除标准
- 未提供
研究组 & 干预措施
Arm 2 (pembrolizumab + tivozanib)
Patients receive pembrolizumab IV on days 1 and 43 of each cycle and tivozanib PO QD on days 1-21, days 29-49, and days 57-77 of each cycle for up to 6 months. Cycles repeat every 12 weeks for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo blood sample collection and MRI or CT throughout the trial and may undergo tissue biopsy on study.
干预措施: Pembrolizumab (Biological)
Arm 2 (pembrolizumab + tivozanib)
Patients receive pembrolizumab IV on days 1 and 43 of each cycle and tivozanib PO QD on days 1-21, days 29-49, and days 57-77 of each cycle for up to 6 months. Cycles repeat every 12 weeks for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo blood sample collection and MRI or CT throughout the trial and may undergo tissue biopsy on study.
干预措施: MRI (Procedure)
Arm 2 (pembrolizumab + tivozanib)
Patients receive pembrolizumab IV on days 1 and 43 of each cycle and tivozanib PO QD on days 1-21, days 29-49, and days 57-77 of each cycle for up to 6 months. Cycles repeat every 12 weeks for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo blood sample collection and MRI or CT throughout the trial and may undergo tissue biopsy on study.
干预措施: Computed Tomography (Procedure)
Arm 1 (Pembrolizumab)
Patients receive pembrolizumab IV on days 1 and 43 of each cycle, or on days 1, 22, 43 and 64 of each cycle. Cycles repeat every 12 weeks for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo blood sample collection and MRI or CT throughout the trial and may undergo tissue biopsy on study.
干预措施: Biospecimen Collection (Procedure)
Arm 2 (pembrolizumab + tivozanib)
Patients receive pembrolizumab IV on days 1 and 43 of each cycle and tivozanib PO QD on days 1-21, days 29-49, and days 57-77 of each cycle for up to 6 months. Cycles repeat every 12 weeks for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo blood sample collection and MRI or CT throughout the trial and may undergo tissue biopsy on study.
干预措施: Biopsy (Procedure)
Arm 1 (Pembrolizumab)
Patients receive pembrolizumab IV on days 1 and 43 of each cycle, or on days 1, 22, 43 and 64 of each cycle. Cycles repeat every 12 weeks for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo blood sample collection and MRI or CT throughout the trial and may undergo tissue biopsy on study.
干预措施: Computed Tomography (Procedure)
Arm 1 (Pembrolizumab)
Patients receive pembrolizumab IV on days 1 and 43 of each cycle, or on days 1, 22, 43 and 64 of each cycle. Cycles repeat every 12 weeks for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo blood sample collection and MRI or CT throughout the trial and may undergo tissue biopsy on study.
干预措施: Biopsy (Procedure)
Arm 2 (pembrolizumab + tivozanib)
Patients receive pembrolizumab IV on days 1 and 43 of each cycle and tivozanib PO QD on days 1-21, days 29-49, and days 57-77 of each cycle for up to 6 months. Cycles repeat every 12 weeks for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo blood sample collection and MRI or CT throughout the trial and may undergo tissue biopsy on study.
干预措施: Biospecimen Collection (Procedure)
Arm 1 (Pembrolizumab)
Patients receive pembrolizumab IV on days 1 and 43 of each cycle, or on days 1, 22, 43 and 64 of each cycle. Cycles repeat every 12 weeks for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo blood sample collection and MRI or CT throughout the trial and may undergo tissue biopsy on study.
干预措施: MRI (Procedure)
Arm 1 (Pembrolizumab)
Patients receive pembrolizumab IV on days 1 and 43 of each cycle, or on days 1, 22, 43 and 64 of each cycle. Cycles repeat every 12 weeks for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo blood sample collection and MRI or CT throughout the trial and may undergo tissue biopsy on study.
干预措施: Questionnaire Administration (Other)
Arm 2 (pembrolizumab + tivozanib)
Patients receive pembrolizumab IV on days 1 and 43 of each cycle and tivozanib PO QD on days 1-21, days 29-49, and days 57-77 of each cycle for up to 6 months. Cycles repeat every 12 weeks for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo blood sample collection and MRI or CT throughout the trial and may undergo tissue biopsy on study.
干预措施: Questionnaire Administration (Other)
Arm 1 (Pembrolizumab)
Patients receive pembrolizumab IV on days 1 and 43 of each cycle, or on days 1, 22, 43 and 64 of each cycle. Cycles repeat every 12 weeks for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo blood sample collection and MRI or CT throughout the trial and may undergo tissue biopsy on study.
干预措施: Pembrolizumab (Biological)
Arm 2 (pembrolizumab + tivozanib)
Patients receive pembrolizumab IV on days 1 and 43 of each cycle and tivozanib PO QD on days 1-21, days 29-49, and days 57-77 of each cycle for up to 6 months. Cycles repeat every 12 weeks for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo blood sample collection and MRI or CT throughout the trial and may undergo tissue biopsy on study.
干预措施: Tivozanib (Drug)
结局指标
主要结局
Disease-free survival (DFS)
时间窗: From time of randomization until disease recurrence or death, assessed up to 10 years
The primary analysis will be a comparison of DFS between the two study arms using a stratified log-rank test. The treatment effect will be estimated with a hazard ratio (HR) and corresponding 95% confidence interval obtained from a stratified Cox model with treatment group (experimental group versus control group) as the explanatory variable. Interim analyses: There will be several futility analyses for the trial. These analyses will employ the linear 20% method proposed by Freidlin, Korn and Gray. Based on the current design parameters, the first analysis would be performed at 37% information (99 DFS events), and the trial would be stopped for futility if the observed hazard ratio (experimental versus \[vs.\] control) were worse than 1. Additional analyses will be performed at 50% (133 DFS events), 60% (159 DFS events), and 70% information (186 DFS events), the trial would be stopped for futility if the observed HR were worse than 0.983, 0.971 and 0.959, respectively.
次要结局
- Overall survival (OS)(From time of randomization until death, assessed up to 10 years)
- Incidence of adverse events (AEs)(From baseline to 10 years after registration)
- Proportion of patients that tolerate pembrolizumab and tivozanib(From day 1 to 6 months)