Phase III Randomized Sequential Open-label Study to Evaluate the Efficacy and Safety of Sorafenib Followed by Pazopanib Versus Pazopanib Followed by Sorafenib in the Treatment of Advanced / Metastatic Renal Cell Carcinoma
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 发起方
- 入组人数
- 544
- 试验地点
- 70
- 主要终点
- To evaluate if progression-free survival from randomization to progression or death during second-line therapy (Total PFS) of sorafenib followed by pazopanib is non-inferior compared to pazopanib followed by sorafenib.
研究概览
简要总结
Sorafenib and pazopanib are both effective and promising treatments for advanced Renal Cell Carcinoma (RCC). Both drugs are registered for this indication. No prospective comparative data in advanced RCC (or other indications) have been published. A search in the clinicaltrials.gov database did not reveal any planned or ongoing studies. As sequential therapy is now the standard of treatment for advanced RCC it is important to evaluate in clinical trials what the value of different sequential strategies is. This needs to be done every time new agents are introduced into the treatment armamentarium. As there are no data yet on the sequential use of sorafenib followed by pazopanib or vice versa, this sequence, however, will most certainly be used in daily practice, it is required to examine efficacy and safety of this sequential approach in a clinical trial in a randomized setting.
Therefore, the investigators have designed an open randomized study in patients not previously treated for advanced RCC. Suitable patients will be randomized (1:1) in 2 groups.
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 85 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patients with metastatic / advanced RCC (all histologies), who are not suitable for cytokine therapy and for whom study medication constitutes first-line treatment. For cytokine- unsuitability at least one of the following criteria must be fulfilled*:
- •Age 66 to 88 years
- •Non-clear cell histology RCC
- •Intermediate risk according to MSKCC score
- •ECOG ≥ 1 and> 1 organ metastasis + < 24 months between diagnosis and establishing indication for interleukin-2-therapy
- •ECOG ≥ 1 and "unable to carry on normal activity or do active work" (Karnofsky Index 70%)
- •Creatinine ≥ 1x ULN and < 2x ULN
- •Total bilirubin ≥ 1x ULN and < 1.5x ULN
- •Present autoimmune disease
- •Patients who might require steroids
- •Hypersensitivity against cytokines
- •Severe organic disease, not interfering with other in-/exclusion criteria of the Switch-2 study
- •Non-symptomatic brain metastases
- •Severe lung disease (e.g. PAH, COPD) with Pa O2 < 60 mmHg on rest
- •Age ≥ 18 and ≤ 85 years
- •Karnofsky Index ≥ 70% (see appendix 15.1)
- •MSKCC prognostic score (2004), low or intermediate (see appendix 15.2)
- •Life expectancy of at least 12 weeks
- •Subjects with at least one uni-dimensional (for RECIST 1.1) measurable lesion. Lesions must be measured by CT/MRI- scan
- •Adequate bone marrow, liver and renal function as assessed by the following laboratory requirements to be conducted within 7 days prior to start of therapy:
- •hemoglobin > 9.0 g/dl
- •absolute neutrophil count (ANC) > 1,500 µl
- •Platelet count ≥ 100,000 / µl
- •total bilirubin < 1.5x the upper limit of normal (Note: Subjects with Gilbert' Syndrome are eligible if their total bilirubin is < 3.0 X ULN and direct bilirubin ≤ 35 %).
- •ALAT and ASAT < 2.5x upper limit of normal (Note: concomitant elevations in bilirubin ans ASAT/ALAT above 1.0x upper limit of normal are not permitted).
- •Alkaline phosphatase < 4x upper limit of normal
- •PT-INR/aPTT < 1.2x upper limit of normal (Patients who are being therapeutically anticoagulated with an agent such as coumadin or heparin will be allowed to participate provided that their INR is stable and within the recommended range for the desired level of anticoagulation and no prior evidence of underlying abnormality in these parameters exists).
- •Serum creatinine < 2x upper limit of normal
- •Written Informed Consent
排除标准
- •History of cardiac disease: congestive heart failure > NYHA class 2 or with LVEF at baseline echocardiography < 50%, (echocardiography is optional); active CAD (MI more than 6 months prior to study entry is allowed); cardiac arrhythmias requiring anti-arrhythmic therapy (beta blockers or digoxin are permitted)
- •Uncontrolled hypertension (defined as blood pressure ≥ 150 mmHg systolic and/or ≥ 90 mmHg diastolic on medication).
- •History of HIV infection or chronic hepatitis B or C
- •Active clinically serious infections (> grade 2 NCI-CTC version 4.03)
- •Symptomatic metastatic brain or meningeal tumors (unless the patient is > 6 months from definitive therapy, has a negative imaging study within 4 weeks of study entry and is clinically stable with respect to the tumor at the time of study entry)
- •Patients with seizure disorder requiring medication (such as steroids or anti-epileptics)
- •Patients with evidence or history of bleeding diathesis
- •History of organ allograft
- •Major surgery within 4 weeks of start of study
- •Autologous bone marrow transplant or stem cell rescue within 4 months before study start.
- •Any significant condition that increases the risk for bleeding, including, but not limited to active peptic ulcer disease, inflammatory bowel disease, known intraluminal or endobronchial metastatic lesions and/or lesions infiltrating major pulmonary vessels with risk of bleeding, presence of non-healing wound or trauma within 4 weeks prior to first dose of investigational drug
- •History of cerebrovascular accident including transient ischemic attack (TIA), pulmonary embolism or untreated deep vein thrombosis (DVT) within the past 6 months (Note: Subjects with recent DVT who have been treated with therapeutic anti-coagulating agents for at least 6 weeks are eligible)
- •Corrected QT Interval (QTc) > 480 msecs
- •Untreated hypothyroidism
- •Patients undergoing renal dialysis
- •Previous or concurrent cancer that is distinct in primary site or histology from the cancer being evaluated in this study EXCEPT cervical carcinoma in situ, treated basal cell carcinoma, superficial bladder tumors [Ta, Tis & T1] or any cancer curatively treated > 3 years prior to study entry
- •Pregnant or breast-feeding patients. Women of childbearing potential must have a negative pregnancy test performed within 7 days of the start of treatment. Both men and women enrolled in this trial must use adequate barrier birth control measures (with a Pearl Index < 1) during the course of the trial and 3 months after the completion of trial
- •Substance abuse, medical, psychological or social conditions that may interfere with the patient's participation in the study or evaluation of the study results
- •Any condition that is unstable or could jeopardize the safety of the patient and their compliance in the study
- •Patients unable to swallow oral medications
- •Clinically significant gastrointestinal abnormalities that may affect absorption of investigational product
- •Known allergy to Votrient or Nexavar (i.e. to active substance or one of the constituents)
- •Prior exposure to study drugs.
- •Investigational drug therapy within 4 weeks of study entry.
- •Use of biologic response modifiers, such as G-CSF and other hematopoietic growth factors, within 3 weeks of study entry
- •Radiotherapy within 3 weeks of start of study drug and planned radiotherapy during the study
- •Concomitant medication: Any condition at the discretion of the investigator that precludes compliance with concomitant therapy restrictions described below.
研究组 & 干预措施
Sorafenib followed by pazopanib
Sorafenib 400 mg bid orally until progression or intolerable toxicity, followed by pazopanib 800 mg once daily orally until progression or intolerable toxicity.
During first- and second-line, treatment visits are scheduled in weeks 0,2,4,8,12, and every 4 weeks thereafter, with tumor assessments and electrocardiogram after every second cycle (every 8 weeks).
干预措施: Sorafenib+Pazopanib (Drug)
Pazopanib followed by Sorafenib
Pazopanib 800 mg once daily orally until progression or intolerable toxicity, followed by Sorafenib 400 mg bid orally until progression or intolerable toxicity:
During first- and second-line, treatment visits are scheduled in weeks, 0,2,4,8,12, and every 4 weeks thereafter, with tumor assessments and electrocardiogram after every second cycle (every 8 weeks).
干预措施: Pazopanib+Sorafenib (Drug)
结局指标
主要结局
To evaluate if progression-free survival from randomization to progression or death during second-line therapy (Total PFS) of sorafenib followed by pazopanib is non-inferior compared to pazopanib followed by sorafenib.
时间窗: 4 years
次要结局
- Time from randomization to progression during second-line therapy (total TTP)(1 year)
- Health-related Quality of Life (FACIT-F, FKSI-10)(4 years)
- Biomarker programme(4 years)
- Safety and tolerability(4 years)
- Time to first-line treatment failure (progression, death, discontinuation due to toxicity) descriptively in each arm(1 year)
- PFS in first-line and second-line treatment, descriptively(4 years)
- Overall survival, descriptively (data cut-off same as for primary endpoint(4 years)
- Disease Control Rate (DCR); Response rates in first-line and in second-line (CR, PR, SD according to RECIST criteria)(4 years)