A Randomized, Double-blind, Placebo-controlled Phase III Study to Evaluate the Efficacy and Safety of Pazopanib as Adjuvant Therapy for Subjects With Localized or Locally Advanced RCC Following Nephrectomy
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 1,538
- 试验地点
- 1
- 主要终点
- Disease-free Survival (DFS) With Pazopanib 600 mg Daily Initial Dose vs. Placebo
研究概览
简要总结
This randomized Phase III study is to evaluate whether pazopanib compared with placebo can prevent or delay recurrence of kidney cancer in patients with moderately high or high risk of developing recurrence after undergoing kidney cancer surgery.
详细描述
The primary objective of this ongoing study was to evaluate DFS with pazopanib 600 mg daily initial dose as compared with placebo as adjuvant therapy for subjects with localized/locally advanced RCC following nephrectomy.
Subjects with locally recurrent renal cell carcinoma (RCC), bilateral RCC, or history of another malignancy were excluded from enrolling in the study.
The study was comprised of three successive study periods: 1) the Screening/Baseline period, 2) the study treatment period, and 3) the DFS /OS follow-up period. The Screening/Baseline period had a maximum duration of 12 weeks from the date of nephrectomy to the date of randomization.
After a subject met all the eligibility criteria and completed all the required baseline assessments, the subject was randomized in a 1:1 ratio to receive once daily blinded treatment with either pazopanib 600 mg as initial dose or matching placebo based on pre-defined stratification factors.
Subjects received continuous daily treatment until completion of the 12-month treatment period, disease recurrence, or unacceptable toxicity/intolerance. Subsequent adjuvant therapies for RCC were not allowed. During the study treatment and DFS follow-up periods, subjects received routine safety and efficacy assessments.
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
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
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
- •Signed written informed consent
- •Diagnosis of RCC with clear-cell or predominant clear-cell histology
- •Subjects with non-metastatic disease (M0) fulfilling any of the following combinations of pathologic staging based on American Joint Committee on Cancer (AJCC) TNM staging version 2010 and Fuhrman nuclear grading.
- •pT2, G3 or G4, N0; or,
- •pT3, G any, N0; or,
- •pT4, G any, N0; or,
- •pT any, G any, N1
- •Fulfill all of the following criteria of disease-free status at baseline:
- •Had complete gross surgical resection of all RCC via radical or partial nephrectomy using either open or laparoscopic technique.
- •Baseline imaging of chest, abdomen and pelvis shows no metastasis or residual tumor lesions as confirmed centrally by an independent radiologist.
- •Received no prior adjuvant or neo-adjuvant treatment for RCC
- •Recovered from nephrectomy: any surgery related toxicities should be reduced to ≤ grade 1 per NCI Common Terminology Criteria for Adverse Events (CTCAE) (Version 4)
- •Karnofsky performance scale (KPS) of ≥ 80
- •Adequate organ system function
排除标准
- •History of another malignancy. Exception: Subjects who have had another malignancy and have been disease-free for 5 years, or subjects with a history of completely resected non-melanomatous skin carcinoma or successfully treated in situ carcinoma are eligible
- •Clinically significant gastrointestinal abnormalities that may increase the risk for gastrointestinal bleeding including, but not limited to:
- •Active peptic ulcer disease
- •Inflammatory bowel disease (e.g. ulcerative colitis, Crohn's disease), or other gastrointestinal conditions with increased risk of perforation
- •History of abdominal fistula, gastrointestinal perforation, or intra abdominal abscess within 28 days prior to beginning study treatment
- •Active diarrhea of any grade
- •Clinically significant gastrointestinal abnormalities that may affect absorption of investigational product including, but not limited to:
- •Malabsorption syndrome
- •Major resection of the stomach or small bowel
- •History of human immunodeficiency virus (HIV) infection
- •History of active hepatitis
- •Presence of uncontrolled infection.
- •History of any one or more of the following cardiovascular conditions within the past 6 months:
- •Cardiac angioplasty or stenting
- •Myocardial infarction
- •Unstable angina
- •Coronary artery bypass graft surgery
- •Symptomatic peripheral vascular disease
- •History of Class III or IV congestive heart failure, as defined by the New York Heart Association Classification of Congestive Heart Failure
- •History of cerebrovascular accident including transient ischemic attack (TIA), pulmonary embolism or untreated deep venous thrombosis (DVT) within the past 6 months.
- •Corrected QT interval (QTc) > 480 milliseconds (msec)
- •Poorly controlled hypertension, defined as systolic blood pressure (SBP) of ≥140 mmHg or diastolic blood pressure (DBP) of ≥ 90mmHg.
- •Note: Initiation or adjustment of antihypertensive medication(s) is permitted prior to study entry. Blood pressure (BP) must be re-assessed on two occasions that are separated by a minimum of 1 hour; on each of these occasions, the mean (of 3 readings) SBP / DBP values from each BP assessment must be <140/90 mmHg in order for a subject to be eligible for the study (see Section 7.6.2 for instruction on blood pressure measurement and obtaining mean blood pressure values).
- •Evidence of active bleeding or bleeding diathesis
- •Any serious and/or unstable pre-existing medical, psychiatric, or other condition that could interfere with subject's safety, provision of informed consent, or compliance to study procedures
- •Unable or unwilling to discontinue use of prohibited medications for at least 14 days or five half-lives of a drug (whichever is longer) prior to the first dose of study treatment and for the duration of the study.
- •Concurrent therapy given to treat cancer including treatment with an investigational agent or concurrent participation in another clinical trial involving anti-cancer investigational drug.
- •Administration of an investigational drug within 30 days or 5 half-lives, whichever is longer, preceding the first dose of study treatment.
- •Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to pazopanib or excipients that in the opinion of the investigator contraindicates their participation.
- •Prior or current use of systemic anti-VEGF inhibitors, cytokines (e.g. interferon, interleukin 2).
研究组 & 干预措施
pazopanib
Pazopanib oral agent, administered at 600 mg daily initial dose for 8-12 weeks. Dose can be escalated to 800 mg daily based on safety evaluation. Complete treatment is 12 months. Dose can be reduced, interrupted or discontinued due to adverse events or intolerance.
干预措施: pazopanib (Drug)
placebo
placebo matching pazopanib 200 mg tablets, administered at 600 mg daily initial dose for 8-12 weeks. Dose can be escalated to 800 mg daily based on safety evaluation. Complete treatment is 12 months. Dose can be reduced, interrupted or discontinued due to adverse events or intolerance.
干预措施: placebo (Drug)
结局指标
主要结局
Disease-free Survival (DFS) With Pazopanib 600 mg Daily Initial Dose vs. Placebo
时间窗: approximately 5 years
DFS is defined as the interval between the date of randomization and the earliest date of disease recurrence/metastasis or death due to any cause.
次要结局
- DFS Rates at Yearly Time Points With Pazopanib vs. Placebo(yearly for 4 years)
- Overall Survival (OS) With Pazopanib 600 mg Daily Initial Dose vs. Placebo(approximately 8.5 years)
- OS With Pazopanib vs. Placebo(approximately 8.5 years)
- Health-related Quality of Life (HRQoL) With Pazopanib 600 mg Daily Initial Dose vs. Placebo Assessed Using NCCN/FACT FKSI-19 Scale Treatment Side Effects (TSE) Domain Score(Week 52, 24M DFS FU, 36M DFS FU,48M DFS FU, 54M DFS FU)
- Health-related Quality of Life (HRQoL) With Pazopanib 600 mg Daily Initial Dose vs. Placebo Assessed Using EuroQoL-5D (EQ-5D) Score(Week 52, 24M DFS FU, 36M DFS FU, 48M DFS FU, 54M DFS FU)
- DFS Rates at Yearly Time Points With Pazopanib 600 mg Daily Initial Dose vs. Placebo(yearly for 4 years)
- DFS With Pazopanib vs. Placebo(approximately 5 years)
- DFS Pazopanib 800 mg Daily Initial Dose vs. Placebo(approximately 5 years)
- Health-related Quality of Life (HRQoL) With Pazopanib 600 mg Daily Initial Dose vs. Placebo Assessed Using NCCN/FACT FKSI-19 Scale Functional Well Being (FWB) Domain Score(Week 52, 24M DFS FU, 36M DFS FU,48M DFS FU, 54M DFS FU)
- Health-related Quality of Life (HRQoL) With Pazopanib vs. Placebo for ITT ALL Assessed Using National Comprehensive Cancer Network (NCCN)/FACT FKSI-19 Total Score(Week 52, 24M DFS FU, 36M DFS FU, 48M DFS FU, 54M DFS FU)
- Health-related Quality of Life (HRQoL) With Pazopanib 600 mg Daily Initial Dose vs. Placebo Assessed Using NCCN/FACT FKSI-19 Scale Disease-related Symptoms-physical (DRS-P) Domain Score(Week 52, 24M DFS FU, 36M DFS FU, 48M DFS FU, 54M DFS FU)
- Health-related Quality of Life (HRQoL) With Pazopanib vs. Placebo for ITT ALL Assessed Using National Comprehensive Cancer Network (NCCN)/FACT FKSI-19 Scale Disease-related Symptoms-physical (DRS-P) Domain Score(Week 52, 24M DFS FU, 36M DFS FU, 48M DFS FU, 54M DFS FU)
- Health-related Quality of Life (HRQoL) With Pazopanib vs. Placebo for ITT ALL Assessed Using National Comprehensive Cancer Network (NCCN)/FACT FKSI-19 Scale Disease-related Symptoms-emotional (DRS-E) Domain Score(Week 52, 24M DFS FU, 36M DFS FU, 48M DFS FU, 54M DFS FU)
- OS With Pazopanib 800 mg Daily Initial Dose vs. Placebo(approximately 8.5 years)
- Health-related Quality of Life (HRQoL) With Pazopanib 600 mg Daily Initial Dose vs. Placebo Assessed Using NCCN/Functional Assessment of Cancer Therapy-Kidney Symptom Index -19 (FACT FKSI-19) Total Score(Week 52, 24M DFS FU, 36M DFS FU, 48M DFS FU, 54M DFS FU)
- Health-related Quality of Life (HRQoL) With Pazopanib 600 mg Daily Initial Dose vs. Placebo Assessed Using NCCN/FACT FKSI-19 Scale Disease Related Symptoms-emotional (DRS-E) Domain Score(Week 52, 24M DFS FU, 36M DFS FU,48M DFS FU, 54M DFS FU)
- Health-related Quality of Life (HRQoL) With Pazopanib vs. Placebo for ITT ALL Assessed Using National Comprehensive Cancer Network (NCCN)/FACT FKSI-19 Scale Functional Well Being (FWB) Domain Score(Week 52, 24M DFS FU, 36M DFS FU, 48M DFS FU, 54M DFS FU)
- Health-related Quality of Life (HRQoL) With Pazopanib vs. Placebo for ITT ALL Assessed Using EuroQoL-5D (EQ-5D) Score(Week 52, 24M DFS FU, 36M DFS FU, 48M DFS FU, 54M DFS FU)
- Health-related Quality of Life (HRQoL) With Pazopanib vs. Placebo for ITT ALL Assessed Using National Comprehensive Cancer Network (NCCN)/FACT FKSI-19 Scale Treatment Side Effects (TSE) Domain Score(Week 52, 24M DFS FU, 36M DFS FU, 48M DFS FU, 54M DFS FU)