Randomized, Double-Blind Phase III Study of Pazopanib vs. Placebo in Patients With Metastatic Renal Cell Carcinoma Who Have No Evidence of Disease Following Metastatectomy
Randomized, Double-Blind Phase III Study of Pazopanib vs. Placebo in Patients With Metastatic Renal Cell Carcinoma Who Have No Evidence of Disease Following Metastatectomy
This randomized phase III trial studies how well pazopanib hydrochloride works compared to placebo in treating patients with kidney cancer that has spread to other parts of the body and have no evidence of disease after surgery. Pazopanib hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor.
PRIMARY OBJECTIVES:
I. To evaluate disease-free survival with pazopanib (pazopanib hydrochloride) as compared to placebo, defined as the time from randomization to the development of recurrent disease, second primary cancer (other than localized breast, localized prostate, or non-melanoma skin cancer) or death from any cause for patients with metastatic renal cell carcinoma (RCC) with no evidence of disease following metastasectomy.
SECONDARY OBJECTIVES:
I. To describe the overall survival of patients with advanced RCC randomly assigned to receive placebo or pazopanib for one year following metastasectomy to no evidence of disease (NED).
II. To describe treatment and (at recurrence) disease-related adverse events in the two treatment arms.
III. To analyze quality-adjusted time without symptoms of disease or treatment (Q-TWiST) for subjects in the two treatment arms.
IV. To characterize changes in patient-reported fatigue and (at recurrence) kidney cancer-related symptoms during and following treatment with pazopanib compared to placebo.
V. To explore the association between plasma trough levels of pazopanib and disease-free and overall survival.
VI. To prospectively bank preserved tissue from primary tumors and associated metastatic sites in patients with RCC.
OUTLINE: Patients are randomized to 1of 2 treatment arms.
ARM A: Patients receive pazopanib hydrochloride orally (PO) once daily (QD) on days 1-28. Treatment repeats every 28 days for up to 13 courses in the absence of disease progression or unacceptable toxicity.
ARM B: Patients receive placebo PO QD on days 1-28. Treatment repeats every 28 days for up to 13 courses in the absence of disease progression or unacceptable toxicity.
Patients also undergo computed tomography (CT) or magnetic resonance imaging (MRI) throughout the study.
After completion of study treatment, patients are followed up every 3 months for the first two years, every 6 months for the next 3 years, and then annually up to 10 years.
Inclusion Criteria:
Patient must be at least 18 years of age at the time of randomization
Patient must have pathologically confirmed renal cell carcinoma with a clear cell component; pure papillary and chromophobe histologies are excluded; there must be pathologic confirmation of metastatic disease in the resected metastasectomy specimen
Patient must have undergone nephrectomy or partial nephrectomy to remove primary renal cell carcinoma (at any time in the past)
Patient must have undergone surgical resection to remove one or more sites of metastatic disease, with successful removal of all known sites 2-12 weeks prior to randomization. Any number of prior metastasectomies may have been performed in the past, so long as the most recent procedure was within the 12 weeks of registration. The most recent procedure may be nephrectomy for a renal primary tumor
Patients with synchronous disease at initial diagnosis must have metastatic (M1) disease (American Joint Committee on Cancer [AJCC] 7th edition T1-4N0-1M1)
Positive surgical margins are permitted if the surgeon confirms complete resection of gross metastatic disease, and post-operative scans are negative
Patients presenting with metachronous disease may have distant metastases, regional lymph node or renal bed recurrence. Recurrences at a partial nephrectomy resection site are not eligible if it is the only site of disease
Patient must have no evidence of disease on post-operative imaging:
Patient must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 at the time of randomization
Absolute granulocyte count > 1,500/mcL (within 2 weeks prior to randomization)
Platelets > 100,000/mcL (within 2 weeks prior to randomization)
Total bilirubin < 1.5 x institutional upper limit of normal (ULN) (within 2 weeks prior to randomization)
Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) < 2.5 x upper limit of normal (ULN) (within 2 weeks prior to randomization)
Calculated creatinine clearance (CrCl) > 30 mL/min (within 2 weeks prior to randomization)
Subjects must have a urine protein/creatinine (UPC) ratio < 1; if UPC >= 1, then a 24-hour urine total protein must be obtained; subjects must have a 24-hour urine protein value < 1 g to be eligible; use of urine dipstick for renal function assessment is not acceptable (within 2 weeks prior to randomization)
All females of childbearing potential must have a blood test or urine study within 2 weeks prior to randomization to rule out pregnancy; a female of childbearing potential is any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months)
Women of childbearing potential and sexually active males must be strongly advised to use an accepted and effective method of contraception or to abstain from sexual intercourse for the duration of their participation in the study; should a woman become pregnant while participating in this study, she should inform her treating physician immediately; if a man impregnates a woman while participating in this study, he should inform his treating physician immediately
Patient must be able to swallow pills and have no significant impairment in gastrointestinal absorption including history of gastric bypass surgery
Patient must have a corrected QT (QTc) interval on electrocardiogram (ECG) =< 0.48 seconds by Bazett's calculation (=< Common Terminology Criteria for Adverse Events [CTCAE] version [v.]4 grade 2) prior to randomization
Patient must have a systolic blood pressure =< 140 mmHg and diastolic blood pressure must be =< 90 mmHg, measured within 4 weeks prior to randomization; initiation or adjustment of anti-hypertensives prior to starting study treatment is allowed
Patient must have no history of cerebrovascular accident (CVA) within 6 months of randomization
Exclusion Criteria:
Patients presenting with tumors within the kidneys (multiple synchronous or single/multiple metachronous) are not eligible if there are no extrarenal sites of disease (i.e. potential multifocal primary disease)
Patient must not have received any prior or concurrent systemic therapy for RCC. Adjuvant placebo administration is permitted
Patient must have no active peptic ulcer disease
Patient must have no active inflammatory bowel disease
Patient must have no New York Heart Association (NYHA) class II or greater congestive heart failure
Patient must have no prior history or current clinically apparent central nervous system metastases
Women must not be pregnant or breast-feeding due to the unknown effects of pazopanib on the developing fetus
Patient must have no history of allergic reactions attributed to compounds of similar chemical or biologic composition to pazopanib
Patient must have no uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
Patient must not have serious or non-healing wound, ulcer, or bone fracture at the time of randomization
Patient must have no history of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 4 weeks prior to randomization
Patient must have no history of myocardial infarction, hospital admission for unstable angina, cardiac angioplasty or stenting within 6 months of randomization
Patient must have no history venous thrombosis within 12 weeks of randomization
Patient cannot be taking strong cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) inhibitors such as:
Patient must not have history of hemoptysis in excess of 2.5 mL (1/2 teaspoon) within 8 weeks prior to randomization
Patient must not be taking drugs known to prolong the QTc interval; such drugs should be discontinued at least 5 half-lives prior to randomization
Patients must not have any history of other cancer within 3 years from time of randomization with the exception of basal cell skin cancer, squamous cell skin cancer, in situ cervical cancer, ductal or lobular carcinoma in situ of the breast, or resected non-invasive (Ta) urothelial carcinoma
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