Pazopanib Hydrochloride in Treating Patients With Metastatic Kidney Cancer Who Have No Evidence of Disease After Surgery

Study Overview
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Brief Summary
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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.

Detailed Description
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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. 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.

Official Title
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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

Conditions
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Clear Cell Renal Cell Carcinoma, Stage IV Renal Cell Cancer AJCC v7

Intervention / Treatment
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* Drug: Pazopanib
* Other: Placebo Administration


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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: A computed tomography (CT) of the chest must be obtained within 4 weeks prior to randomization with or without contrast A CT of the abdomen/pelvis must be obtained within 4 weeks prior to randomization with intravenous (IV) contrast (oral contrast may be added at the radiologist's discretion); an magnetic resonance imaging (MRI) of the abdomen/pelvis with gadolinium may be substituted for the CT if the CT with IV contrast is contra-indicated An MRI of the brain with and without gadolinium must be done within 8 weeks prior to randomization; a CT of the brain with and without IV contrast is permitted if MRI is contra-indicated (i.e., pacemaker) 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 Platelets > 100,000/mcL Total bilirubin < 1.5 x institutional upper limit of normal (ULN) Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) < 2.5 x upper limit of normal (ULN) Calculated creatinine clearance (CrCl) > 30 mL/min 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 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 Exclusion Criteria: Patients presenting with tumors within the kidneys (multiple synchronous or single/multiple metachronous) if there are no extrarenal sites of disease (i.e. potential multifocal primary disease) Prior or concurrent systemic therapy for RCC; adjuvant placebo administration is permitted Active peptic ulcer disease Active inflammatory bowel disease New York Heart Association (NYHA) class II or greater congestive heart failure History or current clinically apparent central nervous system metastases Pregnant or breast-feeding History of allergic reactions attributed to compounds of similar chemical or biologic composition to pazopanib 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 Serious or non-healing wound, ulcer, or bone fracture at the time of randomization History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 4 weeks prior to randomization History of cerebrovascular accident (CVA) within 6 months of randomization History of myocardial infarction, hospital admission for unstable angina, cardiac angioplasty or stenting within 6 months of randomization History of venous thrombosis within 12 weeks of randomization Taking strong cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) inhibitors such as: Antibiotics: clarithromycin, telithromycin, troleandomycin Human immunodeficiency virus (HIV) antiviral protease inhibitors: ritonavir, indinavir, saquinavir, nelfinavir, amprenavir, lopinavir Antifungals: itraconazole, ketoconazole, voriconazole, fluconazole Antidepressants: nefazodone History of hemoptysis in excess of 2.5 mL (1/2 teaspoon) within 8 weeks prior to randomization Taking drugs known to prolong the QTc interval; such drugs should be discontinued at least 5 half-lives prior to randomization 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A (Pazopanib)<br>Patients receive pazopanib hydrochloride 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. | Drug: Pazopanib<br>* Given PO<br>* Other names: Pazopanib HCI;|
| Placebo Comparator: Arm B (Placebo)<br>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. | Other: Placebo Administration<br>* Given PO<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease-free Survival (DFS) | Disease-free survival (DFS) is 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. | Assessed every 3 months for the first 2 years, every 6 months for the next 3 years, and then annually up to 6 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 3-year Overall Survival (OS) Rate | Overall survival is defined as the time from randomization to death or date last known alive. Kaplan-Meier method was used to estimate 3-year overall survival rate. | Assessed every 3 months for the first 2 years, and then every 6 months for the 3rd year. | 
| Quality-adjusted Time Without Symptoms of Disease or Treatment (Q-TWiST) | OS for each arm is divided into 3 health states: toxicity (TOX), time without symptoms of disease or toxicity (TWiST), and recurrence (REC). TOX is defined as the time spent with grade 3/4 adverse events (AEs) prior to disease recurrence. TWiST is defined as the time prior to disease recurrence when no AEs of grade 3/4 were experienced. REC health state is defined as the time from disease recurrence or second primary cancer until death. Patients alive will be censored at the date of last contact. For each health state, a patient-reported utility weight will be assigned. The mean amount of time in each state will be estimated using Kaplan and Meier method. TWiST = mean recurrence-free survival (RFS) - mean time with toxicities REC = mean OS - mean RFS Q-TWiST = (uTOX x TOX) + (uTWiST x TWiST) + (uREC x REC) Where uTOX, uTWiST, and uREC represent the average group utility value for each state for that arm and TOX, TWiST and REC represent the mean duration of the state for that arm. | Assessed every 3 months for the first 2 years, every 6 months for the next 3 years, then annually up to 10 years | 
| Change in Functional Assessment of Chronic Illness Therapy (FACIT) - Fatigue Score From Baseline to 6 Months | FACIT-Fatigue subscale (13 items) was used to evaluate fatigue in this patient population. The score ranges between 0 and 52. The higher the score, the better the quality of life. The change in FACIT-Fatigue score from baseline to 6 months will be compared between the two arms. | Assessed at baseline and 6 months | 
| Change in Functional Assessment of Cancer Therapy-Kidney Symptom Index Score From Baseline to 6 Months | Functional Assessment of Cancer Therapy Kidney Cancer Symptom Index - 15 Item Version (FKSI-15) will be used to evaluate the quality of life concerns among this patient population. The change in score from baseline to 6 months will be compared between the two arms. The score ranges between 0 and 60. A score of 0 is a severely symptomatic patient and the highest possible score is an asymptomatic patient. | Assessed at baseline and 6 months | 
| Change in Plasma Levels of Pazopanib From Baseline to Cycle 2 Day 1 | Plasma concentration of pazopanib will be assessed at baseline and cycle 2 day 1. | Assessed at baseline and cycle 2 day 1 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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pazopanib, metastatic renal cell carcinoma, double-blind placebo control