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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

Description

Detailed Description
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 I: 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 II: 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.

Phase

N/A

Inclusion and Exclusion Criteria

  • 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
  • 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 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 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 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
  • 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
  • Women must not be pregnant or breast-feeding
  • 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 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 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 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 cerebrovascular accident (CVA) within 6 months of 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 of venous thrombosis within 12 weeks of randomization
  • Patient cannot be 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
  • 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

Sites

  • California

    • Los Angeles County-USC Medical Center, Los Angeles, California, 90033
    • USC / Norris Comprehensive Cancer Center, Los Angeles, California, 90033
    • City of Hope Comprehensive Cancer Center, Duarte, California, 91010
    • UC San Diego Moores Cancer Center, La Jolla, California, 92093

  • Nevada

    • Children's Specialty Center of Nevada II, Las Vegas, Nevada, 89109

  • Arizona

    • Arizona Cancer Center at UMC Orange Grove, Tucson, Arizona, 85704
    • Arizona Cancer Center at University Medical Center North, Tucson, Arizona, 85719
    • University of Arizona Health Sciences Center, Tucson, Arizona, 85724

  • Utah

    • Huntsman Cancer Institute/University of Utah, Salt Lake City, Utah, 84112

  • Idaho

    • Idaho Urologic Institute-Meridian, Meridian, Idaho, 83642

  • Oklahoma

    • Natalie Warren Bryant Cancer Center at Saint Francis, Tulsa, Oklahoma, 74136

  • Nebraska

    • Nebraska Methodist Hospital, Omaha, Nebraska, 68114

  • Minnesota

    • Mayo Clinic, Rochester, Minnesota, 55905

  • Missouri

    • Saint John's Mercy Medical Center, Saint Louis, Missouri, 63141
    • Saint Louis-Cape Girardeau CCOP, Saint Louis, Missouri, 63141
    • Saint Louis Cancer and Breast Institute-South City, Saint Louis, Missouri, 63109
    • Washington University School of Medicine, Saint Louis, Missouri, 63110
    • Saint Francis Medical Center, Cape Girardeau, Missouri, 63703

  • Wisconsin

    • Sacred Heart Hospital, Eau Claire, Wisconsin, 54701
    • Marshfield Clinic Cancer Center at Sacred Heart, Eau Claire, Wisconsin, 54701
    • Lakeview Medical Center-Marshfield Clinic, Rice Lake, Wisconsin, 54868
    • Marshfield Clinic-Rice Lake Center, Rice Lake, Wisconsin, 54868
    • Marshfield Clinic-Chippewa Center, Chippewa Falls, Wisconsin, 54729
    • Marshfield Clinic - Ladysmith Center, Ladysmith, Wisconsin, 54848
    • Marshfield Clinic, Marshfield, Wisconsin, 54449
    • Saint Joseph's Hospital, Marshfield, Wisconsin, 54449
    • Marshfield Clinic - Wisconsin Rapids Center, Wisconsin Rapids, Wisconsin, 54494
    • Saint Michael's Hospital, Stevens Point, Wisconsin, 54481
    • Marshfield Clinic Cancer Care at Saint Michael's Hospital, Stevens Point, Wisconsin, 54481
    • Marshfield Clinic-Wausau Center, Wausau, Wisconsin, 54401
    • Saint Clare's Hospital, Weston, Wisconsin, 54476
    • Marshfield Clinic - Weston Center, Weston, Wisconsin, 54476
    • Diagnostic and Treatment Center, Weston, Wisconsin, 54476
    • Marshfield Clinic-Minocqua Center, Minocqua, Wisconsin, 54548
    • Saint Mary's Hospital, Rhinelander, Wisconsin, 54501
    • Marshfield Clinic at James Beck Cancer Center, Rhinelander, Wisconsin, 54501
    • Aurora Health Center-Fond du Lac, Fond Du Lac, Wisconsin, 54937
    • Froedtert and the Medical College of Wisconsin, Milwaukee, Wisconsin, 53226
    • Wheaton Franciscan Healthcare - Saint Joseph, Milwaukee, Wisconsin, 53210

  • Illinois

    • Good Samaritan Regional Health Center, Mount Vernon, Illinois, 62864
    • Carle Physician Group-Effingham, Effingham, Illinois, 62401
    • Carle Physician Group-Mattoon/Charleston, Mattoon, Illinois, 61938
    • Rush-Copley Healthcare Center, Yorkville, Illinois, 60560
    • Carle Cancer Center, Urbana, Illinois, 61801
    • The Carle Foundation Hospital, Urbana, Illinois, 61801
    • Rush - Copley Medical Center, Aurora, Illinois, 60504
    • Cadence Cancer Center in Warrenville, Warrenville, Illinois, 60555
    • Presence Saint Mary's Hospital, Kankakee, Illinois, 60901
    • Carle on Vermilion, Danville, Illinois, 61832
    • North Shore Hematology Oncology, Libertyville, Illinois, 60048
    • Loyola University Medical Center, Maywood, Illinois, 60153
    • Illinois Cancer Specialists-Niles, Niles, Illinois, 60714
    • Hematology Oncology Associates of Illinois-Highland Park, Highland Park, Illinois, 60035
    • Hematology Oncology Associates of Illinois - Skokie, Skokie, Illinois, 60076
    • Northwestern University, Chicago, Illinois, 60611

  • Louisiana

    • East Jefferson General Hospital, Metairie, Louisiana, 70006

  • Indiana

    • Woodland Cancer Care Center, Michigan City, Indiana, 46360
    • Franciscan Saint Anthony Health-Michigan City, Michigan City, Indiana, 46360
    • Indiana University/Melvin and Bren Simon Cancer Center, Indianapolis, Indiana, 46202

  • Georgia

    • Saint Joseph's Hospital of Atlanta, Atlanta, Georgia, 30342
    • Emory University/Winship Cancer Institute, Atlanta, Georgia, 30322
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