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About
This randomized phase II trial studies how well pazopanib hydrochloride with or without ascorbic acid work in treating patients with kidney cancer that has spread to other places in the body (metastatic) or cannot be removed by surgery. Pazopanib hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Ascorbic acid may help pazopanib hydrochloride stop tumor growth and improve treatment survival. Giving pazopanib hydrochloride and ascorbic acid may work better in treating patients with kidney cancer.
Full description
PRIMARY OBJECTIVES:
I. To estimate and compare treatment failure-free rate at 40 weeks from randomization of patients with unresectable/metastatic clear cell renal cell carcinoma (ccRCC) receiving one of the following regimens: Arm A: pazopanib hydrochloride (pazopanib) 800 mg daily plus intravenous (IV) ascorbic acid 1g/kg 3 times/week and Arm B: pazopanib 800 mg daily.
SECONDARY OBJECTIVES:
I. To estimate and compare the overall survival (OS) in patients receiving pazopanib with or without IV ascorbic acid.
II. To estimate and compare the progression-free survival (PFS) in patients receiving pazopanib with or without IV ascorbic acid.
III. To estimate and compare the overall response rate (ORR) in patients receiving pazopanib with or without IV ascorbic acid.
IV. To estimate and compare the duration on pazopanib treatment in patients receiving pazopanib with or without IV ascorbic acid.
V. To assess the adverse events (AE) profile and safety of each treatment arm using the Common Terminology Criteria for Adverse Events (CTCAE).
CORRELATIVE RESEARCH:
I. Correlation between 5 mC, 5 hmC and H3K27me3 expression (as determined by immunohistochemistry [IHC]), as well as MeDIP/hMeDIP sequencing (seq), and response to combination of IV ascorbic acid and pazopanib.
II. Correlation between iron content in tumor microenvironment (as determined by Prussian blue staining) and response to combination of IV ascorbic acid and pazopanib combination.
III. Correlation between HIF-1alpha and HIF-2alpha expression (as determined by immunohistochemistry [IHC]) and response to combination of IV ascorbic acid and pazopanib combination.
IV. Correlation between GLUT1 expression (as determined by IHC) and response to combination of IV ascorbic acid and pazopanib.
V. Correlation between PDL1 expression (as determined by IHC) and response to combination of IV ascorbic acid and pazopanib.
OUTLINE: Patients are randomized to 1 of 2 arms.
ARM A: Patients receive pazopanib hydrochloride orally (PO) once daily (QD) on days 1-28 and ascorbic acid IV three times per week. Treatment repeats every 28 days for up to 10 cycles in the absence of disease progression or unacceptable toxicity.
ARM B: Patients receive pazopanib hydrochloride PO QD on days 1-28. Treatment repeats every 28 days for up to 10 cycles in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up every 8 weeks for up to 2 years.
Enrollment
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Volunteers
Inclusion criteria
Histological confirmation of clear cell renal cancer
Documented metastatic or unresectable disease and at least one measurable lesion by Response Evaluation Criteria in Solid Tumors (RECIST) criteria; NOTE: Nephrectomy or ablation of the primary tumor is allowed prior to enrollment
No prior systemic therapy for clear cell renal cancer or have progressed after immunotherapy such as ipilimumab plus nivolumab in the first line; other immunotherapies (e.g. interleukin-2) or additional lines of immunotherapy may be allowed after discussion with the principal investigator
Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1 or 2
Absolute neutrophil count (ANC) >= 1500/mm^3 (obtained =< 21 days prior to registration)
Platelet (PLT) >= 100,000/mm^3 (obtained =< 21 days prior to registration)
Hemoglobin (Hgb) >= 9.0 g/dL (obtained =< 21 days prior to registration); NOTE: Subjects may not have had a transfusion =< 7 days of registration
Total Bilirubin =< 1.5 x upper limit of normal (ULN) (obtained =< 21 days prior to registration)
Alanine amino transferase (ALT) < 2.5 X ULN, with normal bilirubin (obtained =< 21 days prior to registration); NOTE: Concomitant elevations in bilirubin and ALT above 1.5 x ULN (upper limit of normal) is not permitted
Aspartate aminotransferase (AST) < 2.5 X ULN, with normal bilirubin (obtained =< 21 days prior to registration); NOTE: Concomitant elevations in bilirubin and AST above 1.5 x ULN (upper limit of normal) is not permitted
Creatinine =< 1.5 mg/dl OR creatinine > 1.5 mg/dl, estimated creatinine clearance must be >= 55 mL/minute by Cockcroft Gault formula (obtained =< 21 days prior to registration)
International normalized ratio (INR) and activated partial thromboplastin time (aPTT) =< 1.5 x ULN (obtained =< 21 days prior to registration); NOTE: This applies only to patients who are not receiving therapeutic anticoagulation; patients receiving therapeutic anticoagulation should be on a stable dose
Individuals of non-childbearing potential, or individual of childbearing potential with negative serum pregnancy test =< 7 days prior to randomization and willing to practice total abstinence or use a highly effective method of contraception, as outlined below:
Non-childbearing potential (i.e., physiologically incapable of becoming pregnant), including any female individual who has had the following:
Childbearing potential, including any individual who has had a negative serum pregnancy test, =< 7 days prior to randomization
Agrees to use adequate contraception; acceptable contraceptive methods, when used consistently and in accordance with both the product label and the instructions of the physician, are as follows:
Provide informed written consent
Willing to provide archive tissue samples for correlative research purposes
Exclusion criteria
Any of the following:
Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens
Immunocompromised patients (other than that related to the use of corticosteroids) including patients known to be human immunodeficiency virus (HIV) positive
Prior history of receiving pazopanib or any other tyrosine kinase inhibitor treatments for malignancy
Uncontrolled intercurrent illness including, but not limited to:
History of a major thromboembolic event =< 6 months prior to randomization, including cerebrovascular accident, transient ischemic attack (TIA), myocardial infarction, symptomatic pulmonary embolism (PE) or untreated deep venous thrombosis (DVT), or coronary artery bypass graft surgery; NOTE: Subjects with recent DVT or asymptomatic PE who have been treated with therapeutic anticoagulating agents for at least 6 weeks are eligible
Receiving any other investigational agent which would be considered as a treatment for the primary neoplasm
Other active malignancy =< 5 years prior to randomization; EXCEPTIONS: Nonmelanoma skin cancer or carcinoma-in-situ of the cervix, or cancers with low metastatic potential (e.g. Gleason score 6 prostate cancer) treated with curative therapy; NOTE: If there is a history or prior malignancy, they must not be receiving other specific treatment for their cancer
History or clinical evidence of central nervous system (CNS) metastases or leptomeningeal carcinomatosis, except for individuals who have previously treated CNS metastases, are asymptomatic, and have had no requirement for steroids or anti-seizure medication for =< 6 months prior to randomization; Note: Screening with CNS imaging studies (computed tomography [CT] or magnetic resonance imaging [MRI]) is required only if clinically indicated or if the subject has a history of CNS metastases
Clinically significant gastrointestinal abnormalities that may increase the risk for gastrointestinal bleeding including, but not limited to:
Active peptic ulcer disease
Known intraluminal metastatic lesion/s with risk of bleeding
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 =< 28 days prior to randomization
Clinically significant gastrointestinal abnormalities that may affect absorption of investigational product including, but not limited to:
Corrected QT interval (QTc) > 480 msecs using Bazett?s formula
Receiving any medications or substances with risk of Torsades de Pointes; Note: medications or substances on the list ?Drugs with Risk of Torsades de Pointes? are prohibited; medications or substances on the list ?Drugs with Possible or Conditional Risk of Torsades de Pointes? may be used while on study with extreme caution and careful monitoring
Treatment with any of the following anti-cancer therapies =< 14 days prior to registration:
Prior autologous or allogeneic organ or tissue transplantation
Elective or planned major surgery to be performed during the course of the trial
Receiving any medications or substances that are strong or moderate inhibitors of CYP3A4; use of strong or moderate inhibitors are prohibited =< 7 days prior to randomization
Receiving any medications or substances that are inducers of CYP3A4; use of inducers are prohibited =< 7 days prior to randomization
Glucose-6-phosphate dehydrogenase (G6PD) deficiency (i.e. below normal limits)
End-stage renal disease (estimated glomerular filtration rate [GFR] < 55 ml/min/body surface area [BSA]), unless the estimated creatinine clearance by Cockcroft Gault is >= 55 ml/min prior to randomization
History of calcium oxalate stones
History of iron overload
Unable to swallow oral medications
History of myocardial infarction =< 6 months, current symptomatic CHF or left ventricular ejection fraction (LVEF) < 40% or > grade 2 diastolic dysfunction, with no symptoms or signs of heart failure
Primary purpose
Allocation
Interventional model
Masking
5 participants in 2 patient groups
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Data sourced from clinicaltrials.gov
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