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Pazopanib Hydrochloride and Bevacizumab in Treating Patients With Previously Untreated Metastatic Kidney Cancer

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ClinicalTrials.gov Identifier: NCT01684397
Recruitment Status : Recruiting
First Posted : September 13, 2012
Last Update Posted : March 16, 2020
Sponsor:
Collaborators:
National Cancer Institute (NCI)
GlaxoSmithKline
Information provided by (Responsible Party):
Roswell Park Cancer Institute

Tracking Information
First Submitted Date  ICMJE August 24, 2012
First Posted Date  ICMJE September 13, 2012
Last Update Posted Date March 16, 2020
Actual Study Start Date  ICMJE October 5, 2012
Estimated Primary Completion Date June 13, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 21, 2015)
  • Median PFS (Phase II) [ Time Frame: Up to 30 days post-treatment ]
    Distributions of continuous variables will be summarized with commonly used statistics (mean, standard deviation, median, etc.), with sub-group associations tested using the Wilcoxon Rank Sum test.
  • Optimal phase II dose, defined as the largest dose level at which less than 2 out of the 6 patients experienced dose-limiting toxicity, graded according to Common Terminology Criteria for Adverse Events version 4.0 (Phase I) [ Time Frame: Up to 140 days ]
    The frequency of toxicities will be tabulated for the dose estimated to be the maximum-tolerated dose.
Original Primary Outcome Measures  ICMJE
 (submitted: September 10, 2012)
  • Optimal phase II dose defined as the largest dose level at which less than 2 out of the 6 patients experienced dose-limiting toxicity (DLT) assessed based on Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 (Phase I) [ Time Frame: Up to 140 days ]
  • Median PFS (Phase II) [ Time Frame: Up to 30 days post-treatment ]
    Distributions of continuous variables will be summarized with commonly used statistics (mean, standard deviation, median, etc.), with sub-group associations tested using the Wilcoxon Rank Sum test.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: August 21, 2015)
  • Incidence of grade 3 or higher toxicities, graded according to CTCAE version 4.0 [ Time Frame: Up to 30 days post-treatment ]
    Categorical variables will be summarized in contingency tables, with associations of interest assessed using Fisher's exact test. The frequency of toxicities will be tabulated by grade across all dose levels and courses.
  • Overall survival (Phase II) [ Time Frame: From the date of study enrollment to the date of death from any cause, assessed up to 30 days post-treatment ]
    Will be obtained using Kaplan-Meier and Proportional Hazards methods.
  • PFS rate at 12 months (Phase II) [ Time Frame: At 12 months ]
    Distributions of continuous variables will be summarized with commonly used statistics (mean, standard deviation, median, etc.), with sub-group associations tested using the Wilcoxon Rank Sum test.
  • Response rate according to RECIST 1.1 (Phase I) [ Time Frame: Up to 30 days post-treatment ]
Original Secondary Outcome Measures  ICMJE
 (submitted: September 10, 2012)
  • Incidence of grade 3 or higher toxicities accessed based on CTCAE version 4.0 (Phase I) [ Time Frame: Up to 30 days post-treatment ]
  • Response rate according to RECIST 1.1 (Phase I) [ Time Frame: Up to 30 days post-treatment ]
  • Pharmacokinetics of pazopanib (Phase I) [ Time Frame: Course 1 on day 1 at pre-dose, 2 hours, and 4 hours post-dose; day 15 at pre-dose and 2 hours post-dose; and day 29 ]
  • VEGF levels, IL-8 levels and MDSC levels (Phase I) [ Time Frame: Up to 30 days post-treatment ]
  • Incidence of grade 3 or higher toxicities accessed based on CTCAE version 4.0 (Phase II) [ Time Frame: Up to 30 days post-treatment ]
    Categorical variables will be summarized in contingency tables, with associations of interest assessed using Fisherâs exact test.
  • VEGF levels, IL-8 levels and MDSC levels (Phase II) [ Time Frame: Up to 30 days post-treatment ]
    Distributions of continuous variables will be summarized with commonly used statistics (mean, standard deviation, median, etc.), with sub-group associations tested using the Wilcoxon Rank Sum test.
  • PFS rate at 12 months (Phase II) [ Time Frame: At 12 months ]
    Distributions of continuous variables will be summarized with commonly used statistics (mean, standard deviation, median, etc.), with sub-group associations tested using the Wilcoxon Rank Sum test.
  • Overall survival (Phase II) [ Time Frame: From the date of study enrollment to the date of death from any cause, assessed up to 30 days post-treatment ]
    Will be obtained using Kaplan-Meier and Proportional Hazards methods.
Current Other Pre-specified Outcome Measures
 (submitted: August 21, 2015)
  • IL-8 levels [ Time Frame: Up to 30 days post-treatment ]
    Distributions of continuous variables will be summarized with commonly used statistics (mean, standard deviation, median, etc.), with sub-group associations tested using the Wilcoxon Rank Sum test.
  • MDSC levels [ Time Frame: Up to 30 days post-treatment ]
    Distributions of continuous variables will be summarized with commonly used statistics (mean, standard deviation, median, etc.), with sub-group associations tested using the Wilcoxon Rank Sum test.
  • Pazopanib exposure as measured by pharmacokinetics parameters [ Time Frame: Course 1 on day 1 at pre-dose, 2 hours, and 4 hours post-dose; day 15 at pre-dose and 2 hours post-dose; and day 29 ]
  • VEGF levels [ Time Frame: Up to 30 days post-treatment ]
    Distributions of continuous variables will be summarized with commonly used statistics (mean, standard deviation, median, etc.), with sub-group associations tested using the Wilcoxon Rank Sum test.
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Pazopanib Hydrochloride and Bevacizumab in Treating Patients With Previously Untreated Metastatic Kidney Cancer
Official Title  ICMJE A Phase I/II Trial of Pazopanib Alternating With Bevacizumab in Treatment-Naive Metastatic Clear Cell Renal Cell Carcinoma Patients
Brief Summary This phase I/II trial studies the side effects and best dose of pazopanib hydrochloride and bevacizumab and to see how well they work in treating patients with previously untreated kidney cancer that has spread to other places in the body (metastatic). Pazopanib hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Pazopanib hydrochloride may also stop the growth of tumor cells by blocking blood flow to the tumor. Monoclonal antibodies, such as bevacizumab, can prevent tumor growth by blocking the ability of tumor cells to grow and spread. Giving pazopanib hydrochloride together with bevacizumab may kill more tumor cells.
Detailed Description

PRIMARY OBJECTIVES:

  • I. To determine the safe phase II dose of this novel regimen. (Phase I)
  • II. To determine the median progression free survival (PFS) from this novel regimen. (Phase II)

SECONDARY OBJECTIVES:

I. To evaluate the safety and toxicity of the proposed regimen. (Phase I) II. To evaluate the response rate. (Phase I) III. To evaluate the pharmacokinetics of pazopanib (pazopanib hydrochloride). (Phase I) IV. To evaluate the vascular endothelial growth factor (VEGF) levels and myeloid derived suppressor cell (MDSC) levels at various time points and correlate with response. (Phase I) V. To evaluate the safety and toxicity of this new regimen. (Phase II) VI. To evaluate the VEGF levels, interleukin (IL)-8 levels and MDSC levels at various time points and correlate with outcome. (Phase II) VII. To evaluate the PFS rate at 12 months. (Phase II) VIII. To evaluate overall survival. (Phase II)

OUTLINE: This is a phase I, dose-escalation study followed by a phase II study.

Patients receive pazopanib hydrochloride orally (PO) on days 1-28, and bevacizumab intravenously (IV) over 30-90 minutes on days 36 and 50. Courses repeat every 70 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days and Phase II patients are followed up by telephone every 12 months

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Clear Cell Renal Cell Carcinoma
  • Stage IV Renal Cell Cancer
Intervention  ICMJE
  • Biological: Bevacizumab
    Given IV
    Other Names:
    • Anti-VEGF
    • Anti-VEGF Humanized Monoclonal Antibody
    • Anti-VEGF rhuMAb
    • Avastin
    • Bevacizumab Biosimilar BEVZ92
    • Bevacizumab Biosimilar BI 695502
    • Immunoglobulin G1 (Human-Mouse Monoclonal rhuMab-VEGF Gamma-Chain Anti-Human Vascular Endothelial Growth Factor), Disulfide With Human-Mouse Monoclonal rhuMab-VEGF Light Chain, Dimer
    • Recombinant Humanized Anti-VEGF Monoclonal Antibody
    • rhuMab-VEGF
  • Other: Laboratory Biomarker Analysis
    Correlative studies
  • Drug: Pazopanib Hydrochloride
    Given PO
    Other Names:
    • GW786034B
    • Votrient
  • Other: Pharmacological Study
    Correlative studies
Study Arms  ICMJE Experimental: Treatment (pazopanib hydrochloride and bevacizumab)
Patients receive pazopanib hydrochloride PO on days 1-28 and bevacizumab IV over 30-90 minutes on days 36 and 50. Courses repeat every 70 days in the absence of disease progression or unacceptable toxicity.
Interventions:
  • Biological: Bevacizumab
  • Other: Laboratory Biomarker Analysis
  • Drug: Pazopanib Hydrochloride
  • Other: Pharmacological Study
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: February 27, 2020)
51
Original Estimated Enrollment  ICMJE
 (submitted: September 10, 2012)
88
Estimated Study Completion Date  ICMJE July 13, 2021
Estimated Primary Completion Date June 13, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Biopsy/pathology-proven clear cell renal cell carcinoma (CCRCC) with metastases
  • Have an Eastern Cooperative Oncology Group (ECOG) performance status =< 1
  • Hemoglobin >= 10 gm/dL
  • Absolute neutrophil count (ANC) >= 1.5 x 10^9/L
  • Platelets >= 100 x 10^9/L
  • Total bilirubin =< upper limit of normal (ULN)
  • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< ULN
  • International normalization ratio (INR) and activated partial thromboplastin time (aPTT) < 1.2 x ULN
  • Serum creatinine < 1.5 mg/dL or if serum creatinine > 1.5 mg/dL then calculate creatinine clearance (CrCL) > 30 mL/min
  • Urine protein to creatinine ratio =< 1 (if urine protein creatinine ratio is > 1, then a 24-hour urine total protein must be assessed; subjects will be ineligible if the 24-hour urine protein is found to be > 1 gm)
  • Normal cardiac ejection fraction (> 50%) by multi gated acquisition scan (MUGA) or echocardiogram
  • Have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria present
  • Ability to swallow and retain oral medication
  • Subjects of child-bearing potential must agree to use adequate contraceptive methods (e.g., hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately
  • Subject or legal representative must understand the investigational nature of this study and sign an Independent Ethics Committee/Institutional Review Board approved written informed consent form prior to receiving any study related procedure

Exclusion Criteria:

  • Subjects with known brain metastases should be excluded from this clinical trial
  • Prior VEGF targeted therapies for renal cell carcinoma (RCC) including adjuvant or neoadjuvant treatments; in phase 1 only, one prior therapy with high dose IL-2 or anti-programmed cell death (PD)-1 compound alone or in combination with cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) targeting drug is allowed on the trial
  • Subjects diagnosed with another cancer in the past 3 years; excluding basal cell carcinoma or squamous cell carcinoma, of skin which were completely cured by resection
  • Concurrent use of another anti-cancer drug including an investigational anti-cancer agent
  • Major surgery within 28 days prior to treatment or major surgery planned during the next 6 months
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic or psychiatric illness/social situations that would limit compliance with study requirements
  • History of any of the following cardio-vascular condition:

    • Myocardial infarction (MI)
    • Unstable angina
    • Coronary artery bypass grafting (CABG)-unless patient had a negative stress test within 6 months of screening
    • Coronary angioplasty or stenting
    • Symptomatic peripheral arterial disease (PAD)
    • History of symptomatic chronic congestive heart failure (CHF)
    • History of cerebrovascular accidents including transient ischemic attacks (TIA)
    • Corrected QT interval (QTc) > 480 msec
    • Uncontrolled hypertension (systolic blood pressure [BP] > 150 mm Hg or diastolic BP of > 90 mm Hg); if the screening BP is elevated, adjustments in anti-hypertensives are permitted and a re-screening will be permitted for BP assessment with three consecutive values obtained 2 minutes apart; the 3 values have to be below 150/90 mm Hg for eligibility and can only be obtained after 2 days of the last change in anti-hypertensive medication; use of clonidine is not permissible for adjusting the BP during this period
  • History of deep vein thrombosis (DVT) or pulmonary embolism (PE) in the past 6 months
  • Subjects should not have packed red blood cells (PRBC) or platelet transfusion within 14 days of the screening
  • Evidence of active bleeding or bleeding disorder
  • Subjects currently on anti-coagulation therapy are not eligible
  • Unable to discontinue the use of prohibited medications
  • Pregnant or nursing female subjects
  • Unwilling or unable to follow protocol requirements
  • Any condition which in the investigator's opinion deems the subject an unsuitable candidate to receive study drug
  • Received an investigational agent within 30 days prior to enrollment
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01684397
Other Study ID Numbers  ICMJE I 191711
NCI-2012-01247 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
13-069
I 191711 ( Other Identifier: Roswell Park Cancer Institute )
P30CA016056 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Roswell Park Cancer Institute
Study Sponsor  ICMJE Roswell Park Cancer Institute
Collaborators  ICMJE
  • National Cancer Institute (NCI)
  • GlaxoSmithKline
Investigators  ICMJE
Principal Investigator: Saby George Roswell Park Cancer Institute
PRS Account Roswell Park Cancer Institute
Verification Date March 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP