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

A Phase I/II Trial of Pazopanib Alternating With Bevacizumab in Treatment-Naive Metastatic Clear Cell Renal Cell Carcinoma Patients

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Clear Cell Renal Cell Carcinoma; Stage IV Renal Cell Cancer
• Intervention / Treatment: Other: Laboratory Biomarker Analysis; Other: Pharmacological Study; Drug: Pazopanib Hydrochloride; Biological: Bevacizumab

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: Interventional
• Enrollment (Actual): 51
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Kansas
    • Westwood, Kansas, United States, 66205
      • The University of Kansas Cancer Center
  • Michigan
    • Detroit, Michigan, United States, 482018
      • Karamanos Cancer Institute
  • New York
    • Buffalo, New York, United States, 14263
      • Roswell Park Cancer Institute
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15232
      • University of Pittsburgh Cancer Institute (UPCI)
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Medical College of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

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.

Other: Laboratory Biomarker Analysis; Correlative studies; Other: Pharmacological Study; Correlative studies; Drug: Pazopanib Hydrochloride; Given PO; Other Names: GW786034B; Votrient; Biological: Bevacizumab; Given IV; Other Names: Avastin; Anti-VEGF; Anti-VEGF Humanized Monoclonal Antibody; Anti-VEGF rhuMAb; 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Median PFS (Phase II)	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.	Up to 30 days post-treatment
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)	The frequency of toxicities will be tabulated for the dose estimated to be the maximum-tolerated dose.	Up to 140 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of grade 3 or higher toxicities, graded according to CTCAE version 4.0	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.	Up to 30 days post-treatment
Overall survival (Phase II)	Will be obtained using Kaplan-Meier and Proportional Hazards methods.	From the date of study enrollment to the date of death from any cause, assessed up to 30 days post-treatment
PFS rate at 12 months (Phase II)	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.	At 12 months
Response rate according to RECIST 1.1 (Phase I)		Up to 30 days post-treatment

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
IL-8 levels	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.	Up to 30 days post-treatment
MDSC levels	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.	Up to 30 days post-treatment
Pazopanib exposure as measured by pharmacokinetics parameters		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	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.	Up to 30 days post-treatment

Collaborators and Investigators

• Sponsor: Roswell Park Cancer Institute
• Collaborators: GlaxoSmithKline
• Investigators: Principal Investigator: Saby George, Roswell Park Cancer Institute

Study record dates

Study Major Dates

• Study Start (Actual): November 21, 2012
• Primary Completion (Estimated): January 2, 2025
• Study Completion (Estimated): January 2, 2025

Study Registration Dates

• First Submitted: August 24, 2012
• First Submitted That Met QC Criteria: September 10, 2012
• First Posted (Estimated): September 13, 2012

Study Record Updates

• Last Update Posted (Estimated): January 31, 2024
• Last Update Submitted That Met QC Criteria: January 30, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Kidney Diseases; Urologic Diseases; Adenocarcinoma; Neoplasms, Glandular and Epithelial; Kidney Neoplasms; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Carcinoma, Renal Cell; Carcinoma; Physiological Effects of Drugs; Antineoplastic Agents; Immunologic Factors; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Antibodies; Immunoglobulins; Bevacizumab; Antibodies, Monoclonal; Antineoplastic Agents, Immunological; Immunoglobulin G; Endothelial Growth Factors
• Other Study ID Numbers: I 191711 (Other Identifier: Roswell Park Cancer Institute); 13-069; NCI-2012-01247 (Registry Identifier: CTRP (Clinical Trial Reporting Program))