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

Study Description

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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.

Condition or disease	Intervention/treatment	Phase
Clear Cell Renal Cell Carcinoma; Stage IV Renal Cell Cancer	Biological: Bevacizumab; Other: Laboratory Biomarker Analysis; Drug: Pazopanib Hydrochloride; Other: Pharmacological Study	Phase 1; Phase 2

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.

Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	35 participants
Intervention Model:	Single Group Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	A Phase I/II Trial of Pazopanib Alternating With Bevacizumab in Treatment-Naive Metastatic Clear Cell Renal Cell Carcinoma Patients
Actual Study Start Date :	October 5, 2012
Estimated Primary Completion Date :	May 5, 2018
Estimated Study Completion Date :	May 5, 2019

Arms and Interventions

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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.

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

Outcome Measures

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Primary Outcome Measures :

1. 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.
2. 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.

Secondary Outcome Measures :

1. 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.
2. 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.
3. 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.
4. Response rate according to RECIST 1.1 (Phase I) [ Time Frame: Up to 30 days post-treatment ]

Other Outcome Measures:

1. 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.
2. 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.
3. 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 ]
4. 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.

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Senior)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

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)
  • 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

Contacts and Locations

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Locations

United States, New York
Roswell Park Cancer Institute	Recruiting
Buffalo, New York, United States, 14263
Contact: Roswell Park 877-275-7724 ASKRPCI@roswellpark.org
Principal Investigator: Saby George
United States, Pennsylvania
University of Pittsburgh Cancer Institute (UPCI)	Recruiting
Pittsburgh, Pennsylvania, United States, 15232
Contact: Rahul A. Parikh 412-692-4724 parikhr@upmc.edu
Principal Investigator: Rahul A. Parikh

Sponsors and Collaborators

Roswell Park Cancer Institute

National Cancer Institute (NCI)

GlaxoSmithKline

Investigators

Principal Investigator:	Saby George	Roswell Park Cancer Institute

More Information

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Responsible Party:	Roswell Park Cancer Institute
ClinicalTrials.gov Identifier:	NCT01684397 History of Changes
Other Study ID Numbers:	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 )
First Posted:	September 13, 2012
Last Update Posted:	February 20, 2018
Last Verified:	February 2018

Additional relevant MeSH terms:

Carcinoma; Carcinoma, Renal Cell; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Adenocarcinoma; Kidney Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Kidney Diseases; Urologic Diseases; Bevacizumab	Endothelial Growth Factors; Antibodies; Immunoglobulins; Antibodies, Monoclonal; Immunoglobulin G; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Physiological Effects of Drugs; Growth Inhibitors; Antineoplastic Agents; Immunologic Factors