Pazopanib Hydrochloride and Bevacizumab in Treating Patients With Previously Untreated Metastatic Kidney Cancer - Full Text View

Purpose

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, metastatic kidney cancer. 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 block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Giving pazopanib hydrochloride together with bevacizumab may kill more tumor cells

Condition	Intervention	Phase
Clear Cell Renal Cell Carcinoma Stage IV Renal Cell Cancer	Drug: pazopanib hydrochloride Biological: bevacizumab Other: pharmacological study Other: laboratory biomarker analysis	Phase 1 Phase 2


Study Type:	Interventional
Study Design:	Endpoint Classification: Safety/Efficacy Study Intervention Model: Single Group Assignment Masking: 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

Resource links provided by NLM:

MedlinePlus related topics: Cancer

Drug Information available for: Bevacizumab Pazopanib Pazopanib hydrochloride

Genetic and Rare Diseases Information Center resources: Clear Cell Renal Cell Carcinoma Kidney Cancer Renal Cancer

U.S. FDA Resources

Further study details as provided by Roswell Park Cancer Institute:

Primary Outcome Measures:

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 ] [ Designated as safety issue: Yes ]
Median PFS (Phase II) [ Time Frame: Up to 30 days post-treatment ] [ Designated as safety issue: No ]
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.

Secondary Outcome Measures:

Incidence of grade 3 or higher toxicities accessed based on CTCAE version 4.0 (Phase I) [ Time Frame: Up to 30 days post-treatment ] [ Designated as safety issue: Yes ]
Response rate according to RECIST 1.1 (Phase I) [ Time Frame: Up to 30 days post-treatment ] [ Designated as safety issue: No ]
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 ] [ Designated as safety issue: No ]
VEGF levels, IL-8 levels and MDSC levels (Phase I) [ Time Frame: Up to 30 days post-treatment ] [ Designated as safety issue: No ]
Incidence of grade 3 or higher toxicities accessed based on CTCAE version 4.0 (Phase II) [ Time Frame: Up to 30 days post-treatment ] [ Designated as safety issue: Yes ]
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 ] [ Designated as safety issue: No ]
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 ] [ Designated as safety issue: No ]
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 ] [ Designated as safety issue: No ]
Will be obtained using Kaplan-Meier and Proportional Hazards methods.


Estimated Enrollment:	66
Study Start Date:	October 2012
Estimated Primary Completion Date:	March 2016 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
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.	Drug: pazopanib hydrochloride Given PO Other Names: GW786034B Votrient Biological: bevacizumab Given IV Other Names: anti-VEGF humanized monoclonal antibody anti-VEGF monoclonal antibody Avastin rhuMAb VEGF Other: pharmacological study Correlative studies Other Name: pharmacological studies Other: laboratory biomarker analysis Correlative studies

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 dose-escalation 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.

Eligibility


Ages Eligible for Study:	18 Years and older
Genders Eligible for Study:	Both
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 ([NR) 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
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

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01684397

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 Pittsburg Medical Center, Hillman Cancer Center	Recruiting
Pittsburgh, Pennsylvania, United States, 15232
Contact: Rahul A Parikh, MD, PhD 412-692-4724 parikhr@upmc.edu
Contact: Bethany Flaherty 412-623-8962 schnelbachb@upmc.edu
Principal Investigator: Rahul A Parikh, MD, PhD

Sponsors and Collaborators

Roswell Park Cancer Institute

National Cancer Institute (NCI)

GlaxoSmithKline

Investigators


Principal Investigator:	Saby George	Roswell Park Cancer Institute

More Information

No publications provided


Responsible Party:	Roswell Park Cancer Institute
ClinicalTrials.gov Identifier:	NCT01684397 History of Changes
Other Study ID Numbers:	I 191711, NCI-2012-01247
Study First Received:	August 24, 2012
Last Updated:	February 9, 2015
Health Authority:	United States: Food and Drug Administration

Additional relevant MeSH terms:


Carcinoma, Renal Cell Adenocarcinoma Carcinoma Kidney Diseases Kidney Neoplasms Neoplasms Neoplasms by Histologic Type Neoplasms by Site Neoplasms, Glandular and Epithelial Urogenital Neoplasms Urologic Diseases Urologic Neoplasms	Antibodies Antibodies, Monoclonal Bevacizumab Angiogenesis Inhibitors Angiogenesis Modulating Agents Antineoplastic Agents Growth Inhibitors Growth Substances Immunologic Factors Pharmacologic Actions Physiological Effects of Drugs Therapeutic Uses

ClinicalTrials.gov processed this record on March 03, 2015