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Axitinib (AG-013736) With Or Without Dose Titration (Increase) In Patients With Kidney Cancer

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Pfizer
ClinicalTrials.gov Identifier:
NCT00835978
First received: February 2, 2009
Last updated: April 18, 2017
Last verified: April 2017
  Purpose
Axitinib dose titration (giving a higher dose of the drug above its standard starting dose) among certain patients may improve the response to treatment.

Condition Intervention Phase
Carcinoma, Renal Cell Drug: axitinib Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Masking: Participant, Care Provider, Investigator, Outcomes Assessor
Primary Purpose: Treatment
Official Title: Randomized, Double-blind Phase 2 Study Of Axitinib (Ag-013736) With Or Without Dose Titration In Patients With Metastatic Renal Cell Carcinoma

Resource links provided by NLM:


Further study details as provided by Pfizer:

Primary Outcome Measures:
  • Objective Response Rate (ORR) - Percentage of Participants With Objective Response [ Time Frame: Baseline up to disease progression, death, or withdrawal; performed at baseline and repeated every 8 weeks for 24 weeks, then every 12 weeks. ]
    ORR was defined as the proportion of participants with objective response based assessment of complete response (CR) or partial response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST v1.0). CR was defined as complete disappearance of all target lesions and non-target disease. No new lesions. PR was defined as >=30% decrease on study under baseline of the sum of longest diameters of all target lesions. No unequivocal progression of non-target disease. No new lesions.


Secondary Outcome Measures:
  • Progression-Free Survival (PFS) [ Time Frame: Baseline up to disease progression, death, or withdrawal; performed at baseline and repeated every 8 weeks for 24 weeks, then every 12 weeks. ]
    The time from first dose administration to first documentation of objective tumor progression or to death due to any cause. PFS in each arm was assessed using the Kaplan-Meier method and estimates of the PFS curves from the Kaplan-Meier method were presented.

  • Duration of Response (DR) [ Time Frame: Baseline up to disease progression, death, or withdrawal; performed at baseline and repeated every 8 weeks for 24 weeks, then every 12 weeks ]
    DR was defined as the time from the first documentation of objective tumor response (complete response - CR or Partial response - PR) to the first documentation of objective tumor progression or to death due to any cause, whichever occurred first. The median values were estimated based on Kaplan-Meier method. 95% confidence interval was based on the Brookmeyer and Crowley method.

  • Overall Survival (OS) [ Time Frame: Baseline up to disease progression, death, or withdrawal; performed at baseline and repeated every 8 weeks for 24 weeks, then every 12 weeks. ]
    OS was defined as the time from date of the first dose of the study medication to date of death due to any cause. For participants who did not die, their survival times were to be censored at the last date they were known to be alive.

  • Maximum Observed Plasma Concentration (Cmax) of Axitinib [ Time Frame: Cycle 2 Day 15 (C2D15): pre-dose, 0.5, 1, 2, 4, and 6 hours post-dose ]
    Cmax for steady-state axitinib was evaluated on Cycle 2 Day 15. Results were normalized to axitinib 7 mg dose for active titration arm and axitinib 5 mg dose for placebo titration arm. Results were normalized to axitinib 7 mg dose for active titration arm and axitinib 5 mg dose for placebo titration arm.

  • Time to Reach Maximum Observed Plasma Concentration (Tmax) for Axitinib, [ Time Frame: C2D15: pre-dose, 0.5, 1, 2, 4, and 6 hours post-dose ]
    Tmax for steady-state axitinib was evaluated on Cycle 2 Day 15.

  • Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) for Axitinib [ Time Frame: C2D15: pre-dose, 0.5, 1, 2, 4, and 6 hours post-dose ]
    Area under the plasma concentration time-curve from zero to the last measurable concentration (AUClast). AUClast for steady-state axitinib was evaluated on Cycle 2 Day 15. Results were normalized to axitinib 7 mg dose for active titration arm and axitinib 5 mg dose for placebo titration arm.

  • Area Under the Curve From Time Zero to 24 Hours[AUC(0-24)] for Axitinib [ Time Frame: C2D15: pre-dose, 0.5, 1, 2, 4, and 6 hours post-dose ]
    Area under the plasma concentration time-curve from zero 24 hours[AUC(0-24). AUC(0-24) for steady-state axitinib was evaluated on Cycle 2 Day 15. Results were normalized to axitinib 7 mg dose for active titration arm and axitinib 5 mg dose for placebo titration arm.

  • Plasma Decay Half-Life (t1/2) for Axitinib [ Time Frame: C2D15: pre-dose, 0.5, 1, 2, 4, and 6 hours post-dose ]
    Plasma decay half-life is the time measured for the plasma concentration to decrease by one half. Plasma decay half life for steady-state axitinib was evaluated on Cycle 2 Day 15.

  • Apparent Oral Clearance (CL/F) of Axitinib [ Time Frame: C2D15: pre-dose, 0.5, 1, 2, 4, and 6 hours post-dose ]
    Clearance (CL) of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed (F). Clearance is defined as the volume of blood from which drug can be completely removed per unit of time. CL/F for steady-state axitinib was evaluated on Cycle 2 Day 15.

  • Apparent Volume of Distribution During the Elimination Phase (Vz/F) for Axitinib [ Time Frame: C2D15: pre-dose, 0.5, 1, 2, 4, and 6 hours post-dose ]
    Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired blood concentration of a drug. Vz/F is influenced by the fraction absorbed. Vz/F for steady-state axitinb was evaluated on Cycle 2 Day 15.

  • Change From Baseline in Systolic Blood Pressure [ Time Frame: At screening (D-14 to D-1); lead-in period: Cycle 1 - Day 1 and Day 15; Cycle 2 - Day 1 and Day 15; Cycle 3 & subsequent cycles Day 1; end of study and follow-up 28 days after last dose. ]
    Value at respective visit minus value at baseline

  • Change From Baseline in Diastolic Blood Pressure [ Time Frame: At screening (D-14 to D-1); lead-in period: Cycle 1 - Day 1 and Day 15; Cycle 2 - Day 1 and Day 15; Cycle 3 & subsequent cycles Day 1; end of study and follow-up 28 days after last dose. ]
    Value at respective visit minus value at baseline.

  • Comparison of Circulating Endothelial Cells (CECs) in Blood: Cluster of Differentiation (CD)146+/CD105+ at Baseline [ Time Frame: At baseline - Beginning of the lead-in period (Cycle 1 Day 1) ]
    CECs are noninvasive marker of vascular damage, remodeling, and dysfunction. Samples were collected and following proteins were analyzed: CD146+/CD105+ CECs, CD146+/CD105+ mean fluorescence intensity (MFI) platelet derived growth factor receptor (PDGFR)-beta, CD146+/CD105+ MFI phospho-PDGFR (pPDGFR)-beta, CD146+/CD105+ phospho-Vascular endothelial growth factor receptor (pVEGFR), CD146+/CD105+ MFI VEGFR. The ratio of plasma levels of the biomarkers at the selected time point vs baseline is reported.

  • Comparison of the Ratio of CECs in Blood: CD146+/CD105+ at Each Time Point to Baseline [ Time Frame: At end of the lead-in period (Cycle 1 Day 15), Cycle 2 Day 15 and End of therapy (EOT) ]
    CECs are noninvasive marker of vascular damage, remodeling, and dysfunction. Samples were collected and following proteins were analyzed: CD146+/CD105+ CECs, CD146+/CD105+ MFI platelet derived growth factor receptor (PDGFR)-beta, CD146+/CD105+ MFI phospho-PDGFR (pPDGFR)-beta, CD146+/CD105+ phospho-VEGFR (pVEGFR), CD146+/CD105+ MFI VEGFR. The ratio of plasma levels of the biomarkers at the selected time point vs baseline is reported.

  • Circulating Endothelial Cells (CECs) in Blood: CD31+/CD146+ [ Time Frame: At baseline - Beginning of the lead-in period (Cycle 1 Day 1) ]
    CECs are noninvasive marker of vascular damage, remodeling, and dysfunction. Samples were collected and following proteins were analyzed: CD31+/CD146+ CECs, CD31+/CD146+ MFI PDGFR-beta, CD31+/CD146+ MFI pPDGFR-beta, CD31+/CD146+ pVEGFR, CD31+/CD146+ MFI VEGFR. The ratio of plasma levels of the biomarkers at the selected time point vs baseline is reported.

  • Comparison of Ratio of CECs in Blood: CD31+/CD146+ at Each Time Point to Baseline [ Time Frame: At end of the lead-in period (Cycle 1 Day 15), Cycle 2 Day 15 and End of therapy (EOT) ]
    CECs are noninvasive marker of vascular damage, remodeling, and dysfunction. Samples were collected and following proteins were analyzed: CD31+/CD146+ CECs, CD31+/CD146+ MFI PDGFR-beta, CD31+/CD146+ MFI pPDGFR-beta, CD31+/CD146+ pVEGFR, CD31+/CD146+ MFI VEGFR. The ratio of plasma levels of the biomarkers at the selected time point vs baseline is reported.

  • ORR in Subgroups That Were Defined by Vascular Endothelial Growth Factor A (VEGFA) or Vascular Endothelial Growth Factor Receptor 3 (VEGFR3) Polymorphisms [ Time Frame: At baseline - Beginning of the lead-in period (Cycle 1 Day 1) ]
    ORR, defined as proportion of participants with CR or PR according to RECIST, in subgroups that were defined by VEGFA or VEGFR3 polymorphisms.

  • PFS in Subgroups That Were Defined by Vascular Endothelial Growth Factor A (VEGFA) or Vascular Endothelial Growth Factor Receptor 3 (VEGFR3) Polymorphisms [ Time Frame: At baseline - Beginning of the lead-in period (Cycle 1 Day 1) ]
    PFS, defined as the time from randomization to first documentation of objective tumor progression or to death due to any cause, in subgroups that were defined by VEGFA or VEGFR3 polymorphisms. Estimates of the PFS curves from the Kaplan-Meier method were presented.


Enrollment: 213
Study Start Date: August 2009
Study Completion Date: February 2016
Primary Completion Date: October 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
A
Randomized arm
Drug: axitinib
axitinib 5mg BID (open-label) + axitinib dose titration (blinded)
B
Randomized arm
Drug: axitinib
axitinib 5mg BID (open-label) + placebo dose titration (blinded)
C
Non-randomized arm
Drug: axitinib
axitinib 5mg BID (open-label)

  Eligibility

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

Inclusion Criteria:

  • metastatic renal cell carcinoma (kidney cancer) with clear cell component
  • no prior systemic therapy (including no prior adjuvant or neoadjuvant)
  • Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1
  • Blood Pressure < or = 140/90mmHg

Exclusion Criteria:

  • brain/CNS metastasis
  • using more than 2 blood pressure medications
  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: NCT00835978

  Hide Study Locations
Locations
United States, California
East Bay Medical Oncology/Hematology Medical Associates Inc.
Antioch, California, United States, 94531
Comprehensive Blood and Cancer Center
Bakersfield, California, United States, 93309
Bay Area Cancer Research Group, LLC
Pleasant Hill, California, United States, 94523
Diablo Valley Oncology and Hematology Medical Group Inc
Pleasant Hill, California, United States, 94523
East Bay Medical Oncology/Hematology Medical Associates Inc
Pleasant Hill, California, United States, 94523
East Bay Medical Oncology/Hematology Medical Associates Inc
San Leandro, California, United States, 94578
United States, Florida
H. Lee Moffitt Cancer Center and Research Institute
Tampa, Florida, United States, 33612
United States, Indiana
Indiana University Melvin and Bren Simon Cancer Center
Indianapolis, Indiana, United States, 46202
Investigational Drug Services, IUHSCC
Indianapolis, Indiana, United States, 46202
IU Health University Hospital
Indianapolis, Indiana, United States, 46202
United States, Maryland
University of Maryland Greenebaum Cancer Center
Baltimore, Maryland, United States, 21201
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Baltimore, Maryland, United States, 21231
Johns Hopkins Hospital
Baltimore, Maryland, United States, 21287
United States, Massachusetts
Massachusetts General Hospital
Boston, Massachusetts, United States, 02114
Beth Israel Deaconess Medical Center
Boston, Massachusetts, United States, 02215
United States, Michigan
Cancer and Hematology Centers of Western Michigan
Grand Rapids, Michigan, United States, 49503
United States, Missouri
Barnes-Jewish Hospital
Saint Louis, Missouri, United States, 63110-1094
Washington University
Saint Louis, Missouri, United States, 63110
United States, Nebraska
Nebraska Methodist Hospital
Omaha, Nebraska, United States, 68114
University of Nebraska Medical Center
Omaha, Nebraska, United States, 68198-7680
United States, Nevada
Nevada Cancer Institute
Las Vegas, Nevada, United States, 89135
United States, Ohio
The University Hospital
Cincinnati, Ohio, United States, 45219
University of Cincinnati
Cincinnati, Ohio, United States, 45219
Cleveland Clinic
Cleveland, Ohio, United States, 44195
The Ohio State University, James Cancer Hospital
Columbus, Ohio, United States, 43210
JamesCare in Kenny
Columbus, Ohio, United States, 43221
West Chester Hospital Medical Building
West Chester, Ohio, United States, 45069
United States, Oregon
Oregon Health and Science University
Portland, Oregon, United States, 97239
United States, Texas
Texas Oncology, Sammons Cancer Center
Dallas, Texas, United States, 75246
The University of Texas MD Anderson Cancer Center
Houston, Texas, United States, 77030-4004
United States, Washington
Virginia Mason Medical Center
Seattle, Washington, United States, 98101
Czechia
Masarykuv onkologicky ustav
Brno, CZE, Czechia, 656 53
Fakultni nemocnice Olomouc Onkologicka klinika
Olomouc, Czechia, 775 20
Fakultni nemocnice Na Bulovce
Praha 8, Czechia, 180 81
Krajska zdravotni, a.s. - Masarykova nemocnice V Usti nad Labem, o.z.
Usti nad Labem, Czechia, 401 13
Germany
Universitaetsklinikum Duesseldorf
Duesseldorf, Germany, 40225
Klinikum der J. W. Goethe-Universitaet, Medizinische Klinik II
Frankfurt, Germany, 60590
Medizinische Hochschule Hannover, Abt. Haematologie, Haemostaseologie & Onkologie
Hannover, Germany, 30625
Eberhardt-Karls-Universitaet Tuebingen, Klinik fuer Urologie
Tuebingen, Germany, 72076
Klinikum Weiden Klinik fuer Urologie, Andrologie und Kinderurologie
Weiden, Germany, 92637
Japan
Nagoya University Hospital
Nagoya, Aichi, Japan, 466-8560
Sapporo Medical University Hospital
Sapporo, Hokkaido, Japan, 060-8543
Hokkaido University Hospital
Sapporo, Hokkaido, Japan, 060-8638
Kobe University Hospital
Kobe, Hyogo, Japan, 650-0017
Kinki University Hospital
Osakasayama, Osaka, Japan, 589-8511
Hamamatsu University School of Medicine, University Hospital
Hamamatsu-City, Shizuoka, Japan, 431-3192
National Cancer Center
Chuo-ku, Tokyo, Japan, 104-0045
Japanese Foundation For Cancer Research Cancer Institute Hospital
Koto-ku, Tokyo, Japan, 135-8550
Keio University Hospital
Shinjuku-ku, Tokyo, Japan, 160-8582
Akita University Hospital
Akita, Japan, 010-8543
Chiba Cancer Center
Chiba, Japan, 260-8717
Kyushu University Hospital
Fukuoka, Japan, 812-8582
Nagasaki University Hospital
Nagasaki, Japan, 852-8501
Tokushima University Hospital
Tokushima, Japan, 770-8503
Yamagata University Hospital
Yamagata, Japan, 990-9585
Russian Federation
Medical Radiology Research Center of the Minzdravsotsrazvitiya of Russia
Obninsk, Kaluga Region, Russian Federation, 249036
State Healthcare Institution "Leningrad Regional Oncology Dispensary"
Poselok Kuzmolovskiy, Vsevolozhskiy Region, Leningradskaya Oblast, Russian Federation, 188663
FSBSI "N.N. Blokhin Russian Cancer Research Center"
Moscow, Russian Federation, 115478
FSBI"Russian Scientific Center of Roengenoradiology" of the MH of RF
Moscow, Russian Federation, 117997
Saint-Petersburg's State Healthcare Institution 'City Clinical Oncology Dispensary'
Saint-Petersburg, Russian Federation, 197022
Saint-Petersburg's State Healthcare Institution 'City Clinical Oncology Dispensary'
Saint-Petersburg, Russian Federation, 198255
GBUZ "Samara Regional Clinical Oncology Dispensary"
Samara, Russian Federation, 443031
Spain
Hospital de La Princesa
Madrid, Spain, 28006
Hospital General Universitario Gregorio Marañon
Madrid, Spain, 28007
Hospital Universitario La Paz
Madrid, Spain, 28046
Sponsors and Collaborators
Pfizer
Investigators
Study Director: Pfizer CT.gov Call Center Pfizer
  More Information

Additional Information:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Pfizer
ClinicalTrials.gov Identifier: NCT00835978     History of Changes
Other Study ID Numbers: A4061046
2008-007786-23 ( EudraCT Number )
Study First Received: February 2, 2009
Results First Received: October 11, 2013
Last Updated: April 18, 2017

Keywords provided by Pfizer:
axitinib or AG-013736 dose titration (increase) renal cell carcinoma
kidney cancer

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
Axitinib
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on July 26, 2017