Axitinib (AG-013736) With Or Without Dose Titration (Increase) In Patients With Kidney Cancer
- Registration Number
- NCT00835978
- Lead Sponsor
- Pfizer
- Brief Summary
Axitinib dose titration (giving a higher dose of the drug above its standard starting dose) among certain patients may improve the response to treatment.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 213
- 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
- brain/CNS metastasis
- using more than 2 blood pressure medications
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- Not specified
- Arm && Interventions
Group Intervention Description A axitinib Randomized arm C axitinib Non-randomized arm B axitinib Randomized arm
- Primary Outcome Measures
Name Time Method Objective Response Rate (ORR) - Percentage of Participants With Objective Response 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
Name Time Method Progression-Free Survival (PFS) 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.
Overall Survival (OS) 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.
Time to Reach Maximum Observed Plasma Concentration (Tmax) for Axitinib, 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.
Duration of Response (DR) 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.
Maximum Observed Plasma Concentration (Cmax) of Axitinib 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.
Apparent Oral Clearance (CL/F) of Axitinib 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.
Change From Baseline in Diastolic Blood Pressure 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 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.
PFS in Subgroups That Were Defined by Vascular Endothelial Growth Factor A (VEGFA) or Vascular Endothelial Growth Factor Receptor 3 (VEGFR3) Polymorphisms 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.
Change From Baseline in Systolic Blood Pressure 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
Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) for Axitinib 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.
Apparent Volume of Distribution During the Elimination Phase (Vz/F) for Axitinib 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.
Comparison of the Ratio of CECs in Blood: CD146+/CD105+ at Each Time Point to Baseline 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+ 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 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.
Area Under the Curve From Time Zero to 24 Hours[AUC(0-24)] for Axitinib 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 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.
ORR in Subgroups That Were Defined by Vascular Endothelial Growth Factor A (VEGFA) or Vascular Endothelial Growth Factor Receptor 3 (VEGFR3) Polymorphisms 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.
Trial Locations
- Locations (63)
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
🇺🇸Baltimore, Maryland, United States
Massachusetts General Hospital
🇺🇸Boston, Massachusetts, United States
The University of Texas MD Anderson Cancer Center
🇺🇸Houston, Texas, United States
Indiana University Melvin and Bren Simon Cancer Center
🇺🇸Indianapolis, Indiana, United States
National Cancer Center
🇯🇵Chuo-ku, Tokyo, Japan
Keio University Hospital
🇯🇵Shinjuku-ku, Tokyo, Japan
Japanese Foundation For Cancer Research Cancer Institute Hospital
🇯🇵Koto-ku, Tokyo, Japan
Oregon Health and Science University
🇺🇸Portland, Oregon, United States
East Bay Medical Oncology/Hematology Medical Associates Inc
🇺🇸San Leandro, California, United States
The University Hospital
🇺🇸Cincinnati, Ohio, United States
West Chester Hospital Medical Building
🇺🇸West Chester, Ohio, United States
Texas Oncology, Sammons Cancer Center
🇺🇸Dallas, Texas, United States
East Bay Medical Oncology/Hematology Medical Associates Inc.
🇺🇸Antioch, California, United States
Comprehensive Blood and Cancer Center
🇺🇸Bakersfield, California, United States
Diablo Valley Oncology and Hematology Medical Group Inc
🇺🇸Pleasant Hill, California, United States
H. Lee Moffitt Cancer Center and Research Institute
🇺🇸Tampa, Florida, United States
Johns Hopkins Hospital
🇺🇸Baltimore, Maryland, United States
IU Health University Hospital
🇺🇸Indianapolis, Indiana, United States
University of Maryland Greenebaum Cancer Center
🇺🇸Baltimore, Maryland, United States
Washington University
🇺🇸Saint Louis, Missouri, United States
Cancer and Hematology Centers of Western Michigan
🇺🇸Grand Rapids, Michigan, United States
The Ohio State University, James Cancer Hospital
🇺🇸Columbus, Ohio, United States
Virginia Mason Medical Center
🇺🇸Seattle, Washington, United States
Fakultni nemocnice Olomouc Onkologicka klinika
🇨🇿Olomouc, Czechia
JamesCare in Kenny
🇺🇸Columbus, Ohio, United States
Masarykuv onkologicky ustav
🇨🇿Brno, CZE, Czechia
Universitaetsklinikum Duesseldorf
🇩🇪Duesseldorf, Germany
Fakultni nemocnice Na Bulovce
🇨🇿Praha 8, Czechia
Klinikum der J. W. Goethe-Universitaet, Medizinische Klinik II
🇩🇪Frankfurt, Germany
Kinki University Hospital
🇯🇵Osakasayama, Osaka, Japan
Hamamatsu University School of Medicine, University Hospital
🇯🇵Hamamatsu-City, Shizuoka, Japan
Kobe University Hospital
🇯🇵Kobe, Hyogo, Japan
Akita University Hospital
🇯🇵Akita, Japan
Chiba Cancer Center
🇯🇵Chiba, Japan
Nagasaki University Hospital
🇯🇵Nagasaki, Japan
Kyushu University Hospital
🇯🇵Fukuoka, Japan
GBUZ "Samara Regional Clinical Oncology Dispensary"
🇷🇺Samara, Russian Federation
Yamagata University Hospital
🇯🇵Yamagata, Japan
Hospital General Universitario Gregorio Marañon
🇪🇸Madrid, Spain
FSBSI "N.N. Blokhin Russian Cancer Research Center"
🇷🇺Moscow, Russian Federation
Hospital de La Princesa
🇪🇸Madrid, Spain
Hospital Universitario La Paz
🇪🇸Madrid, Spain
University of Nebraska Medical Center
🇺🇸Omaha, Nebraska, United States
Bay Area Cancer Research Group, LLC
🇺🇸Pleasant Hill, California, United States
Investigational Drug Services, IUHSCC
🇺🇸Indianapolis, Indiana, United States
Beth Israel Deaconess Medical Center
🇺🇸Boston, Massachusetts, United States
Nebraska Methodist Hospital
🇺🇸Omaha, Nebraska, United States
Nevada Cancer Institute
🇺🇸Las Vegas, Nevada, United States
Cleveland Clinic
🇺🇸Cleveland, Ohio, United States
University of Cincinnati
🇺🇸Cincinnati, Ohio, United States
Krajska zdravotni, a.s. - Masarykova nemocnice V Usti nad Labem, o.z.
🇨🇿Usti nad Labem, Czechia
Klinikum Weiden Klinik fuer Urologie, Andrologie und Kinderurologie
🇩🇪Weiden, Germany
Medizinische Hochschule Hannover, Abt. Haematologie, Haemostaseologie & Onkologie
🇩🇪Hannover, Germany
Nagoya University Hospital
🇯🇵Nagoya, Aichi, Japan
Hokkaido University Hospital
🇯🇵Sapporo, Hokkaido, Japan
Eberhardt-Karls-Universitaet Tuebingen, Klinik fuer Urologie
🇩🇪Tuebingen, Germany
Sapporo Medical University Hospital
🇯🇵Sapporo, Hokkaido, Japan
Tokushima University Hospital
🇯🇵Tokushima, Japan
Medical Radiology Research Center of the Minzdravsotsrazvitiya of Russia
🇷🇺Obninsk, Kaluga Region, Russian Federation
FSBI"Russian Scientific Center of Roengenoradiology" of the MH of RF
🇷🇺Moscow, Russian Federation
Saint-Petersburg's State Healthcare Institution 'City Clinical Oncology Dispensary'
🇷🇺Saint-Petersburg, Russian Federation
State Healthcare Institution "Leningrad Regional Oncology Dispensary"
🇷🇺Poselok Kuzmolovskiy, Vsevolozhskiy Region, Leningradskaya Oblast, Russian Federation
Barnes-Jewish Hospital
🇺🇸Saint Louis, Missouri, United States