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

Randomized, Double-blind Phase 2 Study Of Axitinib (Ag-013736) With Or Without Dose Titration In Patients With Metastatic Renal Cell Carcinoma

Axitinib dose titration (giving a higher dose of the drug above its standard starting dose) among certain patients may improve the response to treatment.

Study Overview

• Status: Completed
• Conditions: Carcinoma, Renal Cell
• Intervention / Treatment: Drug: axitinib; Drug: axitinib; Drug: axitinib

• Study Type: Interventional
• Enrollment (Actual): 213
• Phase: Phase 2

Contacts and Locations

Study Locations

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

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: A; Randomized arm	Drug: axitinib; axitinib 5mg BID (open-label) + axitinib dose titration (blinded); Drug: axitinib; axitinib 5mg BID (open-label) + placebo dose titration (blinded); Drug: axitinib; axitinib 5mg BID (open-label)
Other: B; Randomized arm	Drug: axitinib; axitinib 5mg BID (open-label) + axitinib dose titration (blinded); Drug: axitinib; axitinib 5mg BID (open-label) + placebo dose titration (blinded); Drug: axitinib; axitinib 5mg BID (open-label)
Other: C; Non-randomized arm	Drug: axitinib; axitinib 5mg BID (open-label) + axitinib dose titration (blinded); Drug: axitinib; axitinib 5mg BID (open-label) + placebo dose titration (blinded); Drug: axitinib; axitinib 5mg BID (open-label)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective Response Rate (ORR) - Percentage of Participants With Objective Response	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.	Baseline up to disease progression, death, or withdrawal; performed at baseline and repeated every 8 weeks for 24 weeks, then every 12 weeks.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-Free Survival (PFS)	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.	Baseline up to disease progression, death, or withdrawal; performed at baseline and repeated every 8 weeks for 24 weeks, then every 12 weeks.
Duration of Response (DR)	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.	Baseline up to disease progression, death, or withdrawal; performed at baseline and repeated every 8 weeks for 24 weeks, then every 12 weeks
Overall Survival (OS)	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.	Baseline up to disease progression, death, or withdrawal; performed at baseline and repeated every 8 weeks for 24 weeks, then every 12 weeks.
Maximum Observed Plasma Concentration (Cmax) of Axitinib	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.	Cycle 2 Day 15 (C2D15): pre-dose, 0.5, 1, 2, 4, and 6 hours post-dose
Time to Reach Maximum Observed Plasma Concentration (Tmax) for Axitinib,	Tmax for steady-state axitinib was evaluated on Cycle 2 Day 15.	C2D15: pre-dose, 0.5, 1, 2, 4, and 6 hours post-dose
Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) for Axitinib	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.	C2D15: pre-dose, 0.5, 1, 2, 4, and 6 hours post-dose
Area Under the Curve From Time Zero to 24 Hours[AUC(0-24)] for Axitinib	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.	C2D15: pre-dose, 0.5, 1, 2, 4, and 6 hours post-dose
Plasma Decay Half-Life (t1/2) for Axitinib	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.	C2D15: pre-dose, 0.5, 1, 2, 4, and 6 hours post-dose
Apparent Oral Clearance (CL/F) of Axitinib	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.	C2D15: pre-dose, 0.5, 1, 2, 4, and 6 hours post-dose
Apparent Volume of Distribution During the Elimination Phase (Vz/F) for Axitinib	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.	C2D15: pre-dose, 0.5, 1, 2, 4, and 6 hours post-dose
Change From Baseline in Systolic Blood Pressure	Value at respective visit minus value at baseline	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.
Change From Baseline in Diastolic Blood Pressure	Value at respective visit minus value at baseline.	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.
Comparison of Circulating Endothelial Cells (CECs) in Blood: Cluster of Differentiation (CD)146+/CD105+ at Baseline	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.	At baseline - Beginning of the lead-in period (Cycle 1 Day 1)
Comparison of the Ratio of CECs in Blood: CD146+/CD105+ at Each Time Point to Baseline	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.	At end of the lead-in period (Cycle 1 Day 15), Cycle 2 Day 15 and End of therapy (EOT)
Circulating Endothelial Cells (CECs) in Blood: CD31+/CD146+	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.	At baseline - Beginning of the lead-in period (Cycle 1 Day 1)
Comparison of Ratio of CECs in Blood: CD31+/CD146+ at Each Time Point to Baseline	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.	At end of the lead-in period (Cycle 1 Day 15), Cycle 2 Day 15 and End of therapy (EOT)
ORR in Subgroups That Were Defined by Vascular Endothelial Growth Factor A (VEGFA) or Vascular Endothelial Growth Factor Receptor 3 (VEGFR3) Polymorphisms	ORR, defined as proportion of participants with CR or PR according to RECIST, in subgroups that were defined by VEGFA or VEGFR3 polymorphisms.	At baseline - Beginning of the lead-in period (Cycle 1 Day 1)
PFS in Subgroups That Were Defined by Vascular Endothelial Growth Factor A (VEGFA) or Vascular Endothelial Growth Factor Receptor 3 (VEGFR3) Polymorphisms	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.	At baseline - Beginning of the lead-in period (Cycle 1 Day 1)

Collaborators and Investigators

• Sponsor: Pfizer

Publications and helpful links

General Publications

• de Velasco G, McKay RR, Lin X, Moreira RB, Simantov R, Choueiri TK. Comprehensive Analysis of Survival Outcomes in Non-Clear Cell Renal Cell Carcinoma Patients Treated in Clinical Trials. Clin Genitourin Cancer. 2017 Dec;15(6):652-660.e1. doi: 10.1016/j.clgc.2017.03.004. Epub 2017 Mar 21.
• Grunwald V, Lin X, Kalanovic D, Simantov R. Early Tumour Shrinkage: A Tool for the Detection of Early Clinical Activity in Metastatic Renal Cell Carcinoma. Eur Urol. 2016 Dec;70(6):1006-1015. doi: 10.1016/j.eururo.2016.05.010. Epub 2016 May 26.
• Tomita Y, Uemura H, Oya M, Shinohara N, Habuchi T, Fujii Y, Kamei Y, Umeyama Y, Bair AH, Rini BI. Patients with metastatic renal cell carcinoma who benefit from axitinib dose titration: analysis from a randomised, double-blind phase II study. BMC Cancer. 2019 Jan 7;19(1):17. doi: 10.1186/s12885-018-5224-6.
• Rini BI, Melichar B, Ueda T, Grunwald V, Fishman MN, Arranz JA, Bair AH, Pithavala YK, Andrews GI, Pavlov D, Kim S, Jonasch E. Axitinib with or without dose titration for first-line metastatic renal-cell carcinoma: a randomised double-blind phase 2 trial. Lancet Oncol. 2013 Nov;14(12):1233-42. doi: 10.1016/S1470-2045(13)70464-9. Epub 2013 Oct 18. Erratum In: Lancet Oncol. 2014 Jun;15(7):e253.

Helpful Links

• To obtain contact information for a study center near you, click here.

Study record dates

Study Major Dates

• Study Start: August 1, 2009
• Primary Completion (Actual): October 1, 2012
• Study Completion (Actual): February 1, 2016

Study Registration Dates

• First Submitted: February 2, 2009
• First Submitted That Met QC Criteria: February 2, 2009
• First Posted (Estimate): February 4, 2009

Study Record Updates

• Last Update Posted (Actual): May 30, 2017
• Last Update Submitted That Met QC Criteria: April 18, 2017
• Last Verified: April 1, 2017

More Information

Terms related to this study

• Keywords: kidney cancer; axitinib or AG-013736 dose titration (increase) renal cell carcinoma
• 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; Carcinoma, Renal Cell; Carcinoma; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Axitinib
• Other Study ID Numbers: A4061046; 2008-007786-23 (EudraCT Number)