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

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
Pfizer
ClinicalTrials.gov Identifier:
NCT00835978
First received: February 2, 2009
Last updated: August 5, 2014
Last verified: August 2014
  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
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, 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 with minimum follow-up of 12 months; assessments performed at baseline and repeated every 8 weeks. ] [ Designated as safety issue: No ]
    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). 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:
  • Objective Response Rate (ORR) - Percentage of Participants With Objective Response (All Participants) [ Time Frame: Baseline up to disease progression, death, or withdrawal with minimum follow-up of 12 months; assessments performed at baseline and repeated every 8 weeks. ] [ Designated as safety issue: No ]
    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). 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.

  • 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 ] [ Designated as safety issue: No ]
    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.

  • Progression-Free Survival (PFS) - All Participants [ 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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    DR was defined as the time from the first documentation of objective tumor response 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 at least one year after the last patient has been randomized. ] [ Designated as safety issue: Yes ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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: Baseline up to follow-up visit ] [ Designated as safety issue: Yes ]
    Value at respective visit minus value at baseline

  • Change From Baseline in Diastolic Blood Pressure [ Time Frame: Baseline up to follow-up visit ] [ Designated as safety issue: Yes ]
    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: Baseline ] [ Designated as safety issue: No ]
    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: Cycle 1 Day 1 (C1D1), C1D15, C2D15, End of therapy (EOT) ] [ Designated as safety issue: No ]
    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: Baseline ] [ Designated as safety issue: No ]
    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: C1D1, C1D15, C2D15, EOT ] [ Designated as safety issue: No ]
    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: Baseline, C1D1 ] [ Designated as safety issue: No ]
    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: Baseline, C1D1 ] [ Designated as safety issue: No ]
    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
Estimated Study Completion Date: August 2014
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
Genders Eligible for Study:   Both
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

  Show 61 Study Locations
Sponsors and Collaborators
Pfizer
Investigators
Study Director: Pfizer CT.gov Call Center Pfizer
  More Information

Additional Information:
No publications provided by Pfizer

Additional 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
Study First Received: February 2, 2009
Results First Received: October 11, 2013
Last Updated: August 5, 2014
Health Authority: United States: Food and Drug Administration

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
Pharmacologic Actions

ClinicalTrials.gov processed this record on September 18, 2014