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

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ClinicalTrials.gov Identifier: NCT00835978
Recruitment Status : Completed
First Posted : February 4, 2009
Results First Posted : May 26, 2014
Last Update Posted : May 30, 2017
Sponsor:
Information provided by (Responsible Party):
Pfizer

Study Description
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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.

Condition or disease Intervention/treatment Phase
Carcinoma, Renal Cell Drug: axitinib Phase 2

Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 213 participants
Allocation: Randomized
Masking: Quadruple (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
Study Start Date : August 2009
Actual Primary Completion Date : October 2012
Actual Study Completion Date : February 2016

Resource links provided by the National Library of Medicine

Drug Information available for: Axitinib

Arms and Interventions
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Arm Intervention/treatment
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)


Outcome Measures
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Primary Outcome Measures :
  1. 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 :
  1. 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.

  2. 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.

  3. 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.

  4. 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.

  5. 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.

  6. 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.

  7. 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.

  8. 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.

  9. 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.

  10. 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.

  11. 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

  12. 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.

  13. 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.

  14. 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.

  15. 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.

  16. 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.

  17. 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.

  18. 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.


Eligibility Criteria
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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
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
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00835978


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

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: Pfizer
ClinicalTrials.gov Identifier: NCT00835978    
Other Study ID Numbers: A4061046
2008-007786-23 ( EudraCT Number )
First Posted: February 4, 2009    Key Record Dates
Results First Posted: May 26, 2014
Last Update Posted: May 30, 2017
Last Verified: April 2017
Keywords provided by Pfizer:
axitinib or AG-013736 dose titration (increase) renal cell carcinoma
kidney cancer
Additional relevant MeSH terms:
Layout table for 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
Female Urogenital Diseases
 Female Urogenital Diseases and Pregnancy Complications
Urogenital Diseases
Kidney Diseases
Urologic Diseases
Male Urogenital Diseases
Axitinib
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action