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

• 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: Pfizer
• Information provided by (Responsible Party): Pfizer

Tracking Information

• First Submitted Date: February 2, 2009
• First Posted Date: February 4, 2009
• Results First Submitted Date: October 11, 2013
• Results First Posted Date: May 26, 2014
• Last Update Posted Date: May 30, 2017
• Study Start Date: August 2009
• Actual Primary Completion Date: October 2012 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: April 18, 2017)

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.

• Original Primary Outcome Measures (submitted: February 2, 2009): Overall Response Rate [ Time Frame: 3 years ]

Current Secondary Outcome Measures (submitted: April 18, 2017)

• 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.

Original Secondary Outcome Measures (submitted: February 2, 2009)

• Progression Free Survival [ Time Frame: 3 years ]
• Overall Survival [ Time Frame: 3 years ]
• Safety Profile [ Time Frame: 3 years ]
• Response Duration [ Time Frame: 3 years ]
• Pharmacokinetics [ Time Frame: 3 years ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

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

Intervention

• 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)

Study Arms

• A
  Randomized arm
  Intervention: Drug: axitinib
• B
  Randomized arm
  Intervention: Drug: axitinib
• C
  Non-randomized arm
  Intervention: Drug: axitinib

Publications *

• 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.
• 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.
• 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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: September 3, 2013): 213
• Original Estimated Enrollment (submitted: February 2, 2009): 200
• Actual Study Completion Date: February 2016
• Actual Primary Completion Date: October 2012 (Final data collection date for primary outcome measure)

Eligibility 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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Czechia, Germany, Japan, Russian Federation, Spain, United States
• Removed Location Countries: Czech Republic

Administrative Information

• NCT Number: NCT00835978
• Other Study ID Numbers: A4061046; 2008-007786-23 ( EudraCT Number )
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Pfizer
• Original Responsible Party: Director, Clinical Trial Disclosure Group, Pfizer, Inc.
• Current Study Sponsor: Pfizer
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Pfizer CT.gov Call Center; Pfizer

• PRS Account: Pfizer
• Verification Date: April 2017