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

Study Overview
=================
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.

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

Conditions
-----------------
Carcinoma, Renal Cell

Intervention / Treatment
-----------------
* Drug: axitinib
* Drug: axitinib
* Drug: axitinib


Participation Criteria
=================
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Masking: Quadruple


Arms and Interventions

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

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) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
axitinib or AG-013736 dose titration (increase) renal cell carcinoma, kidney cancer