Carcinoma, Renal Cell
Conditions
Keywords
axitinib or AG-013736 dose titration (increase) renal cell carcinoma, kidney cancer
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.
Interventions
DRUGaxitinib
axitinib 5mg BID (open-label) + axitinib dose titration (blinded)
Sponsors
Pfizer
Study design
Allocation
RANDOMIZED
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) - Percentage of Participants With Objective Response | 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
| Measure | Time frame | Description |
|---|---|---|
| Duration of Response (DR) | 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) | 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 | 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, | 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 | 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 | 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 | 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 | 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. |
| Progression-Free Survival (PFS) | 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. |
| Change From Baseline in Systolic Blood Pressure | 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 | 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 | 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 | 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+ | 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 | 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 | 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 | 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. |
| Apparent Volume of Distribution During the Elimination Phase (Vz/F) for Axitinib | 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. |
Countries
Czechia, Germany, Japan, Russia, Spain, United States
Participant flow
Recruitment details
This study was conducted at 49 centers in Czech Republic, Germany, Japan, Russian Federation, Spain, and the United States (US).
Pre-assignment details
Participants were enrolled in a 4-week lead-in period, during which they received axitinib 5 milligram (mg) twice a day (BID). After the lead-in period, participants meeting randomization criteria were then randomized to one of the two treatment arms. Participants, not meeting criteria, continued study without dose titration (non-randomized arm).
Participants by arm
| Arm | Count |
|---|---|
| Active Titration Arm Participants initially received axitinib 5 mg twice a day (BID) + axitinib (blinded therapy) 2 mg BID. After at least 2 consecutive weeks, participants satisfying the dose titration criteria had their dose level increased by one additional dose level, to axitinib 5 mg BID + axitinib (blinded therapy) 5 mg BID, unless otherwise contraindicated per the investigator's clinical judgment. The maximum total daily dose was 10 mg BID (axitinib 5mg BID + axitinib \[blinded therapy\] 5 mg BID). | 56 |
| Placebo Titration Arm Participants initially received axitinib 5mg BID + placebo (blinded therapy) 2 mg BID. After at least 2 consecutive weeks, participants satisfying the dose titration criteria had their dose level increased by one additional dose level, to axitinib 5 mg BID + placebo (blinded therapy) 5 mg BID, unless otherwise contraindicated per the investigator's clinical judgment. The maximum total daily dose was 10 mg BID (axitinib 5mg BID + placebo \[blinded therapy\] 5 mg BID). | 56 |
| Non-randomized Arm Participants not eligible for randomization were assigned to receive axitinib 5 mg BID or a reduced dose per the dose modification guideline. Dose titration was not permitted in this treatment arm. | 91 |
| Discontinued Prior to Randomization Participants who discontinued before they were randomized to any of the treatment or non-randomized arms. | 10 |
| Total | 213 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 | 1 | 0 |
| Overall Study | Death | 33 | 40 | 49 | 4 |
| Overall Study | Lost to Follow-up | 3 | 4 | 2 | 1 |
| Overall Study | Objective progression or relapse | 2 | 0 | 1 | 0 |
| Overall Study | Other | 5 | 1 | 8 | 0 |
| Overall Study | Study terminated by sponsor | 12 | 8 | 30 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 3 | 0 | 5 |
Baseline characteristics
| Characteristic | Active Titration Arm | Placebo Titration Arm | Non-randomized Arm | Discontinued Prior to Randomization | Total |
|---|---|---|---|---|---|
| Age, Continuous | 59.7 Years STANDARD_DEVIATION 10.2 | 59.6 Years STANDARD_DEVIATION 10.5 | 62.9 Years STANDARD_DEVIATION 8.9 | 62.9 Years STANDARD_DEVIATION 7.5 | 61.2 Years STANDARD_DEVIATION 9.7 |
| Age, Customized < 65 Years | 38 Participants | 38 Participants | 54 Participants | 6 Participants | 136 Participants |
| Age, Customized >= 65 Years | 18 Participants | 18 Participants | 37 Participants | 4 Participants | 77 Participants |
| Sex: Female, Male Female | 19 Participants | 11 Participants | 36 Participants | 4 Participants | 70 Participants |
| Sex: Female, Male Male | 37 Participants | 45 Participants | 55 Participants | 6 Participants | 143 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 55 / 56 | 51 / 56 | 91 / 91 | 9 / 10 |
| serious Total, serious adverse events | 25 / 56 | 14 / 56 | 39 / 91 | 2 / 10 |
Outcome results
Primary
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.
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.
Population: The Full Analysis (FA) population included all randomized participants who received study drug or different drug to which they were randomized. The Safety Analysis (SA) population included all non-randomized patients who received at least 1 dose of study medication with treatment assignments designated according to actual study treatment received.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Active Titration Arm | Objective Response Rate (ORR) - Percentage of Participants With Objective Response | 53.6 Percentage of Participants |
| Placebo Titration Arm | Objective Response Rate (ORR) - Percentage of Participants With Objective Response | 33.9 Percentage of Participants |
| Non-randomized Arm | Objective Response Rate (ORR) - Percentage of Participants With Objective Response | 59.3 Percentage of Participants |
| All Participants | Objective Response Rate (ORR) - Percentage of Participants With Objective Response | 48.4 Percentage of Participants |
Comparison: ORR for the 2 treatment arms was compared with the Cochran-Mantel-Haenszel test stratified by ECOG performance status. The relative risk ratio estimator was used to contrast the treatment effects on the endpoint. Both a point estimate and a 2-sided 95% CI were calculated using a normal approximation.p-value: 0.018995% CI: [1.017, 2.448]Cochran-Mantel-Haenszel
Secondary
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.
Time frame: C2D15: pre-dose, 0.5, 1, 2, 4, and 6 hours post-dose
Population: The pharmacokinetic (PK) population included all participants who were treated and had at least 1 concentration on 1 PK assessment day. The PK parameter analysis data set included all participants treated who had at least 1 estimated PK parameter of primary interest.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Active Titration Arm | Apparent Oral Clearance (CL/F) of Axitinib | 54.15 L/hr |
| Placebo Titration Arm | Apparent Oral Clearance (CL/F) of Axitinib | 61.93 L/hr |
Secondary
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.
Time frame: C2D15: pre-dose, 0.5, 1, 2, 4, and 6 hours post-dose
Population: The pharmacokinetic (PK) population included all participants who were treated and had at least 1 concentration on 1 PK assessment day. The PK parameter analysis data set included all participants treated who had at least 1 estimated PK parameter of primary interest.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Active Titration Arm | Apparent Volume of Distribution During the Elimination Phase (Vz/F) for Axitinib | 158.18 L |
| Placebo Titration Arm | Apparent Volume of Distribution During the Elimination Phase (Vz/F) for Axitinib | 216.62 L |
Secondary
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.
Time frame: C2D15: pre-dose, 0.5, 1, 2, 4, and 6 hours post-dose
Population: The pharmacokinetic (PK) population included all participants who were treated and had at least 1 concentration on 1 PK assessment day. The PK parameter analysis data set included all participants treated who had at least 1 estimated PK parameter of primary interest.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Active Titration Arm | Area Under the Curve From Time Zero to 24 Hours[AUC(0-24)] for Axitinib | 258.68 ng.hr/mL |
| Placebo Titration Arm | Area Under the Curve From Time Zero to 24 Hours[AUC(0-24)] for Axitinib | 161.38 ng.hr/mL |
Secondary
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.
Time frame: C2D15: pre-dose, 0.5, 1, 2, 4, and 6 hours post-dose
Population: The pharmacokinetic (PK) population included all participants who were treated and had at least 1 concentration on 1 PK assessment day. The PK parameter analysis data set included all participants treated who had at least 1 estimated PK parameter of primary interest.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Active Titration Arm | Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) for Axitinib | 105.33 ng.hr/mL |
| Placebo Titration Arm | Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) for Axitinib | 78.44 ng.hr/mL |
Secondary
Change From Baseline in Diastolic Blood Pressure
Value at respective visit minus value at baseline.
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.
Population: The SA population consists of all participatns who received at least one dose of study medication.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Active Titration Arm | Change From Baseline in Diastolic Blood Pressure | Follow-up (n=16,25,36) | -4.5 mmHg | Standard Deviation 10.1 |
| Active Titration Arm | Change From Baseline in Diastolic Blood Pressure | Cycle 1 Day 1 (n=52,51,73) | -1.6 mmHg | Standard Deviation 8.2 |
| Active Titration Arm | Change From Baseline in Diastolic Blood Pressure | Cycle 2 Day 15 (n=55,55,86) | 5.5 mmHg | Standard Deviation 10.5 |
| Active Titration Arm | Change From Baseline in Diastolic Blood Pressure | Cycle 2 Day 1 (n=56,56,91) | 4.2 mmHg | Standard Deviation 9 |
| Active Titration Arm | Change From Baseline in Diastolic Blood Pressure | Cycle 1 Day 15 (n=56,56,91) | 4.8 mmHg | Standard Deviation 8.5 |
| Active Titration Arm | Change From Baseline in Diastolic Blood Pressure | Cycle 3 Day 1 (n=48,49,84) | 6.6 mmHg | Standard Deviation 8.3 |
| Active Titration Arm | Change From Baseline in Diastolic Blood Pressure | End of treatment (n=35,44,51) | 0.6 mmHg | Standard Deviation 10.8 |
| Active Titration Arm | Change From Baseline in Diastolic Blood Pressure | Cycle 4 Day 1 (n=45,48,79) | 7.4 mmHg | Standard Deviation 8.2 |
| Placebo Titration Arm | Change From Baseline in Diastolic Blood Pressure | Cycle 1 Day 15 (n=56,56,91) | 3.0 mmHg | Standard Deviation 7.7 |
| Placebo Titration Arm | Change From Baseline in Diastolic Blood Pressure | Cycle 4 Day 1 (n=45,48,79) | 4.6 mmHg | Standard Deviation 8.5 |
| Placebo Titration Arm | Change From Baseline in Diastolic Blood Pressure | Cycle 1 Day 1 (n=52,51,73) | -2.6 mmHg | Standard Deviation 7.4 |
| Placebo Titration Arm | Change From Baseline in Diastolic Blood Pressure | End of treatment (n=35,44,51) | 3.5 mmHg | Standard Deviation 6.3 |
| Placebo Titration Arm | Change From Baseline in Diastolic Blood Pressure | Follow-up (n=16,25,36) | -1.3 mmHg | Standard Deviation 8.5 |
| Placebo Titration Arm | Change From Baseline in Diastolic Blood Pressure | Cycle 2 Day 1 (n=56,56,91) | 3.5 mmHg | Standard Deviation 8 |
| Placebo Titration Arm | Change From Baseline in Diastolic Blood Pressure | Cycle 2 Day 15 (n=55,55,86) | 4.4 mmHg | Standard Deviation 10.7 |
| Placebo Titration Arm | Change From Baseline in Diastolic Blood Pressure | Cycle 3 Day 1 (n=48,49,84) | 5.9 mmHg | Standard Deviation 9.3 |
| Non-randomized Arm | Change From Baseline in Diastolic Blood Pressure | Follow-up (n=16,25,36) | 1.8 mmHg | Standard Deviation 9 |
| Non-randomized Arm | Change From Baseline in Diastolic Blood Pressure | Cycle 1 Day 1 (n=52,51,73) | 0.5 mmHg | Standard Deviation 8.4 |
| Non-randomized Arm | Change From Baseline in Diastolic Blood Pressure | Cycle 1 Day 15 (n=56,56,91) | 11.5 mmHg | Standard Deviation 10 |
| Non-randomized Arm | Change From Baseline in Diastolic Blood Pressure | Cycle 2 Day 1 (n=56,56,91) | 10.5 mmHg | Standard Deviation 10.5 |
| Non-randomized Arm | Change From Baseline in Diastolic Blood Pressure | Cycle 2 Day 15 (n=55,55,86) | 9.7 mmHg | Standard Deviation 11.3 |
| Non-randomized Arm | Change From Baseline in Diastolic Blood Pressure | Cycle 3 Day 1 (n=48,49,84) | 9.1 mmHg | Standard Deviation 13.6 |
| Non-randomized Arm | Change From Baseline in Diastolic Blood Pressure | Cycle 4 Day 1 (n=45,48,79) | 8.7 mmHg | Standard Deviation 11.8 |
| Non-randomized Arm | Change From Baseline in Diastolic Blood Pressure | End of treatment (n=35,44,51) | 3.0 mmHg | Standard Deviation 10.5 |
Secondary
Change From Baseline in Systolic Blood Pressure
Value at respective visit minus value at baseline
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.
Population: The SA population consists of all participatns who received at least one dose of study medication.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Active Titration Arm | Change From Baseline in Systolic Blood Pressure | Cycle 1 Day 1 (n=52,51,73) | -4.3 mmHg | Standard Deviation 11.1 |
| Active Titration Arm | Change From Baseline in Systolic Blood Pressure | End of treatment (n=35,44,51) | 2.4 mmHg | Standard Deviation 17 |
| Active Titration Arm | Change From Baseline in Systolic Blood Pressure | Cycle 1 Day 15 (n=56,56,91) | 3.8 mmHg | Standard Deviation 12.2 |
| Active Titration Arm | Change From Baseline in Systolic Blood Pressure | Cycle 4 Day 1 (n=45,48,79) | 4.3 mmHg | Standard Deviation 12.7 |
| Active Titration Arm | Change From Baseline in Systolic Blood Pressure | Follow-up (n=16,25,36) | -3.6 mmHg | Standard Deviation 16.9 |
| Active Titration Arm | Change From Baseline in Systolic Blood Pressure | Cycle 2 Day 1 (n=56,56,91) | 1.9 mmHg | Standard Deviation 12.4 |
| Active Titration Arm | Change From Baseline in Systolic Blood Pressure | Cycle 3 Day 1 (n=48,49,84) | 3.5 mmHg | Standard Deviation 15.1 |
| Active Titration Arm | Change From Baseline in Systolic Blood Pressure | Cycle 2 Day 15 (n=55,55,86) | 3.6 mmHg | Standard Deviation 13.8 |
| Placebo Titration Arm | Change From Baseline in Systolic Blood Pressure | Follow-up (n=16,25,36) | -0.4 mmHg | Standard Deviation 16.3 |
| Placebo Titration Arm | Change From Baseline in Systolic Blood Pressure | Cycle 2 Day 15 (n=55,55,86) | 2.7 mmHg | Standard Deviation 16.6 |
| Placebo Titration Arm | Change From Baseline in Systolic Blood Pressure | End of treatment (n=35,44,51) | 1.7 mmHg | Standard Deviation 14 |
| Placebo Titration Arm | Change From Baseline in Systolic Blood Pressure | Cycle 3 Day 1 (n=48,49,84) | 8.4 mmHg | Standard Deviation 15.4 |
| Placebo Titration Arm | Change From Baseline in Systolic Blood Pressure | Cycle 4 Day 1 (n=45,48,79) | 3.5 mmHg | Standard Deviation 13 |
| Placebo Titration Arm | Change From Baseline in Systolic Blood Pressure | Cycle 1 Day 1 (n=52,51,73) | -2.9 mmHg | Standard Deviation 9.2 |
| Placebo Titration Arm | Change From Baseline in Systolic Blood Pressure | Cycle 1 Day 15 (n=56,56,91) | 4.1 mmHg | Standard Deviation 12.5 |
| Placebo Titration Arm | Change From Baseline in Systolic Blood Pressure | Cycle 2 Day 1 (n=56,56,91) | 0.9 mmHg | Standard Deviation 13.6 |
| Non-randomized Arm | Change From Baseline in Systolic Blood Pressure | Cycle 1 Day 15 (n=56,56,91) | 11.5 mmHg | Standard Deviation 18 |
| Non-randomized Arm | Change From Baseline in Systolic Blood Pressure | End of treatment (n=35,44,51) | -2.8 mmHg | Standard Deviation 19 |
| Non-randomized Arm | Change From Baseline in Systolic Blood Pressure | Follow-up (n=16,25,36) | -0.6 mmHg | Standard Deviation 16.7 |
| Non-randomized Arm | Change From Baseline in Systolic Blood Pressure | Cycle 1 Day 1 (n=52,51,73) | -1.8 mmHg | Standard Deviation 14.2 |
| Non-randomized Arm | Change From Baseline in Systolic Blood Pressure | Cycle 4 Day 1 (n=45,48,79) | 5.5 mmHg | Standard Deviation 18.2 |
| Non-randomized Arm | Change From Baseline in Systolic Blood Pressure | Cycle 2 Day 1 (n=56,56,91) | 9.9 mmHg | Standard Deviation 18.7 |
| Non-randomized Arm | Change From Baseline in Systolic Blood Pressure | Cycle 2 Day 15 (n=55,55,86) | 5.9 mmHg | Standard Deviation 20.3 |
| Non-randomized Arm | Change From Baseline in Systolic Blood Pressure | Cycle 3 Day 1 (n=48,49,84) | 5.2 mmHg | Standard Deviation 20.2 |
Secondary
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.
Time frame: At baseline - Beginning of the lead-in period (Cycle 1 Day 1)
Population: The Biomarker Analysis Set included participants receiving at least one dose of treatment, with a Cycle 1 Day 1 biomarker result for at least one biomarker.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Active Titration Arm | Circulating Endothelial Cells (CECs) in Blood: CD31+/CD146+ | Baseline MFI pVEGFR (n=17,22,20) | 385617 Fluorescent Intensity Unit (FIU) | Standard Deviation 203956 |
| Active Titration Arm | Circulating Endothelial Cells (CECs) in Blood: CD31+/CD146+ | Baseline MFI pPDGFR-BETA (n=17,21,20) | 380139 Fluorescent Intensity Unit (FIU) | Standard Deviation 205600 |
| Active Titration Arm | Circulating Endothelial Cells (CECs) in Blood: CD31+/CD146+ | Baseline CECs Count (n=17,22,20) | 74668 Fluorescent Intensity Unit (FIU) | Standard Deviation 50558.9 |
| Active Titration Arm | Circulating Endothelial Cells (CECs) in Blood: CD31+/CD146+ | Baseline MFI PDGFR-BETA (n=17,21,20) | 333760 Fluorescent Intensity Unit (FIU) | Standard Deviation 164604 |
| Active Titration Arm | Circulating Endothelial Cells (CECs) in Blood: CD31+/CD146+ | Baseline MFI VEGFR (n=17,22,20) | 330333 Fluorescent Intensity Unit (FIU) | Standard Deviation 151710 |
| Placebo Titration Arm | Circulating Endothelial Cells (CECs) in Blood: CD31+/CD146+ | Baseline MFI pPDGFR-BETA (n=17,21,20) | 355441 Fluorescent Intensity Unit (FIU) | Standard Deviation 147046 |
| Placebo Titration Arm | Circulating Endothelial Cells (CECs) in Blood: CD31+/CD146+ | Baseline CECs Count (n=17,22,20) | 76258 Fluorescent Intensity Unit (FIU) | Standard Deviation 46779.5 |
| Placebo Titration Arm | Circulating Endothelial Cells (CECs) in Blood: CD31+/CD146+ | Baseline MFI PDGFR-BETA (n=17,21,20) | 380886 Fluorescent Intensity Unit (FIU) | Standard Deviation 147261 |
| Placebo Titration Arm | Circulating Endothelial Cells (CECs) in Blood: CD31+/CD146+ | Baseline MFI pVEGFR (n=17,22,20) | 352644 Fluorescent Intensity Unit (FIU) | Standard Deviation 128803 |
| Placebo Titration Arm | Circulating Endothelial Cells (CECs) in Blood: CD31+/CD146+ | Baseline MFI VEGFR (n=17,22,20) | 401909 Fluorescent Intensity Unit (FIU) | Standard Deviation 165235 |
| Non-randomized Arm | Circulating Endothelial Cells (CECs) in Blood: CD31+/CD146+ | Baseline MFI VEGFR (n=17,22,20) | 359097 Fluorescent Intensity Unit (FIU) | Standard Deviation 146943 |
| Non-randomized Arm | Circulating Endothelial Cells (CECs) in Blood: CD31+/CD146+ | Baseline MFI pVEGFR (n=17,22,20) | 380184 Fluorescent Intensity Unit (FIU) | Standard Deviation 173578 |
| Non-randomized Arm | Circulating Endothelial Cells (CECs) in Blood: CD31+/CD146+ | Baseline CECs Count (n=17,22,20) | 77437 Fluorescent Intensity Unit (FIU) | Standard Deviation 63419.4 |
| Non-randomized Arm | Circulating Endothelial Cells (CECs) in Blood: CD31+/CD146+ | Baseline MFI pPDGFR-BETA (n=17,21,20) | 383202 Fluorescent Intensity Unit (FIU) | Standard Deviation 211174 |
| Non-randomized Arm | Circulating Endothelial Cells (CECs) in Blood: CD31+/CD146+ | Baseline MFI PDGFR-BETA (n=17,21,20) | 442642 Fluorescent Intensity Unit (FIU) | Standard Deviation 267436 |
Secondary
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.
Time frame: At baseline - Beginning of the lead-in period (Cycle 1 Day 1)
Population: The Biomarker Analysis Set included participants receiving at least one dose of treatment, with a Cycle 1 Day 1 biomarker result for at least one biomarker.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Active Titration Arm | Comparison of Circulating Endothelial Cells (CECs) in Blood: Cluster of Differentiation (CD)146+/CD105+ at Baseline | Baseline MFI pVEGFR (n=16,22,20) | 456086 Fluorescent Intensity Unit (FIU) | Standard Deviation 290174 |
| Active Titration Arm | Comparison of Circulating Endothelial Cells (CECs) in Blood: Cluster of Differentiation (CD)146+/CD105+ at Baseline | Baseline MFI pPDGFR-BETA (n=17,22,20) | 401226 Fluorescent Intensity Unit (FIU) | Standard Deviation 195445 |
| Active Titration Arm | Comparison of Circulating Endothelial Cells (CECs) in Blood: Cluster of Differentiation (CD)146+/CD105+ at Baseline | Baseline CECs Count (n=17,22,20) | 23584 Fluorescent Intensity Unit (FIU) | Standard Deviation 18213.1 |
| Active Titration Arm | Comparison of Circulating Endothelial Cells (CECs) in Blood: Cluster of Differentiation (CD)146+/CD105+ at Baseline | Baseline MFI PDGFR-BETA (n=17,22,20) | 346815 Fluorescent Intensity Unit (FIU) | Standard Deviation 179563 |
| Active Titration Arm | Comparison of Circulating Endothelial Cells (CECs) in Blood: Cluster of Differentiation (CD)146+/CD105+ at Baseline | Baseline MFI VEGFR (n=16,22,20) | 367799 Fluorescent Intensity Unit (FIU) | Standard Deviation 181320 |
| Placebo Titration Arm | Comparison of Circulating Endothelial Cells (CECs) in Blood: Cluster of Differentiation (CD)146+/CD105+ at Baseline | Baseline MFI pPDGFR-BETA (n=17,22,20) | 395509 Fluorescent Intensity Unit (FIU) | Standard Deviation 136933 |
| Placebo Titration Arm | Comparison of Circulating Endothelial Cells (CECs) in Blood: Cluster of Differentiation (CD)146+/CD105+ at Baseline | Baseline CECs Count (n=17,22,20) | 28544 Fluorescent Intensity Unit (FIU) | Standard Deviation 27694.4 |
| Placebo Titration Arm | Comparison of Circulating Endothelial Cells (CECs) in Blood: Cluster of Differentiation (CD)146+/CD105+ at Baseline | Baseline MFI PDGFR-BETA (n=17,22,20) | 455238 Fluorescent Intensity Unit (FIU) | Standard Deviation 238157 |
| Placebo Titration Arm | Comparison of Circulating Endothelial Cells (CECs) in Blood: Cluster of Differentiation (CD)146+/CD105+ at Baseline | Baseline MFI pVEGFR (n=16,22,20) | 436197 Fluorescent Intensity Unit (FIU) | Standard Deviation 128225 |
| Placebo Titration Arm | Comparison of Circulating Endothelial Cells (CECs) in Blood: Cluster of Differentiation (CD)146+/CD105+ at Baseline | Baseline MFI VEGFR (n=16,22,20) | 473290 Fluorescent Intensity Unit (FIU) | Standard Deviation 228619 |
| Non-randomized Arm | Comparison of Circulating Endothelial Cells (CECs) in Blood: Cluster of Differentiation (CD)146+/CD105+ at Baseline | Baseline MFI VEGFR (n=16,22,20) | 359092 Fluorescent Intensity Unit (FIU) | Standard Deviation 167706 |
| Non-randomized Arm | Comparison of Circulating Endothelial Cells (CECs) in Blood: Cluster of Differentiation (CD)146+/CD105+ at Baseline | Baseline MFI pVEGFR (n=16,22,20) | 398754 Fluorescent Intensity Unit (FIU) | Standard Deviation 188137 |
| Non-randomized Arm | Comparison of Circulating Endothelial Cells (CECs) in Blood: Cluster of Differentiation (CD)146+/CD105+ at Baseline | Baseline CECs Count (n=17,22,20) | 29663 Fluorescent Intensity Unit (FIU) | Standard Deviation 30651 |
| Non-randomized Arm | Comparison of Circulating Endothelial Cells (CECs) in Blood: Cluster of Differentiation (CD)146+/CD105+ at Baseline | Baseline MFI pPDGFR-BETA (n=17,22,20) | 397672 Fluorescent Intensity Unit (FIU) | Standard Deviation 193172 |
| Non-randomized Arm | Comparison of Circulating Endothelial Cells (CECs) in Blood: Cluster of Differentiation (CD)146+/CD105+ at Baseline | Baseline MFI PDGFR-BETA (n=17,22,20) | 327567 Fluorescent Intensity Unit (FIU) | Standard Deviation 167728 |
Secondary
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.
Time frame: At end of the lead-in period (Cycle 1 Day 15), Cycle 2 Day 15 and End of therapy (EOT)
Population: The Biomarker Analysis Set included participants receiving at least one dose of treatment, with a Cycle 1 Day 1 biomarker result for at least one biomarker.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Active Titration Arm | Comparison of Ratio of CECs in Blood: CD31+/CD146+ at Each Time Point to Baseline | EOT:C1D1 MFI pPDGFRBETA (n=6,8,4) | 0.7 Ratio | Standard Deviation 0.63 |
| Active Titration Arm | Comparison of Ratio of CECs in Blood: CD31+/CD146+ at Each Time Point to Baseline | C1D15:C1D1 CECs Count (n=11,18,14) | 2.7 Ratio | Standard Deviation 3.17 |
| Active Titration Arm | Comparison of Ratio of CECs in Blood: CD31+/CD146+ at Each Time Point to Baseline | C2D15:C1D1 CECs Count (n=13,16,11) | 1.4 Ratio | Standard Deviation 1.38 |
| Active Titration Arm | Comparison of Ratio of CECs in Blood: CD31+/CD146+ at Each Time Point to Baseline | EOT:C1D1 CECs COUNT (n=7,9,4) | 1.5 Ratio | Standard Deviation 1.95 |
| Active Titration Arm | Comparison of Ratio of CECs in Blood: CD31+/CD146+ at Each Time Point to Baseline | C1D15:C1D1 MFI PDGFRBETA (n=11,15,13) | 1.2 Ratio | Standard Deviation 0.74 |
| Active Titration Arm | Comparison of Ratio of CECs in Blood: CD31+/CD146+ at Each Time Point to Baseline | C2D15:C1D1 MFI PDGFRBETA (n=13,14,11) | 1.4 Ratio | Standard Deviation 1.36 |
| Active Titration Arm | Comparison of Ratio of CECs in Blood: CD31+/CD146+ at Each Time Point to Baseline | EOT:C1D1 MFI PDGFRBETA (n=6,8,4) | 1.2 Ratio | Standard Deviation 1.23 |
| Active Titration Arm | Comparison of Ratio of CECs in Blood: CD31+/CD146+ at Each Time Point to Baseline | C1D15:C1D1 MFI pPDGFR-BETA (n=11,15,13) | 1.2 Ratio | Standard Deviation 1.07 |
| Active Titration Arm | Comparison of Ratio of CECs in Blood: CD31+/CD146+ at Each Time Point to Baseline | C2D15:C1D1 MFI pPDGFR-BETA (n=13,14,11) | 1.2 Ratio | Standard Deviation 0.89 |
| Active Titration Arm | Comparison of Ratio of CECs in Blood: CD31+/CD146+ at Each Time Point to Baseline | C1D15:C1D1 MFI pVEGFR (n=11,18,14) | 1.1 Ratio | Standard Deviation 0.75 |
| Active Titration Arm | Comparison of Ratio of CECs in Blood: CD31+/CD146+ at Each Time Point to Baseline | C2D15:C1D1 MFI pVEGFR (n=13,16,10) | 1.2 Ratio | Standard Deviation 1 |
| Active Titration Arm | Comparison of Ratio of CECs in Blood: CD31+/CD146+ at Each Time Point to Baseline | EOT:C1D1 MFI pVEGFR (n=7,9,4) | 0.7 Ratio | Standard Deviation 0.59 |
| Active Titration Arm | Comparison of Ratio of CECs in Blood: CD31+/CD146+ at Each Time Point to Baseline | C1D15:C1D1 MFI VEGFR (n=11,18,14) | 1.3 Ratio | Standard Deviation 0.93 |
| Active Titration Arm | Comparison of Ratio of CECs in Blood: CD31+/CD146+ at Each Time Point to Baseline | C2D15:C1D1 MFI VEGFR n=13,16,10) | 1.5 Ratio | Standard Deviation 1.44 |
| Active Titration Arm | Comparison of Ratio of CECs in Blood: CD31+/CD146+ at Each Time Point to Baseline | EOT:C1D1 MFI VEGFR (n=7,9,4) | 1.2 Ratio | Standard Deviation 1.27 |
| Placebo Titration Arm | Comparison of Ratio of CECs in Blood: CD31+/CD146+ at Each Time Point to Baseline | C2D15:C1D1 MFI PDGFRBETA (n=13,14,11) | 1.1 Ratio | Standard Deviation 1.03 |
| Placebo Titration Arm | Comparison of Ratio of CECs in Blood: CD31+/CD146+ at Each Time Point to Baseline | EOT:C1D1 MFI PDGFRBETA (n=6,8,4) | 0.6 Ratio | Standard Deviation 0.51 |
| Placebo Titration Arm | Comparison of Ratio of CECs in Blood: CD31+/CD146+ at Each Time Point to Baseline | C1D15:C1D1 MFI VEGFR (n=11,18,14) | 1.3 Ratio | Standard Deviation 0.9 |
| Placebo Titration Arm | Comparison of Ratio of CECs in Blood: CD31+/CD146+ at Each Time Point to Baseline | C1D15:C1D1 MFI pPDGFR-BETA (n=11,15,13) | 1.4 Ratio | Standard Deviation 0.81 |
| Placebo Titration Arm | Comparison of Ratio of CECs in Blood: CD31+/CD146+ at Each Time Point to Baseline | C2D15:C1D1 MFI pPDGFR-BETA (n=13,14,11) | 0.8 Ratio | Standard Deviation 0.38 |
| Placebo Titration Arm | Comparison of Ratio of CECs in Blood: CD31+/CD146+ at Each Time Point to Baseline | EOT:C1D1 MFI VEGFR (n=7,9,4) | 1.1 Ratio | Standard Deviation 0.9 |
| Placebo Titration Arm | Comparison of Ratio of CECs in Blood: CD31+/CD146+ at Each Time Point to Baseline | C1D15:C1D1 MFI pVEGFR (n=11,18,14) | 1.4 Ratio | Standard Deviation 0.74 |
| Placebo Titration Arm | Comparison of Ratio of CECs in Blood: CD31+/CD146+ at Each Time Point to Baseline | C2D15:C1D1 MFI VEGFR n=13,16,10) | 1.2 Ratio | Standard Deviation 0.96 |
| Placebo Titration Arm | Comparison of Ratio of CECs in Blood: CD31+/CD146+ at Each Time Point to Baseline | EOT:C1D1 MFI pPDGFRBETA (n=6,8,4) | 0.8 Ratio | Standard Deviation 0.91 |
| Placebo Titration Arm | Comparison of Ratio of CECs in Blood: CD31+/CD146+ at Each Time Point to Baseline | C2D15:C1D1 MFI pVEGFR (n=13,16,10) | 0.9 Ratio | Standard Deviation 0.68 |
| Placebo Titration Arm | Comparison of Ratio of CECs in Blood: CD31+/CD146+ at Each Time Point to Baseline | C1D15:C1D1 CECs Count (n=11,18,14) | 1.6 Ratio | Standard Deviation 2.32 |
| Placebo Titration Arm | Comparison of Ratio of CECs in Blood: CD31+/CD146+ at Each Time Point to Baseline | C2D15:C1D1 CECs Count (n=13,16,11) | 2.2 Ratio | Standard Deviation 3.91 |
| Placebo Titration Arm | Comparison of Ratio of CECs in Blood: CD31+/CD146+ at Each Time Point to Baseline | EOT:C1D1 CECs COUNT (n=7,9,4) | 1.4 Ratio | Standard Deviation 2.66 |
| Placebo Titration Arm | Comparison of Ratio of CECs in Blood: CD31+/CD146+ at Each Time Point to Baseline | EOT:C1D1 MFI pVEGFR (n=7,9,4) | 1.1 Ratio | Standard Deviation 1.24 |
| Placebo Titration Arm | Comparison of Ratio of CECs in Blood: CD31+/CD146+ at Each Time Point to Baseline | C1D15:C1D1 MFI PDGFRBETA (n=11,15,13) | 1.3 Ratio | Standard Deviation 0.89 |
| Non-randomized Arm | Comparison of Ratio of CECs in Blood: CD31+/CD146+ at Each Time Point to Baseline | C2D15:C1D1 CECs Count (n=13,16,11) | 2.5 Ratio | Standard Deviation 3.98 |
| Non-randomized Arm | Comparison of Ratio of CECs in Blood: CD31+/CD146+ at Each Time Point to Baseline | C2D15:C1D1 MFI PDGFRBETA (n=13,14,11) | 2.2 Ratio | Standard Deviation 2.64 |
| Non-randomized Arm | Comparison of Ratio of CECs in Blood: CD31+/CD146+ at Each Time Point to Baseline | EOT:C1D1 MFI VEGFR (n=7,9,4) | 1.5 Ratio | Standard Deviation 1.42 |
| Non-randomized Arm | Comparison of Ratio of CECs in Blood: CD31+/CD146+ at Each Time Point to Baseline | C2D15:C1D1 MFI VEGFR n=13,16,10) | 2.1 Ratio | Standard Deviation 1.8 |
| Non-randomized Arm | Comparison of Ratio of CECs in Blood: CD31+/CD146+ at Each Time Point to Baseline | EOT:C1D1 MFI PDGFRBETA (n=6,8,4) | 1.7 Ratio | Standard Deviation 1.49 |
| Non-randomized Arm | Comparison of Ratio of CECs in Blood: CD31+/CD146+ at Each Time Point to Baseline | EOT:C1D1 MFI pVEGFR (n=7,9,4) | 3.1 Ratio | Standard Deviation 0.95 |
| Non-randomized Arm | Comparison of Ratio of CECs in Blood: CD31+/CD146+ at Each Time Point to Baseline | EOT:C1D1 CECs COUNT (n=7,9,4) | 0.6 Ratio | Standard Deviation 0.71 |
| Non-randomized Arm | Comparison of Ratio of CECs in Blood: CD31+/CD146+ at Each Time Point to Baseline | C1D15:C1D1 MFI pPDGFR-BETA (n=11,15,13) | 1.0 Ratio | Standard Deviation 0.87 |
| Non-randomized Arm | Comparison of Ratio of CECs in Blood: CD31+/CD146+ at Each Time Point to Baseline | C1D15:C1D1 MFI VEGFR (n=11,18,14) | 1.0 Ratio | Standard Deviation 0.57 |
| Non-randomized Arm | Comparison of Ratio of CECs in Blood: CD31+/CD146+ at Each Time Point to Baseline | C1D15:C1D1 CECs Count (n=11,18,14) | 1.5 Ratio | Standard Deviation 2.31 |
| Non-randomized Arm | Comparison of Ratio of CECs in Blood: CD31+/CD146+ at Each Time Point to Baseline | C2D15:C1D1 MFI pPDGFR-BETA (n=13,14,11) | 1.1 Ratio | Standard Deviation 0.71 |
| Non-randomized Arm | Comparison of Ratio of CECs in Blood: CD31+/CD146+ at Each Time Point to Baseline | EOT:C1D1 MFI pPDGFRBETA (n=6,8,4) | 3.0 Ratio | Standard Deviation 0.47 |
| Non-randomized Arm | Comparison of Ratio of CECs in Blood: CD31+/CD146+ at Each Time Point to Baseline | C2D15:C1D1 MFI pVEGFR (n=13,16,10) | 1.3 Ratio | Standard Deviation 0.7 |
| Non-randomized Arm | Comparison of Ratio of CECs in Blood: CD31+/CD146+ at Each Time Point to Baseline | C1D15:C1D1 MFI PDGFRBETA (n=11,15,13) | 0.8 Ratio | Standard Deviation 0.51 |
| Non-randomized Arm | Comparison of Ratio of CECs in Blood: CD31+/CD146+ at Each Time Point to Baseline | C1D15:C1D1 MFI pVEGFR (n=11,18,14) | 1.2 Ratio | Standard Deviation 0.9 |
Secondary
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.
Time frame: At end of the lead-in period (Cycle 1 Day 15), Cycle 2 Day 15 and End of therapy (EOT)
Population: The Biomarker Analysis Set included participants receiving at least one dose of treatment, with a Cycle 1 Day 1 biomarker result for at least one biomarker.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Active Titration Arm | Comparison of the Ratio of CECs in Blood: CD146+/CD105+ at Each Time Point to Baseline | EOT:C1D1 MFI pVEGFR (n=7,9,4) | 0.8 Ratio | Standard Deviation 0.53 |
| Active Titration Arm | Comparison of the Ratio of CECs in Blood: CD146+/CD105+ at Each Time Point to Baseline | EOT:C1D1 MFI PDGFRBETA (n=7,9,4) | 1.5 Ratio | Standard Deviation 1.75 |
| Active Titration Arm | Comparison of the Ratio of CECs in Blood: CD146+/CD105+ at Each Time Point to Baseline | C2D15:C1D1 MFI PDGFRBETA (n=13,16,11) | 1.4 Ratio | Standard Deviation 1.24 |
| Active Titration Arm | Comparison of the Ratio of CECs in Blood: CD146+/CD105+ at Each Time Point to Baseline | C1D15:C1D1 CECs Count (n=11,18,14) | 2.3 Ratio | Standard Deviation 2.52 |
| Active Titration Arm | Comparison of the Ratio of CECs in Blood: CD146+/CD105+ at Each Time Point to Baseline | EOT:C1D1 CECs Count (n=7,9,4) | 2.8 Ratio | Standard Deviation 4.81 |
| Active Titration Arm | Comparison of the Ratio of CECs in Blood: CD146+/CD105+ at Each Time Point to Baseline | C1D15:C1D1 MFI PDGFRBETA (n=11,17,13) | 1.3 Ratio | Standard Deviation 1.03 |
| Active Titration Arm | Comparison of the Ratio of CECs in Blood: CD146+/CD105+ at Each Time Point to Baseline | C2D15:C1D1 CECs Count (n=13,16,11) | 1.3 Ratio | Standard Deviation 1.43 |
| Active Titration Arm | Comparison of the Ratio of CECs in Blood: CD146+/CD105+ at Each Time Point to Baseline | EOT:C1D1 MFI VEGFR (n=7,9,4) | 1.1 Ratio | Standard Deviation 1.03 |
| Active Titration Arm | Comparison of the Ratio of CECs in Blood: CD146+/CD105+ at Each Time Point to Baseline | C1D15:C1D1 MFI VEGFR (n=10,18,14) | 1.4 Ratio | Standard Deviation 1.25 |
| Active Titration Arm | Comparison of the Ratio of CECs in Blood: CD146+/CD105+ at Each Time Point to Baseline | C1D15:C1D1 MFI pVEGFR (n=10,18,14) | 1.0 Ratio | Standard Deviation 0.46 |
| Active Titration Arm | Comparison of the Ratio of CECs in Blood: CD146+/CD105+ at Each Time Point to Baseline | EOT:C1D1 MFI pPDGFRBETA (n=7,9,4) | 0.8 Ratio | Standard Deviation 0.71 |
| Active Titration Arm | Comparison of the Ratio of CECs in Blood: CD146+/CD105+ at Each Time Point to Baseline | C2D15:C1D1 MFI pPDGFR-BETA (n=13,16,11) | 1.0 Ratio | Standard Deviation 0.69 |
| Active Titration Arm | Comparison of the Ratio of CECs in Blood: CD146+/CD105+ at Each Time Point to Baseline | C2D15:C1D1 MFI pVEGFR (n=12,16,11) | 1.0 Ratio | Standard Deviation 0.74 |
| Active Titration Arm | Comparison of the Ratio of CECs in Blood: CD146+/CD105+ at Each Time Point to Baseline | C2D15:C1D1 MFI VEGFR (n=12,16,11) | 1.5 Ratio | Standard Deviation 1.48 |
| Active Titration Arm | Comparison of the Ratio of CECs in Blood: CD146+/CD105+ at Each Time Point to Baseline | C1D15:C1D1 MFI pPDGFR-BETA (n=11,17,13) | 1.1 Ratio | Standard Deviation 0.63 |
| Placebo Titration Arm | Comparison of the Ratio of CECs in Blood: CD146+/CD105+ at Each Time Point to Baseline | C1D15:C1D1 MFI pVEGFR (n=10,18,14) | 1.2 Ratio | Standard Deviation 0.88 |
| Placebo Titration Arm | Comparison of the Ratio of CECs in Blood: CD146+/CD105+ at Each Time Point to Baseline | EOT:C1D1 CECs Count (n=7,9,4) | 8.9 Ratio | Standard Deviation 21.7 |
| Placebo Titration Arm | Comparison of the Ratio of CECs in Blood: CD146+/CD105+ at Each Time Point to Baseline | EOT:C1D1 MFI PDGFRBETA (n=7,9,4) | 0.6 Ratio | Standard Deviation 0.52 |
| Placebo Titration Arm | Comparison of the Ratio of CECs in Blood: CD146+/CD105+ at Each Time Point to Baseline | EOT:C1D1 MFI pPDGFRBETA (n=7,9,4) | 0.8 Ratio | Standard Deviation 0.93 |
| Placebo Titration Arm | Comparison of the Ratio of CECs in Blood: CD146+/CD105+ at Each Time Point to Baseline | C2D15:C1D1 MFI pVEGFR (n=12,16,11) | 0.9 Ratio | Standard Deviation 0.82 |
| Placebo Titration Arm | Comparison of the Ratio of CECs in Blood: CD146+/CD105+ at Each Time Point to Baseline | EOT:C1D1 MFI pVEGFR (n=7,9,4) | 1.3 Ratio | Standard Deviation 0.96 |
| Placebo Titration Arm | Comparison of the Ratio of CECs in Blood: CD146+/CD105+ at Each Time Point to Baseline | C1D15:C1D1 CECs Count (n=11,18,14) | 3.7 Ratio | Standard Deviation 6.92 |
| Placebo Titration Arm | Comparison of the Ratio of CECs in Blood: CD146+/CD105+ at Each Time Point to Baseline | C2D15:C1D1 CECs Count (n=13,16,11) | 4.4 Ratio | Standard Deviation 9.27 |
| Placebo Titration Arm | Comparison of the Ratio of CECs in Blood: CD146+/CD105+ at Each Time Point to Baseline | C1D15:C1D1 MFI PDGFRBETA (n=11,17,13) | 1.5 Ratio | Standard Deviation 1.14 |
| Placebo Titration Arm | Comparison of the Ratio of CECs in Blood: CD146+/CD105+ at Each Time Point to Baseline | C2D15:C1D1 MFI PDGFRBETA (n=13,16,11) | 1.1 Ratio | Standard Deviation 1.14 |
| Placebo Titration Arm | Comparison of the Ratio of CECs in Blood: CD146+/CD105+ at Each Time Point to Baseline | C1D15:C1D1 MFI pPDGFR-BETA (n=11,17,13) | 1.2 Ratio | Standard Deviation 0.77 |
| Placebo Titration Arm | Comparison of the Ratio of CECs in Blood: CD146+/CD105+ at Each Time Point to Baseline | C2D15:C1D1 MFI pPDGFR-BETA (n=13,16,11) | 0.8 Ratio | Standard Deviation 0.45 |
| Placebo Titration Arm | Comparison of the Ratio of CECs in Blood: CD146+/CD105+ at Each Time Point to Baseline | C1D15:C1D1 MFI VEGFR (n=10,18,14) | 1.3 Ratio | Standard Deviation 0.94 |
| Placebo Titration Arm | Comparison of the Ratio of CECs in Blood: CD146+/CD105+ at Each Time Point to Baseline | C2D15:C1D1 MFI VEGFR (n=12,16,11) | 1.3 Ratio | Standard Deviation 0.99 |
| Placebo Titration Arm | Comparison of the Ratio of CECs in Blood: CD146+/CD105+ at Each Time Point to Baseline | EOT:C1D1 MFI VEGFR (n=7,9,4) | 0.7 Ratio | Standard Deviation 0.48 |
| Non-randomized Arm | Comparison of the Ratio of CECs in Blood: CD146+/CD105+ at Each Time Point to Baseline | EOT:C1D1 MFI VEGFR (n=7,9,4) | 1.9 Ratio | Standard Deviation 1.63 |
| Non-randomized Arm | Comparison of the Ratio of CECs in Blood: CD146+/CD105+ at Each Time Point to Baseline | C1D15:C1D1 MFI pPDGFR-BETA (n=11,17,13) | 1.0 Ratio | Standard Deviation 1.12 |
| Non-randomized Arm | Comparison of the Ratio of CECs in Blood: CD146+/CD105+ at Each Time Point to Baseline | C1D15:C1D1 MFI pVEGFR (n=10,18,14) | 1.2 Ratio | Standard Deviation 1 |
| Non-randomized Arm | Comparison of the Ratio of CECs in Blood: CD146+/CD105+ at Each Time Point to Baseline | C2D15:C1D1 MFI VEGFR (n=12,16,11) | 2.1 Ratio | Standard Deviation 1.72 |
| Non-randomized Arm | Comparison of the Ratio of CECs in Blood: CD146+/CD105+ at Each Time Point to Baseline | C2D15:C1D1 MFI pPDGFR-BETA (n=13,16,11) | 1.2 Ratio | Standard Deviation 0.79 |
| Non-randomized Arm | Comparison of the Ratio of CECs in Blood: CD146+/CD105+ at Each Time Point to Baseline | C2D15:C1D1 CECs Count (n=13,16,11) | 1.3 Ratio | Standard Deviation 1.22 |
| Non-randomized Arm | Comparison of the Ratio of CECs in Blood: CD146+/CD105+ at Each Time Point to Baseline | EOT:C1D1 MFI pPDGFRBETA (n=7,9,4) | 1.9 Ratio | Standard Deviation 1.57 |
| Non-randomized Arm | Comparison of the Ratio of CECs in Blood: CD146+/CD105+ at Each Time Point to Baseline | EOT:C1D1 CECs Count (n=7,9,4) | 1.2 Ratio | Standard Deviation 1.5 |
| Non-randomized Arm | Comparison of the Ratio of CECs in Blood: CD146+/CD105+ at Each Time Point to Baseline | C1D15:C1D1 CECs Count (n=11,18,14) | 2.2 Ratio | Standard Deviation 3.1 |
| Non-randomized Arm | Comparison of the Ratio of CECs in Blood: CD146+/CD105+ at Each Time Point to Baseline | C1D15:C1D1 MFI VEGFR (n=10,18,14) | 1.0 Ratio | Standard Deviation 0.64 |
| Non-randomized Arm | Comparison of the Ratio of CECs in Blood: CD146+/CD105+ at Each Time Point to Baseline | C1D15:C1D1 MFI PDGFRBETA (n=11,17,13) | 1.1 Ratio | Standard Deviation 0.73 |
| Non-randomized Arm | Comparison of the Ratio of CECs in Blood: CD146+/CD105+ at Each Time Point to Baseline | EOT:C1D1 MFI pVEGFR (n=7,9,4) | 3.0 Ratio | Standard Deviation 1.16 |
| Non-randomized Arm | Comparison of the Ratio of CECs in Blood: CD146+/CD105+ at Each Time Point to Baseline | C2D15:C1D1 MFI PDGFRBETA (n=13,16,11) | 2.2 Ratio | Standard Deviation 1.62 |
| Non-randomized Arm | Comparison of the Ratio of CECs in Blood: CD146+/CD105+ at Each Time Point to Baseline | EOT:C1D1 MFI PDGFRBETA (n=7,9,4) | 1.2 Ratio | Standard Deviation 1.78 |
| Non-randomized Arm | Comparison of the Ratio of CECs in Blood: CD146+/CD105+ at Each Time Point to Baseline | C2D15:C1D1 MFI pVEGFR (n=12,16,11) | 1.2 Ratio | Standard Deviation 0.8 |
Secondary
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.
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
Population: Subset of Full Analysis (FA) and Safety Analysis (SA) patients who achieved confirmed complete or partial response. FA included all randomized patients and was based on randomized treatment assignment regardless of whether or not study drug was administered. SA included all non randomized patients who received at least one dose of study medication.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Active Titration Arm | Duration of Response (DR) | NA Months |
| Placebo Titration Arm | Duration of Response (DR) | 21.2 Months |
| Non-randomized Arm | Duration of Response (DR) | 23.3 Months |
Secondary
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.
Time frame: Cycle 2 Day 15 (C2D15): pre-dose, 0.5, 1, 2, 4, and 6 hours post-dose
Population: The pharmacokinetic (PK) population included all participants who were treated and had at least 1 concentration on 1 PK assessment day. The PK parameter analysis data set included all participants treated who had at least 1 estimated PK parameter of primary interest.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Active Titration Arm | Maximum Observed Plasma Concentration (Cmax) of Axitinib | 31.74 ng/mL |
| Placebo Titration Arm | Maximum Observed Plasma Concentration (Cmax) of Axitinib | 23.05 ng/mL |
Secondary
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.
Time frame: At baseline - Beginning of the lead-in period (Cycle 1 Day 1)
Population: The Safety Analysis (SA) population consisted of all participants who received at least one dose of study medication with treatment assignments designated according to actual study treatment received.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Active Titration Arm | ORR in Subgroups That Were Defined by Vascular Endothelial Growth Factor A (VEGFA) or Vascular Endothelial Growth Factor Receptor 3 (VEGFR3) Polymorphisms | VEGFA/rs1570360 Genotype: A/A (n = 2, 4, 7) | 50.0 Percentage of participants |
| Active Titration Arm | ORR in Subgroups That Were Defined by Vascular Endothelial Growth Factor A (VEGFA) or Vascular Endothelial Growth Factor Receptor 3 (VEGFR3) Polymorphisms | VEGFA/rs699947 Genotype: C/C (n = 14, 14, 24) | 50.0 Percentage of participants |
| Active Titration Arm | ORR in Subgroups That Were Defined by Vascular Endothelial Growth Factor A (VEGFA) or Vascular Endothelial Growth Factor Receptor 3 (VEGFR3) Polymorphisms | VEGFR3/rs307826 Genotype: A/G (n = 6, 4, 9) | 50.0 Percentage of participants |
| Active Titration Arm | ORR in Subgroups That Were Defined by Vascular Endothelial Growth Factor A (VEGFA) or Vascular Endothelial Growth Factor Receptor 3 (VEGFR3) Polymorphisms | VEGFR3/rs448012 Genotype: G/G (n = 16, 15, 28) | 81.3 Percentage of participants |
| Active Titration Arm | ORR in Subgroups That Were Defined by Vascular Endothelial Growth Factor A (VEGFA) or Vascular Endothelial Growth Factor Receptor 3 (VEGFR3) Polymorphisms | VEGFA/rs699947 Genotype: A/C (n = 22, 20, 41) | 54.5 Percentage of participants |
| Active Titration Arm | ORR in Subgroups That Were Defined by Vascular Endothelial Growth Factor A (VEGFA) or Vascular Endothelial Growth Factor Receptor 3 (VEGFR3) Polymorphisms | VEGFR3/rs307826 Genotype: A/A (n = 36, 39, 79) | 58.3 Percentage of participants |
| Active Titration Arm | ORR in Subgroups That Were Defined by Vascular Endothelial Growth Factor A (VEGFA) or Vascular Endothelial Growth Factor Receptor 3 (VEGFR3) Polymorphisms | VEGFR3/rs448012 Genotype: G/C (n = 22, 22, 35) | 45.5 Percentage of participants |
| Active Titration Arm | ORR in Subgroups That Were Defined by Vascular Endothelial Growth Factor A (VEGFA) or Vascular Endothelial Growth Factor Receptor 3 (VEGFR3) Polymorphisms | VEGFR3/rs307821 Genotype: G/G (n = 36, 38, 79) | 55.6 Percentage of participants |
| Active Titration Arm | ORR in Subgroups That Were Defined by Vascular Endothelial Growth Factor A (VEGFA) or Vascular Endothelial Growth Factor Receptor 3 (VEGFR3) Polymorphisms | VEGFR3/rs448012 Genotype: C/C (n = 5, 6, 16) | 40.0 Percentage of participants |
| Active Titration Arm | ORR in Subgroups That Were Defined by Vascular Endothelial Growth Factor A (VEGFA) or Vascular Endothelial Growth Factor Receptor 3 (VEGFR3) Polymorphisms | VEGFA/rs1570360 Genotype: G/G (n = 22, 23, 43) | 59.1 Percentage of participants |
| Active Titration Arm | ORR in Subgroups That Were Defined by Vascular Endothelial Growth Factor A (VEGFA) or Vascular Endothelial Growth Factor Receptor 3 (VEGFR3) Polymorphisms | VEGFR3/rs307821 Genotype: T/T (n = 1, 0, 0) | 100.0 Percentage of participants |
| Active Titration Arm | ORR in Subgroups That Were Defined by Vascular Endothelial Growth Factor A (VEGFA) or Vascular Endothelial Growth Factor Receptor 3 (VEGFR3) Polymorphisms | VEGFA/rs699947 Genotype: A/A (n = 7, 9, 14) | 85.7 Percentage of participants |
| Active Titration Arm | ORR in Subgroups That Were Defined by Vascular Endothelial Growth Factor A (VEGFA) or Vascular Endothelial Growth Factor Receptor 3 (VEGFR3) Polymorphisms | VEGFA/rs1570360 Genotype: G/A (n = 19, 16, 29) | 57.9 Percentage of participants |
| Active Titration Arm | ORR in Subgroups That Were Defined by Vascular Endothelial Growth Factor A (VEGFA) or Vascular Endothelial Growth Factor Receptor 3 (VEGFR3) Polymorphisms | VEGFR3/rs307821 Genotype: G/T (n = 6, 5, 10) | 66.7 Percentage of participants |
| Active Titration Arm | ORR in Subgroups That Were Defined by Vascular Endothelial Growth Factor A (VEGFA) or Vascular Endothelial Growth Factor Receptor 3 (VEGFR3) Polymorphisms | VEGFR3/rs307826 Genotype: G/G (n = 1, 0, 0) | 100.0 Percentage of participants |
| Placebo Titration Arm | ORR in Subgroups That Were Defined by Vascular Endothelial Growth Factor A (VEGFA) or Vascular Endothelial Growth Factor Receptor 3 (VEGFR3) Polymorphisms | VEGFR3/rs307826 Genotype: G/G (n = 1, 0, 0) | 0 Percentage of participants |
| Placebo Titration Arm | ORR in Subgroups That Were Defined by Vascular Endothelial Growth Factor A (VEGFA) or Vascular Endothelial Growth Factor Receptor 3 (VEGFR3) Polymorphisms | VEGFA/rs699947 Genotype: A/A (n = 7, 9, 14) | 22.2 Percentage of participants |
| Placebo Titration Arm | ORR in Subgroups That Were Defined by Vascular Endothelial Growth Factor A (VEGFA) or Vascular Endothelial Growth Factor Receptor 3 (VEGFR3) Polymorphisms | VEGFA/rs699947 Genotype: A/C (n = 22, 20, 41) | 35.0 Percentage of participants |
| Placebo Titration Arm | ORR in Subgroups That Were Defined by Vascular Endothelial Growth Factor A (VEGFA) or Vascular Endothelial Growth Factor Receptor 3 (VEGFR3) Polymorphisms | VEGFA/rs699947 Genotype: C/C (n = 14, 14, 24) | 35.7 Percentage of participants |
| Placebo Titration Arm | ORR in Subgroups That Were Defined by Vascular Endothelial Growth Factor A (VEGFA) or Vascular Endothelial Growth Factor Receptor 3 (VEGFR3) Polymorphisms | VEGFA/rs1570360 Genotype: G/G (n = 22, 23, 43) | 39.1 Percentage of participants |
| Placebo Titration Arm | ORR in Subgroups That Were Defined by Vascular Endothelial Growth Factor A (VEGFA) or Vascular Endothelial Growth Factor Receptor 3 (VEGFR3) Polymorphisms | VEGFA/rs1570360 Genotype: G/A (n = 19, 16, 29) | 18.8 Percentage of participants |
| Placebo Titration Arm | ORR in Subgroups That Were Defined by Vascular Endothelial Growth Factor A (VEGFA) or Vascular Endothelial Growth Factor Receptor 3 (VEGFR3) Polymorphisms | VEGFA/rs1570360 Genotype: A/A (n = 2, 4, 7) | 50.0 Percentage of participants |
| Placebo Titration Arm | ORR in Subgroups That Were Defined by Vascular Endothelial Growth Factor A (VEGFA) or Vascular Endothelial Growth Factor Receptor 3 (VEGFR3) Polymorphisms | VEGFR3/rs448012 Genotype: G/G (n = 16, 15, 28) | 53.3 Percentage of participants |
| Placebo Titration Arm | ORR in Subgroups That Were Defined by Vascular Endothelial Growth Factor A (VEGFA) or Vascular Endothelial Growth Factor Receptor 3 (VEGFR3) Polymorphisms | VEGFR3/rs448012 Genotype: G/C (n = 22, 22, 35) | 18.2 Percentage of participants |
| Placebo Titration Arm | ORR in Subgroups That Were Defined by Vascular Endothelial Growth Factor A (VEGFA) or Vascular Endothelial Growth Factor Receptor 3 (VEGFR3) Polymorphisms | VEGFR3/rs448012 Genotype: C/C (n = 5, 6, 16) | 33.3 Percentage of participants |
| Placebo Titration Arm | ORR in Subgroups That Were Defined by Vascular Endothelial Growth Factor A (VEGFA) or Vascular Endothelial Growth Factor Receptor 3 (VEGFR3) Polymorphisms | VEGFR3/rs307826 Genotype: A/A (n = 36, 39, 79) | 30.8 Percentage of participants |
| Placebo Titration Arm | ORR in Subgroups That Were Defined by Vascular Endothelial Growth Factor A (VEGFA) or Vascular Endothelial Growth Factor Receptor 3 (VEGFR3) Polymorphisms | VEGFR3/rs307826 Genotype: A/G (n = 6, 4, 9) | 50.0 Percentage of participants |
| Placebo Titration Arm | ORR in Subgroups That Were Defined by Vascular Endothelial Growth Factor A (VEGFA) or Vascular Endothelial Growth Factor Receptor 3 (VEGFR3) Polymorphisms | VEGFR3/rs307821 Genotype: G/G (n = 36, 38, 79) | 28.9 Percentage of participants |
| Placebo Titration Arm | ORR in Subgroups That Were Defined by Vascular Endothelial Growth Factor A (VEGFA) or Vascular Endothelial Growth Factor Receptor 3 (VEGFR3) Polymorphisms | VEGFR3/rs307821 Genotype: G/T (n = 6, 5, 10) | 60.0 Percentage of participants |
| Placebo Titration Arm | ORR in Subgroups That Were Defined by Vascular Endothelial Growth Factor A (VEGFA) or Vascular Endothelial Growth Factor Receptor 3 (VEGFR3) Polymorphisms | VEGFR3/rs307821 Genotype: T/T (n = 1, 0, 0) | 0 Percentage of participants |
| Non-randomized Arm | ORR in Subgroups That Were Defined by Vascular Endothelial Growth Factor A (VEGFA) or Vascular Endothelial Growth Factor Receptor 3 (VEGFR3) Polymorphisms | VEGFA/rs1570360 Genotype: A/A (n = 2, 4, 7) | 42.9 Percentage of participants |
| Non-randomized Arm | ORR in Subgroups That Were Defined by Vascular Endothelial Growth Factor A (VEGFA) or Vascular Endothelial Growth Factor Receptor 3 (VEGFR3) Polymorphisms | VEGFR3/rs307821 Genotype: G/T (n = 6, 5, 10) | 40.0 Percentage of participants |
| Non-randomized Arm | ORR in Subgroups That Were Defined by Vascular Endothelial Growth Factor A (VEGFA) or Vascular Endothelial Growth Factor Receptor 3 (VEGFR3) Polymorphisms | VEGFR3/rs307826 Genotype: A/G (n = 6, 4, 9) | 44.4 Percentage of participants |
| Non-randomized Arm | ORR in Subgroups That Were Defined by Vascular Endothelial Growth Factor A (VEGFA) or Vascular Endothelial Growth Factor Receptor 3 (VEGFR3) Polymorphisms | VEGFA/rs1570360 Genotype: G/A (n = 19, 16, 29) | 58.6 Percentage of participants |
| Non-randomized Arm | ORR in Subgroups That Were Defined by Vascular Endothelial Growth Factor A (VEGFA) or Vascular Endothelial Growth Factor Receptor 3 (VEGFR3) Polymorphisms | VEGFA/rs1570360 Genotype: G/G (n = 22, 23, 43) | 67.4 Percentage of participants |
| Non-randomized Arm | ORR in Subgroups That Were Defined by Vascular Endothelial Growth Factor A (VEGFA) or Vascular Endothelial Growth Factor Receptor 3 (VEGFR3) Polymorphisms | VEGFR3/rs307826 Genotype: G/G (n = 1, 0, 0) | 0 Percentage of participants |
| Non-randomized Arm | ORR in Subgroups That Were Defined by Vascular Endothelial Growth Factor A (VEGFA) or Vascular Endothelial Growth Factor Receptor 3 (VEGFR3) Polymorphisms | VEGFA/rs699947 Genotype: C/C (n = 14, 14, 24) | 66.7 Percentage of participants |
| Non-randomized Arm | ORR in Subgroups That Were Defined by Vascular Endothelial Growth Factor A (VEGFA) or Vascular Endothelial Growth Factor Receptor 3 (VEGFR3) Polymorphisms | VEGFA/rs699947 Genotype: A/A (n = 7, 9, 14) | 42.9 Percentage of participants |
| Non-randomized Arm | ORR in Subgroups That Were Defined by Vascular Endothelial Growth Factor A (VEGFA) or Vascular Endothelial Growth Factor Receptor 3 (VEGFR3) Polymorphisms | VEGFR3/rs307821 Genotype: G/G (n = 36, 38, 79) | 65.2 Percentage of participants |
| Non-randomized Arm | ORR in Subgroups That Were Defined by Vascular Endothelial Growth Factor A (VEGFA) or Vascular Endothelial Growth Factor Receptor 3 (VEGFR3) Polymorphisms | VEGFR3/rs448012 Genotype: G/C (n = 22, 22, 35) | 57.1 Percentage of participants |
| Non-randomized Arm | ORR in Subgroups That Were Defined by Vascular Endothelial Growth Factor A (VEGFA) or Vascular Endothelial Growth Factor Receptor 3 (VEGFR3) Polymorphisms | VEGFA/rs699947 Genotype: A/C (n = 22, 20, 41) | 65.9 Percentage of participants |
| Non-randomized Arm | ORR in Subgroups That Were Defined by Vascular Endothelial Growth Factor A (VEGFA) or Vascular Endothelial Growth Factor Receptor 3 (VEGFR3) Polymorphisms | VEGFR3/rs448012 Genotype: C/C (n = 5, 6, 16) | 75.0 Percentage of participants |
| Non-randomized Arm | ORR in Subgroups That Were Defined by Vascular Endothelial Growth Factor A (VEGFA) or Vascular Endothelial Growth Factor Receptor 3 (VEGFR3) Polymorphisms | VEGFR3/rs448012 Genotype: G/G (n = 16, 15, 28) | 60.7 Percentage of participants |
| Non-randomized Arm | ORR in Subgroups That Were Defined by Vascular Endothelial Growth Factor A (VEGFA) or Vascular Endothelial Growth Factor Receptor 3 (VEGFR3) Polymorphisms | VEGFR3/rs307821 Genotype: T/T (n = 1, 0, 0) | 0 Percentage of participants |
| Non-randomized Arm | ORR in Subgroups That Were Defined by Vascular Endothelial Growth Factor A (VEGFA) or Vascular Endothelial Growth Factor Receptor 3 (VEGFR3) Polymorphisms | VEGFR3/rs307826 Genotype: A/A (n = 36, 39, 79) | 64.3 Percentage of participants |
Secondary
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.
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.
Population: The Full Analysis (FA) population included all randomized participants who received study drug or different drug to which they were randomized. The Safety Analysis (SA) population included all non-randomized patients who received at least 1 dose of study medication with treatment assignments designated according to actual study treatment received.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Active Titration Arm | Overall Survival (OS) | 42.7 Months |
| Placebo Titration Arm | Overall Survival (OS) | 30.4 Months |
| Non-randomized Arm | Overall Survival (OS) | 41.6 Months |
Secondary
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.
Time frame: At baseline - Beginning of the lead-in period (Cycle 1 Day 1)
Population: The Safety Analysis (SA) population consisted of all participants who received at least one dose of study medication with treatment assignments designated according to actual study treatment received.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Active Titration Arm | PFS in Subgroups That Were Defined by Vascular Endothelial Growth Factor A (VEGFA) or Vascular Endothelial Growth Factor Receptor 3 (VEGFR3) Polymorphisms | VEGFA/rs1570360 Genotype: A/A (n = 2, 4, 29) | NA Months |
| Active Titration Arm | PFS in Subgroups That Were Defined by Vascular Endothelial Growth Factor A (VEGFA) or Vascular Endothelial Growth Factor Receptor 3 (VEGFR3) Polymorphisms | VEGFA/rs699947 Genotype: A/A (n = 7, 9, 14) | NA Months |
| Active Titration Arm | PFS in Subgroups That Were Defined by Vascular Endothelial Growth Factor A (VEGFA) or Vascular Endothelial Growth Factor Receptor 3 (VEGFR3) Polymorphisms | VEGFR3/rs307826 Genotype: A/G (n = 6, 4, 9) | 16.52 Months |
| Active Titration Arm | PFS in Subgroups That Were Defined by Vascular Endothelial Growth Factor A (VEGFA) or Vascular Endothelial Growth Factor Receptor 3 (VEGFR3) Polymorphisms | VEGFR3/rs448012 Genotype: G/G (n = 16, 15, 28) | 17.44 Months |
| Active Titration Arm | PFS in Subgroups That Were Defined by Vascular Endothelial Growth Factor A (VEGFA) or Vascular Endothelial Growth Factor Receptor 3 (VEGFR3) Polymorphisms | VEGFR3/rs307821 Genotype: G/T (n = 36, 38, 10) | 24.80 Months |
| Active Titration Arm | PFS in Subgroups That Were Defined by Vascular Endothelial Growth Factor A (VEGFA) or Vascular Endothelial Growth Factor Receptor 3 (VEGFR3) Polymorphisms | VEGFR3/rs307826 Genotype: A/A (n = 36, 39, 70) | 13.73 Months |
| Active Titration Arm | PFS in Subgroups That Were Defined by Vascular Endothelial Growth Factor A (VEGFA) or Vascular Endothelial Growth Factor Receptor 3 (VEGFR3) Polymorphisms | VEGFR3/rs448012 Genotype: G/C (n = 22, 22, 35) | 9.18 Months |
| Active Titration Arm | PFS in Subgroups That Were Defined by Vascular Endothelial Growth Factor A (VEGFA) or Vascular Endothelial Growth Factor Receptor 3 (VEGFR3) Polymorphisms | VEGFA/rs699947 Genotype: C/C (n = 14, 14, 41) | 18.74 Months |
| Active Titration Arm | PFS in Subgroups That Were Defined by Vascular Endothelial Growth Factor A (VEGFA) or Vascular Endothelial Growth Factor Receptor 3 (VEGFR3) Polymorphisms | VEGFR3/rs448012 Genotype: C/C (n = 5, 6, 16) | 11.07 Months |
| Active Titration Arm | PFS in Subgroups That Were Defined by Vascular Endothelial Growth Factor A (VEGFA) or Vascular Endothelial Growth Factor Receptor 3 (VEGFR3) Polymorphisms | VEGFR3/rs307821 Genotype: T/T (n = 1, 0, 0) | NA Months |
| Active Titration Arm | PFS in Subgroups That Were Defined by Vascular Endothelial Growth Factor A (VEGFA) or Vascular Endothelial Growth Factor Receptor 3 (VEGFR3) Polymorphisms | VEGFA/rs1570360 Genotype: G/G (n = 22, 23, 43) | 14.62 Months |
| Active Titration Arm | PFS in Subgroups That Were Defined by Vascular Endothelial Growth Factor A (VEGFA) or Vascular Endothelial Growth Factor Receptor 3 (VEGFR3) Polymorphisms | VEGFR3/rs307821 Genotype: G/G (n = 36, 38, 69) | 12.78 Months |
| Active Titration Arm | PFS in Subgroups That Were Defined by Vascular Endothelial Growth Factor A (VEGFA) or Vascular Endothelial Growth Factor Receptor 3 (VEGFR3) Polymorphisms | VEGFA/rs1570360 Genotype: G/A (n = 19, 16, 29) | 12.78 Months |
| Active Titration Arm | PFS in Subgroups That Were Defined by Vascular Endothelial Growth Factor A (VEGFA) or Vascular Endothelial Growth Factor Receptor 3 (VEGFR3) Polymorphisms | VEGFA/rs699947 Genotype: A/C (n = 22, 20, 41) | 11.07 Months |
| Active Titration Arm | PFS in Subgroups That Were Defined by Vascular Endothelial Growth Factor A (VEGFA) or Vascular Endothelial Growth Factor Receptor 3 (VEGFR3) Polymorphisms | VEGFR3/rs307826 Genotype: G/G (n = 0, 0, 0) | NA Months |
| Placebo Titration Arm | PFS in Subgroups That Were Defined by Vascular Endothelial Growth Factor A (VEGFA) or Vascular Endothelial Growth Factor Receptor 3 (VEGFR3) Polymorphisms | VEGFR3/rs307826 Genotype: G/G (n = 0, 0, 0) | NA Months |
| Placebo Titration Arm | PFS in Subgroups That Were Defined by Vascular Endothelial Growth Factor A (VEGFA) or Vascular Endothelial Growth Factor Receptor 3 (VEGFR3) Polymorphisms | VEGFA/rs1570360 Genotype: G/G (n = 22, 23, 43) | 19.42 Months |
| Placebo Titration Arm | PFS in Subgroups That Were Defined by Vascular Endothelial Growth Factor A (VEGFA) or Vascular Endothelial Growth Factor Receptor 3 (VEGFR3) Polymorphisms | VEGFA/rs699947 Genotype: A/A (n = 7, 9, 14) | 11.50 Months |
| Placebo Titration Arm | PFS in Subgroups That Were Defined by Vascular Endothelial Growth Factor A (VEGFA) or Vascular Endothelial Growth Factor Receptor 3 (VEGFR3) Polymorphisms | VEGFA/rs699947 Genotype: A/C (n = 22, 20, 41) | 9.67 Months |
| Placebo Titration Arm | PFS in Subgroups That Were Defined by Vascular Endothelial Growth Factor A (VEGFA) or Vascular Endothelial Growth Factor Receptor 3 (VEGFR3) Polymorphisms | VEGFA/rs699947 Genotype: C/C (n = 14, 14, 41) | 24.64 Months |
| Placebo Titration Arm | PFS in Subgroups That Were Defined by Vascular Endothelial Growth Factor A (VEGFA) or Vascular Endothelial Growth Factor Receptor 3 (VEGFR3) Polymorphisms | VEGFA/rs1570360 Genotype: G/A (n = 19, 16, 29) | 8.34 Months |
| Placebo Titration Arm | PFS in Subgroups That Were Defined by Vascular Endothelial Growth Factor A (VEGFA) or Vascular Endothelial Growth Factor Receptor 3 (VEGFR3) Polymorphisms | VEGFA/rs1570360 Genotype: A/A (n = 2, 4, 29) | 10.04 Months |
| Placebo Titration Arm | PFS in Subgroups That Were Defined by Vascular Endothelial Growth Factor A (VEGFA) or Vascular Endothelial Growth Factor Receptor 3 (VEGFR3) Polymorphisms | VEGFR3/rs448012 Genotype: G/G (n = 16, 15, 28) | 19.42 Months |
| Placebo Titration Arm | PFS in Subgroups That Were Defined by Vascular Endothelial Growth Factor A (VEGFA) or Vascular Endothelial Growth Factor Receptor 3 (VEGFR3) Polymorphisms | VEGFR3/rs448012 Genotype: G/C (n = 22, 22, 35) | 8.31 Months |
| Placebo Titration Arm | PFS in Subgroups That Were Defined by Vascular Endothelial Growth Factor A (VEGFA) or Vascular Endothelial Growth Factor Receptor 3 (VEGFR3) Polymorphisms | VEGFR3/rs448012 Genotype: C/C (n = 5, 6, 16) | 15.67 Months |
| Placebo Titration Arm | PFS in Subgroups That Were Defined by Vascular Endothelial Growth Factor A (VEGFA) or Vascular Endothelial Growth Factor Receptor 3 (VEGFR3) Polymorphisms | VEGFR3/rs307826 Genotype: A/A (n = 36, 39, 70) | 15.67 Months |
| Placebo Titration Arm | PFS in Subgroups That Were Defined by Vascular Endothelial Growth Factor A (VEGFA) or Vascular Endothelial Growth Factor Receptor 3 (VEGFR3) Polymorphisms | VEGFR3/rs307826 Genotype: A/G (n = 6, 4, 9) | 7.93 Months |
| Placebo Titration Arm | PFS in Subgroups That Were Defined by Vascular Endothelial Growth Factor A (VEGFA) or Vascular Endothelial Growth Factor Receptor 3 (VEGFR3) Polymorphisms | VEGFR3/rs307821 Genotype: G/G (n = 36, 38, 69) | 15.67 Months |
| Placebo Titration Arm | PFS in Subgroups That Were Defined by Vascular Endothelial Growth Factor A (VEGFA) or Vascular Endothelial Growth Factor Receptor 3 (VEGFR3) Polymorphisms | VEGFR3/rs307821 Genotype: G/T (n = 36, 38, 10) | 8.34 Months |
| Placebo Titration Arm | PFS in Subgroups That Were Defined by Vascular Endothelial Growth Factor A (VEGFA) or Vascular Endothelial Growth Factor Receptor 3 (VEGFR3) Polymorphisms | VEGFR3/rs307821 Genotype: T/T (n = 1, 0, 0) | NA Months |
| Non-randomized Arm | PFS in Subgroups That Were Defined by Vascular Endothelial Growth Factor A (VEGFA) or Vascular Endothelial Growth Factor Receptor 3 (VEGFR3) Polymorphisms | VEGFA/rs1570360 Genotype: A/A (n = 2, 4, 29) | 8.57 Months |
| Non-randomized Arm | PFS in Subgroups That Were Defined by Vascular Endothelial Growth Factor A (VEGFA) or Vascular Endothelial Growth Factor Receptor 3 (VEGFR3) Polymorphisms | VEGFR3/rs307821 Genotype: G/T (n = 36, 38, 10) | 13.86 Months |
| Non-randomized Arm | PFS in Subgroups That Were Defined by Vascular Endothelial Growth Factor A (VEGFA) or Vascular Endothelial Growth Factor Receptor 3 (VEGFR3) Polymorphisms | VEGFR3/rs307826 Genotype: A/G (n = 6, 4, 9) | 16.26 Months |
| Non-randomized Arm | PFS in Subgroups That Were Defined by Vascular Endothelial Growth Factor A (VEGFA) or Vascular Endothelial Growth Factor Receptor 3 (VEGFR3) Polymorphisms | VEGFA/rs1570360 Genotype: G/A (n = 19, 16, 29) | 13.90 Months |
| Non-randomized Arm | PFS in Subgroups That Were Defined by Vascular Endothelial Growth Factor A (VEGFA) or Vascular Endothelial Growth Factor Receptor 3 (VEGFR3) Polymorphisms | VEGFA/rs699947 Genotype: C/C (n = 14, 14, 41) | 25.13 Months |
| Non-randomized Arm | PFS in Subgroups That Were Defined by Vascular Endothelial Growth Factor A (VEGFA) or Vascular Endothelial Growth Factor Receptor 3 (VEGFR3) Polymorphisms | VEGFR3/rs307826 Genotype: G/G (n = 0, 0, 0) | NA Months |
| Non-randomized Arm | PFS in Subgroups That Were Defined by Vascular Endothelial Growth Factor A (VEGFA) or Vascular Endothelial Growth Factor Receptor 3 (VEGFR3) Polymorphisms | VEGFA/rs1570360 Genotype: G/G (n = 22, 23, 43) | 25.13 Months |
| Non-randomized Arm | PFS in Subgroups That Were Defined by Vascular Endothelial Growth Factor A (VEGFA) or Vascular Endothelial Growth Factor Receptor 3 (VEGFR3) Polymorphisms | VEGFA/rs699947 Genotype: A/A (n = 7, 9, 14) | 7.33 Months |
| Non-randomized Arm | PFS in Subgroups That Were Defined by Vascular Endothelial Growth Factor A (VEGFA) or Vascular Endothelial Growth Factor Receptor 3 (VEGFR3) Polymorphisms | VEGFR3/rs307821 Genotype: G/G (n = 36, 38, 69) | 16.59 Months |
| Non-randomized Arm | PFS in Subgroups That Were Defined by Vascular Endothelial Growth Factor A (VEGFA) or Vascular Endothelial Growth Factor Receptor 3 (VEGFR3) Polymorphisms | VEGFR3/rs448012 Genotype: G/C (n = 22, 22, 35) | 13.83 Months |
| Non-randomized Arm | PFS in Subgroups That Were Defined by Vascular Endothelial Growth Factor A (VEGFA) or Vascular Endothelial Growth Factor Receptor 3 (VEGFR3) Polymorphisms | VEGFA/rs699947 Genotype: A/C (n = 22, 20, 41) | 16.59 Months |
| Non-randomized Arm | PFS in Subgroups That Were Defined by Vascular Endothelial Growth Factor A (VEGFA) or Vascular Endothelial Growth Factor Receptor 3 (VEGFR3) Polymorphisms | VEGFR3/rs448012 Genotype: C/C (n = 5, 6, 16) | NA Months |
| Non-randomized Arm | PFS in Subgroups That Were Defined by Vascular Endothelial Growth Factor A (VEGFA) or Vascular Endothelial Growth Factor Receptor 3 (VEGFR3) Polymorphisms | VEGFR3/rs448012 Genotype: G/G (n = 16, 15, 28) | 22.54 Months |
| Non-randomized Arm | PFS in Subgroups That Were Defined by Vascular Endothelial Growth Factor A (VEGFA) or Vascular Endothelial Growth Factor Receptor 3 (VEGFR3) Polymorphisms | VEGFR3/rs307821 Genotype: T/T (n = 1, 0, 0) | NA Months |
| Non-randomized Arm | PFS in Subgroups That Were Defined by Vascular Endothelial Growth Factor A (VEGFA) or Vascular Endothelial Growth Factor Receptor 3 (VEGFR3) Polymorphisms | VEGFR3/rs307826 Genotype: A/A (n = 36, 39, 70) | 16.56 Months |
Secondary
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.
Time frame: C2D15: pre-dose, 0.5, 1, 2, 4, and 6 hours post-dose
Population: The pharmacokinetic (PK) population included all participants who were treated and had at least 1 concentration on 1 PK assessment day. The PK parameter analysis data set included all participants treated who had at least 1 estimated PK parameter of primary interest.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Active Titration Arm | Plasma Decay Half-Life (t1/2) for Axitinib | 2.48 hr | Standard Deviation 1.902 |
| Placebo Titration Arm | Plasma Decay Half-Life (t1/2) for Axitinib | 2.81 hr | Standard Deviation 1.685 |
Secondary
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.
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.
Population: The Full Analysis (FA) population included all randomized participants who received study drug or different drug to which they were randomized. The Safety Analysis (SA) population included all non-randomized patients who received at least 1 dose of study medication with treatment assignments designated according to actual study treatment received.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Active Titration Arm | Progression-Free Survival (PFS) | 14.5 Months |
| Placebo Titration Arm | Progression-Free Survival (PFS) | 15.7 Months |
| Non-randomized Arm | Progression-Free Survival (PFS) | 16.6 Months |
| All Participants | Progression-Free Survival (PFS) | 14.6 Months |
p-value: 0.244495% CI: [0.535, 1.348]Log Rank
Secondary
Time to Reach Maximum Observed Plasma Concentration (Tmax) for Axitinib,
Tmax for steady-state axitinib was evaluated on Cycle 2 Day 15.
Time frame: C2D15: pre-dose, 0.5, 1, 2, 4, and 6 hours post-dose
Population: The pharmacokinetic (PK) population included all participants who were treated and had at least 1 concentration on 1 PK assessment day. The PK parameter analysis data set included all participants treated who had at least 1 estimated PK parameter of primary interest.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Active Titration Arm | Time to Reach Maximum Observed Plasma Concentration (Tmax) for Axitinib, | 2.04 hrs |
| Placebo Titration Arm | Time to Reach Maximum Observed Plasma Concentration (Tmax) for Axitinib, | 2.00 hrs |