Carcinoma
Conditions
Keywords
Safety, PK, Biomarker
Brief summary
To evaluate the clinically recommended dose of AG-013736 (Axitinib) in Japanese patients by reviewing the safety of AG-013736 (Axitinib) following single and multiple dosing.
Interventions
AG-013736 5mg twice daily \[BID\]
Sponsors
Pfizer
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
20 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Patients histologically or cytologically diagnosed with advanced malignant solid tumors * Patients for whom standard therapies have not been effective, or for whom there are no suitable therapies
Exclusion criteria
* Central lung lesions involving major blood vessels * Patients who have been treated with bevacizumab or other VEGFR inhibitor(s)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Adverse Events | Up to 795 days of treatment plus 28-days follow-up | Number of participants with any adverse events, adverse events graded as Common Terminology Criteria for Adverse Events Version 3.0 (CTCAE) Grade 3 or higher, serious adverse events, and adverse events resulted in discontinuation. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Observed Plasma Concentration (Cmax): Single Dose | Single dose: predose, 0.5, 1, 2, 4, 6, 8, 12, 24, and 32 hours postdose | — |
| Time to Reach Maximum Observed Plasma Concentration (Tmax): Single Dose | Single dose: predose, 0.5, 1, 2, 4, 6, 8, 12, 24, and 32 hours postdose | — |
| Area Under The Plasma Concentration-Time Curve From Time Zero to Time Infinity (AUCinf): Single Dose | Single dose: predose, 0.5, 1, 2, 4, 6, 8, 12, 24, and 32 hours postdose | AUCinf is obtained from AUC (0 - t) plus AUC (t - infinity). |
| Terminal Phase Plasma Half-Life (t1/2): Single Dose | Single dose: predose, 0.5, 1, 2, 4, 6, 8, 12, 24, and 32 hours postdose | t1/2 is the time measured for the plasma concentration to decrease by one half. |
| Maximum Observed Plasma Concentration (Cmax): Multiple Dose | Multiple dose Cycle 1 Day 1 and 15: predose, 0.5, 1, 2, 4, 8 and 12 hours postdose | — |
| Time to Reach Maximum Observed Plasma Concentration (Tmax): Multiple Dose | Multiple dose Cycle 1 Day 1 and 15: predose, 0.5, 1, 2, 4, 8 and 12 hours postdose | — |
| Area Under The Plasma Concentration-Time Curve Over Dosing Interval Tau (AUCtau): Multiple Dose | Multiple dose Cycle 1 Day 1 and 15: predose, 0.5, 1, 2, 4, 8 and 12 hours postdose | Dosing Interval was 12 hours in this study. |
| Accumulation Ratio for Cmax (Rac Cmax) and Accumulation Ratio for AUCtau (Rac AUCtau): Multiple Dose | Multiple dose Cycle 1 Day 1 and 15: predose, 0.5, 1, 2, 4, 8 and 12 hours postdose | Rac Cmax is obtained from Cmax (Cycle 1, Day 15) divided by Cmax (Cycle 1, Day 1) Rac AUCtau is obtained from AUCtau (Cycle 1, Day 15) divided by AUCtau (Cycle 1, Day 1) |
| Percent Change From Baseline in Soluble Vascular Endothelial Growth Factor Receptor 2 and 3 (s-VEGFR2 and s-VEGFR3), Vascular Endothelial Growth Factor (VEGF), Soluble Stem Cell Factor Receptor (s-KIT) | Prior to the initial dose (baseline), Day 1 of Cycle 2 and at the discontinuation | Percent change from baseline is obtained from (observed value minus baseline value) divided by baseline value multiplied by 100 in each parameter, i.e., VEGFR2, s-VEGFR3, s-KIT, and VEGF. |
| The Numbers of Participants With Best Overall Response of Complete Response (CR), Partial Response (PR), Stable Disease (SD), and Progression of Disease (PD) According to the Response Evaluation Criteria in Solid Tumors (RECIST Version 1.0) | Up to 795 days | CR was defined as the disappearance of all target and nontarget lesions and no appearance of new lesions. PR was defined as at least a 30% decrease in the sum of the longest diameters (SLD) of the targeted lesions. CR and PR had to be documented on 2 occasions separated by at least 4 weeks. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify as PD being demonstrated during the first 8 weeks. PD was defined as at least a 20% increase in the SLD of target lesions compared to the smallest SLD since the study treatment started. |
Countries
Japan
Participant flow
Pre-assignment details
Six participants initially received a single dose of AG-013736 5 mg followed by 5 mg twice daily (BID) multiple dosing. They were monitored for dose limiting toxicity (DLT) up to multiple dosing Cycle 1. Since no more than 1 of the first 6 participants had a DLT, 6 additional participants initiated AG-013736 from multiple dosing per the protocol.
Participants by arm
| Arm | Count |
|---|---|
| AG-013736 Single dose (first 6 participants only): Single AG-013736 5 mg was administered orally.
Multiple dose (all participants): AG-013736 5 mg twice daily (BID) was administered orally in fed state, 12 hours apart at approximately the same time each day. AG-013736 dose was titrated or reduced based on the dose modification criteria: the available dose was 2, 3, 5, 7, or 10 mg at a time. One cycle length was 28 days and participants continued the study treatment until intolerable toxicity or disease progression occurred. | 12 |
| Total | 12 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 1 |
| Overall Study | Lack of Efficacy | 11 |
Baseline characteristics
| Characteristic | AG-013736 |
|---|---|
| Age Continuous | 60.2 years STANDARD_DEVIATION 13.1 |
| Sex: Female, Male Female | 5 Participants |
| Sex: Female, Male Male | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 12 / 12 |
| serious Total, serious adverse events | 5 / 12 |
Outcome results
Primary
Number of Participants With Adverse Events
Number of participants with any adverse events, adverse events graded as Common Terminology Criteria for Adverse Events Version 3.0 (CTCAE) Grade 3 or higher, serious adverse events, and adverse events resulted in discontinuation.
Time frame: Up to 795 days of treatment plus 28-days follow-up
Population: All subjects who received at least 1 dose of the study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| AG-013736 | Number of Participants With Adverse Events | Any adverse events | 12 participants |
| AG-013736 | Number of Participants With Adverse Events | Any serious adverse events | 5 participants |
| AG-013736 | Number of Participants With Adverse Events | Any Grade-3 or -4 adverse events | 7 participants |
| AG-013736 | Number of Participants With Adverse Events | Any Grade-5 adverse events (= death) | 0 participants |
| AG-013736 | Number of Participants With Adverse Events | Discontinuation due to adverse events | 1 participants |
Secondary
Accumulation Ratio for Cmax (Rac Cmax) and Accumulation Ratio for AUCtau (Rac AUCtau): Multiple Dose
Rac Cmax is obtained from Cmax (Cycle 1, Day 15) divided by Cmax (Cycle 1, Day 1) Rac AUCtau is obtained from AUCtau (Cycle 1, Day 15) divided by AUCtau (Cycle 1, Day 1)
Time frame: Multiple dose Cycle 1 Day 1 and 15: predose, 0.5, 1, 2, 4, 8 and 12 hours postdose
Population: Participants who received at least one study drug and completed pharmacokinetic blood sampling for at least one day (Pharmacokinetic Analysis Set); n= number of participants assessed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| AG-013736 | Accumulation Ratio for Cmax (Rac Cmax) and Accumulation Ratio for AUCtau (Rac AUCtau): Multiple Dose | Rac Cmax (n=11) | 1.449 ratio | Standard Deviation 0.471 |
| AG-013736 | Accumulation Ratio for Cmax (Rac Cmax) and Accumulation Ratio for AUCtau (Rac AUCtau): Multiple Dose | Rac AUCtau (n=11) | 1.541 ratio | Standard Deviation 0.489 |
Secondary
Area Under The Plasma Concentration-Time Curve From Time Zero to Time Infinity (AUCinf): Single Dose
AUCinf is obtained from AUC (0 - t) plus AUC (t - infinity).
Time frame: Single dose: predose, 0.5, 1, 2, 4, 6, 8, 12, 24, and 32 hours postdose
Population: Participants who received at least one study drug and completed pharmacokinetic blood sampling for at least one day (Pharmacokinetic Analysis Set). Only the first 6 participants were administered a single dose.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AG-013736 | Area Under The Plasma Concentration-Time Curve From Time Zero to Time Infinity (AUCinf): Single Dose | 210.3 ng*hr/mL | Standard Deviation 146.5 |
Secondary
Area Under The Plasma Concentration-Time Curve Over Dosing Interval Tau (AUCtau): Multiple Dose
Dosing Interval was 12 hours in this study.
Time frame: Multiple dose Cycle 1 Day 1 and 15: predose, 0.5, 1, 2, 4, 8 and 12 hours postdose
Population: Participants who received at least one study drug and completed pharmacokinetic blood sampling for at least one day (Pharmacokinetic Analysis Set); n= number of participants assessed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| AG-013736 | Area Under The Plasma Concentration-Time Curve Over Dosing Interval Tau (AUCtau): Multiple Dose | Cycle 1 Day 1 (n=12) | 137.3 ng*h/mL | Standard Deviation 84.3 |
| AG-013736 | Area Under The Plasma Concentration-Time Curve Over Dosing Interval Tau (AUCtau): Multiple Dose | Cycle 1 Day 15 (n=11) | 187.8 ng*h/mL | Standard Deviation 125.3 |
Secondary
Maximum Observed Plasma Concentration (Cmax): Multiple Dose
Time frame: Multiple dose Cycle 1 Day 1 and 15: predose, 0.5, 1, 2, 4, 8 and 12 hours postdose
Population: Participants who received at least one study drug and completed pharmacokinetic blood sampling for at least one day (Pharmacokinetic Analysis Set); n= number of participants assessed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| AG-013736 | Maximum Observed Plasma Concentration (Cmax): Multiple Dose | Cycle 1 Day 1 (n=12) | 23.85 ng/mL | Standard Deviation 10.94 |
| AG-013736 | Maximum Observed Plasma Concentration (Cmax): Multiple Dose | Cycle 1 Day 15 (n=11) | 32.14 ng/mL | Standard Deviation 18.04 |
Secondary
Maximum Observed Plasma Concentration (Cmax): Single Dose
Time frame: Single dose: predose, 0.5, 1, 2, 4, 6, 8, 12, 24, and 32 hours postdose
Population: Participants who received at least one study drug and completed pharmacokinetic blood sampling for at least one day (Pharmacokinetic Analysis Set). Only the first 6 participants were administered a single dose.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AG-013736 | Maximum Observed Plasma Concentration (Cmax): Single Dose | 29.97 ng/mL | Standard Deviation 9.97 |
Secondary
Percent Change From Baseline in Soluble Vascular Endothelial Growth Factor Receptor 2 and 3 (s-VEGFR2 and s-VEGFR3), Vascular Endothelial Growth Factor (VEGF), Soluble Stem Cell Factor Receptor (s-KIT)
Percent change from baseline is obtained from (observed value minus baseline value) divided by baseline value multiplied by 100 in each parameter, i.e., VEGFR2, s-VEGFR3, s-KIT, and VEGF.
Time frame: Prior to the initial dose (baseline), Day 1 of Cycle 2 and at the discontinuation
Population: Participants who received at least one study drug and completed pharmacodynamic blood sampling for at least one day (Pharmacodynamic Analysis Set); n= number of participants assessed.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| AG-013736 | Percent Change From Baseline in Soluble Vascular Endothelial Growth Factor Receptor 2 and 3 (s-VEGFR2 and s-VEGFR3), Vascular Endothelial Growth Factor (VEGF), Soluble Stem Cell Factor Receptor (s-KIT) | s-VEGFR3: At discontinuation (n=11) | -65.48 percent change |
| AG-013736 | Percent Change From Baseline in Soluble Vascular Endothelial Growth Factor Receptor 2 and 3 (s-VEGFR2 and s-VEGFR3), Vascular Endothelial Growth Factor (VEGF), Soluble Stem Cell Factor Receptor (s-KIT) | s-VEGFR2: Cycle 2 Day 1 (n=12) | -41.73 percent change |
| AG-013736 | Percent Change From Baseline in Soluble Vascular Endothelial Growth Factor Receptor 2 and 3 (s-VEGFR2 and s-VEGFR3), Vascular Endothelial Growth Factor (VEGF), Soluble Stem Cell Factor Receptor (s-KIT) | s-VEGFR2: At discontinuation (n=11) | -40.57 percent change |
| AG-013736 | Percent Change From Baseline in Soluble Vascular Endothelial Growth Factor Receptor 2 and 3 (s-VEGFR2 and s-VEGFR3), Vascular Endothelial Growth Factor (VEGF), Soluble Stem Cell Factor Receptor (s-KIT) | s-VEGFR3: Cycle 2 Day 1 (n=12) | -52.50 percent change |
| AG-013736 | Percent Change From Baseline in Soluble Vascular Endothelial Growth Factor Receptor 2 and 3 (s-VEGFR2 and s-VEGFR3), Vascular Endothelial Growth Factor (VEGF), Soluble Stem Cell Factor Receptor (s-KIT) | s-KIT: Cycle 2 Day 1 (n=12) | -0.26 percent change |
| AG-013736 | Percent Change From Baseline in Soluble Vascular Endothelial Growth Factor Receptor 2 and 3 (s-VEGFR2 and s-VEGFR3), Vascular Endothelial Growth Factor (VEGF), Soluble Stem Cell Factor Receptor (s-KIT) | s-KIT: At discontinuation (n=11) | 4.66 percent change |
| AG-013736 | Percent Change From Baseline in Soluble Vascular Endothelial Growth Factor Receptor 2 and 3 (s-VEGFR2 and s-VEGFR3), Vascular Endothelial Growth Factor (VEGF), Soluble Stem Cell Factor Receptor (s-KIT) | VEGF: Cycle 2 Day 1 (n=12) | 266.92 percent change |
| AG-013736 | Percent Change From Baseline in Soluble Vascular Endothelial Growth Factor Receptor 2 and 3 (s-VEGFR2 and s-VEGFR3), Vascular Endothelial Growth Factor (VEGF), Soluble Stem Cell Factor Receptor (s-KIT) | VEGF: At discontinuation (n=11) | 43.48 percent change |
Secondary
Terminal Phase Plasma Half-Life (t1/2): Single Dose
t1/2 is the time measured for the plasma concentration to decrease by one half.
Time frame: Single dose: predose, 0.5, 1, 2, 4, 6, 8, 12, 24, and 32 hours postdose
Population: Participants who received at least one study drug and completed pharmacokinetic blood sampling for at least one day (Pharmacokinetic Analysis Set). Only the first 6 participants were administered a single dose.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AG-013736 | Terminal Phase Plasma Half-Life (t1/2): Single Dose | 4.8 hours | Standard Deviation 1.146 |
Secondary
The Numbers of Participants With Best Overall Response of Complete Response (CR), Partial Response (PR), Stable Disease (SD), and Progression of Disease (PD) According to the Response Evaluation Criteria in Solid Tumors (RECIST Version 1.0)
CR was defined as the disappearance of all target and nontarget lesions and no appearance of new lesions. PR was defined as at least a 30% decrease in the sum of the longest diameters (SLD) of the targeted lesions. CR and PR had to be documented on 2 occasions separated by at least 4 weeks. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify as PD being demonstrated during the first 8 weeks. PD was defined as at least a 20% increase in the SLD of target lesions compared to the smallest SLD since the study treatment started.
Time frame: Up to 795 days
Population: Participants with at least 1 target lesion according to RECIST and who received at least 1 dose of study drug (Anti-tumor Response Analysis Set).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| AG-013736 | The Numbers of Participants With Best Overall Response of Complete Response (CR), Partial Response (PR), Stable Disease (SD), and Progression of Disease (PD) According to the Response Evaluation Criteria in Solid Tumors (RECIST Version 1.0) | CR | 0 participants |
| AG-013736 | The Numbers of Participants With Best Overall Response of Complete Response (CR), Partial Response (PR), Stable Disease (SD), and Progression of Disease (PD) According to the Response Evaluation Criteria in Solid Tumors (RECIST Version 1.0) | PR | 0 participants |
| AG-013736 | The Numbers of Participants With Best Overall Response of Complete Response (CR), Partial Response (PR), Stable Disease (SD), and Progression of Disease (PD) According to the Response Evaluation Criteria in Solid Tumors (RECIST Version 1.0) | SD | 10 participants |
| AG-013736 | The Numbers of Participants With Best Overall Response of Complete Response (CR), Partial Response (PR), Stable Disease (SD), and Progression of Disease (PD) According to the Response Evaluation Criteria in Solid Tumors (RECIST Version 1.0) | PD | 2 participants |
Secondary
Time to Reach Maximum Observed Plasma Concentration (Tmax): Multiple Dose
Time frame: Multiple dose Cycle 1 Day 1 and 15: predose, 0.5, 1, 2, 4, 8 and 12 hours postdose
Population: Participants who received at least one study drug and completed pharmacokinetic blood sampling for at least one day (Pharmacokinetic Analysis Set); n= number of participants assessed.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| AG-013736 | Time to Reach Maximum Observed Plasma Concentration (Tmax): Multiple Dose | Cycle 1 Day 1 (n=12) | 3 hours |
| AG-013736 | Time to Reach Maximum Observed Plasma Concentration (Tmax): Multiple Dose | Cycle 1 Day 15 (n=11) | 4 hours |
Secondary
Time to Reach Maximum Observed Plasma Concentration (Tmax): Single Dose
Time frame: Single dose: predose, 0.5, 1, 2, 4, 6, 8, 12, 24, and 32 hours postdose
Population: Participants who received at least one study drug and completed pharmacokinetic blood sampling for at least one day (Pharmacokinetic Analysis Set). Only the first 6 participants were administered a single dose.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| AG-013736 | Time to Reach Maximum Observed Plasma Concentration (Tmax): Single Dose | 4 hours |