Neoplasms
Conditions
Keywords
solid tumor, Axitinib, Pharmacokinetics, Phase 1
Brief summary
This study designed to evaluate the pharmacokinetics and safety of AG-013736 at single doses and multiple doses
Interventions
Three single dose level of AG-013736 (5 mg, 7 mg and 10 mg) will be given for all patient. After single dosing at each dose level, multiple doses of 5 mg twice a day (BID) will be started.
Sponsors
Pfizer
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
20 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients histologically or cytologically diagnosed with advanced solid tumors * Patients for whom standard therapies have not been effective, or for whom there are no suitable therapies * Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0, 1 or 2 * Patients with no uncontrolled hypertension
Exclusion criteria
* Patients who have central lung lesions involving major blood vessels * Patients who require anticoagulant therapy. * Patients with active epilepsy seizure or symptoms, with brain metastases requiring treatment, with spinal cord compression and with carcinomatous meningitis.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Single Dose: Maximum Observed Plasma Concentration (Cmax) | Predose, 0.5, 1, 2, 4, 6, 8, 10, 24, and 32-hour postdose | — |
| Area Under the Plasma Concentration-Time Curve From Time Zero to Time Infinity (AUCinf) | Predose, 0.5, 1, 2, 4, 6, 8, 10, 24, and 32-hour postdose | AUCinf is obtained from AUC (0 - t) plus AUC (t - infinity). |
| Single Dose: Time to Reach Maximum Observed Plasma Concentration (Tmax) | Predose, 0.5, 1, 2, 4, 6, 8, 10, 24, and 32-hour postdose | — |
| Single Dose: Plasma Decay Half-Life (t1/2) | Predose, 0.5, 1, 2, 4, 6, 8, 10, 24, and 32-hour postdose | Plasma decay half-life is the time measured for the plasma concentration to decrease by one half. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline in Soluble Vascular Endothelial Growth Factor Receptor 1, 2, and 3 (s-VEGFR1, s-VEGFR2 and s-VEGFR3), Vascular Endothelial Growth Factor (VEGF), Soluble Stem Cell Factor Receptor (s-KIT ) | Prior to the initial dose (baseline) and Day 1 of Cycle 2 | Percent change from baseline is obtained from (observed value minus baseline value) divided by baseline value multiplied by 100 in each parameter, i.e., s-VEGFR1, VEGFR2, s-VEGFR3, s-KIT, and VEGF |
| Multiple Dose: Maximum Observed Plasma Concentration (Cmax) | Cycle 1 Day 15 predose in the morning, and 0.5, 1, 2, 4, 8 and 12 hour postdose | Cmax at multiple dosing |
| Number of Participants With Adverse Events | Up to 470 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 (CTCAE) Version 3.0 Grade 3 or higher , serious adverse events, and adverse events resulted in discontinuation. |
| Number 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 470 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. |
| Multiple Dose: Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) | Cycle 1 Day 15 predose in the morning, and 0.5, 1, 2, 4, 8 and 12 hour postdose | The dosing interval was 12 hours in this study. |
| Multiple Dose: Time to Reach Maximum Observed Plasma Concentration (Tmax) | Cycle 1 Day 15 predose in the morning, and 0.5, 1, 2, 4, 8 and 12 hour postdose | Tmax at multiple dosing |
| Multiple Dose: Accumulation Ratio for Cmax (Rac Cmax) and Accumulation Ratio for AUCtau (Rac AUCtau) | Cycle 1 Day 15 predose in the morning, and 0.5, 1, 2, 4, 8 and 12 hour 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) |
Countries
Japan
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| AG-013736 Single Dosing: Participants received single AG-013736 5 mg, followed by 7 mg, and subsequently 10 mg. After the single dose at each dose level, participants were monitored for at least 48 hours prior to the next dosing. Multiple Dosing (28-day cycle ): After the monitoring period following the 10 mg single dose, participants received multiple doses of AG-013736 at 5 mg twice daily (BID) at approximately 12 hours apart. The treatment was continued until participants experienced intolerable toxicity or progressive disease. | 6 |
| Total | 6 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Lack of Efficacy | 6 |
Baseline characteristics
| Characteristic | AG-013736 |
|---|---|
| Age Continuous | 53.8 years STANDARD_DEVIATION 15.8 |
| Sex: Female, Male Female | 3 Participants |
| Sex: Female, Male Male | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 6 / 6 |
| serious Total, serious adverse events | 1 / 6 |
Outcome results
Primary
Area Under the Plasma Concentration-Time Curve From Time Zero to Time Infinity (AUCinf)
AUCinf is obtained from AUC (0 - t) plus AUC (t - infinity).
Time frame: Predose, 0.5, 1, 2, 4, 6, 8, 10, 24, and 32-hour postdose
Population: Pharmacokinetic analysis set was defined as all enrolled participants who received at least 1 dose of the study medication and who completed pharmacokinetic blood sampling for at least 1 day.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| AG-013736 | Area Under the Plasma Concentration-Time Curve From Time Zero to Time Infinity (AUCinf) | 5 mg Single Dose | 180.25 ng*hr/mL | Standard Deviation 154.9 |
| AG-013736 | Area Under the Plasma Concentration-Time Curve From Time Zero to Time Infinity (AUCinf) | 7 mg Single Dose | 228.45 ng*hr/mL | Standard Deviation 183.12 |
| AG-013736 | Area Under the Plasma Concentration-Time Curve From Time Zero to Time Infinity (AUCinf) | 10 mg Single Dose | 379.12 ng*hr/mL | Standard Deviation 345.5 |
Primary
Single Dose: Maximum Observed Plasma Concentration (Cmax)
Time frame: Predose, 0.5, 1, 2, 4, 6, 8, 10, 24, and 32-hour postdose
Population: Pharmacokinetic analysis set was defined as all enrolled participants who received at least 1 dose of the study medication and who completed pharmacokinetic blood sampling for at least 1 day.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| AG-013736 | Single Dose: Maximum Observed Plasma Concentration (Cmax) | 5 mg Single Dose | 20.732 ng/mL | Standard Deviation 14.492 |
| AG-013736 | Single Dose: Maximum Observed Plasma Concentration (Cmax) | 7 mg Single Dose | 32.007 ng/mL | Standard Deviation 28.223 |
| AG-013736 | Single Dose: Maximum Observed Plasma Concentration (Cmax) | 10 mg Single Dose | 53.123 ng/mL | Standard Deviation 60.921 |
Primary
Single Dose: Plasma Decay Half-Life (t1/2)
Plasma decay half-life is the time measured for the plasma concentration to decrease by one half.
Time frame: Predose, 0.5, 1, 2, 4, 6, 8, 10, 24, and 32-hour postdose
Population: Pharmacokinetic analysis set was defined as all enrolled participants who received at least 1 dose of the study medication and who completed pharmacokinetic blood sampling for at least 1 day.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| AG-013736 | Single Dose: Plasma Decay Half-Life (t1/2) | 5 mg Single Dose | 4.778 hours | Standard Deviation 2.815 |
| AG-013736 | Single Dose: Plasma Decay Half-Life (t1/2) | 7 mg Single Dose | 5.088 hours | Standard Deviation 2.592 |
| AG-013736 | Single Dose: Plasma Decay Half-Life (t1/2) | 10 mg Single Dose | 5.880 hours | Standard Deviation 3.456 |
Primary
Single Dose: Time to Reach Maximum Observed Plasma Concentration (Tmax)
Time frame: Predose, 0.5, 1, 2, 4, 6, 8, 10, 24, and 32-hour postdose
Population: Pharmacokinetic analysis set was defined as all enrolled participants who received at least 1 dose of the study medication and who completed pharmacokinetic blood sampling for at least 1 day.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| AG-013736 | Single Dose: Time to Reach Maximum Observed Plasma Concentration (Tmax) | 5 mg Single Dose | 4.1000 hours |
| AG-013736 | Single Dose: Time to Reach Maximum Observed Plasma Concentration (Tmax) | 7 mg Single Dose | 4.0000 hours |
| AG-013736 | Single Dose: Time to Reach Maximum Observed Plasma Concentration (Tmax) | 10 mg Single Dose | 4.0150 hours |
Secondary
Multiple Dose: Accumulation Ratio for Cmax (Rac Cmax) and Accumulation Ratio for AUCtau (Rac AUCtau)
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: Cycle 1 Day 15 predose in the morning, and 0.5, 1, 2, 4, 8 and 12 hour postdose
Population: Pharmacokinetic analysis set was defined as all enrolled participants who received at least 1 dose of the study medication and who completed pharmacokinetic blood sampling for at least 1 day.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| AG-013736 | Multiple Dose: Accumulation Ratio for Cmax (Rac Cmax) and Accumulation Ratio for AUCtau (Rac AUCtau) | Rac Cmax | 1.3540 ratio | Standard Deviation 0.5335 |
| AG-013736 | Multiple Dose: Accumulation Ratio for Cmax (Rac Cmax) and Accumulation Ratio for AUCtau (Rac AUCtau) | Rac AUCtau | 1.4185 ratio | Standard Deviation 0.3951 |
Secondary
Multiple Dose: Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau)
The dosing interval was 12 hours in this study.
Time frame: Cycle 1 Day 15 predose in the morning, and 0.5, 1, 2, 4, 8 and 12 hour postdose
Population: Pharmacokinetic analysis set was defined as all enrolled participants who received at least 1 dose of the study medication and who completed pharmacokinetic blood sampling for at least 1 day.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AG-013736 | Multiple Dose: Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) | 164.55 ng*h/mL | Standard Deviation 128.15 |
Secondary
Multiple Dose: Maximum Observed Plasma Concentration (Cmax)
Cmax at multiple dosing
Time frame: Cycle 1 Day 15 predose in the morning, and 0.5, 1, 2, 4, 8 and 12 hour postdose
Population: Pharmacokinetic analysis set was defined as all enrolled participants who received at least 1 dose of the study medication and who completed pharmacokinetic blood sampling for at least 1 day.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AG-013736 | Multiple Dose: Maximum Observed Plasma Concentration (Cmax) | 25.933 ng/mL | Standard Deviation 21.703 |
Secondary
Multiple Dose: Time to Reach Maximum Observed Plasma Concentration (Tmax)
Tmax at multiple dosing
Time frame: Cycle 1 Day 15 predose in the morning, and 0.5, 1, 2, 4, 8 and 12 hour postdose
Population: Pharmacokinetic analysis set was defined as all enrolled participants who received at least 1 dose of the study medication and who completed pharmacokinetic blood sampling for at least 1 day.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| AG-013736 | Multiple Dose: Time to Reach Maximum Observed Plasma Concentration (Tmax) | 4.0400 hours |
Secondary
Number of Participants With Adverse Events
Number of participants with any adverse events, adverse events graded as Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 Grade 3 or higher , serious adverse events, and adverse events resulted in discontinuation.
Time frame: Up to 470 days of treatment plus 28-days follow-up
Population: Safety analysis set was defined as all enrolled participants who received the study drug at least once in this study (same as the full analysis set:FAS).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| AG-013736 | Number of Participants With Adverse Events | Any adverse events | 6 participants |
| AG-013736 | Number of Participants With Adverse Events | Any serious adverse events | 1 participants |
| AG-013736 | Number of Participants With Adverse Events | Discontinuation due to adverse events | 0 participants |
| AG-013736 | Number of Participants With Adverse Events | Any Grade-3 or -4 adverse events | 4 participants |
| AG-013736 | Number of Participants With Adverse Events | Any Grade-5 adverse events (= death) | 1 participants |
Secondary
Number 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 470 days
Population: Anti-tumor response analysis set was defined as all participants with at least 1 target lesion according to RECIST and who received at least 1 dose of study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| AG-013736 | Number 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 | Number 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 | Number 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 | 3 participants |
| AG-013736 | Number 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 | 3 participants |
Secondary
Percent Change From Baseline in Soluble Vascular Endothelial Growth Factor Receptor 1, 2, and 3 (s-VEGFR1, 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., s-VEGFR1, VEGFR2, s-VEGFR3, s-KIT, and VEGF
Time frame: Prior to the initial dose (baseline) and Day 1 of Cycle 2
Population: Pharmacodynamic analysis set was defined as all enrolled participants who received at least 1 dose of the study medication and who completed pharmacodynamic blood sampling for at least 1 day.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| AG-013736 | Percent Change From Baseline in Soluble Vascular Endothelial Growth Factor Receptor 1, 2, and 3 (s-VEGFR1, s-VEGFR2 and s-VEGFR3), Vascular Endothelial Growth Factor (VEGF), Soluble Stem Cell Factor Receptor (s-KIT ) | s-VEGFR1 | -29.15 percent |
| AG-013736 | Percent Change From Baseline in Soluble Vascular Endothelial Growth Factor Receptor 1, 2, and 3 (s-VEGFR1, s-VEGFR2 and s-VEGFR3), Vascular Endothelial Growth Factor (VEGF), Soluble Stem Cell Factor Receptor (s-KIT ) | s-VEGFR2 | -33.16 percent |
| AG-013736 | Percent Change From Baseline in Soluble Vascular Endothelial Growth Factor Receptor 1, 2, and 3 (s-VEGFR1, s-VEGFR2 and s-VEGFR3), Vascular Endothelial Growth Factor (VEGF), Soluble Stem Cell Factor Receptor (s-KIT ) | s-VEGFR3 | -56.38 percent |
| AG-013736 | Percent Change From Baseline in Soluble Vascular Endothelial Growth Factor Receptor 1, 2, and 3 (s-VEGFR1, s-VEGFR2 and s-VEGFR3), Vascular Endothelial Growth Factor (VEGF), Soluble Stem Cell Factor Receptor (s-KIT ) | s-KIT | -14.59 percent |
| AG-013736 | Percent Change From Baseline in Soluble Vascular Endothelial Growth Factor Receptor 1, 2, and 3 (s-VEGFR1, s-VEGFR2 and s-VEGFR3), Vascular Endothelial Growth Factor (VEGF), Soluble Stem Cell Factor Receptor (s-KIT ) | VEGF | 179.52 percent |