Carcinoma, Renal Cell
Conditions
Keywords
AG-013736, RCC, Phase 2
Brief summary
To investigate objective tumor response of AG-013736 for metastatic Renal Cell Cancer (mRCC)
Interventions
DRUGAG-013736
AG-013736 5 mg BID will be administered orally on continuous schedule. Cycle length is 28 days. If the drug is well tolerated at 5 mg BID, the dose of AG-013736 may be titrated to 7 mg BID and then to a maximum of 10 mg BID. Number of cycles: until progression or unacceptable toxicity develops.
Sponsors
Pfizer
Study design
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
20 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients histologically diagnosed as metastatic renal cell cancer with a component of clear cell cancer. * Patients who are refractory to cytokine therapy as 1st line. * Patients who experienced nephrectomy. * Patients with at least 1 target lesion, as defined by RECIST. * Patients with no uncontrolled hypertension.
Exclusion criteria
* Gastrointestinal abnormalities * Current use or anticipated inability to avoid potent CYP3A4 inhibitors or CYP1A2/3A4 inducers. * Active seizure disorder or evidence of brain metastases. * Patients with hemoptysis.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (Percentage of Participants With Complete Response [CR] or Partial Response [PR]): Independent Review Committee Assessment | Up to 765 days of treatment at the data cut-off date | Percentage of participants with objective response based assessment of confirmed CR or confirmed PR by the Independent Review Committee, according to 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 of the targeted lesions. CR and PR had to be documented on 2 occasions separated by at least 4 weeks. |
| Objective Response Rate (Percentage of Participants With Complete Response [CR] or Partial Response [PR]): Investigators Assessment | Up to 765 days of treatment at the data cut-off date | Percentage of participants with objective response based assessment of confirmed CR or confirmed PR by the investigator, according to 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 of the targeted lesions. CR and PR had to be documented on 2 occasions separated by at least 4 weeks. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Duration of Response | Start of first confirmed CR or PR to the date of the first event (PD or death) or the last tumor assessment, whichever came first, assessed up to 1709 days. | Time in months from the first documentation of objective tumor response to objective tumor progression or death due to any cause. Duration of tumor response was calculated as (the date of the first documentation of objective tumor progression or death due to cancer minus the date of the first CR or PR that was subsequently confirmed plus 1) divided by 30.44. DR was calculated for the subgroup of participants with a confirmed objective tumor response. |
| Overall Survival (OS) | Up to 2002 days (maximum duration of treatment plus follow-up observation) | OS was defined as the time from date of first dose of AG-013736 to date of death due to any cause. Subjects in whom death is not reported will have their event time censored on the last date the subject is known to be alive. |
| Number of Participants Analyzed for Population Pharmacokinetics of AG-013736 | Cycle 1 Day 1 (2 hours after morning dose); Cycles 3, 5, and 7 Day 1 predose and 2 hours post morning dose | Population pharmacokinetic analysis of AG-013736 is conducted by combining current study data with other AG-013736 studies. |
| Plasma Concentration of Soluble Vascular Endothelial Growth Factor Receptor 1 (s-VEGFR1) | Cycle 1 Day 1 predose, Day 1 of Cycle 2 to Cycle 7, and end of treatment/discontinuation (assessed up to 1709 days) | — |
| Progression-Free Survival (PFS) | Up to 1709 days of treatment | Time in months from start of study treatment to first documentation of objective tumor progression or death due to any cause whichever comes first. PFS was calculated as (first event date minus the date of first dose of study medication plus 1) divided by 30.44. Tumor progression was determined from radiological image (where data meet the criteria for progressive disease \[PD\]). |
| Plasma Concentration of Soluble Vascular Endothelial Growth Factor Receptor 3 (s-VEGFR3) | Cycle 1 Day 1 predose, Day 1 of Cycle 2 to Cycle 7, and end of treatment/discontinuation (assessed up to 1709 days) | — |
| Plasma Concentration of Soluble Stem Cell Factor Receptor (s-KIT) | Cycle 1 Day 1 predose, Day 1 of Cycle 2 to Cycle 7, and end of treatment/discontinuation (assessed up to 1709 days) | — |
| Plasma Concentration of Vascular Endothelial Growth Factor (VEGF) | Cycle 1 Day 1 predose, Day 1 of Cycle 2 to Cycle 7, and end of treatment/discontinuation (assessed up to 1709 days) | — |
| Number of Participants With Adverse Events | Up to 1709 days of treatment plus 28-days follow-up | Number of participants with any adverse events, adverse events graded as Common Terminology Criteria (CTCAE) for Adverse Events Version 3.0 Grade 3 or higher , serious adverse events, or adverse events resulted in discontinuation. |
| Plasma Concentration of Soluble Vascular Endothelial Growth Factor Receptor 2 (s-VEGFR2) | Cycle 1 Day 1 predose, Day 1 of Cycle 2 to Cycle 7, and end of treatment/discontinuation (assessed up to 1709 days) | — |
| Time to Tumor Progression (TTP) | Up to 1709 days of treatment | Time in months from start of study treatment to first documentation of objective tumor progression. TTP was calculated as (first event date minus the date of first dose of study medication plus 1) divided by 30.44. Tumor progression was determined from radiological image (where data meet the criteria for progressive disease \[PD\]). |
Countries
Japan
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| AG-013736 The starting dose of AG-013736 was 5 mg twice daily (BID), which was administered orally at approximately 12 hours apart in cycles of 4 weeks (28 days). The treatment is to be continued until the participants meet the discontinuation criteria such as disease progression or intolerable toxicity. The dose of AG-013736 could be titrated to 7 mg BID, and then 10 mg BID or reduced to 3 mg BID, and then 2 mg BID depending on the grade, type, and causality of adverse events experienced. | 64 |
| Total | 64 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 16 |
| Overall Study | Global Deterioration of Health Status | 1 |
| Overall Study | Objective Progression or Relapse | 42 |
Baseline characteristics
| Characteristic | AG-013736 |
|---|---|
| Age, Customized <18 | 0 Participants |
| Age, Customized 18-44 | 6 Participants |
| Age, Customized 45-64 | 30 Participants |
| Age, Customized >= 65 | 28 Participants |
| Sex: Female, Male Female | 20 Participants |
| Sex: Female, Male Male | 44 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 64 / 64 |
| serious Total, serious adverse events | 21 / 64 |
Outcome results
Primary
Objective Response Rate (Percentage of Participants With Complete Response [CR] or Partial Response [PR]): Independent Review Committee Assessment
Percentage of participants with objective response based assessment of confirmed CR or confirmed PR by the Independent Review Committee, according to 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 of the targeted lesions. CR and PR had to be documented on 2 occasions separated by at least 4 weeks.
Time frame: Up to 765 days of treatment at the data cut-off date
Population: The Intent-To-Treat (ITT) population included all participants enrolled in the study who received at least 1 dose of study medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| AG-013736 | Objective Response Rate (Percentage of Participants With Complete Response [CR] or Partial Response [PR]): Independent Review Committee Assessment | 50.0 percentage of participants |
Primary
Objective Response Rate (Percentage of Participants With Complete Response [CR] or Partial Response [PR]): Investigators Assessment
Percentage of participants with objective response based assessment of confirmed CR or confirmed PR by the investigator, according to 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 of the targeted lesions. CR and PR had to be documented on 2 occasions separated by at least 4 weeks.
Time frame: Up to 765 days of treatment at the data cut-off date
Population: The Intent-To-Treat (ITT) population included all participants enrolled in the study who received at least 1 dose of study medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| AG-013736 | Objective Response Rate (Percentage of Participants With Complete Response [CR] or Partial Response [PR]): Investigators Assessment | 54.7 percentage of participants |
Secondary
Duration of Response
Time in months from the first documentation of objective tumor response to objective tumor progression or death due to any cause. Duration of tumor response was calculated as (the date of the first documentation of objective tumor progression or death due to cancer minus the date of the first CR or PR that was subsequently confirmed plus 1) divided by 30.44. DR was calculated for the subgroup of participants with a confirmed objective tumor response.
Time frame: Start of first confirmed CR or PR to the date of the first event (PD or death) or the last tumor assessment, whichever came first, assessed up to 1709 days.
Population: The Intent-To-Treat (ITT) population included all participants enrolled in the study who received at least 1 dose of study medication. DR was calculated for the subgroup of participants with a confirmed objective tumor response. n=number of participants assessed as CR or PR.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| AG-013736 | Duration of Response | Independent Review Committee Assessment (n=33) | 11.1 months |
| AG-013736 | Duration of Response | Investigators Assessment (n=36) | 12.8 months |
Secondary
Number of Participants Analyzed for Population Pharmacokinetics of AG-013736
Population pharmacokinetic analysis of AG-013736 is conducted by combining current study data with other AG-013736 studies.
Time frame: Cycle 1 Day 1 (2 hours after morning dose); Cycles 3, 5, and 7 Day 1 predose and 2 hours post morning dose
Population: No population pharmacokinetic analysis results are available just for the current study.
Secondary
Number of Participants With Adverse Events
Number of participants with any adverse events, adverse events graded as Common Terminology Criteria (CTCAE) for Adverse Events Version 3.0 Grade 3 or higher , serious adverse events, or adverse events resulted in discontinuation.
Time frame: Up to 1709 days of treatment plus 28-days follow-up
Population: The Intent-To-Treat (ITT) population included all participants enrolled in the study who received at least 1 dose of study medication.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| AG-013736 | Number of Participants With Adverse Events | Any adverse events | 64 participants |
| AG-013736 | Number of Participants With Adverse Events | Any serious adverse events | 21 participants |
| AG-013736 | Number of Participants With Adverse Events | Any Grade-3 or -4 adverse events | 58 participants |
| AG-013736 | Number of Participants With Adverse Events | Any Grade-5 adverse events (= death) | 1 participants |
| AG-013736 | Number of Participants With Adverse Events | Discontinuation due to adverse events | 16 participants |
Secondary
Overall Survival (OS)
OS was defined as the time from date of first dose of AG-013736 to date of death due to any cause. Subjects in whom death is not reported will have their event time censored on the last date the subject is known to be alive.
Time frame: Up to 2002 days (maximum duration of treatment plus follow-up observation)
Population: The Intent-To-Treat (ITT) population included all participants enrolled in the study who received at least 1 dose of study medication.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| AG-013736 | Overall Survival (OS) | 37.3 months |
Secondary
Plasma Concentration of Soluble Stem Cell Factor Receptor (s-KIT)
Time frame: Cycle 1 Day 1 predose, Day 1 of Cycle 2 to Cycle 7, and end of treatment/discontinuation (assessed up to 1709 days)
Population: Biomarker analysis set included all participants enrolled in the study who received at least 1 dose of study medication and who submitted at least 1 sample; n=number of participants assessed.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| AG-013736 | Plasma Concentration of Soluble Stem Cell Factor Receptor (s-KIT) | Cycle 1 Day 1 (n=64) | 39050.0 pg/mL |
| AG-013736 | Plasma Concentration of Soluble Stem Cell Factor Receptor (s-KIT) | Cycle 2 Day 1 (n=63) | 35000.0 pg/mL |
| AG-013736 | Plasma Concentration of Soluble Stem Cell Factor Receptor (s-KIT) | Cycle 3 Day 1 (n=60) | 37300.0 pg/mL |
| AG-013736 | Plasma Concentration of Soluble Stem Cell Factor Receptor (s-KIT) | Cycle 4 Day 1 (n=59) | 38100.0 pg/mL |
| AG-013736 | Plasma Concentration of Soluble Stem Cell Factor Receptor (s-KIT) | Cycle 5 Day 1 (n=57) | 39800.0 pg/mL |
| AG-013736 | Plasma Concentration of Soluble Stem Cell Factor Receptor (s-KIT) | Cycle 6 Day 1 (n=52) | 41400.0 pg/mL |
| AG-013736 | Plasma Concentration of Soluble Stem Cell Factor Receptor (s-KIT) | Cycle 7 Day 1 (n=48) | 42400.0 pg/mL |
| AG-013736 | Plasma Concentration of Soluble Stem Cell Factor Receptor (s-KIT) | End of Treatment/Discontinuation (n=55) | 40600.0 pg/mL |
Secondary
Plasma Concentration of Soluble Vascular Endothelial Growth Factor Receptor 1 (s-VEGFR1)
Time frame: Cycle 1 Day 1 predose, Day 1 of Cycle 2 to Cycle 7, and end of treatment/discontinuation (assessed up to 1709 days)
Population: Biomarker analysis set included all participants enrolled in the study who received at least 1 dose of study medication and who submitted at least 1 sample; n=number of participants assessed.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| AG-013736 | Plasma Concentration of Soluble Vascular Endothelial Growth Factor Receptor 1 (s-VEGFR1) | Cycle 1 Day 1 (n=64) | 83.10 pg/mL |
| AG-013736 | Plasma Concentration of Soluble Vascular Endothelial Growth Factor Receptor 1 (s-VEGFR1) | Cycle 2 Day 1 (n=63) | 63.60 pg/mL |
| AG-013736 | Plasma Concentration of Soluble Vascular Endothelial Growth Factor Receptor 1 (s-VEGFR1) | Cycle 3 Day 1 (n=60) | 68.20 pg/mL |
| AG-013736 | Plasma Concentration of Soluble Vascular Endothelial Growth Factor Receptor 1 (s-VEGFR1) | Cycle 4 Day 1 (n=59) | 69.20 pg/mL |
| AG-013736 | Plasma Concentration of Soluble Vascular Endothelial Growth Factor Receptor 1 (s-VEGFR1) | Cycle 5 Day 1 (n=57) | 62.90 pg/mL |
| AG-013736 | Plasma Concentration of Soluble Vascular Endothelial Growth Factor Receptor 1 (s-VEGFR1) | Cycle 6 Day 1 (n=52) | 62.00 pg/mL |
| AG-013736 | Plasma Concentration of Soluble Vascular Endothelial Growth Factor Receptor 1 (s-VEGFR1) | Cycle 7 Day 1 (n=48) | 57.75 pg/mL |
| AG-013736 | Plasma Concentration of Soluble Vascular Endothelial Growth Factor Receptor 1 (s-VEGFR1) | End of Treatment/Discontinuation (n=55) | 76.60 pg/mL |
Secondary
Plasma Concentration of Soluble Vascular Endothelial Growth Factor Receptor 2 (s-VEGFR2)
Time frame: Cycle 1 Day 1 predose, Day 1 of Cycle 2 to Cycle 7, and end of treatment/discontinuation (assessed up to 1709 days)
Population: Biomarker analysis set included all participants enrolled in the study who received at least 1 dose of study medication and who submitted at least 1 sample; n=number of participants assessed.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| AG-013736 | Plasma Concentration of Soluble Vascular Endothelial Growth Factor Receptor 2 (s-VEGFR2) | Cycle 1 Day 1 (n=64) | 8900.0 pg/mL |
| AG-013736 | Plasma Concentration of Soluble Vascular Endothelial Growth Factor Receptor 2 (s-VEGFR2) | Cycle 2 Day 1 (n=63) | 6040.0 pg/mL |
| AG-013736 | Plasma Concentration of Soluble Vascular Endothelial Growth Factor Receptor 2 (s-VEGFR2) | Cycle 3 Day 1 (n=60) | 5980.0 pg/mL |
| AG-013736 | Plasma Concentration of Soluble Vascular Endothelial Growth Factor Receptor 2 (s-VEGFR2) | Cycle 4 Day 1 (n=59) | 6030.0 pg/mL |
| AG-013736 | Plasma Concentration of Soluble Vascular Endothelial Growth Factor Receptor 2 (s-VEGFR2) | Cycle 5 Day 1 (n=57) | 5880.0 pg/mL |
| AG-013736 | Plasma Concentration of Soluble Vascular Endothelial Growth Factor Receptor 2 (s-VEGFR2) | Cycle 6 Day 1 (n=52) | 5790.0 pg/mL |
| AG-013736 | Plasma Concentration of Soluble Vascular Endothelial Growth Factor Receptor 2 (s-VEGFR2) | Cycle 7 Day 1 (n=48) | 5395.0 pg/mL |
| AG-013736 | Plasma Concentration of Soluble Vascular Endothelial Growth Factor Receptor 2 (s-VEGFR2) | End of Treatment/Discontinuation (n=55) | 6540.0 pg/mL |
Secondary
Plasma Concentration of Soluble Vascular Endothelial Growth Factor Receptor 3 (s-VEGFR3)
Time frame: Cycle 1 Day 1 predose, Day 1 of Cycle 2 to Cycle 7, and end of treatment/discontinuation (assessed up to 1709 days)
Population: Biomarker analysis set included all participants enrolled in the study who received at least 1 dose of study medication and who submitted at least 1 sample; n=number of participants assessed.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| AG-013736 | Plasma Concentration of Soluble Vascular Endothelial Growth Factor Receptor 3 (s-VEGFR3) | Cycle 1 Day 1 (n=64) | 20250.0 pg/mL |
| AG-013736 | Plasma Concentration of Soluble Vascular Endothelial Growth Factor Receptor 3 (s-VEGFR3) | Cycle 2 Day 1 (n=63) | 12000.0 pg/mL |
| AG-013736 | Plasma Concentration of Soluble Vascular Endothelial Growth Factor Receptor 3 (s-VEGFR3) | Cycle 3 Day 1 (n=60) | 13100.0 pg/mL |
| AG-013736 | Plasma Concentration of Soluble Vascular Endothelial Growth Factor Receptor 3 (s-VEGFR3) | Cycle 4 Day 1 (n=59) | 13800.0 pg/mL |
| AG-013736 | Plasma Concentration of Soluble Vascular Endothelial Growth Factor Receptor 3 (s-VEGFR3) | Cycle 5 Day 1 (n=57) | 16700.0 pg/mL |
| AG-013736 | Plasma Concentration of Soluble Vascular Endothelial Growth Factor Receptor 3 (s-VEGFR3) | Cycle 6 Day 1 (n=52) | 15550.0 pg/mL |
| AG-013736 | Plasma Concentration of Soluble Vascular Endothelial Growth Factor Receptor 3 (s-VEGFR3) | Cycle 7 Day 1 (n=48) | 13750.0 pg/mL |
| AG-013736 | Plasma Concentration of Soluble Vascular Endothelial Growth Factor Receptor 3 (s-VEGFR3) | End of Treatment/Discontinuation (n=55) | 22300.0 pg/mL |
Secondary
Plasma Concentration of Vascular Endothelial Growth Factor (VEGF)
Time frame: Cycle 1 Day 1 predose, Day 1 of Cycle 2 to Cycle 7, and end of treatment/discontinuation (assessed up to 1709 days)
Population: Biomarker analysis set included all participants enrolled in the study who received at least 1 dose of study medication and who submitted at least 1 sample; n=number of participants assessed.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| AG-013736 | Plasma Concentration of Vascular Endothelial Growth Factor (VEGF) | End of Treatment/Discontinuation (n=55) | 121.00 pg/mL |
| AG-013736 | Plasma Concentration of Vascular Endothelial Growth Factor (VEGF) | Cycle 1 Day 1 (n=64) | 63.40 pg/mL |
| AG-013736 | Plasma Concentration of Vascular Endothelial Growth Factor (VEGF) | Cycle 2 Day 1 (n=63) | 162.00 pg/mL |
| AG-013736 | Plasma Concentration of Vascular Endothelial Growth Factor (VEGF) | Cycle 3 Day 1 (n=60) | 137.00 pg/mL |
| AG-013736 | Plasma Concentration of Vascular Endothelial Growth Factor (VEGF) | Cycle 4 Day 1 (n=59) | 145.00 pg/mL |
| AG-013736 | Plasma Concentration of Vascular Endothelial Growth Factor (VEGF) | Cycle 5 Day 1 (n=57) | 155.00 pg/mL |
| AG-013736 | Plasma Concentration of Vascular Endothelial Growth Factor (VEGF) | Cycle 6 Day 1 (n=52) | 184.50 pg/mL |
| AG-013736 | Plasma Concentration of Vascular Endothelial Growth Factor (VEGF) | Cycle 7 Day 1 (n=48) | 180.00 pg/mL |
Secondary
Progression-Free Survival (PFS)
Time in months from start of study treatment to first documentation of objective tumor progression or death due to any cause whichever comes first. PFS was calculated as (first event date minus the date of first dose of study medication plus 1) divided by 30.44. Tumor progression was determined from radiological image (where data meet the criteria for progressive disease \[PD\]).
Time frame: Up to 1709 days of treatment
Population: The Intent-To-Treat (ITT) population included all participants enrolled in the study who received at least 1 dose of study medication.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| AG-013736 | Progression-Free Survival (PFS) | Independent Review Committee Assessment | 11.0 months |
| AG-013736 | Progression-Free Survival (PFS) | Investigators Assessment | 12.0 months |
Secondary
Time to Tumor Progression (TTP)
Time in months from start of study treatment to first documentation of objective tumor progression. TTP was calculated as (first event date minus the date of first dose of study medication plus 1) divided by 30.44. Tumor progression was determined from radiological image (where data meet the criteria for progressive disease \[PD\]).
Time frame: Up to 1709 days of treatment
Population: The Intent-To-Treat (ITT) population included all participants enrolled in the study who received at least 1 dose of study medication.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| AG-013736 | Time to Tumor Progression (TTP) | Investigators Assessment | 12.0 months |
| AG-013736 | Time to Tumor Progression (TTP) | Independent Review Committee Assessment | 11.0 months |