Advanced Renal Cell Carcinoma
Conditions
Brief summary
This is a study to evaluate the safety, efficacy and pharmacokinetics of temsirolimus in Asian patients with advanced renal cell carcinoma. The trial is only being conducted in Japan, Korea, and China.
Interventions
20 mg/m2 IV TEMSR weekly (Japan, n=6)
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
* Subjects with histologically confirmed, advanced (stage IV or recurrent disease) RCC. The American Joint Committee on Cancer (AJCC) staging and classification criteria will be used. * ECOG performance status of 0-1. * At least one measurable lesion per RECIST. * Age greater than or equal to 20 years. * Japanese, Chinese, or Korean ethnicity.
Exclusion criteria
* CNS metastases at screening or history or CNS metastases. * Prior targeted, chemotherapeutic, cytokine-based, or other investigational agents for the treatment of RCC within 4 weeks before first dose of test article. Subjects must have documented objective progressive disease after any prior systemic RCC treatment and have recovered to grade 1 or lower toxicities from effects of prior systemic therapy for RCC. * In past 5 years, other prior malignancy (except basal cell carcinoma, squamous cell carcinoma of the skin, or cervical carcinoma in situ).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Clinical Benefit | Baseline Up to 4 years | Clinical benefit: confirmed complete response (CR) or partial response (PR) or had stable disease (SD) lasting at least 24 weeks. CR was the disappearance of all target lesions and nontarget lesions. PR was at least a 30 percent (%) decrease in sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD. SD was having neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (PFS) | Baseline Up to 4 years | Median time from the date of enrollment to the first documentation of objective tumor progression or to death due to any cause, whichever occurs first. |
| Percentage of Participants With Objective Response | Baseline Up to 4 years | Percentage of participants with objective response based assessment of confirmed CR or confirmed PR according to Response Evaluation Criteria In Solid Tumors (RECIST). CR is disappearance of all target lesions. PR shows at least a 30% decrease in the sum of the LD of target lesions, taking as reference the baseline sum LD. |
| Duration of Response | Baseline Up to 4 years | Time measurement criteria are met for CR or PR (whichever status is recorded first) until the first date that recurrence or PD is objectively documented, taking as reference for PD the smallest sum longest diameters (LD) recorded since enrollment. |
| Time to Treatment Failure (TTF) | Baseline Up to 4 years | TTF is defined as the time from the date of enrollment to the date of the first documentation of PD, the date of treatment discontinuation except completion of treatment, or date of death due to cancer. |
| Overall Survival (OS) | Baseline Until Death (Up to 4 years) | Time in months from the date of enrollment to date of death due to any cause. Death was determined from adverse event data (where outcome was death) or from follow-up contact data (where the participant current status was death). |
Other
| Measure | Time frame | Description |
|---|---|---|
| Maximum Observed Plasma Concentration (Cmax) | 0 hours (pre-dose), 0.5 hours, 1, 2, 6, 24, 72, and 96 hours during Week 1 and 4 of treatment | Sirolimus is a major metabolite of temsirolimus. As per planned analysis, only participants in Temsirolimus 20 mg/m\^2 treatment arm were to be drawn blood samples intensively for pharmacokinetic analysis. |
| Time to Reach Maximum Observed Plasma Concentration (Tmax) | 0 hours (pre-dose), 0.5, 1, 2, 6, 24, 72, and 96 hours during Week 1 and 4 of treatment | Sirolimus is a major metabolite of temsirolimus. As per planned analysis, only participants in Temsirolimus 20 mg/m\^2 treatment arm were to be drawn blood samples intensively for pharmacokinetic analysis. |
| Plasma Decay Half-Life (t1/2) | 0 hours (pre-dose), 0.5, 1, 2, 6, 24, 72, and 96 hours during Week 1 and 4 of treatment | Plasma decay half-life is the time measured for the plasma concentration to decrease by one half. Sirolimus is the major metabolite of temsirolimus. As per planned analysis, only participants in Temsirolimus 20 mg/m\^2 treatment arm were to be drawn blood samples intensively for pharmacokinetic analysis. |
| Area Under the Concentration-Time Curve (AUC) | 0 hours (pre-dose), 0.5 hours, 1, 2, 6, 24, 72, and 96 hours during Week 1 and 4 of treatment | AUC is a measure of the serum concentration of the drug over time. It is used to characterize drug absorption. Sirolimus is the major metabolite of temsirolimus. As per planned analysis, only participants in Temsirolimus 20 mg/m\^2 treatment arm were to be drawn blood samples intensively for pharmacokinetic analysis. |
| Clearance (CLss) of Temsirolimus | 0 hours (pre-dose), 0.5, 1, 2, 6, 24, 72, and 96 hours during Week 1 and 4 of treatment | Steady state total body clearance equals infusion rate (zero order) divided by steady state plasma concentration of temsirolimus (R0/Css). As per planned analysis, only participants in Temsirolimus 20 mg/m\^2 treatment arm were to be drawn blood samples intensively for pharmacokinetic analysis. |
| Volume of Distribution at Steady State (Vss) of Temsirolimus | 0 hours (pre-dose), 0.5, 1, 2, 6, 24, 72, and 96 hours during Week 1 and 4 of treatment | Vss is an estimate of the volume of distribution at steady state. It is used to predict the plasma concentrations following multiple dosing to a steady-state or pseudo-equilibrium. Vss is proportional to the amount of drug in the body versus the plasma concentration of the drug at steady state. As per planned analysis, only participants in Temsirolimus 20 mg/m\^2 treatment arm were to be drawn blood samples intensively for pharmacokinetic analysis. |
Countries
China, Japan, South Korea
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Temsirolimus 20 mg/m^2 Temsirolimus 20 milligrams per square meter (mg/m\^2) intravenously (IV) once weekly until disease progression, unacceptable toxicity, or withdrawal of consent. | 6 |
| Temsirolimus 25 mg Temsirolimus 25 mg IV once weekly until disease progression, unacceptable toxicity, or withdrawal of consent. | 76 |
| Total | 82 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 5 | 54 |
| Overall Study | Lost to Follow-up | 0 | 4 |
| Overall Study | Other | 1 | 11 |
| Overall Study | Withdrawal by Subject | 0 | 7 |
Baseline characteristics
| Characteristic | Temsirolimus 20 mg/m^2 | Temsirolimus 25 mg | Total |
|---|---|---|---|
| Age Continuous | 59.67 years STANDARD_DEVIATION 10.29 | 55.20 years STANDARD_DEVIATION 11.52 | 55.52 years STANDARD_DEVIATION 11.43 |
| Sex: Female, Male Female | 0 Participants | 23 Participants | 23 Participants |
| Sex: Female, Male Male | 6 Participants | 53 Participants | 59 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 6 / 6 | 76 / 76 |
| serious Total, serious adverse events | 4 / 6 | 28 / 76 |
Outcome results
Primary
Percentage of Participants With Clinical Benefit
Clinical benefit: confirmed complete response (CR) or partial response (PR) or had stable disease (SD) lasting at least 24 weeks. CR was the disappearance of all target lesions and nontarget lesions. PR was at least a 30 percent (%) decrease in sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD. SD was having neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD).
Time frame: Baseline Up to 4 years
Population: Intent-to-treat (ITT) population included all participants who were enrolled in this study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Temsirolimus 20 mg/m^2 | Percentage of Participants With Clinical Benefit | 50.0 percentage of participants |
| Temsirolimus 25 mg | Percentage of Participants With Clinical Benefit | 48.7 percentage of participants |
Secondary
Duration of Response
Time measurement criteria are met for CR or PR (whichever status is recorded first) until the first date that recurrence or PD is objectively documented, taking as reference for PD the smallest sum longest diameters (LD) recorded since enrollment.
Time frame: Baseline Up to 4 years
Population: Intent-to-treat ITT population included all participants who were enrolled in this study. Here N (number of participants analyzed) signifies participants with objective disease response.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Temsirolimus 25 mg | Duration of Response | 31.3 months |
Secondary
Overall Survival (OS)
Time in months from the date of enrollment to date of death due to any cause. Death was determined from adverse event data (where outcome was death) or from follow-up contact data (where the participant current status was death).
Time frame: Baseline Until Death (Up to 4 years)
Population: ITT population included all participants who were enrolled in this study.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Temsirolimus 20 mg/m^2 | Overall Survival (OS) | 29.1 months |
| Temsirolimus 25 mg | Overall Survival (OS) | 17.8 months |
Secondary
Percentage of Participants With Objective Response
Percentage of participants with objective response based assessment of confirmed CR or confirmed PR according to Response Evaluation Criteria In Solid Tumors (RECIST). CR is disappearance of all target lesions. PR shows at least a 30% decrease in the sum of the LD of target lesions, taking as reference the baseline sum LD.
Time frame: Baseline Up to 4 years
Population: ITT population included all participants who were enrolled in this study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Temsirolimus 20 mg/m^2 | Percentage of Participants With Objective Response | 0 percentage of participants |
| Temsirolimus 25 mg | Percentage of Participants With Objective Response | 11.8 percentage of participants |
Secondary
Progression-free Survival (PFS)
Median time from the date of enrollment to the first documentation of objective tumor progression or to death due to any cause, whichever occurs first.
Time frame: Baseline Up to 4 years
Population: ITT population included all participants who were enrolled in this study.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Temsirolimus 20 mg/m^2 | Progression-free Survival (PFS) | 8.7 months |
| Temsirolimus 25 mg | Progression-free Survival (PFS) | 7.3 months |
Secondary
Time to Treatment Failure (TTF)
TTF is defined as the time from the date of enrollment to the date of the first documentation of PD, the date of treatment discontinuation except completion of treatment, or date of death due to cancer.
Time frame: Baseline Up to 4 years
Population: ITT population included all participants who were enrolled in this study.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Temsirolimus 20 mg/m^2 | Time to Treatment Failure (TTF) | 7.7 months |
| Temsirolimus 25 mg | Time to Treatment Failure (TTF) | 5.4 months |
Other Pre-specified
Area Under the Concentration-Time Curve (AUC)
AUC is a measure of the serum concentration of the drug over time. It is used to characterize drug absorption. Sirolimus is the major metabolite of temsirolimus. As per planned analysis, only participants in Temsirolimus 20 mg/m\^2 treatment arm were to be drawn blood samples intensively for pharmacokinetic analysis.
Time frame: 0 hours (pre-dose), 0.5 hours, 1, 2, 6, 24, 72, and 96 hours during Week 1 and 4 of treatment
Population: PK population included all participants who received at least 1 dose of study treatment and had at least 3 measurable blood concentration samples available. Here N (number of participants analyzed) signifies participants who were evaluable for this measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Temsirolimus 20 mg/m^2 | Area Under the Concentration-Time Curve (AUC) | AUC for temsirolimus at Week 1 | 2819 ng*h/mL | Standard Deviation 1065 |
| Temsirolimus 20 mg/m^2 | Area Under the Concentration-Time Curve (AUC) | AUC for temsirolimus at Week 4 | 2163 ng*h/mL | Standard Deviation 822 |
| Temsirolimus 20 mg/m^2 | Area Under the Concentration-Time Curve (AUC) | AUC for sirolimus at Week 1 | 6902 ng*h/mL | Standard Deviation 3127 |
| Temsirolimus 20 mg/m^2 | Area Under the Concentration-Time Curve (AUC) | AUC for sirolimus at Week 4 | 5582 ng*h/mL | Standard Deviation 3420 |
Other Pre-specified
Clearance (CLss) of Temsirolimus
Steady state total body clearance equals infusion rate (zero order) divided by steady state plasma concentration of temsirolimus (R0/Css). As per planned analysis, only participants in Temsirolimus 20 mg/m\^2 treatment arm were to be drawn blood samples intensively for pharmacokinetic analysis.
Time frame: 0 hours (pre-dose), 0.5, 1, 2, 6, 24, 72, and 96 hours during Week 1 and 4 of treatment
Population: Pharmacokinetic (PK) population included all participants who received at least 1 dose of study treatment and had at least 3 measurable blood concentration samples available. Here N (number of participants analyzed) signifies participants who were evaluable for this measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Temsirolimus 20 mg/m^2 | Clearance (CLss) of Temsirolimus | Week 1 | 13.6 Liter per hour (L/h) | Standard Deviation 4.74 |
| Temsirolimus 20 mg/m^2 | Clearance (CLss) of Temsirolimus | Week 4 | 17.1 Liter per hour (L/h) | Standard Deviation 5.71 |
Other Pre-specified
Maximum Observed Plasma Concentration (Cmax)
Sirolimus is a major metabolite of temsirolimus. As per planned analysis, only participants in Temsirolimus 20 mg/m\^2 treatment arm were to be drawn blood samples intensively for pharmacokinetic analysis.
Time frame: 0 hours (pre-dose), 0.5 hours, 1, 2, 6, 24, 72, and 96 hours during Week 1 and 4 of treatment
Population: Pharmacokinetic (PK) population included all participants who received at least 1 dose of study treatment and had at least 3 measurable blood concentration samples available. Here N (number of participants analyzed) signifies participants who were evaluable for this measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Temsirolimus 20 mg/m^2 | Maximum Observed Plasma Concentration (Cmax) | Cmax for temsirolimus at Week 1 | 704 nanogram per milliliter (ng/mL) | Standard Deviation 207 |
| Temsirolimus 20 mg/m^2 | Maximum Observed Plasma Concentration (Cmax) | Cmax for temsirolimus at Week 4 | 640 nanogram per milliliter (ng/mL) | Standard Deviation 308 |
| Temsirolimus 20 mg/m^2 | Maximum Observed Plasma Concentration (Cmax) | Cmax for sirolimus at Week 1 | 69.6 nanogram per milliliter (ng/mL) | Standard Deviation 13.1 |
| Temsirolimus 20 mg/m^2 | Maximum Observed Plasma Concentration (Cmax) | Cmax for sirolimus at Week 4 | 83.0 nanogram per milliliter (ng/mL) | Standard Deviation 38 |
Other Pre-specified
Plasma Decay Half-Life (t1/2)
Plasma decay half-life is the time measured for the plasma concentration to decrease by one half. Sirolimus is the major metabolite of temsirolimus. As per planned analysis, only participants in Temsirolimus 20 mg/m\^2 treatment arm were to be drawn blood samples intensively for pharmacokinetic analysis.
Time frame: 0 hours (pre-dose), 0.5, 1, 2, 6, 24, 72, and 96 hours during Week 1 and 4 of treatment
Population: Pharmacokinetic (PK) population included all participants who received at least 1 dose of study treatment and had at least 3 measurable blood concentration samples available. Here N (number of participants analyzed) signifies participants who were evaluable for this measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Temsirolimus 20 mg/m^2 | Plasma Decay Half-Life (t1/2) | t1/2 for temsirolimus at Week 1 | 18.6 hours | Standard Deviation 6.5 |
| Temsirolimus 20 mg/m^2 | Plasma Decay Half-Life (t1/2) | t1/2 for temsirolimus at Week 4 | 18.2 hours | Standard Deviation 5.43 |
| Temsirolimus 20 mg/m^2 | Plasma Decay Half-Life (t1/2) | t1/2 for sirolimus at Week 1 | 54.7 hours | Standard Deviation 15.2 |
| Temsirolimus 20 mg/m^2 | Plasma Decay Half-Life (t1/2) | t1/2 for sirolimus at Week 4 | 52.4 hours | Standard Deviation 12.4 |
Other Pre-specified
Time to Reach Maximum Observed Plasma Concentration (Tmax)
Sirolimus is a major metabolite of temsirolimus. As per planned analysis, only participants in Temsirolimus 20 mg/m\^2 treatment arm were to be drawn blood samples intensively for pharmacokinetic analysis.
Time frame: 0 hours (pre-dose), 0.5, 1, 2, 6, 24, 72, and 96 hours during Week 1 and 4 of treatment
Population: PK population included all participants who received at least 1 dose of study treatment and had at least 3 measurable blood concentration samples available. Here N (number of participants analyzed) signifies participants who were evaluable for this measure.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Temsirolimus 20 mg/m^2 | Time to Reach Maximum Observed Plasma Concentration (Tmax) | Tmax for temsirolimus | 0.50 hours |
| Temsirolimus 20 mg/m^2 | Time to Reach Maximum Observed Plasma Concentration (Tmax) | Tmax for sirolimus | 2.0 hours |
Other Pre-specified
Volume of Distribution at Steady State (Vss) of Temsirolimus
Vss is an estimate of the volume of distribution at steady state. It is used to predict the plasma concentrations following multiple dosing to a steady-state or pseudo-equilibrium. Vss is proportional to the amount of drug in the body versus the plasma concentration of the drug at steady state. As per planned analysis, only participants in Temsirolimus 20 mg/m\^2 treatment arm were to be drawn blood samples intensively for pharmacokinetic analysis.
Time frame: 0 hours (pre-dose), 0.5, 1, 2, 6, 24, 72, and 96 hours during Week 1 and 4 of treatment
Population: PK population included all participants who received at least 1 dose of study treatment and had at least 3 measurable blood concentration samples available. Here N (number of participants analyzed) signifies participants who were evaluable for this measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Temsirolimus 20 mg/m^2 | Volume of Distribution at Steady State (Vss) of Temsirolimus | Week 1 | 243 Liter | Standard Deviation 64.7 |
| Temsirolimus 20 mg/m^2 | Volume of Distribution at Steady State (Vss) of Temsirolimus | Week 4 | 250 Liter | Standard Deviation 75.7 |