Renal Cell Carcinoma
Conditions
Keywords
Metastatic or Advanced Renal Cell Carcinoma
Brief summary
This is an international, randomized, open-label, outpatient, multicenter study. Subjects will be assigned in a 1:1 ratio to 1 of 2 treatment arms: temsirolimus 25 mg once weekly by intravenous (IV) infusion or sorafenib 400 mg by mouth (PO) twice daily (BID). These investigational drugs will be administered in 6-week cycles for the duration of the study, up to 24 months. Subjects will be stratified by nephrectomy status, duration of response to sunitinib therapy, Memorial Sloan Kettering Cancer Center (MSKCC) prognostic group, and RCC tumor histology.
Interventions
DRUGSorafenib
Subjects randomized to arm B will take sorafenib 400 mg (2 x 200 mg tablets) PO, BID (total daily dose of 800 mg).
Subjects randomized to arm A will receive temsirolimus (Torisel) 25 mg via IV infusion once weekly. This infusion is to be administered over a 30-60 minute period. Subjects are to be pre-treated with 25-50 mg IV diphenhydramine (or comparable IV antihistamine) approximately 30 minutes before temsirolimus infusion.
Sponsors
Pfizer
Study design
Allocation
RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically confirmed diagnosis of mRCC (regardless of histology or nephrectomy status) with well-documented Radiological PD by RECIST criteria or clinical PD as judged by the investigator while receiving first-line sunitinib therapy. Subjects must have at least 1 cycle of sunitinib therapy (minimum of four weeks continuously). * At time of randomization, at least 2 weeks since prior treatment with sunitinib, palliative radiation therapy, and/or surgery. * At time of randomization, there must be at least 1 measurable lesion per RECIST. Lesions that have been previously irradiated or embolized cannot be selected as target lesions. * More criteria apply
Exclusion criteria
* Metastatic CNS from RCC. * Subjects who discontinued Sutent therapy due specifically to intolerance. * Prior systemic therapy for mRCC other than sunitinib. * Active ketonuria, secondary to poorly controlled diabetes mellitus * More criteria apply
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-Free Survival (PFS) | Baseline up to 24 Months | Interval from date of randomization until documentation of progressive disease (PD) by an independent tumor assessment according to Response Evaluation Criteria in Solid Tumor (RECIST) or death for any reason whichever occurred first. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (PFS) by Investigator Assessment | Baseline up to 24 Months | Interval from date of randomization until documentation of PD by an investigator tumor assessment, symptomatic deterioration, or death for any reason whichever occurred first. |
| Percentage of Participants With Tumor Response | Baseline up to 24 Months | Percentage of participants with tumor response based on assessment of confirmed complete response (CR) or confirmed partial response (PR) according to RECIST and evaluated by independent central review. CR/PR persisted on repeat imaging study at least 4 weeks after initial documentation of response. PR had at least 30 percent decrease in the sum of the longest diameter (LD) of target lesions taking as reference the baseline sum LD. |
| Percentage of Participants With PFS Events at 12, 24 and 36 Weeks by Independent Assessment | Weeks 12, 24, and 36 | PFS: Interval from date of randomization until documentation of PD by an independent tumor assessment according to RECIST or death for any reason whichever occurred first. PFS calculated as (Weeks)=(randomization date minus first dose date plus 1) divided by 7. |
| Duration of Response (DR) | Baseline up to 24 Months | Duration of response as defined by the time from CR or PR (whichever status recorded first) until the date of death or PD was objectively documented. Median and its 95 percent confidence interval (95% CI) were estimated using Kaplan-Meier method. |
| Overall Survival (OS) | Baseline to date of death from any cause (up to 24 months) | Overall survival was the duration from randomization to death. For participants who are alive, overall survival was censored at the last contact. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Baseline up to 24 months | Counts of participants who had treatment-emergent adverse events (TEAEs), defined as newly occurring or worsening after first dose. Relatedness to \[study drug\] was assessed by the investigator (Yes/No). Participants with multiple occurrences of an AE within a category were counted once within the category. |
Countries
Argentina, Australia, Austria, Canada, Chile, China, Denmark, Finland, France, Germany, Hungary, Italy, Netherlands, Singapore, South Korea, Spain, Sweden, Switzerland, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Temsirolimus Temsirolimus 25 milligrams (mg) once weekly by intravenous (IV) infusion administered in 6 week cycles for up to 24 months, participants were premedicated with 25-50 mg IV diphenydramine 30 minutes before temsirolimus infusion. In event of toxicity, dose could be modified or held according to the protocol or at the discretion of the investigator. | 259 |
| Sorafenib Sorafenib 400 mg (two 200 mg tablets) by mouth (PO) twice daily (BID) administered in 6 week cycles for up to 24 months. In event of toxicity, dose could be modified or held according to the protocol or at the discretion of the investigator. | 253 |
| Total | 512 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 189 | 170 |
| Overall Study | Discontinuation of Study by Sponsor | 42 | 59 |
| Overall Study | Investigator Request | 2 | 1 |
| Overall Study | Lost to Follow-up | 4 | 7 |
| Overall Study | Not Meeting Study Criteria | 0 | 1 |
| Overall Study | Other | 5 | 0 |
| Overall Study | Protocol Violation | 2 | 0 |
| Overall Study | Withdrawal by Subject | 15 | 15 |
Baseline characteristics
| Characteristic | Temsirolimus | Sorafenib | Total |
|---|---|---|---|
| Age Continuous | 59.96 years STANDARD_DEVIATION 10.2 | 59.74 years STANDARD_DEVIATION 10.33 | 59.85 years STANDARD_DEVIATION 10.25 |
| Sex: Female, Male Female | 66 Participants | 61 Participants | 127 Participants |
| Sex: Female, Male Male | 193 Participants | 192 Participants | 385 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 243 / 249 | 249 / 252 |
| serious Total, serious adverse events | 104 / 249 | 87 / 252 |
Outcome results
Primary
Progression-Free Survival (PFS)
Interval from date of randomization until documentation of progressive disease (PD) by an independent tumor assessment according to Response Evaluation Criteria in Solid Tumor (RECIST) or death for any reason whichever occurred first.
Time frame: Baseline up to 24 Months
Population: Intent to Treat Population (ITT): all randomized participants according to their assigned treatment, regardless of whether they were received any study drug.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Temsirolimus | Progression-Free Survival (PFS) | 4.28 months |
| Sorafenib | Progression-Free Survival (PFS) | 3.91 months |
p-value: 0.193395% CI: [0.71, 1.07]Log Rank
Secondary
Duration of Response (DR)
Duration of response as defined by the time from CR or PR (whichever status recorded first) until the date of death or PD was objectively documented. Median and its 95 percent confidence interval (95% CI) were estimated using Kaplan-Meier method.
Time frame: Baseline up to 24 Months
Population: ITT population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Temsirolimus | Duration of Response (DR) | 8.26 months |
| Sorafenib | Duration of Response (DR) | 6.96 months |
Secondary
Overall Survival (OS)
Overall survival was the duration from randomization to death. For participants who are alive, overall survival was censored at the last contact.
Time frame: Baseline to date of death from any cause (up to 24 months)
Population: ITT population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Temsirolimus | Overall Survival (OS) | 12.27 months |
| Sorafenib | Overall Survival (OS) | 16.64 months |
p-value: 0.014495% CI: [1.05, 1.63]Log Rank
Secondary
Percentage of Participants With PFS Events at 12, 24 and 36 Weeks by Independent Assessment
PFS: Interval from date of randomization until documentation of PD by an independent tumor assessment according to RECIST or death for any reason whichever occurred first. PFS calculated as (Weeks)=(randomization date minus first dose date plus 1) divided by 7.
Time frame: Weeks 12, 24, and 36
Population: ITT population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Temsirolimus | Percentage of Participants With PFS Events at 12, 24 and 36 Weeks by Independent Assessment | Baseline to Week 12 | 31.2 percentage of participants |
| Temsirolimus | Percentage of Participants With PFS Events at 12, 24 and 36 Weeks by Independent Assessment | Week 13 to Week 24 | 20.9 percentage of participants |
| Temsirolimus | Percentage of Participants With PFS Events at 12, 24 and 36 Weeks by Independent Assessment | Week 25 to Week 36 | 12.3 percentage of participants |
| Sorafenib | Percentage of Participants With PFS Events at 12, 24 and 36 Weeks by Independent Assessment | Baseline to Week 12 | 36.7 percentage of participants |
| Sorafenib | Percentage of Participants With PFS Events at 12, 24 and 36 Weeks by Independent Assessment | Week 13 to Week 24 | 20.1 percentage of participants |
| Sorafenib | Percentage of Participants With PFS Events at 12, 24 and 36 Weeks by Independent Assessment | Week 25 to Week 36 | 11.2 percentage of participants |
Secondary
Percentage of Participants With Tumor Response
Percentage of participants with tumor response based on assessment of confirmed complete response (CR) or confirmed partial response (PR) according to RECIST and evaluated by independent central review. CR/PR persisted on repeat imaging study at least 4 weeks after initial documentation of response. PR had at least 30 percent decrease in the sum of the longest diameter (LD) of target lesions taking as reference the baseline sum LD.
Time frame: Baseline up to 24 Months
Population: ITT population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Temsirolimus | Percentage of Participants With Tumor Response | 7.7 percentage of participants |
| Sorafenib | Percentage of Participants With Tumor Response | 7.9 percentage of participants |
Secondary
Progression Free Survival (PFS) by Investigator Assessment
Interval from date of randomization until documentation of PD by an investigator tumor assessment, symptomatic deterioration, or death for any reason whichever occurred first.
Time frame: Baseline up to 24 Months
Population: ITT population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Temsirolimus | Progression Free Survival (PFS) by Investigator Assessment | 5.43 months |
| Sorafenib | Progression Free Survival (PFS) by Investigator Assessment | 4.14 months |
p-value: 0.188895% CI: [0.7, 1.07]Log Rank
Other Pre-specified
Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
Counts of participants who had treatment-emergent adverse events (TEAEs), defined as newly occurring or worsening after first dose. Relatedness to \[study drug\] was assessed by the investigator (Yes/No). Participants with multiple occurrences of an AE within a category were counted once within the category.
Time frame: Baseline up to 24 months
Population: Safety population: all participants who received at least 1 dose of test article.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Temsirolimus | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Serious AE | 103 participants |
| Temsirolimus | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Any AE | 248 participants |
| Sorafenib | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Serious AE | 86 participants |
| Sorafenib | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Any AE | 251 participants |