Renal Cell Carcinoma
Conditions
Keywords
Carcinoma, Renal Cell, Receptor, Epidermal Growth Factor, mTOR protein, Sirolimus, Erlotinib
Brief summary
The purpose of this study is to test the safety and efficacy of the combination of erlotinib hydrochloride (Tarceva™) and sirolimus (Rapamune™) in the treatment of patients with metastatic kidney cancer.
Detailed description
Despite recent advances metastatic renal cell carcinoma remains an incurable condition. Currently available treatment with high-dose interleukin-2 can lead to complete responses in a small minority of selected patients but is markedly toxic and not broadly available. FDA-approved multikinase inhibitors (sorafenib and sunitinib malate) often cause partial and transient tumor regression. There is no standard treatment metastatic renal cell carcinoma for patients whose disease progressed on multikinase inhibitors. The kinase mammalian target of rapamycin (mTOR) is overstimulated in a subset of renal cell carcinomas and other malignancies and can be blocked by sirolimus leading to growth arrest. Erlotinib hydrochloride is a drug that blocks the function of the epidermal growth factor receptor (EGFR), often over expressed in kidney cancer. Sirolimus and EGFR inhibitors and been safely used in combination. In vitro experiments show that erlotinib enhances the sirolimus induced growth impairment in a panel of renal cell carcinoma cells. In the present study patients with metastatic renal cell carcinoma whose disease progressed on multikinase inhibitors will be treated with the combination of erlotinib hydrochloride (Tarceva™) and sirolimus (Rapamune™). This is a single arm trial with no placebo or drug-based control arm
Interventions
DRUGErlotinib hydrochloride
Patients will receive single-agent Tarceva, 150 mg/day
DRUGSirolimus
Patients will receive a loading dose of 6 mg of Rapamune seven days after beginning treatment with Tarceva™ followed by a dose of 2mg/day.
Sponsors
Genentech, Inc.
University of Colorado, Denver
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Signed informed consent to participate in this study. * Histological diagnosis of renal cell carcinoma. * Age greater or equal 18 years. * Eastern Cooperative Oncology Group (ECOG) Performance status of 2 or better. * Life expectancy of at least 3 months. * Failure or intolerance to previous treatment with Sutent® and/or Nexavar®. * Most recent systemic treatment at least 1 month from the beginning of treatment. * Most recent local treatment (surgery or irradiation) \> 2 weeks from the beginning of treatment. * At least one site of measurable disease by CT scan or MRI (RECIST criteria). * Baseline hemoglobin \>9 g/dl, platelets \> 100,000/mm3, absolute neutrophil count (ANC \>1500/mm3.
Exclusion criteria
* Previous treatment with Tarceva™, Iressa™, Rapamune™, temsirolimus or everolimus. * Untreated metastasis to the central nervous system. * Previous solid organ, bone marrow or stem-cell transplant. * Known AIDS or HIV infection. * Symptomatic or poorly controlled chronic heart failure. * Chronic renal failure requiring dialysis on a regular basis. * Chronic liver failure. * Serum aspartate aminotransferase (AST), Alanine Aminotransferase (ALT), alkaline phosphatase or bilirubin \>1.5 x the upper limit of normal for the local laboratory. * Pregnant or breast-feeding women. * Other invasive malignant diseases within 5 years (other than squamous or basal cell carcinoma of the skin). * Inability to provide informed consent * Any other serious and/or unstable medical, psychiatric, or other condition considered by the P.I. to preclude safe or reasonably compliant participation in the protocol.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival | Physical exam assessments were performed every 4 weeks during the treatment phase. Survival follow-up information was collected every 4 months following the termination visit until death, loss to follow-up, or study termination up to 275 weeks. | Time to progression was defined as the time from beginning of therapy until disease progression or death. For subjects who had not progressed at the time of statistical analysis, progression-free survival was censored at the date of their last tumor assessment. Kaplan-Meier method was used to estimate median progression-free survival. Progression was defined as radiographic progression according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria (year 2000 version), non-compliance in obtaining scans, unequivocal clinical progression or the initiation of another medication for the treatment of renal cell carcinoma. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | Survival follow-up information was collected every 4 months following the termination visit until death, loss to follow-up, or study termination up to 275 weeks. | For all subjects who had not died at the time of statistical analysis, duration of survival will was censored at the date of last contact. Kaplan-Meier methodology was used to estimate the magnitude of the treatment effect as described for progression-free survival. |
Countries
United States
Participant flow
Recruitment details
This was a phase II, single-arm, single-institution trial. A total of 25 patients were enrolled between July 2006 and March 2008 from University of Colorado Cancer Center.
Pre-assignment details
Patients with previous treatment with erlotinib, gefitinib, sirolimus, temsirolimus or everolimus, untreated central nervous system metastasis, renal failure requiring dialysis or significant liver dysfunction were excluded from the trial.
Participants by arm
| Arm | Count |
|---|---|
| Erlotinib and Sirolimus Erlotinib (Tarceva) therapy was started at 150 mg by mouth daily from day 1 to be taken at least 1 hour before or 2 hours after a meal. Sirolimus was initiated on day 8 (D8) with a loading dose of 6mg by mouth, followed by a daily dose of 2mg by mouth, on the basis of the product prescribing information for low-to-moderate immunologic risk renal transplant patients. | 25 |
| Total | 25 |
Baseline characteristics
| Characteristic | Erlotinib and Sirolimus |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 9 Participants |
| Age, Categorical Between 18 and 65 years | 16 Participants |
| Age, Continuous | 60 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 21 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 25 Participants |
| Region of Enrollment United States | 25 Participants |
| Sex: Female, Male Female | 5 Participants |
| Sex: Female, Male Male | 20 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 25 / 25 |
| serious Total, serious adverse events | 2 / 25 |
Outcome results
Primary
Progression-free Survival
Time to progression was defined as the time from beginning of therapy until disease progression or death. For subjects who had not progressed at the time of statistical analysis, progression-free survival was censored at the date of their last tumor assessment. Kaplan-Meier method was used to estimate median progression-free survival. Progression was defined as radiographic progression according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria (year 2000 version), non-compliance in obtaining scans, unequivocal clinical progression or the initiation of another medication for the treatment of renal cell carcinoma.
Time frame: Physical exam assessments were performed every 4 weeks during the treatment phase. Survival follow-up information was collected every 4 months following the termination visit until death, loss to follow-up, or study termination up to 275 weeks.
Population: Per protocol analysis was used and 25 participants that were enrolled in the study were included in the analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Erlotinib and Sirolimus | Progression-free Survival | 12 Weeks |
Secondary
Overall Survival
For all subjects who had not died at the time of statistical analysis, duration of survival will was censored at the date of last contact. Kaplan-Meier methodology was used to estimate the magnitude of the treatment effect as described for progression-free survival.
Time frame: Survival follow-up information was collected every 4 months following the termination visit until death, loss to follow-up, or study termination up to 275 weeks.
Population: Per protocol analysis was used and 25 participants that were enrolled in the study were included in the analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Erlotinib and Sirolimus | Overall Survival | 40 Weeks |