Metastatic Renal Cell Carcinoma
Conditions
Keywords
Metastatic Renal Cell Carcinoma, Second Line, Everolimus, RAD001
Brief summary
This study will evaluate everolimus as second-line therapy in patients with metastatic renal cell carcinoma. Each patient will be enrolled and stratified in one of three cohorts based upon their first-line therapy: 1) prior cytokines, 2) prior sunitinib, or 3) prior anti-VEGF therapy other than sunitinib.
Interventions
DRUGRAD001
Study drug was supplied as 5 mg tablets in blister packs.
Sponsors
Novartis Pharmaceuticals
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
1. Age ≥ 18 years old. 2. Patients with advanced renal cell carcinoma of a histological or cytological confirmation of clear cell (or with a component of clear cell) renal carcinoma that have previously progressed on or were intolerant to first-line therapy with sunitinib, sorafenib, pazopanib, axitinib, bevacizumab, or cytokine therapy. 3. Patients must have had prior nephrectomy (partial or total). 4. Patients with at least one measurable lesion at baseline as per the RECIST 1.0 criteria. If skin lesions are reported as target lesions, they should be documented (at baseline and at every physical exam) using color photography and a measuring device (such as a caliper) in clear focus to allow the size of the lesion(s) to be determined from the photograph. 5. Patients with a Karnofsky Performance Status ≥ 70%. 6. Adequate bone marrow function as shown by: 1. ANC ≥ 1.5 x 109/L, 2. Platelets ≥ 100 x 109/L, 3. Hemoglobin \>9 g/dL 7. Adequate liver function as shown by: 1. Serum bilirubin ≤ 1.5 x ULN, 2. ALT and AST ≤ 2.5 x ULN. Patients with known liver metastases may enroll if their AST and ALT ≤ 5 x ULN, 3. INR \< 1.3 (INR \< 3 in patients treated with anticoagulants) 8. Adequate renal function: serum creatinine ≤ 2.0 x ULN. 9. Fasting serum cholesterol ≤300 mg/dl OR ≤7.75 mmol/L AND fasting triglycerides ≤2.5 x ULN. 10. Written informed consent obtained before any trial related activity and according to local guidelines.
Exclusion criteria
1. Patients with brain metastases. 2. Patients within 4 weeks post-major surgery (e.g., intra-thoracic, intra-abdominal or intrapelvic), open biopsy, or significant traumatic injury to avoid wound healing complications. Minor procedures and percutaneous biopsies or placement of vascular access device require 7 days prior to study entry. 3. Patients in anticipation of the need for major surgical procedure during the course of the study. 4. Patients who had radiation therapy within 4 weeks prior to start of study treatment (palliative radiotherapy to bone lesions allowed up to 2 weeks prior to study treatment start). 5. Patients with a serious non-healing wound, ulcer, or bone fracture. 6. Patients with a history of seizure(s) not controlled with standard medical therapy. 7. Patients who have received more than one prior treatment regimen for metastatic renalcell carcinoma 8. Patients who have received adjuvant therapy for RCC 9. Patients who have previously received systemic mTOR inhibitors (eg, sirolimus, temsirolimus, everolimus) 10. Patients with a known hypersensitivity to everolimus or other rapamycins (eg, sirolimus, temsirolimus) or to its excipients. 11. History or clinical evidence of central nervous system (CNS) metastases. 12. Clinically significant gastrointestinal abnormalities including, but not limited to: 1. Malabsorption syndrome: 2. Major resection of the stomach or small bowel that could affect the absorption of study drug 3. Active peptic ulcer disease 4. Inflammatory bowel disease: i. Ulcerative colitis, or other gastrointestinal conditions with increased risk of perforation ii. History of abdominal fistula, gastrointestinal perforation, or intra abdominal abscess within 28 days prior to beginning study treatment. 13. Patients with a known history of HIV seropositivity. Screening for HIV infection at baseline is not required. 14. Active bleeding diathesis 15. Uncontrolled diabetes mellitus as defined by fasting serum glucose \> 2.0 x ULN. 16. Patients who have any severe and/or uncontrolled medical conditions such as: 1. unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction ≤ 6 months prior to enrollment, serious uncontrolled cardiac arrhythmia, 2. active or uncontrolled severe infection, 3. history of invasive fungal infections, 4. severe hepatic impairment (Child-Pugh class C), 5. severely impaired lung function 17. History of cerebrovascular accident (CVA) including transient ischemic attack (TIA) ≤ 6 months before start of study treatment. 18. History of pulmonary embolism or untreated deep venous thrombosis (DVT) within the past 6 months. Note: Subjects with recent DVT who have been treated with therapeutic anti-coagulating agents for at least 6 weeks are eligible. 19. Patients who have a history of another primary malignancy and off treatment for ≤ 3 years, with the exception of non-melanoma skin cancer and carcinoma in situ of the uterine cervix or breast, and localized cancer of the bladder (T1) and prostate (T1 - T2). 20. Female patients who are pregnant or nursing (lactating). 21. Adults of reproductive potential who are not using effective birth control methods. Adequate contraceptives must be used throughout the trial and for 8 weeks after last study drug administration in female patients. Women of child-bearing potential must have a negative serum pregnancy test within 7 days prior to first administration of study drug. 22. Patients who are using other investigational agents or who had received investigational drugs ≤ 2 weeks prior to study treatment start. This should not include sunitinib, sorafenib, axitinib, pazopanib and cytokines. 23. Patients unwilling or unable to comply with the protocol.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (PFS) - All Participants | 20 months | PFS during second-line treatment was defined as the time from the date of enrollment to the date of the first documented disease progression or death due to any cause. The primary analysis of PFS was based on a local radiology review of CT scans and MRI collected until the participant experienced disease progression according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.0. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Duration of PFS for Each First-line Treatment Cohort | 20 months | Duration of PFS during second-line treatment was defined as the time from the date of enrollment to the date of the first documented disease progression or death due to any cause. Participants' assessment was based on the local radiological data according to the RECIST 1.0 Criteria. |
| Overall Survival (OS) | 28 months | OS was defined as the time from date of enrollment to date of death due to any cause. |
| Clinical Benefit Rate (CBR) | 20 months | CBR was defined as the proportion of patients with best overall response of complete response (CR) or partial response (PR) or stable disease based on the local radiological data according to the RECIST 1.0 criteria. |
| Objective Response Rate (ORR) | 20 months | ORR was defined as the proportion of participants with best overall response of CR or PR based on the local radiological data according to the RECIST 1.0 Criteria |
| Duration of Response (DoR) | 20 months | DoR was defined as the time from the first occurrence of PR or CR (as per local radiological review) until the date of the first documented disease progression or death due to underlying cancer. |
Countries
Argentina, Brazil, Bulgaria, China, Russia, United States
Participant flow
Recruitment details
This was an open-label study where all eligible participants were enrolled into one of 3 cohorts based upon prior first-line therapy.
Participants by arm
| Arm | Count |
|---|---|
| Prior Sunitinib Participants, who received prior sunitinib therapy, received RAD001 10 mg orally once daily. | 58 |
| Other Prior Vascular Endothelial Growth Factor (VEGF) Participants, who received prior anti-VEGF other than sunitinib, received RAD001 10 mg orally once daily. | 62 |
| Prior Cytokines Participants, who received prior cytokine therapy, received RAD001 10 mg orally once daily. | 14 |
| Total | 134 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 8 | 10 | 4 |
| Overall Study | Death | 0 | 4 | 0 |
| Overall Study | Disease progression | 42 | 34 | 6 |
| Overall Study | Lost to Follow-up | 0 | 4 | 1 |
| Overall Study | Protocol deviation | 0 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 6 | 7 | 0 |
Baseline characteristics
| Characteristic | Prior Sunitinib | Other Prior Vascular Endothelial Growth Factor (VEGF) | Prior Cytokines | Total |
|---|---|---|---|---|
| Age, Continuous | 56.0 Years STANDARD_DEVIATION 12.06 | 56.5 Years STANDARD_DEVIATION 11.14 | 60.3 Years STANDARD_DEVIATION 10.59 | 56.7 Years STANDARD_DEVIATION 11.48 |
| Sex: Female, Male Female | 15 Participants | 22 Participants | 6 Participants | 43 Participants |
| Sex: Female, Male Male | 43 Participants | 40 Participants | 8 Participants | 91 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 28 / 58 | 33 / 61 | 12 / 14 |
| serious Total, serious adverse events | 13 / 58 | 16 / 61 | 3 / 14 |
Outcome results
Primary
Progression-free Survival (PFS) - All Participants
PFS during second-line treatment was defined as the time from the date of enrollment to the date of the first documented disease progression or death due to any cause. The primary analysis of PFS was based on a local radiology review of CT scans and MRI collected until the participant experienced disease progression according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.0.
Time frame: 20 months
Population: The full analysis set (FAS) was used. It included all enrolled participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| All Participants | Progression-free Survival (PFS) - All Participants | 7.4 months |
Secondary
Clinical Benefit Rate (CBR)
CBR was defined as the proportion of patients with best overall response of complete response (CR) or partial response (PR) or stable disease based on the local radiological data according to the RECIST 1.0 criteria.
Time frame: 20 months
Population: The FAS was used. It included all enrolled participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| All Participants | Clinical Benefit Rate (CBR) | 41 Participants |
| Other Prior Vascular Endothelial Growth Factor (VEGF) | Clinical Benefit Rate (CBR) | 48 Participants |
| Prior Cytokines | Clinical Benefit Rate (CBR) | 11 Participants |
| All Participants | Clinical Benefit Rate (CBR) | 100 Participants |
Secondary
Duration of PFS for Each First-line Treatment Cohort
Duration of PFS during second-line treatment was defined as the time from the date of enrollment to the date of the first documented disease progression or death due to any cause. Participants' assessment was based on the local radiological data according to the RECIST 1.0 Criteria.
Time frame: 20 months
Population: The FAS was used. It included all enrolled participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| All Participants | Duration of PFS for Each First-line Treatment Cohort | 5.6 months |
| Other Prior Vascular Endothelial Growth Factor (VEGF) | Duration of PFS for Each First-line Treatment Cohort | 7.8 months |
| Prior Cytokines | Duration of PFS for Each First-line Treatment Cohort | 12.9 months |
Secondary
Duration of Response (DoR)
DoR was defined as the time from the first occurrence of PR or CR (as per local radiological review) until the date of the first documented disease progression or death due to underlying cancer.
Time frame: 20 months
Population: The FAS was considered for this analysis. The FAS included all enrolled participants. Only participants who achieved a CR or PR were analyzed. Therefore, actual n=4,3,3,10.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| All Participants | Duration of Response (DoR) | 10.8 months |
| Other Prior Vascular Endothelial Growth Factor (VEGF) | Duration of Response (DoR) | 7.4 months |
| Prior Cytokines | Duration of Response (DoR) | 9.2 months |
| All Participants | Duration of Response (DoR) | 9.2 months |
Secondary
Objective Response Rate (ORR)
ORR was defined as the proportion of participants with best overall response of CR or PR based on the local radiological data according to the RECIST 1.0 Criteria
Time frame: 20 months
Population: The FAS was used. It included all enrolled participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| All Participants | Objective Response Rate (ORR) | 4 Participants |
| Other Prior Vascular Endothelial Growth Factor (VEGF) | Objective Response Rate (ORR) | 3 Participants |
| Prior Cytokines | Objective Response Rate (ORR) | 3 Participants |
| All Participants | Objective Response Rate (ORR) | 10 Participants |
Secondary
Overall Survival (OS)
OS was defined as the time from date of enrollment to date of death due to any cause.
Time frame: 28 months
Population: The FAS was used. It included all enrolled participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| All Participants | Overall Survival (OS) | 23.8 months |
| Other Prior Vascular Endothelial Growth Factor (VEGF) | Overall Survival (OS) | 17.2 months |
| Prior Cytokines | Overall Survival (OS) | NA months |
| All Participants | Overall Survival (OS) | 23.8 months |