Metastatic Renal Cell Carcinoma
Conditions
Keywords
Renal Cell Carcinoma
Brief summary
Immune therapies, such as a IL-2, for metastatic renal cell carcinoma (mRCC) are designed to mobilize immune effector cells that recognize and destroy cancer. The investigators have recently observed a 50% objective response rate (16% CR) in mRCC patients treated with autologous tumor lysate -dendritic cell (DC)-vaccine, IL-2 and interferon alfa (IFN). New agents inhibiting vascular endothelial growth factor (VEGF) pathways have demonstrated significant benefit in mRCC patients as well, but rarely induce CRs. High blood VEGF is associated with poor response to IL-2 and can cause tumor specific immune dysregulation. To test whether complementary mechanisms of immune activation and disruption of regulatory pathways enhance outcome the investigators plan to treat 24 mRCC patients in a phase II trial using bevacizumab, DC vaccine, IL-2, and IFN. Observations from this project will be used in the development of novel cancer therapies which, if successful, will decrease the burden of cancer on the public. The investigators propose to determine 1) the objective clinical response rate to treatment and progression free survival, 2) the clinical and autoimmune related toxicity profile of therapy, and 3) the treatment related tumor-specific immune response and the relationship of tumor-specific immune response and objective clinical response.
Detailed description
All eligible patients will receive a total of five treatment weeks, each consisting of approximately 5 days. Prior to therapy, patients will undergo apheresis for DC preparation. DC-Tumor vaccines will be frozen in 90% pooled human AB serum/ 10% DMSO to be used for treatment Patients will be dosed with bevacizumab (10mg/kg, Genentech) intravenously every two weeks beginning four weeks prior to the first vaccine. Each treatment week includes ultrasound guided intranodal DC-vaccine injection (1 X 107 cells/1mL), followed by 5 days of continuous intravenous infusion of IL-2 (18 MiU/m2, Novartis), and three subcutaneous injections of IFNa-2b (6 MiU, Schering -Plough Corp.) (every other day). The first two treatment weeks, the induction phase, will be separated by a 9 day rest. Three additional treatment weeks, the maintenance phase, will be separated by 23 rest days.
Interventions
BIOLOGICALDC vaccine
DC Vaccine therapy 10E7 intranodally every cycle
DRUGBevacizumab
Bevacizumab 10mg/kg iv every 2 weeks
BIOLOGICALIL-2
IL-2 18 MiU/m2 CI 5 days
BIOLOGICALIFN
IFN 6 MiU subc TIW
Sponsors
National Cancer Institute (NCI)
Dartmouth-Hitchcock Medical Center
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. Histologically confirmed metastatic renal cell carcinoma with measurable disease. 2. Adequate tumor tissue properly stored and available to produce lysate for a minimum of three vaccine preparations. 3. Patients must be at least 4 weeks from their last therapy (tyrosine kinase inhibitors, immunotherapy, radiation, surgery or chemotherapy (6 weeks for nitrosureas) and recovered from all ill effects. 4. Have measurable disease. 5. Patients must be at least 4 weeks from major surgery, 1 week from minor surgery, and recovered from all ill effects. 6. Karnofsky Performance Status ≥80%. 7. Adequate end organ function: 8. Women should not be lactating and, if of childbearing age, have a negative pregnancy test within two weeks of entry to the study. 9. Appropriate contraception in both genders. 10. The patient must be competent and have signed informed consent. 11. Patients may have received one prior therapy with targeted therapies (e.g. sorafenib and sunitinib).
Exclusion criteria
1. Patients who have previously received bevacizumab or IL-2 are not eligible. 2. Concomitant second malignancy except for non-melanoma skin cancer, and non-invasive cancer such as cervical CIS, superficial bladder cancer without local recurrence or breast CIS. 3. In patients with a prior history of invasive malignancy, less than five years in complete remission. 4. Positive serology for HIV, hepatitis B or hepatitis C which should be confirmed with antigenemia. 5. Significant co-morbid illness such as uncontrolled diabetes or active infection that would preclude treatment on this regimen. 6. Use of corticosteroids or other immunosuppression (if patient had been taking steroids, at least 2 weeks must have passed since the last dose). Inhaled steroids \> 1000mcg beclomethasone per day or its equivalent. 7. History of inflammatory bowel disease or other serious autoimmune disease. (Not including thyroiditis and rheumatoid arthritis). 8. Patients with organ allografts. 9. Uncontrolled hypertension (BP \>150/100 mmHg). 10. Proteinuria dipstick \> 3+ or \> 2gm/24 hours, or a urine protein:creatinine ratio \> 1.0 at screening. 11. Major surgery, open biopsy, significant traumatic injury within 28 days of starting treatment or anticipation of need for major surgical procedure during the course of the study. 12. Minor surgical procedures, fine needle aspirations or core biopsies within 7 days prior to starting treatment. Central venous catheter placements are permitted. 13. History of abdominal fistula, gastrointestinal perforation, or intrabdominal abscess within 6 months prior to starting treatment. 14. Serious, non-healing wound, ulcer, or bone fracture. 15. History of tumor-related or other serious hemorrhage, bleeding diathesis, or underlying coagulopathy. 16. History of deep venous thrombosis, or other thrombotic event within the past six months or clinically significant peripheral vascular disease. 17. Inability to comply with study and/or follow-up procedures.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival | 5 years | median progression free survival |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| To Characterize the Number of Participants With Clinical and Autoimune Related Toxicity of Treatment | 5 years | To characterize the clinical and autoimmune related toxicity profile of the combined treatment regimen using CTCAE 3. Toxicity reported are those expected from high dose IL-2 and were not considered adverse events. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Measure of Percent of CD4 and CD8 Lymphocyte Subsets | Baseline, day 28, day 70 | percent of CD4 and CD8 positive lymphocyte subsets |
| Clinical Response | Day 70 | clinical response by RECIST 1.1 |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Bevacizumab,IL-2, IFN, DC Vaccine Patients will be dosed with bevacizumab (10mg/kg) intravenously every two weeks beginning four weeks prior to the first vaccine. Each treatment week includes ultrasound guided intranodal DC-vaccine injection (1 X 107 cells/1mL), followed by 5 days of continuous intravenous infusion of IL-2 (18 MiU/m2), and three subcutaneous injections of IFNa-2b (6 MiU) (every other day)
DC vaccine: DC Vaccine therapy 10E7 intranodally every cycle
Bevacizumab: Bevacizumab 10mg/kg iv every 2 weeks
IL-2: IL-2 18 MiU/m2 CI 5 days
IFN: IFN 6 MiU subc TIW | 8 |
| Total | 8 |
Baseline characteristics
| Characteristic | Bevacizumab,IL-2, IFN, DC Vaccine |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 1 Participants |
| Age, Categorical Between 18 and 65 years | 7 Participants |
| Age, Continuous | 55 years |
| Region of Enrollment United States | 8 participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 0 / 8 |
| serious Total, serious adverse events | 1 / 8 |
Outcome results
Primary
Progression Free Survival
median progression free survival
Time frame: 5 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Bevacizumab,IL-2, IFN, DC Vaccine | Progression Free Survival | 340 DAYS |
Secondary
To Characterize the Number of Participants With Clinical and Autoimune Related Toxicity of Treatment
To characterize the clinical and autoimmune related toxicity profile of the combined treatment regimen using CTCAE 3. Toxicity reported are those expected from high dose IL-2 and were not considered adverse events.
Time frame: 5 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bevacizumab,IL-2, IFN, DC Vaccine | To Characterize the Number of Participants With Clinical and Autoimune Related Toxicity of Treatment | 8 participants |
Other Pre-specified
Clinical Response
clinical response by RECIST 1.1
Time frame: Day 70
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bevacizumab,IL-2, IFN, DC Vaccine | Clinical Response | 4 participants |
Other Pre-specified
Measure of Percent of CD4 and CD8 Lymphocyte Subsets
percent of CD4 and CD8 positive lymphocyte subsets
Time frame: Baseline, day 28, day 70
Population: Peripheral blood lymphocyte subsets: 5 subjects at baseline and same 5 at day 70. 6 subjects analyzed at day 28
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Bevacizumab,IL-2, IFN, DC Vaccine | Measure of Percent of CD4 and CD8 Lymphocyte Subsets | CD4 Central memory: baseline | 0.50 percentage of total lymphocytes |
| Bevacizumab,IL-2, IFN, DC Vaccine | Measure of Percent of CD4 and CD8 Lymphocyte Subsets | CD4 Central memory: Day 28 | 1.71 percentage of total lymphocytes |
| Bevacizumab,IL-2, IFN, DC Vaccine | Measure of Percent of CD4 and CD8 Lymphocyte Subsets | CD4 Central memory: Day 70 | 0.69 percentage of total lymphocytes |
| Bevacizumab,IL-2, IFN, DC Vaccine | Measure of Percent of CD4 and CD8 Lymphocyte Subsets | CD8 Central memory: baseline | 1.61 percentage of total lymphocytes |
| Bevacizumab,IL-2, IFN, DC Vaccine | Measure of Percent of CD4 and CD8 Lymphocyte Subsets | CD8 Central memory: day 28 | 4.74 percentage of total lymphocytes |
| Bevacizumab,IL-2, IFN, DC Vaccine | Measure of Percent of CD4 and CD8 Lymphocyte Subsets | CD8 Central memory: day 70 | 2.76 percentage of total lymphocytes |