Clinical trial NCT00913913: Bevacizumab, Autologous Tumor/DC Vaccine, IL-2 and IFNα-2b in Metastatic Renal Cell Carcinoma (RCC) Patients
Official title: A Phase II Study of VEGF Blockade With Bevacizumab Combined With Autologous Tumor/Dendritic Cell Vaccine (DC Vaccine), Interleukin-2 (IL-2) and Interferon-α-2b (IFNα-2b) in Patients With Metastatic Renal Cell Carcinoma (RCC)
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Metastatic Renal Cell Carcinoma
Keywords: Renal Cell Carcinoma
Lead sponsor: Dartmouth-Hitchcock Medical Center
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
First posted: 2009-06-04
Enrollment: 8
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Progression Free Survival
timeFrame: 5 years
Secondary outcomes:
measure: To Characterize the Number of Participants With Clinical and Autoimune Related Toxicity of Treatment
timeFrame: 5 years
Other outcomes:
measure: Measure of Percent of CD4 and CD8 Lymphocyte Subsets
timeFrame: Baseline, day 28, day 70
measure: Clinical Response
timeFrame: Day 70
Locations:
city: Lebanon
country: United States
facility: Dartmouth-Hitchcock Medical Center
state: New Hampshire
Study officials:
affiliation: Dartmouth-Hitchcock Medical Center
name: Marc S Ernstoff, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Ernstoff MS, Crocenzi TS, Seigne JD, Crosby NA, Cole BF, Fisher JL, Uhlenhake JC, Mellinger D, Foster C, Farnham CJ, Mackay K, Szczepiorkowski ZM, Webber SM, Schned AR, Harris RD, Barth RJ Jr, Heaney JA, Noelle RJ. Developing a rational tumor vaccine therapy for renal cell carcinoma: immune yin and yang. Clin Cancer Res. 2007 Jan 15;13(2 Pt 2):733s-740s. doi: 10.1158/1078-0432.CCR-06-2064.