Bevacizumab, Autologous Tumor/DC Vaccine, IL-2 and IFNα-2b in Metastatic Renal Cell Carcinoma (RCC) Patients

Metastatic Renal Cell Carcinoma Clinical Trial

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)

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT00913913
• Other study ID #: D0708
• Secondary ID: R01CA095648
• Status: Terminated
• Phase: Phase 2
• First received: June 2, 2009
• Last updated: October 28, 2015
• Start date: February 2009
• Est. completion date: January 2013

Study information

• Verified date: February 2014
• Source: Dartmouth-Hitchcock Medical Center
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 8
• Est. completion date: January 2013
• Est. primary completion date: January 2013
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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.

Study Design

Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Carcinoma
• Carcinoma, Renal Cell
• Metastatic Renal Cell Carcinoma

Intervention

Biological:
• DC vaccine
DC Vaccine therapy 10E7 intranodally every cycle

Drug:
• Bevacizumab
Bevacizumab 10mg/kg iv every 2 weeks

Biological:
• IL-2
IL-2 18 MiU/m2 CI 5 days
• IFN
IFN 6 MiU subc TIW

Locations

Country	Name	City	State
United States	Dartmouth-Hitchcock Medical Center	Lebanon	New Hampshire

Sponsors (2)

Lead Sponsor	Collaborator
Dartmouth-Hitchcock Medical Center	National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

References & Publications (1)

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. Review. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Measure of Percent of CD4 and CD8 Lymphocyte Subsets	percent of CD4 and CD8 positive lymphocyte subsets	Baseline, day 28, day 70	No
Other	Clinical Response	clinical response by RECIST 1.1	Day 70	No
Primary	Progression Free Survival	median progression free survival	5 years	No
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.	5 years	Yes

External Links

•   Dartmouth-Hitchcock Norris Cotton Cancer Center