Clinical and immunomodulatory effects of bevacizumab and low-dose interleukin-2 in patients with metastatic renal cell carcinoma: results from a phase II trial.

OBJECTIVE: Low-dose interleukin-2 (IL-2) is a historical treatment for metastatic renal cell carcinoma (mRCC). Increased vascular endothelial growth factor (VEGF) levels inhibit dendritic cell (DC) differentiation and augment production of immunosuppressive regulatory T (Treg) cells. Bevacizumab is an antibody that binds to VEGF, has activity in mRCC and may augment the anti-tumour immune effects of IL-2. To determine the clinical and immunomodulatory effects of this combination, a prospective, phase II trial of bevacizumab plus low-dose IL-2 was conducted. PATIENTS AND METHODS: Patients with untreated mRCC received bevacizumab (10 mg/kg i.v. every 2 weeks) and IL-2 (125,000 units/kg/day subcutaneously from Monday to Friday for 6 consecutive weeks followed by a 2-week rest period). Endpoints included progression-free survival, Response Evaluation Criteria in Solid Tumors-defined objective response rate, immunomodulatory effects and safety. RESULTS: Between January 2005 and September 2007, twenty-six patients with untreated mRCC were enrolled. The median progression-free survival was 9.6 months (95% CI, 4.1-16.9 months) The objective response rate was 15% and an additional 38% of patients had tumour burden reduction of <30%. Grade 3 constitutional adverse events (fatigue, fever/chills) and neutropenia were observed in 42% and 12% of patients, respectively. Peripheral blood CD1c(+) myeloid and CD303(+) plasmacytoid DC increased during treatment as did IL-8 levels and CD4(+) CD25(+) FoxP3(+) Treg cells. No changes in T helper type 1/2-associated cytokines were observed. CONCLUSION: Bevacizumab plus low-dose IL-2 has modest clinical activity in mRCC. Toxicity was largely IL-2 related without enhancement of bevacizumab-related toxicity. Biological data indicate inhibition of VEGF levels and increase of immunosuppressive Treg cells without an effect on DC activation.

Sorafenib in patients with metastatic renal cell carcinoma refractory to either sunitinib or bevacizumab.

BACKGROUND: Bevacizumab and sunitinib are standard initial therapy in metastatic renal cell carcinoma (mRCC). Despite common use, the safety and activity of sorafenib in bevacizumab- or sunitinib-refractory mRCC have not been prospectively investigated. METHODS: Metastatic RCC patients with Response Evaluation Criteria in Solid Tumors (RECIST)-defined disease progression (PD) after treatment with either bevacizumab or sunitinib received twice daily 400 mg of sorafenib in a multicenter, prospective phase 2 study. Dose escalation was permitted in the absence of significant toxicity. The primary endpoint was tumor burden reduction rate, defined as the proportion of patients with ≥5% reduction in the sum of RECIST-defined target lesions without other PD. Secondary endpoints included progression-free survival (PFS), duration of response, overall survival, and safety. A 2-stage accrual design was used to test the alternative hypothesis that the tumor burden reduction rate was >20% versus <5%. RESULTS: Forty-eight patients were enrolled. The tumor burden reduction rate was 30% (95% confidence interval [CI], 17%-45%). One unconfirmed objective partial response was observed. The median PFS was 4.4 months (95% CI, 3.6-5.9). There was no association of PFS and tumor shrinkage with response to prior therapy. Most treatment-related adverse events were of mild-to-moderate intensity, and included fatigue, hypertension, diarrhea, and palmoplantar erythrodysesthesia (PPE). Patients previously treated with bevacizumab tended to develop more PPE (P=.03) and mucositis (P=.06), whereas sunitinib-treated patients tended to develop more skin rash (P=.06). CONCLUSIONS: Administration of sorafenib is safe and feasible in patients with mRCC refractory to either bevacizumab or sunitinib. Modest clinical activity was observed supporting current practice patterns of sequential vascular endothelial growth factor-targeted therapy in mRCC.

Clinical and immunologic effects of subcutaneously administered interleukin-12 and interferon alfa-2b: phase I trial of patients with metastatic renal cell carcinoma or malignant melanoma.

PURPOSE: Interleukin-12 (IL-12) and interferon alfa-2b (IFN-alpha-2b) are pleiotropic cytokines with activity in renal cell carcinoma (RCC) and malignant melanoma (MM) as single agents. Preclinical studies suggest concurrent administration may have synergistic antitumor effects. We conducted a phase I trial of concurrent subcutaneous (SC) administration of IL-12 and IFN-alpha-2b in patients with metastatic RCC or MM to determine toxicity, maximum-tolerated dose, preliminary efficacy, and effects on chemokine/cytokine gene expression in peripheral blood mononuclear cells (PBMCs). PATIENTS AND METHODS: Cohorts of three to six patients were treated with escalating doses of IL-12 (dose I, 100 ng/kg; dose II, 300 ng/kg; dose III, 500 ng/kg; dose IV, 500 ng/kg SC) given twice weekly and IFN-alpha-2b (dose I, 1.0 MU/m(2); dose II, 1.0 MU/m(2); dose III, 1.0 MU/m(2); dose IV, 3.0 MU/m(2) SC) three times weekly in 4-week cycles. Effects on gene expression were assessed by reverse transcriptase polymerase chain reaction. RESULTS: Twenty-six patients (19 with RCC, seven with MM) were accrued at dose levels I (n = 3), II (n = 3), III (n = 13), and IV (n = 7). Dose-limiting toxicity included grades 3 and 4 hepatotoxicity and neutropenia/leukopenia. Patients received a median of three cycles of treatment. Two patients with RCC and one patient with MM had partial responses. Median survival was 13.8 months. Reverse transcriptase polymerase chain reaction on PBMCs revealed induction of IP-10, Mig, B7.1 (CD80), interleukin-5, and interferon gamma in selected patients. CONCLUSION: Concurrent SC administration of IL-12 and IFN-alpha-2b is possible at the dose levels utilized. Recommended doses for phase II trials are 500 ng/kg IL-12 and 1.0 MU/m(2) IFN-alpha-2b. Consistent induction of IP-10 and Mig, as well as variable induction of B7.1, interleukin-5, and interferon gamma expression was noted in PBMCs.