Predictive impact of circulating vascular endothelial growth factor in four phase III trials evaluating bevacizumab.

PURPOSE: We evaluated the prognostic and predictive use of circulating VEGF-A levels in phase III trials of bevacizumab in colorectal cancer, lung cancer, and renal cell carcinoma. METHODS: Baseline plasma samples from 1,816 patients were analyzed for VEGF-A using an ELISA, which recognizes the major isoforms with equivalent sensitivity. HR and 95% confidence intervals (CI) for study end points were estimated using Cox regression analysis. A subset of matched archival tumor samples was analyzed for VEGF-A expression using in situ hybridization. RESULTS: Higher VEGF-A levels showed trends toward adverse prognostic significance in the control arms of multiple trials, reaching statistical significance for overall survival (OS) in AVF2107 (highest vs. lowest 50%: HR = 1.76; 95% CI, 1.28-2.41), AVAiL (HR = 1.52; 95% CI, 1.16-2.00), and AVOREN (HR = 1.67; 95% CI, 1.18-2.36). In predictive analyses, the HRs for progression-free survival were similar across low and high VEGF-A subgroups and favored bevacizumab-containing treatment. In the low VEGF-A subgroups, HRs (95% CIs) were 0.61 (0.43-0.87) in AVF2107, 0.71 (0.43-1.16) in E4599, 0.74 (0.59-0.94) in AVAiL (low-dose), 0.89 (0.70-1.13) in AVAiL (high-dose), and 0.56 (0.40-0.78) in AVOREN. Analyses of OS data have shown similar results. No correlation between primary tumor VEGF-A expression and plasma VEGF-A levels was observed. CONCLUSIONS: In this comprehensive evaluation, pretreatment total circulating VEGF-A was prognostic for outcome in metastatic colorectal, lung, and renal cell cancers, but it was not predictive for bevacizumab-based treatment benefit.

Rituximab pharmacokinetics in patients with rheumatoid arthritis: B-cell levels do not correlate with clinical response.

This study characterized the relationship between clinical response, serum rituximab concentrations, and peripheral B-cell levels in patients with rheumatoid arthritis treated with rituximab. Data were analyzed from a double-blind, phase IIa trial in which 161 patients with active rheumatoid arthritis despite continuing methotrexate were randomized to methotrexate alone (10-25 mg/wk), rituximab alone (single course: 1000 mg administered intravenously on days 1 and 15), rituximab plus cyclophosphamide (750 mg administered intravenously on days 3 and 17), or rituximab plus methotrexate. Serum samples for pharmacokinetic analysis were collected through 24 weeks, and peripheral circulating CD19+ B-cell levels were measured through 48 weeks. All treatments were generally well tolerated, with no clinically relevant excess of adverse events leading to withdrawal among patients who received rituximab compared with those who received methotrexate alone. The proportions of patients who achieved an American College of Rheumatology score of 50 at week 24 were 13% (methotrexate alone), 33% (rituximab alone), 41% (rituximab plus cyclophosphamide), and 43% (rituximab plus methotrexate). Peripheral B-cell depletion occurred by day 15 in all patients treated with rituximab. There was no relationship between B-cell depletion and clinical response. Recovery of peripheral B cells was variable and showed no relationship with return of disease activity in patients who responded to rituximab. The mean terminal half-life of rituximab was 19 to 22 days; pharmacokinetic parameters were similar whether rituximab was administered alone or with methotrexate or cyclophosphamide. Because the level of peripherally circulating B cells does not appear to correlate with a maintained clinical response in patients with rheumatoid arthritis, the timing of rituximab retreatment should be based on clinical symptoms rather than peripheral B-cell levels.

The efficacy and safety of rituximab in patients with active rheumatoid arthritis despite methotrexate treatment: results of a phase IIB randomized, double-blind, placebo-controlled, dose-ranging trial.

OBJECTIVE: To examine the efficacy and safety of different rituximab doses plus methotrexate (MTX), with or without glucocorticoids, in patients with active rheumatoid arthritis (RA) resistant to disease-modifying antirheumatic drugs (DMARDs), including biologic agents. METHODS: A total of 465 patients were randomized into 9 treatment groups: 3 rituximab groups (placebo [n = 149], 500 mg [n = 124], or 1,000 mg [n = 192] on days 1 and 15) each also taking either placebo glucocorticoids, intravenous methylprednisolone premedication, or intravenous methylprednisolone premedication plus oral prednisone for 2 weeks. All patients received MTX (10-25 mg/week); no other DMARDs were permitted. RESULTS: Significantly more patients who received 2 500-mg or 2 1,000-mg infusions of rituximab met the American College of Rheumatology 20% improvement criteria (achieved an ACR20 response) at week 24 (55% and 54%, respectively) compared with placebo (28%; P < 0.0001). ACR50 responses were achieved by 33%, 34%, and 13% of patients, respectively (P < 0.001), and ACR70 responses were achieved by 13%, 20%, and 5% of patients (P < 0.05). Changes in the Disease Activity Score in 28 joints (-1.79, -2.05, -0.67; P < 0.0001) and moderate to good responses on the European League Against Rheumatism criteria (P < 0.0001) reflected the ACR criteria responses. Glucocorticoids did not contribute significantly to the primary efficacy end point, ACR20 response at 24 weeks. Intravenous glucocorticoid premedication reduced the frequency and intensity of first infusion-associated events; oral glucocorticoids conferred no additional safety benefit. Rituximab was well tolerated; the type and severity of infections was similar to those for placebo. CONCLUSION: Both rituximab doses were effective and well tolerated when added to MTX therapy in patients with active RA. The primary end point (ACR20 response) was independent of glucocorticoids, although intravenous glucocorticoid premedication improved tolerability during the first rituximab infusion.

A multicenter, randomized, investigator-blinded study of 5- and 10-day gatifloxacin versus 10-day amoxicillin/clavulanate in patients with acute bacterial sinusitis.

BACKGROUND: Treatment guidelines for acute bacterial sinusitis recommend 10 to 14 days of therapy with amoxicillin/clavulanate, high-dose amoxicillin, cefpodoxime, cefuroxime, or a newer fluoroquinolone. OBJECTIVE: This study compared the clinical efficacy of short-course (5-day) gatifloxacin with standard 10-day regimens of amoxicillin/clavulanate or gatifloxacin in patients with a diagnosis of acute, uncomplicated maxillary sinusitis. METHODS: This was a multicenter, investigator-blinded study in adult patients (age >18 years) with physical findings, signs and symptoms (for at least 7 days), and radiographic findings indicating acute, uncomplicated maxillary sinusitis. Patients were randomized to receive gatifloxacin 400 mg once daily for 5 days, gatifloxacin 400 mg once daily for 10 days, or amoxicillin/clavulanate 875 mg twice daily for 10 days. Clinical response was assessed once between days 3 and 5 of treatment, once I to 3 days after the completion of study treatment, once 7 to 14 days posttreatment (test-of-cure visit), and once 21 to 28 days posttreatment. Safety was assessed throughout the study. RESULTS: The study enrolled 445 patients. The treatment groups were similar in terms of history of sinusitis, presenting signs and symptoms, and radiographic findings. The most common presenting symptoms were nasal congestion, sinus tenderness, and purulent nasal discharge (>90% of patients); 99% of patients had abnormal radiographic findings. At the test-of-cure visit, clinical cure rates for clinically evaluable patients in the 3 treatment groups were 74% (102/137) for 5-day gatifloxacin, 80% (101/127) for 10-day gatifloxacin, and 72% (101/ 141) for 10-day amoxicillin/clavulanate (95% CI for the difference in cure rates: 5-day gatifloxacin vs amoxicillin/clavulanate, -7.6 to 13.2; 5- vs 10-day gatifloxacin, -15.2 to 5.1; 10-day gatifloxacin vs amoxicillin/clavulanate, -2.3 to 18.1). The distribution and incidence of drug-related adverse events (AEs) were comparable between treatment groups, and the majority (>95%) were mild or moderate in severity. The most common drug-related AEs included vaginitis, diarrhea, and nausea. CONCLUSION: In this population of patients with acute, uncomplicated sinusitis of presumed bacterial origin, a short course (5 days) of gatifloxacin therapy was associated with comparable clinical cure rates and tolerability to those of standard 10-day therapy with gatifloxacin or amoxicillin/clavulanate.