1.
Phase II Study of Modified FOLFOX6 With Bevacizumab in Metastatic Gastroesophageal Adenocarcinoma.
Li, J, Yao, X, Kortmansky, JS, Fischbach, NA, Stein, S, Deng, Y, Zhang, Y, Doddamane, I, Karimeddini, D, Hochster, HS, et al
American journal of clinical oncology. 2017;(2):146-151
Abstract
BACKGROUND The median survival for patients with metastatic gastroesophageal adenocarcinoma is <12 months. Bevacizumab has demonstrated promising activity in metastatic gastroesophageal adenocarcinoma when used in combination with cisplatin-based regimens for patients from the Americas. We conducted a prospective phase II trial to investigate the efficacy of bevacizumab in combination with the oxaliplatin-based regimen, modified FOLFOX6, in patients with metastatic gastroesophageal adenocarcinoma. METHODS Patients with untreated metastatic adenocarcinoma of the stomach, gastroesophageal junction, or distal esophagus received mFOLFOX6 (leucovorin 400 mg/m, fluorouracil 400 mg/m bolus and 2400 mg/m continuous infusion over 46 h, oxaliplatin 85 mg/m) and bevacizumab (10 mg/kg) every 2 weeks until disease progression or intolerance. Response by RECIST was evaluated by CT scan every 8 weeks. The primary objective was progression-free survival (PFS); secondary objectives were safety, response rate, and overall survival (OS). RESULTS A total of 39 patients with untreated metastastic gastroesophageal adenocarcinoma were enrolled between September 2008 and June 2012. Median number of cycles administered was 12 (range, 4 to 86). The confirmed response rate was 56.4% (3 complete response and 19 partial response). The median PFS was 7.8 months and median OS was 14.7 months. Three patients remain on treatment, and 11 patients are alive, of whom 6 have survived >24 months. Treatment-related grade 3/4 toxicities included neutropenia (33.3%), neuropathy (20.5%), thromboembolism (VTE) (7.7%), thrombocytopenia (7.7%), anemia (2.6%), hypertension (2.6%), and proteinuria (2.6%). We observed no GI perforations or grade 3/4 GI hemorrhagic events. CONCLUSIONS First-line mFOLFOX6 with bevacizumab for metastatic gastroesophageal adenocarcinoma was well tolerated and associated with longer PFS and OS compared with historical data from similar populations treated without bevacizumab. Our results suggest that the addition of bevacizumab to mFOLFOX6 may provide clinical benefit in American patients with metastatic gastroesophageal adenocarcinoma, a finding consistent with previous studies of first-line bevacizumab in combination with chemotherapy for this disease.
2.
Pharmacokinetics of ranibizumab after intravitreal administration in patients with retinal vein occlusion or diabetic macular edema.
Zhang, Y, Yao, Z, Kaila, N, Kuebler, P, Visich, J, Maia, M, Tuomi, L, Ehrlich, JS, Rubio, RG, Campochiaro, PA
Ophthalmology. 2014;(11):2237-46
Abstract
OBJECTIVE To describe the systemic pharmacokinetics of ranibizumab after intravitreal administration in patients with retinal vein occlusion (RVO) or diabetic macular edema (DME). DESIGN A population approach of nonlinear mixed-effect pharmacokinetics modeling based on serum concentrations of ranibizumab measured at various times after intravitreal administration. PARTICIPANTS Patients with RVO (n = 441) and DME (n = 435) from 4 large, randomized, phase 3 clinical trials of monthly ranibizumab intravitreal administration. METHODS A 1-compartment pharmacokinetics model with first-order absorption and elimination rate constants previously developed in patients with age-related macular degeneration (AMD) was fitted separately to RVO and DME data. Population pharmacokinetic parameters and interindividual variability were estimated for each model. Baseline covariates were evaluated for potential effects on systemic pharmacokinetics. Model performance was validated using general diagnostic plots and a visual predictive check. MAIN OUTCOME MEASURES Ranibizumab disposition was determined in RVO and DME patients and compared with that previously seen in AMD patients. RESULTS The AMD pharmacokinetics model correctly predicted the measured serum ranibizumab concentration data for RVO and DME patients. Most observed data points were within the simulated 90% confidence interval, indicating that systemic ranibizumab concentrations were comparable among AMD, RVO, and DME patients. No disease-related covariates were identified by the population pharmacokinetics analysis. CONCLUSIONS The systemic pharmacokinetics of ranibizumab were similar among patients with AMD, RVO, or DME. Disease-related differences and patient demographics, measured in this study, did not lead to variability in ocular elimination or in systemic exposure of ranibizumab after intravitreal administration. In all disease processes tested, ranibizumab exits the eye slowly and then is eliminated rapidly from the circulation, thus minimizing systemic exposure.