Bevacizumab Pharmacokinetics Research Articles

Distribution of Bevacizumab into the Cerebrospinal Fluid of Children and Adolescents with Recurrent Brain Tumors.

To date, evidence has been lacking regarding bevacizumab pharmacokinetics in the cerebrospinal fluid (CSF). This study assessed the penetration of bevacizumab, as part of a metronomic antiangiogenic treatment regimen, into the CSF of children, adolescents, and young adults with recurrent brain tumors. Serum and CSF concentrations, malignant cells, and vascular endothelial growth factor A (VEGF-A) were analyzed in 12 patients (5-27 years) following 10 mg/kg bevacizumab intravenous biweekly administration (EudraCT number 2009-013024-23). A population pharmacokinetic model including body weight, albumin, and tumor type as influential factors was extended to quantify the CSF penetration of bevacizumab. Apart from in serum (minimum concentration/maximum concentration [Cmin/Cmax] 77.0-305/267-612 mg/L, median 144/417mg/L), bevacizumab could be quantified in the CSF (0.01-2.26mg/L, median 0.35 mg/L). The CSF/serum ratio was 0.16 and highly variable between patients. Malignant cells could be detected in CSF before initiation of treatment in five of 12 patients; after treatment, the CSF was cleared in all patients. VEGF-A was detected in three patients before treatment (mean ± SD: 20 ± 11 pg/mL), and was still measurable in one of these patients despite treatment (16 pg/mL). This pharmacokinetic pilot study indicated penetration of bevacizumab into the CSF in a population of children, adolescents, and young adults with recurrent brain tumors.

Confounding mitigation for the exposure-response relationship of bevacizumab in colorectal cancer patients.

The exposure-response relationship of bevacizumab may be confounded by various factors, including baseline characteristics, time-dependent target engagement and recursive relationships between exposure and response, requiring effective mitigation. This study aimed to investigate the exposure-response relationships of bevacizumab in metastatic colorectal cancer (mCRC) patients while mitigating potential biases. Bevacizumab pharmacokinetics was described using target-mediated drug disposition modelling. Relationships between target kinetics, progression-free (PFS) and overall (OS) survivals were assessed using joint pharmacokinetic and parametric hazard function models. Both prognostic-driven and response-driven potential biases were mitigated. These models evaluated the impact of increased antigen target levels, clearance and intensified dosing regimen on survival. Estimated target-mediated pharmacokinetic parameters in 130 assessed patients were baseline target levels (R0 = 8.4nM), steady-state dissociation constant (KSS = 10 nM) and antibody-target complexes elimination constant (kint = 0.52 day-1). The distribution of R0 was significantly associated with increased baseline concentrations of carcinoembryonic antigen, circulating vascular endothelial growth factor and the presence of extrahepatic metastases. Unbound target levels (R) significantly influenced both progression and death hazard functions. Increasing baseline target levels and/or clearance values led to decreased bevacizumab unbound concentrations, increased R levels and shortened PFS and OS, while increasing bevacizumab dose led to decreased R and longer survival. This study is the first to demonstrate the relationship between bevacizumab concentrations, target involvement and clinical efficacy by effectively mitigating potential sources of bias. Most of the target amount may be tumoural in mCRC. Future studies should provide a more in-depth description of this relationship.

Translation of Monoclonal Antibodies Pharmacokinetics from Animal to Human Using Physiologically Based Modeling in Open Systems Pharmacology (OSP) Suite: A Retrospective Analysis of Bevacizumab.

Interspecies translation of monoclonal antibodies (mAbs) pharmacokinetics (PK) in presence of target-mediated drug disposition (TMDD) is particularly challenging. Incorporation of TMDD in physiologically based PK (PBPK) modeling is recent and needs to be consolidated and generalized to provide better prediction of TMDD regarding inter-species translation during preclinical and clinical development steps of mAbs. The objective of this study was to develop a generic PBPK translational approach for mAbs using the open-source software (PK-Sim® and Mobi®). The translation of bevacizumab based on data in non-human primates (NHP), healthy volunteers (HV), and cancer patients was used as a case example for model demonstration purpose. A PBPK model for bevacizumab concentration-time data was developed using data from literature and the Open Systems Pharmacology (OSP) Suite version 10. PK-sim® was used to build the linear part of bevacizumab PK (mainly FcRn-mediated), whereas MoBi® was used to develop the target-mediated part. The model was first developed for NHP and used for a priori PK prediction in HV. Then, the refined model obtained in HV was used for a priori prediction in cancer patients. A priori predictions were within 2-fold prediction error (predicted/observed) for both area under the concentration-time curve (AUC) and maximum concentration (Cmax) and all the predicted concentrations were within 2-fold average fold error (AFE) and average absolute fold error (AAFE). Sensitivity analysis showed that FcRn-mediated distribution and elimination processes must be accounted for at all mAb concentration levels, whereas the lower the mAb concentration, the more significant the target-mediated elimination. This project is the first step to generalize the full PBPK translational approach in Model-Informed Drug Development (MIDD) of mAbs using OSP Suite.

Population pharmacokinetics and exposure-response relationship of trastuzumab and bevacizumab in early-stage breast cancer.

To describe the sources of interindividual variability of bevacizumab and trastuzumab pharmacokinetics in early-stage breast cancer, and to study the relationship between exposure and both early clinical response and specific adverse events. Patients (n = 86) received 6 cycles of docetaxel + trastuzumab. Early tumour response was assessed by determination of the maximum standard uptake value (SUVmax) variation (ΔSUVmax) after 1 cycle using [18F]-fluorodeoxyglucose (FDG) PET. Early poor responders (ΔSUVmax < 70%) also received bevacizumab from cycle 3 to cycle 6. Sources of interindividual variability in pharmacokinetics of both antibodies were studied by population compartment modelling. Exposure as assessed by area under the concentration-versus-time curve (AUC) was compared between responders and non-responders and between patients experiencing specific adverse events or not. A two-compartment model described the pharmacokinetics of both antibodies satisfactorily. Their central volume of distributions (Vc) increased with body surface area and their elimination half-lives were shorter (~14days) than previously reported (~26-28days). There was a time-dependent increase in trastuzumab Vc, positively correlated to baseline SUVmax. Bevacizumab elimination rate (k10) was positively correlated with ΔSUVmax measured at the end of the first cycle. Bevacizumab had no significantly influence on trastuzumab pharmacokinetics. No relationship between exposure and clinical response or occurrence of adverse events was found. Tumour uptake as assessed by SUVmax influences the pharmacokinetics of bevacizumab and trastuzumab. In early-stage breast cancer, elimination half-lives of these therapeutic monoclonal antibodies may be shorter than those previously reported in more advanced disease.

Circulating Tumor Cells and Bevacizumab Pharmacokinetics during Neoadjuvant Treatment Combining Chemotherapy and Bevacizumab for Early Breast Cancer: Ancillary Analysis of the AVASTEM Trial.

Simple SummaryWe recently published the results of the AVASTEM study, in which we explored the impact of the addition of an angiogenesis inhibitor (bevacizumab) to standard pre-operative chemotherapy for breast cancer. In this work, we aimed to identify biological parameters correlated to prognosis and treatment efficacy. To do so we explored if circulating tumor cells (CTCs), that are cells released by the tumor and that can be detected in the bloodstream of a patient; can predict the outcome of the women treated in this study. We also analyzed if bevacizumab concentration in the blood during treatment was associated with outcome, i.e., response to treatment and survival. We observed that CTCs detection before treatment initiation is associated with survival but was not correlated to local response to treatment. We moreover found that CTC status after three weeks of chemotherapy was not correlated to outcome as well as bevacizumab levels before and during treatment. However, bevacizumab concentration tended to be associated with an increase of hematological toxicities during the study. We thus show in this work that CTCs detection at baseline is prognostic for patients with breast cancer receiving a pre-operative chemotherapy-bevacizumab combination, and that this prognostic value was independent of tumor response.The phase II AVASTEM trial explored the impact of chemotherapy-bevacizumab combination on breast cancer stem cells in the neoadjuvant setting. We aimed to identify biological features associated with preoperative chemotherapy efficacy and prognosis by analyses of circulating tumor cells (CTCs) and bevacizumab pharmacokinetics (PK). The main objective was to assess the prognostic (relapse-free survival and overall survival) and predictive (pathological complete response, pCR) values of CTCs (CellSearch technology) and bevacizumab PK (ELISA). Seventy-five patients were included. Out of them 50 received bevacizumab-chemotherapy and 25 received chemotherapy alone. CTC results were available for 60 patients and PK data for 29 patients in the experimental arm. The absence of CTC at inclusion was correlated to better outcome. Five-years overall survival (OS) was 91% for CTC-negative patients vs. 54% for CTC-positive cases (HR = 6.21; 95%CI (1.75–22.06), p = 0.001, log-rank test). Similar results were observed for RFS with 5 y-RFS of 78% vs. 44% (HR = 3.51; 95%CI (1.17–10.52), p = 0.017, log-rank test). However, CTC status at baseline was not predictive of pCR (p = 0.74). CTC status after one cycle was not a significant prognostic factor (HR = 1.56; 95%CI (0.19–12.67); p = 0.68 for OS and HR = 2.76; 95%CI (0.60–12.61); p = 0.17 for RFS, log-rank test). Bevacizumab serum levels could not predict pCR and survival. PK values were not associated with treatment-related toxicities. In conclusion, CTCs detection at baseline is a prognostic marker for breast cancer receiving a neoadjuvant chemotherapy-bevacizumab combination independently of tumor response.

Efferent therapy in the first-line drug treatment of metastatic colorectal cancer

The aim of this study is to analyse the efficacy of efferent therapy (hemosorption) as part of drug treatment in patients with metastatic colorectal cancer (mCRC) based on the use of standard first-line chemotherapy combined with the bevacizumab biosimilar. The study included 54 patients with histologically verified mCRC who received the first-line FOLFOX + bevacizumab therapy in combination with and without hemosorption. All patients of the FOLFOX + bevacizumab (+) hemosorption group (n = 32) received the hemosorption using Hemophoenix apparatus on Day 4 of the cycle during the first 6 cycles. A total of 182 hemosorption procedures were performed. The control group included 22 patients receiving the FOLFOX + bevacizumab regimen without hemosorption. The bevacizumab biosimilar was introduced in both groups throughout the treatment at standard doses once every 2 weeks. There was no statistically significant difference between the study groups in the main clinical, pathomorphological, molecular genetic characteristics (sex, age, ECOG status, localization of primary tumor, tumor differentiation, RAS, BRAF mutations, microsatellite instability, etc.).Blood sampling to evaluate the effect of hemosorption on the pharmacokinetics (PK) of bevacizumab biosimilar was performed during the 2nd cycle before (PK1) and after (PK2) hemosorption procedures. The bevacizumab biosimilar concentration in the blood of patients before and after hemosorption showed no statistically significant difference (p = 0,423).The use of pharmaceutical treatment in the FOLFOX + bevacizumab (+) hemosorption group contributed to the achievement of an objective response (OR) in 62% of patients (p = 0.001). Median progression-free survival (PFS) was 10 ± 0.9 months [95% CI 8.3-11.7] in the FOLFOX + bevacizumab (+) hemosorption group, and 7 ± 0.5 months [95% CI 4.4-11.6] in the FOLFOX + bevacizumab (-) hemosorption group. There was no significant difference in PFS between the groups of patients treated with FOLFOX + bevacizumab regimen with and without hemosorption (p = 0.445).There were statistically significant differences in the frequency of nausea, diarrhoea and asthenia in the FOLFOX + bevacizumab (+) hemosorption group. The analysis of the dynamics of the quality of life (QoL) level before and after treatment showed that QoL level related to health (p = 0.0001) as well as the emotional (p = 0.0001) and social (p = 0,04) functioning increased in patients receiving the FOLFOX + bevacizumab regimen in combination with hemosorption, 0,039).Thus, the addition of hemosorption to the first-line drug treatment according to the FOLFOX + bevacizumab regimen does not affect bevacizumab pharmacokinetics, increases the frequency of objective response, reduces toxicity of the therapy and improves the quality of patients’ life indicators.

O1-4-4 - Association of the bevacizumab pharmacokinetics with efficacy and toxicity in advanced non-small cell lung cancer

Biomarkers predicting the efficacy and toxicity of bevacizumab (Bev) have not yet been established. We conducted this pharmacokinetic study to elucidate the role of plasma concentration of Bev as a biomarker to predict outcome in the treatment of patients with lung cancer. Patients with non-squamous non-small cell lung cancer who were treated using tri-weekly Bev (15mg/kg) with platinum-doublet chemotherapy were enrolled. Plasma samples were collected from all patients before the administration of every dose of Bev until disease progression or treatment discontinuation owing to toxicity. Plasma concentrations of Bev were analyzed via nano-surface and molecular-orientation limited proteolysis coupled with liquid chromatography-mass spectrometry. Between July 2010 and May 2014, 30 patients were enrolled in this study. Majority of the patients received pemetrexed with cisplatin or carboplatin (24 patients, 80%) and others received paclitaxel with carboplatin. The trough concentrations of Bev after first administration (day 22) were 63.19 ± 19.57 µg/mL. Trough concentrations gradually increased until the six cycle of Bev and reached a steady state. Plasma concentrations of Bev did not decrease until disease progression in patients with a long treatment period. Higher mean plasma concentrations of Bev correlated with female sex (p = 0.034) and high serum albumin levels (p = 0.034). Patients who received pemetrexed had higher mean concentrations of Bev (p = 0.038) than those who received paclitaxel. The response rate and progression-free survival did not correlate with the plasma concentration of Bev. Proteinuria (≥Grade 2) correlated with higher concentrations of Bev. Our study demonstrated that various types of chemotherapy influenced the concentrations of Bev, and a higher concentration of Bev may predict the incidence of proteinuria.

Association of the bevacizumab pharmacokinetics with efficacy and toxicity in advanced non-squamous non-small cell lung cancer: Kumamoto Thoracic Oncology Study Group (KTOSG) 1003 study.

e20559 Background: Biomarkers predicting the efficacy and toxicity of bevacizumab (Bev) have not yet been established. Therefore we conducted this pharmacokinetic study to elucidate the role of plasma concentration of Bev as a biomarker to predict outcome in the treatment of patients with lung cancer. Methods: This multicenter prospective pharmacokinetic study was conducted among nine centers in Kumamoto Prefecture, Japan. Patients with non-squamous non-small cell lung cancer who were treated using tri-weekly Bev (15mg/kg) with platinum-doublet chemotherapy were enrolled. Plasma samples were collected from all patients before the administration of every dose of Bev until disease progression or treatment discontinuation owing to toxicity. Plasma concentrations of Bev were analyzed via nano-surface and molecular-orientation limited proteolysis coupled with liquid chromatography-mass spectrometry. Results: Between July 2010 and May 2014, 30 patients were enrolled in this study. Majority of the patients received pemetrexed with cisplatin or carboplatin (24 patients, 80%) and others received paclitaxel with carboplatin. The trough concentrations of Bev after first administration (day 22) were 63.19 ± 19.57 μg/mL. Trough concentrations gradually increased until the six cycle of Bev and reached a steady state. Plasma concentrations of Bev did not decrease until disease progression in patients with a long treatment period. Higher mean plasma concentrations of Bev correlated with female sex (p = 0.034) and high serum albumin levels (p = 0.034). Patients who received pemetrexed had higher mean concentrations of Bev (p = 0.038) than those who received paclitaxel. The response rate and progression-free survival did not correlate with the plasma concentration of Bev. Proteinuria (≥Grade 2) correlated with higher concentrations of Bev. Conclusions: Our study demonstrated that various types of chemotherapy influenced the concentrations of Bev, and a higher concentration of Bev may predict the incidence of proteinuria. In addition, clearance of Bev did not change after long treatment period until disease progression. Clinical trial information: 000007630.

Population pharmacokinetics of bevacizumab in cancer patients with external validation.

BackgroundBevacizumab is approved for various cancers. This analysis aimed to comprehensively evaluate bevacizumab pharmacokinetics and the influence of patient variables on bevacizumab pharmacokinetics.MethodsRich and sparse bevacizumab serum concentrations were collected from Phase I through IV studies in early and metastatic cancers. Bevacizumab was given intravenously as single agent or in combination with chemotherapy for single- and multiple-dose schedules.ResultsModel-building used 8943 bevacizumab concentrations from 1792 patients with colon/colorectal, non-small cell lung, kidney, pancreatic, breast, prostate and brain cancer. Bevacizumab doses ranged from 1 to 20 mg/kg given once every 1, 2 or 3 weeks. A two-compartment model best described the data. The population estimates of clearance (CL), central volume of distribution (V1) and half-life for a typical 70-kg patient were 9.01 mL/h, 2.88 L and 19.6 days. CL and V1 increased with body weight and were higher in males than females by 14 and 18 %, respectively. CL decreased with increasing albumin and decreasing alkaline phosphatase. The final model was externally validated using 1670 concentrations from 146 Japanese patients that were not used for model-building. Mean prediction errors were −2.1, 3.1 and 1.0 % for concentrations, CL and V1, respectively, confirming adequate predictive performance.ConclusionsA robust bevacizumab pharmacokinetic model was developed and externally validated, which may be used to simulate bevacizumab exposure to optimize dosing strategies. Asian and non-Asian patients exhibited similar bevacizumab pharmacokinetics. Given the similarity in pharmacokinetics among monoclonal antibodies, this may inform pharmacokinetic studies in different ethnic groups for other therapeutic antibodies.Electronic supplementary materialThe online version of this article (doi:10.1007/s00280-016-3079-6) contains supplementary material, which is available to authorized users.

Bevacizumab Pharmacokinetics Influence Overall and Progression-Free Survival in Metastatic Colorectal Cancer Patients.

Clinical response to bevacizumab varies between patients treated for metastatic colorectal cancer (mCRC). The aim of this study was to quantify individual factors affecting bevacizumab pharmacokinetic variability and assess the relationship between bevacizumab concentrations and clinical outcomes. Bevacizumab pharmacokinetics were assessed in 130 mCRC patients using a two-compartment pharmacokinetic population model. Overall and progression-free survival (PFS) were analyzed using Cox models. The bevacizumab volume of distribution increased with height (p=10-10) and was higher in patients with a 3/3 variable number tandem repeat of the FCGRT (Fc fragment of IgG receptor and transporter) gene (p=0.039). The elimination rate constant increased with baseline carcinoembryonic antigen (CEA) and vascular endothelial growth factor (VEGF) concentrations, and was higher in patients with extra-hepatic metastases (p=0.00029, 0.011, and 0.014). A bevacizumab trough concentration ≤15.5mg/L was associated with both shorter overallsurvival and PFS (hazard ratio [95% CI] 1.90 [1.20-2.99] and 1.76 [1.20-2.58], respectively). High tumour burden is associated with low bevacizumab concentrations, and high bevacizumab concentration are associated with both decreased overall and progression-free survivals.

Similar exposure and pharmacokinetics of bevacizumab in pediatric and adult cancer patients: Analysis of individual data of 152 pediatric patients.

10062 Background: Bevacizumab (BEV) is approved for various cancers. BEV pharmacokinetics (PK) is well established by a population PK (PPK) model in adults, but has not been comprehensively evaluat...

Population Pharmacokinetics of Bevacizumab in Children with Osteosarcoma: Implications for Dosing

To describe sources of interindividual variability in bevacizumab disposition in pediatric patients and explore associations among bevacizumab pharmacokinetics and clinical wound healing outcomes. Before tumor resection, three doses of bevacizumab (15 mg/kg) were administered to patients (median age, 12.2 years) enrolled in a multi-institutional osteosarcoma trial. Serial sampling for bevacizumab pharmacokinetics was obtained from 27 patients. A population pharmacokinetic model was fit to the data, and patient demographics and clinical chemistry values were systematically tested as predictive covariates on model parameters. Associations between bevacizumab exposure and wound healing status were evaluated by logistic regression. Bevacizumab concentration-time data were adequately described by a two-compartment model. Pharmacokinetic parameter estimates were similar to those previously reported in adults, with a long median (range) terminal half-life of 12.2 days (8.6 to 32.4 days) and a volume of distribution indicating confinement primarily to the vascular space, 49.1 mL/kg (27.1 to 68.3 mL/kg). Body composition was a key determinant of bevacizumab exposure, as body mass index percentile was significantly (P < 0.05) correlated to body-weight normalized clearance and volume of distribution. Furthermore, bevacizumab exposure before primary tumor resection was associated with increased risk of major wound healing complications after surgery (P < 0.05). A population pharmacokinetic model for bevacizumab was developed, which demonstrated that variability in bevacizumab exposure using weight-based dosing is related to body composition. Bevacizumab dosage scaling using ideal body weight would provide an improved dosing approach in children by minimizing pharmacokinetic variability and reducing likelihood of major wound healing complications.

Exposure and clearance of bevacizumab in patients with first-line advanced gastric cancer.

2603 Background: Bevacizumab (BEV), rhuMAB VEGF, in combination with chemotherapy (CT) is currently approved in various types of cancer. Recently, BEV+CT was evaluated in 1st line advanced gastric cancer (AGC) in a double-blind randomized phase 3 trial (AVAGAST), but failed to meet the primary OS endpoint (HR=0.87; p=0.1002). BEV pharmacokinetics (PK) is well established by a reference population PK (PPK) model, and BEV PK is consistent across multiple cancer indications. However, BEV PK in AGC was never evaluated. We aimed to assess BEV exposure (EXP) and PK in AGC and to explore the influence of demographic, prognostic and biochemical (DPB) factors. Methods: BEV concentrations (Cp) were measured from plasma samples collected following disease progression from 182 patients (7.5mg/kg Q2W) in AVAGAST. Expected BEV Cp [median and 90% prediction interval (PI)] were simulated using the PPK model and compared to the observed BEV EXP. BEV clearance (CL) in AGC was estimated using NONMEM and compared between subgroups stratified by DPB factors. Results: All DPB factors of AGC are similar to those in other cancers except for lower body weight. No cachexia was observed. BEV Cp was detectable in 162 patients. 85% of observed BEV Cp was below the median BEV Cp simulated using PPK model and 38% below the lower limit of the 90% PI. Median BEV CL in AGC was 4.5 L/day/kg vs. 3 L/day/kg in other cancers. BEV CL was significantly higher (p=0.0012) in patients without prior gastrectomy (4.9 L/day/kg, n=120) than those with gastrectomy (4.1 L/day/kg, n=42). CL appeared to be higher in AGC patients with higher ECOG scores, lower albumin, more metastatic sites, poorer response and later stage AGC. Tumor location (GE Jct vs. Stomach), VEGF-A and ethnicity (Asian vs. Non-Asian) did not correlate with BEV CL. Conclusions: Overall, AGC patients exhibited significantly lower BEV EXP due to a 50% increase in BEV CL vs. other cancers. In addition, BEV is cleared significantly faster in patients without prior gastrectomy. The low BEV EXP in AGC could potentially reduce the effect of BEV in AGC. The underlying mechanism for faster BEV CL in AGC is unknown and warrants further research and potential BEV dose modifications.

Characterization of the long-term pharmacokinetics of bevacizumab following last dose in patients with resected stage II and III carcinoma of the colon

The study characterizes the long-term pharmacokinetics (PK) following last dose of bevacizumab as adjuvant therapy in patients with resected stage II and III colon carcinoma in a Phase III clinical study (AVF3077s). Patients in AVF3077s received bevacizumab (5 mg/kg every 2 weeks) as adjuvant therapy for 1 year. Following the last dose bevacizumab concentration, data at 3 and 6 months were used to characterize long-term bevacizumab PK based on the population-modeling approach. The long-term bevacizumab PK were consistent with previously reported results based on short-term bevacizumab PK. The clearance (CL), central volume of distribution (V(1)), intercompartmental clearance (Q), and the peripheral volume of distribution (V(2)) were 214 mL/day, 2,830 mL, 636 mL/day, and 2,490 mL, which correspond to a disposition and elimination half-life of 1.33 and 19.1 days, respectively. The empirical Bayes estimates of median post-treatment bevacizumab drug levels at 3 and 6 months were 6.14 and 0.23 μg/mL, respectively. For test covariates, the change in CL and V(1) of bevacizumab was less than 20% of the typical value. Body weight is the important covariate explaining the inter-individual variability on CL and V(1). Long-term bevacizumab PK in this study was predictable based on short-term PK data from metastatic settings in other tumor types. An exploratory analysis demonstrated no apparent association of the tested covariates with bevacizumab PK. Further, the extended serum persistence of bevacizumab following last dose should be considered in clinical study designs and post-treatment evaluations that may be affected by bevacizumab.

Transarterial chemoembolization plus or minus intravenous bevacizumab in the treatment of hepatocellular cancer: A pilot study

BackgroundStimulation of vascular endothelial growth factor (VEGF) has been observed following transarterial chemoembolization (TACE) in hepatocellular cancer (HCC) and may contribute to tumor regrowth. This pilot study examined whether intravenous (IV) bevacizumab, a monoclonal antibody against VEGF, could inhibit neovessel formation after TACE.Methods30 subjects with HCC undergoing TACE at a single academic institution were randomized with a computer-generated allocation in a one to one ratio to either bevacizumab at a dose of 10 mg/kg IV every 14 days beginning 1 week prior to TACE (TACE-BEV arm) or observation (TACE-O arm). Angiography was performed with TACE at day 8, and again at weeks 10 and 14. Repeat TACE was performed at week 14 if indicated. TACE-BEV subjects were allowed to continue bevacizumab beyond week 16. TACE-O subjects were allowed to cross-over to bevacizumab at week 16 in the setting of progressive disease. The main outcome measure was a comparison of neovessel formation by serial angiography. Secondary outcome measures were progression free survival (PFS) at 16 weeks, overall survival (OS), bevacizumab safety, and an analysis of VEGF levels before and after TACE with and without bevacizumab.ResultsAmong the 30 subjects enrolled, 9 of 15 randomized to the TACE-O arm and 14 of 15 randomized to the TACE-BEV arm completed all 3 angiograms. At week 14, 3 of 9 (33%) TACE-O subjects and 2 of 14 (14%) TACE-BEV subjects demonstrated neovascularity. The PFS at 16 weeks was 0.19 in the TACE-O arm and 0.79 in the TACE-BEV arm (p = 0.021). The median OS was 61 months in the TACE-O arm and 49 months in the TACE-BEV arm (p = 0.21). No life-threatening bevacizumab-related toxicities were observed. There were no substantial differences in bevacizumab pharmacokinetics compared to historical controls. Bevacizumab attenuated the increase in VEGF observed post-TACE.ConclusionsIV bevacizumab was well tolerated in selected HCC subjects undergoing TACE, and appeared to diminish neovessel formation at week 14.Trial registrationClinicalTrials.gov NCT00049322.

Pharmacokinetics of Pars Plana Intravitreal Injections versus Microcannula Suprachoroidal Injections of Bevacizumab in a Porcine Model

To compare the pharmacokinetics and tissue response between intravitreal and microcannulation injections into the suprachoroidal space using bevacizumab. Sixty-two pigs were studied. Either a pars plana intravitreal bevacizumab or a viscoelastic-enhanced microcannula suprachoroidal injection was performed with either 1.25 mg (group 1) or 3 mg (group 2). In group 1, six animals were euthanatized at 0.5, 7, 30, 60, 90, and 120 days after injection (n = 36). In group 2, six animals were euthanatized at 0.5, 7, 14, and 32 days (n = 24). Eyes were enucleated, dissected, and snap-frozen, or they were fixed for histology. Analysis of drug tissue levels was performed at two separate laboratories using masked specimens. Both laboratories were confirmatory. Intravitreal bevacizumab pharmacokinetics demonstrated a gradual decline in tissue levels over 30 to 60 days in both groups 1 and 2. In addition, suprachoroidal bevacizumab tissue levels declined rapidly and were not measurable at or beyond 7 days. Vitreitis and granulomatous vasculitis were noted in 7 of 30 intravitreal injection eyes. Immunohistology suggested a distinctive drug distribution. Direct intravitreal injection of bevacizumab has a more sustained pharmacologic profile than does a similar dose delivered to the suprachoroidal space. Intravitreal injections distributed more to the inner retina, whereas suprachoroidal delivery occurred primarily at the choroid, retinal pigment epithelium, and photoreceptor outer segments. Sustained release formulation of larger biological molecules should be considered to optimize suprachoroidal delivery. Inflammation from injections is granulomatous, seen only with intravitreal injections, and may result from either an altered immune response or a dose-related effect.

Descending doses of intravitreal bevacizumab for the regression of diabetic neovascularization

To report short-term regression of neovascularization after varying intravitreal doses of bevacizumab (Avastin®; Genentech, San Francisco, California, USA) in patients with proliferative diabetic retinopathy (PDR). Eighty eyes from 76 patients with active neovascularization of the disc (NVD) or elsewhere (NVE) caused by PDR were divided into four groups and treated with a single intravitreal bevacizumab (IVB) injection of 1.25 mg, 600 μg, 300 μg or 150 μg, respectively. All patients underwent ophthalmoscopic examination and fluorescein angiography at baseline, 1 week, 1 month and 2 months later. No significant ocular or systemic adverse events were observed. In all patients with NVD or NVE, complete resolution of leakage was recorded within the first week or the first month of the injection. Even with the lowest dose (150 μg), regression of neovascularization appeared as early as the first week and lasted for over a month. Recurrence of fluorescein leakage was observed in all groups after the first month and did not correlate with the extent of neovascularization or IVB dose. Short-term results suggest that IVB given below the standard dosage (150–300 μg compared to 1.25 mg) can lead to the achievement of complete regression of diabetic retinal neovascularization within 30–45 days of injection.

A multicenter, randomized, open-label study to assess the steady-state pharmacokinetics of bevacizumab given with either XELOX or FOLFOX-4 in patients with metastatic colorectal cancer

To compare the pharmacokinetics (PK) of bevacizumab (BV) at steady-state under two different dosing regimens, 7.5mg/kg q3w and 5.0mg/kg q2w, concomitantly with a combination of capecitabine and oxaliplatin (XELOX) and FOLFOX-4 (oxaliplatin in combination with infusional 5-FU/LV), respectively, in patients with metastatic colorectal cancer (mCRC). Patients were randomized in a 1:1 ratio to either XELOX+BV or FOLFOX-4+BV. Blood samples for steady-state PK of BV were collected on day 1 of cycle 5 (at the earliest) for XELOX+BV treatment and day 1 of cycle 7 (at the earliest) for FOLFOX-4+BV treatment. A total of 64 patients were enrolled, of which 37 were eligible for PK analyses. The primary PK parameter of BV, AUC(ss(per week)), was statistically similar between the two dosing regimens with the 90% confidence interval in the commonly used no-effect boundaries of 0.8 and 1.25. The V (ss) and CL did not differ between the two regimens; t (½) during the PK cycle was also similar for both arms at approximately 16days. These results demonstrated no clinically relevant change in BV PK when co-administered with either XELOX or FOLFOX-4. BV in combination with XELOX and FOLFOX-4 was generally well tolerated with no unexpected safety signals and no deaths. Nine patients in the XELOX+BV arm and 15 patients in the FOLFOX-4+BV arm experienced at least one SAE (most commonly gastrointestinal disorders) which led to dose modification in 7 and 2 patients, respectively, and to premature withdrawal in 9 and 5 patients, respectively. All 64 patients experienced at least one non-serious AE. Laboratory tests and vital signs were unremarkable. No clinically relevant differences in overall steady-state exposure of BV occurred when BV was given 7.5mg/kg q3w in combination with XELOX or 5.0mg/kg q2w with FOLFOX-4 in patients with mCRC, and the pharmacokinetics of BV were very similar between the two regimens. No unexpected adverse events or deaths were identified.

Evaluation of combined bevacizumab and intraperitoneal carboplatin or paclitaxel therapy in a mouse model of ovarian cancer

To evaluate the pharmacokinetics of bevacizumab following IP and IV administration, and to investigate combined bevacizumab therapy (IP or IV) with IP paclitaxel or carboplatin in a mouse model of ovarian cancer. Bevacizumab pharmacokinetics were investigated following IV or IP dosing, and mice bearing peritoneal A2780 xenografts were treated with vehicle, IV or IP bevacizumab, IP paclitaxel, IP paclitaxel with co-administration of IV or IP bevacizumab, IP carboplatin, and IP carboplatin with co-administration of IV or IP bevacizumab. Survival time was defined as the time to death or the time to reach 120% of baseline body weight. Following IP administration, bevacizumab was rapidly absorbed and bioavailability was 92.8%. Median survival time, which was 33days for control mice, was increased by 24% with IP paclitaxel. IP carboplatin failed to increase survival time when administered alone. IV and IP bevacizumab increased survival time by 42 and 33%. Combined bevacizumab and IP paclitaxel was superior to paclitaxel alone (P=0.01 for IV and P=0.04 for IP bevacizumab), and combined bevacizumab and IP carboplatin was superior to carboplatin alone (P=0.002 for IV and P=0.02 for IP bevacizumab). There were no significant differences in survival between groups receiving bevacizumab IV or IP, either alone (P=0.586), in combination with paclitaxel (P=0.467), or in combination with carboplatin (P=0.149). Following IP administration to mice, bevacizumab demonstrates rapid and near complete absorption. Bevacizumab therapy, initiated prior to IP carboplatin or paclitaxel administration, increased survival time significantly in mice, and results were not dependent on the route of bevacizumab administration (IV vs. IP).

Lack of Efficacy of Bevacizumab Plus Irinotecan in Children With Recurrent Malignant Glioma and Diffuse Brainstem Glioma: A Pediatric Brain Tumor Consortium Study

A phase II study of bevacizumab (BVZ) plus irinotecan (CPT-11) was conducted in children with recurrent malignant glioma (MG) and intrinsic brainstem glioma (BSG). Eligible patients received two doses of BVZ intravenously (10 mg/kg) 2 weeks apart and then BVZ plus CPT-11 every 2 weeks until progressive disease, unacceptable toxicity, or a maximum of 2 years of therapy. Correlative studies included diffusion weighted and T1 dynamic contrast-enhanced permeability imaging, BVZ pharmacokinetics, and estimation of vascular endothelial growth factor receptor 2 (VEGFR-2) phosphorylation in peripheral blood mononuclear cells (PBMC) after single-agent BVZ. Thirty-one evaluable patients received a median of two courses of BVZ plus CPT-11 (range, 1 to 19). No sustained responses were observed in either stratum. Median time to progression for all 34 eligible patients enrolled was 127 days for MG and 71 days for BSG. Progression-free survival rates at 6 months were 41.8% and 9.7% for MG and BSG, respectively. Toxicities related to BVZ included grade 1 to 3 fatigue in seven patients, grade 1 to 2 hypertension in seven patients, grade 1 CNS hemorrhage in four patients, and grade 4 CNS ischemia in two patients. The mean diffusion ratio decreased after two doses of BVZ in patients with MG only. Vascular permeability parameters did not change significantly after therapy in either stratum. Inhibition of VEGFR-2 phosphorylation in PBMC was detected in eight of 11 patients after BVZ exposure. BVZ plus CPT-11 was well-tolerated but had minimal efficacy in children with recurrent malignant glioma and brainstem glioma.