Dataset Information

A study assessing the similarity of Avastin (Registered Trademark) and the trial drug DRL_BZ.

ABSTRACT: Interventions: Three Bevacizumab Preperations Arm 1: DRL_BZ 100 mg in 4 mL - 1mg/kg Recombinant humanised monoclonal antibody - bevacizumab 1 time only Intravenous infusion. Arm 2: Avastin (Registered Trademark) United States-licenced (bevacizumab) 100 mg in 4 mL- 1mg/kg Recombinant humanised monoclonal antibody - bevacizumab 1 time only Intravenous infusion. Arm 3: Avastin (Registered Trademark) European Approved (bevacizumab) 100 mg in 4 mL- 1mg/kg Recombinant humanised monoclonal antibody - bevacizumab 1 time only Intravenous infusion. As the Infusion will be administered while the participants are inpatients of the facility, no strategy for adherence is required. Primary outcome(s): To demonstrate pharmacokinetic (PK) similarity of DRL_BZ versus the Reference Medicinal Product (RMP; Avastin (Registered Trademark) [EU-approved]) and the Reference Product (RP; Avastin (Registered Trademark) [US-licensed]) after administration of a single 1 mg/kg intravenous (IV) dose in healthy male subjects.[Blood samples for analysis of serum concentrations of the study drugs will be collected at the following specified times to perform a comparison of PK similarity. All PK sampling time points are relative to end of infusion (i.e., after fixed infusion of 90 minutes, or up to 93 minutes, considering the maximum of 3 minutes infusion interruption allowed). Sampling time points relative to end of infusion will have a designated nominal time point: End of infusion, 1 hour, 2 hours, 5 hours, 8 hours, 12 hours, and 24 hours post end of infusion and so on up to Day 85. Mid infusion (at 45 minutes) and end of infusion (at 90 minutes +/- 3 minutes) are relative to the start of infusion. The primary PK parameters will consist of: - Cmax, AUC(08) and AUC(0t).] Study Design: Purpose: Treatment; Allocation: Randomised controlled trial; Masking: Blinded (masking used);Assignment: Parallel;Type of endpoint: Pharmacokinetics

DISEASE(S): Metastatic Colorectal Cancer,Metastatic Breast Cancer,Healthy Human Volunteers,Cancer-bowel-back Passage (rectum) Or Large Bowel (colon),Non-squamous Non-small Cell Lung Cancer,Cancer-breast,Cancer-lung-non Small Cell

PROVIDER: 2462876 | ecrin-mdr-crc |

REPOSITORIES: ECRIN MDR

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Project description:Bevacizumab induces glioblastoma resistance in two in vivo xenograft models. Two cell lines were developed with acquired resistance to bevacizumab. Gene expression difference were analyzed between treated and untreated tumors. Purpose: Antiangiogenic therapy reduces vascular permeability and delays progression but may ultimately promote an aggressive treatment-resistant phenotype. The aim of the present study was to identify mechanisms responsible for glioblastoma resistance to antiangiogenic therapy. Experimental Design: Glioma stem cell (GSC) NSC11 and U87 cell lines with acquired resistance to bevacizumab were developed from orthotopic xenografts in nude mice treated with bevacizumab. Genome-wide analyses were used to identify changes in tumor subtype and specific factors associated with resistance. Results: Mice with established parental NSC11 and U87 cells responded to bevacizumab, whereas glioma cell lines derived at the time of acquired resistance to anti-VEGF therapy were resistant to bevacizumab and did not have prolongation of survival compared to untreated controls. Gene expression profiling comparing anti-VEGF therapy-resistant cell lines to untreated controls demonstrated an increase in genes associated with a mesenchymal origin, cellular migration/invasion, and inflammation. Gene Set Enrichment Analysis (GSEA) demonstrated that bevacizumab-treated tumors showed a highly significant correlation to published mesenchymal gene signatures. Mice bearing resistant tumors showed significantly greater infiltration of myeloid cells in NSC11 and U87 resistant tumors. Invasion-related genes were also upregulated in both NSC11 and U87 resistant cells, which had higher invasion rates in vitro compared with their respective parental cell lines. Conclusions: Our studies identify multiple pro-inflammatory factors associated with resistance and identify a proneural-to-mesenchymal transition (PMT) in tumors resistant to antiangiogenic therapy. Glioma cell lines were injected into the caudate of nude mice and were allowed to grow untreated (samples labeled control) or were treated with 10 mg/kg IP twice weekly with bevacizumab (samples labeled Avastin). At the time of animal death, tumor tissue from the mouse was removed, and RNA was isolated and analyzed using gene expression. U87R and NSC11R represent cells resistant to bevacizumab (Avastin).

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A study assessing the similarity of Avastin (Registered Trademark) and the trial drug DRL_BZ.

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