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A study assessing the similarity of Avastin (Registered Trademark) and the trial drug BAT1706.

ABSTRACT: Interventions: Three Bevacizumab Preperations Arm 1:BAT1706 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 establish pairwise pharmacokinetic (PK) similarity between BAT1706, EU Avastin and US-Avastin after a single intravenous (IV) infusion in healthy male subjects. The primary PK parameters will consist of: Area under the concentration-time curve from time 0 extrapolated to infinity (AUC0-inf).[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. Pre infusion - 0 hour or within 1 hour prior to the start of the infusion. Mid infusion - at 45 minutes - relative to the start of infusion. End of infusion - 1 hour, 2 hours, 5 hours, 8 hours, 12 hours from the end of infusion, and 24 hours (Day 2), 48 hours (Day 3), 96 hours (day 5), 168 hours (day 8), 240 hours (Day 11), 336 hours (Day 15), 504 hours (day 22), 672 hours (Day 29), 840 hours (Day 36), 1008 hours (Day 43), 1344 hours (Day 57), 1680 hours (Day 71), 2016 hours (Day85) and 2352 hours (Day 99) post start of infusion. ] 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,Cancer-bowel-back Passage (rectum) Or Large Bowel (colon),Non-squamous Non-small Cell Lung Cancer,Cancer-breast,Cancer-lung-non Small Cell

PROVIDER: 2463333 | 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).

Project description:Interventions: Arm 1: 25 mg/mL BP01 (bevacizumab biosimilar) administered as single intravenous infusion of 1 mg/kg over a period of approximately 90 minutes. Primary outcome(s): To determine the pharmacokinetic profile of BP01 following a single intravenous administration of 1 mg/kg in healthy male subjects. PK parameters determined are to include AUC(0-inf), AUC(0-t), C(max), residual area, T(max), T(1/2 el), K(el), Cl and V(d).[Blood PK samples will be collected for analysis during the treatment period at: pre-infusion (0 hour), prior to end of infusion (within 5 minutes before end of infusion), and at 2, 4, 6, 9, 12, 24, 48 (Day 3), 72 (Day 4), 168 (Day 8), 336 (Day 15), 504 (Day 22), 1008 (Day 43), 1512 (Day 64), and 2016 hours (Day 85).];To determine the pharmacokinetic profile of US-licensed Avastin following a single intravenous administration of 1 mg/kg in healthy male subjects. PK parameters determined are to include AUC(0-inf), AUC(0-t), C(max), residual area, T(max), T(1/2 el), K(el), Cl and V(d).[Blood PK samples will be collected for analysis during the treatment period at: pre-infusion (0 hour), prior to end of infusion (within 5 minutes before end of infusion), and at 2, 4, 6, 9, 12, 24, 48 (Day 3), 72 (Day 4), 168 (Day 8), 336 (Day 15), 504 (Day 22), 1008 (Day 43), 1512 (Day 64), and 2016 hours (Day 85).];To determine the pharmacokinetic profile of EU-licensed Avastin following a single intravenous administration of 1 mg/kg in healthy male subjects. PK parameters determined are to include AUC(0-inf), AUC(0-t), C(max), residual area, T(max), T(1/2 el), K(el), Cl and V(d).[Blood PK samples will be collected for analysis during the treatment period at: pre-infusion (0 hour), prior to end of infusion (within 5 minutes before end of infusion), and at 2, 4, 6, 9, 12, 24, 48 (Day 3), 72 (Day 4), 168 (Day 8), 336 (Day 15), 504 (Day 22), 1008 (Day 43), 1512 (Day 64), and 2016 hours (Day 85).] Study Design: Purpose: Treatment; Allocation: Randomised controlled trial; Masking: Blinded (masking used);Assignment: Parallel;Type of endpoint: Bio-equivalence

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A study assessing the similarity of Avastin (Registered Trademark) and the trial drug BAT1706.

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