A randomized, single-blind, Phase I trial (INVICTAN-1) assessing the bioequivalence and safety of BI 695502, a bevacizumab biosimilar candidate, in healthy subjects

Hettema, Willem; Wynne, Christopher; Lang, Benjamin; Altendorfer, Mario; Czeloth, Niklas; Lohmann, Ragna; Athalye, Sandeep N.; Schliephake, Dorothee

doi:10.1080/13543784.2017.1347635

Cited by 25 publications

(23 citation statements)

References 3 publications

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“…The treatment group ratios of LS geometric means for the three primary PK parameters were fully contained within the bioequivalence limits of 80–125%. These results were consistent with other similar studies in Caucasian, Japanese, Korean, and Chinese healthy volunteers ( Table 5 ) (Knight et al, 2016; Hettema et al, 2017; Markus et al, 2017; Tajima et al, 2017; Hanes et al, 2018; Zhang et al, 2018; Cho et al, 2019; Wu et al, 2019; Zhang et al, 2019).…”

Section: Discussionsupporting

confidence: 93%

“…TEAEs considered related to the study drug in this study were reported for 19 (38.8%) subjects in the TAB008 group and 19 (38.0%) subjects in the Avastin ® group. AE seemed to vary widely between these studies (Knight et al, 2016; Hettema et al, 2017; Markus et al, 2017; Tajima et al, 2017; Hanes et al, 2018; Zhang et al, 2018; Cho et al, 2019; Wu et al, 2019; Zhang et al, 2019), but there was no significant correlation with the dose. The %AE with 1 mg/kg ranged across studies from 33.3% to 55.0% for biosimilars and 32.3% to 48.8% for Avastin ® (EU-sourced).…”

Section: Discussionmentioning

confidence: 87%

“…Since the PK profile of Avastin ® was linear for doses of 1–10 mg/kg (Avastin: EPAR-Scientific Discussion. EMA; Hettema et al, 2017; Wu et al, 2019), 1 mg/kg was selected to minimize drug exposure. The number of healthy male volunteers in this study was 50 per arm of treatment.…”

Section: Discussionmentioning

confidence: 99%

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A Phase I, Randomized, Single-Dose Study Evaluating the Biosimilarity of TAB008 to Bevacizumab in Healthy Volunteers

Wang

Лонг

et al. 2019

Front. Pharmacol.

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Objective: This study compared the pharmacokinetics (PK), safety, and immunogenicity of the biosimilar TAB008 monoclonal antibody to bevacizumab (Avastin ® ) in normal healthy Chinese male volunteers. Methods: In this randomized, double-blind, parallel controlled study, a total of 100 healthy Chinese male subjects were randomized (1:1) to receive a single 1 mg/kg intravenous dose of TAB008 or Avastin ® over a 90-min infusion. The subjects were followed for 99 days after drug administration. Primary endpoints were bioequivalence of major pharmacokinetic parameters (AUC 0-t and AUC 0-∞ ) and maximum observed serum concentration (C max ). Secondary endpoints included safety and immunogenicity parameters. Results: The two groups of test subjects (49 subjects in the TAB008 group and 50 subjects in the Avastin ® group) were well matched in regards to all demographic and baseline characteristics. The treatment group ratios of LS geometric means for the three primary PK parameters were fully contained within the bioequivalence limits of 80.00–125.00% (90% CI was 103.66–118.33% for C max , 94.32–111.72% for AUC 0-t , and 94.69–112.23% for AUC 0-∞ ). Treatment-emergent adverse events (TEAEs) were reported for 24 (49.0%) subjects in the TAB008 group and 22 (44.0%) subjects in the Avastin ® group. TEAEs related to the study drug were reported for 19 (38.8%) subjects in the TAB008 group and 19 (38.0%) subjects in the Avastin ® group. National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) Grade 3 TEAEs were reported for 1 (2.0%) subject in the TAB008 group and 3 (6.0%) subjects in the Avastin ® group. There were no Grade 4 or 5 TEAEs or serious adverse events (SAEs) during the study. Anti-drug antibody generation was reported once only in each group, and neutralizing antibody (Nab) analysis was negative upon follow-up. Conclusion: TAB008 attained pharmacokinetic similarity to bevacizumab, and was safe and well tolerated.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 87%

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A Phase I, Randomized, Single-Dose Study Evaluating the Biosimilarity of TAB008 to Bevacizumab in Healthy Volunteers

Wang

Лонг

et al. 2019

Front. Pharmacol.

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“…Moreover, results confirm that bevacizumab-EU and bevacizumab-US are bioequivalent to each other, consistent with results from other phase I studies of bevacizumab biosimilars [16,17]. The PK results of this study are consistent with those of other phase I PK studies of (proposed) bevacizumab biosimilars which also demonstrated equivalence to the reference product [16][17][18][19][20][21][22][23][24][25][26]. However, direct comparisons of absolute PK parameters values between studies are generally not appropriate due to differences between the doses used (1 mg/kg, 3 mg/kg or 5 mg/kg), sample collection, and assessment methods [16][17][18][19][20][21][22][23][24][25][26].…”

Section: Discussionsupporting

confidence: 89%

A phase I, randomized, single-dose pharmacokinetic study comparing sb8 (bevacizumab biosimilar) with reference bevacizumab in healthy volunteers

Shin

Lee

Choi

et al. 2020

Cancer Chemother Pharmacol

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Purpose To compare pharmacokinetics, safety, tolerability, and immunogenicity between SB8, a bevacizumab biosimilar, and the European Union (EU) and United States (US) reference products (bevacizumab-EU, bevacizumab-US). Methods In this randomized, double-blind, parallel-group, and single-dose study, healthy volunteers were randomized to receive a 3 mg/kg dose of SB8, bevacizumab-EU, or bevacizumab-US via intravenous infusion. Primary endpoints were area under the concentration–time curve from time zero to infinity (AUCinf) and to the last quantifiable concentration (AUClast), and maximum observed serum concentration (Cmax). Bioequivalence was achieved if 90% confidence intervals (CIs) for the ratios of the geometric least squares means (LSMeans) of primary endpoints were within the predefined bioequivalence margins of 80.00–125.00%. Safety and immunogenicity were also investigated. Results The 90% CIs for the geometric LSMean ratios of AUCinf, AUClast and Cmax were all within the prespecified bioequivalence margins. Geometric LSMean ratios for SB8/bevacizumab-EU, SB8/bevacizumab-US and bevacizumab-EU/bevacizumab-US were 88.01%, 88.48% and 100.54% for AUCinf, 88.65%, 89.08% and 100.49% for AUClast and 99.59%, 101.15% and 101.56% for Cmax, respectively. Incidence of treatment-emergent adverse events (TEAEs) across treatment groups was comparable (SB8: 50.0%, bevacizumab-EU: 37.5%, bevacizumab-US: 53.8%). Most TEAEs were mild and considered as not related to the study drug. No deaths or treatment discontinuations due to adverse events occurred. Incidence of anti-drug antibodies was also comparable between all groups and no neutralizing antibodies were detected. Conclusion This study demonstrated pharmacokinetic bioequivalence and similar safety and immunogenicity profiles of SB8 to both reference products, bevacizumab-EU and bevacizumab-US, and of bevacizumab-EU to bevacizumab-US. Clinicaltrials.gov identifier NCT02453672 (submitted date); EudraCT number: 2015-001,026-41.

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“…In this study, we referred to the research design of similar products abroad, such as PF-06439535 [20], BI-695502 [21], ABP-215 [22] and so on, in which ABP-215 (Mvasi ® ) has been approved by the FDA and the EU. According to previous data [20][21][22][23], we assumed that the coefficient of intra-individual variation was 25%. If the geometric mean ratio (GMR) was set to be 95-105% to achieve 90% power (1-β) at the 5% nominal level (α = 5%), 37 evaluable subjects were required to be in each treatment group to meet the bioequivalence in the range of 80-125.00%.…”

Section: Discussionmentioning

confidence: 99%

A randomized, double-blind, single-dose study to evaluate the biosimilarity of QL1101 with bevacizumab in healthy male subjects

Liu

Huang

Guo

et al. 2020

Cancer Chemother Pharmacol

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Purpose This is the first study to compare the pharmacokinetics of QL1101, a proposed bevacizumab biosimilar, with Avastin ® sourced from Roche Diagnostics GmbH. Methods In this double-blind, single-dose, parallel-group study, healthy male subjects were randomized 1:1 to receive QL1101 or Avastin ® 3 mg/kg intravenously. Pharmacokinetic assessments were conducted for 85 days, with additional safety and immunogenicity assessments until day 90. Primary study endpoints were area under the concentration-time curve (AUC) from time zero to infinity (AUC 0-∞), AUC from time zero to the last quantifiable concentration (AUC 0-last), and maximum serum concentration (C max). Pharmacokinetic equivalence was shown if the 90% confidence intervals (CIs) of the geometric mean ratios (GMRs) of the C 0-max , AUC 0-last , and AUC 0-∞ were within the predefined bioequivalence margin of 80-125.00%. Results A total of 82 subjects were randomized to the following groups: 42 to QL1101 and 40 to Avastin ®. The 90% CIs of the GMRs of AUC 0-∞ , AUC 0-last , and C max of QL1101 and Avastin® were (97.8%, 107.0%), (94.5%, 106.9%), and (94.1%, 107.3%), respectively, which were all within the bioequivalence margin. The incidence of adverse events was 90.5% and 95.0% in the QL1101 and Avastin® groups, respectively. Mean serum concentration-time profiles, secondary pharmacokinetic parameters, and safety and immunogenicity profiles were comparable across the two treatment groups. Conclusions The study demonstrated the pharmacokinetic equivalence of QL1101 to Avastin ®. QL1101 (3 mg/kg, iv) is safe and tolerable in healthy Chinese subjects. These data support the further clinical evaluation of QL1101 as a bevacizumab biosimilar.

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A randomized, single-blind, Phase I trial (INVICTAN-1) assessing the bioequivalence and safety of BI 695502, a bevacizumab biosimilar candidate, in healthy subjects

Abstract: NCT01608087.

Cited by 25 publications

References 3 publications

A Phase I, Randomized, Single-Dose Study Evaluating the Biosimilarity of TAB008 to Bevacizumab in Healthy Volunteers

A Phase I, Randomized, Single-Dose Study Evaluating the Biosimilarity of TAB008 to Bevacizumab in Healthy Volunteers

A phase I, randomized, single-dose pharmacokinetic study comparing sb8 (bevacizumab biosimilar) with reference bevacizumab in healthy volunteers

A randomized, double-blind, single-dose study to evaluate the biosimilarity of QL1101 with bevacizumab in healthy male subjects

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