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Randomized double-blind clinical trial comparing safety and efficacy of the biosimilar BCD-022 with reference trastuzumab.

ABSTRACT: BACKGROUND:BCD-022 is a trastuzumab biosimilar which was shown to be equivalent to reference trastuzumab in a wide panel of physicochemical studies as well as preclinical studies in vitro and in vivo. International multicenter phase III clinical trial was conducted to comparatively assess efficacy and safety of BCD-022 and reference trastuzumab in combination with paclitaxel used as the therapy of metastatic HER2(+) breast cancer. Pharmacokinetics and immunogenicity were also studied. METHODS:Patients with no previous treatment for metastatic HER2(+) breast cancer were randomly assigned 1:1 to BCD-022 or reference trastuzumab and were treated with trastuzumab + paclitaxel. Therapy continued for 6?cycles of therapy (every 3?weeks), until progression of the disease or unbearable toxicity. Primary study endpoint was overall response rate. Study goal was to prove equivalent efficacy of BCD-022 and reference trastuzumab. Equivalence margins for 95% CI for difference in overall response rates were set at [-?20%; 20%]. RESULTS:In total 225 patients were enrolled into the study, 115 in BCD-022 arm and 110 in reference trastuzumab arm. Overall response rate was 49.6% in BCD-022 arm and 43.6% in reference trastuzumab arm. Limits of 95% CI for difference of overall response rates between arms were [(-?8.05)-19.89%], thus, they lied within predetermined equivalence margins [-?20%; 20%]. Profile of adverse events was similar between groups (any AEs were reported in 93.81% of patients in BCD-022 arm and 94.55% of patients in reference arm). No unexpected adverse reactions were reported throughout the study. No statistically significant differences regarding antibody occurrence rate (either BAb or NAb) was found between BCD-022 (n?=?3; 2.65%) and comparator (n?=?4; 3.64%). Both drug products are characterized with low occurrence rate and short life of anti-trastuzumab antibodies. Pharmacokinetics assessment after 1st and 6th study drug injection also demonstrated equivalent PK parameters by all outcome measures: AUC0-504, ?m??, ?max, T1/2. Analysis of Ctrough did not reveal any significant inter-group differences as well. CONCLUSIONS:Thus, results of this study have demonstrated therapeutic equivalence of trastuzumab biosimilar BCD-022 and referent trastuzumab drug. TRIAL REGISTRATION:The trial was registered with ClinicalTrials.gov (Study Number NCT01764022 ). The date of registration was January 9, 2013.

SUBMITTER: Alexeev SM

PROVIDER: S-EPMC7439710 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Randomized double-blind clinical trial comparing safety and efficacy of the biosimilar BCD-022 with reference trastuzumab.

Alexeev Sergey M SM Khorinko Andrey V AV Mukhametshina Guzel Z GZ Shelepen Konstantin G KG Burdaeva Olga N ON Kulik Sergey A SA Satheesh Chiradoni Thugappa CT Srivastava Kirti K Vikranth Mummaneni M Kryukov Fedor F Paltusova Anastasia N AN Shustova Mariya S MS Ivanov Roman A RA

BMC cancer 20200820 1

<h4>Background</h4>BCD-022 is a trastuzumab biosimilar which was shown to be equivalent to reference trastuzumab in a wide panel of physicochemical studies as well as preclinical studies in vitro and in vivo. International multicenter phase III clinical trial was conducted to comparatively assess efficacy and safety of BCD-022 and reference trastuzumab in combination with paclitaxel used as the therapy of metastatic HER2(+) breast cancer. Pharmacokinetics and immunogenicity were also studied.<h4 ...[more]

PMID: 32819305

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Project description:BackgroundBCD-021 is a bevacizumab biosimilar which was shown to be equivalent to reference bevacizumab in a wide panel of physicochemical studies as well as preclinical studies in vitro and in vivo. International multicenter phase III clinical trial was conducted to compare efficacy and safety of BCD-021 and reference bevacizumab in combination with paclitaxel and carboplatin in a first-line treatment of inoperable or advanced non-squamous non-small-cell lung cancer (NSCLC).MethodsPatients with no previous treatment for advanced non-squamous NSCLC were randomly assigned 3:2 to BCD-021 or reference bevacizumab and were treated with bevacizumab + paclitaxel + carboplatin. Therapy continued for 6 cycles (every 3 weeks), until progression of the disease or unbearable toxicity. The primary study endpoint was the overall response rate. The study goal was to prove the equivalent efficacy of BCD-021 and reference bevacizumab. Equivalence margins for 95% CI for the difference in the overall response rates were set at [-18%; 18%], for 90% CI for the ratio of overall response rate were set at [67%; 150%].ResultsIn total 357 patients were enrolled in the study, 212 in the BCD-021 group and 145 in the reference bevacizumab group. The ORR was 34.63% in the BCD-022 group and 33.82% in the reference bevacizumab group. Limits of 95% CI for the difference in overall response rates between the groups were [-9.47%; 11.09%]. Limits of 90% CI for the ratio of overall response rate between the groups were [79.6%; 131.73%]. For both approaches CI lied within predetermined equivalence margins. Profile of adverse events (AEs) was similar between the groups (any AEs were reported in 86.89% of patients in BCD-021 group and 89.05% of patients in reference group). No unexpected adverse reactions were reported throughout the study. No statistically significant differences regarding anti-drug antibody occurrence rate was found between BCD-022 (n=4; 1.96%) and comparator (n=5; 3.65%). Both drug products showed low occurrence rate and short life of anti-bevacizumab antibodies. Pharmacokinetics assessment after 1st and 6th study drug injection also demonstrated equivalent PK parameters by all outcome measures.ConclusionsThus, the results of this study demonstrated therapeutic equivalence of bevacizumab biosimilar BCD-021 and referent bevacizumab drug.Trial registrationThe trial was registered with ClinicalTrials.gov (Study Number NCT01763645, date of registration 09/01/2013).

Project description:PurposeThis phase III study compared the efficacy and safety of proposed biosimilar MYL-1402O with reference bevacizumab (BEV), as first-line treatment for patients with stage IV non-squamous non-small-cell lung cancer.Patients and methodsPatients were randomly assigned (1:1) to receive MYL-1402O or bevacizumab with carboplatin-paclitaxel up to 18 weeks (6 cycles), followed by up to 24 weeks (8 cycles) of bevacizumab monotherapy. The primary objective was comparison of overall response rate (ORR), based on independently reviewed best tumor responses as assessed during the first 18 weeks. ORR was analyzed per US Food and Drug Administration (ratio of ORR) and European Medicines Agency (difference in ORRs) requirements for equivalence evaluation. Secondary end points included progression-free survival, disease control rate, duration of response, overall survival, safety, and immunogenicity over a period of 42 weeks, and pharmacokinetics (up to 18 weeks).ResultsA total of 671 patients were included in the intent-to-treat population. The ratio of ORR was 0.96 [confidence interval (CI) 0.83, 1.12] and the difference in ORR was -1.6 (CI -9.0, 5.9) between treatment arms; CIs were within the predefined equivalence margins. Overall, the incidence of treatment-emergent adverse events and serious adverse events was comparable. Treatment-emergent anti-drug antibody (ADA) positivity was transient, with no notable differences between treatment arms (6.5% versus 4.8% ADA positivity rate in MYL-1402O versus BEV, respectively). The incidence of neutralizing antibody post-baseline was lower in the MYL-1402O arm (0.6%) compared to the bevacizumab arm (2.5%).ConclusionsMYL-1402O is therapeutically equivalent to bevacizumab, based on the ORR analyses, with comparable secondary endpoints.Trial registry informationEU Clinical Trials Register, Registration # EudraCT no. 2015-005141-32https://www.clinicaltrialsregister.eu/ctr-search/search?query=2015-005141-32.Plain language summaryPrevious studies established bioequivalence of the proposed bevacizumab biosimilar MYL-1402O to reference bevacizumab. In this randomized, double-blind, phase III trial, MYL-1402O (n = 337) demonstrated comparable efficacy to bevacizumab (n = 334) in treating advanced non-squamous non-small-cell lung cancer per Food and Drug Administration and European Medicines Agency requirements for equivalence; the ratio of objective response rate (ORR) was 0.96 [90% confidence interval (CI) 0.83, 1.12] and the difference in ORR (MYL-1402O:bevacizumab) was -1.6 (95% CI -9.0, 5.9). Median progression-free survival at 42 weeks was comparable: 7.6 (7.0, 9.5) with MYL-1402O versus 9.0 (7.2, 9.7) months (p = 0.0906) with bevacizumab, by independent review. Treatment-emergent adverse events leading to death (2.4% vs 1.5%), serious adverse events (17.6% vs 16.7%), and antidrug antibodies (6.5% vs 4.8%), were comparable in the MYL-1402O vs bevacizumab arms, respectively. The incidence of neutralizing antibody post-baseline was lower with MYL-1402O (0.6%) than with bevacizumab (2.5%). These findings confirm therapeutic equivalence of MYL-1402O to bevacizumab, providing opportunities for improving access to bevacizumab.

Project description:Background/objectivesABP 798 is a proposed biosimilar to the originator biologic rituximab, an anti-CD20 monoclonal antibody. This comparative clinical study evaluated the pharmacokinetics (PK), safety, and efficacy of ABP 798 versus rituximab reference product (RP) in patients with moderate-to-severe rheumatoid arthritis (RA).MethodsAdults with moderate-to-severe RA with an inadequate response or intolerance to other disease-modifying anti-rheumatic drugs including 1 or more tumor necrosis factor inhibitor therapies (n = 311) received ABP 798, US-sourced rituximab RP (rituximab US), or EU-sourced rituximab RP (rituximab EU) (1000 mg, 2 weeks apart). At week 24, ABP 798- or rituximab EU-treated subjects received a second dose of the same treatment, while rituximab US-treated subjects transitioned to receive ABP 798. The key efficacy endpoint was DAS28-CRP change from baseline at week 24. Other efficacy endpoints included DAS28-CRP at other time points; ACR20, ACR50, and ACR70 criteria; and hybrid ACR. The rituximab RP groups were pooled for all efficacy endpoints since PK equivalence had been established between rituximab US and rituximab EU.ResultsClinical equivalence between ABP 798 and rituximab RP was established as the 90% confidence interval for DAS28-CRP change from baseline at week 24 fell within the prespecified equivalence margin (- 0.6, 0.6). Safety and immunogenicity profiles of ABP 798 were comparable across treatment groups and not affected by single transition from RP to ABP 798.ConclusionsClinical equivalence in terms of efficacy, safety, and immunogenicity was established between ABP 798 and rituximab RP in this comparative clinical trial in patients with moderate-to-severe RA. Key Points • ABP 798 provided similar efficacy as rituximab reference product (RP) in patients with moderate-severe rheumatoid arthritis. • The safety and immunogenicity profiles for ABP 798 were similar to those for the rituximab RP. • The single transition from rituximab RP to ABP 798 did not show differences in efficacy, safety, or immunogenicity.

Project description:BACKGROUND:This randomised, double-blind study compared PF-05280014 (a trastuzumab biosimilar) with reference trastuzumab (Herceptin®) sourced from the European Union (trastuzumab-EU), when each was given with paclitaxel as first-line treatment for HER2-positive metastatic breast cancer. METHODS:Between 4 April 2014 and 22 January 2016, 707 participants were randomised 1:1 to receive intravenous PF-05280014 plus paclitaxel (PF-05280014 group; n = 352) or trastuzumab-EU plus paclitaxel (trastuzumab-EU group; n = 355). PF-05280014 or trastuzumab-EU was administered weekly (first dose 4 mg/kg, subsequent doses 2 mg/kg), with the option to change to a 3-weekly regimen (6 mg/kg) from Week 33. Treatment with PF-05280014 or trastuzumab-EU could continue until disease progression. Paclitaxel (starting dose 80 mg/m2) was administered on Days 1, 8 and 15 of 28-day cycles for at least six cycles or until maximal benefit of response. The primary endpoint was objective response rate (ORR), evaluating responses achieved by Week 25 and confirmed by Week 33, based on blinded central radiology review. RESULTS:The risk ratio for ORR was 0.940 (95% CI: 0.842-1.049). The 95% CI fell within the pre-specified equivalence margin of 0.80-1.25. ORR was 62.5% (95% CI: 57.2-67.6%) in the PF-05280014 group and 66.5% (95% CI: 61.3-71.4%) in the trastuzumab-EU group. As of data cut-off on 11 January 2017 (using data up to 378 days post-randomisation), there were no notable differences between groups in progression-free survival (median: 12.16 months in the PF-05280014 group vs. 12.06 months in the trastuzumab-EU group; 1-year rate: 54% vs. 51%) or overall survival (median: not reached in either group; 1-year rate: 89.31% vs. 87.36%). Safety outcomes and immunogenicity were similar between the treatment groups. CONCLUSION:When given as first-line treatment for HER2-positive metastatic breast cancer, PF-05280014 plus paclitaxel demonstrated equivalence to trastuzumab-EU plus paclitaxel in terms of ORR. CLINICAL TRIAL REGISTRATION:ClinicalTrials.gov, NCT01989676.

Project description:BackgroundFollowing the functional and physicochemical characterization of a proposed biosimilar, comparative clinical studies help to confirm biosimilarity by demonstrating similar safety and efficacy to the reference product in a sensitive patient population.Patients and methodsLA-EP2006 is a proposed biosimilar that has been developed for pegfilgrastim, a long-acting form of granulocyte colony-stimulating factor for the prevention of neutropenia. The current analysis reports data pooled from two independent, multinational, prospective, randomized, controlled, double-blind phase III studies of similar design comparing the safety and efficacy of reference pegfilgrastim with LA-EP2006 in patients with breast cancer receiving myelotoxic (neo)adjuvant TAC (docetaxel, doxorubicin, and cyclophosphamide) chemotherapy and requiring granulocyte colony-stimulating factor.ResultsA total of 624 patients were randomized in the PROTECT-1 and PROTECT-2 studies (NCT01735175; NCT01516736) (LA-EP2006: n = 314; reference: n = 310). Baseline characteristics of patients were well balanced across treatment groups. The primary end point, mean duration of severe neutropenia in the first chemotherapy cycle was similar in both the LA-EP2006 and reference groups (1.05 ± 1.055 days versus 1.01 ± 0.958 days), with a treatment difference of - 0.04 days [95% confidence interval (CI): -0.19 to 0.11] that met the equivalence criteria (the 95% CI were within the defined margin of ±1 day). Secondary end points, such as the nadir of absolute neutrophil count and the incidence of febrile neutropenia, were also similar between LA-EP2006 and reference pegfilgrastim. The safety and tolerability profile of LA-EP2006 was similar to that observed with reference pegfilgrastim, and there were no reports of neutralizing antibodies.ConclusionsThis pooled analysis confirms, as a part of totality of evidence approach, that the proposed biosimilar pegfilgrastim LA-EP2006 has a comparable efficacy and safety profile to reference pegfilgrastim in patients with breast cancer receiving TAC chemotherapy.Clinical trial numbersNCT01735175 and NCT01516736.

Project description:BackgroundMB02 (bevacizumab biosimilar) showed similar structural, functional, and pharmacokinetic properties to reference bevacizumab (Avastin®; EU-bevacizumab).ObjectivesTo confirm clinical similarity between MB02 and EU-bevacizumab, a comparability study was undertaken in the first-line treatment of stage IIIB/IV non-squamous non-small cell lung cancer (NSCLC).Patients and methodsThis multinational, double-blind, randomized, phase III study (STELLA) compared MB02 or EU-bevacizumab (15 mg/kg) administered with chemotherapy (paclitaxel 200 mg/m2 and carboplatin AUC6) on Day 1 of every 3-week cycle for 6 cycles (Week 18), followed by MB02/EU-bevacizumab in blinded monotherapy until disease progression, unacceptable toxicity, death, withdrawal of consent or end of study (Week 52). The primary efficacy endpoint was objective response rate (ORR) evaluated by an independent radiological review committee (IRC) at Week 18 (intent-to-treat population). Secondary endpoints included progression-free survival (PFS), overall survival (OS), safety and immunogenicity.ResultsA total of 627 subjects were randomized 1:1 to MB02 (n = 315) or EU-bevacizumab (n = 312). ORR, assessed by the IRC at Week 18, was comparable in MB02 (40.3%) and EU-bevacizumab (44.6%) groups. ORR risk ratio of 0.910 (90% CI 0.780 to 1.060; 95% CI 0.758 to 1.092) and ORR risk difference of -4.02 (90% CI -10.51 to 2.47; 95% CI -11.76 to 3.71) were within the similarity predefined margins. There were no significant differences between MB02 and EU-bevacizumab groups in median PFS (36.0 vs 37.3 weeks, respectively; HR 1.187; 95% CI 0.98 to 1.44) and median OS (not achieved; HR 1.108; 95% CI: 0.83 to 1.49) at the end of study. The safety profile of MB02 and EU-bevacizumab regarding nature, frequency and severity of the adverse events (AE) was comparable. The most frequent grade ≥3 investigational-product-related AEs were hypertension and anemia, with a difference between treatment groups of <5%. Anti-drug antibodies (ADA) and neutralizing ADA (NAb) incidence were similar in both treatment groups.ConclusionMB02 demonstrated similar efficacy to EU-bevacizumab, in combination with carboplatin and paclitaxel, in subjects with advanced non-squamous NSCLC, with comparable safety and immunogenicity profiles.Clinical trial registrationEudraCT No. 2017-001769-26; ClinicalTrials.gov: NCT03296163.

Project description:IntroductionThis study evaluated the pharmacokinetic (PK) equivalence between BP02 (a proposed trastuzumab biosimilar) and the reference trastuzumab approved in the EU (EU-trastuzumab) and the US (US-trastuzumab).MethodsIn this phase 1, double-blind, parallel-group trial, 111 healthy male volunteers were randomized 1:1:1 to receive a single 6-mg/kg intravenous infusion of BP02, EU-trastuzumab, or US-trastuzumab and were evaluated for 78 days. Serum drug concentration-time data were analyzed by non-compartmental methods. The PK similarity of BP02 to the two reference products, and between EU-trastuzumab and US-trastuzumab, was determined using the standard 80-125% bioequivalence criteria.ResultsBaseline demographics for the 111 subjects with evaluable pharmacokinetics were similar across all treatment groups. PK profiles were similar for the three products. The 90% confidence intervals (CIs) for the ratios of area under the serum concentration-time curve (AUC) from the time of dosing to infinity (AUC0-inf), AUC from the time of dosing until the time of the last quantifiable concentration (AUC0-t), and peak serum concentration of trastuzumab (Cmax) were within 80% to 125% for all three pairwise comparisons. Adverse events (AEs) were similar across all arms, with treatment-related AEs reported by 73.0%, 73.0%, and 89.2% of the subjects in the BP02, EU-trastuzumab, and US-trastuzumab groups, respectively. The most common AEs were headache, infusion-related reactions, and upper-respiratory-tract infections. Four subjects-three in the US-trastuzumab group and one in the BP02 group-discontinued the study due to AEs. All post-dose samples except for two tested negative for anti-drug antibodies.ConclusionThis study demonstrates the PK similarity among BP02, EU-trastuzumab, and US-trastuzumab. The safety and immunogenicity profiles observed for the three products in this study are consistent with previous reports for trastuzumab.Trial registrationANZCTR number: ACTRN12621000573853.

Dataset Information

Randomized double-blind clinical trial comparing safety and efficacy of the biosimilar BCD-022 with reference trastuzumab.

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Randomized double-blind clinical trial comparing safety and efficacy of the biosimilar BCD-022 with reference trastuzumab.

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