IMPORTANCEThe drug HD201 is a biosimilar candidate for breast cancer treatment as the reference trastuzumab.OBJECTIVE To compare the efficacy of HD201 with referent trastuzumab.DESIGN, SETTING, AND PARTICIPANTS This randomized clinical trial (TROIKA) included 502 women with ERBB2-positive early breast cancer treated with either HD201 or referent trastuzumab. It was conducted across 70 centers in 12 countries, including Western and Eastern Europe and Asian countries. Randomization was stratified by tumor hormone receptor status, clinical stage, and geographic region of recruitment. This analysis was conducted on February 12, 2021, after the completion of the adjuvant phase at a median of 31 months (IQR, 28-33 months) of follow-up.INTERVENTIONS Patients with ERBB2-positive early breast cancer were randomly assigned to receive HD201 or referent trastuzumab in the neoadjuvant setting for 8 cycles, concurrently with 4 cycles of docetaxel, which was followed by 4 cycles of epirubicin and cyclophosphamide. Patients then underwent surgery, which was followed by treatment with 10 cycles of adjuvant HD201 or referent trastuzumab. MAIN OUTCOME AND MEASURESThe primary end point was the total pathological complete response (tpCR) assessed after neoadjuvant treatment. Equivalence was concluded if the 95% CI of the absolute difference in tpCR between arms in the per-protocol set was within the margin of more or less than 15%. Other objectives included the breast pathological complete response, overall response, event-free and overall survival, safety, pharmacokinetics, and immunogenicity.RESULTS A total of 502 female patients (mean [range] age, 53 [26-82] years) were randomized to receive either HD201 or referent trastuzumab, and 474 (94.2%) were eligible for inclusion in the per-protocol set. The baseline characteristics were well balanced between the 2 arms; 195 tumors (38.8%) were hormone receptor-negative , and 213 patients (42.4%) had clinical stage III disease. The tpCR rates were 45% and 48.7% for HD201 and referent trastuzumab, respectively. The difference between the 2 groups was not significant at −3.8% (95% CI, −12.8% to 5.4%) and fell within the predefined equivalence margins. The ratio of the tpCR rates between the 2 arms was 0.92 (95% CI, 0.76 to 1.12). A total of 433 patients (86.1%) presented with 2232 treatment-emergent adverse events of special interest for trastuzumab during the entire treatment period, with 220 (88.0%) and 213 (84.5%) patients in the HD201 and referent trastuzumab groups, respectively. CONCLUSIONS AND RELEVANCEThe results of this randomized clinical trial found that HD201 demonstrated equivalence to referent trastuzumab in terms of efficacy for the end point of tpCR, with a similar safety profile.
579 Background: Trastuzumab, an approved prescription drug by EMA and FDA under the name Herceptin has become the key treatment in patients with HER2−positive breast cancer. HD201, developed by Prestige Biopharma Pte Ltd is a biosimilar candidate to Herceptin. The biosimilarity of HD201 was established based on systematic stepwise comparisons between HD201 and reference product, Herceptin. In order to confirm clinical similarity of HD201 to Trastuzumab, two clinical studies were undertaken. Methods: First, in a double-blind, randomised and parallel group study, 101 randomised healthy human subjects were subjected to a single 6 mg/kg IV dose by body weight over 90-min infusion of either HD201, EU- and US-Herceptin group by assessing pharmacokinetic (PK) and safety (TROIKA-I). The second study was a randomised, double-blind, parallel group, equivalence, multicentre clinical phase III trial (TROIKA) designed to compare the efficacy based on total pathological complete response rate (tpCR), safety, and pharmacokinetics of HD201 to EU-Herceptin in patients with HER2 positive early breast cancer. Each group of ~250 subjects were administered with either HD201 or EU-Herceptin in combination with chemotherapy in neoadjuvant followed by the antibody alone in the adjuvant phase. Results: TROIKA-I study demonstrated that HD201 was safe and well tolerated with comparable PK as EU- and US-Herceptin. Based on the neoadjuvant data from TROIKA study, the tpCR rate in the HD201 and Herceptin treatment groups was comparable and the 95% CI was included within the pre-defined margins of equivalence (Table). The incidence and severity of reported TEAEs did not imply any significant safety concerns and were comparable between both groups. In addition, the comparison of steady-state Ctrough between both arms in TROIKA study has established equivalence. Conclusions: The overall comparison exercise demonstrated the equivalence of HD201 to Herceptin. Clinical trial information: 2016-0040019-11 . [Table: see text]
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Purpose This first-in-human study was designed to evaluate the pharmacokinetic (PK) equivalence between HD204 and the European Union (EU)-sourced bevacizumab, between HD204 and the United States of America (US)-sourced bevacizumab, and between EU-sourced and US-sourced bevacizumab (NCT 03390673). Methods In this randomized, double-blind, 3-way parallel group, single-dose comparative PK study, healthy male subjects were randomized to receive a single 1 mg/kg intravenous dose of HD204, EU-sourced bevacizumab or US-sourced bevacizumab. PK parameters were calculated using non-compartmental methods. PK equivalence was determined using the pre-defined equivalence margin of 0.8–1.25 in terms of AUC(0-∞) for the pairwise comparisons. Findings Baseline demographics for the 119 randomized subjects were similar across the three groups. The 90% CIs for the ratio of the geometric means of HD204 to US-sourced bevacizumab, HD204 to EU-sourced bevacizumab, and EU-sourced to US-sourced bevacizumab were all within the interval of 80% to 125% for AUC0-inf, thus demonstrating equivalency in the PK properties for all three treatment groups. Similarly, the ratio of the geometric means for AUC0-last and Cmax were all within the 80% and 125% margins, supporting the robustness of the primary findings. All other PK parameters, including the half-life (t1⁄2) clearance (CL), volume of distribution (Vd) and time of maximum concentration (tmax), were comparable. There was no difference between the 3 treatment arms in terms of vital signs, laboratory tests and adverse events. None of the subjects treated with HD204 had positive ADA results. Implications HD204 demonstrates equivalent pharmacokinetic profiles compared to those of both US-sourced and EU-sourced bevacizumab. (NCT 03390673).
e15014 Background: Prestige Biopharma Pte Ltd is developing HD204, a biosimilar of the EU-approved and US-licensed Bevacizumab (Avastin) that is approved treatment for a variety of tumour types. Bevacizumab is a recombinant humanized monoclonal antibody (IgG1) that binds to soluble vascular endothelial growth factor (VEGF), thus prevent interaction with VEGF receptors. Due to heterogeneity nature of antibody drug, extensive characterization of antibody from physicochemical and biological properties using multiple bioanalytical assays is required. The development of HD204 from analytical biocomparability to clinical trial I are demonstrated. Methods: Analytical biocomparability in physiocochemical and biological properties of HD204 was compared to Avastin sourced from EU and US using multiple bioanalytical assays as below. Clinical phase I (SAMSON), a randomized, double-blind, single dose and 3-way parallel group was initiated recently to compare pharmacokinetic and to evaluate the safety, tolerability and immunogenicity of HD204, EU-Avastin and US-Avastin. Approximately 120 healthy human subjects (assigned to 3 treatment group) was administered with a single intravenous infusion of 1 mg/kg of either HD204, EU- and US-Avastin. Results: HD204 shows equivalent in physicochemical and biological properties compared to EU- and US-Herceptin. For phase I study, patient recruitment was completed with treatment for come patients initiated but still ongoing. Conclusions: HD204 was shown to be equivalent in all parameters in the analytical biocomparability testing. Clinical Phase 1 trial (SAMSON) is ongoing on and key data from SAMSON trial will be reported in ASCO meeting. [Table: see text]
e12505 Background: Trastuzumab, an approved prescription drug by EMA and FDA under the name Herceptin has become the key treatment in patients with HER2 positive breast cancer. HD201, developed and owned by Prestige Biopharma Pte Ltd is a biosimilar product to Herceptin (Trastuzumab). The development of HD201 from analytical biocomparability to clinical trial progression are demonstrated. Methods: Analytical biocomparability in terms of physicochemical (primary, higher order structure, glycan profiles, molecular and charge variants) and biological properties (inclusive of binding to Fcγ receptors and neonatal receptor) between HD201 and EU and US-Herceptin were compared. The first human study of HD201 (clinical phase I) was designed to assess the pharmacokinetic (PK) equivalence between HD201 and EU-Herceptin. In this randomised, blinded, single-dose comparative PK study, randomised healthy human subjects were subjected to a single 6 mg/kg IV dose of HD201 and EU-Herceptin following by PK and safety evaluations. Following this, a randomised, double-blind, parallel group, equivalence, multicentre clinical phase III trial (TROIKA) was designed to compare the efficacy, safety, and pharmacokinetics of HD201 to EU-Herceptin in 500 patients with HER2+ early breast cancer. Each group of patients (250 patients) were administered with either HD201 or EU-Herceptin once every 3 weeks up to 8 cycles in combination of a neoadjuvant chemotherapy comprising of docetazel followed by an anthracycline-containing regimen. Results: HD201 shows equivalent in physicochemical and biological properties compared to EU- and US-Herceptin. Clinical phase I study demonstrated that HD201 is safe and well tolerated with comparable PK profiles as EU-Herceptin after single dose administration to healthy male adults (Pivot et al., 2018). Analysis of sub study from clinical phase III has demonstrated comparable results with EU- Herceptin in terms of patient demographic, clinical response, safety and pharmacokinetic profile. Conclusions: HD201 is demonstrated to be equivalent in analytical biocomparability and in clinical response, safety and PK profile to Herceptin in human study. Additional data for Pharmacokinetic from Troika trial will be reported in Asco meeting. Clinical trial information: 2012-000805-56.
Background: Biomarkers in clinical trials as well as the need for correlative studies have led to the massive incorporation of research biopsies and archival tissue collection, with potentially risks and no direct benefit for patients. In 2019, ASCO has released an ethical framework (Levit LA et al. JCO 2019) to provide guidance on incorporating research biopsies in clinical trials. abstracts Annals of OncologyVolume 31 -Issue S4 -2020 S497
e21556 Background: Prestige Biopharma Pte Ltd is developing HD204, a biosimilar candidate of Bevacizumab (Avastin). Bevacizumab has been approved in the treatment of a variety of metastatic tumours. Bevacizumab, a recombinant humanized monoclonal antibody block angiogenesis which is required for cancer progression by preventing binding of soluble vascular endothelial growth factor (VEGF) to VEGF receptors. Due to heterogeneity nature of antibody therapeutic, the impact on quality of HD204 on safety and pharmacokinetic (PK) was reaffirmed through clinical study to establish clinical similarity between HD204 and Avastin. Methods: Quality attributes identified to influence PK and safety established through comprehensive analytical characterization was used to correlate any potential differences (structural or biological) between the two compounds if any, could result in any clinical meaningful differences in safety and PK in the clinical settings. The PK and safety equivalence of HD204 relative to Avastin was demonstrated in a randomized, single-blind, single-dose, three-arm and parallel-group study clinical Phase I (SAMSON). A total of 120 healthy male subjects randomized 1:1:1 were to receive 1 mg/kg intravenous infusion of either HD204, EU- or US-Avastin. Various PK parameters, safety assessments not limiting to adverse events (AE) and measurement of antidrug antibodies (ADA) and neutralizing antibodies (NAb) were evaluated. Results: The pairwise comparisons of Exposure (AUC0-inf and AUC0-last), maximal concentration (Cmax) established equivalence between the 3 arms. All other PK parameters including half-life, clearance and volume of distribution were comparable between HD204 and Avastin treatment groups. Treatment related TEAEs reported for each group were 25.0%, 30.0% and 25.6% respectively and comparable. There were no treatment-emergent SAEs. Furthermore, none of the subjects treated with HD204 was ADA positive. Conclusions: HD204 demonstrated equivalent PK and safety profile to both US-Avastin and EU-Avastin at 1mg/kg administered as a 90-minute IV infusion to healthy male subjects. A prospective clinical study aimed to demonstrate equivalence in terms of efficacy, PK and safety is currently ongoing. Clinical trial information: 2017-005174-19.
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