Demonstration of Clinical Comparability of the Biosimilar Filgrastim to Neupogen, in Terms of Safety and Efficacy, in Healthy Volunteers and Patients Receiving Myelosuppressive Chemotherapy

2014 ◽  
Vol 10 (02) ◽  
pp. 107 ◽  
Author(s):  
Bernd Jilma ◽  
Agnieszka Jagiełło-Gruszfeld ◽  
Piotr Tomczak ◽  
Himanshu Gadgil ◽  
Grzegorz Orlik ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Phase I ◽  
Healthy Volunteers ◽  
Reference Product ◽  
Phase Iii ◽  
Published Data ◽  
Efficacy And Safety ◽  
Phase I Studies ◽  
Safety And Efficacy ◽  
Phase Iii Study

Aim: To demonstrate biosimilarity as evidenced by the pharmacokinetic (PK), pharmacodynamics (PD), efficacy and safety comparability of AccofilR/GrastofilR (filgrastim), a recombinant human granulocyte colony-stimulating factor, and the reference product, NeupogenR. Patients and methods: Four phase I studies were conducted to demonstrate the comparative efficacy of Accofil/Grastofil and Neupogen. PD and PK parameters of Accofil/Grastofil (filgrastim) at and around the main clinical dose (5 μg/kg), using both the intravenous (IV) and subcutaneous (SC) routes of administration, were compared with Neupogen (EU) in healthy volunteers in three phase I clinical studies in a single-dose setting and following multiple-dose administration. An additional phase I PK/PD study was performed to compare Accofil/ Grastofil (filgrastim) to both EU-approved Neupogen and US-licensed Neupogen following the administration of a fixed SC dose of 300 μg. The efficacy and safety of Accofil/Grastofil was also evaluated in chemotherapy-naive women with stage IIA, IIB and IIIA breast cancer receiving docetaxel, doxorubicin, cyclophosphamide (TAC) chemotherapy. No comparator arm was included in this study so the efficacy and safety comparison was made with published data for the reference product, Neupogen. Results: A total of 235 healthy subjects were enrolled in the phase I studies and 120 patients in the phase III study. The PK and PD data demonstrated high comparability of the Accofil/ Grastofil and Neupogen products, with the 90 % confidence interval (CI) for primary PK parameters and 95 % CI for primary PD parameters falling within the pre-defined equivalence limits. In the phase III study, Accofil/Grastofil (filgrastim) demonstrated a safety and efficacy profile that was similar to the published data for the reference product Neupogen for the reduction of the duration of neutropenia in patients with breast cancer who were undergoing chemotherapy. Conclusion: Lack of clinically meaningful differences was convincingly demonstrated between Accofil/Grastofil (filgrastim) and the reference product, Neupogen.

AMEERA-5: A randomized, double-blind phase III study of amcenestrant (SAR439859) + palbociclib versus letrozole + palbociclib for previously untreated ER+/HER2- advanced breast cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS1104-TPS1104
Author(s):  
Aditya Bardia ◽  
Javier Cortes ◽  
Sara A. Hurvitz ◽  
Suzette Delaloge ◽  
Hiroji Iwata ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Phase I ◽  
Advanced Breast Cancer ◽  
Progression Free Survival ◽  
Advanced Breast ◽  
Phase Iii ◽  
Double Blind ◽  
Free Survival ◽  
Phase Iii Study

TPS1104 Background: Selective estrogen receptor degraders (SERDs) block estrogen receptor (ER) associated signaling and have created interest for treating patients (pts) with advanced ER+ breast cancer (BC). Fulvestrant is currently the only SERD available for advanced BC but requires intramuscular administration, limiting the applied dose, exposure and receptor engagement. Amcenestrant (SAR439859) is an oral SERD that binds with high affinity to both wild-type and mutant ER, blocking estradiol binding and promoting up to 98% ER degradation in preclinical studies. In the phase I AMEERA-1 study of pretreated pts with ER+/HER2- advanced BC, amcenestrant 150–600 mg once daily (QD) showed a mean ER occupancy of 94% with plasma concentrations > 100 ng/mL and a favorable safety profile (Bardia, 2019; data on file). Combination therapy with amcenestrant + palbociclib (palbo) was also evaluated as part of this ongoing phase I study. CDK 4/6 inhibitors (CDK4/6i) combined with an aromatase inhibitor (AI), the gold standard for first line treatment for advanced breast cancer, prolong progression free survival (PFS) in pts with no prior treatment for ER+/HER2- advanced BC, but OS benefit has not been shown yet in postmenopausal pts. There remains a clinical need for more effective treatments in this setting. Methods: AMEERA-5 (NCT04478266) is an ongoing, prospective, randomized, double-blind phase III study comparing the efficacy and safety of amcenestrant + palbo with that of letrozole + palbo in pts with advanced, locoregional recurrent or metastatic ER+/HER2- BC who have not received prior systemic therapy for advanced disease. The study includes men, pre/peri-menopausal (with goserelin) and post-menopausal women. Pts with progression during or within 12 months of (neo)adjuvant endocrine therapy using any of the following agents are excluded: AI, selective estrogen receptor modulators, CDK4/6i. Pts are randomized 1:1 to either continuous amcenestrant 200 mg or letrozole 2.5 mg QD orally with matching placebos; both combined with palbo 125 mg QD orally (d1–21 every 28-d cycle). Randomization is stratified according to disease type (de novo metastatic vs recurrent disease), the presence of visceral metastasis, and menopausal status. The primary endpoint is investigator assessed progression free survival (PFS) (RECIST v1.1). Secondary endpoints are overall survival, PFS2, objective response rate, duration of response, clinical benefit rate, pharmacokinetics of amcenestrant and palbo, health-related quality of life, time to chemotherapy, and safety. Biomarkers will be measured in paired tumor biopsies and cell free deoxyribonucleic acid (cfDNA) over time. Target enrolment = 1066 pts; enrolment as of 1/2021 = 33 pts. Bardia A, et al., J Clin Oncol. 2019; 37 (15 suppl):1054 Clinical trial information: NCT04478266 .

Efficacy and safety of BCD-017, a novel pegylated filgrastim: Results of open-label controlled phase II study in patients with breast cancer receiving myelosuppressive chemotherapy.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e20593-e20593 ◽  
Author(s):  
Olga V. Salafet ◽  
Tatiana V. Chernovskaya ◽  
Ludmila P. Sheveleva ◽  
Andrey V. Khorinko ◽  
Tatiana I. Prokopenko ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Phase Iii ◽  
Severe Neutropenia ◽  
Comparable Efficacy ◽  
Efficacy And Safety ◽  
Open Label ◽  
Group A ◽  
Phase Iii Study ◽  
Study Support ◽  
To Receive

e20593 Background: Pegfilgrastim (conjugate of filgrastim and 20 kDa polyethylene glycol (PEG) is approved for treatment of chemotherapy-associated neutropenia. BCD-017 (empegfilgrastim) is a covalent conjugate of filgrastim with 30 kDa PEG. Increased molecular weight of PEG molecule may provide additional benefits compared to pegfilgrastim. Methods: To compare efficacy and safety of filgrastim and BCD-017 at 3 mg and 6 mg doses an open-label, randomized, active-comparator, non-inferiority trial was conducted. 60 patients with histologically or cytologically confirmed breast cancer were randomly assigned to receive either subcutaneous (s.c.) injection of 3 mg BCD-017 (n=21), 6 mg BCD-017 (n = 20), or 5 mg/kg s.c. injections of filgrastim (n=19) administered daily until ANC ≥ 10x109 cells/L (maximum of 14 days) after chemotherapy (doxorubicin 60 mg/m2 and docetaxel 75 mg/m2) with stratification for weight and prior chemotherapy exposure. The primary efficacy endpoint was the incidence of severe neutropenia (ANC < 1.0x109 cells/L) during the first cycle of chemotherapy. Results: Incidence of severe neutropenia during the first chemotherapy cycle was 85,7%, 65,0% and 61,1% in BCD-017 3 mg, BCD-017 6 mg and filgrastim groups, respectively. Differences between BCD-017 groups and filgrastim group were not significant. Mean duration of grade 4 neutropenia in cycle 1 was 0,43, 0,40 and 0,33 days, accordingly (95% CI for difference between BCD-017 3 mg and filgrastim groups -0.22 to 0.41; 95% CI for difference between BCD-017 6 mg and filgrastim groups -0.25 to 0.38). Febrile neutropenia was observed only in BCD-017 3 mg and BCD-017 6 mg groups (one case in each group). A single administration of BCD-017 at the doses of 3 mg and 6 mg was as safe and well tolerated as standard daily filgrastim administration. There were no unexpected adverse events in all groups. Conclusions: The results of this study support comparable efficacy of single s.c. injection of 6 mg BCD-017 versus daily 5 mg/kg s.c. injections of filgrastim. Further phase III study of BCD-017 for treatment and prophylaxis of neutropenia in patients receiving chemotherapy is necessary. Clinical trial information: NCT01569087.

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