Study of the Efficacy and Safety of Empegfilgrastim for Neutropenia Prophylaxis in Breast Cancer Patients

Multicenter Randomized Double-blind Phase III Clinical Study Comparing the Efficacy and Safety of a Single Dose Extimia® Versus Daily Filgrastim for Neutropenia Prophylaxis in Breast Cancer Patients Receiving Myelosuppressive Chemotherapy

The purpose of the study is to compare safety and efficacy of a single dose of empegfilgrastim and daily dosing of filgrastim for prevention of neutropenia in patients receiving AT (docetaxel 75 mg/m2 + doxorubicin 50 mg/m2).

Study Overview

• Status: Completed
• Conditions: Chemotherapy-induced Neutropenia
• Intervention / Treatment: Biological: Empegfilrastim 6 mg; Biological: Placebo №2; Biological: Empegfilrastim 7.5 mg; Biological: Filgrastim; Biological: Placebo №1

Detailed Description

BCD-017-3 is an double-blind randomized phase III clinical study to compare the incidence of CTCAE grade 3/4 neutropenia after a single administration of recombinant human pegylated filgrastim empegfilgrastim (Extimia®) at a dose of 6 or 7.5 mg versus daily administration of filgrastim at a dose of 5 μg/kg/day for neutropenia prophylaxis in breast cancer patients receiving myelosuppressive chemotherapy.

The study also includes the following determination of pharmacokinetic parameters after repeated administration of the study drug.

• Study Type: Interventional
• Enrollment (Actual): 135
• Phase: Phase 3

Contacts and Locations

Study Locations

• Russian Federation
  • Arkhangelsk, Russian Federation, 163045
    • Arkhangelsk District Clinical Oncology Dispensary
  • Chelyabinsk, Russian Federation
    • Clinical Hospital at Chelyabinsk Railway Station
  • Kazan, Russian Federation
    • State public health institution "Republican Clinical Oncology Dispensary" of the Ministry of Health of the Republic of Tatarstan
  • Moscow, Russian Federation
    • State Health Care Institution "Moscow City Oncology Hospital № 62" Moscow Health Department
  • Moscow, Russian Federation
    • Non-governmental healthcare institution "Central Clinical Hospital № 2 Semashko" JSC "Russian Railways"
  • Nizhny Novgorod, Russian Federation
    • State public health institution "Nizhny Novgorod Regional Oncology Dispensary"
  • Perm, Russian Federation, 614066
    • Perm Region Oncology Dispensary
  • Pyatigorsk, Russian Federation, 357502
    • Pyatigorsk Oncology Center
  • Saransk, Russian Federation
    • Federal State Educational Institution of Higher Professional Education "Mordovia State University N.P. Ogareva "
  • St.Petersburg, Russian Federation, 197758
    • N.N.Petrov Oncology Research Center
  • Ulyanovsk, Russian Federation
    • State public health institution "Regional Clinical Oncology Dispensary"
  • Volgograd, Russian Federation, 404130
    • Volgograd Regional Oncology Dispensary №3
  • Volgograd, Russian Federation
    • State Health Care Institution "Volgograd Regional Clinical Oncology Dispensary № 1"

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

• Signed informed consent form;
• Histologically verified diagnosis of stage IIb/III/IV breast cancer;
• Age of 18-70 years inclusive;
• Life expectancy of at least 6 months after inclusion in the study;
• If the patient had received the chemotherapy for breast cancer, it should be finished 30 days before the beginning of the study;
• ECOG Performance Status of 0- 2, not increasing within during 2 weeks before randomization;
• ANC level of 1500/μL and more at the beginning of the study
• Platelet count of 100 000/μL and more at the beginning of the study
• Hemoglobin level of 90 g/l and more
• Creatinine level <1.5 mg/dl
• Total bilirubin level <1.5 × the upper limit of normal (ULN)
• ALT and/or AST levels <2.5×ULN (5×ULN for patients with liver metastases);
• Alkaline phosphatase <5×ULN;
• Left ventricular ejection fraction >50% and more;
• If the patient had received adjuvant and/or neoadjuvant therapy, the cumulative dose of anthracyclines should not exceed 250 mg/m2 for doxorubicin or 540 mg/m2 for epirubicin,if in this study planned 6 cycles of chemotherapy ;
• If the patient had received adjuvant and/or neoadjuvant therapy, the cumulative dose of anthracyclines should not exceed 350 mg/m2 for doxorubicin or 660 mg/m2 for epirubicin,if in this study planned 4 cycles of chemotherapy ;
• Ability of the participant to follow the protocol requirements, according to the Investigator's opinion;
• Patients of childbearing potential must implement reliable contraceptive measures during the study treatment, starting 4 weeks prior randomization and for 6 months after the last administration of the study drug;
• Patients should be able to follow the Protocol procedures (according to Investigator's assessment.

Exclusion Criteria:

• Patient has received two or more chemotherapy regimens for the metastatic breast cancer;
• Documented hypersensitivity to filgrastim, pegfilgrastim, docetaxel, doxorubicin, dexamethasone and/or its excipients, PEGylated drugs, recombinant proteins.
• Pregnancy or breastfeeding;
• Systemic antibiotic therapy within 72 h prior empegfilgrastim/filgrastim administration;
• Concomitant radiotherapy (except selective radiotherapy of bone metastases);
• Surgery, radiotherapy (except selective radiotherapy of bone metastases), administration of any experimental drugs within 30 days prior randomization;
• History of bone marrow/stem cell transplantation;
• Conditions limiting the patient's ability to follow the protocol;
• CTCAE grade 3-4 neuropathy;
• HIV, HCV, HBV, T.Pallidum infection(s);
• Acute or active chronic infections;
• Severe concurrent diseases (for example, severe arterial hypertension, severe heart failure, and other);
• Severe depression, schizophrenia, any other mental disorders;
• Obstacles in intravenous administration of study drugs;
• Simultaneous participation in other clinical trials, previous participation in other clinical trials within 30 days before entering into the trial, previous participation in the same trial.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Supportive Care
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Empegfilgrastim 6 mg; Patients will receive a single administration of empegfilgrastim at a dose of 6 mg subcutaneously, 24 h after the chemotherapy and placebo #2 in a dose of 0.0083 ml/kg in 24-27 hour after chemotherapy, then patient received placebo #2 in dose 0.0083 ml/kg until ANC ≥ 10x109/L or during 14 days	Biological: Empegfilrastim 6 mg; Empegfilgrastim is supplied as solution for injection 3 mg/ml. Empegfilgrastim is to be administered 24 h after the chemotherapy at dose of 6 mg.; Other Names: pegylated filgrastim; Extimia; metpegfilgrastim; peg-GCSF; Biological: Placebo №2; Placebo №2 should be administered no earlier than 24 hours after the administration of cytotoxic chemotherapy. Placebo №2 is supplied as solution for injection 0.0083 ml/kg.
Experimental: Empegfilgrastim 7.5 mg; Patients will receive a single administration of empegfilgrastim at a dose of 7.5 mg subcutaneously, 24 h after the chemotherapy and placebo #2 in a dose of 0.0083 ml/kg in 24-27 hour after chemotherapy, then patient received placebo #2 in dose 0.0083 ml/kg until ANC ≥ 10x109/L or during 14 days	Biological: Placebo №2; Placebo №2 should be administered no earlier than 24 hours after the administration of cytotoxic chemotherapy. Placebo №2 is supplied as solution for injection 0.0083 ml/kg.; Biological: Empegfilrastim 7.5 mg; Empegfilgrastim is supplied as solution for injection 3 mg/ml. Empegfilgrastim is to be administered 24 h after the chemotherapy at dose of 6 mg.; Other Names: pegylated filgrastim; Extimia; metpegfilgrastim; peg-GCSF
Active Comparator: Filgrastim; Patients will receive filgrastim at a dose of 5 μg/kg subcutaneously daily (until ANC 10 000/μL or for 14 days, whichever occurred first), starting 24 h after the chemotherapy and placebo #1 in dose 1.0 ml subcutaneously, 24 h after the chemotherapy.	Biological: Filgrastim; Filgrastim should be administered no earlier than 24 hours after the administration of cytotoxic chemotherapy. Filgrastim should be administered daily for up to 2 weeks until the ANC has reached 10 000/mm3 following the expected chemotherapy-induced neutrophil nadir.; Other Names: GCSF; Biological: Placebo №1; Placebo №1 is supplied as solution for injection 1.0 ml. Placebo №1 is to be administered 24 h after the chemotherapy at dose of 1.0.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Duration of Neutropenia CTCAE Grade 4	The primary endpoint, which will allow to compare the efficacy of the single dose of Extimia® versus nonpegylated daily filgrastim is the number of breast cancer patients developing CTCAE grade 3/4 neutropenia after the first AT chemotherapy cycle (doxorubicin+docetaxel).	3 weeks

Secondary Outcome Measures

Outcome Measure	Time Frame
The Duration of Grade 4 Neutropenia From the 2nd (Week 6) to 4th Cycle (Week 12);	2nd cycle (week 6), 3rd cycle (week 9), 4th cycle (week 12)
The Incidence of Severe Neutropenia (Grade 3-4)	16 weeks
Low Level (Nadir) ANC x 10^9/L	1st cycle (week 3), 2nd cycle (week 6), 3rd cycle (week 9), 4th cycle (week 12)
Neutropenia Duration, Any Grade	1st cycle (week 3), 2nd cycle (week 6), 3rd cycle (week 9), 4th cycle (week 12)
Duration From ANC Nadir to ANC < 2.0 x 10^9/L	1st cycle (week 3), 2nd cycle (week 6), 3rd cycle (week 9), 4th cycle (week 12)

Collaborators and Investigators

• Sponsor: Biocad
• Investigators: Study Director: Roman Ivanov, MD, PhD, Biocad; Principal Investigator: Larisa Bolotina, MD, PhD, Federal State Institution "Moscow Research Oncological Institute P.A.Gertsena "of the Ministry of Health of the Russian Federation; Principal Investigator: Olga Brichkova, MD, PhD, State public health institution "Regional Oncology Dispensary №1; Principal Investigator: Olga Burdaeva, MD, State Budget Institution of Health Arkhangelsk region "Arkhangelsk Clinical Oncology Dispensary"; Principal Investigator: Byakhov Michael, MD, PhD, Non-governmental healthcare institution "Central Clinical Hospital № 2 Semashko" JSC "Russian Railways"; Principal Investigator: Vladimir Vladimirov, MD, PhD, State Budget Institution of Health Stavropol area "Piatigorsky Oncology Dispensary"; Principal Investigator: Rinat Galiulin, MD, State budget healthcare institution Omsk region "Clinical Oncology Dispensary"; Principal Investigator: Oleg Gladkov, MD, PhD, State Budget Institution of Health "Chelyabinsk Regional Clinical Oncology Dispensary"; Principal Investigator: Irina Davydenko, PhD, State Budget Institution of Health "Clinical Oncology Dispensary № 1" of the Ministry of Health of the Krasnodar area; Principal Investigator: Victoria Elkova, MD, State public health institution "Voronezh Regional Clinical Oncology Dispensary"; Principal Investigator: Igor Lifirenko, MD, State public health institution "Kursk Regional Oncology Dispensary"; Principal Investigator: Nadezhda Kovalenko, PhD, State Budget Institution of Health "Volgograd regional oncologic dispensary № 3"; Principal Investigator: Michael Kopp, MD, PhD, State Budget Institution of Health "Samara Regional Clinical Oncology Dispensary"; Principal Investigator: Bogdan Kotiv, MD, PhD, S. M. Kirov Military Medical Academy of the Ministry of Defense of the Russian Federation; Principal Investigator: Natalia Levchenko, PhD, State Budget Institution of Health Stavropol area "Stavropol Regional Clinical Oncology Dispensary"; Principal Investigator: Marina Matrosova, MD, State public health institution "Nizhny Novgorod Regional Oncology Dispensary"; Principal Investigator: Guzel Mukhametshina, MD, State public health institution "Republican Clinical Oncology Dispensary" of the Ministry of Health of the Republic of Tatarstan; Principal Investigator: Sergei Panchenko, PhD, State public health institution "Regional Clinical Oncology Dispensary"; Principal Investigator: Alexander Pecheny, PhD, Regional State Health Care Institution "Orlovsky Oncology Dispensary"; Principal Investigator: Igor Pimenov, PhD, State Budget Institution health care "Tula Regional Oncology Dispensary"; Principal Investigator: Andrei Sinykov, PhD, State Health Care Institution of Tyumen Region "Regional Oncological Dispensary"; Principal Investigator: Pavel Skopin, PhD, Federal State Educational Institution of Higher Professional Education "Mordovia State University N.P. Ogareva "; Principal Investigator: Daniil Stroyakovsky, State Health Care Institution "Moscow City Oncology Hospital № 62" Moscow Health Department; Principal Investigator: Sergei Tyulyandin, MD, PhD, "Russian Oncological Scientific Center N.N.Blokhin" Russian Academy of Sciences; Principal Investigator: Dmitriy Udovica, MD, State Health Care Institution "Oncologic Dispensary № 2" Health Department of Krasnodar Area; Principal Investigator: Andrei Horinko, MD, State Health Care Institution "Perm Regional Oncology Dispensary"; Principal Investigator: Petr Krivorotko, MD, N.N. Petrov Oncology Research Center of the Ministry of Health of the Russian Federation; Principal Investigator: Yulia Shapovalova, PhD, Non-governmental healthcare institution "Chelyabinsk Road Clinical Hospital" JSC "Russian Railways"; Principal Investigator: Ludmila Sheveleva, MD, State Health Care Institution "Volgograd Regional Clinical Oncology Dispensary № 1"; Principal Investigator: Vadim Shirinkin, MD, State Health Care Institution "Orenburg Regional Clinical Oncology Dispensary"; Principal Investigator: Shekar Patil, MD, Bangalore Institute of Oncology; Principal Investigator: Prasad Narayanan, MD, Mazumdar Shaw Cancer Center and Narayana Hrudayalaya Multispecialty Hosptial; Principal Investigator: Nalini Kilara, MD, M.S.Ramaiah Memorial Hospital; Principal Investigator: Sergei Kulik, MD, Donetsk City Municipal Oncology Dispensary; Principal Investigator: Igor Sedakov, MD, PhD, Donetsk Regional oncology centers; Principal Investigator: Andrei Rusin, MD,PhD, Zakarpatskii Regional Clinical Oncology Dispensary; Principal Investigator: Yuri Vinnik, MD, PhD, Kharkiv Regional Clinical Oncology Center; Principal Investigator: Sergei Odarchenko, PhD, Vinnitskii Regional Oncology Dispensary

Publications and helpful links

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start: September 1, 2013
• Primary Completion (Actual): June 1, 2014
• Study Completion (Actual): October 1, 2014

Study Registration Dates

• First Submitted: April 2, 2014
• First Submitted That Met QC Criteria: April 3, 2014
• First Posted (Estimate): April 4, 2014

Study Record Updates

• Last Update Posted (Estimate): October 24, 2016
• Last Update Submitted That Met QC Criteria: August 31, 2016
• Last Verified: August 1, 2016

More Information

Terms related to this study

• Keywords: breast cancer; neutropenia; febrile neutropenia; docetaxel; doxorubicin; empegfilgrastim; pegylated filgrastim; chemotherapy-associated neutropenia
• Additional Relevant MeSH Terms: Hematologic Diseases; Agranulocytosis; Leukopenia; Leukocyte Disorders; Neutropenia; Physiological Effects of Drugs; Immunologic Factors; Adjuvants, Immunologic; Lenograstim
• Other Study ID Numbers: BCD-017-3