Study to Compare the Efficacy and Safety of F-627 and GRAN®

Phase 3

Completed

Conditions: Breast Cancer
Neutropenia

Interventions: Biological: F-627
Drug: GRAN®

Registration Number: NCT04174599

Lead Sponsor: EVIVE Biotechnology

Brief Summary: A Phase III, Multi-Center, Randomized, Open-Label, Active-Controlled Trial to Compare the Efficacy and Safety of Recombinant Human Granulocyte Colony Stimulating Factor-Fc Fusion Protein (F-627) and Recombinant Human Granulocyte Colony Stimulating Factor (GRAN®) in the Prophylactic Treatment for Chemotherapy-Induced Neutropenia

Detailed Description: Study Stage: Phase III

Study Population: Female patients with breast cancer will be enrolled to receive at least 4 cycles of Epirubicin + Cyclophosphamide (EC) chemotherapy, that is: epirubicin 100 mg/m\^2 and cyclophosphamide 600 mg/m\^2.

Study Design: A multi-center, randomized, open-label, active-controlled phase III clinical trial

Recruitment & Eligibility

Status: COMPLETED

Sex: Female

Target Recruitment: 242

Inclusion Criteria

Willing to sign the informed consent form and able to comply with protocol requirements;
18-75 years old;
Female postoperative patients with breast cancer who require adjuvant chemotherapy, and are planned to receive at least 4 cycles of EC chemotherapy, namely epirubicin 100 mg/m^2 + cyclophosphamide 600 mg/m^2;
Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2;
Absolute neutrophil count (ANC) ≥ 2.0 × 10^9/L, hemoglobin (Hb) ≥ 11.0 g/dL, and platelet (PLT) ≥ 100 × 10^9/L prior to enrollment;
Hepatic and renal functions: Total bilirubin ≤ 1.5 × upper limit of normal (ULN), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × ULN, serum creatinine ≤ 1.5 × ULN;
Left ventricular ejection fraction > 50%;
Women without child-bearing potential, i.e., women who have had menopause for at least 1 year or who have undergone sterilization (bilateral tubal ligation, double oophorectomy or hysterectomy); patients with child-bearing potential should agree to take appropriate contraceptive measures, including condoms, spermicidal condoms, foams, gels, contraceptive barrier, intrauterine devices (IUD), and contraceptives (oral or injection), starting from 1 month before the start of the study until 30 days after the end of the study.

Exclusion Criteria

Radiation therapy within 4 weeks prior to enrollment;
Patients with breast cancer who have received neoadjuvant chemotherapy before surgery;
Prior bone marrow or stem cell transplant;
With other malignant tumors other than breast cancer;
Patients who have received a treatment with recombinant human granulocyte colony stimulating factor within 6 weeks prior to randomization;
Diagnosed with acute congestive heart failure, cardiomyopathy, or myocardial infarction by clinical diagnosis, ECG or other approaches;
With any disease that may cause splenomegaly;
With acute infection, chronic active Hepatitis B within 1 year (unless patients tested negative for HBsAg prior to enrollment), or Hepatitis C;
Women in pregnancy or breastfeeding;
Known HIV positive or AIDS;
With active tuberculosis (TB); history of TB exposure, unless negative for tuberculin test; TB patients undergoing treatment; or suspected TB evaluated by chest x-ray;
With sickle cell anemia;
With alcohol or drug abuse that may affect the compliance with the study;
With known hypersensitivity to granulocyte colony stimulating factor or excipients;
Have received any other investigational drug within 1 month or 5 half-lives of the investigational drugs prior to enrollment (whichever is longer);
Patients with diseases or symptoms unsuitable for participating in the trial. For example, the study drugs may compromise the health of the patient or the assessment of adverse events may be affected.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
F-627	F-627	Subjects will receive F-627 (20 mg/dose, s.c.) on day 3 of each cycle, i.e., 48 ±4 h after the start of chemotherapy.
GRAN®	F-627	Subjects will receive GRAN® \[5 μg/kg/day, s.c., once daily (± 4 h) up to 2 weeks or until neutrophil count returns to 5.0 ×109/L\] on day 3 of each cycle, i.e., 48 ±4 h after the start of chemotherapy.
F-627	F-627	F-627 (20 mg/dose, s.c.) on day 3 of each cycle, i.e., 48 ± 4 h after the start of chemotherapy
GRAN®	GRAN®	GRAN® \[5 μg/kg/day, s.c., once daily (± 4 h) up to 2 weeks or until neutrophil count returns to 5.0 × 10\^9/L\] on day 3 of each cycle, i.e., 48 ± 4 h after the start of chemotherapy

Primary Outcome Measures

Name	Time	Method
Duration of Grade 3 or 4 Neutropenia (ANC <1.0×10^9/L) in Cycle 1	Cycle 1, the first of 4, 21-day chemotherapy cycles (average 3 weeks)	Grade 3 defined as ANC \<1.0×10\^9/L and Grade 4 defined as ANC\<0.5×10\^9/L. According to the study protocol, the outcome measure "Duration of Grade 3 or 4 Neutropenia (days)" applied to all participants with a valid ANC level, rather than those with an ANC level of \< 1.0 × 109/L. The value of 0 represents the participant experienced 0 days with Grade 3 or 4 Neutropenia (days). Whereas exclusion of a participant from the analysis indicates a lack of ANC data of the participant. The mean value was calculated as the sum of the durations (days) of ANC \< 1.0 × 109/L for all participants with valid ANC level (the numerator) divided by the number of participants (the denominator).

Secondary Outcome Measures

Name	Time	Method
Number of Participants With Grade 3 or 4 Neutropenia in Cycle 1	Cycle 1, the first of 4, 21-day chemotherapy cycles (average 3 weeks)	Grade 3 defined as ANC \<1.0×10\^9/L and Grade 4 defined as ANC\<0.5×10\^9/L
Number of Participants With Grade 3 or 4 Neutropenia in Cycle 2	Cycle 2, the second of 4, 21-day chemotherapy cycles (average 3 weeks)	Grade 3 defined as ANC \<1.0×10\^9/L and Grade 4 defined as ANC\<0.5×10\^9/L
Number of Participants With Grade 3 or 4 Neutropenia in Cycle 3	Cycle 3, the third of 4, 21-day chemotherapy cycles (average 3 weeks)	Grade 3 defined as ANC \<1.0×10\^9/L and Grade 4 defined as ANC\<0.5×10\^9/L
Number of Participants With Grade 3 or 4 Neutropenia in Cycle 4	Cycle 4, the last of 4, 21-day chemotherapy cycles (average 3 weeks)	Grade 3 defined as ANC \<1.0×10\^9/L and Grade 4 defined as ANC\<0.5×10\^9/L
Duration of Grade 3 or 4 Neutropenia in Cycle 2	Cycle 2, the second of 4, 21-day chemotherapy cycles (average 3 weeks)	Grade 3 defined as ANC \<1.0×10\^9/L and Grade 4 defined as ANC\<0.5×10\^9/L. According to the study protocol, the outcome measure "Duration of Grade 3 or 4 Neutropenia (days)" applied to all participants with a valid ANC level, rather than those with an ANC level of \< 1.0 × 109/L. The value of 0 represents the participant experienced 0 days with Grade 3 or 4 Neutropenia (days). Whereas exclusion of a participant from the analysis indicates a lack of ANC data of the participant. The mean value was calculated as the sum of the durations (days) of ANC \< 1.0 × 109/L for all participants with valid ANC level (the numerator) divided by the number of participants (the denominator).
Duration of Grade 3 or 4 Neutropenia in Cycle 3	Cycle 3, the third of 4, 21-day chemotherapy cycles (average 3 weeks)	Grade 3 defined as ANC \<1.0×10\^9/L and Grade 4 defined as ANC\<0.5×10\^9/L. According to the study protocol, the outcome measure "Duration of Grade 3 or 4 Neutropenia (days)" applied to all participants with a valid ANC level, rather than those with an ANC level of \< 1.0 × 109/L. The value of 0 represents the participant experienced 0 days with Grade 3 or 4 Neutropenia (days). Whereas exclusion of a participant from the analysis indicates a lack of ANC data of the participant. The mean value was calculated as the sum of the durations (days) of ANC \< 1.0 × 109/L for all participants with valid ANC level (the numerator) divided by the number of participants (the denominator).
Duration of Grade 3 or 4 Neutropenia in Cycle 4	Cycle 4, the last of 4, 21-day chemotherapy cycles (average 3 weeks)	Grade 3 defined as ANC \<1.0×10\^9/L and Grade 4 defined as ANC\<0.5×10\^9/L. According to the study protocol, the outcome measure "Duration of Grade 3 or 4 Neutropenia (days)" applied to all participants with a valid ANC level, rather than those with an ANC level of \< 1.0 × 109/L. The value of 0 represents the participant experienced 0 days with Grade 3 or 4 Neutropenia (days). Whereas exclusion of a participant from the analysis indicates a lack of ANC data of the participant. The mean value was calculated as the sum of the durations (days) of ANC \< 1.0 × 109/L for all participants with valid ANC level (the numerator) divided by the number of participants (the denominator).
Number of Participants With Grade 4 Neutropenia in Cycle 1	Cycle 1, the first of 4, 21-day chemotherapy cycles (average 3 weeks)	Grade 4 neutropenia is defined as ANC \< 0.5 × 10\^9/L.
Number of Participants With Grade 4 Neutropenia in Cycle 2	Cycle 2, the second of 4, 21-day chemotherapy cycles (average 3 weeks)	Grade 4 neutropenia is defined as ANC \< 0.5 × 10\^9/L.
Number of Participants With Grade 4 Neutropenia in Cycle 3	Cycle 3, the third of 4, 21-day chemotherapy cycles (average 3 weeks)	Grade 4 neutropenia is defined as ANC \< 0.5 × 10\^9/L.
Number of Participants With Grade 4 Neutropenia in Cycle 4	Cycle 4, the last of 4, 21-day chemotherapy cycles (average 3 weeks)	Grade 4 neutropenia is defined as ANC \< 0.5 × 10\^9/L.
Duration of Grade 4 Neutropenia in Cycle 1	Cycle 1, the first of 4, 21-day chemotherapy cycles (average 3 weeks)	Grade 4 neutropenia is defined as ANC \< 0.5 × 10\^9/L. According to the study protocol, the outcome measure "Duration of Grade 3 or 4 Neutropenia (days)" applied to all participants with a valid ANC level, rather than those with an ANC level of \< 1.0 × 109/L. The value of 0 represents the participant experienced 0 days with Grade 3 or 4 Neutropenia (days). Whereas exclusion of a participant from the analysis indicates a lack of ANC data of the participant. The mean value was calculated as the sum of the durations (days) of ANC \< 1.0 × 109/L for all participants with valid ANC level (the numerator) divided by the number of participants (the denominator).
Duration of Grade 4 Neutropenia in Cycle 2	Cycle 2, the second of 4, 21-day chemotherapy cycles (average 3 weeks)	Grade 4 neutropenia is defined as ANC \< 0.5 × 10\^9/L. According to the study protocol, the outcome measure "Duration of Grade 3 or 4 Neutropenia (days)" applied to all participants with a valid ANC level, rather than those with an ANC level of \< 1.0 × 109/L. The value of 0 represents the participant experienced 0 days with Grade 3 or 4 Neutropenia (days). Whereas exclusion of a participant from the analysis indicates a lack of ANC data of the participant. The mean value was calculated as the sum of the durations (days) of ANC \< 1.0 × 109/L for all participants with valid ANC level (the numerator) divided by the number of participants (the denominator).
Duration of Grade 4 Neutropenia in Cycle 3	Cycle 3, the third of 4, 21-day chemotherapy cycles (average 3 weeks)	Grade 4 neutropenia is defined as ANC \< 0.5 × 10\^9/L. According to the study protocol, the outcome measure "Duration of Grade 3 or 4 Neutropenia (days)" applied to all participants with a valid ANC level, rather than those with an ANC level of \< 1.0 × 109/L. The value of 0 represents the participant experienced 0 days with Grade 3 or 4 Neutropenia (days). Whereas exclusion of a participant from the analysis indicates a lack of ANC data of the participant. The mean value was calculated as the sum of the durations (days) of ANC \< 1.0 × 109/L for all participants with valid ANC level (the numerator) divided by the number of participants (the denominator).
Duration of Grade 4 Neutropenia in Cycle 4	Cycle 4, the last of 4, 21-day chemotherapy cycles (average 3 weeks)	Grade 4 neutropenia is defined as ANC \< 0.5 × 10\^9/L. According to the study protocol, the outcome measure "Duration of Grade 3 or 4 Neutropenia (days)" applied to all participants with a valid ANC level, rather than those with an ANC level of \< 1.0 × 109/L. The value of 0 represents the participant experienced 0 days with Grade 3 or 4 Neutropenia (days). Whereas exclusion of a participant from the analysis indicates a lack of ANC data of the participant. The mean value was calculated as the sum of the durations (days) of ANC \< 1.0 × 109/L for all participants with valid ANC level (the numerator) divided by the number of participants (the denominator).
Overall Duration of Grade 3 or 4 Neutropenia in 4 Cycles	Overall 4, 21-day chemotherapy cycles(average 12 weeks)	Grade 3 defined as ANC \<1.0×10\^9/L and Grade 4 defined as ANC\<0.5×10\^9/L According to the study protocol, the outcome measure "Duration of Grade 3 or 4 Neutropenia (days)" applied to all participants with a valid ANC level, rather than those with an ANC level of \< 1.0 × 109/L. The value of 0 represents the participant experienced 0 days with Grade 3 or 4 Neutropenia (days). Whereas exclusion of a participant from the analysis indicates a lack of ANC data of the participant. The mean value was calculated as the sum of the durations (days) of ANC \< 1.0 × 109/L for all participants with valid ANC level (the numerator) divided by the number of participants (the denominator).
Number of Participants With Grade 2 or Greater Neutropenia in Cycle 1	Cycle 1, the first of 4, 21-day chemotherapy cycles (average 3 weeks)	Grade 2 or greater neutropenia is defined as ANC \< 1.5 × 10\^9/L
Number of Participants With Grade 2 or Greater Neutropenia in Cycle 2	Cycle 2, the second of 4, 21-day chemotherapy cycles (average 3 weeks)	Grade 2 or greater neutropenia is defined as ANC \< 1.5 × 10\^9/L
Number of Participants With Grade 2 or Greater Neutropenia in Cycle 3	Cycle 3, the third of 4, 21-day chemotherapy cycles (average 3 weeks)	Grade 2 or greater neutropenia is defined as ANC \< 1.5 × 10\^9/L
Number of Participants With Grade 2 or Greater Neutropenia in Cycle 4	Cycle 4, the last of 4, 21-day chemotherapy cycles (average 3 weeks)	Grade 2 or greater neutropenia is defined as ANC \< 1.5 × 10\^9/L
Duration (Days) of Grade 2 or Greater Neutropenia in Cycle 1	Cycle 1, the first of 4, 21-day chemotherapy cycles (average 3 weeks)	Grade 2 or greater neutropenia is defined as ANC \< 1.5 × 10\^9/L. According to the study protocol, the outcome measure "Duration of Grade 3 or 4 Neutropenia (days)" applied to all participants with a valid ANC level, rather than those with an ANC level of \< 1.0 × 109/L. The value of 0 represents the participant experienced 0 days with Grade 3 or 4 Neutropenia (days). Whereas exclusion of a participant from the analysis indicates a lack of ANC data of the participant. The mean value was calculated as the sum of the durations (days) of ANC \< 1.0 × 109/L for all participants with valid ANC level (the numerator) divided by the number of participants (the denominator).
Duration (Days) of Grade 2 or Greater Neutropenia in Cycle 2	Cycle 2, the second of 4, 21-day chemotherapy cycles (average 3 weeks)	Grade 2 or greater neutropenia is defined as ANC \< 1.5 × 10\^9/L. According to the study protocol, the outcome measure "Duration of Grade 3 or 4 Neutropenia (days)" applied to all participants with a valid ANC level, rather than those with an ANC level of \< 1.0 × 109/L. The value of 0 represents the participant experienced 0 days with Grade 3 or 4 Neutropenia (days). Whereas exclusion of a participant from the analysis indicates a lack of ANC data of the participant. The mean value was calculated as the sum of the durations (days) of ANC \< 1.0 × 109/L for all participants with valid ANC level (the numerator) divided by the number of participants (the denominator).
Duration (Days) of Grade 2 or Greater Neutropenia in Cycle 3	Cycle 3, the third of 4, 21-day chemotherapy cycles (average 3 weeks)	Grade 2 or greater neutropenia is defined as ANC \< 1.5 × 10\^9/L. According to the study protocol, the outcome measure "Duration of Grade 3 or 4 Neutropenia (days)" applied to all participants with a valid ANC level, rather than those with an ANC level of \< 1.0 × 109/L. The value of 0 represents the participant experienced 0 days with Grade 3 or 4 Neutropenia (days). Whereas exclusion of a participant from the analysis indicates a lack of ANC data of the participant. The mean value was calculated as the sum of the durations (days) of ANC \< 1.0 × 109/L for all participants with valid ANC level (the numerator) divided by the number of participants (the denominator).
Duration (Days) of Grade 2 or Greater Neutropenia in Cycle 4	Cycle 4, the last of 4, 21-day chemotherapy cycles (average 3 weeks)	Grade 2 or greater neutropenia is defined as ANC \< 1.5 × 10\^9/L. According to the study protocol, the outcome measure "Duration of Grade 3 or 4 Neutropenia (days)" applied to all participants with a valid ANC level, rather than those with an ANC level of \< 1.0 × 109/L. The value of 0 represents the participant experienced 0 days with Grade 3 or 4 Neutropenia (days). Whereas exclusion of a participant from the analysis indicates a lack of ANC data of the participant. The mean value was calculated as the sum of the durations (days) of ANC \< 1.0 × 109/L for all participants with valid ANC level (the numerator) divided by the number of participants (the denominator).
The Absolute Neutrophil Counts (ANC) Nadir From Day 3 to Day 13 of Cycle 1	From day 3 to day 13 of cycle 1 (11 days)	The minimum value of ANC measured from day 3 to day 13 of cycle 1
Number of Participants With Febrile Neutropenia (FN) in Cycle 1	Cycle 1, the first of 4, 21-day chemotherapy cycles (average 3 weeks)	FN is defined as ANC \< 1.0 × 10\^9/L with fever (a single measurement of body temperature \>38.3 °C or body temperature ≥ 38.0 °C for more than 1 hr).
Time (Days) of ANC Nadir Recovers to 2.0 × 10^9/L in Cycle 1	Cycle 1, the first of 4, 21-day chemotherapy cycles (average 3 weeks)	If the ANC nadir during the first 13 days of the cycle is \< 2.0 × 10\^9/L, the recovery time = ((date of ANC ≥ 2.0 ×10\^9/L) - (date of ANC reaching nadir within the cycle) + 1). If the ANC nadir in the first 13 days of the cycle is ≥2.0 × 10\^9/L, then the recovery time = 0 days.
Time (Days) of ANC Nadir Recovers to 2.0 × 10^9/L in Cycle 2	Cycle 2, the second of 4, 21-day chemotherapy cycles (average 3 weeks)	If the ANC nadir during the first 13 days of the cycle is \< 2.0 × 10\^9/L, the recovery time = ((date of ANC ≥ 2.0 ×10\^9/L) - (date of ANC reaching nadir within the cycle) + 1). If the ANC nadir in the first 13 days of the cycle is ≥2.0 × 10\^9/L, then the recovery time = 0 days.
Time (Days) of ANC Nadir Recovers to 2.0 × 10^9/L in Cycle 3	Cycle 3, the third of 4, 21-day chemotherapy cycles (average 3 weeks)	If the ANC nadir during the first 13 days of the cycle is \< 2.0 × 10\^9/L, the recovery time = ((date of ANC ≥ 2.0 ×10\^9/L) - (date of ANC reaching nadir within the cycle) + 1). If the ANC nadir in the first 13 days of the cycle is ≥2.0 × 10\^9/L, then the recovery time = 0 days.
Time (Days) of ANC Nadir Recovers to 2.0 × 10^9/L in Cycle 4	Cycle 4, the last of 4, 21-day chemotherapy cycles (average 3 weeks)	If the ANC nadir during the first 13 days of the cycle is \< 2.0 × 10\^9/L, the recovery time = ((date of ANC ≥ 2.0 ×10\^9/L) - (date of ANC reaching nadir within the cycle) + 1). If the ANC nadir in the first 13 days of the cycle is ≥2.0 × 10\^9/L, then the recovery time = 0 days.