Study of F-627 in Women With Breast Cancer Receiving Myelotoxic Chemotherapy

A Single-Center, Open-Label, Dose-Escalation Phase I Clinical Trial of Recombinant Human Granulocyte Colony Stimulating Factor-Fc Fusion Protein for Injection as an Adjuvant to Chemotherapy in Subjects With Breast Cancer

A Phase I, dose escalation study to evaluate the safety and pharmacokinetics/pharmacodynamics of F-627 in female breast cancer patients who received up to 4 cycles of Epirubicin and Cyclophosphamide. 18 patients (6 patients each cohort) were assigned to three escalated dose cohorts of 80, 240 and 320 µg/kg.

Study Overview

• Status: Completed
• Conditions: Breast Cancer; Neutropenia
• Intervention / Treatment: Drug: F-627; Drug: EC regimen

Detailed Description

A Phase I, dose escalation study to evaluate the safety and pharmacokinetics/pharmacodynamics of F-627 in female breast cancer patients receiving 4 cycles of EC (Epirubicin plus Cyclophosphamide) chemotherapy.

18 patients (6 patients each cohort) were assigned to three sequential doses cohort of F-627 at the dose of 80, 240 and 320 µg/kg. The patients received chemotherapy (100 mg/m^2 epirubicin and 600 mg/m^2 cyclophosphamide) administrated by i.v. injection on Day 1 and F-627 by s.c. injection on Day 3 of each cycle for 4 cycles. If no dose-limiting toxicity (DLT) was observed in 6 patients during first cycle, the next cohort was escalated.

Blood samples were collected for completed blood counts with differential, serum F-627 concentration and safety evaluation at different point following F-672 injection.

The decision to proceed to the next higher dose was made jointly by the sponsor's medical expert and the investigator based upon the review of safety data in the first cycle treatment.

• Study Type: Interventional
• Enrollment (Actual): 18
• Phase: Phase 1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. 18-75 years old.
2. Female postoperative breast cancer patients who require adjuvant chemotherapy, and are planned to receive 4 cycles of EC chemotherapy;
3. East Cooperative Oncology Group (ECOG) performance 0-1.
4. Absolute neutrophil count (ANC) ≥ 2.0 × 10^9/L, hemoglobin (Hb) ≥ 11.0 g/dl, and platelets (PLT) ≥ 100 × 10^9/L prior to chemotherapy.
5. Hepatic and renal function within the normal range;.
6. Left ventricular ejection fraction (LVEF) > 50%.
7. Willing to sign the informed consent form and able to comply with protocol requirements

Exclusion Criteria:

1. Women in pregnancy or breastfeeding; Women of child-bearing potential have a positive pregnancy test result prior to the first dose;
2. Life expectancy less than 12 months;
3. Radiation therapy within 4 weeks prior to enrollment;
4. Breast cancer patients who have received neoadjuvant chemotherapy before radical mastectomy;
5. Prior bone marrow or stem cell transplant;
6. With other malignant tumors other than breast cancer;
7. Have received granulocyte colony stimulating factor (G-CSF) treatment within 6 weeks prior to enrollment;
8. Diagnosed with acute congestive heart failure, cardiomyopathy, or myocardial infarction by clinical diagnosis, electrocardiograph (ECG) or other approaches;
9. With any disease that may cause splenomegaly;
10. With acute infection, chronic active Hepatitis B within 1 year (unless patients tested negative for HBsAg prior to enrollment), or Hepatitis C;
11. History of tuberculosis (TB); history of TB exposure, unless negative for tuberculin test; TB patients undergoing treatment; or suspected TB evaluated by chest x-ray;
12. Known human immunodeficiency virus (HIV) positive or acquired immune deficiency syndrome (AIDS);
13. With sickle cell anemia;
14. With alcohol or drug abuse that may affect the compliance with the study;
15. With known hypersensitivity to E. coli derived proteins, G-CSF, or excipients;
16. Has received any other investigational drug within 4 weeks prior to enrollment;
17. Patients with diseases or symptoms unsuitable for participating in the clinical trial based on the investigator's judgment;

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: F-627 80 µg/kg; F-627 at the dose of 80 µg/kg administrated by s.c. injection on Day 3 of each cycle for 4 cycles.	Drug: F-627; F-627 subcutaneous injection on Day 3 of each cycle for 4 cycles. Dose-escalation method was used.; Other Names: Recombinant Human Granulocyte Colony Stimulating Factor (rh G-CSF) Fc fusion protein; Drug: EC regimen; Epirubicin 100 mg/m^2 (in vein) and Cyclophosphamide 600 mg/m^2 (in vein) on Day 1 of each cycle for 4 cycles.; Other Names: Epirubicin + Cyclophosphamide
Experimental: F-627 240 µg/kg; F-627 at the dose of 240 µg/kg administrated by s.c. injection on Day 3 of each cycle for 4 cycles.	Drug: F-627; F-627 subcutaneous injection on Day 3 of each cycle for 4 cycles. Dose-escalation method was used.; Other Names: Recombinant Human Granulocyte Colony Stimulating Factor (rh G-CSF) Fc fusion protein; Drug: EC regimen; Epirubicin 100 mg/m^2 (in vein) and Cyclophosphamide 600 mg/m^2 (in vein) on Day 1 of each cycle for 4 cycles.; Other Names: Epirubicin + Cyclophosphamide
Experimental: F-627 320 µg/kg; F-627 at the dose of 320 µg/kg administrated by s.c. injection on Day 3 of each cycle for 4 cycles.	Drug: F-627; F-627 subcutaneous injection on Day 3 of each cycle for 4 cycles. Dose-escalation method was used.; Other Names: Recombinant Human Granulocyte Colony Stimulating Factor (rh G-CSF) Fc fusion protein; Drug: EC regimen; Epirubicin 100 mg/m^2 (in vein) and Cyclophosphamide 600 mg/m^2 (in vein) on Day 1 of each cycle for 4 cycles.; Other Names: Epirubicin + Cyclophosphamide

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Evaluate the Safety of F-627 for Injection in the Treatment of Female Postoperative Patients With Breast Cancer Who Require Adjuvant Chemotherapy.	Safety endpoints include incidence rate and severity of adverse events (AEs), laboratory measurements, physical examinations, vital signs, and performance status. Severity of AEs were assessed according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) 4.03 criteria.	Up to 4 cycles (about 84 days)
Tolerability (Dose-limiting Toxicity) of F-627 for Injection in the Treatment of Female Postoperative Patients With Breast Cancer Who Require Adjuvant Chemotherapy.	Tolerability should be assessed by dose-limiting toxicity (DLT). DLT is defined as any grade 3 or greater adverse event related to the investigational drug that observed in cycle 1 (21 days).	Up to 21 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
T1/2 of F-627 in Each Dose Cohort in Cycle 1 and Cycle 3	There are a total of 13 blood sampling time points in each cycle: pre-dose and 2, 6, 12, 24, 36, 48, 72, 96, 120, 144, 192, and 240 hr after dosing. Two additional sampling time points, 312 and 432 hr after dosing, are included for the 320 μg/kg cohort. Serum drug concentrations of F-627 at different time points will be determined using enzyme linked immunosorbent assay (ELISA).	Cycle 1 and cycle 3 (each cycle was about 21 days)
Cmax of F-627 in Each Dose Cohort in Cycle 1 and Cycle 3	There are a total of 13 blood sampling time points in each cycle: pre-dose and 2, 6, 12, 24, 36, 48, 72, 96, 120, 144, 192, and 240 hr after dosing. Two additional sampling time points, 312 and 432 hr after dosing, are included for the 320 μg/kg cohort. Serum drug concentrations of F-627 at different time points will be determined using ELISA.	Cycle 1 and cycle 3 (each cycle was about 21 days)
Tmax of F-627 in Each Dose Cohort in Cycle 1 and Cycle 3	There are a total of 13 blood sampling time points in each cycle: pre-dose and 2, 6, 12, 24, 36, 48, 72, 96, 120, 144, 192, and 240 hr after dosing. Two additional sampling time points, 312 and 432 hr after dosing, are included for the 320 μg/kg cohort. Serum drug concentrations of F-627 at different time points will be determined using ELISA.	Cycle 1 and cycle 3 (each cycle was about 21 days)
Area Under Curve (AUC)0-t of F-627 in Each Dose Cohort in Cycle 1 and Cycle 3	There are a total of 13 blood sampling time points in each cycle: pre-dose and 2, 6, 12, 24, 36, 48, 72, 96, 120, 144, 192, and 240 hr after dosing. Two additional sampling time points, 312 and 432 hr after dosing, are included for the 320 μg/kg cohort. Serum drug concentrations of F-627 at different time points will be determined using ELISA.	Cycle 1 and cycle 3 (each cycle was about 21 days)
Vz/F of F-627 in Each Dose Cohort in Cycle 1 and Cycle 3	There are a total of 13 blood sampling time points in each cycle: pre-dose and 2, 6, 12, 24, 36, 48, 72, 96, 120, 144, 192, and 240 hr after dosing. Two additional sampling time points, 312 and 432 hr after dosing, are included for the 320 μg/kg cohort. Serum drug concentrations of F-627 at different time points will be determined using ELISA.	Cycle 1 and cycle 3 (each cycle was about 21 days)
Cl/F of F-627 in Each Dose Cohort in Cycle 1 and Cycle 3	There are a total of 13 blood sampling time points in each cycle: pre-dose and 2, 6, 12, 24, 36, 48, 72, 96, 120, 144, 192, and 240 hr after dosing. Two additional sampling time points, 312 and 432 hr after dosing, are included for the 320 μg/kg cohort. Serum drug concentrations of F-627 at different time points will be determined using ELISA.	Cycle 1 and cycle 3 (each cycle was about 21 days)
Mean Residence Time (MRT)0-t of F-627 in Each Dose Cohort in Cycle 1 and Cycle 3	There are a total of 13 blood sampling time points in each cycle: pre-dose and 2, 6, 12, 24, 36, 48, 72, 96, 120, 144, 192, and 240 hr after dosing. Two additional sampling time points, 312 and 432 hr after dosing, are included for the 320 μg/kg cohort. Serum drug concentrations of F-627 at different time points will be determined using ELISA.	Cycle 1 and cycle 3 (each cycle was about 21 days)
Percentage of Subjects With Grade 3 or 4 Neutropenia (< 1.0 × 10^9/L)	For cycle 1, starting on day 3, oral temperature measurement and routine blood test (including ANC) will be performed daily until ANC recovers to no less than 1.0 × 10^9/L from nadir, and once every 3 days thereafter until the next cycle; for chemotherapy cycles 2-4 (day 3-day 21 of each chemotherapy cycle, i.e., day 24-day 84 of the study), starting on day 3, oral temperature measurement and routine blood test will be performed every other day until ANC recovers to no less than 1.0 × 10^9/L from nadir, and once every 3 days thereafter until the next cycle.	Up to 4 cycles (84 days)
Percentage of Subjects With Grade 4 Neutropenia (< 0.5 × 10^9/L)	For cycle 1, starting on day 3, oral temperature measurement and routine blood test (including ANC) will be performed daily until ANC recovers to no less than 1.0 × 10^9/L from nadir, and once every 3 days thereafter until the next cycle; for chemotherapy cycles 2-4 (day 3-day 21 of each chemotherapy cycle, i.e., day 24-day 84 of the study), starting on day 3, oral temperature measurement and routine blood test will be performed every other day until ANC recovers to no less than 1.0 × 10^9/L from nadir, and once every 3 days thereafter until the next cycle.	Up to 4 cycles (84 days)
Duration of Absolute Neutrophil Count (ANC)< 0.5 × 10^9/L (Days)	For cycle 1, starting on day 3, oral temperature measurement and routine blood test (including ANC) will be performed daily until ANC recovers to no less than 1.0 × 10^9/L from nadir, and once every 3 days thereafter until the next cycle; for chemotherapy cycles 2-4 (day 3-day 21 of each chemotherapy cycle, i.e., day 24-day 84 of the study), starting on day 3, oral temperature measurement and routine blood test will be performed every other day until ANC recovers to no less than 1.0 × 10^9/L from nadir, and once every 3 days thereafter until the next cycle.	Up to 4 cycles (84 days)
Duration of Absolute Neutrophil Count (ANC)< 1.0 × 10^9/L (Days)	For cycle 1, starting on day 3, oral temperature measurement and routine blood test (including ANC) will be performed daily until ANC recovers to no less than 1.0 × 10^9/L from nadir, and once every 3 days thereafter until the next cycle; for chemotherapy cycles 2-4 (day 3-day 21 of each chemotherapy cycle, i.e., day 24-day 84 of the study), starting on day 3, oral temperature measurement and routine blood test will be performed every other day until ANC recovers to no less than 1.0 × 10^9/L from nadir, and once every 3 days thereafter until the next cycle.	Up to 4 cycles (84 days)
Absolute Neutrophil Count (ANC) Nadir (10^9 Cells/L)	For cycle 1, starting on day 3, oral temperature measurement and routine blood test (including ANC) will be performed daily until ANC recovers to no less than 1.0 × 10^9/L from nadir, and once every 3 days thereafter until the next cycle; for chemotherapy cycles 2-4 (day 3-day 21 of each chemotherapy cycle, i.e., day 24-day 84 of the study), starting on day 3, oral temperature measurement and routine blood test will be performed every other day until ANC recovers to no less than 1.0 × 10^9/L from nadir, and once every 3 days thereafter until the next cycle.	Up to 4 cycles (84 days)
Time (Days) of Absolute Neutrophil Count (ANC) Recovered to 1.0 × 10^9/L From Nadir	For cycle 1, starting on day 3, oral temperature measurement and routine blood test (including ANC) will be performed daily until ANC recovers to no less than 1.0 × 10^9/L from nadir, and once every 3 days thereafter until the next cycle; for chemotherapy cycles 2-4 (day 3-day 21 of each chemotherapy cycle, i.e., day 24-day 84 of the study), starting on day 3, oral temperature measurement and routine blood test will be performed every other day until ANC recovers to no less than 1.0 × 10^9/L from nadir, and once every 3 days thereafter until the next cycle.	Up to 4 cycles (84 days)

Other Outcome Measures

Outcome Measure	Time Frame
Immunogenicity of F-627 by serum F-627 antibody analysis.	Up to 4 cycles (84 days)

Collaborators and Investigators

• Sponsor: EVIVE Biotechnology
• Collaborators: Fudan University
• Investigators: Principal Investigator: Junning Cao, Professor, Fudan University

Study record dates

Study Major Dates

• Study Start (Actual): December 1, 2012
• Primary Completion (Actual): December 1, 2013
• Study Completion (Actual): December 1, 2013

Study Registration Dates

• First Submitted: July 23, 2015
• First Submitted That Met QC Criteria: August 17, 2015
• First Posted (Estimated): August 19, 2015

Study Record Updates

• Last Update Posted (Estimated): February 23, 2024
• Last Update Submitted That Met QC Criteria: July 18, 2023
• Last Verified: July 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Hematologic Diseases; Breast Diseases; Agranulocytosis; Leukopenia; Leukocyte Disorders; Breast Neoplasms; Neutropenia; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Adjuvants, Immunologic; Antibiotics, Antineoplastic; Cyclophosphamide; Epirubicin; Lenograstim
• Other Study ID Numbers: 2012-F-627-CH1

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO