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

Phase 1

Completed

• Conditions: Neutropenia; Breast Cancer
• Interventions: Drug: F-627; Drug: EC regimen

• Registration Number: NCT02527746
• Lead Sponsor: EVIVE Biotechnology

Brief Summary

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.

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 Timeline

• Study Start: 2012-12
• Primary Completion: 2013-12
• Study Completion: 2013-12
• Study First Submitted: 2015-07-23
• Study First Submitted QC: 2015-08-17
• Study First Posted: 2015-08-19
• Results First Submitted: 2018-02-21
• Status Verified: 2023-07
• Results First Submitted QC: 2023-07-18
• Last Update Submitted: 2023-07-18
• Results First Posted: 2024-02-23
• Last Update Posted: 2024-02-23

Recruitment & Eligibility

• Status: COMPLETED
• Sex: Female
• Target Recruitment: 18

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
F-627 320 µg/kg	EC regimen	F-627 at the dose of 320 µg/kg administrated by s.c. injection on Day 3 of each cycle for 4 cycles.
F-627 80 µg/kg	EC regimen	F-627 at the dose of 80 µg/kg administrated by s.c. injection on Day 3 of each cycle for 4 cycles.
F-627 240 µg/kg	EC regimen	F-627 at the dose of 240 µg/kg administrated by s.c. injection on Day 3 of each cycle for 4 cycles.
F-627 240 µg/kg	F-627	F-627 at the dose of 240 µg/kg administrated by s.c. injection on Day 3 of each cycle for 4 cycles.
F-627 80 µg/kg	F-627	F-627 at the dose of 80 µg/kg administrated by s.c. injection on Day 3 of each cycle for 4 cycles.
F-627 320 µg/kg	F-627	F-627 at the dose of 320 µg/kg administrated by s.c. injection on Day 3 of each cycle for 4 cycles.

Primary Outcome Measures

Name	Time	Method
Evaluate the Safety of F-627 for Injection in the Treatment of Female Postoperative Patients With Breast Cancer Who Require Adjuvant Chemotherapy.	Up to 4 cycles (about 84 days)	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.
Tolerability (Dose-limiting Toxicity) of F-627 for Injection in the Treatment of Female Postoperative Patients With Breast Cancer Who Require Adjuvant Chemotherapy.	Up to 21 days	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).

Secondary Outcome Measures

Name	Time	Method
Percentage of Subjects With Grade 4 Neutropenia (< 0.5 × 10^9/L)	Up to 4 cycles (84 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.
Vz/F of F-627 in Each Dose Cohort in Cycle 1 and Cycle 3	Cycle 1 and cycle 3 (each cycle was about 21 days)	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.
Cl/F of F-627 in Each Dose Cohort in Cycle 1 and Cycle 3	Cycle 1 and cycle 3 (each cycle was about 21 days)	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.
T1/2 of F-627 in Each Dose Cohort in Cycle 1 and Cycle 3	Cycle 1 and cycle 3 (each cycle was about 21 days)	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).
Cmax of F-627 in Each Dose Cohort in Cycle 1 and Cycle 3	Cycle 1 and cycle 3 (each cycle was about 21 days)	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.
Area Under Curve (AUC)0-t of F-627 in Each Dose Cohort in Cycle 1 and Cycle 3	Cycle 1 and cycle 3 (each cycle was about 21 days)	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.
Mean Residence Time (MRT)0-t of F-627 in Each Dose Cohort in Cycle 1 and Cycle 3	Cycle 1 and cycle 3 (each cycle was about 21 days)	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.
Percentage of Subjects With Grade 3 or 4 Neutropenia (< 1.0 × 10^9/L)	Up to 4 cycles (84 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.
Tmax of F-627 in Each Dose Cohort in Cycle 1 and Cycle 3	Cycle 1 and cycle 3 (each cycle was about 21 days)	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.
Duration of Absolute Neutrophil Count (ANC)< 1.0 × 10^9/L (Days)	Up to 4 cycles (84 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.
Absolute Neutrophil Count (ANC) Nadir (10^9 Cells/L)	Up to 4 cycles (84 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.
Duration of Absolute Neutrophil Count (ANC)< 0.5 × 10^9/L (Days)	Up to 4 cycles (84 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.
Time (Days) of Absolute Neutrophil Count (ANC) Recovered to 1.0 × 10^9/L From Nadir	Up to 4 cycles (84 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.