Neulasta-controlled Trial of F-627 in Women With Breast Cancer Receiving Myelotoxic Chemotherapy

• Sponsor: EVIVE Biotechnology (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03252431
• Collaborator: (none)
• Enrollment: 393
• Location: 1
• Arms: 2
• Actual Duration (Months): 22.8
• Patients Per Site Per Month: 17.3

Study Details

Study Description

Brief Summary

This is a randomized, multi-center, single dose, open-label and Neulasta controlled phase 3 study to evaluate the efficacy and safety of F-627 in women with Stage I - III invasive breast cancer receiving chemotherapy treatment.

Condition or Disease	Intervention/Treatment	Phase
Breast Cancer; Neutropenia	Drug: F-627; Drug: Neulasta	Phase 3

Detailed Description

This is a Phase III, global, two arm, open label clinical study will randomize approximately 400 female subjects (approximately 200 per arm) with Stage I - III invasive breast cancer who are to receive neoadjuvant or adjuvant myelotoxic TC chemotherapy treatment (docetaxel + cyclophosphamide, 75 and 600 mg/m2, respectively). Subjects in this study will be those who are scheduled to undergo at least four 21-day cycles of chemotherapy treatment. Subjects may be scheduled for more than 4 cycles of chemotherapy; however, study participation will be limited to a subject's first 4 cycles.

The primary objective of this study will be to evaluate the efficacy of F-627 given as a single fixed dose (20 mg) pre-filled syringe as compared to Neulasta® standard dosing (6 mg) in the first chemotherapy cycle. The primary endpoint will be the duration of grade 4 (severe) neutropenia - the number of days in which the patient has had an absolute neutrophil count (ANC <0.5 x 10^9/L) observed in chemotherapy cycle 1.

Approximately 24 hours after chemotherapy completion in each cycle (Day 2 of the cycle), subjects will receive one of the following treatments:

Arm 1: F-627, 20 mg fixed dose pre-filled syringe, administered on Day 2 of each of 4 chemotherapy cycles.

Arm 2: 6 mg fixed dose Neulasta®, administered on Day 2 of each of 4 chemotherapy cycles Randomization will occur in an equal ratio (1:1) using a central randomization system (IWRS) on Day 1 of the study, the day of chemotherapy administration for the first chemotherapy cycle.

This study is open-label, however, study drug injections are to be administered separately by qualified study personnel to allow study investigators to remain blinded and perform study assessments without knowledge of treatment assignment.

Study Design

• Study Type: Interventional
• Actual Enrollment: 393 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase III, Randomized, Multi-Centre, Open-Label, Fixed Dose, Neulasta® Active-Controlled Clinical Trial of F-627 in Women With Breast Cancer Receiving Myelotoxic Chemotherapy
• Actual Study Start Date: Apr 12, 2018
• Actual Primary Completion Date: Sep 25, 2019
• Actual Study Completion Date: Mar 5, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: F-627 F-627, 20 mg fixed dose pre-filled syringe, administered on Day 2 of each of 4 chemotherapy cycles.	Drug: F-627; single dose pre-filled syringe
Active Comparator: Neulasta 6 mg fixed dose Neulasta®, administered on Day 2 of each of 4 chemotherapy cycles	Drug: Neulasta; single dose pre-filled syringe; Other Names: pegfilgrastim

Outcome Measures

Primary Outcome Measures

1. Duration in Days of Grade 4 Neutropenia in Chemotherapy Cycle 1 [The first of 4, 21-day chemotherapy cycles (average 3 weeks)]

   Eligible subjects were randomized in a 1:1 ratio. Subjects were dosed with either the F 627 20 mg/dose PFS or Neulasta® 6 mg/dose as the study drug in each chemotherapy cycle. Subjects remained in their assigned treatment arm throughout the study. Subjects were dosed subcutaneously (SC) 24 to 28 hours after receiving TC chemotherapy (75 mg/m2 docetaxel + 600 mg/m2 cyclophosphamide) on Day 2 of each chemotherapy cycle that the subject underwent (up to 4 cycles). Grade 4 (severe) neutropenia was defined as ANC <0.5 × 109/L within the first 12 days of chemotherapy.

Secondary Outcome Measures

1. Duration in Days of Use of Intravenous Antibiotic [across all 4 chemotherapy cycles (average 84 days)]

   The duration of use of IV antibiotics was defined as the number of days in which IV antibiotics were administered

2. Duration in Days of Hospitalization [across all 4 chemotherapy cycles (average 84 days)]

   The duration in days of patients been hospitalized for febrile neutropenia (FN) or any infection. Febrile neutropenia is defined as a single oral temperature of ≥38.3°C (101°F) or a temperature of >38.0°C (100.4°F) sustained for >1 hour and ANC <0.5 x 10^9/L on the same day.

3. The Number of Participants With Grade 4 Neutropenia for Chemotherapy Cycle 1 [The first of 4, 21-day chemotherapy cycles (average 3 weeks)]

   The number of participants with grade 4 neutropenia for chemotherapy cycle 1. Grade 4 (severe) neutropenia was defined as ANC <0.5 × 109/L within the first 12 days of chemotherapy.

4. The Number of Participants With Febrile Neutropenia Considering All Chemotherapy Cycles. [across all 4 chemotherapy cycles (average 84 days)]

   The number of participants with febrile neutropenia, considering all chemotherapy cycles.

5. The Number of Participants With Use of IV Antibiotics Considering All Chemotherapy Cycles. [across all 4 chemotherapy cycles (average 84 days)]

   The number of participants with use of IV antibiotics, considering all chemotherapy cycles.

6. The Number of Participants in Hospitalization for Febrile Neutropenia or Any Infection Considering All Chemotherapy Cycles [across all 4 chemotherapy cycles (average 84 days)]

   The number of participants in hospitalization for febrile neutropenia or any infection, .

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Show evidence of a personally signed and dated informed consent document indicating that the patient has been informed of all pertinent aspects of the trial.

2. Females ≥18 years of age.

3. Diagnosed with Stage I-III breast cancer.

4. Subject is scheduled to undergo 4 cycles of neoadjuvant or adjuvant TC chemotherapy (docetaxel, cyclophosphamide, 75, 600 mg/m2, respectively).

5. ECOG Performance status of ≤2.

6. WBC count ≥4.0 × 109/L, hemoglobin ≥11.5 g/dL and a platelet count ≥150 × 109/L.

7. Demonstrate adequate renal, hepatic, and cardiac function (liver function tests [alanine aminotransferase , aspartate aminotransferase , alkaline phosphatase, and total bilirubin]) should be less than 2.5x the upper limits of normal (ULN). Serum creatinine should be less than 1.7x ULN.

8. All subjects must agree to use at least one of the following types of contraception: intrauterine device, implantable progesterone device, progesterone intramuscular injection, or oral contraceptive, which has been started at least one month prior to visit one and will continue for the duration of the trial. The contraceptive patch or condom use with spermicide is also acceptable forms of contraception as long as they will be used continually throughout the duration of the trial.

Exclusion Criteria:

1. Subject is <18 years of age.

2. Disease progression has occurred while receiving a taxane regimen.

3. Subject has undergone radiation therapy within 4 weeks of enrollment.

4. Subject has undergone bone marrow or stem-cell transplantation.

5. Subject has a history of prior malignancy other than breast cancer that is NOT in remission.

6. Subjects that have used G-CSF or any other drug that may potentiate the release of neutrophils (i.e., lithium) within 6 weeks of the screening period are excluded.

7. Subject has had chemotherapy within 180 days of screening.

8. Subject has documented congestive heart failure, cardiomyopathy or myocardial infarction by clinical diagnosis, electrocardiogram (ECG) test, or any other relevant test.

9. History of alcohol or drug abuse that would interfere with the ability to be compliant with the study procedure.

10. Unwillingness to participate in the study.

11. Any underlying medical condition that, in the Investigator's opinion, would make the administration of study drug hazardous to the patient or that would obscure the interpretation of adverse events.

12. Receiving other investigational drugs or biologics within 1 month or five half lives of enrollment (if known), which ever is less.

13. Any condition, which can cause splenomegaly.

14. Chronic constipation or diarrhea, irritable bowel syndrome, inflammatory bowel disease.

15. ALT, AST, alkaline phosphatase, total bilirubin ≥2.5x ULN.

16. Subject with active infection, or known to be infected with chronic active Hepatitis B within the last 1 year (unless shown at the time of study entry to be Hepatitis B antigen negative), or having any history of Hepatitis C.

17. Women who are pregnant or breast-feeding.

18. Subject known to be seropositive for HIV, or who have had an AIDS defining illness or a known immunodeficiency disorder.

19. Subject with a history of tuberculosis or exposure to tuberculosis. Patients that have received a prior chest X-ray for suspicion of tuberculosis are also excluded unless they have been confirmed to be PPD negative or they had latent tuberculosis that has been previously treated.

20. Subjects with Sickle Cell disease

21. Subjects with known hypersensitivity to E.coli derived proteins' pegfilgrastim' filgrastim, or any other component of the study drug.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of California Los Angeles (UCLA) - Jonsson Comprehensive Cancer Center (JCCC)	Los Angeles	California	United States	90095

Sponsors and Collaborators

• EVIVE Biotechnology

Investigators

• Principal Investigator: John Glaspy, MD, University of California at Los Angeles

Study Documents (Full-Text)

• Study Protocol - Aug 14, 2018
• Statistical Analysis Plan - Apr 3, 2017

More Information

Publications

None provided.

• Responsible Party: EVIVE Biotechnology
• ClinicalTrials.gov Identifier: NCT03252431
• Other Study ID Numbers: GC-627-05
• First Posted: Aug 17, 2017
• Last Update Posted: May 7, 2021
• Last Verified: Apr 1, 2021

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Breast Neoplasms; Neutropenia

Study Results

Participant Flow

Arm/Group Title	F-627	Neulasta
Arm/Group Description	F-627, 20 mg fixed dose pre-filled syringe, administered on Day 2 of each of 4 chemotherapy cycles. F-627: single dose pre-filled syringe	6 mg fixed dose Neulasta®, administered on Day 2 of each of 4 chemotherapy cycles Neulasta: single dose pre-filled syringe
Period Title: Overall Study
STARTED	197	196
COMPLETED	186	187
NOT COMPLETED	11	9

Baseline Characteristics

Arm/Group Title	F-627	Neulasta	Total
Arm/Group Description	F-627, 20 mg fixed dose pre-filled syringe, administered on Day 2 of each of 4 chemotherapy cycles. F-627: single dose pre-filled syringe	6 mg fixed dose Neulasta®, administered on Day 2 of each of 4 chemotherapy cycles Neulasta: single dose pre-filled syringe	Total of all reporting groups
Overall Participants	197	196	393
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	51.4 (11.82)	53.4 (11.11)	52.4 (11.50)
Sex: Female, Male (Count of Participants)
Female	197 100%	196 100%	393 100%
Male	0 0%	0 0%	0 0%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	1 0.5%	1 0.3%
Not Hispanic or Latino	197 100%	195 99.5%	392 99.7%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%
White	197 100%	196 100%	393 100%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (Count of Participants)
United States	1 0.5%	0 0%	1 0.3%
Bulgaria	18 9.1%	18 9.2%	36 9.2%
Hungary	23 11.7%	22 11.2%	45 11.5%
Russia	73 37.1%	72 36.7%	145 36.9%
Ukraine	82 41.6%	84 42.9%	166 42.2%
Weight (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	75.84 (16.884)	74.93 (16.873)	75.39 (16.863)
Height (cm) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [cm]	162.6 (6.27)	162.2 (6.67)	162.4 (6.47)
Basal Metabolic Index (kg/m2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m2]	28.72 (6.358)	28.51 (6.197)	28.62 (6.271)

Outcome Measures

1. Primary Outcome

Title	Duration in Days of Grade 4 Neutropenia in Chemotherapy Cycle 1
Description	Eligible subjects were randomized in a 1:1 ratio. Subjects were dosed with either the F 627 20 mg/dose PFS or Neulasta® 6 mg/dose as the study drug in each chemotherapy cycle. Subjects remained in their assigned treatment arm throughout the study. Subjects were dosed subcutaneously (SC) 24 to 28 hours after receiving TC chemotherapy (75 mg/m2 docetaxel + 600 mg/m2 cyclophosphamide) on Day 2 of each chemotherapy cycle that the subject underwent (up to 4 cycles). Grade 4 (severe) neutropenia was defined as ANC <0.5 × 109/L within the first 12 days of chemotherapy.
Time Frame	The first of 4, 21-day chemotherapy cycles (average 3 weeks)

Outcome Measure Data

Analysis Population Description

ITT (Intent-to-Treat) population

Arm/Group Title	F-627	Neulasta
Arm/Group Description	F-627, 20 mg fixed dose pre-filled syringe, administered on Day 2 of each of 4 chemotherapy cycles. F-627: single dose pre-filled syringe	6 mg fixed dose Neulasta®, administered on Day 2 of each of 4 chemotherapy cycles Neulasta: single dose pre-filled syringe
Measure Participants	197	196
Mean (Standard Deviation) [days]	0.2 (0.51)	0.2 (0.45)

2. Secondary Outcome

Title	Duration in Days of Use of Intravenous Antibiotic
Description	The duration of use of IV antibiotics was defined as the number of days in which IV antibiotics were administered
Time Frame	across all 4 chemotherapy cycles (average 84 days)

Outcome Measure Data

Analysis Population Description

ITT (Intent-to-Treat) population

Arm/Group Title	F-627	Neulasta
Arm/Group Description	F-627, 20 mg fixed dose pre-filled syringe, administered on Day 2 of each of 4 chemotherapy cycles. F-627: single dose pre-filled syringe	6 mg fixed dose Neulasta®, administered on Day 2 of each of 4 chemotherapy cycles Neulasta: single dose pre-filled syringe
Measure Participants	197	196
Mean (Standard Deviation) [days]	0.3 (1.36)	0.1 (0.70)

3. Secondary Outcome

Title	Duration in Days of Hospitalization
Description	The duration in days of patients been hospitalized for febrile neutropenia (FN) or any infection. Febrile neutropenia is defined as a single oral temperature of ≥38.3°C (101°F) or a temperature of >38.0°C (100.4°F) sustained for >1 hour and ANC <0.5 x 10^9/L on the same day.
Time Frame	across all 4 chemotherapy cycles (average 84 days)

Outcome Measure Data

Analysis Population Description

ITT (Intent-to-Treat) population

Arm/Group Title	F-627	Neulasta
Arm/Group Description	F-627, 20 mg fixed dose pre-filled syringe, administered on Day 2 of each of 4 chemotherapy cycles. F-627: single dose pre-filled syringe	6 mg fixed dose Neulasta®, administered on Day 2 of each of 4 chemotherapy cycles Neulasta: single dose pre-filled syringe
Measure Participants	197	196
Mean (Standard Deviation) [days]	0.1 (0.78)	0 (0.57)

4. Secondary Outcome

Title	The Number of Participants With Grade 4 Neutropenia for Chemotherapy Cycle 1
Description	The number of participants with grade 4 neutropenia for chemotherapy cycle 1. Grade 4 (severe) neutropenia was defined as ANC <0.5 × 109/L within the first 12 days of chemotherapy.
Time Frame	The first of 4, 21-day chemotherapy cycles (average 3 weeks)

Outcome Measure Data

Analysis Population Description

ITT (Intent-to-Treat) population

Arm/Group Title	F-627	Neulasta
Arm/Group Description	F-627, 20 mg fixed dose pre-filled syringe, administered on Day 2 of each of 4 chemotherapy cycles. F-627: single dose pre-filled syringe	6 mg fixed dose Neulasta®, administered on Day 2 of each of 4 chemotherapy cycles Neulasta: single dose pre-filled syringe
Measure Participants	197	196
Count of Participants [Participants]	23 11.7%	23 11.7%

5. Secondary Outcome

Title	The Number of Participants With Febrile Neutropenia Considering All Chemotherapy Cycles.
Description	The number of participants with febrile neutropenia, considering all chemotherapy cycles.
Time Frame	across all 4 chemotherapy cycles (average 84 days)

Outcome Measure Data

Analysis Population Description

ITT (Intent-to-Treat) population

Arm/Group Title	F-627	Neulasta
Arm/Group Description	F-627, 20 mg fixed dose pre-filled syringe, administered on Day 2 of each of 4 chemotherapy cycles. F-627: single dose pre-filled syringe	6 mg fixed dose Neulasta®, administered on Day 2 of each of 4 chemotherapy cycles Neulasta: single dose pre-filled syringe
Measure Participants	197	196
Count of Participants [Participants]	6 3%	1 0.5%

6. Secondary Outcome

Title	The Number of Participants With Use of IV Antibiotics Considering All Chemotherapy Cycles.
Description	The number of participants with use of IV antibiotics, considering all chemotherapy cycles.
Time Frame	across all 4 chemotherapy cycles (average 84 days)

Outcome Measure Data

Analysis Population Description

ITT (Intent-to-Treat) population

Arm/Group Title	F-627	Neulasta
Arm/Group Description	F-627, 20 mg fixed dose pre-filled syringe, administered on Day 2 of each of 4 chemotherapy cycles. F-627: single dose pre-filled syringe	6 mg fixed dose Neulasta®, administered on Day 2 of each of 4 chemotherapy cycles Neulasta: single dose pre-filled syringe
Measure Participants	197	196
Count of Participants [Participants]	9 4.6%	2 1%

7. Secondary Outcome

Title	The Number of Participants in Hospitalization for Febrile Neutropenia or Any Infection Considering All Chemotherapy Cycles
Description	The number of participants in hospitalization for febrile neutropenia or any infection, .
Time Frame	across all 4 chemotherapy cycles (average 84 days)

Outcome Measure Data

Analysis Population Description

ITT (Intent-to-Treat) population

Arm/Group Title	F-627	Neulasta
Arm/Group Description	F-627, 20 mg fixed dose pre-filled syringe, administered on Day 2 of each of 4 chemotherapy cycles. F-627: single dose pre-filled syringe	6 mg fixed dose Neulasta®, administered on Day 2 of each of 4 chemotherapy cycles Neulasta: single dose pre-filled syringe
Measure Participants	197	196
Count of Participants [Participants]	1 0.5%	1 0.5%

Adverse Events

Time Frame	AEs and SAEs were collected from the time of randomization until end of treatment visit day 84 (total of 9 months).
Adverse Event Reporting Description	Treatment emergent AE was defined as any AE that began on or after study drug (F-627 or Neulasta) treatment up to the EOT visit or was a worsening of a pre-existing medical condition.
Arm/Group Title	F-627		Neulasta
Arm/Group Description	F-627, 20 mg fixed dose pre-filled syringe, administered on Day 2 of each of 4 chemotherapy cycles. F-627: single dose pre-filled syringe		6 mg fixed dose Neulasta®, administered on Day 2 of each of 4 chemotherapy cycles Neulasta: single dose pre-filled syringe
All Cause Mortality
	F-627		Neulasta
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/197 (0.5%)		2/196 (1%)
Serious Adverse Events
	F-627		Neulasta
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	12/197 (6.1%)		3/196 (1.5%)
Blood and lymphatic system disorders
Febrile neutropenia	2/197 (1%)	2	0/196 (0%)	0
anemia	0/197 (0%)	0	1/196 (0.5%)	1
neutropenia	0/197 (0%)	0	1/196 (0.5%)	1
Cardiac disorders
Myocardial infarction	0/197 (0%)	0	1/196 (0.5%)	1
General disorders
fatigue	1/197 (0.5%)	1	0/196 (0%)	0
Hepatobiliary disorders
Hepatitis toxic	0/197 (0%)	0	1/196 (0.5%)	1
Metabolism and nutrition disorders
diabetic ketoacidosis	1/197 (0.5%)	1	0/196 (0%)	0
Nervous system disorders
syncope	1/197 (0.5%)	1	0/196 (0%)	0
Renal and urinary disorders
acute kidney injury	1/197 (0.5%)	1	0/196 (0%)	0
Respiratory, thoracic and mediastinal disorders
pulmonary embolism	1/197 (0.5%)	1	0/196 (0%)	0
pneumonia	2/197 (1%)	2	1/196 (0.5%)	1
Skin and subcutaneous tissue disorders
angioedema	1/197 (0.5%)	1	0/196 (0%)	0
urticaria	1/197 (0.5%)	1	0/196 (0%)	0
Vascular disorders
hypertension	1/197 (0.5%)	1	0/196 (0%)	0
Other (Not Including Serious) Adverse Events
	F-627		Neulasta
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	70/197 (35.5%)		51/196 (26%)
Blood and lymphatic system disorders
Leukocytosis	14/197 (7.1%)	58	10/196 (5.1%)	39
Gastrointestinal disorders
Asthenia	13/197 (6.6%)	26	12/196 (6.1%)	18
Musculoskeletal and connective tissue disorders
Bone pain	31/197 (15.7%)	54	23/196 (11.7%)	44
Arthralgia	12/197 (6.1%)	16	6/196 (3.1%)	9

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.