A Study Comparing Pegylated Filgrastim and Filgrastim in Support for Chemotherapy

A Multicenter, Randomized, Cross-over Phase 3 Comparing Preventive Pegylated Filgrastim and Filgrastim in Cancer Patients Receiving Myelosuppressive Chemotherapy

Neutropenia is one of the most frequent adverse effects of chemotherapy, and the main factor to limit the dosage and delay the schedule of chemotherapy. Preventive filgrastim administration has long been established as the standard of care. A pegylated filgrastim was independently developed by GeneLeuk Biopharmaceutical Co., Ltd, Shandong, China. It composed of filgrastim and a 20 kd polyethylene glycol molecule covalently bound at the N-terminal residue. Preclinical studies phase 1 and phase 2 trials have shown that pegylated filgrastim has decreased renal clearance, increased plasma half-life, and prolonged efficacy in compare with filgrastim. These characters were similar to those of Neulasta.

The investigators designed a multicenter, randomized, cross-over phase Ⅲ trial to compare the efficacy and safety of a single injection of pegylated filgrastim and daily injections of filgrastim in chemotherapy naive patients receiving commonly used regimens. The hypothesis is that pegylated filgrastim is similarly effective and safe with regular filgrastim.

Study Overview

• Status: Completed
• Conditions: Cancer
• Intervention / Treatment: Drug: pegylated filgrastim and filgrastim; Drug: filgrastim and pegylated filgrastim

Detailed Description

This was a multicenter, randomized, open-label, cross-over, noninferiority study to evaluate whether a single injection of pegfilgrastim is as effective and safe as daily injections of filgrastim in patients receiving commonly used chemotherapy regimens. Patients were randomly assigned in a 1:1 ratio to AOB and BOA arm with center as the stratification variables. All the patients received two cycles of chemotherapy of identical regimen and dosage. In arm AOB, patients were administered pegylated filgrastim 100 ug/kg in cycle 1 and filgrastim 5 ug/kg/d in cycle 2; while in arm BOA, patients received filgrastim 5 ug/kg/d in cycle 1 and pegylated filgrastim 100 ug/kg in cycle 2.

Study drugs Both filgrastim and pegylated filgrastim were provided by GeneLeuk Biopharmaceutical Co., Ltd, Shandong, China.

In cycle 1 of AOB arm and cycle 2 of BOA arm, on 9 am of day 3, patients were to receive a dose of 100µg/kg of pegylated filgrastim, based on actual body weight, as a single s.c. injection.

In cycle 2 of AOB arm and cycle 1 of BOA arm, patients were to receive daily s.c. injection of filgrastim at a dose of 5 µg/kg/day. Injections began on 9 am of day 3 and continued daily until an absolute neutrophil count (ANC) ≥10.0 × 109 /l was documented after the expected nadir or for a maximum of 14 days, whichever occurred first.

Chemotherapy Treatment All cytotoxic agents were administrated on day 1 of the 21-day regimens. The regimens include PC(paclitaxel 175 mg/m2; carboplatin area under curve[AUC] 5～6 or cisplatin 75 mg/m2 )； AC (doxorubicin [or pirarubicin]60 mg/m2 or epirubicin 100 mg/m2；cyclophosphamide 600 mg/m2), PA(paclitaxel 175 mg/m2 ；doxorubicin [or pirarubicin]50 mg/m2 or epirubicin 80 mg/m2）； CHOP (cyclophosphamide 750mg/m2；doxorubicin[or pirarubicin] 50 mg/m2 or epirubicin100 mg/m2；vincristine1.4 mg/m2；prednisone 100mg，po，day 1-5)。 Efficacy measurements Blood samples were collected for complete blood counts (cbc) with differential on days 0, 3, 5, 7, 9, 11, 13, 17 and 21 of each cycle. Day 0 was defined as the day before day one, in cycle 1 it is the base line, and in cycle 2 is day 21 of cycle 1.

The primary efficacy end point was protective rate of grade 4 neutropenia after chemotherapy (defined as the rate of ANC keeps above 0.5 × 109 /l through the whole cycle). The secondary efficacy end points included the rate of grade 3/4 neutropenia, time to neutrophil recovery (defined as the time from chemotherapy administration until the patient's ANC increased to 2.0 × 109/l after the expected nadir), incidence of febrile neutropenia (defined as ANC<0.5×109/L and auxiliary temperature>38.0℃), incidence of antibiotic administration and ANC profile.

Safety assessments Patients recorded their auxiliary temperature daily, and were monitored for adverse events throughout the study. Before chemotherapy and in the third week of each chemotherapy cycle, serum hepatic and renal function, electrolysis, urine routine test and electrocardiograph were examined.

The safety endpoint of this study was incidence and severity of adverse events (WHO grade 1-4), side effects, and changes in clinical laboratory values.

• Study Type: Interventional
• Enrollment (Actual): 337
• Phase: Phase 3

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• diagnosis of malignant solid tumours (excluding highly aggressive lymphomas such as lymphoblastic lymphoma and Burkitt lymphoma)
• chemotherapy naive
• Karnofsky Performance Status ≥70
• age 18-70 years; normal white blood cell (WBC) count and platelet count
• adequate renal, hepatic and cardiac function
• life expectancy ≥3 months
• normal bone marrow function

Exclusion Criteria:

• history of systematic chemotherapy (including adjuvant therapy)
• large area radiotherapy (>25% of bone marrow volume)
• uncontrolled infection
• bone marrow involvement
• pregnancy, lactation
• history of blood stem cell or organ transplantation
• antibiotic administration within 72 hours of enrolment
• long time exposure to glucocorticoids and immunosuppressive agents

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Supportive Care
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: AOB,pegylated filgrastim to filgrastim; patients were administered pegylated filgrastim 100 ug/kg in cycle 1 and filgrastim 5 ug/kg/d in cycle 2	Drug: pegylated filgrastim and filgrastim; patients were administered pegylated filgrastim 100 ug/kg in cycle 1 and filgrastim 5 ug/kg/d in cycle 2
Active Comparator: BOA,filgrastim to pegylated filgrastim; patients received filgrastim 5 ug/kg/d in cycle 1 and pegylated filgrastim 100 ug/kg in cycle 2	Drug: filgrastim and pegylated filgrastim; patients received filgrastim 5 ug/kg/d in cycle 1 and pegylated filgrastim 100 ug/kg in cycle 2

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Protective rate of grade 4 neutropenia	the rate of ANC keeps above 0.5 × 109 /l through the whole cycle	21 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
rate of grade 3/4 neutropenia	the rate of ANC lower than 1.0 × 109 /l	21 days
time to neutrophil recovery	the time from chemotherapy administration until the patient's ANC increased to 2.0 × 109/l after the expected nadir	21 days
incidence of antibiotic administration	rate of using antibiotic in a cycle	21 days
ANC profile	the dynamic change of ANC number	21 days
incidence and severity adverse events	unexpected and untoward events	21 days
incidence and severity of side effects	expected and untoward events caused by study drug or control drug	21 days
changes in clinical laboratory values	changes in clinical laboratory values	21 days
incidence of febrile neutropenia	rate of ANC<0.5×109/L and auxiliary temperature>38.0℃	21 days

Collaborators and Investigators

• Sponsor: Cancer Institute and Hospital, Chinese Academy of Medical Sciences
• Collaborators: Zhejiang Cancer Hospital; Changhai Hospital; Fudan University; Fujian Cancer Hospital; Peking University Third Hospital; West China Hospital; Qilu Hospital of Shandong University; Hunan Cancer Hospital; Beijing Chest Hospital; First Hospital of China Medical University; The Second Affiliated Hospital of Dalian Medical University; Tianjin People's Hospital; Hospital affiliated to Academy of Military Medical Sciences; Tianjin Medical University Cancer
• Investigators: Principal Investigator: Yuankai Shi, M.D., Department of Medical Oncology, Cancer Institute/Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100021, China

Publications and helpful links

General Publications

• Yang S, He X, Liu P, Zhou S, Dong M, Qin Y, Yang J, Zhang C, Han X, Shi Y. [Duration of filgrastim prophylaxis for chemotherapy-induced neutropenia and its predictors]. Zhonghua Zhong Liu Za Zhi. 2016 Jan;38(1):69-72. doi: 10.3760/cma.j.issn.0253-3766.2016.01.013. Chinese.

Study record dates

Study Major Dates

• Study Start: January 1, 2006
• Primary Completion (Actual): May 1, 2007
• Study Completion (Actual): December 1, 2008

Study Registration Dates

• First Submitted: January 24, 2011
• First Submitted That Met QC Criteria: January 26, 2011
• First Posted (Estimate): January 27, 2011

Study Record Updates

• Last Update Posted (Estimate): January 27, 2011
• Last Update Submitted That Met QC Criteria: January 26, 2011
• Last Verified: January 1, 2011

More Information

Terms related to this study

• Keywords: Neutropenia; Polyethylene glycols; Granulocyte colony-stimulating factor , recombinant; Drug therapy, combination
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Immunologic Factors; Adjuvants, Immunologic; Lenograstim
• Other Study ID Numbers: PEG3; 2002SL0047 (Registry Identifier: State Food and Drug Administration of China)