Clinical trial NCT01285219: A Study Comparing Pegylated Filgrastim and Filgrastim in Support for Chemotherapy
Official title: A Multicenter, Randomized, Cross-over Phase 3 Comparing Preventive Pegylated Filgrastim and Filgrastim in Cancer Patients Receiving Myelosuppressive Chemotherapy
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Cancer
Keywords: Granulocyte colony-stimulating factor , recombinant
Polyethylene glycols
Neutropenia
Drug therapy, combination
Lead sponsor: ChineseAMS
Sponsor class: UNKNOWN
Collaborators: name: Fujian Cancer Hospital
name: Beijing Chest Hospital
name: Hospital affiliated to Academy of Military Medical Sciences
name: Tianjin Medical University Cancer
name: Fudan University
name: First Hospital of China Medical University
name: Hunan Cancer Hospital
name: West China Hospital
name: The Second Affiliated Hospital of Dalian Medical University
name: Peking University Third Hospital
name: Tianjin People's Hospital
name: Qilu Hospital of Shandong University
name: Zhejiang Cancer Hospital
name: Changhai Hospital
First posted: 2011-01-27
Enrollment: 337
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: SUPPORTIVE_CARE

Brief summary: 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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Protective rate of grade 4 neutropenia
timeFrame: 21 days
Secondary outcomes:
measure: rate of grade 3/4 neutropenia
timeFrame: 21 days
measure: time to neutrophil recovery
timeFrame: 21 days
measure: incidence of antibiotic administration
timeFrame: 21 days
measure: ANC profile
timeFrame: 21 days
measure: incidence and severity adverse events
timeFrame: 21 days
measure: incidence and severity of side effects
timeFrame: 21 days
measure: changes in clinical laboratory values
timeFrame: 21 days
measure: incidence of febrile neutropenia
timeFrame: 21 days
Other outcomes:
Locations:
Study officials:
affiliation: Department of Medical Oncology, Cancer Institute/Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100021, China
name: Yuankai Shi, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.