Efficacy and safety of lipegfilgrastim versus pegfilgrastim: a randomized, multicenter, active-control phase 3 trial in patients with breast cancer receiving doxorubicin/docetaxel chemotherapy

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Abstract

Background

Lipegfilgrastim is a novel glyco-pegylated granulocyte-colony stimulating factor in development for neutropenia prophylaxis in cancer patients receiving chemotherapy. This phase III, double-blind, randomized, active-controlled, noninferiority trial compared the efficacy and safety of lipegfilgrastim versus pegfilgrastim in chemotherapy-naïve breast cancer patients receiving doxorubicin/docetaxel chemotherapy.

Methods

Patients with high-risk stage II, III, or IV breast cancer and an absolute neutrophil count ≥1.5 × 10 ⁹ cells/L were randomized to a single 6-mg subcutaneous injection of lipegfilgrastim (n = 101) or pegfilgrastim (n = 101) on day 2 of each 21-day chemotherapy cycle (4 cycles maximum). The primary efficacy endpoint was the duration of severe neutropenia during cycle 1.

Results

Cycle 1: The mean duration of severe neutropenia for the lipegfilgrastim and pegfilgrastim groups was 0.7 and 0.8 days, respectively (λ = −0.218 [95% confidence interval: –0.498%, 0.062%], p = 0.126), and no severe neutropenia was observed in 56% and 49% of patients in the lipegfilgrastim and pegfilgrastim groups, respectively. All cycles: In the efficacy population, febrile neutropenia occurred in three pegfilgrastim-treated patients (all in cycle 1) and zero lipegfilgrastim-treated patients. Drug-related adverse events in the safety population were reported in 28% and 26% of patients i006E the lipegfilgrastim and pegfilgrastim groups, respectively.

Conclusion

This study demonstrates that lipegfilgrastim 6 mg is as effective as pegfilgrastim in reducing neutropenia in patients with breast cancer receiving myelosuppressive chemotherapy.

Trial Registration

Eudra EEACTA200901599910

The study protocol, two global amendments (Nos. 1 and 2), informed consent documents, and other appropriate study-related documents were reviewed and approved by the Ministry of Health of Ukraine Central Ethics Committee and local independent ethics committees (IECs).

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Most cited references 9

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Impact of primary prophylaxis with granulocyte colony-stimulating factor on febrile neutropenia and mortality in adult cancer patients receiving chemotherapy: a systematic review.

Timothy D Dale, Christopher H Lyman, Nicole M Kuderer … (2007)

Randomized controlled trials (RCTs) of prophylactic granulocyte colony-stimulating factors (G-CSF) have demonstrated a significant reduction in febrile neutropenia (FN) after systemic chemotherapy. Several RCTs have been published recently that investigate the impact of G-CSF on mortality and relative dose-intensity (RDI). A comprehensive systematic review and meta-analysis of all reported RCTs comparing primary prophylactic G-CSF with placebo or untreated controls in adult solid tumor and malignant lymphoma patients was undertaken without language restrictions, using electronic databases, conference proceedings, and hand-searching techniques. Two reviewers extracted data independently. Summary estimates of relative risk (RR) with 95% CIs were estimated based on the method of Mantel-Haenszel and DerSimonian and Laird. Seventeen RCTs were identified including 3,493 patients. For infection-related mortality, RR reduction with G-CSF compared with controls was 45% (RR = 0.55; 95% CI, 0.33 to 0.90; P = .018); for early mortality (all-cause mortality during chemotherapy period), it was 40% (RR = 0.60; 95% CI, 0.43 to 0.83; P = .002); and for FN, it was 46% (RR = 0.54; 95% CI, 0.43 to 0.67; P < .001). Average RDI was significantly higher in patients who received G-CSF compared with control patients (P < .001). Bone or musculoskeletal pain was reported in 10.4% of controls and 19.6% of G-CSF patients (RR = 4.03; 95% CI, 2.15 to 7.52; P < .001). Significant reductions in FN with G-CSF were observed in studies allowing secondary G-CSF prophylaxis in controls and in the three trials with concurrent prophylactic antibiotics in both treatment arms. Prophylactic G-CSF reduces the risk of FN and early deaths, including infection-related mortality, while increasing RDI and musculoskeletal pain. There are insufficient data to assess the impact of G-CSF on disease-free and overall survival.

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Reduction by granulocyte colony-stimulating factor of fever and neutropenia induced by chemotherapy in patients with small-cell lung cancer.

I Tabbara, Mike J. Crawford, Matthew D. Johnson … (1991)

Neutropenia and infection are major dose-limiting side effects of chemotherapy. Previous studies have suggested that recombinant methionyl granulocyte colony-stimulating factor (G-CSF) can reduce chemotherapy-related neutropenia in patients with cancer. We conducted a randomized clinical trial to test this hypothesis and the clinical implications. Patients with small-cell lung cancer were enrolled in a multicenter, randomized, double-blind, placebo-controlled trial of recombinant methionyl G-CSF to study the incidence of infection as manifested by fever with neutropenia (absolute neutrophil count, less than 1.0 x 10(9) per liter, with a temperature greater than or equal to 38.2 degrees C) resulting from up to six cycles of chemotherapy with cyclophosphamide, doxorubicin, and etoposide. The patients were randomly assigned to receive either placebo or G-CSF, with treatment beginning on day 4 and continuing through day 17 of a 21-day cycle. The safety of the study treatment could be evaluated in 207 of the 211 patients assigned to either drug, and its efficacy in 199. At least one episode of fever with neutropenia occurred in 77 percent of the placebo group, as compared with 40 percent of the G-CSF group (P less than 0.001). Over all cycles of chemotherapy, the median duration of grade IV neutropenia (absolute neutrophil count, less than 0.5 x 10(9) per liter) was six days with placebo as compared with one day with G-CSF. During cycles of blinded treatment, the number of days of treatment with intravenous antibiotics, the number of days of hospitalization, and the incidence of confirmed infections were reduced by approximately 50 percent when G-CSF was given, as compared with placebo. Mild-to-moderate medullary bone pain occurred in 20 percent of the patients receiving G-CSF. The use of G-CSF as an adjunct to chemotherapy in patients with small-cell cancer of the lung was well tolerated and led to reductions in the incidence of fever with neutropenia and culture-confirmed infections; in the incidence, duration, and severity of grade IV neutropenia; and in the total number of days of treatment with intravenous antibiotics and days of hospitalization.

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Blinded, randomized, multicenter study to evaluate single administration pegfilgrastim once per cycle versus daily filgrastim as an adjunct to chemotherapy in patients with high-risk stage II or stage III/IV breast cancer.

John Glaspy, Aimee Moore, Jake T. Neumann … (2002)

This multicenter, randomized, double-blind, active-control study was designed to determine whether a single subcutaneous injection of pegfilgrastim (SD/01, sustained-duration filgrastim; 100 microg/kg) is as safe and effective as daily filgrastim (5 microg/kg/d) for reducing neutropenia in patients who received four cycles of myelosuppressive chemotherapy. Sixty-two centers enrolled 310 patients who received chemotherapy with docetaxel 75 mg/m(2) and doxorubicin 60 mg/m(2) on day 1 of each cycle for a maximum of four cycles. Patients were randomized to receive on day 2 either a single subcutaneous injection of pegfilgrastim 100 microg/kg per chemotherapy cycle (154 patients) or daily subcutaneous injections of filgrastim 5 microg/kg/d (156 patients). Absolute neutrophil count (ANC), duration of grade 4 neutropenia, and safety parameters were monitored. One dose of pegfilgrastim per chemotherapy cycle was comparable to daily subcutaneous injections of filgrastim with regard to all efficacy end points, including the duration of severe neutropenia and the depth of ANC nadir in all cycles. Febrile neutropenia across all cycles occurred less often in patients who received pegfilgrastim. The difference in the mean duration of severe neutropenia between the pegfilgrastim and filgrastim treatment groups was less than 1 day. Pegfilgrastim was safe and well tolerated, and it was similar to filgrastim. Adverse event profiles in the pegfilgrastim and filgrastim groups were similar. A single injection of pegfilgrastim 100 microg/kg per cycle was as safe and effective as daily injections of filgrastim 5 microg/kg/d in reducing neutropenia and its complications in patients who received four cycles of doxorubicin 60 mg/m(2) and docetaxel 75 mg/m(2).

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Author and article information

Contributors

Igor Bondarenko

Oleg A Gladkov

Reiner Elsaesser

Anton Buchner

Peter Bias

Journal

Journal ID (nlm-ta): BMC Cancer

Journal ID (iso-abbrev): BMC Cancer

Title: BMC Cancer

Publisher: BioMed Central

ISSN (Electronic): 1471-2407

Publication date Collection: 2013

Publication date (Electronic): 14 August 2013

Volume: 13

Page: 386

Affiliations

[1 ]Dnipropetrovsk, State Medical Academy, 9, Dzerzhinsky Street, 49044, Dnipropetrovsk, Ukraine

[2 ]Chelyabinsk Regional Clinical Oncology Center, Chelyabinsk, Russia

[3 ]Teva Ratiopharm, Ulm, Germany

Article

Publisher ID: 1471-2407-13-386

DOI: 10.1186/1471-2407-13-386

PMC ID: 3751756

PubMed ID: 23945072

SO-VID: adb51662-7cf3-45ed-b036-1d91504cd0c9

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Efficacy and safety of lipegfilgrastim versus pegfilgrastim: a randomized, multicenter, active-control phase 3 trial in patients with breast cancer receiving doxorubicin/docetaxel chemotherapy

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Abstract

Background

Methods

Results

Conclusion

Trial Registration

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Research from Ukraine

Most cited references 9

Impact of primary prophylaxis with granulocyte colony-stimulating factor on febrile neutropenia and mortality in adult cancer patients receiving chemotherapy: a systematic review.

Reduction by granulocyte colony-stimulating factor of fever and neutropenia induced by chemotherapy in patients with small-cell lung cancer.

Blinded, randomized, multicenter study to evaluate single administration pegfilgrastim once per cycle versus daily filgrastim as an adjunct to chemotherapy in patients with high-risk stage II or stage III/IV breast cancer.

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