Randomized and dose-escalation trials of recombinant human serum albumin /granulocyte colony-stimulating factor in patients with breast cancer receiving anthracycline-containing chemotherapy

Shanshan Chen, Yiqun Han, Quchang Ouyang, Jianguo Lu, Qingyuan Zhang, Shun'e Yang, Jingfen Wang, Haixin Huang, Hong Liu, Zhimin Shao, Hui Li, Zhendong Chen, Sanyuan Sun, Cuizhi Geng, Junguo Lu, Jianwei Sun, Jiayu Wang, Binghe Xu, Shanshan Chen, Yiqun Han, Quchang Ouyang, Jianguo Lu, Qingyuan Zhang, Shun'e Yang, Jingfen Wang, Haixin Huang, Hong Liu, Zhimin Shao, Hui Li, Zhendong Chen, Sanyuan Sun, Cuizhi Geng, Junguo Lu, Jianwei Sun, Jiayu Wang, Binghe Xu

Abstract

Background: To evaluate the efficacy and safety of recombinant human serum albumin /granulocyte colony-stimulating factor (rHSA/G-CSF) in breast cancer following receipt of cytotoxic agents.

Methods: The phase 1b trial assessed the pharmacokinetics, pharmacodynamics, and safety of dose-escalation, ranging from rHSA/G-CSF 1800 μg, 2100 μg, and 2400 μg. Randomized controlled phase 2b trial was further conducted to ensure the comparative efficacy and safety of rHSA/G-CSF 2400 μg and rhG-CSF 5 μg/kg. In multicenter, randomized, open-label, parallel, phase 2 study, participants treated with anthracycline-containing chemotherapy were assigned in a ratio 1:1:1 to receive double delivery of rHSA/G-CSF 1200 μg, 1500 μg, and continuous rhG-CSF 5 μg/kg.

Results: Between December 16, 2014, to July 23, 2018, a total of 320 patients were enrolled, including 25 individuals in phase 1b trial, 80 patients in phase 2b trial, and 215 participants in phase 2 study. The mean duration of agranulocytosis during the first chemotherapeutic intermission was observed as 1.14 ± 1.35 days in rHSA/G-CSF 1500 μg, which was comparable with that of 1.07 ± 0.97 days obtained in rhG-CSF control (P = 0.71). Safety profiles were assessed to be acceptable ranging from rHSA/G-CSF 1800 μg to 2400 μg, while the double delivery of HSA/G-CSF 2400 μg failed to meet the noninferiority in comparison with rhG-CSF.

Conclusion: The prospective randomized controlled trials demonstrated that rHSA/G-CSF was efficacious and well-tolerated with an approachable frequency and expense of application for prophylactic management of agranulocytosis. The double delivery of rHSA/G-CSF 1500 μg in comparisons with paralleling G-CSF preparations is warranted in the phase 3 trial.

Trial registration: ClinicalTrials.gov identifiers: NCT02465801 (11/17/2014), NCT03246009 (08/08/2017), NCT03251768 (08/07/2017).

Keywords: Breast cancer; Chemotherapy; Clinical trials; Neutropenia; rHSA/G-CSF; rhG-CSF.

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Flow diagram of enrollment, allocation, follow-up, and analysis of patients included in phase 1b (a), phase 2b (b), and phase 2 (c). * one patient was withdrawn for the occurrence of grade 4 neutropenia
Fig. 2
Fig. 2
Pharmacokinetics analysis of single dosage of rHSA/G-CSF (a) and double dosage of rHSA/G-CSF (b) from dose-escalation phase 1b trial
Fig. 3
Fig. 3
Dynamic measures of ANC and WBC in phase 1b (a-d), phase 2b (e-f), and phase 2 (g-h). The delivery pattern of rHSA/G-CSF in randomized trials were shown on the top of the corresponding curves, while the ranges of grade 4, grade 3, and normalization were demonstrated in accordance with the corresponding values

References

    1. Lluch A, Barrios CH, Torrecillas L, Ruiz-Borrego M, Bines J, Segalla J, et al. Phase III trial of adjuvant capecitabine after standard neo−/adjuvant chemotherapy in patients with early triple-negative breast cancer (GEICAM/2003-11_CIBOMA/2004-01). J Clin Oncol. 2020;38(3):203–13. 10.1200/JCO.19.00904.
    1. Barton MK. Patients of all ages with advanced non-small cell lung cancer are not receiving chemotherapy. CA Cancer J Clin. 2015;65(5):337–338. doi: 10.3322/caac.21290.
    1. Ozer H, Armitage JO, Bennett CL, Crawford J, Demetri GD, Pizzo PA, et al. 2000 update of recommendations for the use of hematopoietic colony-stimulating factors: evidence-based, clinical practice guidelines. American Society of Clinical Oncology Growth Factors Expert Panel. J Clin Oncol. 2000;18(20):3558–85. 10.1200/JCO.2000.18.20.3558.
    1. Trillet-Lenoir V, Green J, Manegold C, Von Pawel J, Gatzemeier U, Lebeau B, et al. Recombinant granulocyte colony stimulating factor reduces the infectious complications of cytotoxic chemotherapy. Eur J Cancer. 1993;29A(3):319–24.
    1. Crawford J, Ozer H, Stoller R, Johnson D, Lyman G, Tabbara I, et al. Reduction by granulocyte colony-stimulating factor of fever and neutropenia induced by chemotherapy in patients with small-cell lung cancer. N Engl J Med. 1991;325(3):164–70. 10.1056/NEJM199107183250305.
    1. Vogel CL, Wojtukiewicz MZ, Carroll RR, Tjulandin SA, Barajas-Figueroa LJ, Wiens BL, et al. First and subsequent cycle use of pegfilgrastim prevents febrile neutropenia in patients with breast cancer: a multicenter, double-blind, placebo-controlled phase III study. J Clin Oncol. 2005;23(6):1178–84. 10.1200/JCO.2005.09.102.
    1. Holmes FA, O'Shaughnessy JA, Vukelja S, Jones SE, Shogan J, Savin M, et al. 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. J Clin Oncol. 2002;20(3):727–31. 10.1200/JCO.2002.20.3.727.
    1. Green MD, Koelbl H, Baselga J, Galid A, Guillem V, Gascon P, et al. A randomized double-blind multicenter phase III study of fixed-dose single-administration pegfilgrastim versus daily filgrastim in patients receiving myelosuppressive chemotherapy. Ann Oncol. 2003;14(1):29–35. 10.1093/annonc/mdg019.
    1. Smith TJ, Khatcheressian J, Lyman GH, Ozer H, Armitage JO, Balducci L, et al. 2006 update of recommendations for the use of white blood cell growth factors: an evidence-based clinical practice guideline. J Clin Oncol. 2006;24(19):3187–205. 10.1200/JCO.2006.06.4451.
    1. Welte K, Gabrilove J, Bronchud MH, Platzer E, Morstyn G. Filgrastim (r-metHuG-CSF): the first 10 years. Blood. 1996;88(6):1907–1929. doi: 10.1182/blood.V88.6.1907.bloodjournal8861907.
    1. Demetri GD, Griffin JD. Granulocyte colony-stimulating factor and its receptor. Blood. 1991;78(11):2791–2808. doi: 10.1182/blood.V78.11.2791.bloodjournal78112791.
    1. Ozer H. American Society of Clinical Oncology guidelines for the use of hematopoietic colony-stimulating factors. Curr Opin Hematol. 1996;3(1):3–10. doi: 10.1097/00062752-199603010-00002.
    1. Aapro MS, Cameron DA, Pettengell R, Bohlius J, Crawford J, Ellis M, et al. EORTC guidelines for the use of granulocyte-colony stimulating factor to reduce the incidence of chemotherapy-induced febrile neutropenia in adult patients with lymphomas and solid tumours. Eur J Cancer. 2006;42(15):2433–53. 10.1016/j.ejca.2006.05.002.
    1. Layton JE, Hockman H, Sheridan WP, Morstyn G. Evidence for a novel in vivo control mechanism of granulopoiesis: mature cell-related control of a regulatory growth factor. Blood. 1989;74(4):1303–1307. doi: 10.1182/blood.V74.4.1303.1303.
    1. Kuwabara T, Kato Y, Kobayashi S, Suzuki H, Sugiyama Y. Nonlinear pharmacokinetics of a recombinant human granulocyte colony-stimulating factor derivative (nartograstim): species differences among rats, monkeys and humans. J Pharmacol Exp Ther. 1994;271(3):1535–1543.
    1. Pelegri-O'Day EM, Lin EW, Maynard HD. Therapeutic protein-polymer conjugates: advancing beyond PEGylation. J Am Chem Soc. 2014;136(41):14323–14332. doi: 10.1021/ja504390x.
    1. Harris JM, Martin NE, Modi M. Pegylation: a novel process for modifying pharmacokinetics. Clin Pharmacokinet. 2001;40(7):539–551. doi: 10.2165/00003088-200140070-00005.
    1. van Der Auwera P, Platzer E, Xu ZX, Schulz R, Feugeas O, Capdeville R, et al. Pharmacodynamics and pharmacokinetics of single doses of subcutaneous pegylated human G-CSF mutant (Ro 25-8315) in healthy volunteers: comparison with single and multiple daily doses of filgrastim. Am J Hematol. 2001;66(4):245–51. 10.1002/ajh.1052.
    1. Knop K, Hoogenboom R, Fischer D, Schubert US. Poly (ethylene glycol) in drug delivery: pros and cons as well as potential alternatives. Angew Chem Int Ed Engl. 2010;49(36):6288–6308. doi: 10.1002/anie.200902672.
    1. Elsadek B, Kratz F. Impact of albumin on drug delivery--new applications on the horizon. J Control Release. 2012;157(1):4–28. doi: 10.1016/j.jconrel.2011.09.069.
    1. Bhagavan NV, Lai EM, Rios PA, Yang J, Ortega-Lopez AM, Shinoda H, et al. Evaluation of human serum albumin cobalt binding assay for the assessment of myocardial ischemia and myocardial infarction. Clin Chem. 2003;49(4):581–5. 10.1373/49.4.581.
    1. Chaudhury C, Mehnaz S, Robinson JM, Hayton WL, Pearl DK, Roopenian DC, et al. The major histocompatibility complex-related Fc receptor for IgG (FcRn) binds albumin and prolongs its lifespan. J Exp Med. 2003;197(3):315–22. 10.1084/jem.20021829.
    1. Brønden A, Naver SV, Knop FK, Christensen M. Albiglutide for treating type 2 diabetes: an evaluation of pharmacokinetics/pharmacodynamics and clinical efficacy. Expert Opin Drug Metab Toxicol. 2015;11(9):1493–1503. doi: 10.1517/17425255.2015.1068288.
    1. Chen N, Brachmann C, Liu X, Pierce DW, Dey J, Kerwin WS, et al. Albumin-bound nanoparticle (nab) paclitaxel exhibits enhanced paclitaxel tissue distribution and tumor penetration. Cancer Chemother Pharmacol. 2015;76(4):699–712. 10.1007/s00280-015-2833-5.
    1. Gradishar WJ, Tjulandin S, Davidson N, Shaw H, Desai N, Bhar P, et al. Phase III trial of nanoparticle albumin-bound paclitaxel compared with polyethylated castor oil-based paclitaxel in women with breast cancer. J Clin Oncol. 2005;23(31):7794–803. 10.1200/JCO.2005.04.937.
    1. McHugh J. A cellular cascade of GM-CSF production. Nat Rev Rheumatol. 2018;14(7):386. doi: 10.1038/s41584-018-0038-0.
    1. Volovat C, Gladkov OA, Bondarenko IM, Barash S, Buchner A, Bias P, et al. Efficacy and safety of balugrastim compared with pegfilgrastim in patients with breast cancer receiving chemotherapy. Clin Breast Cancer. 2014;14(2):101–8. 10.1016/j.clbc.2013.10.001.
    1. Zhang X, Zhang Z, Cao M, Liu B, Mori M, Luoh SW, et al. A randomized parallel controlled phase II Trial of recombinant human endostatin added to neoadjuvant chemotherapy for stage III breast cancer. Clin Breast Cancer. 2020;20(4):291–299.e293.
    1. Liu Y, Xu Z, Zhang Z, Wen G, Sun J, Han F. Efficacy and safety of TE/TEC/intensive paclitaxel neoadjuvant chemotherapy for the treatment of breast cancer. Oncol Lett. 2019;17(1):907–912. doi: 10.3892/ol.2018.9658.
    1. Xu B, Shao Z, Wang S, Jiang Z, Hu X, Zhang X, et al. Treatment patterns for adjuvant docetaxel-based chemotherapy in early-stage breast cancer in China: A pooled retrospective analysis of four observational studies. Chin J Cancer Res = Chung-kuo yen cheng yen chiu. 2018;30(3):327–39.
    1. Gu X, Zhang Y, Chen L, Guo J, Zhang WH. Efficacy of neo-adjuvant chemotherapy with TEC regimen on breast cancer. Cancer Chemother Pharmacol. 2015;75(2):301–308. doi: 10.1007/s00280-014-2646-y.
    1. Russell N, Mesters R, Schubert J, Boogaerts M, Johnsen HE, Canizo CD, et al. A phase 2 pilot study of pegfilgrastim and filgrastim for mobilizing peripheral blood progenitor cells in patients with non-Hodgkin's lymphoma receiving chemotherapy. Haematologica. 2008;93(3):405–12. 10.3324/haematol.11287.
    1. Gladkov O, Moiseyenko V, Bondarenko IN, Shparyk Y, Barash S, Adar L, et al. Phase II dose-finding study of balugrastim in breast cancer patients receiving myelosuppressive chemotherapy. Med Oncol (Northwood, London, England). 2015;32(6):623. 10.1007/s12032-015-0623-x.
    1. Dale DC, Rosenberg PS, Alter BP. Lineage-specific hematopoietic growth factors. N Engl J Med. 2006;355(5):526–527. doi: 10.1056/NEJMc061587.
    1. Gladkov O, Moiseyenko V, Bondarenko IN, Shparyk Y, Barash S, Adar L, et al. A phase III study of balugrastim versus pegfilgrastim in breast cancer patients receiving chemotherapy with doxorubicin and docetaxel. Oncologist. 2016;21(1):7–15. 10.1634/theoncologist.2015-0152.

Source: PubMed

Patrocinadores y Colaboradores

Condiciones médicas

Intervenciones de drogas

3
Suscribir