Open Access RESEARCH. Constantin Volovat 1*, Igor M Bondarenko 2, Oleg A Gladkov 3, Reiner Elsässer 4, Anton Buchner 4, Peter Bias 4 and Udo Müller 5 - PDF

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DOI /s RESEARCH Open Access Phase III, randomized, double blind, placebo controlled, multicenter study of lipegfilgrastim in patients with non small cell lung cancer receiving myelosuppressive

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DOI /s RESEARCH Open Access Phase III, randomized, double blind, placebo controlled, multicenter study of lipegfilgrastim in patients with non small cell lung cancer receiving myelosuppressive therapy Constantin Volovat 1*, Igor M Bondarenko 2, Oleg A Gladkov 3, Reiner Elsässer 4, Anton Buchner 4, Peter Bias 4 and Udo Müller 5 Abstract Purpose: The aim of this study was to demonstrate lipegfilgrastim superiority versus placebo in adults with nonsmall cell lung cancer receiving myelosuppressive chemotherapy. Methods: This phase III, double-blind study randomized chemotherapy-naive patients to receive cisplatin and etoposide with either lipegfilgrastim 6 mg or placebo. Because of the placebo control, patients at individual high risk for febrile neutropenia (FN; 20%) were excluded. Study drug was administered on day 4 (24 h after chemotherapy) of a 21-day cycle for 4 cycles. Primary efficacy measure was FN incidence in cycle 1. Secondary assessments included duration of severe neutropenia (DSN), absolute neutrophil count (ANC) profile, and adverse events (AEs). Results: The study included 375 patients (lipegfilgrastim, n = 250; placebo, n = 125). Lipegfilgrastim superiority for FN incidence in cycle 1 was not achieved but incidence was lower (2.4%) versus placebo (5.6%). Cycle 1 mean DSN was significantly shorter for lipegfilgrastim (0.6 ± 1.1 days) versus placebo (2.3 ± 0.5 days; p ). Incidence of severe neutropenia was significantly lower for lipegfilgrastim versus placebo overall and in each cycle (all, p ). Mean ANC nadir was lowest in cycle 1 but significantly higher for lipegfilgrastim (1.60 ± 1.64) than placebo (0.67 ± 0.85; p ). Mean time to ANC recovery was shorter with lipegfilgrastim in each cycle. Treatment-emergent AEs were similar between treatment groups. Conclusions: Lipegfilgrastim was not statistically superior to placebo for incidence of FN in cycle 1, but was more effective in reducing incidence of severe neutropenia, DSN, and time to ANC recovery, with an acceptable safety profile. Controlled-trials.com identifier: ISRCTN Keywords: Neutropenia, Non-small cell lung cancer, Recombinant granulocyte colony-stimulating factor, Lipegfilgrastim, Phase III clinical trial Background Neutropenia is a major dose-limiting toxicity in many myelosuppressive chemotherapy regimens (Holmes et al. 2002; Crawford et al. 2013). A patient s risk of developing neutropenia or febrile neutropenia (FN) depends on *Correspondence: 1 Centrul de Oncologie Medicala, Vasile Conta 2 Str, Iasi, Romania Full list of author information is available at the end of the article several factors, including the type of cancer, chemotherapy regimen (standard-dose, dose-dense, or high-dose therapy), and patient-related and disease-related factors, such as age and comorbidities (Crawford et al. 2013). Recombinant granulocyte colony-stimulating factors (G-CSFs) promote the proliferation and differentiation of neutrophils, alleviating the severity of chemotherapyinduced neutropenia and FN (Cooper et al. 2011). These agents are well established as primary prophylaxis for FN 2015 Volovat et al. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. Page 2 of 11 and are recommended in European and US guidelines for chemotherapy patients at high ( 20%) risk of FN (Crawford et al. 2010, 2013; Smith et al. 2006; Aapro et al. 2011). Filgrastim, the first recombinant human G-CSF, requires daily subcutaneous (SC) injections (Neupogen [package insert] 2013). With the attachment of polyethylene glycol (PEG) to the G-CSF molecule, the half-life of pegfilgrastim was extended compared with filgrastim, allowing once-per-chemotherapy cycle administration (Neulasta [package insert] 2012). Lipegfilgrastim is a glycopegylated, once-per-cycle recombinant human G-CSF expressed in Escherichia coli. It is approved by the European Medicines Agency for reducing the duration of neutropenia and the incidence of FN in adults treated with cytotoxic chemotherapy for malignancy (with the exception of chronic myeloid leukemia and myelodysplastic syndromes) (Lonquex 2013). A recent phase III trial (controlled-trials.com identifier ISRCTN ) demonstrated the clinical efficacy of lipegfilgrastim to be noninferior to pegfilgrastim in reducing neutropenia in breast cancer patients receiving myelosuppressive chemotherapy (Bondarenko et al. 2013). This trial was conducted to demonstrate superiority of once-per-cycle lipegfilgrastim versus placebo in patients with stage IIIb/IV non-small cell lung cancer (NSCLC) receiving up to four cycles of cisplatin and etoposide chemotherapy. Evaluations of efficacy, tolerability, and pharmacokinetic properties were secondary assessments. Results The study was conducted between May 2010 and April 2011 at 72 centers in eight countries. In total, 427 patients were screened and 376 were randomized (Belarus, n = 34; Bosnia-Herzegovina, n = 2; Bulgaria, n = 16; Poland, n = 4; Romania, n = 25; Russia, n = 160; Serbia, n = 20; Ukraine, n = 115). One patient in the lipegfilgrastim group who was randomized in error and received no chemotherapy or study medication was excluded from the efficacy and safety analyses. Thus, 250 patients in the lipegfilgrastim group and 125 in the placebo group were included in the intent-to-treat population (Figure 1). Of these, 169 (67.6%) patients in the lipegfilgrastim and 81 (64.8%) in the placebo group completed treatment. Two patients in the lipegfilgrastim group who died after randomization but did not receive study medication were included in the efficacy but not safety analyses. Patients Baseline demographics and clinical characteristics were similar between treatment groups (Table 1). Most patients were men, had stage IV NSCLC, an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 1, and were receiving chemotherapy for metastatic disease. The mean age was similar in both groups and was somewhat younger than is typically seen for patients with lung cancer. However, this was expected as one of the risk factors that would have contributed to the exclusion of patients at individual high risk for FN was age 65 years, leading to a relatively low percentage of patients aged 65 years (23.5%) being enrolled. Most patients in both treatment groups received their planned chemotherapy dose in each cycle; 3.3% of patients receiving placebo and 2.3% of those receiving lipegfilgrastim had a dose reduction or omission. The total number of administered doses for both cisplatin and etoposide was similar between treatment groups (data not shown). The proportion of patients with chemotherapy dose delays was significantly lower in patients treated with lipegfilgrastim than in those receiving placebo (cycle 2, 28.5 vs. 65.1%; cycle 3, 42.1 vs. 66.3%; and cycle 4, 40.4 vs. 75.3%, respectively; all p ). The mean duration of chemotherapy delay across all cycles also was shorter for patients receiving lipegfilgrastim (6.4 ± 7.6 days) versus those receiving placebo (12.8 ± 10.2 days). Efficacy The primary efficacy measure, incidence of FN in cycle 1, was lower in the lipegfilgrastim group compared with the placebo group (Table 2), but the difference was not significant. Thus, the study failed to achieve its primary objective of demonstrating superiority of lipegfilgrastim versus placebo in these patients. Seven investigator-assessed cases of FN were observed during cycles 2, 3, and 4 (Table 2), but no significant differences in the incidence of FN between treatment groups were observed (p 0.05). None of the patients switched to open-label lipegfilgrastim experienced FN during chemotherapy cycles 2, 3, and 4. Patients receiving lipegfilgrastim experienced a significantly shorter duration of severe neutropenia (DSN) in cycle 1 compared with patients receiving placebo (p ; Table 3). Similarly, the DSN in cycles 2, 3, and 4 was consistently and significantly shorter in the lipegfilgrastim group compared with the placebo group (p , all cycles). The incidence of severe neutropenia was significantly lower in the lipegfilgrastim group versus the placebo group overall (p ) and in each cycle (p , each cycle; Table 4). Notably, in cycles 2, 3, and 4, approximately 80% of patients in the lipegfilgrastim group experienced no severe neutropenia compared with approximately 40% in the placebo group. Patients treated with lipegfilgrastim experienced a shorter mean duration of very severe neutropenia [absolute neutrophil count (ANC) /L] versus patients receiving placebo in cycle 1: 0.3 ± 0.9 days versus 0.2 ± 0.6 days for lipegfilgrastim and placebo, respectively. The mean duration of very severe neutropenia Page 3 of 11 Screened N=427 Excluded n=51 Did not meet inclusion criteria n=14 Met exclusion criteria n=11 Withdrew consent n=18 Other n=8 Randomized N=376 Excluded n=1* Placebo n=125 (ITT/Efficacy Population) Lipegfilgrastim 6 mg n=250 (ITT/Efficacy Population) Not treated n=0 Not treated n=2 Placebo n=125 (Safety Population) Lipegfilgrastim 6 mg n=248 (Safety Population) Discontinued n=44 Death n=7 AE n=14 PD n=11 Withdrew consent n=6 Protocol violation n=2 Other n=4 Discontinued n=79 Death n=22 AE n=13 PD n=22 Withdrew consent n=11 Protocol violation n=1 Other n=10 Completed n=81 Completed n=169 Figure 1 Patient disposition from randomization to study completion. *One patient randomized in error received no chemotherapy and no study medication and was excluded from all statistical analyses and populations. Two patients who received chemotherapy but died after randomization, before study medication was administered, were included in the efficacy population but not in the safety population. Adverse events listed as the primary reason for study discontinuation include placebo patients: two patients each with febrile neutropenia, cerebral infarction, and pneumonia; one patient each with back pain, general physical health deterioration, arterial thrombosis in a limb, pain in the extremities, inadequate control of diabetes mellitus, tumor lysis syndrome, and neutropenia; and one patient with anemia, thrombocytopenia, and neutropenia; lipegfilgrastim patients: two patients with anemia; one patient each with wound necrosis, syphilis, atrial fibrillation, pyothorax, fatigue, increased aspartate aminotransferase, gastric hemorrhage, dementia, pulmonary embolism, asthenia, and hemoptysis. Includes patients lost to follow-up (n = 2), treatment failure (n = 3), and other (n = 5). AE adverse event, ITT intent to treat, PD progression of underlying disease. was also shorter for patients in the lipegfilgrastim group compared with the placebo group in cycles 2, 3, and 4. Patients receiving lipegfilgrastim had a significantly lower incidence of very severe neutropenia over all cycles versus those receiving placebo (p = 0.017). Differences between groups also were significant in cycles 2 (p = 0.031) and 4 (p = 0.007), with the lipegfilgrastim group having a lower incidence (Table 4). The time course of median ANC during cycle 1 is shown in Figure 2. The mean depth of the ANC nadir in both treatment groups was lowest in cycle 1, but was significantly higher in patients treated with lipegfilgrastim (1.6 ± /L) versus patients receiving placebo (0.7 ± /L); p ). In cycles 2, 3, and 4, the mean ANC nadir was greater than /L for the lipegfilgrastim group, but remained below /L for the placebo group (mean 2.8 vs. 0.8, 2.8 vs. 0.8, and 2.6 vs /L, respectively; p in each case). The mean time to ANC nadir was consistently shorter in the lipegfilgrastim group compared with the placebo group in each cycle (cycle 1: 8.2 vs. 13.7; cycle 2: 9.6 vs. 13.6; cycle 3: 9.8 vs. 13.6; cycle 4: 9.6 vs days). In Page 4 of 11 Table 1 Patient demographics and baseline characteristics (intent-to-treat population) Characteristic Placebo (n = 125) Lipegfilgrastim 6 mg SC (n = 250) Age, years Mean ± SD 58.7 ± ± , n (%) 94 (75.2) 193 (77.2) 65 74, n (%) 29 (23.2) 54 (21.6) 75, n (%) 2 (1.6) 3 (1.2) Weight, kg Mean ± SD 70.4 ± ± , n (%) 34 (27.2) 70 (28.0) 60 to 75, n (%) 53 (42.4) 106 (42.4) 75, n (%) 38 (30.4) 74 (29.6) Sex, n (%) Female 20 (16.0) 30 (12.0) Male 105 (84.0) 220 (88.0) Region, n (%) Russia 54 (43.2) 106 (42.4) Ukraine 38 (30.4) 77 (30.8) Rest of Europe 33 (26.4) 67 (26.8) NSCLC stage at enrolment, n (%) Stage IIIB 49 (39.2) 97 (38.8) Stage IV 76 (60.8) 152 (60.8) Unknown 0 (0) 1 (0.4) Time since diagnosis, months Mean ± SD 3.4 ± ± 6.2 Median (range) 1.0 (0 58.0) 1.0 (0 52.0) ECOG PS, n (%) 0 19 (15.2) 28 (11.2) 1 96 (76.8) 194 (77.6) 2 10 (8.0) 28 (11.2) Reason for chemotherapy, n (%) Adjuvant therapy 21 (16.8) 35 (14.0) Treatment for metastatic 104 (83.2) 215 (86.0) disease Lung cancer surgery No 98 (78.4) 215 (86.0) Yes 27 (21.6) 35 (14.0) ECOG PS Eastern Cooperative Oncology Group Performance Status, NSCLC nonsmall cell lung cancer, SC subcutaneously, SD standard deviation. addition, the mean time to ANC recovery from ANC nadir was significantly shorter in the lipegfilgrastim versus placebo group in each cycle (cycle 1: 1.1 vs. 2.7; cycle 2: 0.6 vs. 2.6; cycle 3: 0.8 vs. 2.3; cycle 4: 0.7 vs. 2.6 days; p between groups in each cycle). Patients treated with lipegfilgrastim also experienced a significantly shorter mean time to ANC recovery after chemotherapy in each chemotherapy cycle compared with patients receiving placebo (cycle 1: 6.8 vs. 13.0; cycle 2: 5.6 vs. 13.8; cycle 3: 6.0 vs. 13.7; cycle 4: 5.4 vs days, respectively; p between groups in each cycle). Safety During the double-blind phase, 171 (69.0%) patients in the lipegfilgrastim group and 81 (64.8%) in the placebo group received four doses of study medication. The mean total amount of study medication administered was 19.9 ± 6.7 mg and 19.3 ± 7.0 mg in the lipegfilgrastim and placebo groups, respectively. Adverse events (AEs) were similar between treatment groups. The most common AEs (total incidence of 10% in either treatment group) in the lipegfilgrastim and placebo groups were alopecia (40.7 and 33.6%), anemia (25.4 and 24.0%), nausea (23.8 and 21.6%), neutropenia (20.6 and 35.2%), thrombocytopenia (12.9 and 8.0%), asthenia (11.3 and 18.4%), vomiting (11.3 and 12.0%), and leukopenia (6.5 and 11.2%), respectively (Table 5). In total, 57 (23.0%) patients in the lipegfilgrastim group and 33 (26.4%) patients in the placebo group experienced an AE that lead to discontinuation from the study. Bone-pain-related symptoms (defined as arthralgia, back pain, bone pain, myalgia, noncardiac chest pain, and pain in extremity) were reported in 21 (8.5%) patients treated with lipegfilgrastim and 8 (6.4%) patients receiving placebo. These events were generally mild or moderate in severity and led to study discontinuation in only two patients (both receiving placebo). Serious AEs in the lipegfilgrastim and placebo groups included anemia (3.2 and 1.6%), NSCLC (3.2 and 0.8%), disease progression (2.4 and 0%), FN (2.0 and 4.0%), neutropenia (1.6 and 0.8%), pulmonary embolism (1.2 and 1.6%), cardio-respiratory arrest (1.2% and 0), thrombocytopenia (1.2% and 0), pneumonia (0.8 and 2.4%), pulmonary hemorrhage (0.8% and 0), renal failure (0.8% and 0), and sudden death (0.8% and 0), respectively. A total of 31 (12.5%) patients treated with lipegfilgrastim and nine (7.2%) patients receiving placebo died during the course of the study or up to 30 days after the last study drug injection. General disorders and administration site conditions accounted for eight deaths in the lipegfilgrastim group and two in the placebo group; benign, malignant, and unspecified neoplasms for eight in the lipegfilgrastim group and two in the placebo group; respiratory, thoracic, and mediastinal disorders for five in the lipegfilgrastim group and three in the placebo group; cardiac disorders for four in the lipegfilgrastim group and one in the placebo group; vascular disorders for two in the lipegfilgrastim group; renal and urinary disorders for two in the lipegfilgrastim group; nervous system disorders for one in the lipegfilgrastim group and one in the placebo group; and metabolism and nutrition disorders for one in the lipegfilgrastim group. Changes over time in laboratory assessments were consistent with the underlying disease and with the Page 5 of 11 Table 2 Febrile neutropenia in cycles 1, 2, 3, and 4 (intent-to-treat population) Cycle Placebo Lipegfilgrastim 6 mg SC Lipegfilgrastim 6 mg SC vs. placebo N FN % N FN % OR 95% CI P value* NE NE CI confidence interval, FN febrile neutropenia, NE not evaluable, OR odds ratio, SC subcutaneously. * P values based on a null hypothesis of odds ratio = 1. Table 3 Duration of severe neutropenia in cycles 1, 2, 3, and 4 (ITT population) Cycle Duration of severe neutropenia (days) Placebo 1 N Mean ± SD 2.3 ± ± 1.1 Median (range) 2.0 (0 11.0) 0 (0 5.0) LSM* % CI* to P value* N Mean ± SD 2.2 ± ± 0.7 Median (range) 1.0 (0 11.0) 0 (0 4.0) LSM* % CI* to P value* N Mean ± SD 2.0 ± ± 0.9 Median (range) 1.0 (0 11.0) 0 (0 5.0) LSM* % CI* to P value* N Mean ± SD 2.3 ± ± 1.1 Median (range) 1.0 (0 11.0) 0 (0 0.8) LSM* % CI* to P value* Lipegfilgrastim 6 mg SC Includes patients from the ITT population who were withdrawn from the study. CI confidence interval, ITT intent to treat, LSM least squares mean, SC subcutaneously, SD standard deviation. *Least squares mean, 95% CI, and P value are for Poisson regression analysis lipegfilgrastim placebo. chemotherapy treatment received and, in the lipegfilgrastim group, with G-CSF therapy. Discussion In this study, patients with NSCLC and a low individual risk of FN who received lipegfilgrastim had a lower incidence of FN during cycle 1 (2.4%) compared with patients receiving placebo (5.6%). The incidence of FN was in line with previously published results for pegfilgrastim (Vogel et al. 2005). Because the difference between treatment groups was not statistically significant, the study did not achieve its primary efficacy measure of demonstrating the superiority of lipegfilgrastim versus placebo. Nevertheless, the reduction in the incidence of FN in cycle 1 of 50% in the lipegfilgrastim group versus the placebo group is clinically important, particularly when considering the potential serious effects of FN on the overall health of patients. The actual incidence of FN was lower than anticipated for the placebo group and higher than anticipated for the lipegfilgrastim group, affecting the statistical power of the study. The use of prophylactic G-CSFs is not recommended by treatment guidelines unless a patient s risk for developing FN is high ( 20%); however, the current study used chemotherapy with a reported incidence of FN 20% and excluded patients with an individual high risk of developing FN ( 20% risk). Thus, the use of prophylactic G-CSF therapy in this study was experimental in nature and provides additional evidence for the recommendation that prophylactic G-CSFs should not be used in patients with a risk of FN 20% (Crawford et al. 2010, 2013; Smith et al. 2006; Aapro et al. 2011). The use of cisplatin and etoposide, along with the strict definition of FN, may have contributed to the overall rate of FN being lower than the rate reported for patients receiving placebo in previously published lung cancer studies using the same chemotherapy regimen (Bonomi et al. 2000; Cardenal et al. 1999; Eckardt et al. 2006; Hanna et al. 2006). In particular, excluding patients thought to be at high risk for FN led to a relatively low percentage of patients aged 65 years (24.8%). In a similar study of patients with NSCLC receiving myelosuppressive chemotherapy and adjuvant filgrastim th
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