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Study design: two long-term observational studies of the biosimilar filgrastim Nivestim™ (Hospira filgrastim) in the treatment and prevention of chemotherapy-induced neutropenia.

ABSTRACT: Nivestim™ (filgrastim) is a follow-on biologic agent licensed in the EU for the treatment of neutropenia and febrile neutropenia induced by myelosuppressive chemotherapy. Nivestim™ has been studied in phase 2 and 3 clinical trials where its efficacy and safety was found to be similar to its reference product, Neupogen®. Follow-on biologics continue to be scrutinised for safety. We present a design for two observational phase IV studies that are evaluating the safety profile of Nivestim™ for the prevention and treatment of febrile neutropenia (FN) in patients treated with cytotoxic chemotherapy in general clinical practice.The NEXT (Tolérance de Nivestim chez les patiEnts traités par une chimiothérapie anticancéreuse cytotoXique en praTique courante) and VENICE (VErträglichkeit von NIvestim unter zytotoxischer Chemotherapie in der Behandlung malinger Erkrankungen) trials are multicentre, prospective, longitudinal, observational studies evaluating the safety profile of Nivestim™ in 'real-world' clinical practice. Inclusion criteria include patients undergoing cytotoxic chemotherapy for malignancy and receiving Nivestim as primary or secondary prophylaxis (NEXT and VENICE), or as treatment for ongoing FN (NEXT only). In accordance with European Union pharmacovigilance guidelines, the primary objective is to evaluate the safety of Nivestim™ by gathering data on adverse events in all system organ classes. Secondary objectives include obtaining information on patient characteristics, efficacy of Nivestim™ therapy (including chemotherapy dose intensity), patterns of use of Nivestim™, and physician knowledge regarding filgrastim prescription and the reasons for choosing Nivestim™. Data will be gathered at three visits: 1. At the initial inclusion visit, 2. At a 1-month follow-up visit, and 3. At the end of chemotherapy.Recruitment for VENICE commenced in July 2011 and in November 2011 for NEXT. VENICE completed recruitment in July 2013 with 407 patients, and NEXT in September 2013 with 2123 patients. Last patient, last visit for each study will be December 2013 and March 2014 respectively.The NEXT and VENICE studies will provide long-term safety, efficacy and practice pattern data in patients receiving Nivestim™ to support myelosuppressive chemotherapy in real world clinical practice. These data will improve our understanding of the performance of Nivestim™ in patients encountered in the general patient population.NEXT NCT01574235, VENICE NCT01627990.

SUBMITTER: Kamioner D

PROVIDER: S-EPMC3832750 | biostudies-literature | 2013 Nov

REPOSITORIES: biostudies-literature

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Study design: two long-term observational studies of the biosimilar filgrastim Nivestim™ (Hospira filgrastim) in the treatment and prevention of chemotherapy-induced neutropenia.

Kamioner Didier D Fruehauf Stefan S Maloisel Fréderic F Cals Laurent L Lepretre Stéphane S Berthou Christian C

BMC cancer 20131116

<h4>Background</h4>Nivestim™ (filgrastim) is a follow-on biologic agent licensed in the EU for the treatment of neutropenia and febrile neutropenia induced by myelosuppressive chemotherapy. Nivestim™ has been studied in phase 2 and 3 clinical trials where its efficacy and safety was found to be similar to its reference product, Neupogen®. Follow-on biologics continue to be scrutinised for safety. We present a design for two observational phase IV studies that are evaluating the safety profile of ...[more]

PMID: 24237790

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Project description:Background:The granulocyte-colony stimulating factor (G-CSF) biosimilar filgrastim (Nivestim™) reduces the duration and severity of neutropenia and the frequency of occurrence of febrile neutropenia (FN). Administration of this biosimilar filgrastim and the patient population receiving it at home have not been sufficiently documented in day-to-day medical practice. Insight into home administration may help optimize the management of FN in this setting, potentially at a reduced cost and patient burden vs hospital administration. Materials and methods:This was a prospective, non-interventional, non-comparative, multisite study involving 171 patients across 29 sites treated with at least one dose of filgrastim. Mean age was 59.3 years, and most patients were female and G-CSF-naïve. The data collected originated from paper-based patient questionnaires and routine documentation by the treating physicians. The primary endpoint was the characterization of patients treated with filgrastim. Secondary endpoints were satisfaction with filgrastim, effectiveness, safety and tolerability, and compliance with prescription. Results:Most patients had solid tumors (95.9%), mainly located in the breast, while 4.7% had malignant hematological disease. Solid tumors were recorded as grade 1 (7.9%), grade 2 (28.0%), grade 3 (45.7%), and grade 4 (3.0%), and the majority of patients classified at TNM Stages I and II. Many patients (71.0%) could self-inject filgrastim and 72.2% found the handling instructions "extremely straightforward and easy to understand" at least once. Nearly all (99.4%) patients found the syringes "easy to use" at least once and 91.7% were willing to continue home administration. The mean patient satisfaction score for home administration was 1.9±0.9, ranging from 1 (very satisfied) to 6 (absolutely dissatisfied). No cases of neutropenia were observed and only one event of FN occurred. Conclusion:Home-based prophylaxis for FN with filgrastim was found to be effective, well tolerated, and well received by patients (ClinicalTrials.gov Identifier: NCT02956967).

Project description:BackgroundRisk models of chemotherapy-induced (CIN) and febrile neutropenia (FN) have to date focused on determinants measured at the start of chemotherapy. We extended this static approach with a dynamic approach of CIN/FN risk modeling at the start of each cycle.DesignWe applied predictive modeling using multivariate logistic regression to identify determinants of CIN/FN episodes and related hospitalizations and chemotherapy disturbances (CIN/FN consequences) in analyses at the patient ('ever' during the whole period of chemotherapy) and cycle-level (during a given chemotherapy cycle). Statistical dependence of cycle data being 'nested' under patients was managed using generalized estimation equations. Predictive performance of each model was evaluated using bootstrapped c concordance statistics.ResultsStatic patient-level risk models of 'ever' experiencing CIN/FN adverse events and consequences during a planned chemotherapy regimen included predictors related to history, risk factors, and prophylaxis initiation and intensity. Dynamic cycle-level risk models of experiencing CIN/FN adverse events and consequences in an upcoming cycle included predictors related to history, risk factors, and prophylaxis initiation and intensity; as well as prophylaxis duration, CIN/FN in prior cycle, and treatment center characteristics.ConclusionsThese 'real-world evidence' models provide clinicians with the ability to anticipate CIN/FN adverse events and their consequences at the start of a chemotherapy line (static models); and, innovatively, to assess risk of CIN/FN adverse events and their consequences at the start of each cycle (dynamic models). This enables individualized patient treatment and is consistent with the EORTC recommendation to re-appraise CIN/FN risk at the start of each cycle. Prophylaxis intensity (under-, correctly-, or over-prophylacted relative to current EORTC guidelines) is a major determinant. Under-prophylaxis is clinically unsafe. Over-prophylaxis of patients administered chemotherapy with intermediate or low myelotoxicity levels may be beneficial, both in patients with and without risk factors, and must be validated in future studies.

Project description:BackgroundThe ZOHé study was a prospective, non-interventional, multicentre study in France to assess the use of biosimilar filgrastim Zarzio® (Sandoz filgrastim) in routine clinical practice in patients at risk of neutropenia-inducing chemotherapy (CT).MethodsPatients ??18 years undergoing CT for a malignant disease and with a first prescription for Zarzio® were enrolled in two cohorts according to tumour type: solid tumour or haematological malignancy; results from the solid tumour cohort are reported here. Analyses primarily described the prescription and use of Zarzio® in current practice, and also included identification of factors linked to prescription for primary prophylaxis and comparison of Zarzio® use in relation to European Organisation for Research and Treatment of Cancer (EORTC) guidelines.ResultsResponses were obtained from 125 physicians and 1179 patients with solid tumours, allowing robust statistical analysis of the data. Use of Zarzio® in clinical practice was relatively standardised and followed label indication. The patient profile was in line with EORTC guidelines for granulocyte colony-stimulating factor (G-CSF) febrile neutropenia (FN) prophylaxis, and the majority of patients had ??1 EORTC factor(s) for increased risk of febrile neutropenia. Some patients (10.8%) received Zarzio® despite receiving CT regimens categorised in guidelines as low (<?10%) FN risk ('over prophylaxis'). Nearly half of patients' CT regimens did not have a recommended FN risk category. Zarzio® was commonly initiated as primary prophylaxis; initiation in Cycle ??2 of the current line of CT was associated more with a history of neutropenia. The safety profile of Zarzio® was confirmed.ConclusionsUse of Zarzio® in routine clinical practice is generally in line with EORTC guidelines for prophylaxis of CT-induced neutropenia. Patient-related risk factors appear to be a stronger driver of clinicians' decision to initiate Zarzio® than CT risk category for FN. The intrinsic risk of FN associated with a specific CT protocol is often miscategorised by physicians. In contrast to earlier reports of underuse of G-CSF prophylaxis, over prophylaxis is observed in a small subgroup of patients with FN risk of <?10%.

Project description:BACKGROUND:Three comparative clinical studies assessed the pharmacokinetics (PK), pharmacodynamics (PD), immunogenicity and safety of PF-06881893 (filgrastim-aafi; Nivestym™), a filgrastim biosimilar, versus US-licensed reference product (filgrastim; US-Neupogen®) in healthy volunteers (HVs). METHODS:Two separate open-label, crossover-design PK/PD studies were conducted: a single-dose study (n?=?24) and a multiple-dose study (n?=?60). In each study, HVs were randomized to Nivestym followed by US-Neupogen, or vice versa. Study drug (5 ?g/kg) was administered subcutaneously as a single injection or as five consecutive daily injections. Primary PK and PD endpoints were area under the filgrastim serum concentration-time curve, maximum observed concentration, area under the effect curve (AUEC) for absolute neutrophil count (ANC), maximum observed ANC, AUEC for cluster of differentiation (CD)-34+ count, and maximum observed CD34+ count. In an open-label, parallel-design, non-inferiority, comparative immunogenicity study, HVs were randomized (n?=?128/treatment) to Nivestym or US-Neupogen. The primary endpoint was the proportion of subjects with a negative baseline antidrug antibody (ADA) test result and one or more confirmed post-dose positive ADA result. RESULTS:Overall demographics were as follows: female (n?=?162/340); White (n?=?274/340), Black (n?=?58/340), and other (n?=?8/340); age (18-65 years); and weight (50.8-96.5 kg). All primary PK and PD endpoints met the pre-specified criteria for PK and PD equivalence. The primary endpoint in the comparative immunogenicity study met pre-specified criteria for non-inferiority. CONCLUSIONS:Nivestym demonstrated PK and PD equivalence in single and multiple subcutaneous-dose settings and non-inferiority for immunogenicity to US-Neupogen, with a comparable safety profile, supporting the demonstration of biosimilarity. TRIAL REGISTRATION:ClinicalTrials.gov C1121002 (NCT02766647); C1121003 (NCT02766634); C1121012 (NCT02923791).

Project description:IntroductionFebrile neutropenia (FN) is a serious and frequent complication of cytotoxic chemotherapy. Biosimilar filgrastim (Nivestim™, Hospira Inc, A Pfizer Company, Lake Forest, IL, USA) is a granulocyte-colony stimulating factor licensed for the treatment of neutropenia and FN induced by myelosuppressive chemotherapy. The primary goal of this VENICE study (ClinicalTrials.gov identifier, NCT01627990) was to observe the tolerability, safety and efficacy of biosimilar filgrastim in patients receiving cancer chemotherapy.MethodsThis was a prospective, multicenter, non-interventional, longitudinal study. Consenting adult patients with solid tumors or hematologic malignancies for whom cytotoxic chemotherapy and treatment with biosimilar filgrastim was planned were enrolled.ResultsAmong the enrolled patients (N = 386), 81% were female, with a median age (range) of 61 (22-92) years, with 39% >65 years old. Most patients (n = 338; 88%) had solid tumors and the remainder (n = 49; 13%) had hematological malignancies. The majority of the patients (64%) received biosimilar filgrastim as primary prophylaxis and 36% as secondary prophylaxis. At the follow-up visits, for the majority of patients (95.6%) there had been no change in chemotherapy dose due to FN. For two patients (0.5%) the chemotherapy was discontinued due to FN and for four patients (1.0%) the chemotherapy dose was reduced due to FN. For the majority of patients (96.9%) the chemotherapy cycle following the first biosimilar filgrastim treatment was not delayed due to FN. For 3 patients (0.8%), the chemotherapy was delayed following the first biosimilar filgrastim treatment. Less than one-third (29.8%) of the patients experienced ≥1 adverse event that was at least potentially related to biosimilar filgrastim treatment.ConclusionsBiosimilar filgrastim was effective and well-tolerated in both the primary and secondary prophylactic setting in patients undergoing chemotherapy for solid tumors and hematological malignancies.Trial registrationClinicalTrials.gov identifier, NCT01627990.FundingHospira Inc, A Pfizer Company, Lake Forest, IL, USA.

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Study design: two long-term observational studies of the biosimilar filgrastim Nivestim™ (Hospira filgrastim) in the treatment and prevention of chemotherapy-induced neutropenia.

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Study design: two long-term observational studies of the biosimilar filgrastim Nivestim™ (Hospira filgrastim) in the treatment and prevention of chemotherapy-induced neutropenia.

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