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Mariana Vasilica - One of the best experts on this subject based on the ideXlab platform.
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efficacy pharmacokinetics and safety of the biosimilar ct p10 compared with rituximab in patients with previously untreated advanced stage follicular lymphoma a randomised double blind parallel group non inferiority phase 3 trial
The Lancet Haematology, 2017Co-Authors: Christian Buske, Michinori Ogura, Wojciech Jurczak, Juanmanuel Sancho, Edvard Zhavrid, Jose Angel Hernandezrivas, Aliaksandr Prokharau, Mariana Vasilica, Rajinish Nagarkar, Dzhelil OsmanovAbstract:Summary Background Studies in patients with rheumatoid arthritis have shown that the rituximab biosimilar CT-P10 (Celltrion, Incheon, South Korea) has equivalent efficacy and pharmacokinetics to rituximab. In this phase 3 study, we aimed to assess the non-inferior efficacy and pharmacokinetic equivalence of CT-P10 compared with rituximab, when used in combination with cyclophosphamide, vincristine, and prednisone (CVP) in patients with newly diagnosed advanced-stage follicular lymphoma. Methods In this ongoing, randomised, double-blind, parallel-group, active-controlled study, patients aged 18 years or older with Ann Arbor stage III–IV follicular lymphoma were assigned 1:1 to CVP plus intravenous infusions of 375 mg/m 2 CT-P10 or rituximab on day 1 of eight 21-day cycles. Randomisation was done by the investigators using an interactive web or voice response system and a computer-generated randomisation schedule, prepared by a clinical research organisation. Randomisation was balanced using permuted blocks and was stratified by country, gender, and Follicular Lymphoma International Prognostic Index score (0–2 vs 3–5). Study teams from the sponsor and clinical research organisation, investigators, and patients were masked to treatment assignment. The study was divided into two parts: part 1 assessing equivalence of pharmacokinetics (in the pharmacokinetics subset), and part 2 assessing efficacy in all randomised patients (patients from the pharmacokinetics subset plus additional patients enrolled in part 2). Equivalence of pharmacokinetics was shown if the 90% CIs for the geometric mean ratio of CT-P10 to rituximab in AUCτ and C maxSS were within the bounds of the equivalence margin of 80% and 125%. Non-inferiority of response was shown if the one-sided 97·5% CI lay on the positive side of the −7% margin, using a one-sided test done at the 2·5% significance level. The primary efficacy endpoint was the proportion of patients who had an overall response over eight cycles and was assessed in the efficacy population (all randomised patients). The primary pharmacokinetic endpoints were area under the serum Concentration–time curve at steady state (AUCτ) and maximum serum Concentration at steady state (C maxSS ) at cycle 4, assessed in the pharmokinetic population. This trial is registered with ClinicalTrials.gov, number NCT02162771. Findings Between July 28, 2014, and Dec 29, 2015, 140 patients were enrolled. Here we report data for the eight-cycle induction period, up to week 24. The proportion of patients with an overall response in the efficacy population was 64 (97·0%) of 66 patients in the CT-P10 treatment group and 63 (92·6%) of 68 patients in the rituximab treatment group (4·3%; one-sided 97·5% CI −4·25), which lay on the positive side of the predefined non-inferiority margin. The ratio of geometric least squares means (CT-P10/rituximab) was 102·25% (90% CI 94·05–111·17) for AUCτ and 100·67% (93·84–108·00) for C maxSS , with all CIs within the bioequivalence margin of 80–125%. Treatment-emergent adverse events were reported for 58 (83%) of 70 patients in the CT-P10 treatment group and 56 (80%) of 70 in the rituximab treatment group. The most common grade 3 or 4 treatment-emergent adverse event in each treatment group was neutropenia (grade 3, 15 [21%] of 70 patients in the CT-P10 group and seven [10%] of 70 patients in the rituximab group). The proportion of patients who experienced at least one treatment-emergent serious adverse event was 16 (23%) of 70 patients in the CT-P10 group and nine (13%) of 70 patients in the rituximab group. Interpretation In this study, we show that CT-P10 exhibits non-inferior efficacy and pharmacokinetic equivalence to rituximab. The safety profile of CT-P10 was comparable to that of rituximab. CT-P10 might represent a new therapeutic option for advanced-stage follicular lymphoma. Funding Celltrion, Inc.
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efficacy pharmacokinetics and safety of the biosimilar ct p10 compared with rituximab in patients with previously untreated advanced stage follicular lymphoma a randomised double blind parallel group non inferiority phase 3 trial
The Lancet Haematology, 2017Co-Authors: Won Seog Kim, Christian Buske, Michinori Ogura, Wojciech Jurczak, Juanmanuel Sancho, Edvard Zhavrid, Jose Angel Hernandezrivas, Aliaksandr Prokharau, Jin Seok Kim, Mariana VasilicaAbstract:Summary Background Studies in patients with rheumatoid arthritis have shown that the rituximab biosimilar CT-P10 (Celltrion, Incheon, South Korea) has equivalent efficacy and pharmacokinetics to rituximab. In this phase 3 study, we aimed to assess the non-inferior efficacy and pharmacokinetic equivalence of CT-P10 compared with rituximab, when used in combination with cyclophosphamide, vincristine, and prednisone (CVP) in patients with newly diagnosed advanced-stage follicular lymphoma. Methods In this ongoing, randomised, double-blind, parallel-group, active-controlled study, patients aged 18 years or older with Ann Arbor stage III–IV follicular lymphoma were assigned 1:1 to CVP plus intravenous infusions of 375 mg/m 2 CT-P10 or rituximab on day 1 of eight 21-day cycles. Randomisation was done by the investigators using an interactive web or voice response system and a computer-generated randomisation schedule, prepared by a clinical research organisation. Randomisation was balanced using permuted blocks and was stratified by country, gender, and Follicular Lymphoma International Prognostic Index score (0–2 vs 3–5). Study teams from the sponsor and clinical research organisation, investigators, and patients were masked to treatment assignment. The study was divided into two parts: part 1 assessing equivalence of pharmacokinetics (in the pharmacokinetics subset), and part 2 assessing efficacy in all randomised patients (patients from the pharmacokinetics subset plus additional patients enrolled in part 2). Equivalence of pharmacokinetics was shown if the 90% CIs for the geometric mean ratio of CT-P10 to rituximab in AUCτ and C maxSS were within the bounds of the equivalence margin of 80% and 125%. Non-inferiority of response was shown if the one-sided 97·5% CI lay on the positive side of the −7% margin, using a one-sided test done at the 2·5% significance level. The primary efficacy endpoint was the proportion of patients who had an overall response over eight cycles and was assessed in the efficacy population (all randomised patients). The primary pharmacokinetic endpoints were area under the serum Concentration–time curve at steady state (AUCτ) and maximum serum Concentration at steady state (C maxSS ) at cycle 4, assessed in the pharmokinetic population. This trial is registered with ClinicalTrials.gov, number NCT02162771. Findings Between July 28, 2014, and Dec 29, 2015, 140 patients were enrolled. Here we report data for the eight-cycle induction period, up to week 24. The proportion of patients with an overall response in the efficacy population was 64 (97·0%) of 66 patients in the CT-P10 treatment group and 63 (92·6%) of 68 patients in the rituximab treatment group (4·3%; one-sided 97·5% CI −4·25), which lay on the positive side of the predefined non-inferiority margin. The ratio of geometric least squares means (CT-P10/rituximab) was 102·25% (90% CI 94·05–111·17) for AUCτ and 100·67% (93·84–108·00) for C maxSS , with all CIs within the bioequivalence margin of 80–125%. Treatment-emergent adverse events were reported for 58 (83%) of 70 patients in the CT-P10 treatment group and 56 (80%) of 70 in the rituximab treatment group. The most common grade 3 or 4 treatment-emergent adverse event in each treatment group was neutropenia (grade 3, 15 [21%] of 70 patients in the CT-P10 group and seven [10%] of 70 patients in the rituximab group). The proportion of patients who experienced at least one treatment-emergent serious adverse event was 16 (23%) of 70 patients in the CT-P10 group and nine (13%) of 70 patients in the rituximab group. Interpretation In this study, we show that CT-P10 exhibits non-inferior efficacy and pharmacokinetic equivalence to rituximab. The safety profile of CT-P10 was comparable to that of rituximab. CT-P10 might represent a new therapeutic option for advanced-stage follicular lymphoma. Funding Celltrion, Inc.
Christian Buske - One of the best experts on this subject based on the ideXlab platform.
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efficacy pharmacokinetics and safety of the biosimilar ct p10 compared with rituximab in patients with previously untreated advanced stage follicular lymphoma a randomised double blind parallel group non inferiority phase 3 trial
The Lancet Haematology, 2017Co-Authors: Christian Buske, Michinori Ogura, Wojciech Jurczak, Juanmanuel Sancho, Edvard Zhavrid, Jose Angel Hernandezrivas, Aliaksandr Prokharau, Mariana Vasilica, Rajinish Nagarkar, Dzhelil OsmanovAbstract:Summary Background Studies in patients with rheumatoid arthritis have shown that the rituximab biosimilar CT-P10 (Celltrion, Incheon, South Korea) has equivalent efficacy and pharmacokinetics to rituximab. In this phase 3 study, we aimed to assess the non-inferior efficacy and pharmacokinetic equivalence of CT-P10 compared with rituximab, when used in combination with cyclophosphamide, vincristine, and prednisone (CVP) in patients with newly diagnosed advanced-stage follicular lymphoma. Methods In this ongoing, randomised, double-blind, parallel-group, active-controlled study, patients aged 18 years or older with Ann Arbor stage III–IV follicular lymphoma were assigned 1:1 to CVP plus intravenous infusions of 375 mg/m 2 CT-P10 or rituximab on day 1 of eight 21-day cycles. Randomisation was done by the investigators using an interactive web or voice response system and a computer-generated randomisation schedule, prepared by a clinical research organisation. Randomisation was balanced using permuted blocks and was stratified by country, gender, and Follicular Lymphoma International Prognostic Index score (0–2 vs 3–5). Study teams from the sponsor and clinical research organisation, investigators, and patients were masked to treatment assignment. The study was divided into two parts: part 1 assessing equivalence of pharmacokinetics (in the pharmacokinetics subset), and part 2 assessing efficacy in all randomised patients (patients from the pharmacokinetics subset plus additional patients enrolled in part 2). Equivalence of pharmacokinetics was shown if the 90% CIs for the geometric mean ratio of CT-P10 to rituximab in AUCτ and C maxSS were within the bounds of the equivalence margin of 80% and 125%. Non-inferiority of response was shown if the one-sided 97·5% CI lay on the positive side of the −7% margin, using a one-sided test done at the 2·5% significance level. The primary efficacy endpoint was the proportion of patients who had an overall response over eight cycles and was assessed in the efficacy population (all randomised patients). The primary pharmacokinetic endpoints were area under the serum Concentration–time curve at steady state (AUCτ) and maximum serum Concentration at steady state (C maxSS ) at cycle 4, assessed in the pharmokinetic population. This trial is registered with ClinicalTrials.gov, number NCT02162771. Findings Between July 28, 2014, and Dec 29, 2015, 140 patients were enrolled. Here we report data for the eight-cycle induction period, up to week 24. The proportion of patients with an overall response in the efficacy population was 64 (97·0%) of 66 patients in the CT-P10 treatment group and 63 (92·6%) of 68 patients in the rituximab treatment group (4·3%; one-sided 97·5% CI −4·25), which lay on the positive side of the predefined non-inferiority margin. The ratio of geometric least squares means (CT-P10/rituximab) was 102·25% (90% CI 94·05–111·17) for AUCτ and 100·67% (93·84–108·00) for C maxSS , with all CIs within the bioequivalence margin of 80–125%. Treatment-emergent adverse events were reported for 58 (83%) of 70 patients in the CT-P10 treatment group and 56 (80%) of 70 in the rituximab treatment group. The most common grade 3 or 4 treatment-emergent adverse event in each treatment group was neutropenia (grade 3, 15 [21%] of 70 patients in the CT-P10 group and seven [10%] of 70 patients in the rituximab group). The proportion of patients who experienced at least one treatment-emergent serious adverse event was 16 (23%) of 70 patients in the CT-P10 group and nine (13%) of 70 patients in the rituximab group. Interpretation In this study, we show that CT-P10 exhibits non-inferior efficacy and pharmacokinetic equivalence to rituximab. The safety profile of CT-P10 was comparable to that of rituximab. CT-P10 might represent a new therapeutic option for advanced-stage follicular lymphoma. Funding Celltrion, Inc.
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efficacy pharmacokinetics and safety of the biosimilar ct p10 compared with rituximab in patients with previously untreated advanced stage follicular lymphoma a randomised double blind parallel group non inferiority phase 3 trial
The Lancet Haematology, 2017Co-Authors: Won Seog Kim, Christian Buske, Michinori Ogura, Wojciech Jurczak, Juanmanuel Sancho, Edvard Zhavrid, Jose Angel Hernandezrivas, Aliaksandr Prokharau, Jin Seok Kim, Mariana VasilicaAbstract:Summary Background Studies in patients with rheumatoid arthritis have shown that the rituximab biosimilar CT-P10 (Celltrion, Incheon, South Korea) has equivalent efficacy and pharmacokinetics to rituximab. In this phase 3 study, we aimed to assess the non-inferior efficacy and pharmacokinetic equivalence of CT-P10 compared with rituximab, when used in combination with cyclophosphamide, vincristine, and prednisone (CVP) in patients with newly diagnosed advanced-stage follicular lymphoma. Methods In this ongoing, randomised, double-blind, parallel-group, active-controlled study, patients aged 18 years or older with Ann Arbor stage III–IV follicular lymphoma were assigned 1:1 to CVP plus intravenous infusions of 375 mg/m 2 CT-P10 or rituximab on day 1 of eight 21-day cycles. Randomisation was done by the investigators using an interactive web or voice response system and a computer-generated randomisation schedule, prepared by a clinical research organisation. Randomisation was balanced using permuted blocks and was stratified by country, gender, and Follicular Lymphoma International Prognostic Index score (0–2 vs 3–5). Study teams from the sponsor and clinical research organisation, investigators, and patients were masked to treatment assignment. The study was divided into two parts: part 1 assessing equivalence of pharmacokinetics (in the pharmacokinetics subset), and part 2 assessing efficacy in all randomised patients (patients from the pharmacokinetics subset plus additional patients enrolled in part 2). Equivalence of pharmacokinetics was shown if the 90% CIs for the geometric mean ratio of CT-P10 to rituximab in AUCτ and C maxSS were within the bounds of the equivalence margin of 80% and 125%. Non-inferiority of response was shown if the one-sided 97·5% CI lay on the positive side of the −7% margin, using a one-sided test done at the 2·5% significance level. The primary efficacy endpoint was the proportion of patients who had an overall response over eight cycles and was assessed in the efficacy population (all randomised patients). The primary pharmacokinetic endpoints were area under the serum Concentration–time curve at steady state (AUCτ) and maximum serum Concentration at steady state (C maxSS ) at cycle 4, assessed in the pharmokinetic population. This trial is registered with ClinicalTrials.gov, number NCT02162771. Findings Between July 28, 2014, and Dec 29, 2015, 140 patients were enrolled. Here we report data for the eight-cycle induction period, up to week 24. The proportion of patients with an overall response in the efficacy population was 64 (97·0%) of 66 patients in the CT-P10 treatment group and 63 (92·6%) of 68 patients in the rituximab treatment group (4·3%; one-sided 97·5% CI −4·25), which lay on the positive side of the predefined non-inferiority margin. The ratio of geometric least squares means (CT-P10/rituximab) was 102·25% (90% CI 94·05–111·17) for AUCτ and 100·67% (93·84–108·00) for C maxSS , with all CIs within the bioequivalence margin of 80–125%. Treatment-emergent adverse events were reported for 58 (83%) of 70 patients in the CT-P10 treatment group and 56 (80%) of 70 in the rituximab treatment group. The most common grade 3 or 4 treatment-emergent adverse event in each treatment group was neutropenia (grade 3, 15 [21%] of 70 patients in the CT-P10 group and seven [10%] of 70 patients in the rituximab group). The proportion of patients who experienced at least one treatment-emergent serious adverse event was 16 (23%) of 70 patients in the CT-P10 group and nine (13%) of 70 patients in the rituximab group. Interpretation In this study, we show that CT-P10 exhibits non-inferior efficacy and pharmacokinetic equivalence to rituximab. The safety profile of CT-P10 was comparable to that of rituximab. CT-P10 might represent a new therapeutic option for advanced-stage follicular lymphoma. Funding Celltrion, Inc.
Jeannine S Mccune - One of the best experts on this subject based on the ideXlab platform.
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harmonization of busulfan plasma exposure unit bpeu a community initiated consensus statement
Biology of Blood and Marrow Transplantation, 2019Co-Authors: Jaap Jan Boelens, Jeannine S Mccune, Claudio Anasetti, Christine M Quinones, James C Ritchie, Paul A Carpenter, Erik M Van Maarseveen, Nelson HamerschlakAbstract:ABSTRACT Busulfan therapeutic drug monitoring (TDM) is often used to achieve target plasma exposures. Variability in busulfan plasma exposure units (BPEU) is a potential source for misinterpretation of publications and protocols and is a barrier to data capture by hematopoietic cell transplantation (HCT) registry databases. We sought to harmonize to a single BPEU for international use. Using Delphi consensus methodology, iterative surveys were sent to an increasing number of relevant clinical stakeholders. In survey 1, 14 stakeholders were asked to identify ideal properties of a BPEU. In survey 2, 52 stakeholders were asked (1) to evaluate BPEU candidates according to ideal BPEU properties established by survey 1 and local position statements for TDM and (2) to identify potential facilitators and barriers to adoption of the harmonized BPEU. The most frequently used BPEU identified, in descending order, were area under the curve (AUC) in μM × min, AUC in mg × h/L, Concentration at steady state (Css) in ng/mL, AUC in μM × h, and AUC in μg × h/L. All respondents conceptually agreed on the ideal properties of a BPEU and to adopt a harmonized BPEU. Respondents were equally divided between selecting AUC in μM × min versus mg × h/L for harmonization. AUC in mg × h/L was finally selected as the harmonized BPEU, because it satisfied most of the survey-determined ideal properties for the harmonized BPEU and is read easily understood in the clinical practice environment. Furthermore, 10 major professional societies have endorsed AUC in mg × h/L as the harmonized unit for reporting to HCT registry databases and for use in future protocols and publications.
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busulfan in infant to adult hematopoietic cell transplant recipients a population pharmacokinetic model for initial and bayesian dose personalization
Clinical Cancer Research, 2014Co-Authors: Jeannine S Mccune, Alan S Gamis, Meagan J Bemer, Scott K Baker, Jeffrey S. Barrett, Nicholas H. G. HolfordAbstract:Purpose: Personalizing intravenous busulfan doses to a target plasma Concentration at steady state ( C ss ) is an essential component of hematopoietic cell transplantation (HCT). We sought to develop a population pharmacokinetic model to predict i.v. busulfan doses over a wide age spectrum (0.1–66 years) that accounts for differences in age and body size. Experimental Design: A population pharmacokinetic model based on normal fat mass and maturation based on postmenstrual age was built from 12,380 busulfan Concentration time points obtained after i.v. busulfan administration in 1,610 HCT recipients. Subsequently, simulation results of the initial dose necessary to achieve a target C ss with this model were compared with pediatric-only models. Results: A two-compartment model with first-order elimination best fit the data. The population busulfan clearance was 12.4 L/h for an adult male with 62 kg normal fat mass (equivalent to 70 kg total body weight). Busulfan clearance, scaled to body size—specifically normal fat mass, is predicted to be 95% of the adult clearance at 2.5 years postnatal age. With a target C ss of 770 ng/mL, a higher proportion of initial doses achieved the therapeutic window with this age- and size-dependent model (72%) compared with dosing recommended by the U.S. Food and Drug Administration (57%) or the European Medicines Agency (70%). Conclusion: This is the first population pharmacokinetic model developed to predict initial i.v. busulfan doses and personalize to a target C ss over a wide age spectrum, ranging from infants to adults. Clin Cancer Res; 20(3); 754–63. ©2013 AACR .
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cyclophosphamide followed by intravenous targeted busulfan for allogeneic hematopoietic cell transplantation pharmacokinetics and clinical outcomes
Biology of Blood and Marrow Transplantation, 2013Co-Authors: Andrew R Rezvani, Jeannine S Mccune, Joachim H Deeg, Barry E Storer, Ami Batchelder, Aiko KidaAbstract:Abstract Targeted busulfan ( T BU) and cyclophosphamide (CY) for allogeneic hematopoietic cell transplantation carries a high risk of sinusoidal obstruction syndrome (SOS) in patients undergoing transplantation for myelofibrosis. We tested the hypothesis that reversing the sequence of administration (from T BU/CY to CY/ T BU) would reduce SOS and day +100 nonrelapse mortality. We enrolled 51 patients with myelofibrosis (n = 20), acute myelogenous leukemia (n = 20), or myelodysplastic syndrome (n = 11) in a prospective trial of CY/ T BU conditioning for allogeneic hematopoietic cell transplantation. CY 60 mg/kg/day i.v. for 2 days was followed by daily i.v. BU for 4 days, targeted to a Concentration at steady state (Css) of 800-900 ng/mL. Compared with T BU/CY-conditioned patients, CY/ T BU-conditioned patients had greater exposure to CY ( P P T BU/CY for the same indications. In patients with myelofibrosis, CY/ T BU conditioning was associated with a significantly reduced incidence of SOS (0% versus 30% after T BU/CY; P = .006), whereas the incidence of SOS was low in both cohorts with acute myelogenous leukemia/myelodysplastic syndrome. Day +100 mortality was significantly lower in the CY/ T BU cohort (2% versus 13%; P = .01). CY/ T BU conditioning had a marked affect on the pharmacokinetics of CY and was associated with significantly lower incidence of SOS and day +100 mortality, suggesting that CY/ T BU is superior to T BU/CY as conditioning for patients with myelofibrosis.
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a phase i ii study of mycophenolate mofetil in combination with cyclosporine for prophylaxis of acute graft versus host disease after myeloablative conditioning and allogeneic hematopoietic cell transplantation
Biology of Blood and Marrow Transplantation, 2005Co-Authors: John T. Slattery, Jeannine S Mccune, Barry E Storer, Richard A Nash, Laura Johnston, Pablo ParkerAbstract:Abstract In a phase I/II study, the combination of cyclosporine (CSP) and mycophenolate mofetil (MMF) was investigated as graft-versus-host disease (GVHD) prophylaxis after myeloablative conditioning and hematopoietic cell transplantation from an HLA-matched sibling donor. In phase I, 3 groups, each with 10 or 11 patients, received MMF (15 mg/kg) from day 0 to day 27 at decreasing dose intervals of every 12, 8, and 6 hours to determine a safe and effective total daily dose. at the 45 mg/kg/d dosage level, 4 of 11 patients developed only grade II GVHD, and a Concentration at steady state of mycophenolic acid (the active moiety of MMF) consistent with a therapeutic range described for solid-organ transplantation was achieved. There was a suggestion of increased toxicity without improved efficacy at the 60 mg/kg/d dosage level. Accordingly, the 45 mg/kg/d dosage was therefore selected for phase II, and another 15 patients were added to this group from the phase I study (n = 26). The Concentrations at steady state for this dosage at days 0, 6, 13, 20, and 27 were 2.73, 3.02, 3.20, 2.62, and 2.64 μg/mL, respectively. No toxicities were attributed to MMF at this dose. The median time to engraftment after hematopoietic cell transplantation was 15 days (range, 10–20 days). The incidence of acute GVHD was 62%, which was comparable to a group of historical controls receiving CSP and methotrexate (MTX) for GVHD prophylaxis. Although a significant improvement in the prevention of GVHD was not suggested, compared with CSP and MTX, MMF in combination with CSP could be considered in cases in which MTX is contraindicated.
Dzhelil Osmanov - One of the best experts on this subject based on the ideXlab platform.
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efficacy pharmacokinetics and safety of the biosimilar ct p10 compared with rituximab in patients with previously untreated advanced stage follicular lymphoma a randomised double blind parallel group non inferiority phase 3 trial
The Lancet Haematology, 2017Co-Authors: Christian Buske, Michinori Ogura, Wojciech Jurczak, Juanmanuel Sancho, Edvard Zhavrid, Jose Angel Hernandezrivas, Aliaksandr Prokharau, Mariana Vasilica, Rajinish Nagarkar, Dzhelil OsmanovAbstract:Summary Background Studies in patients with rheumatoid arthritis have shown that the rituximab biosimilar CT-P10 (Celltrion, Incheon, South Korea) has equivalent efficacy and pharmacokinetics to rituximab. In this phase 3 study, we aimed to assess the non-inferior efficacy and pharmacokinetic equivalence of CT-P10 compared with rituximab, when used in combination with cyclophosphamide, vincristine, and prednisone (CVP) in patients with newly diagnosed advanced-stage follicular lymphoma. Methods In this ongoing, randomised, double-blind, parallel-group, active-controlled study, patients aged 18 years or older with Ann Arbor stage III–IV follicular lymphoma were assigned 1:1 to CVP plus intravenous infusions of 375 mg/m 2 CT-P10 or rituximab on day 1 of eight 21-day cycles. Randomisation was done by the investigators using an interactive web or voice response system and a computer-generated randomisation schedule, prepared by a clinical research organisation. Randomisation was balanced using permuted blocks and was stratified by country, gender, and Follicular Lymphoma International Prognostic Index score (0–2 vs 3–5). Study teams from the sponsor and clinical research organisation, investigators, and patients were masked to treatment assignment. The study was divided into two parts: part 1 assessing equivalence of pharmacokinetics (in the pharmacokinetics subset), and part 2 assessing efficacy in all randomised patients (patients from the pharmacokinetics subset plus additional patients enrolled in part 2). Equivalence of pharmacokinetics was shown if the 90% CIs for the geometric mean ratio of CT-P10 to rituximab in AUCτ and C maxSS were within the bounds of the equivalence margin of 80% and 125%. Non-inferiority of response was shown if the one-sided 97·5% CI lay on the positive side of the −7% margin, using a one-sided test done at the 2·5% significance level. The primary efficacy endpoint was the proportion of patients who had an overall response over eight cycles and was assessed in the efficacy population (all randomised patients). The primary pharmacokinetic endpoints were area under the serum Concentration–time curve at steady state (AUCτ) and maximum serum Concentration at steady state (C maxSS ) at cycle 4, assessed in the pharmokinetic population. This trial is registered with ClinicalTrials.gov, number NCT02162771. Findings Between July 28, 2014, and Dec 29, 2015, 140 patients were enrolled. Here we report data for the eight-cycle induction period, up to week 24. The proportion of patients with an overall response in the efficacy population was 64 (97·0%) of 66 patients in the CT-P10 treatment group and 63 (92·6%) of 68 patients in the rituximab treatment group (4·3%; one-sided 97·5% CI −4·25), which lay on the positive side of the predefined non-inferiority margin. The ratio of geometric least squares means (CT-P10/rituximab) was 102·25% (90% CI 94·05–111·17) for AUCτ and 100·67% (93·84–108·00) for C maxSS , with all CIs within the bioequivalence margin of 80–125%. Treatment-emergent adverse events were reported for 58 (83%) of 70 patients in the CT-P10 treatment group and 56 (80%) of 70 in the rituximab treatment group. The most common grade 3 or 4 treatment-emergent adverse event in each treatment group was neutropenia (grade 3, 15 [21%] of 70 patients in the CT-P10 group and seven [10%] of 70 patients in the rituximab group). The proportion of patients who experienced at least one treatment-emergent serious adverse event was 16 (23%) of 70 patients in the CT-P10 group and nine (13%) of 70 patients in the rituximab group. Interpretation In this study, we show that CT-P10 exhibits non-inferior efficacy and pharmacokinetic equivalence to rituximab. The safety profile of CT-P10 was comparable to that of rituximab. CT-P10 might represent a new therapeutic option for advanced-stage follicular lymphoma. Funding Celltrion, Inc.
Aliaksandr Prokharau - One of the best experts on this subject based on the ideXlab platform.
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efficacy pharmacokinetics and safety of the biosimilar ct p10 compared with rituximab in patients with previously untreated advanced stage follicular lymphoma a randomised double blind parallel group non inferiority phase 3 trial
The Lancet Haematology, 2017Co-Authors: Christian Buske, Michinori Ogura, Wojciech Jurczak, Juanmanuel Sancho, Edvard Zhavrid, Jose Angel Hernandezrivas, Aliaksandr Prokharau, Mariana Vasilica, Rajinish Nagarkar, Dzhelil OsmanovAbstract:Summary Background Studies in patients with rheumatoid arthritis have shown that the rituximab biosimilar CT-P10 (Celltrion, Incheon, South Korea) has equivalent efficacy and pharmacokinetics to rituximab. In this phase 3 study, we aimed to assess the non-inferior efficacy and pharmacokinetic equivalence of CT-P10 compared with rituximab, when used in combination with cyclophosphamide, vincristine, and prednisone (CVP) in patients with newly diagnosed advanced-stage follicular lymphoma. Methods In this ongoing, randomised, double-blind, parallel-group, active-controlled study, patients aged 18 years or older with Ann Arbor stage III–IV follicular lymphoma were assigned 1:1 to CVP plus intravenous infusions of 375 mg/m 2 CT-P10 or rituximab on day 1 of eight 21-day cycles. Randomisation was done by the investigators using an interactive web or voice response system and a computer-generated randomisation schedule, prepared by a clinical research organisation. Randomisation was balanced using permuted blocks and was stratified by country, gender, and Follicular Lymphoma International Prognostic Index score (0–2 vs 3–5). Study teams from the sponsor and clinical research organisation, investigators, and patients were masked to treatment assignment. The study was divided into two parts: part 1 assessing equivalence of pharmacokinetics (in the pharmacokinetics subset), and part 2 assessing efficacy in all randomised patients (patients from the pharmacokinetics subset plus additional patients enrolled in part 2). Equivalence of pharmacokinetics was shown if the 90% CIs for the geometric mean ratio of CT-P10 to rituximab in AUCτ and C maxSS were within the bounds of the equivalence margin of 80% and 125%. Non-inferiority of response was shown if the one-sided 97·5% CI lay on the positive side of the −7% margin, using a one-sided test done at the 2·5% significance level. The primary efficacy endpoint was the proportion of patients who had an overall response over eight cycles and was assessed in the efficacy population (all randomised patients). The primary pharmacokinetic endpoints were area under the serum Concentration–time curve at steady state (AUCτ) and maximum serum Concentration at steady state (C maxSS ) at cycle 4, assessed in the pharmokinetic population. This trial is registered with ClinicalTrials.gov, number NCT02162771. Findings Between July 28, 2014, and Dec 29, 2015, 140 patients were enrolled. Here we report data for the eight-cycle induction period, up to week 24. The proportion of patients with an overall response in the efficacy population was 64 (97·0%) of 66 patients in the CT-P10 treatment group and 63 (92·6%) of 68 patients in the rituximab treatment group (4·3%; one-sided 97·5% CI −4·25), which lay on the positive side of the predefined non-inferiority margin. The ratio of geometric least squares means (CT-P10/rituximab) was 102·25% (90% CI 94·05–111·17) for AUCτ and 100·67% (93·84–108·00) for C maxSS , with all CIs within the bioequivalence margin of 80–125%. Treatment-emergent adverse events were reported for 58 (83%) of 70 patients in the CT-P10 treatment group and 56 (80%) of 70 in the rituximab treatment group. The most common grade 3 or 4 treatment-emergent adverse event in each treatment group was neutropenia (grade 3, 15 [21%] of 70 patients in the CT-P10 group and seven [10%] of 70 patients in the rituximab group). The proportion of patients who experienced at least one treatment-emergent serious adverse event was 16 (23%) of 70 patients in the CT-P10 group and nine (13%) of 70 patients in the rituximab group. Interpretation In this study, we show that CT-P10 exhibits non-inferior efficacy and pharmacokinetic equivalence to rituximab. The safety profile of CT-P10 was comparable to that of rituximab. CT-P10 might represent a new therapeutic option for advanced-stage follicular lymphoma. Funding Celltrion, Inc.
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efficacy pharmacokinetics and safety of the biosimilar ct p10 compared with rituximab in patients with previously untreated advanced stage follicular lymphoma a randomised double blind parallel group non inferiority phase 3 trial
The Lancet Haematology, 2017Co-Authors: Won Seog Kim, Christian Buske, Michinori Ogura, Wojciech Jurczak, Juanmanuel Sancho, Edvard Zhavrid, Jose Angel Hernandezrivas, Aliaksandr Prokharau, Jin Seok Kim, Mariana VasilicaAbstract:Summary Background Studies in patients with rheumatoid arthritis have shown that the rituximab biosimilar CT-P10 (Celltrion, Incheon, South Korea) has equivalent efficacy and pharmacokinetics to rituximab. In this phase 3 study, we aimed to assess the non-inferior efficacy and pharmacokinetic equivalence of CT-P10 compared with rituximab, when used in combination with cyclophosphamide, vincristine, and prednisone (CVP) in patients with newly diagnosed advanced-stage follicular lymphoma. Methods In this ongoing, randomised, double-blind, parallel-group, active-controlled study, patients aged 18 years or older with Ann Arbor stage III–IV follicular lymphoma were assigned 1:1 to CVP plus intravenous infusions of 375 mg/m 2 CT-P10 or rituximab on day 1 of eight 21-day cycles. Randomisation was done by the investigators using an interactive web or voice response system and a computer-generated randomisation schedule, prepared by a clinical research organisation. Randomisation was balanced using permuted blocks and was stratified by country, gender, and Follicular Lymphoma International Prognostic Index score (0–2 vs 3–5). Study teams from the sponsor and clinical research organisation, investigators, and patients were masked to treatment assignment. The study was divided into two parts: part 1 assessing equivalence of pharmacokinetics (in the pharmacokinetics subset), and part 2 assessing efficacy in all randomised patients (patients from the pharmacokinetics subset plus additional patients enrolled in part 2). Equivalence of pharmacokinetics was shown if the 90% CIs for the geometric mean ratio of CT-P10 to rituximab in AUCτ and C maxSS were within the bounds of the equivalence margin of 80% and 125%. Non-inferiority of response was shown if the one-sided 97·5% CI lay on the positive side of the −7% margin, using a one-sided test done at the 2·5% significance level. The primary efficacy endpoint was the proportion of patients who had an overall response over eight cycles and was assessed in the efficacy population (all randomised patients). The primary pharmacokinetic endpoints were area under the serum Concentration–time curve at steady state (AUCτ) and maximum serum Concentration at steady state (C maxSS ) at cycle 4, assessed in the pharmokinetic population. This trial is registered with ClinicalTrials.gov, number NCT02162771. Findings Between July 28, 2014, and Dec 29, 2015, 140 patients were enrolled. Here we report data for the eight-cycle induction period, up to week 24. The proportion of patients with an overall response in the efficacy population was 64 (97·0%) of 66 patients in the CT-P10 treatment group and 63 (92·6%) of 68 patients in the rituximab treatment group (4·3%; one-sided 97·5% CI −4·25), which lay on the positive side of the predefined non-inferiority margin. The ratio of geometric least squares means (CT-P10/rituximab) was 102·25% (90% CI 94·05–111·17) for AUCτ and 100·67% (93·84–108·00) for C maxSS , with all CIs within the bioequivalence margin of 80–125%. Treatment-emergent adverse events were reported for 58 (83%) of 70 patients in the CT-P10 treatment group and 56 (80%) of 70 in the rituximab treatment group. The most common grade 3 or 4 treatment-emergent adverse event in each treatment group was neutropenia (grade 3, 15 [21%] of 70 patients in the CT-P10 group and seven [10%] of 70 patients in the rituximab group). The proportion of patients who experienced at least one treatment-emergent serious adverse event was 16 (23%) of 70 patients in the CT-P10 group and nine (13%) of 70 patients in the rituximab group. Interpretation In this study, we show that CT-P10 exhibits non-inferior efficacy and pharmacokinetic equivalence to rituximab. The safety profile of CT-P10 was comparable to that of rituximab. CT-P10 might represent a new therapeutic option for advanced-stage follicular lymphoma. Funding Celltrion, Inc.