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

Won Seog Kim, Christian Buske, Michinori Ogura, Wojciech Jurczak, Juan Manuel Sancho, Edvard Zhavrid, Jinseok Kim, José Ángel Hernández-Rivas, Aliaksandr Prokharau, Mariana Vasilica, Rajinish Nagarkar, Dzhelil Osmanov, Larry W. Kwak, Sang Joon Lee, Sung Young Lee, Yun Ju Bae, Bertrand Coiffier

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

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/m2 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 CmaxSS 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 (CmaxSS) 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 CmaxSS, 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.

Original languageEnglish
Pages (from-to)e362-e373
JournalThe Lancet Haematology
Volume4
Issue number8
DOIs
Publication statusPublished - 2017 Aug 1

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Biosimilar Pharmaceuticals
Follicular Lymphoma
Pharmacokinetics
Safety
Random Allocation
Rituximab
Area Under Curve
Therapeutics
Vincristine
Prednisone

All Science Journal Classification (ASJC) codes

  • Hematology

Cite this

Kim, Won Seog ; Buske, Christian ; Ogura, Michinori ; Jurczak, Wojciech ; Sancho, Juan Manuel ; Zhavrid, Edvard ; Kim, Jinseok ; Hernández-Rivas, José Ángel ; Prokharau, Aliaksandr ; Vasilica, Mariana ; Nagarkar, Rajinish ; Osmanov, Dzhelil ; Kwak, Larry W. ; Lee, Sang Joon ; Lee, Sung Young ; Bae, Yun Ju ; Coiffier, Bertrand. / 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. In: The Lancet Haematology. 2017 ; Vol. 4, No. 8. pp. e362-e373.
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title = "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",
abstract = "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/m2 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 CmaxSS 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 (CmaxSS) 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 CmaxSS, 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.",
author = "Kim, {Won Seog} and Christian Buske and Michinori Ogura and Wojciech Jurczak and Sancho, {Juan Manuel} and Edvard Zhavrid and Jinseok Kim and Hern{\'a}ndez-Rivas, {Jos{\'e} {\'A}ngel} and Aliaksandr Prokharau and Mariana Vasilica and Rajinish Nagarkar and Dzhelil Osmanov and Kwak, {Larry W.} and Lee, {Sang Joon} and Lee, {Sung Young} and Bae, {Yun Ju} and Bertrand Coiffier",
year = "2017",
month = "8",
day = "1",
doi = "10.1016/S2352-3026(17)30120-5",
language = "English",
volume = "4",
pages = "e362--e373",
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Kim, WS, Buske, C, Ogura, M, Jurczak, W, Sancho, JM, Zhavrid, E, Kim, J, Hernández-Rivas, JÁ, Prokharau, A, Vasilica, M, Nagarkar, R, Osmanov, D, Kwak, LW, Lee, SJ, Lee, SY, Bae, YJ & Coiffier, B 2017, '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, vol. 4, no. 8, pp. e362-e373. https://doi.org/10.1016/S2352-3026(17)30120-5

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. / Kim, Won Seog; Buske, Christian; Ogura, Michinori; Jurczak, Wojciech; Sancho, Juan Manuel; Zhavrid, Edvard; Kim, Jinseok; Hernández-Rivas, José Ángel; Prokharau, Aliaksandr; Vasilica, Mariana; Nagarkar, Rajinish; Osmanov, Dzhelil; Kwak, Larry W.; Lee, Sang Joon; Lee, Sung Young; Bae, Yun Ju; Coiffier, Bertrand.

In: The Lancet Haematology, Vol. 4, No. 8, 01.08.2017, p. e362-e373.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Efficacy, pharmacokinetics, and safety of the biosimilar CT-P10 compared with rituximab in patients with previously untreated advanced-stage follicular lymphoma

T2 - a randomised, double-blind, parallel-group, non-inferiority phase 3 trial

AU - Kim, Won Seog

AU - Buske, Christian

AU - Ogura, Michinori

AU - Jurczak, Wojciech

AU - Sancho, Juan Manuel

AU - Zhavrid, Edvard

AU - Kim, Jinseok

AU - Hernández-Rivas, José Ángel

AU - Prokharau, Aliaksandr

AU - Vasilica, Mariana

AU - Nagarkar, Rajinish

AU - Osmanov, Dzhelil

AU - Kwak, Larry W.

AU - Lee, Sang Joon

AU - Lee, Sung Young

AU - Bae, Yun Ju

AU - Coiffier, Bertrand

PY - 2017/8/1

Y1 - 2017/8/1

N2 - 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/m2 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 CmaxSS 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 (CmaxSS) 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 CmaxSS, 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.

AB - 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/m2 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 CmaxSS 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 (CmaxSS) 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 CmaxSS, 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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