Won Seog Kim1, Christian Buske2, Michinori Ogura3, Wojciech Jurczak4, Juan-Manuel Sancho5, Edvard Zhavrid6, Jin Seok Kim7, José-Ángel Hernández-Rivas8, Aliaksandr Prokharau9, Mariana Vasilica10, Rajinish Nagarkar11, Dzhelil Osmanov12, Larry W Kwak13, Sang Joon Lee14, Sung Young Lee14, Yun Ju Bae14, Bertrand Coiffier15. 1. Division of Hematology and Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea. 2. Comprehensive Cancer Center Ulm, University Hospital of Ulm, Ulm, Germany. 3. Department of Haematology, Tokai Central Hospital, Kakamigahara, Gifu, Japan. 4. Department of Haematology, Jagiellonian University, Kraków, Poland. 5. Hematology Department, ICO-IJC-Hospital Germans Trias i Pujol, Badalona, Spain. 6. N N Alexandrov Republican Scientific and Practical Centre of Oncology and Medical Radiology, Minsk, Belarus. 7. Department of Internal Medicine, Yonsei University College of Medicine, Severance Hospital, Seoul, South Korea. 8. Hematology Department, Hospital Universitario Infanta Leonor, Universidad Complutense, Madrid, Spain. 9. Minsk City Clinical Oncology Dispensary, Minsk, Belarus. 10. Hematology Department, Fundeni Clinical Institute, Bucharest, Romania. 11. Curie Manavata Cancer Centre, Nashik, India. 12. N N Blokhin Russian Cancer Research Centre, Moscow, Russia. 13. Toni Stephenson Lymphoma Center and Department of Haematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA, USA. 14. Celltrion, Incheon, South Korea. 15. Hospices Civils de Lyon, Lyon, France. Electronic address: bertrand.coiffier@me.com.
Abstract
BACKGROUND: Studies in patients with rheumatoid arthritis have shown that the rituximabbiosimilar 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.
RCT Entities:
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.
Authors: Pier Luigi Zinzani; Martin Dreyling; William Gradishar; Marc Andre; Francisco J Esteva; Suliman Boulos; Eva González Barca; Giuseppe Curigliano Journal: Drugs Date: 2019-10 Impact factor: 9.546