Clinical Pharmacokinetic (PK) and Safety (Immunogenicity) of Rituximab Biosimilar RTXM83 in Combination with Chemotherapy CHOP in Patients with Diffuse Large B-Cell Lymphoma (DLBCL)

Abstract

Background: RTXM83 is a rituximab biosimilar candidate manufactured by MAbxience Company. Full spectrum of physicochemical and preclinical studies showed biosimilarity of RTXM83 and originator drug MabThera®/Rituxan® marketed by Roche. MabThera®/Rituxan® product is approved to treat Non-Hodgkin´s Lymphoma, chronic lymphocytic leukemia and rheumatoid arthritis in the EU and US, plus it is approved to treat Diffuse Large B-cell lymphoma (DLBCL) in the EU. Rituximab is also used for other types of lymphoma (e.g. Mantle cell lymphoma) in certain parts of the word. Objective: To demonstrate comparable pharmacokinetics (PK) and safety profile (immunogenicity) to MabThera®, a clinical PK/immunogenicity analysis was designed to compare RTXM83 and MabThera® when administered with CHOP to patients with DLBCL. Methods: Analysis of an interim PK/Safety report from randomized and blinded study, where 24 patients with newly diagnosed DLBCL treated with R-CHOP as part of a multi-center study undertaken to assess the PK and immunogenicity. R-CHOP (rituximab-375mg/m2; cyclophopsphamide-750mg/m2; adriamycin-50mg/m2; vincristine-1.4mg/m2 on day 1 and prednisolone-60mg/m2 on days 1 to 5) was given every 3 weeks for a total of 6 cycles. The PK analysis were conducted on quality control (QC) checked analytical data for Cycle 1 and Cycle 6 using nominal blood sampling times. PK parameters were determined from the serum Rituximab concentration-time profiles obtained following administration of the first (Cycle 1) and last intravenous infusion of study medication (Cycle 6) using non-compartmental procedures in Phoenix WinNonlin (Version 6.2.1). The immunogenicity assessments were based on a specific and validated method for systematic evaluation of an unwanted immune response against RTXM83 and MabThera®. In fact, a confirmatory assay and specific cut point was established as current described recommendations in white papers and guidance documents. This part assures the assay sensitivity and a “characterization step” in the study sample analysis. A screening assay that picks up 5% positives that are subsequently shown to be due to non-specific binding in a confirmatory (immunodepletion) assay provides assurance that true low positives can be detected. Finally, the clinical immunogenicity measurements were performed on Cycle 5, Cycle 6 and follow-up patient samples. Results: Following the end of infusion of 375 mg/m2 q3w RTXM83 or MabThera® (Rituximab) (3 hours infusion) administered in combination with CHOP in Cycle 1 and Cycle 6, serum concentrations of Rituximab declined steadily in a generally bi-phasic manner. The arithmetic mean ±SD of PK parameters (T1/2(hrs); Cmax (ug/ml); Cmin (ug/ml); AUC0-∞ (ug*hrs/ml) of Rituximab during cycle 1, cycle 6 and follow-up patients were determined. All these data are comparable with values previously reported for rituximab in other conditions. No anti-drug antibody case was reported, so RTXM83 and MabThera® displaying null or undetectable immunogenicity. Conclusions: The data indicate that therapeutic levels of rituximab (RTXM83/Mabthera®) were observed across studied cycles. All data are comparable with values previously reported for rituximab. Therefore, PK profile and immunogenicity profile of RTXM83 is comparable with Mabthera® in treating DLBCL. Disclosures No relevant conflicts of interest to declare.

REFLECT: prospective multicenter non-interventional study evaluating the effectiveness and safety of Sandoz rituximab (SDZ-RTX; Rixathon®) in combination with CHOP for the treatment of patients with previously untreated CD20-positive diffuse large B-cell lymphoma

“…26 In addition, a prospective study with limited comparability due to the selection of patients with a good prognosis is reported, 27 and several small studies have been carried out investigating the use of rituximab biosimilars licensed outside of the EU in DLBCL, including China, India, and Turkey. [28][29][30][31] In REFLECT, R-CHOP therapy achieved similar results for PFS rate (78.5%) and ORR (94.7%, according to best overall response) to those reported in other studies, although CR results differ from study to study as shown in Table 5. This difference in CR rate may be partially explained by variation in study design and patient population.…”

“… 26 In addition, a prospective study with limited comparability due to the selection of patients with a good prognosis is reported, 27 and several small studies have been carried out investigating the use of rituximab biosimilars licensed outside of the EU in DLBCL, including China, India, and Turkey. 28 – 31 …”

A Randomized, Multiple-Dose, Multicenter, Comparative Parallel Study to Evaluate the Safety and Efficacy of Intravenous Infusion of Rituximab (Hetero) and Reference Medicinal Product (Rituximab, Roche) in Indian Patients of Non-Hodgkin's Lymphoma (HERILY)

“…The results were consistent with the study conducted by Florez et al in which none of the patients of the DLBCL treated with rituximab showed immunogenicity. [13] However, in a developmental study of rituximab conducted by Roche Drugs Limited in patients with low-grade or follicular NHL, anti-human anti-chimeric antibody was detected in 4 out of 356 (1.1%). [2] Thus, the available data suggest that immunogenic potential of the test drug was comparable to the reference drug DLBCL patients and is also consistent to the previously conducted studies with the similar molecule.…”

A clinician’s guide to biosimilars in oncology

“…Pfizer ORR LTBFL Preclinical: PF-05280586 showed similar structural and in vitro functional characteristics and similar in vivo PK and immunogenicity profiles to rituximab [43] Phase I: PF-05280586 showed similar PK, effectiveness, and safety to rituximab in subjects with active rheumatoid arthritis [44] CT-P10 Celtrion ORR FL Phase III: CT-P10 showed equivalent PK and similar efficacy (ACR20/ 50/70), PD, safety [45], and immunogenicity [46] to rituximab in subjects with rheumatoid arthritis RTXM83 mAbxience ORR DLBCL Preclinical: RTXM83 showed similar structural and in vitro functional characteristics and similar in vivo PK/PD profiles to rituximab [47] Phase III: RTXM83 showed comparable PK and safety profile (immunogenicity) to rituximab when combined with CHOP for firstline treatment of DLBCL [48] ABP…”