Rituximab In Japanese Patients Research Articles

A phase 2, open-label study of ibrutinib plus rituximab in Japanese patients with Waldenstrom's macroglobulinemia.

Ibrutinib is a first-in-class Bruton kinase inhibitor against B-cell neoplasms including Waldenström macroglobulinemia (WM). This study evaluated the efficacy and safety of ibrutinib-rituximab in Japanese patients with WM. Patients received ibrutinib 420mg orally once daily plus weekly rituximab 375mg/m2 IV (8 infusions total). The primary end point was major response rate (MRR; PR or better) by Independent Review Committee assessment. Secondary endpoints were progression-free survival (PFS), safety, pharmacokinetics, and biomarkers. Primary analysis was conducted in 16 patients [baseline, treatment naïve: 8 (50.0%); relapsed/refractory WM: 8 (50.0%)] who received ibrutinib-rituximab, after all patients completed Week 57 or end of treatment. At primary analysis, MRR was 87.5% [14/16 patients; 95% CI: 61.7, 98.4%; p < 0.0001 (null hypothesis: 32% response rate)]. At final analysis (median study intervention duration: 34.4months, median follow-up: 35.0months), MRR was unchanged at 87.5%, but VGPR [6/16 (37.5%)] and PR [8/16 (50.0%)] improved. Prior treatment status did not affect response. At final analysis, median PFS was not reached [36-month PFS rate: 86% (95% CI: 55, 96%)]. No critical safety signals were reported. This study demonstrated a positive benefit/risk profile of ibrutinib-rituximab in Japanese patients with WM, consistent with the iNNOVATE study.

Nation-wide Cohort Study of Remission Induction Therapy using Rituximab in Japanese patients with ANCA-Associated Vasculitis: effectiveness and safety in the first six months.

To evaluate effectiveness and safety of rituximab (RTX) for microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA) in Japan. In this prospective observational study, all patients with MPA and GPA administered RTX were enrolled at each institution. During observation period of two years, data up to six months was analysed. Cox proportional hazards analysis was used to assess the factors associated with an outcome. Of the 75 patients who received RTX for remission induction therapy, 53 achieved remission by 6th month and 50 were in remission at 6th month. During therapy, 38 serious adverse events (SAE) were observed in 24 patients, 21 serious infections (SI) in 16 patients, and nine patients died. No factors were associated with remission; however, there was a significant difference between patients with and without remission in SAE (22.6 vs. 54.5 %), SI (11.3 vs. 45.4 %), and death (1.9 vs. 36.4 %). The hazard ratio (95 % CI) for SI was 3.49 (1.29-9.74) for patients aged ≥ 75 years and 3.53 (1.31-9.53) for pulmonary complications. Four patients maintained remission for 6 months. Effectiveness and safety of RTX for MPA and GPA for up to 6 months was demonstrated.

Bendamustine plus rituximab in Japanese patients with relapsed or refractory diffuse large B-cell lymphoma

This single-arm phase 3 study was conducted to confirm the results of our phase 2 study of bendamustine (B)-rituximab (R) in patients with relapsed/refractory diffuse large B cell lymphoma (rrDLBCL). The primary endpoint was overall response rate (ORR). Autologous stem cell transplantation-ineligible rrDLBCL patients with ≤ 2 prior chemotherapy regimens received R 375 mg/m2 IV on day 1 and B 120 mg/m2/day IV on days 2 and 3 every 21 days up to 6 cycles. Thirty-eight patients with a median age of 74 years (range, 43–86) received BR. The ORR and complete response rates were 76.3% and 47.4%, respectively. With a median follow-up of 19.5 months including long-term follow-up, median progression-free survival was 11.9 months. Median OS was 29.2 months. Discontinuation of treatment due to Gr3-5 TEAE was observed among 13 of 38 patients (34.2%). One patient with cytomegalovirus enterocolitis died during follow-up. This BR regimen was confirmed to be effective and tolerable in studied patients. ClinicalTrials.gov Identifier: NCT03372837 registered on 14 December 2017, NCT04354402 registered on 21 April, 2020.

Investigator-Initiated Phase 2 Trial of Rituximab in Adult Japanese Patients with Treatment-Resistant Acquired Thrombotic Thrombocytopenic Purpura

About 500 persons in Japan are estimated to have thrombotic thrombocytopenic purpura (TTP), which is a life-threatening disorder. In contrast with the USA and EU, off-label use of rituximab for TTP is not allowed by the Japanese public health insurance system. We therefore have limited experience of the effects of rituximab in Japanese patients with adult TTP and have not investigated possible ethnicity-related differences in its effects. To evaluate the safety and efficacy of rituximab in Japanese adult patients with TTP, we conducted an investigator-initiated phase 2 clinical trial in Japan between January and December of 2014. This study was sponsored by the Japanese government and the study design was based instructions from the regulatory agency, PMDA (Phamaceuticals and Medical Devices Agency). Adult Japanese patients with acquired TTP that had proven refractory to at least five plasma exchanges (PEX) or had serum concentrations of more than 2 BU/mL of ADAMTS13 inhibitor or both were eligible for this study. Rituximab was infused at 375 mg/m2 weekly for 4 weeks. The study protocol allowed use of both plasma exchange and corticosteroids with the investigational drug. Thirteen patients were registered and seven found to be eligible and treated with rituximab. All seven patients were evaluable for safety and six for efficacy. Three of these six (50%) were women; the median age was 41.5 years. Median platelet counts at baseline were 22 × 109/L. All of these six patients were refractory to previous PEX and ADMTS13 inhibitor concentrations were higher than 2 BU/mL in two (33%) of them. All six patients no longer required PEX after receiving rituximab treatment. Five (83%) and two (33%) patients achieved platelet counts of 100 × 109/L and 150 × 109/L 4 weeks after initiating rituximab, respectively. Median platelet counts at week 4 after commencing rituximab were 136 × 109/L (range: 64-201 × 109/L). The median time from initiating PEX to achieving platelet counts over 150 × 109/L was 22 days. By the study endpoint (4 weeks after initiating rituximab treatment), ADAMTS13 activity had normalized to 77.3% from 3.4%, accompanied by disappearance of ADAMTS13 inhibitor. Both anemia and neurological impairment also improved in all patients. The median percentages of peripheral blood CD20-positive B cells were 22.9% and 0.2% before and at the completion of treatment with rituximab, respectively. Serum IgG decreased slightly from 1,116 mg/dL at baseline to 921 mg/dL 4 weeks after rituximab treatment. Five of seven patients experienced adverse events, two of which were severe; namely septic shock and cytomegalovirus infection; no patients died. No unpublished severe adverse events were noted. No recurrence of TTP occurred during a median follow-up of 7 months. These data suggest that rituximab is safe and effective for acute refractory/high risk acquired TTP in Japanese patients and that there are no ethnic differences in effectiveness or safety of rituximab for adult TTP. However, there were too few patients to draw any firm conclusions. Further investigation is necessary to optimize the treatment schedule of rituximab. We are preparing to apply to the Japanese regulatory agency for approval of new indications for rituximab for TTP. DisclosuresOff Label Use: Investigational drug, rituximab, was provided by Zenyaku Kogyo Co. Ltd.. Matsumoto:Baxter Bioscience: Consultancy.

Efficacy and safety of rituximab in Japanese patients with systemic lupus erythematosus and lupus nephritis who are refractory to conventional therapy

Objectives. To evaluate the efficacy and safety of rituximab in Japanese patients with systemic lupus erythematosus (SLE) and lupus nephritis (LN) who are refractory to conventional immunosuppressive therapy.Methods. Eligible patients received rituximab at a dose of 1,000 mg at days 1, 15, 169, and 183, and were followed for 53 weeks after the first dose of rituximab. Overall disease activity was assessed monthly using a British Isles Lupus Assessment Group activity index. Patients with LN (Upr/Ucr ≥ 1.0 at study entry) were identified and their renal responses were evaluated according to the criteria proposed by the American College of Rheumatology (ACR) and the Lupus Nephritis Assessment with Rituximab (LUNAR) study.Results. A total of 34 patients were enrolled and received at least one dose of rituximab. Decrease in disease activity was achieved in 16 (76.5%) out of 34 patients. In 17 patients with LN, response rates of 58.8% and 52.9% by ACR and LUNAR criteria, respectively, were seen. Successful steroid tapering was achieved in association with disease remission. Rituximab was well tolerated, and most adverse drug reactions were grade 1–2 in severity.Conclusions. Rituximab is effective for treatment of Japanese patients with SLE and LN refractory to conventional therapy.

Rituximab As Second-Line Treatment For Chronic Immune Thrombocytopenia: Investigator-Initiated Clinical Trial In Japan

The American Society of Hematology guidelines recommend rituximab as second-line treatment, as well as splenectomy and thrombopoietin receptor agonists (TPO-RAs), for chronic immune thrombocytopenia (ITP). However, rituximab has not been approved for the treatment of chronic ITP in Japan. To establish chronic ITP as a new indication for rituximab, we conducted an investigator-initiated clinical trial to clarify the efficacy and safety of rituximab for Japanese patients with ITP.This study was designed as a single-arm, multicenter phase III study. Patients diagnosed with chronic ITP who were previously treated with at least one therapy for ITP and whose platelet count was ≤ 30,000/μL were included. Patients with a past history or current hepatitis B virus, hepatitis C virus or HIV infection, who were treated with splenectomy within 12 weeks or with TPO-RA within 4 weeks were excluded. Rituximab at a dose of 375 mg/m2was intravenously infused once weekly for 4 weeks. Patients were premedicated with acetaminophen, restamin and hydrocortisone to prevent infusion reactions. Platelet counts, bleeding symptoms, and B lymphocyte counts were observed once monthly following the protocol. The primary endpoint was the proportion of patients whose platelet count was ≥ 50,000/μL 24 weeks after treatment with rituximab.Between October 2011 and January 2013, 26 patients were enrolled in this study from 10 hospitals in Japan. Median age of the patients was 40 years and 89% were female. Baseline platelet counts were 23,000/μL. Median interval from diagnosis of ITP to commencing rituximab therapy was 5.9 years. Previous treatment of ITP was corticosteroids (69%), splenectomy (15%), TPO-RA (27%) and intravenous immunoglobulins (39%). At baseline, 58% of patients had some bleeding symptoms. Median number of previous ITP treatments was two. All patients completed the study. At 24 weeks after treatment, 30.8% (95% CI: 14.3–51.8%) of patients achieved platelet counts > 50,000/μL. Seven of eight responders demonstrated improvement until 8 weeks. Platelet count was significantly increased compared with baseline (P<0.001). No unknown severe adverse events were observed. Subgroup analyses showed that ITP duration was numerically associated with the efficacy rate (46% vs 15% for duration< median vs ≥ median, respectively). Bleeding symptoms measured with the WHO bleeding scale were improved compared with baseline.We demonstrated the efficacy and safety of rituximab in Japanese patients with chronic ITP. The response rate was similar to that in previous reports in the US and Europe. We plan to propose that the Japanese government approve chronic ITP as a new indication for rituximab. Disclosures:Miyakawa:Fuji film: Consultancy; Alexion pharmaceuticals: Honoraria; GlaxoSmithKline: Consultancy, Honoraria; KyowaHakkoKirin: Consultancy, Honoraria; Shire: Honoraria. Off Label Use: rituximab, clinical trial. Nishiwaki:Chugai pharmaceutical: Research Funding; Zenyaku Kogyo: Research Funding. Higashihara:Alexion: Honoraria; Asahi Kasei Pharma: Honoraria; Janssen pharma: Honoraria, Research Funding; Takeda: Honoraria; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Shionogi: Honoraria, Research Funding; Nippon Shinyaku: Honoraria, Research Funding; GlaxoSmithKline: Honoraria, Research Funding; Eisai: Honoraria, Research Funding; Chugai: Honoraria, Research Funding; KyowaHakkoKirin: Honoraria, Research Funding; Boehringer-Ingeheim: Honoraria; Daiichi Sankyo: Honoraria; Yakurt: Honoraria; Astellas: Research Funding; Pfizer: Research Funding; Teijin: Research Funding; Meiji Seika pharma: Research Funding; Venesis: Research Funding; Baxter: Research Funding; Torii pharmaceutical: Research Funding; Bristol-Myers Squibb: Research Funding; Dainippon Sumitomo: Research Funding; Taiho: Research Funding; Taisho Tomiyama: Research Funding; MSD: Research Funding. Nishikawa:Daiichi-Sankyo: Research Funding. Ozaki:Chugai pharmaceutical: Honoraria; Novartis: Honoraria; Celgene: Honoraria; Kyowa Hakko Kirin: Honoraria. Kanakura:Alexion Pharmaceuticals: Research Funding, Speakers Bureau. Okamoto:Novartis : Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; GlaxoSmithKlein: Honoraria, Research Funding; KyowaHakkoKirin: Honoraria, Research Funding; Chugai: Honoraria, Research Funding.

Phase I study of anti‐CD22 immunoconjugate inotuzumab ozogamicin plus rituximab in relapsed/refractory B‐cell non‐Hodgkin lymphoma

Inotuzumab ozogamicin (CMC-544), a humanized anti-CD22 antibody conjugated to the potent cytotoxic antibiotic calicheamicin, targets the CD22 antigen expressed on the majority of B-cell non-Hodgkin lymphomas. This phase I study assessed the tolerability, safety, pharmacokinetics, and preliminary efficacy of inotuzumab ozogamicin administered intravenously in combination with rituximab in Japanese patients with relapsed or refractory B-cell non-Hodgkin lymphoma. Ten patients were administered rituximab 375 mg/m(2) followed by inotuzumab ozogamicin at the maximum tolerated dose (1.8 mg/m(2)). Treatment was repeated every 28 days up to eight cycles, or until occurrence of disease progression or intolerable toxicity. The safety profile was similar to that of inotuzumab ozogamicin monotherapy, with hematologic adverse events occurring most frequently. The most common grade three or higher adverse events were thrombocytopenia (70%), neutropenia (50%), leukopenia (30%), and lymphopenia (30%). The overall response rate was 80% (8/10; 95% CI, 44-98%). Drug exposure increased with successive doses, similar to the pharmacokinetic profiles observed in previous phase I monotherapy studies. Efficacy results suggested promising antitumor activity, and the overall findings support the continued clinical development of this therapeutic regimen in patients with relapsed or refractory B-cell non-Hodgkin lymphoma. This trial was registered at www.ClinicalTrials.gov as NCT00724971.

Phase 1 Study of Anti-CD22 Immunoconjugate Inotuzumab Ozogamicin (CMC-544) Plus Rituximab In Japanese Patients with Relapsed/Refractory B-Cell Non-Hodgkin Lymphoma

AbstractAbstract 2872 Background:Inotuzumab ozogamicin (CMC-544) is a humanized anti-CD22 antibody conjugated to calicheamicin, a potent cytotoxic agent. Inotuzumab ozogamicin targets CD22, which is expressed in the majority of B-cell non-Hodgkin lymphomas (NHL). The maximum tolerated dose of inotuzumab ozogamicin administered as a single agent was previously determined to be 1.8 mg/m2 administered intravenously every 28 days, and clinical activity was shown in both non-Japanese and Japanese patients with relapsed or refractory B-cell NHL. Safety and efficacy data in non-Japanese patients with relapsed or refractory B-cell NHL treated with inotuzumab ozogamicin given in combination with rituximab was previously reported. Objectives:To assess safety, pharmacokinetics, and preliminary efficacy of inotuzumab ozogamicin in combination with rituximab in Japanese patients with relapsed or refractory B-cell NHL. Methods:Patients were eligible if they had both CD20 and CD22-positive B-cell NHL, which had not responded to or progressed after 1 or 2 therapies. At least 1 prior regimen had to contain rituximab, and patients could not have progressed under treatment or within 6 months of start of rituximab-containing therapy. Patients received 375 mg/m2 of rituximab on Day 1 followed by 1.8 mg/m2 of inotuzumab ozogamicin on Day 2 of each 28-day cycle for up to 8 cycles, provided that there was no disease progression or intolerable toxicity. Adverse events (AEs) were reported according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 3.0 in patients who received at least 1 dose of the study drug. Objective response rate (ORR) was evaluated according to the International Response Criteria for NHL. Results:Ten patients were enrolled and treated with 1.8 mg/m2 of inotuzumab ozogamicin in combination with rituximab for a median of 4 cycles. Median age was 60.5 (range 46 – 74), 50% were male, and 50% each had 1 and 2 prior chemotherapy regimens. Six patients were diagnosed as having follicular lymphoma (FL), 2 patients as mantle cell lymphoma (MCL), 1 patient each as diffuse large B-cell lymphoma (DLBCL) and mucosa-associated lymphoid tissue (MALT) lymphoma. Grade 3 or 4 treatment-emergent AEs reported in >20% of the patients were thrombocytopenia (70%), neutropenia (50%), leukopenia (30%), and lymphopenia (30%). AEs resulting in treatment discontinuation were neutropenia (30%) and hyperbilirubinemia (20%). No serious AEs were observed. An ORR of 80% (95% CI, 44 – 98%) was observed in the 10 patients treated. Five out of 6 patients with FL and 1 patient with MALT lymphoma achieved a complete response (CR). One out of 2 patients with MCL achieved unconfirmed CR (CRu), and 1 patient with FL attained partial response (PR). Progression-free survival (PFS) rate at 52 weeks was estimated to be 89% (95% CI, 43 – 98). ORR was 88% (95% CI, 47 – 100%) in the 8 patients that received at least 2 doses of the study drug and had at least 1 post-baseline tumor assessment (5 FL, 2 MCL, and 1 MALT lymphoma). Results of the pharmacokinetics assessment will be presented at the meeting. Conclusion:The combination of inotuzumab ozogamicin plus rituximab has a safety profile similar to that previously reported for inotuzumab ozogamicin as a single agent, with hematologic AEs being the most frequent toxicities. The preliminary but encouraging evidence of clinical activity in Japanese patients with relapsed or refractory B-cell NHL warrants continued clinical development of this combination. Disclosures:Tokushige:Pfizer Japan Inc.: Employment. Ono:Pfizer Japan Inc.: Employment. Vandendries:Pfizer Inc.: Employment, Equity Ownership.