Analysis of Japanese patients from the AUGMENT phase III study of lenalidomide + rituximab (R2) vs. rituximab + placebo in relapsed/refractory indolent non-Hodgkin lymphoma.

Patients with indolent non-Hodgkin lymphoma (iNHL) typically respond to first-line immunochemotherapy, but relapse is common. Treatment options for relapsed iNHL include chemotherapy ± rituximab and rituximab monotherapy. Lenalidomide plus rituximab (R2) is an immunomodulatory regimen that enhances rituximab-mediated cytotoxicity and improves clinical activity in iNHL. AUGMENT was a double-blind phase III randomized trial of R2 vs. rituximab + placebo (R-placebo) in patients with relapsed/refractory follicular lymphoma or marginal zone lymphoma who were not refractory to rituximab. The primary endpoint was progression-free survival (PFS). Data reported here focus on Japanese patients from AUGMENT and reflect 36 patients (n = 18, each group). PFS was superior in the R2 group, HR = 0.32 (95% CI 0.11-0.96). Median PFS was not reached (95% CI 19.7-NE) in the R2 group vs. 16.5 months (95% CI 11.3-30.6) in the R-placebo group. Grade 3/4 adverse events were more frequent in patients treated with R2 (67%) than with R-placebo (22%), primarily attributable to increased neutropenia (50% vs 17%). R2 resulted in significantly longer median PFS than R-placebo in Japanese patients with R/R iNHL, and the efficacy and the safety profile of R2 were similar to those reported in the global population.

Current treatment patterns and medical costs for multiple myeloma in Japan: a cross-sectional analysis of a health insurance claims database.

Aims: Various drugs have recently been launched for the treatment of multiple myeloma (MM). This increase in the number of treatment options has potentially changed treatment patterns and medical costs for patients with MM. Japanese public health insurance claims were analyzed to examine the change in the treatment patterns of MM drugs and medical costs per patient.Materials and methods: A claims database provided by Medical Data Vision was used, which includes data from ∼20 million patients from >300 acute care hospitals across Japan. The type of MM drugs prescribed and medical costs for patients with MM between April 2008 and December 2016 were examined using monthly cross-sectional analyses. Patients with an International Classification of Diseases, 10th Revision (ICD-10) diagnosis code of C90.0 were classified as having MM. MM drugs were defined by generic names.Results: In total, 19,137 patients with MM (average age at first diagnosis: 69.6 years; percentage of women: 47.9%) were identified from the database. The percentage of patients prescribed each MM drug changed substantially as novel drugs were launched. Total medical costs increased until 2010, then stabilized. MM drug costs increased from approximately 2010, but costs for other care decreased, particularly for hospitalization (including surgery).Limitations: The database contained data from large, acute care hospitals, which may have caused bias in terms of patients' clinical history and disease severity.Conclusions: Total medical costs for MM have remained stable since 2010. MM drug costs increased, but costs for other care decreased after the launch of lenalidomide in 2010 and other drugs in 2015 and later. More detailed research is required to confirm whether the launch of novel drugs caused the changes in medical costs.

[Romidepsin (Istodax® for intravenous injection 10†mg): pharmacokinetics, pharmacodynamics and clinical study outcome].

Romidepsin (Brand name: ISTODAX® for Injection 10 mg) is a novel antitumor drug that inhibits histone deacetylase (HDAC). Romidepsin strongly inhibited class I HDAC activity in vitro and demonstrated a strong antitumor activity against human tumor cell line xenograft in vivo. Based on its demonstrated efficacy against T-cell lymphoma in early clinical studies, multicenter phase II clinical studies in overseas with romidepsin were conducted in patients with cutaneous T-cell lymphoma (CTCL) and peripheral T-cell lymphoma (PTCL), followed by approval for the treatment of CTCL and PTCL in the U.S. and other countries. Thereafter, domestic phase I/II studies were planned. The phase I study was designed to evaluate the tolerability of romidepsin in Japanese patients with relapsed or refractory PTCL/CTCL and thereby determine the recommended dose, as patients were administered romidepsin by intravenous infusion at a dose of 9 or 14 mg/m2 over 4 hours on days 1, 8 and 15 of each 28-day cycle, and 14 mg/m2 was determined as the recommended dose for phase II. While the phase II study was designed to include 40 Japanese patients with relapsed or refractory PTCL to evaluate the efficacy and safety of romidepsin. Treatment response was 42.5% and the most common AEs of Grade ≥ 3 were lymphopenia (74.0%), neutropenia (54.0%), leukocytopenia (46.0%) and thrombocytopenia (38.0%). The overall safety profile was considered to be within the acceptable range. On the basis of these result, romidepsin was approved in July 2017 for the treatment of relapsed or refractory PTCL in Japan.

Romidepsin in Japanese patients with relapsed or refractory peripheral T-cell lymphoma: a phase I/II and pharmacokinetics study.

This phase I/II multicenter study evaluated romidepsin treatment in Japanese patients with relapsed/refractory peripheral T-cell lymphoma (PTCL) or cutaneous T-cell lymphoma (CTCL). Patients aged ≥20 years received romidepsin via a 4-h intravenous infusion on days 1, 8, and 15 of each 28-day cycle. Phase I used a 3 + 3 design to identify any dose-limiting toxicity (DLT) for regimens of romidepsin 9 and 14 mg/m2. The primary endpoints for phase I and II were DLT and overall response rate (ORR), respectively. Intent-to-treat patients were those who received ≥1 romidepsin dose (PTCL, n = 48; CTCL, n = 2). In phase I, none of the patients (n = 3, 9 mg/m2; n = 6, 14 mg/m2) exhibited DLT. In phase II, 40 patients with PTCL were treated with 14 mg/m2 romidepsin. The most common treatment-emergent grade ≥3 adverse events were lymphopenia (74%), neutropenia (54%), leukopenia (46%), and thrombocytopenia (38%). Patients in phase II showed a 43% ORR, including 25% complete responses. Median progression-free survival was 5.6 months and median duration of response was 11.1 months. This phase I/II study identified a well-tolerated dose of romidepsin, with an acceptable toxicity profile and clinically meaningful efficacy in Japanese patients with relapsed/refractory PTCL. ClinicalTrials.gov Identifier NCT01456039.

Multicenter Phase II Study of Lenalidomide in Relapsed or Recurrent Adult T-Cell Leukemia/Lymphoma: ATLL-002.

Purpose Few treatment options exist for adult T-cell leukemia/lymphoma (ATL), and the prognosis for this disease is poor. A phase I study of lenalidomide demonstrated preliminary antitumor activity in patients with relapsed ATL. The current phase II study evaluated the efficacy and safety of lenalidomide monotherapy in patients with relapsed or recurrent ATL. Patients and Methods Patients 20 years of age or older with acute, lymphoma, or unfavorable chronic subtype ATL, who had received one or more prior anti-ATL systemic chemotherapy and achieved stable disease or better on their last anti-ATL therapy with subsequent relapse or recurrence, were eligible. Patients received oral lenalidomide 25 mg/d continuously until disease progression or unacceptable toxicity. The primary end point was overall response rate; secondary end points included safety, tumor control rate (stable disease or better), time to response, duration of response, time to progression, progression-free survival, and overall survival. Results Objective responses were noted in 11 of 26 patients (overall response rate, 42%; 95% CI, 23% to 63%), including four complete responses and one unconfirmed complete response. The tumor control rate was 73%. The median time to response and duration of response were 1.9 months and not estimable, respectively, and the median time to progression was 3.8 months. The median progression-free survival and overall survival were 3.8 and 20.3 months, respectively. The most frequent grade ≥ 3 adverse events were neutropenia (65%), leukopenia (38%), lymphopenia (38%), and thrombocytopenia (23%), which were all manageable and reversible. Conclusion Lenalidomide demonstrated clinically meaningful antitumor activity and an acceptable toxicity profile in patients with relapsed or recurrent aggressive ATL, hinting at its potential to become a treatment option. Further investigations of lenalidomide in ATL and other mature T-cell neoplasms are warranted.

Lenalidomide in relapsed adult T-cell leukaemia-lymphoma or peripheral T-cell lymphoma (ATLL-001): a phase 1, multicentre, dose-escalation study.

BACKGROUND: Patients with adult T-cell leukaemia-lymphoma have few treatment options after relapse and poor survival outcomes with current therapies. We aimed to determine the maximum tolerated dose of lenalidomide, an oral immunomodulator, in Japanese patients with relapsed adult T-cell leukaemia-lymphoma and other peripheral T-cell lymphomas. METHODS: In this phase 1 study, we enrolled patients aged 20 years or older with Eastern Cooperative Oncology Group performance status 0-2, documented diagnosis of aggressive adult T-cell leukaemia-lymphoma or other peripheral T-cell lymphoma subtypes, and at least one previous antilymphoma therapy. Patients were sequentially assigned to lenalidomide 25 mg/day, days 1-21 of a 28-day cycle (cohort 1), 25 mg/day continuously (cohort 2), and 35 mg/day continuously (cohort 3) in a 3 + 3 design. The primary study endpoint was to identify the maximum tolerated dose of lenalidomide. Analyses were performed per protocol for efficacy and in the intent-to-treat patient population for safety. This completed trial is registered with ClinicalTrials.gov, number NCT01169298. FINDINGS: We enrolled 14 patients from six centres in Japan. Of 13 assessable patients (nine with adult T-cell leukaemia-lymphoma, four with other peripheral T-cell lymphomas) receiving lenalidomide, dose-limiting toxic effects were reported in three patients during cycle 1 (one grade 4 thrombocytopenia [cohort 2], one grade 3 QT prolongation on electrocardiogram [cohort 3], and one grade 3 fatigue and grade 4 thrombocytopenia [cohort 3]). The maximum tolerated dose was identified as lenalidomide 25 mg/day given continuously. The most common grade 3 or worse adverse events were neutropenia (eight [62%] patients), lymphopenia (seven [54%] patients), and thrombocytopenia (four [31%] patients); myelosuppression was similar in each cohort. Serious adverse events occurred in eight (62%) patients; thrombocytopenia, which occurred in three (23%) patients, was the only serious adverse event reported in more than one patient. INTERPRETATION: We were able to determine the dose and schedule for lenalidomide treatment in previously treated patients with aggressive, adult T-cell leukaemia-lymphoma. This dose will be used in a subsequent phase 2 study. FUNDING: Celgene Corporation.

Phase II study of ABVd therapy for newly diagnosed clinical stage II-IV Hodgkin lymphoma: Japan Clinical Oncology Group study (JCOG 9305).

Although ABVD (doxorubicin, bleomycin, vinblastine and dacarbazine) therapy has been regarded as a standard of care for advanced-stage Hodgkin lymphoma (HL) since 1992, there has been no prospective data of ABVD therapy in Japan. To investigate the efficacy and safety of ABVd therapy with the lower dose of dacarbazine (250 mg/m(2)) in patients with newly diagnosed stage II-IV HL, Lymphoma Study Group of Japan Clinical Oncology Group conducted a phase II study. The primary endpoints were complete response rate (%CR) and progression-free survival (PFS). A total of 128 patients with age less than 70 years were enrolled and received 6-8 cycles of ABVd followed by radiation to initial bulky mass. The %CR in 118 eligible patients was 81.4% [95% confidence interval (CI) 73.1-87.9%]. Major toxicity was grade 4 neutropenia (45.3%). Grade 3 nausea/vomiting was the most frequent non-hematological toxicity (10.9%). Transient grade 4 constipation, infection (abscess), hypoxemia and hyperbilirubinemia were observed in 4 patients. No treatment-related death was observed. PFS and overall survival at 5 years were 78.4% (95% CI 70.9-85.9%) and 91.3% (95% CI 86.1-96.5%), respectively. In conclusion, ABVd is effective in Japanese patients with stage II-IV HL with acceptable toxicities (UMIN-CTR Number: C000000092).

Safety and pharmacokinetics of panitumumab in Japanese patients with advanced solid tumors.

BACKGROUND: Panitumumab is a fully human, monoclonal antibody against the epidermal growth factor receptor. Previous studies in non-Japanese patients with solid tumors showed that panitumumab exhibited nonlinear pharmacokinetics, was well tolerated (skin toxicities were the most common treatment-related adverse events), and had antitumor activity in some patients. This open-label, phase 1 study investigated panitumumab safety and pharmacokinetics in Japanese patients. METHODS: Japanese patients with advanced solid tumors were enrolled into one of three sequential panitumumab dose cohorts (cohort 1, 2.5 mg/kg weekly; cohort 2, 6.0 mg/kg every 2 weeks; and cohort 3, 9.0 mg/kg every 3 weeks) and received panitumumab until disease progression or drug intolerability. Safety endpoints included the incidence of adverse events, changes in laboratory values, and the appearance of anti-panitumumab antibodies. Serial pharmacokinetic samples were collected after the first and third doses of panitumumab. Tumors were assessed at week 8 and every 8 weeks thereafter. RESULTS: Eighteen patients (6 per cohort) were enrolled. No dose-limiting toxicities, investigator-reported infusion reactions, or deaths occurred. Seven patients had grade-3/4 adverse events; fatigue and anorexia were most common. The most common skin toxicities were rash and acneiform dermatitis. No neutralizing anti-panitumumab antibodies were detected. Panitumumab exhibited nonlinear pharmacokinetics, and antitumor activity was observed in 31% (4/13) of the patients with colorectal cancer. CONCLUSION: In Japanese patients with solid tumors, panitumumab was well tolerated, demonstrated pharmacokinetic and safety profiles similar to those observed previously in non-Japanese patients, and exhibited encouraging antitumor activity in patients with colorectal cancer.

A phase II, open-label, sequential-cohort, dose-escalation study of romiplostim in Japanese patients with chronic immune thrombocytopenic purpura.

This phase II, multicenter, open-label, sequential-cohort, dose-escalation study was designed to evaluate the safety and efficacy of romiplostim, a novel peptibody that increases platelet production, in Japanese patients with chronic immune thrombocytopenic purpura (ITP). Sequential cohorts of four patients each received romiplostim (1, 3, or 6 microg/kg) subcutaneously on days 1 and 8 of the dose-escalation phase. Patients who achieved platelet responses (doubling of baseline platelet counts to > or =50 x 10(9)/L) continued romiplostim weekly during the treatment-continuation phase. Romiplostim produced dose-dependent increases in mean and peak platelet counts. Five patients received romiplostim during the treatment-continuation phase, with platelet counts > or =50 x 10(9)/L maintained in approximately half of the weekly assessments. Romiplostim was well tolerated. No severe, serious, or life-threatening adverse events were reported. No binding antibodies to romiplostim or thrombopoietin were detected. Romiplostim is safe and well tolerated in Japanese patients with chronic ITP and is effective in producing platelet count increases, consistent with the results from studies in non-Japanese patients. On the basis of these findings, a starting dose of 3 microg/kg was recommended for phase III evaluation of romiplostim in Japanese patients with chronic ITP.

Phase 1 trial of denosumab safety, pharmacokinetics, and pharmacodynamics in Japanese women with breast cancer-related bone metastases.

Denosumab, a fully human monoclonal antibody to receptor activator of nuclear factor-kappa B ligand (RANKL), suppresses bone resorption. This open-label, multicenter, phase 1 study evaluated the safety, pharmacodynamics, and pharmacokinetics of denosumab in Japanese women with breast cancer-related bone metastases. Patients (n = 18; median age, 57 years) received a single subcutaneous injection of denosumab 60 mg or 180 mg or three doses of denosumab 180 mg on days 1, 29, and 57 (every 4 weeks) and were followed for > or = 141 days. No major safety concerns related to denosumab were noted in any cohort. All patients experienced at least 1 adverse event (AE); most were mild (grade < or = 2). One patient reported grade 4 myositis and grade 3 anemia, malaise, and dysphagia that the investigator deemed treatment-related; other treatment-related AE were grade < or = 2. No antidenosumab antibodies or clinically significant changes in laboratory findings, vital signs, or electrocardiograms were observed. Pharmacokinetics were approximately dose-linear. Denosumab caused rapid, substantial, and sustained suppression of urinary N-telopeptide corrected for creatinine (uNTx/Cr) across all doses; at day 85, the median change from baseline uNTx/Cr ranged from -61.9% to -90.8%. No dose-limiting toxicity was observed at any dosage. Coupled with pharmacokinetic and pharmacodynamic data, these results were consistent with those observed in non-Japanese populations.

Pharmacodynamics and pharmacokinetics of AMG 531, a thrombopoiesis-stimulating peptibody, in healthy Japanese subjects: a randomized, placebo-controlled study.

AMG 531 is a novel thrombopoiesis-stimulating peptibody being investigated for the treatment of chronic immune thrombocytopenic purpura. This double-blind, phase I study evaluated the safety, pharmacodynamics, and pharmacokinetics of AMG 531 in healthy Japanese men. Thirty subjects were randomly assigned 4:1 (AMG 531/placebo) to receive 1 dose of AMG 531 (0.3, 1, or 2 microg/kg) or placebo by subcutaneous injection; subjects were evaluated for 6 weeks. AMG 531 was generally well tolerated, with adverse events similar to placebo. Treatment-related adverse events (headache, "feeling hot," malaise) were reported for 5 of 24 AMG 531-treated subjects. Platelets generated after exposure to AMG 531 functioned normally. Four of 8 subjects receiving 1 microg/kg and 7 of 8 receiving 2 microg/kg had platelet count increases > or =1.5-fold over baseline, an effect similar to that seen in non-Japanese subjects. Serum AMG 531 concentrations were below the lower limit of quantification in all but 2 subjects receiving 2 microg/kg.

A randomized controlled trial investigating the survival benefit of dose-intensified multidrug combination chemotherapy (LSG9) for intermediate- or high-grade non-Hodgkin's lymphoma: Japan Clinical Oncology Group Study 9002.

The effect of enhancing the dose intensity (DI) of the key drugs in multidrug combination chemotherapy for malignant lymphoma is uncertain. We investigated the survival benefit of dose-intensified multidrug combination chemotherapy for intermediate- or high-grade non-Hodgkin's lymphoma (NHL). Patients without any prior chemotherapy were randomly assigned either to dose-intensified multidrug combination chemotherapy, LSG9 (VEPA-B/FEPP-AB/M-FEPA, treated 3 times every 10 weeks for 28 weeks total), or to control-arm combination chemotherapy, mLSG4 (VEPA-B/FEPP-B/M-FEPA, treated 4 times every 14 weeks for 54 weeks total). The planned DI of doxorubicin and cyclophosphamide were 1.96 and 1.47 times higher, respectively, in LSG9 than in mLSG4. Overall survival, complete response (CR) rate, and toxicities were evaluated. The 447 patients (230 for LSG9 and 217 for mLSG4) were enrolled between February 1991 and March 1995. The 5-year overall survival rates were 56.8% for LSG9 patients and 55.1% for mLSG4 patients (log-rank P = .42). The rates for CR plus uncertain CR were 70.0% for LSG9 and 64.5% for mLSG4. The toxicities of both regimens were similar and tolerable. The median actual DI of doxorubicin and cyclophosphamide were 1.56 and 1.17 times higher, respectively, in LSG9 than in mLSG4. Compared with the control regimen mLSG4, the dose-intensified regimen LSG9 did not show significant survival benefit. An increase in the DI of doxorubicin in multidrug combination chemotherapy did not improve the survival of patients with intermediate- or high-grade NHL.