Two Phase I and Pharmacokinetic Studies of Darinaparsin (Organic Arsenic Compound) in Japanese and Korean Patients with Relapsed or Refractory (R/R) Peripheral T-Cell Lymphoma (PTCL)

Abstract Background: Darinaparsin is a novel organic arsenic compound composed of dimethylated arsenic linked to glutathione, and has similar structure to one of the intermediates of the arsenic detoxification pathway. The mechanism of action includes induction of apoptosis in tumor cells, primarily through disruption of mitochondrial functions and increase in reactive oxygen species production. Two phase I studies of darinaparsin for injection were conducted in patients with relapsed or refractory (r/r) PTCL to evaluate its safety, efficacy and pharmacokinetics in Japan and Korea, respectively. Methods: Patients with histologically confirmed PTCL not otherwise specified (PTCL-NOS), angioimmunoblastic T-cell lymphoma (AITL), anaplastic lymphoma kinase (ALK) -positive anaplastic large cell lymphoma (ALCL) or ALK-negative ALCL who failed or were refractory to 1 or more prior systemic therapy were eligible. Darinaparsin was administered for 5 consecutive days at 200 mg/m2/day or 300 mg/m2/day every 4 weeks, or at 300 mg/m2/day every 3 weeks in the Japanese phase I study, and at 300 mg/m2/day every 4 weeks or every 3 weeks in the Korean phase I study. Darinaparsin was given intravenously over 1 hour, and the treatment was continued until disease progression or unacceptable toxicity. As one of the secondary endpoints, tumor response was explanatorily assessed by using the Revised Response Criteria for Malignant Lymphoma (Cheson BD et al, J Clin Oncol 2007) in patients who completed at least 2 cycles of treatment and who had evaluable data of FDG-PET and CT scan. Since use of an inorganic arsenic compound is limited by cardiotoxicity, the potential of darinaparsin to prolong QTcF and any possible relationship between darinaparsin plasma concentration and change in QTcF were assessed. Results: In these 2 studies, 17 Japanese patients and 6 Korean patients; a total of 23 patients, included 16 PTCL-NOS, 6 AITL and 1 ALK-negative ALCL; 14 males and 9 females, with a median age of 63 (range 22-83) years were enrolled. Dose-limiting toxicities occurred in 1 Japanese patient who received 300 mg/m2/day (grade [G] 3 hepatic dysfunction). Drug-related adverse events >= G3 were reported in 4 Japanese patients who received 300 mg/m2/day. Occurrence of diffuse large B-cell lymphoma was reported in 1 patient, anemia in 1, leukopenia in 1, neutropenia in 2, febrile neutropenia in 1, lymphopenia in 2, thrombocytopenia in 2, hepatic dysfunction in 1, nausea in 1 and activated partial thromboplastin time (APTT) prolonged in 1. No drug-related adverse event >= G3 was reported in Korean patients. No patient showed QTcF >500 msec or delta QTcF >60 msec throughout the study period. Concentration-dependent or treatment-duration-independent effect on the QTcF was not identified. There was no significant relationship between the plasma concentration of darinaparsin and a change in QTcF interval (r=0.003). Tumor response was assessed in 14 patients who completed at least 2 cycles of treatment, and objective response was observed in 4 patients (1 complete response and 3 partial responses). Five of 6 patients with stable disease showed tumor shrinkage to some extent. In Japanese and Korean patients who received 300 mg/m2/day, the mean (± SD) values of Cmax were 838 ± 181 and 708 ± 81 ng/mL, AUC0-24 were 12759 ± 3419 and 11282 ± 905 ng•h/mL, and t1/2 were 20 ± 6.3 and 20.6 ± 2.8 h, respectively. The systemic arsenic exposures were similar between Japanese and Korean patients. There was no apparent difference in the mean plasma concentration-time profiles between Japanese and Korean patients at the doses studied. Conclusion: The results from integrated data analysis of these 2 phase I studies revealed that darinaparsin was well tolerated at all doses and dosing schedules studied, and demonstrated its potential efficacy against r/r PTCL. Furthermore, it was suggested that 300 mg/m2/day for 5-consecutive days every 3 weeks would be the recommendable dosing schedule of darinaparsin for subsequent studies. Based on the promising results of these phase I studies, we are planning to conduct an Asian multicenter phase II study for r/r PTCL. Disclosures Kim: Kyowa-Kirin: Research Funding; Takeda: Research Funding; Novartis: Research Funding; Roche: Research Funding; Donga: Research Funding; Merck: Research Funding. Ogura:Eisai Co., Ltd.: Research Funding; Kyowa Hakko Kirin co., Ltd.: Research Funding; Zenyaku Kogyo Co., Ltd.: Research Funding; Chugai Pharmaceutical Co., Ltd.: Research Funding; Phizer Japan Inc.: Research Funding; Janssen Pharmaceutical K.K.: Research Funding; GlaxoSmithKline K.K.: Research Funding; MSD K.K.: Research Funding; AstraZeneca K.K.: Research Funding; Takeda Pharmaceutical Company Limited: Research Funding; Symbio Pharmaceuticals Limited: Research Funding; Solasia Phama K.K.: Research Funding; Mundipharma K.K.: Research Funding; Celgene K.K.: Research Funding; Sumitomo Dainippon Pharma Co., Ltd.: Research Funding. Uchida:Eisai Co., Ltd.: Research Funding. Ishizawa:Takeda: Speakers Bureau; Janssen: Research Funding; Takeda: Research Funding; Kyowa Kirin: Speakers Bureau; GSK: Research Funding; Kyowa Kirin: Research Funding; Celgin: Research Funding; Pfizer: Speakers Bureau; Celgin: Speakers Bureau. Tobinai:Gilead Sciences: Research Funding. Nagahama:Solasia Pharma K.K.: Employment. Sonehara:Solasia Pharma K.K.: Employment. Nagai:Servier: Research Funding; Mundipharma: Research Funding; Otsuka: Research Funding; Takeda: Research Funding; CMIC: Research Funding; Janssen: Research Funding; Gilead Sciences: Research Funding.

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Phase I studies of darinaparsin in patients with relapsed or refractory peripheral T-cell lymphoma: a pooled analysis of two phase I studies conducted in Japan and Korea

Japanese Journal of Clinical Oncology ◽

10.1093/jjco/hyaa177 ◽

2020 ◽

Author(s):

Michinori Ogura ◽

Won-Seog Kim ◽

Toshiki Uchida ◽

Naokuni Uike ◽

Youko Suehiro ◽

...

Keyword(s):

T Cell ◽

Phase I ◽

Cell Lymphoma ◽

Pharmacokinetic Profile ◽

T Cell Lymphoma ◽

Peripheral T Cell Lymphoma ◽

Two Phase ◽

Phase I Studies ◽

Korean Patients ◽

Grade 3

Abstract Objective Two phase I studies of darinaparsin including Japanese and Korean patients with relapsed/refractory peripheral T-cell lymphoma were performed to evaluate its safety (primary purpose), efficacy and pharmacokinetic profile (ClinicalTrials.gov: NCT01435863 and NCT01689220). Methods Patients received intravenous darinaparsin for 5 consecutive days at 200 mg/m2/day in 4-week cycles, 300 mg/m2/day in 4-week cycles or 300 mg/m2/day in 3-week cycles. Results Seventeen Japanese and 6 Korean patients were enrolled and treated. Drug-related adverse events developed in 18 patients (78%). Dose-limiting toxicity, grade 3 hepatic dysfunction, was reported on Day 15 of cycle 1 in 1 Japanese patient who received 300 mg/m2/day. The most common drug-related, grade ≥ 3 adverse events were lymphopenia (9%), neutropenia (9%) and thrombocytopenia (9%). No deaths occurred. In 14 evaluable patients, 1 and 3 patients had complete response and partial response, respectively. The plasma concentration-time profiles of arsenic, a surrogate marker for darinaparsin, were similar between Japanese and Korean patients. No significant difference was found in its pharmacokinetic profile. Conclusions These data indicate the good tolerability and potential efficacy of darinaparsin in patients with relapsed/refractory peripheral T-cell lymphoma. Darinaparsin 300 mg/m2/day for 5 consecutive days in 3-week cycles is the recommended regimen for phase II study.

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Comparison of Single Agent GA101 In Japanese and European Patients with Relapsed/Refractory B-Cell Non-Hodgkin Lymphoma (B-NHL) – Results From Two Phase I Studies

Blood ◽

10.1182/blood.v116.21.4921.4921 ◽

2010 ◽

Vol 116 (21) ◽

pp. 4921-4921 ◽

Cited By ~ 1

Author(s):

Michinori Ogura ◽

Franck Morschhauser ◽

Kensei Tobinai ◽

Guillaume Cartron ◽

Kiyohiko Hatake ◽

...

Keyword(s):

Phase I ◽

Ethnic Differences ◽

Response Rates ◽

Japanese Patients ◽

Small Sample ◽

Two Phase ◽

Advisory Committees ◽

Phase I Studies ◽

Chugai Pharmaceutical ◽

Anti Cd20

Abstract Abstract 4921 Background: Most studies regarding the chimeric anti-CD20-antibody rituximab have reported no ethnic differences including response or safety in B-NHL. GA101 is the first type II, glycoengineered and humanized anti-CD20 monoclonal antibody to enter clinical trials. Results in B-NHL patients have previously been reported from three phase I studies, conducted in Europe, Canada and Japan (Salles 2008, 2010, Sehn 2009, Tobinai 2010), and all have demonstrated good tolerability along with promising activity, with a safety profile largely similar to rituximab when compared to historical rituximab data. Here we report a comparison of the phase I studies BO20999 and JO21900, conducted in Europe and Japan, respectively, to analyze any potential ethnic differences in safety/efficacy. Both studies were conducted in patients with relapsed/refractory B-NHL, with the majority of patients being of indolent histology and both studies used identical drug administration and response assessment schedules. Methods: In both studies GA101 was administered IV as monotherapy (as an absolutely flat dose) on days 1, 8 and 22, and then every 3 wks, for a total of 9 infusions. The dose was escalated using a 3+3 design, with study JO21900 starting at a higher dose of 200/400mg (with doses up to 2,000mg, a dose level judged safe and well tolerated in BO20999 (doses ranging from 50-2, 000mg). Patient and disease characteristics, prior treatments, response rates and safety parameters from both studies were compared. Given the small sample sizes, heterogeneity, the dose-escalation design and the cross-trial comparison, no formal statistical analysis was applied. Results: Patient age and other baseline parameters were substantially similar between the two studies (Table 1). The safety profiles in both studies were comparable, with the most common AEs being infusion-related reactions (86% BO20999; 100% JO21900) of grade 1–2 mainly associated with the first infusion and decreasing with subsequent infusions. Incidence of SAEs were similar (BO20999 [n=4], JO21900 [n=2]). Importantly, no dose-limiting toxicities and no dose reductions were observed in either study. No patients with aggressive histology were enrolled into study JO21900, and Japanese patients were less heavily pretreated (median of 1 vs 4 prior treatments for European patients) and no Japanese patient had received prior autologous stem cell transplant. End of treatment response rates were slightly higher in Japanese study than those in the European study (Table 1). GA101 plasma drug concentrations in both studies were comparable, with the observation of a large inter-patient variability, however, a dose-dependent increase in mean plasma concentrations, increasing with dose, was observed in both studies. Conclusion: These clinical, safety and pharmacokinetic results from two phase I studies suggest that there appears to be no apparent differences between Japanese and European patients with respect to the safety or efficacy of GA101 monotherapy in indolent B-NHL patients, although analyses on larger datasets would be required to confirm these initial results. The slightly higher response rates observed in Japanese patients may be attributable to the small sample size, and a less heavily pre-treated population that comprised of patients solely of indolent histology only. Disclosures: Morschhauser: Roche: Consultancy, Honoraria. Cartron: Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Hatake: Chugai Pharmaceutical Co., Ltd.: Honoraria, Research Funding. Wenger: Roche: Employment. Birkett: Roche: Employment. Oya: Chugai Pharmaceutical Co., Ltd.: Employment. Nishima: Chugai Pharmaceutical Co., Ltd.: Employment. Salles: Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

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Oral HDAC Inhibitor HBI8000 in Japanese Patients with Non-Hodgkin Lymphoma (NHL): Phase I Safety and Efficacy Results

Blood ◽

10.1182/blood.v128.22.1827.1827 ◽

2016 ◽

Vol 128 (22) ◽

pp. 1827-1827 ◽

Cited By ~ 2

Author(s):

Makoto Onizuka ◽

Kiyoshi Ando ◽

Makoto Yoshimitsu ◽

Takashi Ishida ◽

S Yoshida ◽

...

Keyword(s):

T Cell ◽

Phase I ◽

Phase Ii ◽

Research Funding ◽

Phase I Trial ◽

Cell Lymphoma ◽

Japanese Patients ◽

Dose Cohort ◽

Grade 3 ◽

Anti Tumor Activity

Abstract Background: HBI-8000 is an orally bioavailable member of the benzamide class of histone deacetylase inhibitors (HDACi), that inhibits cancer-associated HDAC enzymes (Class I and IIb). HBI-8000 has anti-tumor activity through various mechanisms of action, including epigenetic reprogramming and immunomodulation. It was recently approved by the Chinese FDA under the name chidamide (Epidaza) for relapsed or refractory (R/R) peripheral T-cell lymphoma (PTCL) with a recommended dose of 30 mg twice weekly (BIW). HBI-8000 is also being manufactured in the USA for clinical development outside of China. The preliminary results of a phase I trial of HBI-8000 to confirm the safety and maximum tolerated dose (MTD) in Japanese patients (pts) with advanced NHL are presented (NCT02697552). Methods: This is a multicenter, prospective phase I trial in Japan. Inclusion criteria: patients are eligible if they have histologically or cytologically proven NHL and no other standard therapy is available. The primary endpoint is the MTD based on the frequency of dose-limiting toxicities (DLTs) observed within 28 days of the first dose. Secondary endpoints include pharmacokinetic (PK) profile and anti-tumor activity. At the time of this abstract submission, the trial is still ongoing. Results: Thirteen out of 14 pts were eligible for the 1st cycle DLT assessment (6 pts in the 30 mg, 7 pts in the 40 mg cohort). Median age was 68 years, gender well balanced, and the majority of pts had ≥ 2 prior treatment regimens. Five pts had the diagnosis of adult T-cell leukemia-lymphoma (ATL), 2 pts presented with PTCL, 3 with diffuse large B-cell lymphoma (DLBLC), 2 with follicular lymphoma (FL), 1 with cutaneous T-cell lymphoma (CTCL), and 1 with marginal zone lymphoma. Overall, the treatment was well tolerated, and adverse drug reactions (ADRs) were predominantly hematologic, consistent with the previous experiences. There were 7 pts in the 40 mg dose cohort because one of the first 3 pts had to be replaced for incomplete dosing due to grade 3 hypertriglyceridemia which was not regarded as DLT by the Data Monitoring Safety Committee (DMC/SMC). In the 40 mg cohort, 2 pts were considered as DLTs by definition in the protocol: grade 4 neutropenia and grade 3 alanine transaminase (ALT) increase. Both pts were asymptomatic. The grade 4 neutropenia promptly resolved with the administration of G-CSF and the grade 3 ALT elevation resolved with dose interruption. The 30 mg dose cohort completed with no DLT after the 1st cycle in 6 pts. The following hematologic grade 3/4 toxicities were noted in the 40 mg dose cohort (N=7): leukopenia (2 pts, 29%), neutropenia (3 pts, 43%), and thrombocytopenia (3 pts, 43%). Non-hematologic ADRs included fatigue, nausea, diarrhea, decreased appetite, erythema and pyrexia. The preliminary pharmacokinetic (PK) results from the 3 patients in the 30 mg cohort, and 7 patients in the 40 mg dose cohort show inter-patient variability as expected of an oral agent. Mean half-life (t ½ ) was between16.5 and 20 hours (h) with a Tmax between 2.5 and 3.5h and consistent with previous findings. Mean Cmax and AUC increased with dose (30 mg: 210 ng/mL; 3660 h*ng/mL and 40 mg: 590 ng/mL; 7200 h*ng/mL). The patient with neutropenia as DLT presented with the highest exposure. Cardiovascular assessments including serial ECGs and troponin assessments did not reveal clinically relevant findings. Best overall response was noted in 40 mg BIW cohort (N=7): 1 CR (10%), 5 PR (30%), 1 SD (20%). Four of the partial responders were ATL patients. In the 30 mg BIW dose cohort, 4/6 patients had stable disease after the 1st cycle. Summary: In this phase l trial evaluating the safety of twice weekly 30 mg and 40 mg doses, HBI-8000 was well tolerated with expected toxicities that could be managed with dose interruptions/reductions. Tumor response results in pts who completed at least one cycle of treatment indicate some clinical benefit especially in pts who started with the 40 mg dose level. The DMC/SMC has provided an opinion that the 2 observed DLTs with HBI-8000 in the phase I trial were clinically manageable and that 40 mg BIW would be recommended as the dosage for subsequent phase II studies. Registration enabling phase II trials to evaluate efficacy and safety in R/R ATL pts (Japan) and R/R PTCL pts (Japan and Korea) are being initiated. Disclosures Ando: SymBio Pharmaceuticals: Research Funding. Yoshimitsu:HUYA Bioscience International: Research Funding. Ishida:Kyowa Hakko Kirin, Co., Ltd.: Honoraria, Research Funding; Celgene KK: Research Funding; Bayer Pharma AG: Research Funding. Hidaka:Chugai-pharm: Research Funding. Nagashima:HUYA Bioscience International: Employment. Miyazato:HUYA Bioscience International: Employment. Schupp:HUYA Bioscience International: Employment. Rolland:HUYA Bioscience International: Employment. Gillings:HUYA Bioscience International: Employment. Lee:HUYA Bioscience International: Employment. Tobinai:Eisai: Honoraria, Research Funding; GlaxoSmithKline: Research Funding; HUYA Bioscience: Honoraria; Janssen Pharmaceuticals: Honoraria, Research Funding; Kyowa Hakko Kirin: Research Funding; Mundipharma: Honoraria, Research Funding; Ono Pharmaceuticals: Research Funding; Servier: Research Funding; Takeda: Honoraria, Research Funding; Zenyaku Kogyo: Honoraria; Chugai Pharma: Research Funding; Celgene: Research Funding; Abbvie: Research Funding.

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Phase I/II Multicenter Study of Romidepsin in Japanese Patients with Relapsed or Refractory Peripheral T-Cell Lymphoma

Blood ◽

10.1182/blood.v128.22.3012.3012 ◽

2016 ◽

Vol 128 (22) ◽

pp. 3012-3012

Author(s):

Michinori Ogura ◽

Dai Maruyama ◽

Kensei Tobinai ◽

Toshiki Uchida ◽

Kiyohiko Hatake ◽

...

Keyword(s):

T Cell ◽

Phase I ◽

Phase Ii ◽

Research Funding ◽

Cell Lymphoma ◽

Japanese Patients ◽

T Cell Lymphoma ◽

Employment Equity ◽

Equity Ownership ◽

The Common

Abstract Introduction: Peripheral T-cell lymphoma (PTCL) is an aggressive lymphoma associated with poor prognosis. There is no consensus on standard therapy, and options are limited for patients with relapsed/refractory (R/R) disease. Romidepsin, a potent histone deacetylase inhibitor, has US FDA approval for patients with >=1 prior treatment for PTCL based on 25%-38% overall response rates (ORR) and durable responses (Piekarz et al, Blood. 2011;117:5827; Coiffier et al, J Clin Oncol. 2012;30:631). Here we report results from the phase I/II, multicenter, open-label study of romidepsin in Japanese patients with R/R PTCL or cutaneous T-cell lymphoma (CTCL) (TCL-001; NCT01456039). Methods: Patients aged >=20 years with R/R PTCL or CTCL received romidepsin via a 4-hour IV infusion on days 1, 8, and 15 of each 28-day cycle until progressive disease or unacceptable toxicity. The phase I portion of the study used a 3+3 design to identify any dose-limiting toxicity (DLT; phase I primary endpoint) with romidepsin 9 mg/m2 (cohort 1) and 14 mg/m2 (cohort 2). The phase II dose was based on the highest dose where <=2 of 6 patients experienced a DLT in phase I. The primary endpoint for phase II was ORR; secondary endpoints included time to response (TTR), duration of response (DOR), time to progression (TTP), and toxicity. Toxicity was assessed per NCI CTCAE version 3.0. Efficacy was assessed per modified 1999 IWG response criteria for non-Hodgkin lymphoma, descriptive statistics, and Kaplan-Meier method. Pharmacokinetic (PK) assessments included all patients in phase I with concentration-time data to enable PK parameter calculations for >=1 day. Assessments of the intent-to-treat (ITT) population included all patients receiving at least 1 dose of romidepsin. Results: The ITT population comprised 48 patients with PTCL and 2 with CTCL (1 each in the 9 and 14 mg/m2 cohorts). The common PTCL subtypes were angioimmunoblastic T-cell lymphoma (AITL, n=21, 44%), PTCL not otherwise specified (PTCL-NOS, n=20, 42%), and anaplastic large-cell lymphoma (ALCL ALK-1 negative, n=3, 6%). Most patients had a favorable ECOG performance status (86% 0-1) and 72% were >=65 years of age. Patients had received a median of 2 prior therapies (range, 1-9). Of 9 patients assessable in phase I (n=3 at 9 mg/m2 and n=6 at 14 mg/m2), none experienced a DLT. The recommended phase II dose was 14 mg/m2 in 40 subsequently treated patients. The overall population received a median of 10 doses (range, 1-135) for a median treatment duration of 12.9 weeks (range, 0.1-184.3; 8 patients were treated for >=36 weeks). The common all-grade adverse events (AEs) were thrombocytopenia (n=49, 98%), lymphopenia (n=44, 88%), leukopenia (n=42, 84%), neutropenia (n=40, 80%), pyrexia (n=33, 66%), dysgeusia (n=31, 62%), decreased appetite (n=28, 56%), and nausea (n=27, 54%). The common grade >=3 AEs were lymphopenia (n=37, 74%), neutropenia (n=27, 54%), leukopenia (n=23, 46%), and thrombocytopenia (n=19, 38%). Of the 39 patients whose CD4+ T-cell counts were monitored, while decreased CD4+ T-cell counts (<200 uL) were observed in 82% of patients, opportunistic infection occurred only in 1 patient (3%). Among the 40 patients with PTCL (phase II), the ORR was 43% (95% CI, 27%-58%), including 10 patients (25%) with complete response (CR) or CR unconfirmed (CRu) and 7 (17%) with partial responses (PR) (Table 1). The obtained ORR was significantly higher compared with the threshold ORR of 10% (P<0.0001, one sample binomial test, H0: P<=0.1). The ORR was not different across PTCL subtypes: 44% (8/18) AITL, 41% (7/17) PTCL-NOS, and 100% (2/2) ALCL. In 17 responding patients, the median TTR was 1.8 months (range, 1.6-2.3) and median DOR was 11.1 months (95% CI, 1.6 to not reached). Median TTP was 5.6 months (95% CI, 3.3-12.9; n=40). For 2 patients with CTCL in phase I, best responses (investigator assessment) were 1 PR (9 mg/m2 cohort) and 1 stable disease (14 mg/m2 cohort). Pharmacokinetic analysis indicated a dose-proportional relationship, with no accumulation following multiple doses; results were similar to data reported for non-Japanese patients. Conclusions: Results from this phase I/II study identified a tolerable dose of romidepsin and indicated that romidepsin has an acceptable toxicity profile with clinically meaningful, efficacy in Japanese patients with R/R PTCL. The efficacy and safety data were comparable with results from other romidepsin phase II studies. Disclosures Ogura: Celltrion, Inc.: Consultancy, Honoraria; SymBio Pharmaceuticals: Consultancy, Honoraria. Maruyama:Janssen: Honoraria; Takeda: Honoraria. Tobinai:Chugai Pharma: Research Funding; Daiichi Sankyo Co., Ltd.: Consultancy; Mundipharma KK: Honoraria, Research Funding; SERVIER: Research Funding; HUYA Bioscience: Honoraria; Celgene: Research Funding; Kyowa Hakko Kirin: Research Funding; GlaxoSmithKline: Research Funding; Janssen Pharmaceuticals: Honoraria, Research Funding; Abbvie: Research Funding; Takeda: Honoraria, Research Funding; Zenyaku Kogyo: Honoraria; Eisai: Honoraria, Research Funding; Ono Pharmaceutical: Research Funding. Uchida:SymBio Pharmaceuticals: Research Funding. Hatake:Chugai: Research Funding; Meiji-Seika: Consultancy; Otsuka: Consultancy; Kyowa Kirin: Honoraria, Research Funding. Tsukasaki:Daiichi Sankyo Co., Ltd.: Consultancy; Takeda: Research Funding. Ishida:Celgene KK: Research Funding; Kyowa Hakko Kirin, Co., Ltd.: Honoraria, Research Funding; Bayer Pharma AG: Research Funding. Ishizawa:SymBio Pharmaceuticals: Research Funding. Laille:Celgene: Employment, Equity Ownership. Ro:Celgene: Employment, Equity Ownership. Tamakoshi:Celgene: Employment, Equity Ownership. Sakurai:Celgene: Employment. Ohtsu:Celgene: Employment, Equity Ownership.

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