{"@context":{"@vocab":"https://cir.nii.ac.jp/schema/1.0/","rdfs":"http://www.w3.org/2000/01/rdf-schema#","dc":"http://purl.org/dc/elements/1.1/","dcterms":"http://purl.org/dc/terms/","foaf":"http://xmlns.com/foaf/0.1/","prism":"http://prismstandard.org/namespaces/basic/2.0/","cinii":"http://ci.nii.ac.jp/ns/1.0/","datacite":"https://schema.datacite.org/meta/kernel-4/","ndl":"http://ndl.go.jp/dcndl/terms/","jpcoar":"https://github.com/JPCOAR/schema/blob/master/2.0/"},"@id":"https://cir.nii.ac.jp/crid/1360588388340103424.json","@type":"Article","productIdentifier":[{"identifier":{"@type":"DOI","@value":"10.1182/blood-2021-152225"}},{"identifier":{"@type":"URI","@value":"https://ashpublications.org/blood/article/138/Supplement%201/2488/478839/TAK-981-a-First-in-Class-SUMO-Activating-Enzyme"}}],"dc:title":[{"@value":"TAK-981, a First-in-Class SUMO-Activating Enzyme Inhibitor, Combined with Rituximab in Adult Patients (Pts) with CD20-Positive Relapsed/Refractory (R/R) Non-Hodgkin Lymphoma (NHL): Phase 1 Data"}],"description":[{"type":"abstract","notation":[{"@value":"<jats:title>Abstract</jats:title>\n               <jats:p>Background: TAK-981 is the first small-molecule inhibitor of SUMOylation to enter clinical trials. SUMOylation is a post-translational modification in which small ubiquitin-like modifier (SUMO) proteins are activated and covalently attached to substrate proteins. SUMOylation has a central role in constraining type I interferon (IFN-I)-dependent responses (Decque Nat Immunol 2016). By blocking SUMOylation, TAK-981 promotes IFN-I production and increases innate immunity. The ability of TAK-981 to promote activation of macrophages and NK cells and increase their cytotoxic/phagocytic activity provides a mechanistic rationale for its use in combination with monoclonal antibodies (mAbs) reliant on antibody-dependent cellular cytotoxicity and phagocytosis. Preclinical studies have demonstrated synergistic antitumor activity between TAK-981 and the anti-CD20 monoclonal antibody rituximab in xenograft models of human B cell lymphoma (Nakamura AACR 2019). Based on these data, and a single-agent TAK-981 study (TAK-981-1002), this phase 1b/2, open-label, dose-escalation and expansion study is investigating the safety and efficacy of TAK-981 plus rituximab in adults with CD20-positive R/R NHL (NCT04074330); here, we report data from the phase 1b dose-escalation part of the study.</jats:p>\n               <jats:p>Methods: Eligible pts were aged ≥18 years with CD20-positive, R/R aggressive B-cell NHL (aNHL) or indolent NHL (iNHL). aNHL included diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), and grade 3b follicular lymphoma (FL); iNHL included grade 1-3a FL and marginal zone lymphoma. aNHL pts had to have received prior R-CHOP or equivalent plus 1 additional line of therapy in the R/R setting; iNHL pts had to be refractory to rituximab or another anti-CD20 mAb, and to have received at least 1 prior therapy for R/R disease. TAK-981 IV was given at increasing doses (starting: 10 mg) on days 1 and 8 (QW) or days 1, 4, 8, and 11 (BIW) of 21-day cycles. Rituximab 375 mg/m 2 IV was given on days 1, 8, and 15 of cycle 1 and on day 1 thereafter. Dose escalation was based on adaptive Bayesian logistic regression modelling with overdose control based on the posterior probability of having a dose-limiting toxicity (DLT). Primary phase 1b objectives were safety, tolerability, and recommended phase 2 dose (RP2D) of TAK-981 in combination with rituximab; data cutoff was 28 June 2021.</jats:p>\n               <jats:p>Results: 24 pts have been enrolled and treated: 19 QW (10-120 mg) and 5 BIW (90 mg); 4 are currently on treatment. Enrollment continues in the 90 mg BIW and 120 mg QW cohorts. Median age was 65 years (range 29-80); 67% were male. No DLTs have been reported to date. RP2D and schedule will be determined based on safety, pharmacokinetic (PK), and pharmacodynamic (PD) data. Treatment-emergent adverse events (TEAEs) are shown in the Table. Most common TEAEs (≥15%) were similar between the QW/BIW schedules with the exception of dizziness (2 pts at 10 mg, 2 at 40 mg, and 1 at 90 mg) and hypokalemia (1 pt at 40 mg, 2 at 90 mg, and 1 at 120 mg); all QW. TEAEs were consistent with induction of IFN signalling (transient flu-like symptoms: fever, chills, fatigue) and with those observed in the single-agent study (data on file); no further TAK-981- or immune-related TEAEs were observed. Grade ≥3 TEAEs related to TAK-981 were reported in 2 pts: grade 3 atrial fibrillation (ongoing cardiac history) and grade 4 neutropenia; both in the 40 mg QW cohort and transient. In this population of rituximab-refractory pts, there were 5 objective responses in 17 response-evaluable pts: 4 partial responses (2 at 10 mg, FL and DLBCL; 1 at 60 mg, DLBCL; 1 at 90 mg, primary mediastinal thymic large B-cell lymphoma) and 1 complete response (40 mg, MCL), all in the QW cohort. TAK-981 PK was linear and declined in a tri-phasic manner. TAK-981 exhibited PD activity in peripheral blood including target engagement, decreased SUMOylation, and increased IFN-regulated gene expression (Figure).</jats:p>\n               <jats:p>Conclusion: The combination of TAK-981 and rituximab was well tolerated in pts across each dose level and schedule. TAK-981 PK showed minimal accumulation after repeat dosing and PD assays confirmed inhibition of SUMOylation and activation of IFN-I signalling. More importantly, the combination of TAK-981 and rituximab resulted in promising clinical activity (ORR 29%) in the R/R setting, supporting the continued development of this combination in pts with NHL.</jats:p>\n               <jats:p>Figure 1 Figure 1.</jats:p>\n               <jats:p/>\n               <jats:sec>\n                  <jats:title>Disclosures</jats:title>\n                  <jats:p>Assouline: Johnson&Johnson: Current equity holder in publicly-traded company; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; AbbVie: Consult ..."}]}],"creator":[{"@id":"https://cir.nii.ac.jp/crid/1380588388340103426","@type":"Researcher","foaf:name":[{"@value":"Sarit Assouline"}],"jpcoar:affiliationName":[{"@value":"Division of Hematology, Jewish General Hospital, Montreal, Canada"}]},{"@id":"https://cir.nii.ac.jp/crid/1380588388340103436","@type":"Researcher","foaf:name":[{"@value":"Amitkumar Mehta"}],"jpcoar:affiliationName":[{"@value":"Department of Hematology/Oncology Medicine, The University of Alabama,, Birmingham, AL"}]},{"@id":"https://cir.nii.ac.jp/crid/1380588388340103432","@type":"Researcher","foaf:name":[{"@value":"Tycel Phillips"}],"jpcoar:affiliationName":[{"@value":"Division of Hematology and Oncology, University of Michigan, Ann Arbor, MI"}]},{"@id":"https://cir.nii.ac.jp/crid/1380588388340103433","@type":"Researcher","foaf:name":[{"@value":"Lapo Alinari"}],"jpcoar:affiliationName":[{"@value":"Department of Internal Medicine, The Ohio State University, Columbus, OH"}]},{"@id":"https://cir.nii.ac.jp/crid/1380588388340103438","@type":"Researcher","foaf:name":[{"@value":"Alexey V. Danilov"}],"jpcoar:affiliationName":[{"@value":"Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, CA"}]},{"@id":"https://cir.nii.ac.jp/crid/1380588388340103437","@type":"Researcher","foaf:name":[{"@value":"Stéphane Doucet"}],"jpcoar:affiliationName":[{"@value":"Department of Hematology, Centre Hospitalier de l'Université de Montreal, Montreal, Canada"}]},{"@id":"https://cir.nii.ac.jp/crid/1380588388340103435","@type":"Researcher","foaf:name":[{"@value":"Steven I. Park"}],"jpcoar:affiliationName":[{"@value":"Hematology Oncology Translational Research Laboratory, Levine Cancer Institute/Atrium Health, Charlotte, NC"}]},{"@id":"https://cir.nii.ac.jp/crid/1380588388340103424","@type":"Researcher","foaf:name":[{"@value":"Deborah Berg"}],"jpcoar:affiliationName":[{"@value":"Takeda Development Center Americas, Inc. (TDCA), Lexington, MA"}]},{"@id":"https://cir.nii.ac.jp/crid/1380588388340103429","@type":"Researcher","foaf:name":[{"@value":"Alejandro Gomez-Pinillos"}],"jpcoar:affiliationName":[{"@value":"Takeda Development Center Americas, Inc. (TDCA), Lexington, MA"}]},{"@id":"https://cir.nii.ac.jp/crid/1380588388340103430","@type":"Researcher","foaf:name":[{"@value":"Alonzo Martinez"}],"jpcoar:affiliationName":[{"@value":"Takeda Development Center Americas, Inc. (TDCA), Lexington, MA"}]},{"@id":"https://cir.nii.ac.jp/crid/1380588388340103434","@type":"Researcher","foaf:name":[{"@value":"Bo Chao"}],"jpcoar:affiliationName":[{"@value":"Takeda Development Center Americas, Inc. (TDCA), Lexington, MA"}]},{"@id":"https://cir.nii.ac.jp/crid/1380588388340103425","@type":"Researcher","foaf:name":[{"@value":"Allison J Berger"}],"jpcoar:affiliationName":[{"@value":"Takeda Development Center Americas, Inc. (TDCA), Lexington, MA"}]},{"@id":"https://cir.nii.ac.jp/crid/1380588388340103440","@type":"Researcher","foaf:name":[{"@value":"John Gibbs"}],"jpcoar:affiliationName":[{"@value":"Takeda Development Center Americas, Inc. (TDCA), Lexington, MA"}]},{"@id":"https://cir.nii.ac.jp/crid/1380588388340103439","@type":"Researcher","foaf:name":[{"@value":"Sharon Friedlander"}],"jpcoar:affiliationName":[{"@value":"Takeda Development Center Americas, Inc. (TDCA), Lexington, MA"}]},{"@id":"https://cir.nii.ac.jp/crid/1380588388340103427","@type":"Researcher","foaf:name":[{"@value":"Christine K. Ward"}],"jpcoar:affiliationName":[{"@value":"Takeda Development Center Americas, Inc. (TDCA), Lexington, MA"}]},{"@id":"https://cir.nii.ac.jp/crid/1380588388340103428","@type":"Researcher","foaf:name":[{"@value":"Igor Proscurshim"}],"jpcoar:affiliationName":[{"@value":"Takeda Development Center Americas, Inc. (TDCA), Lexington, MA"}]},{"@id":"https://cir.nii.ac.jp/crid/1380588388340103441","@type":"Researcher","foaf:name":[{"@value":"Brenda W. Cooper"}],"jpcoar:affiliationName":[{"@value":"Department of Medicine, Division of Hematology/Oncology, University Hospitals of Cleveland, Cleveland, OH"}]},{"@id":"https://cir.nii.ac.jp/crid/1380588388340103431","@type":"Researcher","foaf:name":[{"@value":"Paolo F Caimi"}],"jpcoar:affiliationName":[{"@value":"University Hospitals Cleveland Medical Center, Case Western Reserve University, Cleveland, OH"}]}],"publication":{"publicationIdentifier":[{"@type":"PISSN","@value":"00064971"},{"@type":"EISSN","@value":"15280020"}],"prism:publicationName":[{"@value":"Blood"}],"dc:publisher":[{"@value":"American Society of Hematology"}],"prism:publicationDate":"2021-11-05","prism:volume":"138","prism:number":"Supplement 1","prism:startingPage":"2488","prism:endingPage":"2488"},"reviewed":"false","url":[{"@id":"https://ashpublications.org/blood/article/138/Supplement%201/2488/478839/TAK-981-a-First-in-Class-SUMO-Activating-Enzyme"}],"createdAt":"2021-11-24","modifiedAt":"2021-11-24","relatedProduct":[{"@id":"https://cir.nii.ac.jp/crid/1360306906091006592","@type":"Article","resourceType":"学術雑誌論文(journal article)","relationType":["isReferencedBy"],"jpcoar:relatedTitle":[{"@value":"Dual inhibition of SUMOylation and MEK conquers MYC-expressing KRAS-mutant cancers by accumulating DNA damage"}]}],"dataSourceIdentifier":[{"@type":"CROSSREF","@value":"10.1182/blood-2021-152225"},{"@type":"CROSSREF","@value":"10.1186/s12929-024-01060-3_references_DOI_Jy4DKxmDPEpWNfhgsa7zoFfGGzc"}]}