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2488 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

Program: Oral and Poster Abstracts
Session: 626. Aggressive Lymphomas: Prospective Therapeutic Trials: Poster II
Hematology Disease Topics & Pathways:
Clinical Trials, Biological therapies, Adults, Lymphomas, non-Hodgkin lymphoma, Workforce, Diseases, Therapies, Immunotherapy, Lymphoid Malignancies, Monoclonal Antibody Therapy, Study Population
Sunday, December 12, 2021, 6:00 PM-8:00 PM

Sarit Assouline, MD, MSc1, Amitkumar Mehta, MD2, Tycel Phillips, MD3*, Lapo Alinari, MD, PhD4, Alexey V. Danilov, MD, PhD5, Stéphane Doucet6*, Steven I. Park, MD7, Deborah Berg, RN, MSN8, Alejandro Gomez-Pinillos8*, Alonzo Martinez8*, Bo Chao8*, Allison J Berger, PhD8*, John Gibbs8*, Sharon Friedlander8*, Christine K. Ward8*, Igor Proscurshim, MD8*, Brenda W. Cooper, MD9 and Paolo F Caimi, MD10*

1Division of Hematology, Jewish General Hospital, Montreal, QC, Canada
2Department of Hematology/Oncology Medicine, The University of Alabama,, Birmingham, AL
3Division of Hematology and Oncology, University of Michigan, Ann Arbor, MI
4Department of Internal Medicine, The Ohio State University, Columbus, OH
5Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, CA
6Department of Hematology, Centre Hospitalier de l'Université de Montreal, Montreal, QC, Canada
7Hematology Oncology Translational Research Laboratory, Levine Cancer Institute/Atrium Health, Charlotte, NC
8Takeda Development Center Americas, Inc. (TDCA), Lexington, MA
9Department of Medicine, Division of Hematology/Oncology, University Hospitals of Cleveland, Cleveland, OH
10University Hospitals Cleveland Medical Center, Case Western Reserve University, Cleveland, OH

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.

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/m2 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.

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).

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.

Disclosures: 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: Consultancy, Honoraria, Research Funding, Speakers Bureau; AstraZeneca: Consultancy, Honoraria; BeiGene: Consultancy, Honoraria, Research Funding; Takeda: Research Funding; Roche/Genentech: Research Funding; Eli Lilly: Research Funding; Novartis: Honoraria, Research Funding; Amgen: Current equity holder in publicly-traded company, Research Funding; Gilead: Speakers Bureau; Jewish General Hospital, Montreal, Quebec: Current Employment. Mehta: Affirmed; Kite/Gilead; Roche-Genetech; Celgene/BMS; Oncotartis; Innate Pharmaceuticals; Seattle Genetics; Incyte; Takeda; Fortyseven Inc/Gilead; TG Therapeutics; Merck; Juno Pharmaceuticals/Bristol Myers Squibb: Research Funding; Seattle Genetics; Incyte; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Seattle Genetics; Incyte; TG Therapeutics: Consultancy. Phillips: Bayer: Consultancy, Research Funding; ADCT, BeiGene, Bristol Myers Squibb, Cardinal Health, Incyte, Karyopharm, Morphosys, Pharmacyclics, Seattle Genetics: Consultancy; AstraZeneca: Consultancy; AbbVie: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Consultancy, Other: received travel expenses from Incyte, Research Funding. Danilov: Rigel Pharm: Honoraria; Bristol-Meyers-Squibb: Honoraria, Research Funding; Gilead Sciences: Research Funding; Pharmacyclics: Consultancy, Honoraria; Beigene: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; TG Therapeutics: Consultancy, Research Funding; Takeda Oncology: Research Funding; Genentech: Consultancy, Honoraria, Research Funding; Astra Zeneca: Consultancy, Honoraria, Research Funding; SecuraBio: Research Funding; Bayer Oncology: Consultancy, Honoraria, Research Funding. Doucet: Amgen: Consultancy; Novartis: Consultancy; Astra-Zeneca: Consultancy; BMS: Consultancy; Jannsen: Consultancy; Servier: Consultancy; Abbvie: Consultancy; Seattle Genetics: Consultancy; Roche: Consultancy; Gilead: Consultancy. Park: Morphosys: Membership on an entity's Board of Directors or advisory committees; G1 Therapeutics: Consultancy; Gilead: Speakers Bureau; Takeda: Research Funding; Rafael Pharma: Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; Seattle Genetics: Research Funding, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Teva: Consultancy, Membership on an entity's Board of Directors or advisory committees. Berg: Takeda: Current Employment, Current equity holder in publicly-traded company, Current holder of stock options in a privately-held company. Gomez-Pinillos: Takeda: Current Employment. Martinez: Takeda: Current Employment. Chao: Takeda: Current Employment. Berger: Takeda Development Center Americas, Inc.: Current Employment. Gibbs: Takeda: Current Employment. Friedlander: Takeda: Current Employment. Ward: Takeda: Current Employment. Proscurshim: Takeda Pharmaceuticals: Current Employment, Current holder of individual stocks in a privately-held company. Caimi: TG Therapeutics: Consultancy; Kite: Consultancy; ADC Therapeutics: Consultancy; Verastem: Consultancy; Amgen: Consultancy; XaTek Inc.: Patents & Royalties; Celgene: Speakers Bureau.

*signifies non-member of ASH