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2742 Phase 1b/2 Study of the First-in-Class SUMO-Activating Enzyme Inhibitor TAK-981 in Combination with Monoclonal Antibodies in Patients with Triple-Class Refractory Multiple Myeloma

Program: Oral and Poster Abstracts
Session: 653. Myeloma and Plasma Cell Dyscrasias: Clinical-Prospective Therapeutic Trials: Poster II
Hematology Disease Topics & Pathways:
Clinical Trials, Biological, Clinical Research, Plasma Cell Disorders, Immune Mechanism, Diseases, Therapies, Lymphoid Malignancies, Monoclonal Antibody Therapy, Biological Processes
Sunday, December 12, 2021, 6:00 PM-8:00 PM

Sagar Lonial, MD, FACP1, Stefano R. Tarantolo, MD2, Ralph V. Boccia, MD3, Habte Yimer, MD4, Moshe Y. Levy, MD5, Rafat Abonour, MD6, Meera Mohan, MD7, Vivek Roy, MD8, Jeremy T. Larsen9, Saulius K. Girnius, MD10, Cara A. Rosenbaum, MD11*, Omar Nadeem, MD12, Deborah Berg, RN, MSN13, Bo Chao13*, Allison J Berger, PhD13*, Akito Nakamura13*, Yuhong Zhang13*, Keli Song13*, Christine K. Ward13*, Igor Proscurshim, MD13* and Shaji K Kumar, MD14

1Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA
2Nebraska Cancer Specialists, Omaha, NE
3The Center for Cancer and Blood Disorders, Bethesda, MD
4Texas Oncology-Tyler/US Oncology Research, Tyler, TX
5Baylor University Medical Center, Dallas, TX
6Indiana University School of Medicine, Indianapolis, IN
7Division of Hematology-Oncology, Medical College of Wisconsin, Milwaukee, WI
8Department of Hematology- and Oncology, Mayo Clinic, Jacksonville, FL
9Division of Hematology, Mayo Clinic, Phoenix, AZ
10TriHealth Cancer Institute, Cincinnati, OH
11Center for Myeloma, New York Presbyterian Hospital–Weill Cornell Medical Center, New York, NY
12Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
13Takeda Development Center Americas, Inc. (TDCA), Lexington, MA
14Division of Hematology, Mayo Clinic, Rochester, MN

Background: SUMOylation, a post-translational modification analogous to ubiquitination, attaches a small, ubiquitin-like modifier (SUMO) to target proteins. SUMOylation plays a central role in the immune system by regulating type I interferon (IFN-I) expression, thereby functioning to constrain the innate immune response (Decque Nat Immunol 2016), and limit tumor immune surveillance. The SUMOylation pathway is often overexpressed in multiple myeloma (MM) and is associated with poor outcomes (Driscoll Blood 2010).

TAK-981 is a first-in-class, small-molecule inhibitor of SUMO-activating enzyme, which blocks the SUMOylation cascade (Langston J Med Chem 2021) and increases IFN-I production and signaling in innate immune cells (Nakamura AACR 2019). In ex vivo assays, TAK-981 activated the IFN-I pathway, increased phagocytic activity of monocyte-derived macrophages, and increased natural killer (NK) cell cytotoxicity via IFN-I signaling (Nakamura AACR 2019). The ability of TAK-981 to promote activation of macrophages and NK cells provides a mechanistic rationale for its use in combination with monoclonal antibodies (mAbs) reliant on antibody-dependent cellular cytotoxicity and phagocytosis; in vivo experiments have demonstrated synergistic activity between TAK-981 and rituximab, and between TAK-981 and the anti-CD38 mAbs daratumumab (dara) (Nakamura SITC 2020) or mezagitamab (meza; TAK-079; Figure 1).

Patients with MM who have disease refractory to the three most effective classes of anti-myeloma therapies (proteasome inhibitors [PIs], immunomodulatory drugs [IMiDs], and anti-CD38 mAbs) have a poor prognosis, with median survival 9.2 months (Gandhi Leukemia 2019). Given the incurable nature of advanced MM and the highly complex mechanisms of resistance, continued efforts to better understand MM biology at the time of relapse and to translate this into effective treatment combinations are needed. Combination therapies that engage the immune system to treat MM may offer substantial clinical benefit.

Methods: To be eligible for this multicenter, open-label, Phase 1b/2 trial (NCT04776018), patients must have failed at least 3 prior lines of anti-myeloma therapy, have MM disease that is triple-class refractory (defined as refractory/intolerant to ≥1 PI and ≥1 IMiD, and refractory to ≥1 anti-CD38 mAb), and have demonstrated disease progression on their last therapy. Prior CAR-T therapy is allowed. Patients will be assigned to TAK-981 plus subcutaneous (SC) meza (Phase 1 Part 1) or SC dara (dara and hyaluronidase-fihj; Phase 1 Part 2). The primary objectives of Phase 1b are to determine safety and tolerability, and to select the recommended Phase 2 dose (RP2D) and schedule for TAK-981 with each mAb; secondary objectives are to evaluate preliminary antitumor activity, to characterize TAK-981 pharmacokinetics (PK), and to explore pharmacodynamic (PD) markers of TAK-981 target engagement and SUMOylation pathway inhibition. Approximately 30 patients will participate in the Phase 1b Part 1 dose escalation of TAK-981 plus meza (~15 patients per dosing schedule), and ~15 patients will participate in the Phase 1b Part 2 dose escalation of TAK-981 plus SC dara. The primary objective of Phase 2 is to evaluate the efficacy of TAK-981 at the RP2D in combination with an anti-CD38 mAb; ~36 patients will be enrolled.

In Phase 1b, patients will receive TAK-981 via a 1-hour intravenous infusion either on days 1, 4, 8, 11, and 15 (twice weekly; BIW) or on days, 1, 8, 15, and 22 (weekly; QW) for 2x 28-day cycles, then 8x every other week, then monthly. Meza 600 mg SC or dara 1800 mg SC will be given 8x weekly, 8x every other week, then monthly, in a 28-day cycle (Figure 2). Treatment will continue until disease progression or unacceptable toxicity (max. 24 cycles). TAK-981 dose escalation will proceed from 60 mg BIW, a dose shown to be pharmacologically active in a first-in-human, single-agent TAK-981 study (TAK-981-1002; data on file). Dose escalation will be guided by Bayesian Optimal Internal Design with Informative Prior (iBOIN) plus consideration of other safety, clinical, PK, and PD data. The iBOIN design selects the true maximum tolerated dose (if any) with high accuracy by allocating more patients to dose levels with a prior dose-limiting toxicity probability closest to the target of 0.3. This study is currently enrolling patients, with the first patient dosed in May 2021.

Disclosures: Lonial: AMGEN: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Consultancy, Honoraria, Research Funding; Merck: Honoraria; Abbvie: Consultancy, Honoraria. Boccia: BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Abbvie: Consultancy, Honoraria, Speakers Bureau; Takeda: Honoraria, Research Funding, Speakers Bureau; Amgen: Research Funding, Speakers Bureau; Epizyme: Honoraria, Speakers Bureau; Morphosis: Honoraria, Speakers Bureau. Yimer: Beigene: Speakers Bureau; Astrazeneca: Speakers Bureau; Karyopharm: Current equity holder in publicly-traded company, Speakers Bureau; Janssen: Speakers Bureau; GSK: Speakers Bureau; Sanofi: Speakers Bureau; Amgen: Speakers Bureau; Pharmacyclics: Speakers Bureau; Texas Oncology: Current Employment. Levy: Jazz Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau; Morphosys: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Karyopharm: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Dova: Consultancy, Other: Promotional speaker; Janssen Pharmaceuticals: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Amgen Inc.: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; GSK: Consultancy, Other: Promotional speaker; Epizyme: Consultancy, Other: Promotional speaker; Novartis: Consultancy, Other: Promotional speaker; AbbVie: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Beigene: Consultancy, Honoraria, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Speakers Bureau; Gilead Sciences, Inc.: Consultancy, Honoraria, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Takeda: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; TG Therapeutics: Consultancy, Honoraria, Speakers Bureau. Abonour: Takeda: Research Funding; GSK: Consultancy, Honoraria, Research Funding; Celgene-BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jensen: Honoraria, Research Funding. Mohan: Medical College of Wisconsin: Current Employment. Girnius: BMS: Honoraria, Speakers Bureau; Celgene: Speakers Bureau; Genentech: Honoraria; GSK: Honoraria, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Beigene: Speakers Bureau. Rosenbaum: Takeda: Honoraria; Akcea: Honoraria; Janssen: Honoraria. Nadeem: Karyopharm: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; GSK: 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. Chao: Takeda: Current Employment. Berger: Takeda Development Center Americas, Inc.: Current Employment. Nakamura: Takeda Development Center Americas, Inc.: Current Employment. Zhang: Takeda: Current Employment. Song: Takeda Pharmaceuticals International Co.: Current Employment. Ward: Takeda: Current Employment. Proscurshim: Takeda Pharmaceuticals: Current Employment, Current holder of individual stocks in a privately-held company. Kumar: Antengene: Consultancy, Honoraria; Amgen: Consultancy, Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Carsgen: Research Funding; BMS: Consultancy, Research Funding; Beigene: Consultancy; Tenebio: Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Consultancy; Merck: Research Funding; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Roche-Genentech: Consultancy, Research Funding; Bluebird Bio: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding.

OffLabel Disclosure: Study of the investigational agent TAK-981 in combination with daratumumab and hyaluronidase-fihj or the investigational agent mezagitamab (TAK-079).

*signifies non-member of ASH