A Phase 1b/2 Study of TAK-981, a First-in-Class Sumoylation Inhibitor, in Combination with Rituximab in Patients with Relapsed/Refractory (r/r) CD20-Positive Non-Hodgkin Lymphoma (NHL)
Authors: Assouline Sarit , Mehta Amitkumar , Caimi Paolo F , Wang Bingxia , Patel Chirag , Kim Mi-Sook , Huszar Dennis , Berger Allison J , Friedlander Sharon , Gomez-Pinillos Alejandro , Proscurshim Igor 
Published: November 2019

Background
TAK-981 is a first-in-class, small molecule inhibitor of SUMOylation, a reversible post-translational modification that regulates protein function by covalent attachment of small ubiquitin-like modifier (SUMO) proteins to a protein substrate. SUMOylation has a key role in restraining Type I interferon (IFN) responses (Decque, Nature Immunology 2016; Seeler, Nat Rev Cancer 2017). In-vivo preclinical studies have demonstrated that inhibition of SUMOylation by TAK-981 promotes innate and adaptive antitumor immune responses dependent on induction of Type I IFN signaling. This includes modulating the activity of innate effector cells. In macrophages, TAK-981 induced polarization towards the M1 phenotype, upregulated Fcγ receptors, and enhanced phagocytosis and antibody-dependent cellular phagocytosis (ADCP) in an ex-vivo assay. In natural killer (NK) cells, TAK-981 promoted upregulation of the activation marker CD69 and the degranulation marker CD107, increased the number of IFNγ+ NK cells in tumors, and enhanced cytotoxicity and antibody-dependent cellular cytotoxicity (ADCC) in an ex-vivo assay. This enhancement of ADCP and ADCC supports the combination of TAK-981 with IgG1 therapeutic monoclonal antibodies.
In-vivo studies have demonstrated synergistic antitumor activity with TAK-981 combined with rituximab in severe combined immunodeficient mice (lacking lymphocytes but retaining a functional innate immune system) bearing human diffuse large B-cell lymphoma xenografts. Specifically, in OCI-Ly-10 and TMD8 tumor models, the combination reproducibly resulted in complete regression (CR) of all treated tumors at doses at which no CRs were achieved with either single agent. In the PHTX-166L patient-derived xenograft model, tumor growth delay and 1 CR were achieved at doses that showed only very modest tumor growth delay with single agents.
Methods
This is an open-label, multicenter, non-randomized, phase 1b/2 study investigating the safety and efficacy of TAK-981 in combination with rituximab in adult patients with CD20-positive r/r NHL. The study comprises Phase 1b (dose escalation) and Phase 2 (2 treatment arms: indolent [iNHL] and aggressive [aNHL] NHL).
Eligible patients must have CD20-positive r/r NHL (excluding mantle cell lymphoma in Phase 2) and have failed ≥2 prior lines of therapy; one prior line of therapy must have included a CD20-directed antibody.
TAK-981 will be administered intravenously (IV) on Days 1 and 8 in 21-day cycles. The starting dose will be informed by the ongoing first-in-human TAK-981-1002 Phase 1 trial (NCT03648372). Rituximab will be administered IV weekly at 375 mg/m2 x 3 doses followed by 375 mg/m2 on Day 1 of subsequent 21-day cycles. Treatment will continue until disease progression or unacceptable toxicity.
Phase 1b will enroll ~34 patients to identify the maximum tolerated dose and/or pharmacologically active dose of the combination. Dose escalation will be guided by an adaptive Bayesian logistic regression model that implements escalation with overdose control.
Phase 2 will enroll ~56 patients in 2 parallel arms (iNHL/aNHL). Efficacy of the combination will be assessed by the investigator per Lugano 2014 response criteria. The primary endpoint for Phase 2 is overall response rate (ORR). The design is based on Simon's 2-stage design, in which the null hypothesis for each arm (true ORR is 20%) will be tested against a one-sided alternative. In the first stage, 12 patients will be accrued in each arm. If there are ≤2 responses in the 12 patients in either arm, the arm(s) will be stopped. Otherwise, 13 additional patients will be accrued per arm. The null hypothesis will be rejected for an arm if ≥8 responses are observed in the 25 patients on that arm. This design yields a type I error rate of 0.1 and 80% power when the true ORR is 40%.
Tumor biopsies will be collected to determine SUMO pathway inhibition by immunohistochemistry and the induction of innate and/or adaptive immune response by measuring levels of IFN-regulated gene transcripts and the activation state of tumor-infiltrating lymphocytes and myeloid cells, including NK cells and macrophages. Innate and/or adaptive immune response and IFN signalling activation will also be assessed in peripheral blood by immunoprofiling, gene expression analysis, and measurement of cytokine and/or chemokine secretion.
Enrollment is planned to open in October 2019.

Disclosures
Assouline: Pfizer: Consultancy, Honoraria, Speakers Bureau; Abbvie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Speakers Bureau; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria. Mehta:Seattle Genetics: Research Funding, Speakers Bureau; Astex: Research Funding; TG Therapeutics: Research Funding; Incyte: Research Funding; Spectrum: Consultancy, Speakers Bureau; Imbrium therapeutics: Consultancy; Roche-Genentech: Research Funding; miRagen: Research Funding; Kyowa-Kirin: Consultancy, Speakers Bureau; Astra-Zeneca: Speakers Bureau; Sanofi: Consultancy; Affimed: Research Funding; Forty Seven Inc: Research Funding; Juno/Celgene: Research Funding; Kite/Gilead: Research Funding, Speakers Bureau; Takeda: Research Funding; Rhizen: Research Funding; ADC therapeutics: Research Funding; Pharmacyclics: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau. Caimi:Fate Therapeutics: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ADC Therapeutics: Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Speakers Bureau; Kite Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Wang:Millennium Pharmaceuticals, Inc., Cambridge, MA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Patel:Millennium Pharmaceuticals, Inc., Cambridge, MA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Kim:Millennium Pharmaceuticals, Inc., Cambridge, MA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Huszar:Millennium Pharmaceuticals, Inc., Cambridge, MA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment, Other: Shareholder. Berger:Millennium Pharmaceuticals, Inc., Cambridge, MA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Friedlander:Millennium Pharmaceuticals, Inc., Cambridge, MA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Gomez-Pinillos:Millennium Pharmaceuticals, Inc., Cambridge, MA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Proscurshim:Millennium Pharmaceuticals, Inc., Cambridge, MA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment.

OffLabel Disclosure:
TAK-981 is a first-in-class, small molecule inhibitor of SUMOylation, a reversible post-translational modification that regulates protein function by covalent attachment of small ubiquitin-like modifier (SUMO) proteins to a protein substrate.