Karuppiah Kannan, Ph.D. Senior Director – Global Program Leader at Takeda Oncology speaks about the ASH 2021 Abstracts – 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, and 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.
Link to Abstract 2488:
https://ash.confex.com/ash/2021/webprogram/Paper152225.html
Background:
TAK-981 is the first SUMOylation small-molecule inhibitor to reach clinical studies. Small ubiquitin-like modifier (SUMO) proteins are activated and covalently bound to substrate proteins during SUMOylation, a post-translational modification. Type I interferon (IFN-I)-dependent responses are mostly regulated by SUMOylation (Decque Nat Immunol 2016). TAK-981 enhances IFN-I production and boosts innate immunity by inhibiting SUMOylation. TAK-981’s potential to boost macrophage and NK cell activation and increase cytotoxic/phagocytic activity provides a molecular basis for its usage in combination with monoclonal antibodies (mAbs) that are dependent on antibody-dependent cellular cytotoxicity and phagocytosis. TAK-981 and the anti-CD20 monoclonal antibody rituximab have shown synergistic antitumor efficacy in xenograft models of human B cell lymphoma in preclinical trials (Nakamura AACR 2019). This phase 1b/2, open-label, dose-escalation and expansion study (NCT04074330) is investigating the safety and efficacy of TAK-981 plus rituximab in adults with CD20-positive R/R NHL based on these data and a single-agent TAK-981 study (TAK-981-1002); here, we report data from the phase 1b dose-escalation part of the study.
Methods: Patients with CD20-positive, R/R aggressive B-cell NHL (aNHL) or indolent NHL were eligible (iNHL). DLBCL, MCL, and grade 3b follicular lymphoma (FL) were included in the aNHL category, while grade 1-3a FL and marginal zone lymphoma were included in the iNHL category. iNHL pts required to be refractory to rituximab or another anti-CD20 mAb, and had to have undergone at least one prior therapy for R/R illness. On days 1 and 8 (QW) or days 1, 4, 8, and 11 (BIW) of 21-day cycles, TAK-981 IV was given at escalating doses (beginning at 10 mg). Rituximab 375 mg/m2 was given intravenously on days 1, 8, and 15 of cycle 1 and every day after that. Overdose control was based on the posterior chance of having a dose-limiting toxicity, and dose escalation was based on adaptive Bayesian logistic regression modeling (DLT). The primary phase 1b objectives of TAK-981 in conjunction with rituximab were safety, tolerability, and the recommended phase 2 dose (RP2D); the data cutoff date was June 28, 2021.
Results:
A total of 24 patients have been enrolled and treated, with 19 receiving QW (10–120 mg) and 5 receiving BIW (90 mg); four are currently receiving treatment. Enrollment in the 90 mg BIW and 120 mg QW cohorts is still open. The median age was 65 (range 29–80), and 67 percent of the participants were men. To date, no DLTs have been reported. Safety, pharmacokinetic (PK), and pharmacodynamic (PD) data will be used to define the RP2D and schedule. The Table lists treatment-emergent adverse events (TEAEs). 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), the most prevalent TEAEs (15%) were comparable between the QW/BIW schedules; all QW. TAK-981- or immune-related TEAEs were consistent with IFN signaling induction (transient flu-like symptoms: fever, chills, exhaustion) and those found in the single-agent research (data on file); no further TAK-981- or immune-related TEAEs were identified. Both in the 40 mg QW cohort and transiently, grade 3 TEAEs attributable to TAK-981 were reported in two patients: grade 3 atrial fibrillation (ongoing cardiac history) and grade 4 neutropenia. There were five objective responses in 17 rituximab-refractory patients: four partial responses (2 at 10 mg, FL and DLBCL; one at 60 mg, DLBCL; one at 90 mg, primary mediastinal thymic large B-cell lymphoma) and one complete response (40 mg, MCL) in the QW cohort. TAK-981 PK was tri-phasic in nature and linear in nature. In peripheral blood, TAK-981 showed PD action, including target engagement, decreased SUMOylation, and enhanced IFN-regulated gene expression (Figure).
Conclusion:
Pts tolerated the combination of TAK-981 and rituximab well at all dose levels and schedules. After repeated dosage, TAK-981 PK exhibited low accumulation, and PD tests validated SUMOylation inhibition and IFN-I signaling activation. More importantly, the combination of TAK-981 and rituximab showed excellent clinical activity (ORR 29%) in the R/R context, indicating that this combination should be further developed in patients with NHL.
Link to Abstract 2742:
https://ash.confex.com/ash/2021/webprogram/Paper148385.html
Background:
SUMOylation is a post-translational modification that attaches a tiny ubiquitin-like modifier (SUMO) to target proteins, similar to ubiquitination. SUMOylation is important in the immune system because it regulates type I interferon (IFN-I) expression, which helps to control the innate immune response and tumor immune surveillance (Decque Nat Immunol 2016). In multiple myeloma (MM), the SUMOylation pathway is frequently overexpressed and is linked to poor outcomes (Driscoll Blood 2010).
TAK-981 is a first-in-class small-molecule inhibitor of the SUMO-activating enzyme that disrupts the SUMOylation cascade and promotes IFN-I production and signaling in innate immune cells (Langston J Med Chem 2021). (Nakamura AACR 2019). TAK-981 triggered the IFN-I pathway in ex vivo experiments, increasing monocyte-derived macrophage phagocytic activity and natural killer (NK) cell cytotoxicity through IFN-I signaling (Nakamura AACR 2019). TAK-981’s ability to promote macrophage and NK cell activation provides a mechanistic rationale for its use in combination with monoclonal antibodies (mAbs) that rely on antibody-dependent cellular cytotoxicity and phagocytosis; in vivo experiments have shown synergistic activity between TAK-981 and rituximab, as well as TAK-981 and the anti-CD38 mAbs daratumumab (dar (meza; TAK-079; Figure 1).
Patients with MM who are resistant to the three most successful anti-myeloma therapy (protease inhibitors [PIs], immunomodulatory medicines [IMiDs], and anti-CD38 monoclonal antibodies [mAbs]) have a poor prognosis, with a median survival time of 9.2 months (Gandhi Leukemia 2019). Given the incurable nature of advanced MM and the highly complicated mechanisms of resistance, further research is essential to better understand MM biology during relapse and translate this information into successful therapy combinations. Combination medicines that target the immune system to treat MM could have a big impact.
Methods:
Patients must have failed at least three prior lines of anti-myeloma therapy, have MM disease that is triple-class refractory (defined as refractory/intolerant to one PI and one IMiD, and refractory to one anti-CD38 mAb), and have demonstrated disease progression on their last therapy to be eligible for this multicenter, open-label, Phase 1b/2 trial (NCT04776018). Prior CAR-T therapy is permissible. TAK-981 plus SC meza (Phase 1 Part 1) or SC dara (Phase 1 Part 2) will be given to patients (dara and hyaluronidase-fihj; Phase 1 Part 2). The primary goals of Phase 1b are to determine safety and tolerability, as well as to determine the recommended Phase 2 dose (RP2D) and schedule for TAK-981 with each mAb; secondary goals include preliminary antitumor activity, pharmacokinetics (PK), and pharmacodynamic (PD) markers of TAK-981 target engagement and SUMOylation pathway inhibition. In the Phase 1b Part 1 dose escalation of TAK-981 plus meza (15 patients per dosing schedule), approximately 30 patients will be enrolled, and 15 patients will be included in the Phase 1b Part 2 dose escalation of TAK-981 plus SC dara. The major goal of Phase 2 is to assess TAK-981’s efficacy in combination with an anti-CD38 mAb at the RP2D; 36 patients will be enrolled.
TAK-981 will be given to patients in Phase 1b as a 1-hour intravenous infusion on days 1, 4, 8, 11, and 15 (twice weekly; BIW) or days 1, 8, 15, and 22 (weekly; QW) for 2x 28-day cycles, then 8x every other week, then monthly. In a 28-day cycle, meza 600 mg SC or dara 1800 mg SC will be administered 8 times weekly, 8 times every other week, and then monthly (Figure 2). Treatment will be continued until the disease progresses or there is an unacceptable level of toxicity (max. 24 cycles). TAK-981 dose escalation will begin at 60 mg BIW, a dose that has been found to be pharmacologically active in a single-agent, first-in-human TAK-981 research (TAK-981-1002; data on file). Bayesian Optimal Internal Design with Informative Prior (iBOIN) will be used to guide dose escalation, as well as other safety, clinical, PK, and PD data. By allocating more patients to dose levels with a prior dose-limiting toxicity probability closest to the target of 0.3, the iBOIN design picks the genuine maximum tolerated dose (if any) with high accuracy. Patients are now being enrolled in this study, with the first patient being dosed in May 2021.
