BackgroundSUMOylation is a post-translational modification that serves as an important modulator of immune responses via its role in constraining the type I interferon (IFN-1) response. TAK-981 is a small molecule that inhibits SUMOylation and increases IFN-1-dependent innate immune responses with the potential to enhance adaptive immunity. Here, we report dose-escalation data from a TAK-981 Phase 1/2 clinical study (NCT03648372), the first clinical data for a SUMOylation inhibitor.MethodsAdults with advanced/metastatic solid tumors or relapsed/refractory lymphomas received TAK-981 IV twice-weekly (BIW; days 1, 4, 8, 11) or once-weekly (QW; days 1, 8) in 21-day cycles. Dose escalation was guided by a Bayesian Logistic Regression Model (BLRM) with overdose control, plus available pharmacokinetic/pharmacodynamic (PK/PD) data. Phase 1 objectives were to determine TAK-981 safety/tolerability and establish the recommended phase 2 dose (RP2D).ResultsSeventy-six patients received TAK-981 at 10 dose levels (3–40 mg BIW; 60–120 mg QW/BIW). Median age was 61 years (range, 38–79); 42 (55.3%) patients were female. Four dose-limiting toxicities were seen in 62 evaluable patients (transient grade 3 ALT/AST elevation, 60 mg BIW; grade 3 pneumonitis, 90 mg BIW; grade 3 stomatitis and grade 3 cognitive disturbance, 120 mg BIW). Per BLRM, 120 mg BIW was determined to be the maximum tolerated dose. At data cut-off, median treatment duration was 2 cycles (range, 1–12); 13 (17.1%) patients were ongoing. table 1 summarizes TAK-981 safety. The most common (≥20%) treatment-emergent adverse events (TEAEs) were fatigue (42.1%), nausea (39.5%), headache (31.6%), diarrhea (28.9%), pyrexia (27.6%), vomiting (23.7%), decreased appetite (22.4%). Common (≥5%) grade ≥3 TEAEs were hypokalemia (9.2%), anemia (7.9%), lymphocyte count decreased (6.6%), abdominal pain (5.3%). Grade 2 cytokine release syndrome was reported in 4 (5.2%) patients; symptoms resolved within 12–24 hours with supportive oxygen and/or IV fluids. One partial response was observed at 40 mg TAK-981 BIW in a patient with relapsed/refractory HER2-negative, hormone receptor-positive breast cancer. TAK-981 exhibited linear PK, with approximately dose-proportional exposure and a mean terminal half-life of 3.8–10.8 hours at ≥60 mg. Evidence of dose-dependent target engagement (figure 1), and PD (figures 2–4) in blood were observed. The single-agent TAK-981 RP2D was 90 mg BIW.Abstract 476 Table 1Summary of TAK-981 safety profileAbstract 476 Figure 1PD in patients receiving TAK-981 on the BIW schedule: target engagement.Blood samples were collected on Cycle 1 Day 1 pre-dose and at multiple timepoints after TAK-981 administration. Target engagement in T cells was detected by flow cytometry with an antibody recognizing the TAK-981-SUMO adduct formed during the inhibition of the SUMO-activating enzyme by TAK-981; Cycle 1 Day 1 signal increased at 1 hour post-end-of-infusion compared to the background level observed pre-dose.Abstract 476 Figure 2PD in patients receiving TAK-981 on the BIW schedule: SUMOylation.SUMOylation in T cells, detected by flow cytometry with an antibody recognizing SUMO2/3, decreased at 1 hour post-end-of-infusion on Cycle 1 Day 1 compared to pre-dose, indicating that fewer SUMO2/3 chains are formed when the SUMO-activating enzyme is inhibited.Abstract 476 Figure 3PD in patients receiving TAK-981 on the BIW schedule: upregulation of CXCL10 expression.Upregulation of mRNA levels of CXCL10, an IFN-I-regulated gene, in peripheral blood. Gene expression was measured using Nanostring nCounter at Cycle 1 Day 1 pre-dose and at several timepoints post-dose. Data for maximum increase at 8 or 24 hours, relative to pre-dose, is shown.Abstract 476 Figure 4PD in patients receiving TAK-981 on the BIW schedule: NK cell activation.NK cell activation in peripheral blood measured by flow cytometry. Percentage of CD69-positive NK cells at Cycle 1 Day 1 pre-dose and at 24 hours post-end-of-infusion is shown by patient for each dose.ConclusionsThe data generated in this study support continued TAK-981 development for treatment of solid tumors and lymphoma. The Phase 2 study expansion is ongoing in patients with advanced/metastatic non-small-cell lung, cervical, and colorectal cancer, and in relapsed/refractory non-Hodgkin lymphoma.Trial RegistrationClinical Trial identification: ClinicalTrials.gov. Identifier: NCT03648372Ethics ApprovalThe study was approved by the Institutional Review Board or Institutional Ethics Committee of all participating institutions
Flow Cytometry Immunophenotyping for Diagnostic Orientation and Classification of Pediatric Cancer Based on the EuroFlow Solid Tumor Orientation Tube (STOT)