A Phase 1/1b Open-Label, Multicenter, Two-Part Study of SETD2 Inhibitor EZM0414 in Patients with Relapsed/Refractory Multiple Myeloma or Diffuse Large B-Cell Lymphoma

Background: Multiple myeloma (MM) is a heterogeneous disease of monoclonal plasma cells. More than 40% of patients with MM harbor translocations of the immunoglobulin heavy chain (IGH) gene on chromosome 14, leading to overexpression of putative oncogenes which can ultimately lead to plasma cell-derived, post-malignancy MM. One such translocation, t(4;14), is seen in 15% of patients and juxtaposes IGH control elements with two genes on chromosome 4, FGFR3 and MMSET. Patients harboring the (4;14) translocation have a poor response to standard of care therapies and an overall poor prognosis. MMSET expression has been confirmed as a driver in t(4;14) MM pathogenesis, but MMSET inhibitors have not yet been successfully developed in the clinic. Since MMSET generates the substrate for Su(var)3-9, enhancer of zeste, trithorax domain-containing 2 (SETD2) activity, SETD2 inhibition offers promise for targeting the underlying oncogenic mechanism in t(4;14) MM.

Diffuse large B-cell lymphoma (DLBCL) is the most common type of lymphoma in the United States, with a 5-year relative survival rate of 53% in patients diagnosed with stage IV DLBCL. Given the poor survival outcomes and low remission rates for patients with relapsed or refractory (R/R) DLBCL, there is a need for better treatment options. Although SETD2 mutations are described in DLBCL, the mechanism of action of SETD2 inhibitors remains unclear.

EZM0414 is a potent and selective, orally bioavailable small-molecule inhibitor of SETD2. Preclinical data have demonstrated antitumor activity of EZM0414 in both t(4;14) and non-t(4;14) MM and DLBCL models.

This study (enrollment scheduled to begin Q3 2021) will evaluate the safety and efficacy of EZM0414 when administered as monotherapy in patients with R/R MM with or without t(4;14), or with R/R DLBCL.

Study Design and Methods: This first-in-human, 2-part, multicenter, open-label study will enroll patients aged ≥18 years with R/R MM who have received prior treatment with immune modulators, proteasome inhibitors, and anti-CD38 therapy, or who are intolerant to established therapies known to provide clinical benefit in MM, or with R/R DLBCL who have received at least 2 prior lines of therapy, including treatment with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP); rituximab, etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (R-EPOCH); rituximab, cyclophosphamide, vincristine, doxorubicin, and dexamethasone (R-hyper CVAD); or other standard of care therapies. Patients eligible for autologous stem cell transplantation will be excluded from this study.

The first part of the study will be a phase 1 dose escalation study using a Bayesian optimal interval design to evaluate the safety and tolerability of EZM0414 in patients with R/R MM with or without t(4;14), or with R/R DLBCL. Six dose levels of 100, 200, 300, 400, 600, and 900 mg administered once daily will be tested. Patients will be enrolled and treated in a cohort size of 3, and up to 36 patients will be enrolled to evaluate at least 10 patients at the maximum tolerated dose (MTD). The MTD will be selected at the dose level with a target dose-limiting toxicity rate ≤25%.

The second part of the study (phase 1b) will be a dose expansion at the MTD in patients with R/R MM with or without t(4;14), or with R/R DLBCL using the Bayesian optimal phase 2 design. Dose expansion will include 3 cohorts of up to 20 patients each. Cohort 1 will enroll patients with t(4;14)-positive R/R MM, cohort 2 will enroll patients with t(4;14)-negative R/R MM, and cohort 3 will enroll patients with R/R DLBCL.

The primary endpoints will be determining safety, dose-limiting toxicities, the MTD, and a recommended phase 2 dose. Secondary endpoints include the objective response rate, progression-free survival, and duration of response. Exploratory endpoints include a pharmacokinetic/pharmacodynamic profile analysis and the determination of mechanism of action biomarkers, such as histones and histone methylation.

The study design will include a futility assessment in the phase 1b part of the study, which will be initiated when clinical data from the first 10, 15, and 20 enrolled patients in the expansion cohort are available.