A Phase 1 Study of LY3410738, a First-in-Class Covalent Inhibitor of Mutant IDH in Advanced Myeloid Malignancies (Trial in Progress)

Background: Mutations in isocitrate dehydrogenase 1/2 (mIDH) are collectively found in up to 20% of patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Reversible inhibitors of IDH1 (ivosidenib) and IDH2 (enasidenib) are currently approved and achieve response rates of ~40%, with median duration of response of <1 year in the approved relapsed AML setting. Among patients who relapse, restoration of the 2-HG oncometabolite may be mediated by IDH second site mutations or isoform switching. LY3410738 is a potent, selective, and covalent inhibitor of IDH1-R132. LY3410738 is differentiated from prior IDH inhibitors by 1) its unique covalent binding mode, 2) its increased potency against IDH1-R132, and 3) its unique binding site outside of the dimer interface, which enables continued potency in the setting of known common second site IDH mutations. This trial will investigate the activity of LY3410738 in patients with hematologic malignancies harboring mIDH.

Study Design and Methods: This is an open-label, multicenter, global Phase 1 study of oral LY3410738 in relapsed or refractory (R/R) mIDH myeloid malignancies. Enrollment will begin in patients with IDH1-R132 mutations. Key eligibility criteria (in addition to the IDH-R132 mutation) include at least 18 years of age, diagnosis of AML or high risk MDS or other R/R hematologic malignancy, ECOG PS ≤2, and adequate organ function. Key exclusion criteria include a history of hematopoietic stem cell transplant or CAR-T therapy within 60 days of first LY3410738 dose.

Primary objectives of the study are to determine the recommended Phase 2 dose (RP2D) and to assess the preliminary anti-tumor activity of LY3410738 based on overall response rate using modified 2017 ELN recommendations (for AML) or modified IWG Response Criteria (for MDS). Secondary objectives include evaluating safety, tolerability, pharmacokinetics, and pharmacodynamics (expressed by changes in 2-HG levels in plasma).

Dose escalation will follow a 3+3 design, allowing for patient backfill to dose levels cleared that are predicted to achieve therapeutic exposures. Each cycle will be 28 days (4 weeks).

Once the RP2D is determined, patients will be enrolled into one of 4 dose expansion cohorts based on IDH mutation, myeloid malignancy, and prior therapy, including reversible IDH inhibitors. Cohort 1 will enroll patients with R/R AML harboring an IDH1-R132 mutation who have received standard therapy, including a prior IDH inhibitor. Cohort 2 will enroll patients with R/R AML harboring an IDH1-R132 mutation who have received standard therapy, excluding a prior IDH inhibitor. Cohort 3 will enroll patients with R/R MDS, chronic myelomonocytic leukemia (CMML) or other advanced hematologic malignancy harboring an IDH1-R132 mutation who have received standard therapy. Based on preliminary preclinical activity of LY3410738 in mutant IDH2 assays, Cohort 4 will enroll patients with R/R AML, MDS, CMML, or other advanced hematologic malignancy harboring IDH2 mutations who have received standard therapy. Approximately 80 patients (20 patients per cohort) will be enrolled in the 4 exp cohorts. The study is planned to enroll patients in late 2020.