A Study of E7820 in People With Bone Marrow (Myeloid) Cancers

The researchers are doing this study to find out whether E7820 is an effective treatment for people with relapsed/refractory myeloid cancers with mutations in splicing factor genes. Participants will have acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), or chronic myelomonocytic leukemia (CMML).

Inclusion Criteria: 1\. Subject is ≥ 18 years of age at the time of signing informed consent 2. Subject is willing and able to adhere to the study visit schedule and other protocol requirements. 3. Subject has relapsed or refractory MDS, AML or CMML with a previously defined hotspot splicing factor mutation in SF3B1, SRSF2, U2AF1, or U2AF2 (with hotspot mutations as defined by OncoKB) or a nonsense or frameshift mutation in ZRSR2. A splicing factor mutation is required to be detected on next generation sequencing from bone marrow aspirate or peripheral blood at any timepoint within the 6 months prior to screening for the study. a. Relapsed AML is defined as: i. The appearance of 5% or greater myeloblasts in the bone marrow or peripheral blood after achieving a CR (MRD positive or negative), CRh, or CRi 1\. Patients with mutations in FLT3, IDH1 or IDH2 must have failed or been intolerant of an FDA approved FLT3, IDH1 or IDH2 inhibitor before enrolling on study. b. Refractory AML is defined as failure to achieve a CR, CRh, or CRi after one of the following regimens: i. Two cycles of intensive induction chemotherapy with a cytarabine containing regimen (e.g. 7+3, MEC, HIDAC, etc.) ii. Two cycles of HMA/venetoclax or LDAC/glasdegib iii. 4 cycles of HMA monotherapy c. Relapsed MDS is defined as: i. Any relapse after achieving an IWG defined response. d. Refractory MDS is defined as: i. For patients with intermediate, high or very high risk disease by IPSS-R, the failure to achieve a response (as per IWG 2006 criteria) after 4 cycles of HMA monotherapy or 2 cycles of HMA + venetoclax. ii. For patients with very low and low risk disease by IPSS-R failure to achieve hematologic improvement or loss of hematologic improvement after treatment with standard of care agents such as ESAs, Luspatercept (for MDS with ringed sideroblasts) and lenalidomide (for pts with a 5q-). e. Relapsed CMML is defined as: i. Any relapse after achieving an IWG defined response. f. Refractory CMML is defined as: i. Failure to achieve a response (as per IWG 2006 criteria) after 4 cycles of HMA monotherapy or 2 cycles of HMA + venetoclax. 4\. Subject has an Eastern Cooperative Oncology Group (ECOG) performance status of 0-3 5. Subject has adequate organ function defined as: 1. Serum aspartate aminotransferase/serum glutamic oxaloacetic transaminase (AST/SGOT) and alanine aminotransferase (ALT/SGPT) ≤ 3 x ULN, unless considered due to organ involvement by the patient's myeloid malignancy (in that case a cut off of ≤ 5 x ULN will be used) 2. Serum direct bilirubin \< 1.5 x ULN. 3. Creatinine clearance ≥ 60 mL/min based on the Cockroft-Gault glomerular filtration rate (GFR) estimation. 4. Females of childbearing potential may participate provided they have a negative serum pregnancy test at screening and a negative serum OR urine pregnancy test within 72 hours of starting on treatment. Females and male participants with female partners of childbearing potential also must agree to either abstain from sexual intercourse or use a highly effective method of contraception while on study and for 4 months after completing the study treatment. 6\. There are no limits on transfusion and/or growth factor support for enrollment. 7\. In case of leukemic organ involvement, patients with creatinine clearance \> 30 ml/min and bilirubin ≤ 2.0 x ULN will be eligible to be included. Exclusion Criteria: 1. Patients with acute promyelocytic leukemia 2. Subject has immediate life-threatening, severe complications of their myeloid malignancy such as uncontrolled bleeding, pneumonia with hypoxia or shock, and/or disseminated intravascular coagulation 3. Subject has significant active cardiac disease within 6 months prior to the start of study treatment, including New York Heart Association (NYHA) class III or IV congestive heart failure; acute coronary syndrome (ACS); and/or stroke or left ventricular ejection fraction (LVEF) \