Phase 1 Trial to Evaluate the Safety, Pharmacokinetics and Pharmacodynamics of Splicing Modulator H3B-8800 for Subjects With Myelodysplastic Syndromes, Acute Myeloid Leukemia, and Chronic Myelomonocytic Leukemia

Inclusion Criteria

1. Confirmed diagnosis of Myelodysplastic Syndromes (MDS), Chronic Myelomonocytic Leukemia (CMML), or Acute Myeloid Leukemia (AML). 2. The participant must meet the following criteria relevant to their specific diagnosis: 1. Participants with AML must either refuse or not be considered candidates for intensive induction chemotherapy. Previously treated participants should have evidence of persistent or recurrent AML in the peripheral blood and/or bone marrow. Participants must have white blood cell (WBC) < 15 x 10^9cells/L. 2. For International Prognostic Staging System (IPSS) high-risk or intermediate-2 MDS, participants must be intolerant of hypomethylating agents or not have responded to 4 treatment cycles of decitabine or 6 treatment cycles of azacitidine, or must have progressed at any point after initiation of a hypomethylating agent. 3. For IPSS intermediate-1 or low-risk MDS, participants must be transfusion dependent for red blood cells or platelets (as determined by instructional practices or local standard of care). Participants who are red blood cell transfusion dependent must also have failed erythropoiesis stimulating agents (primary resistance or relapse after a response) or have serum erythropoietin (EPO) levels > 500 U/L. 4. For CMML, participants must have been treated with at least one prior therapy (hydroxyurea or an hypomethylating agent [HMA]). 3. Peripheral Blood Samples: 1. Cohort A: Screening visit peripheral blood must be available for retrospective analysis of spliceosome mutations of interest. 2. Cohort B and Expansion: Screening visit peripheral blood must be submitted for central analysis at a sponsor-designated laboratory to identify spliceosome hotspot mutations in SF3B1, SRSF2, U2AF1, mutations in ZRSR2, and SRSF2 deletion including amino acid P95. 4. Male or female, age ? 18 years old at the time of consent. 5. Eastern Cooperative Oncology Group (ECOG) performance score of 0-2. 6. Adequate baseline organ function: 1. Serum creatinine ? 1.7 mg/dL or calculated creatinine clearance ? 50 mL/min per the Cockcroft and Gault formula 2. Direct bilirubin ? 1.5 x upper limit of normal (ULN) 3. c. Aspartate aminotransferase (AST) and alanine transaminase (ALT) ? 3.0 x ULN 4. Albumin ? 2.5 mg/dL 8. Written informed consent.

Exclusion Criteria

1. Females who are breastfeeding or pregnant. 2. Diagnosis of a core binding factor leukemia (t(821), t(1616) or inv(16)). 3. Participant is candidate for hematopoietic stem cell transplants at the time of enrollment. 4. Family history of Leber Hereditary Optic Neuropathy, Autosomal Dominant Optic Atrophy, Late-Onset Retinal Degeneration, Familial Dysautonomia or other hereditary mitochondrial disease, unless the causative mutation(s) in the family have been determined and the participant has tested negative for the mutation(s). 5. Known prior or current retinal or optic nerve disease (eg, Retinitis Pigmentosa, diabetic retinopathy, optic neuritis) based on screening ophthalmology assessment for eligibility. 6. Corrected vision is worse than 20/40 unless due to cataracts. 7. Vitamin B12, folate or vitamin A deficiency. Rescreening following repletion therapy is acceptable. 8. Use of concomitant medications with evidence for an association with drug-induced mitochondrial optic neuropathy including systemic administration of ethambutol, chloramphenicol, linezolid, erythromycin, streptomycin, and zidovudine. 9. Prior exposure to cisplatin, 5-fluorouracil, tamoxifen, and/or MEK inhibitors within 3 months of enrollment and/or ethambutol and/or hydroxychloroquine within 12 months. 10. Use of concomitant medications that are known to be strong inhibitors or inducers of CYP3A4 enzyme unless participant can discontinue or switch medications. 11. Received treatment with chemotherapy, wide-field radiation, or anti-cancer biologic therapy including investigational agents within 14 days of study entry. 12. An active malignancy and/or cancer history for at least 2 years with the exception of non-melanoma skin cancer, carcinoma in situ, cervical intraepithelial neoplasia, organ-confined prostate cancer with no evidence of progressive disease. 13. Clinically severe cardiovascular disease or clinically significant electrocardiogram (ECG) abnormality. 14. Uncontrolled, clinically significant pulmonary disease. 15. Known active or suspected central nervous system (CNS) leukemia. 16. Uncontrolled intercurrent illness. 17. Known history of human immunodeficiency virus (HIV), or active Hepatitis B or C. 18. Cardiac troponin (cTn) levels above the upper limit of normal

Gender

All

Ages

18 Years and older

Accepts Healthy Volunteers

No