Seclidemstat and Azacitidine for the Treatment of Myelodysplastic Syndrome or Chronic Myelomonocytic Leukemia

This phase I/II trial identifies the best dose of seclidemstat when given together with azacitidine in treating patients with myelodysplastic syndrome or chronic myelomonocytic leukemia. Seclidemstat may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Azacitidine may help block the formation of growths that may become cancer. Giving seclidemstat and azacytidine may kill more cancer cells.

PRIMARY OBJECTIVES:

I. To determine the safety, tolerability and maximum tolerable dose (MTD) of seclidemstat in combination with azacitidine.

II. To assess overall response rate (ORR) to seclidemstat in combination with azacitidine.

SECONDARY OBJECTIVES:

I. To assess overall survival (OS), duration of response (DOR), relapse-free survival (RFS), and leukemia-free survival (LFS) and safety profile.

II. Correlative studies including correlation of response with disease subtypes, genomic profile and in vitro studies.

OUTLINE: This is a phase I, dose-escalation study of seclidemstat followed by a phase II dose-expansion study.

Patients receive azacitidine intravenously (IV) over 10-40 minutes or subcutaneously (SC) on days 1-7. Patients also receive seclidemstat orally (PO) once daily (QD) on day 1 of cycle 1 and PO twice daily (BID) on days 2-28 of cycle 1 and on days 1-28 of all subsequent cycles. There are 6 possbile dose levels for seclidemstat: 300 mg, 450 mg, 600 mg, 900 mg, 1200 mg and 1500 mg. Successive cohorts of eligible patients will be treated with azacitidine until the phase 2 recommended dose or maximum tolerated dose is determined. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 30 days, and then every 6 months thereafter

Eligibility Criteria:
Inclusion Criteria:

* Age \>= 18 years as myelodysplastic syndrome (MDS) is a very rare disease in the pediatric setting
* Diagnosis of MDS or chronic myelomonocytic leukemia (CMML) according to World Health Organization (WHO) and:

  * MDS with int-1, int-2, or high risk by International Prognostic Scoring System (IPSS), or CMML-1/CMML-2 , myeloproliferative CMML (white blood cell \[WBC\] \>= 13 x 10\^9/L) or CMML-0 with high-risk molecular features (known mutations in ASXL1, SETBP1, RUNX1, NRAS, TP53 or more than 3 mutations).
  * No response after 6 cycles of azacitidine, decitabine, guadecitabine, ASTX030 or ASTX727 or relapse or progression after any number of cycles
* Serum creatinine =\< 1.5 x upper limit of normal (ULN) OR creatinine clearance \>= 50 ml/min for patients with creatinine levels \> 1.5 x ULN
* Adequate hepatic function with total bilirubin \< 2 x ULN (will allow less than 5 x ULN if Gilbert's syndrome at investigator's discretion)
* Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) =\< 3 x ULN
* Eastern Cooperative Oncology Group (ECOG) performance status 0-2
* Patient (or patient's legally authorized representative) must have signed an informed consent document indicating that the patient understands the purpose of and procedures required for the study and is willing to participate in the study
* Prior hydroxyurea for control of leukocytosis or use of hematopoietic growth factors (e.g., granulocyte colony-stimulating factor \[G-CSF\], granulocyte-macrophage colony-stimulating factor \[GM-CSF\], Procrit, Aranesp, thrombopoietins) is allowed at any time prior to or during study if considered to be in the best interest of the patient

Exclusion Criteria:

* Uncontrolled infection not adequately responding to appropriate antibiotics
* New York Heart Association (NYHA) class III or IV congestive heart failure or left ventricular ejection fraction (LVEF) \< 50% by echocardiogram or multigated acquisition (MUGA) scan
* History of myocardial infarction within the last 6 months or unstable/uncontrolled angina pectoris or history of severe and/or uncontrolled ventricular arrhythmias
* Baseline corrected QT interval by Fridericia formula (QTcF) (Fridericia) \>= 450 msecs and long QT syndrome or family history of idiopathic sudden death or congenital long QT syndrome
* Currently receiving any of the following substances and cannot be discontinued 14 days for CYP inhibitors prior to cycle 1 day 1:

  * Moderate or strong inhibitors or inducers of major CYP isoenzymes, including grapefruit, grapefruit hybrids, pomelos, star fruit and Seville oranges
  * Moderate or strong inhibitors or inducers of major drug transporters
  * Substrates of CYP3A4/5 with a narrow therapeutic index
* Female patients who are pregnant or lactating
* Patients with reproductive potential who are unwilling to following contraception requirements (including condom use for males with sexual partners, and for females: prescription oral contraceptives \[birth control pills\], contraceptive injections, intrauterine devices \[IUD\], double-barrier method \[spermicidal jelly or foam with condoms or diaphragm\], contraceptive patch, or surgical sterilization) throughout the study
* Female patients with reproductive potential who do not have a negative urine or blood beta-human chorionic gonadotropin (beta human chorionic gonadotropin \[HCG\]) pregnancy test at screening
* Patients receiving any other concurrent investigational agent or chemotherapy, radiotherapy, or immunotherapy
* Evidence of graft versus host disease or prior allogeneic (allo)-stem cell transplantation within 6 months of cycle 1 day 1 or receiving immunosuppressants following a stem-cell procedure
* Patients known to be positive for hepatitis B surface antigen expression or with active hepatitis C infection (positive by polymerase chain reaction or on antiviral therapy for hepatitis C within the last 6 months). Patients with history of human immunodeficiency virus (HIV) disease are also excluded from the study