Onvansertib for the Treatment of Recurrent or Refractory Chronic Myelomonocytic Leukemia and Myelodysplastic Syndrome/MPN Overlap Neoplasms

Inclusion Criteria:

PRE-REGISTRATION - INCLUSION CRITERIA:

• Age >= 18 years

• History of World Health Organization (WHO)-defined diagnosis of proliferative CMML (WBC count >= 13,000/mm^3 at time of diagnosis), or MDS/MPN overlap neoplasm withWBC count >= 13,000/mm3 at time of diagnosis (atypical CML and MDS/MPN-NOS).

• NOTE: Hydroxyurea or hypomethylating induced leukopenia does not precludeinclusion. Discussion of WBC < 13,000/mm^3 due to treatment at the time ofpreregistration must be discussed with the Sponsor/Principal Investigator

• Relapsed/refractory following treatment with hydroxyurea; or at least 4 cycles oftreatment with hypomethylating agents; or who are intolerant of treatment witheither therapy. Note: Prior exposure to erythropoiesis stimulating agents isallowed. Hydroxyurea may continue for the first 28 days on study. Continuation ofhydroxyurea beyond the first cycle must be discussed with the Sponsor/PrincipalInvestigator

• Willing and able to review, understand, and provide written consent before startingany study-specific procedures or therapy

• Willing to return to enrolling institution for follow-up (during the activemonitoring phase of the study)

• Willingness to provide mandatory bone marrow specimens for correlative research

• Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1 or 2

• Recovered to grade 1 or baseline or established as sequelae from all toxic effectsof previous therapy except alopecia

• Platelet count >= 20,000/mm^3 (obtained =< 14 days prior to pre-registration)

• NOTE: For platelet count < 20,000/mm3 and in situations where the primaryinvestigator deems the thrombocytopenia to be attributable to the underlyingCMML, patients can be enrolled as long as they are able to achieve a plateletcount of 20,000/mm3 with transfusional support

• Total bilirubin =< 1.5 x upper limit of normal (ULN) (=< 3 x ULN for patients withGilbert's syndrome) (obtained =< 14 days prior to pre-registration)

• Alanine aminotransferase (ALT) and aspartate transaminase (AST) =< 3 x ULN (obtained =< 14 days prior to pre-registration)

• Estimated glomerular filtration rate (eGFR) >= 50 mL/min/m^2 using one of thefollowing methods (obtained =< 14 days prior to pre-registration):

• Chronic Kidney Disease-Epidemiology Collaboration (CKDEPI) 2021 formula

• Corrected creatinine clearance via serum and 24-hour urine creatinineassessment

• Iothalamate/Iohexol glomerular filtrate rate via plasma/urine assessment

• Ability to complete questionnaire(s) by themselves or with assistance

• Willingness to provide mandatory blood specimens for correlative research

REGISTRATION - INCLUSION CRITERIA:

• Histological confirmation of WHO-defined diagnosis of amyelodysplastic/myeloproliferative neoplasm (MDS/MPN) including one of the following (NOTE: to confirm patient is still eligible and has not progressed to

AML):

• Proliferative CMML

• Atypical chronic myeoloid leukemia (aCML)

• MDS/MPN not otherwise specified (MDS/MPN, NOS)

• NOTE: Hydroxyurea or hypomethylating agent induced leukopenia does not precludeinclusion. Discussion of WBC < 13,000/mm^3 due to treatment at the time ofregistration must be discussed with the Sponsor/Principal Investigator.

• For a man or a woman of child-bearing potential (WOCBP): Must agree to usecontraception or take measures to avoid pregnancy during the study and for 180days after the final dose of any study drug. Adequate contraception is definedas follows:

• Complete true abstinence

• Consistent and correct use of one of the following methods of birth control:

• Male partner who is sterile prior to the female patient's entry into the studyand is the sole sexual partner for that female patient

• Implants of levonorgestrel

• Injectable progestogen

• Intrauterine device (IUD) with a documented failure rate of less than 1% peryear

• Oral contraceptive pill (either combined or progesterone only)

• Barrier method, for example: diaphragm with spermicide or condom withspermicide in combination with either implants of levonorgestrel or injectableprogestogen

• WOCBP must have a negative serum or urine pregnancy test =< 7 days priorto registration

• NOTE: WOCBP include any female who has experienced menarche and who has notundergone successful surgical sterilization (hysterectomy, bilateral tubal ligation,or bilateral oophorectomy) or is not postmenopausal (defined as amenorrhea > 12consecutive months); or women on hormone replacement therapy with documented serumfollicle stimulating hormone (FSH) level > 35 mIU/mL. Even women who are using oral,implanted or injectable contraceptive hormones or mechanical products such as an IUDor barrier methods (diaphragm, condoms, spermicides) to prevent pregnancy orpracticing abstinence or where partner is sterile (eg, vasectomy), must beconsidered to be of child-bearing potential

• NOTE: If the urine test is positive or cannot be confirmed as negative, a serumpregnancy test will be required

Exclusion Criteria:

PRE-REGISTRATION - EXCLUSION CRITERIA:

• Previous exposure to an alternative (investigational) PLK1 inhibitor

• Demonstration of transformation to acute leukemia on any prior bone marrow biopsy

• Prior allogeneic hematopoietic stem cell transplantation with active grade 2-4graft-versus-host disease (GVHD) or with moderate to severe chronic GVHD

• NOTE: The patient should not have received calcineurin inhibitors ≤28 daysprior to pre-registration and should not be actively receivingimmunosuppressive therapy for acute or chronic GVHD.

• NOTE: CMML or MDS/MPN overlap neoplasms relapse after allogeneic stem celltransplant is allowed as long as they are >100 days after transplant and do nothave the aforementioned GVHD criteria.

• Active central nervous system disease

• Concurrent active malignancy, except adequately treated nonmelanoma skin cancer.History of curatively treated in situ cancer of the cervix, curatively treated insitu cancer of the breast, or other solid tumors curatively treated is allowed aslong as there is no evidence of disease for > 2 years

• NOTE: Precursor states such as monoclonal gammopathy of undeterminedsignificance (MGUS), monoclonal B-cell lymphocytosis (MBL), and indolentlymphoproliferative disorders must be discussed with the Sponsor/PrincipalInvestigator.

• New York Heart Association (NYHA) class III/IV heart failure or active angina/anginaequivalents

• Anticancer chemotherapy (exception: hydroxyurea) or biologic therapy administeredwithin 2 weeks (and at least 4 elimination half-lives for clinical trial agents)prior to pre-registration. NOTE: Hydroxyurea is allowed for the first 28 days onstudy. Continuation of hydroxyurea beyond the first cycle must be discussed with theSponsor/Principal Investigator

• Receiving any other investigational agent which would be considered as a treatmentfor the primary neoplasm

• Major surgery =< 6 weeks prior to pre-registration

• Gastrointestinal (GI) disorder(s) that, in the opinion of the Investigator, wouldsignificantly impede the absorption of an oral agent (eg, intestinal occlusion,active Crohn's disease, ulcerative colitis, extensive gastric and small intestineresection)

• Unable or unwilling to swallow study drug

• Uncontrolled intercurrent illness including, but not limited to, ongoing or activeinfection, clinically significant nonhealing or healing wounds, clinicallysignificant cardiac arrhythmia, significant pulmonary disease (shortness of breathat rest or mild exertion), uncontrolled infection, or psychiatric illness/socialsituations that would limit compliance with study requirements

• Known active infection with human immunodeficiency virus (HIV) with measurable viraltiter, hepatitis B surface antigen positivity, or hepatitis C with measurable viraltiter. NOTE: Patients with antibody to hepatitis B core antibody are eligible ifthey have no measurable viral titer. Patients who have had a hepatitis B virus (HBV)immunization are eligible

• Patient is receiving any live vaccine (eg, varicella, pneumococcus) =< 28 days priorto pre-registration. NOTE: messenger ribonucleic acid (mRNA)-based (eg, Pfizer orModerna) or replication-deficient virus (eg, Oxford/AstraZeneca) COVID19 vaccinesare permitted

• Disease requiring systemic treatment with systemic immunosuppression with steroidsteroids at a dose of >= 20 mg/day prednisone (or equivalent). Exceptions:Intermittent use of bronchodilators or inhaled steroids, local steroid injections,topical steroids

• Any active disease condition that would render the protocol treatment dangerous orimpair the ability of the patient to receive study drug

• Strong CYP3A4 inhibitors/inducers as identified per institutional guidelines

• QT interval with Fridericia's correction (QTcF) > 470 milliseconds. In the case ofpotentially correctible causes of QT prolongation, (eg, medications, hypokalemia),the electrocardiogram (ECG) may be repeated once during screening and that resultmay be used to determine eligibility

REGISTRATION - EXCLUSION CRITERIA:

• Any of the following because this study involves an investigational agent whosegenotoxic, mutagenic and teratogenic effects on the developing fetus and newborn areunknown:

• Pregnant persons

• Nursing persons

• Persons of childbearing potential who are unwilling to employ adequatecontraception

• Increased risk of Torsade des Pointes (TdP) defined as follows:

• A marked baseline prolongation of QT/QTc interval (eg, repeated demonstrationof a QTc interval > 480 msec [CTCAE Grade >= 2] using Fredericia's QTcorrection formula)

• A history of additional risk factors for TdP (eg. heart failure, family historyof long QT syndrome)

• Transformation to acute leukemia on registration bone marrow biopsy