Eltanexor and Venetoclax in Relapsed or Refractory Myelodysplastic Syndrome and Acute Myeloid Leukemia

- Age >/= 18 years at the time of signing the Informed Consent Form (ICF); must voluntarily sign an ICF; and must be able to meet all study requirements.

For Myelodysplastic Syndrome (MDS):

Morphologically confirmed diagnosis of MDS with increased blasts (>/= 5%), with a prior DNA methyltransferase inhibitor (DNMTi) treatment and progression after 2 cycles or stable disease after 4 cycles

For Acute Myeloid Leukemia (AML):

Morphologically confirmed diagnosis of AML in accordance with WHO diagnostic criteria that is relapsed or refractory following >/= 1 line(s) of therapy.

• WBC must be less than 25,000/ul prior to study start (hydroxyurea allowed).
• A bone marrow aspirate must be performed, and tissue collected for entrance to the trial unless circulating blasts >/= 5% in which case, peripheral blood can be used.
• Eastern Cooperative Oncology Group Performance Status of 0 - 2.
• Must have adequate hepatic and renal function as demonstrated by the following:

ALT(SGPT) and/or AST (SGOT) \</= 3x upper limit of normal (ULN); Total bilirubin \</= 1.5x ULN; Calculated creatinine clearance > 50 ml/min (per the Cockroft-Gault formula).

- Willingness to abide by all study requirements, including contraception, maintenance of a pill diary, and acceptance of recommended supportive care medications.

Exclusion Criteria:

• Anticancer therapy, including investigational agents \</= 2 weeks or \</= 5 half-lives of the drug, whichever is shorter, prior to C1D1. (Use of hydroxyurea is permitted).
• Inadequate recovery from toxicity attributed to prior anti-cancer therapy to \</= Grade 1 (NCI CTCAE v5.0), excluding alopecia or fatigue.
• Prior treatment with SINE compounds or other inhibitors of XPO1.
• History of allogeneic hematopoietic stem cell transplant (HCT), or other cellular therapy product, within 3 months.
• Active acute or chronic GVHD requiring calcineurin inhibitors or steroid dosing >/= 10mg/day or patients within 4 weeks of stopping calcineurin inhibitors for GVHD.
• Radiation therapy or major surgery within 3 weeks.
• Active, uncontrolled infection. Patients with infection under active treatment and controlled with antibiotics are eligible. Prophylaxis, even if parenteral, is acceptable.
• Inability to swallow oral medications.
• Active documented central nervous system leukemia.
• Second active malignancy within past 2 years except for basal or squamous cell carcinoma of the skin, ductal carcinoma of breast in situ or cervical carcinoma in situ.
• Women of childbearing age or potential must have negative pregnancy test and must not be actively breastfeeding to enroll on the study
• Clinically significant cardiovascular disease with major event or cardiac intervention within the past 6 months (e.g. percutaneous intervention, coronary artery bypass graft, documented cardiac heart failure) as determined by the investigator.
• QT interval corrected by Fridericia's formula (QTcF)>470msec for both males and females on screening ECG. Patients with a bundle branch block or in-situ pacemaker must have appropriate QT interval corrections for these conditions.
• Any condition not listed but deemed by the investigator to make the patient a poor candidate for clinical trial and/or treatment with investigational agents.