Clinical Trials

Inclusion Criteria:

• Refractory or relapsed AML defined as the reappearance of > 5% blasts in the bone marrow and who have failed or are ineligible for any approved standard of care therapies, including HSCT.
• ≥ 18 years of age.
• Read, understood, and provided written informed consent and, if applicable, Health Insurance Portability and Accountability Act (HIPAA) authorization after the nature of the study has been fully explained and must be willing to comply with all study requirements and procedures including serial bone marrow and peripheral blood sampling.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.
• Adequate organ function:
  • creatinine ≤ 2.0 × upper limit of normal (ULN);
  • serum bilirubin ≤ 1.5 × ULN; aspartate aminotransferase and alanine aminotransferase ≤ 2.0 × ULN.
• Adequate renal function:
  • creatinine clearance (CLcr) ≥ 60 mL/min using the Cockcroft-Gault equation.
• Hydroxyurea will be allowed prior to enrollment and after the start of KO-539 to control and maintain peripheral white blood cell (WBC) counts ≤ 30,000/μL. Patients can continue on hydroxyurea through Cycle 1 Day 28 or until first disease assessment. After which, patients should be titrated off therapy.
• Both men and women enrolled in this trial must use adequate birth control measures during the course of the trial and for at least 28 days or hematologic recovery whichever is longest after discontinuing study treatment. Patients and/or partners who are surgically sterile or postmenopausal are exempt from this requirement.

Exclusion Criteria:

• Patient has a diagnosis of acute promyelocytic leukemia.
• Patient has a diagnosis of chronic myelogenous leukemia in blast crisis.
• Donor lymphocyte infusion < 30 days prior to study entry.
• WBC count > 30,000/mm^3.
• Clinically active central nervous system (CNS) leukemia.
• Patients who have undergone HSCT and have not had adequate hematologic recovery (i.e. ANC >1000 and platelet count > 100K) or patients on immunosuppressive therapy post HSCT at the time of screening (must be off all immunosuppression therapy for at least 2 weeks), or with Grade > 2 active graft-versus-host disease (GVHD), moderate or severe limited chronic GVHD, or extensive chronic GVHD of any severity. The use of topical steroids for cutaneous GVHD is allowed and stable steroid doses less than or equal to 10 mg of prednisone daily is permitted with Medical Monitor approval.
• Patient has received chemotherapy immunotherapy, or radiotherapy or any ancillary therapy that is considered to be investigational (i.e., used for non-approved indications(s) and in the context of a research investigation) < 14 days prior to the first dose of KO-539 or within 5 drug half-lives (whichever is longer) prior to the first dose of study drug. Patients must have recovered to NCI CTCAE v. 5.01 ≤ Grade 2 from all acute toxicities (excluding Grade 2 toxicities that are not considered a safety risk by the Sponsor and Investigator) or toxicity must be deemed irreversible by the Investigator.
• Patient requires treatment with concomitant drugs that are strong inhibitors or inducers of cytochrome P450-isozyme 3A4 (CYP3A4) with the exception of antibiotics, antifungals, and antivirals that are used as standard of care or to prevent or treat infections and other such drugs that are considered absolutely essential for the care of the patient.
• Patient has a known positive test for human immunodeficiency virus, hepatitis C, or hepatitis B surface antigen indicative of active infection.
• Patient has a pre-existing disorder predisposing the patient to a serious or life-threatening infection (e.g., cystic fibrosis, congenital or acquired immunodeficiency, bleeding disorder, or cytopenias not related to AML).
• Patient has an active uncontrolled acute or chronic systemic fungal, bacterial, viral, or other infection.
• Significant cardiovascular disease including unstable angina pectoris, uncontrolled hypertension or arrhythmia, history of cerebrovascular accident including transient ischemic attack within the past 6 months, congestive heart failure (NYHA Class III or IV) related to primary cardiac disease, ischemic or severe valvular heart disease, or a myocardial infarction within 6 months prior to the first dose of study treatment.
• Mean QTcF or QTcB of > 480 ms on triplicate electrocardiograms (ECGs) performed within 5 minutes of each other as a guide to known drugs associated with QTc prolongation, please refer to the following Credible Meds web page for a list of drugs that prolong QT and/or cause torsades de pointes, https://crediblemeds.org/pdftemp/pdf/CombinedList.pdf.
• Major surgery within 4 weeks prior to the first dose of study treatment. Surgery requiring local/epidural anesthesia must be completed at least 72 hours before study drug administration and patients should be recovered.
• Underlying medical condition that, in the Principal Investigator's opinion, will make the administration of study treatment hazardous or obscure the interpretation of toxicity determination or adverse events (AEs).
• Women who are pregnant or lactating. All female patients with reproductive potential must have a negative pregnancy test prior to starting treatment.
• Known alcohol or drug abuse or dependence.