This first-in-human (FIH) dose escalation will determine the maximum tolerated dose (MTD) of
KO-539, a menin-MLL(KMT2A) inhibitor, in patients with refractory or relapsed AML who have
failed or are ineligible for any approved standard of care therapies, including HSCT.
This Phase 1, first-in-human (FIH), open-label, dose-escalation study of KO-539, a
menin-MLL(KMT2A) inhibitor, will determine the safety and tolerability of escalating doses
using a modified toxicity probability interval (mTPI) adaptive design when administered to
patients with relapsed and/or refractory AML. If an maximum tolerated dose (MTD) cannot be
identified, a recommended phase 2 dose (RP2D) will be determined. A expansion phase in
specific genetic subgroups is planned following determination of the MTD/RP2D. KO-539 will be
administered as a once daily oral dose in 28 continuous day cycles.
1. 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.
2. ≥ 18 years of age.
3. 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
4. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to
5. Adequate organ function: creatinine ≤ 2.0 × upper limit of normal (ULN); serum
bilirubin ≤ 1.5 × ULN; aspartate aminotransferase and alanine aminotransferase ≤ 2.0 ×
6. Adequate renal function: creatinine clearance (CLcr) ≥ 60 mL/min using the
7. 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.
8. 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.
1. Patient has a diagnosis of acute promyelocytic leukemia.
2. Patient has a diagnosis of chronic myelogenous leukemia in blast crisis.
3. Donor lymphocyte infusion < 30 days prior to study entry.
4. WBC count > 30,000/mm3.
5. Clinically active central nervous system (CNS) leukemia.
6. 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.
7. 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.
8. 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.
9. Patient has a known positive test for human immunodeficiency virus, hepatitis C, or
hepatitis B surface antigen indicative of active infection.
10. 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).
11. Patient has an active uncontrolled acute or chronic systemic fungal, bacterial, viral,
or other infection.
12. 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.
13. 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,
14. 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.
15. 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).
16. Women who are pregnant or lactating. All female patients with reproductive potential
must have a negative pregnancy test prior to starting treatment.
17. Known alcohol or drug abuse or dependence.