A Multi-Site Break Through Cancer Trial: Phase ll Study Investigating Dual Inhibition of BCL2 and Menin in AML MRD Using the Combination of Venetoclax and Revumenib

To learn if the combination of venetoclax and revumenib can help to control MRD-positive
AML.

Inclusion Criteria:

1. Age ≥ 12 years with weight ≥ 45Kg.

2. ECOG performance status of ≤ 2. (if aged ≥18 years); Karnofsky Performance Scale of
≥50 (if aged ≥16 years and <18 years); Lansky Performance Score of ≥50 (if aged <16
years).

3. Leukemia status:

- Known history of NPM1mt, or KMT2Ar, or NUP98r AML.

- Bone marrow assessment showing no leukemia by morphology (blasts <5%) in first
remission following high intensity chemotherapy or at least 2 cycles of low
intensity therapy (e.g. hypomethylating agent or low-dose cytarabine-based), or
in second remission following any therapy, with MRD ≥ 0.1% identified by
multiparameter flow cytometry using central lab testing.

- No clinically active extramedullary disease.

4. Baseline ejection fraction must be > 40%.

5. Adequate hepatic function (direct bilirubin < 1.5x upper limit of normal (ULN)
unless increase is due leukemic involvement, and AST and/or ALT < 3x ULN unless
considered due to leukemic involvement, in which case direct bilirubin or AST and/or
ALT < 5x ULN will be considered eligible).

6. Adequate renal function with an estimated glomerular filtration rate ≥ 60 mL/min
based on local institutional practice for age-appropriate determination.

7. Able to swallow pills.

8. Participants or parent/guardian is willing and able to provide informed consent.
Interval from prior treatment to time of initiation will be at least 14 days for
cytotoxic or non-cytotoxic (immunotherapy agent(s), or an interval of 5 half-lives
of the prior therapy, whichever is shorter. Concurrent therapy for central nervous
system (CNS) prophylaxis or continuation of therapy for controlled CNS disease is
permitted.

9. Women of childbearing potential must agree to adequate methods of contraception
during the study and at least 3 months after the last treatment. Males must be
surgically or biologically sterile or agree to use an adequate method of
contraception during the study and at least 3 months after the last treatment.

Exclusion Criteria:

1. Prior treatment with a menin inhibitor.

2. Participants who are expected to receive standard therapy (either intensive or
hypomethylating agent and venetoclax) with continued tolerability and benefit.

3. Participants who are expected to be able to proceed with stem cell transplantation
within the next 30 days.

4. Participants with any concurrent uncontrolled medical condition, laboratory
abnormality, or psychiatric illness which could place the patient at unacceptable
risk of study treatment.

5. The use of other chemotherapeutic agents or anti-leukemic agents is not permitted
during study with the following exceptions (1) intrathecal chemotherapy for
prophylactic use or for controlled CNS leukemia. (2) use of hydroxyurea for patients
with rapidly proliferative disease or for control of counts during differentiation
syndrome. (3) use of steroids for treatment of differentiation syndrome.

6. Participants with any severe gastrointestinal or metabolic condition which could
interfere with the absorption of oral study medications.

7. Participants with a concurrent active malignancy under treatment.

8. Known active hepatitis B (HBV) or Hepatitis C (HCV) or HIV infection.

9. Female subjects who are pregnant or breast-feeding.

10. Participant has an active uncontrolled infection.

11. Any of the following within the 6 months prior to study entry: myocardial
infarction, uncontrolled/unstable angina, congestive heart failure (New York Heart
Association Classification Class ≥II), life-threatening, uncontrolled arrhythmia,
cerebrovascular accident, or transient ischemic attack.

12. QTc >450 msec for males and QTc >470 msec for females using the Fridericia Formula.

13. History of or any concurrent condition, therapy, or laboratory abnormality that in
the Investigator's opinion might confound the results of the study, interfere with
the participants's participation for the full duration of the study, or is not in
the best interest of the patient to participate.

14. Clinically active central nervous system (CNS) leukemia.

15. Participants on immunosuppressive therapy post-HSCT at the time of screening (must
be off all systemic immunosuppression therapy for at least 2 weeks and calcineurin
inhibitors for at least 4 weeks). The use of topical steroids for cutaneous
graft-versus-host disease (GVHD) or stable systemic steroid doses less than or equal
to 20 mg of prednisone daily are permitted.

16. Participants with Grade > 2 active acute GVHD, moderate or severe limited chronic
GVHD, or extensive chronic GVHD of any severity.