Combining venetoclax and revumenib to treat acute myeloid leukemia

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

This study is testing a new combination of two drugs, venetoclax and revumenib, to see if it can help people with acute myeloid leukemia who still have some cancer cells left after treatment.

Quick facts

• Phase: Phase1; Phase2
• Study type: Interventional
• Enrollment: 8 (estimated)
• Ages: 12 Years and up
• Sex: All
• Sponsor: M.D. Anderson Cancer Center (Academic / other)
• Drugs / interventions: chemotherapy, immunotherapy, prednisone
• Locations: 4 sites (Baltimore, Maryland and 3 other locations)
• Trial ID: NCT06284486 on ClinicalTrials.gov

What this trial studies

This clinical trial investigates the safety and efficacy of a combination therapy using venetoclax and revumenib for patients with acute myeloid leukemia (AML) who have detectable minimal residual disease (MRD). The study is divided into two phases: the first phase focuses on determining the recommended dose and safety of the treatment, while the second phase assesses its effectiveness in clearing MRD. Additionally, the trial aims to evaluate overall survival and other clinical outcomes, as well as explore potential predictive markers of treatment response.

Who should consider this trial

Good fit: Ideal candidates include individuals aged 12 and older with specific genetic mutations in AML and detectable MRD after initial treatment.

Not a fit: Patients with active extramedullary disease or those who do not meet the specific genetic and health criteria may not benefit from this study.

Why it matters

Potential benefit: If successful, this treatment could significantly improve outcomes for patients with MRD-positive AML by effectively clearing residual disease.

How similar studies have performed: Other studies have shown promising results with similar dual inhibition approaches in hematologic malignancies, suggesting potential for success in this trial.

Eligibility criteria

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.

Where this trial is running

Baltimore, Maryland and 3 other locations

• Johns Hopkins University — Baltimore, Maryland, United States (Recruiting)
• Dana-Farber Cancer Center — Boston, Massachusetts, United States (Recruiting)
• Memorial Sloan Kettering Cancer Center — New York, New York, United States (Recruiting)
• MD Anderson Cancer Center — Houston, Texas, United States (Recruiting)

Study contacts

• Principal investigator: Ghayas Issa, MD — M.D. Anderson Cancer Center
• Study coordinator: Ghayas Issa, MD

Conditions Acute Myeloid Leukemia