Study of Revumenib, Azacitidine, and Venetoclax in Pediatric and Young Adult Patients With Refractory or Relapsed Acute Myeloid Leukemia

Last updated: April 15, 2025
Sponsor: St. Jude Children's Research Hospital
Overall Status: Active - Recruiting

Phase

1

Condition

Leukemia

Treatment

Revumenib

Cytarabine

Venetoclax

Clinical Study ID

NCT06177067
RAVAML
NCI-2023-10509
  • Ages 1-30
  • All Genders

Study Summary

This is a research study to find out if adding a new study drug called revumenib to commonly used chemotherapy drugs is safe and if they have beneficial effects in treating patients with acute myeloid leukemia (AML) or acute leukemia of ambiguous lineage (ALAL) that did not go into remission after treatment (refractory) or has come back after treatment (relapsed), and to determine the total dose of the 3-drug combination of revumenib, azacitidine and venetoclax that can be given safely in participants also taking an anti-fungal drug.

Primary Objective

  • To determine the safety and tolerability of revumenib + azacitidine + venetoclax in pediatric patients with relapsed or refractory AML or ALAL.

Secondary Objectives

  • Describe the rates of complete remission (CR), complete remission with incomplete count recovery (CRi), and overall survival for patients treated with revumenib + azacitidine + venetoclax at the recommended phase 2 dose (RP2D).

Eligibility Criteria

Inclusion

Inclusion Criteria: Participants must have a diagnosis of AML or ALAL and meet the criteria below:

  • Refractory leukemia, defined as persistent leukemia after at least two courses ofinduction chemotherapy, or relapsed leukemia, defined as the re-appearance ofleukemia after the achievement of remission. Patients must have ≥5% blasts in thebone marrow as assessed by morphology or ≥1% blasts flow cytometry. However, if anadequate bone marrow sample cannot be obtained (e.g., in a patient with acutemegakaryoblastic leukemia with marrow fibrosis), patients may be enrolled if thereis unequivocal evidence of leukemia with ≥5% blasts by morphology or ≥1% blasts flowcytometry in the blood.

  • Presence of KMT2A rearrangement (KMT2Ar), NUP98 rearrangement (NUP98r), NPM1mutation or fusion, PICALM::MLLT10, DEK::NUP214, UBTF-TD, KAT6A::CREBBP, orSET::NUP214

  • Adequate organ function, defined as total bilirubin < 1.5 × institutional upperlimit of normal for age or normal conjugated bilirubin (for patients with knownGilbert's syndrome, total bilirubin <3 × the ULN) unless attributed to leukemia,calculated creatinine clearance ≥60 mL/min/1.73 m^2, and left ventricular ejectionfraction ≥ 40%

  • QTcF < 480 msec (average of triplicate)

  • Age ≥ 1 year and ≤ 30 years. The upper age limit may be defined by each institution,but may not exceed 30 years.

  • Lansky ≥ 60 for patients who are < 16 years old and Karnofsky ≥ 60% for patients whoare > 16 years old.

  • At least 14 days or 5 half-lives (whichever is longer) must have elapsed since thecompletion of myelosuppressive therapy, with the exception of low-dose therapy usedfor cytoreduction according to institutional standards, such as hydroxyurea orlow-dose cytarabine (up to 200 mg/m^2/day). In addition, all toxicities must haveresolved to grade 1 or less.

  • Patients must have a leukocyte count <25,000 cells/uL. Low-dose therapy, such ashydroxyurea or cytarabine as described above, to achieve this limit is acceptable.

  • For patients who have received prior HCT, there can be no evidence of GVHD andgreater than 60 days must have elapsed since the HCT, and patients should be offcalcineurin inhibitors for at least 28 days prior to the start of protocol therapy.Physiologic prednisone for the treatment of adrenal insufficiency is acceptable..

  • Patients must be taking posaconazole or voriconazole, which must be started at least 24 hours prior to the start of therapy.

  • Patients of reproductive potential must agree to use effective contraception for theduration of study participation.

  • Patients must be able to swallow tablets.

Patients who meet the criteria listed above are eligible for enrollment and treatment on the trial. However, patients in first relapse who are suitable for and willing to receive intensive remission induction therapy should be offered such therapy if deemed appropriate by the treating physician.

Exclusion

Exclusion Criteria:

  • Patients who are pregnant or breastfeeding are not eligible.

  • Patients with Down syndrome, acute promyelocytic leukemia, juvenile myelomonocyticleukemia, or bone marrow failure syndromes are not eligible.

  • Patients with uncontrolled infection are not eligible. Patients with infections thatare controlled on concurrent anti-microbial agents are eligible.

Study Design

Total Participants: 24
Treatment Group(s): 6
Primary Treatment: Revumenib
Phase: 1
Study Start date:
April 19, 2024
Estimated Completion Date:
July 31, 2026

Study Description

Patients will receive revumenib + azacitidine + venetoclax in a dose-escalation fashion. The protocol starts at dose level 1. If there are no dose limiting toxicities at dose level 1, then patients will be treated at dose level 2, which equates to the dose of revumenib increasing from 65 to 90 mg/m^2 while the venetoclax exposure remains the same at 21 days. Alternatively, if there are dose limiting toxicities at dose level 1, then the dose level will be deescalated to dose level -1, which equates to the length of exposure of venetoclax being decreased from 21 days to 14 days, while the dose of revumenib stays at 65 mg/m^2. The doses of azacitidine will remain constant at all dose levels.

For patients whose primary physician considers that single agent revumenib is beneficial (e.g., transition to hematopoietic cell transplant), revumenib can be continued after discussing with study principal investigator. Patients who undergo HCT will be taken off therapy at the time of HCT, but will remain on study. Post-transplant therapy will be determined by the HCT physician.

Patients who do not go on to receive an HCT, may continue to receive revumenib, venetoclax and azacitidine as long as their primary physician considers it beneficial and there are no unacceptable side effects.

Connect with a study center

  • Children's Mercy Hospital of Kansas City

    Kansas City, Missouri 64108
    United States

    Active - Recruiting

  • Memorial Sloan- Kettering Cancer Center

    New York, New York 10065
    United States

    Active - Recruiting

  • Cincinnati Children's Hospital Medical Center

    Cincinnati, Ohio 45229
    United States

    Active - Recruiting

  • St. Jude Children's Research Hospital

    Memphis, Tennessee 38105
    United States

    Active - Recruiting

  • UT Southwestern/Simmons Cancer Center

    Dallas, Texas 75390
    United States

    Active - Recruiting

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