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Revumenib, Azacitidine, and Venetoclax for the Treatment of Pediatric and Young Adult Patients with Refractory or Relapsed Acute Myeloid Leukemia or Acute Leukemia of Ambiguous Lineage
Trial Status: active
This phase I trial tests the safety, side effects and effectiveness of revumenib, azacitidine and venetoclax for the treatment of pediatric and young adult patients with acute myeloid leukemia (AML) or acute leukemia of ambiguous lineage (ALAL) that has not responded to previous treatment (refractory) or that has come back after a period of improvement (relapsed). Revumenib works by blocking the action of an abnormal protein that signals cancer cells to multiply, which may help keep cancer cells from growing. Chemotherapy drugs, such as azacitidine, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Venetoclax is in a class of medications called B-cell lymphoma-2 (BCL-2) inhibitors. It may stop the growth of cancer cells by blocking Bcl-2, a protein needed for cancer cell survival. Giving revumenib, azacitidine and venetoclax may work better to treat pediatric and young adult patients with relapsed or refractory AML or ALAL.
Inclusion Criteria
Refractory leukemia, defined as persistent leukemia after at least two courses of induction chemotherapy, or relapsed leukemia, defined as the re-appearance of leukemia after the achievement of remission. Patients must have ≥ 5% blasts in the bone marrow as assessed by morphology or ≥1% blasts flow cytometry. However, if an adequate bone marrow sample cannot be obtained (e.g., in a patient with acute megakaryoblastic leukemia with marrow fibrosis), patients may be enrolled if there is unequivocal evidence of leukemia with ≥5% blasts by morphology or ≥ 1% blasts flow cytometry in the blood
Presence of KMT2A rearrangement (KMT2Ar), NUP98 rearrangement (NUP98r), NPM1 mutation or fusion, PICALM::MLLT10, DEK::NUP214, UBTF-TD, KAT6A::CREBBP, or SET::NUP214
Total bilirubin < 1.5 x institutional upper limit of normal for age or normal conjugated bilirubin (for patients with known Gilbert’s syndrome, total bilirubin < 3 × the ULN) unless attributed to leukemia
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 who are > 16 years old
At least 14 days or 5 half-lives (whichever is longer) must have elapsed since the completion of myelosuppressive therapy, with the exception of low-dose therapy used for cytoreduction according to institutional standards, such as hydroxyurea or low-dose cytarabine (up to 200 mg/m^2/day). In addition, all toxicities must have resolved to grade 1 or less
Patients must have a leukocyte count < 25,000 cells/uL. Low-dose therapy, such as hydroxyurea or cytarabine as described above, to achieve this limit is acceptable
For patients who have received prior hematopoietic stem cell transplant (HCT), there can be no evidence of graft versus host disease (GVHD) greater than 60 days must have elapsed since the HCT and patients should be off calcineurin 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 the duration of study participation
Patients must be able to swallow tablets
Exclusion Criteria
Patients who are pregnant or breastfeeding are not eligible
Patients with Down syndrome, acute promyelocytic leukemia, juvenile myelomonocytic leukemia, or bone marrow failure syndromes are not eligible
Patients with uncontrolled infection are not eligible. Patients with infections that are controlled on concurrent anti-microbial agents are eligible
Additional locations may be listed on ClinicalTrials.gov for NCT06177067.
I. To determine the safety and tolerability of revumenib + azacitidine + venetoclax in pediatric patients with relapsed or refractory AML or ALAL.
SECONDARY OBJECTIVE:
I. 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).
EXPLORATORY OBJECTIVES:
I. Explore associations between leukemia cell genomics and BH3 profiling and response to therapy as assessed by molecular measurable residual disease (MRD) and variant clearance using cell-free DNA (cfDNA).
II. Identify transcriptional signatures that are associated with response to therapy and resistance to therapy, including a characterization of the non-tumor microenvironment.
III. Establish xenografts of high-risk AML and ALAL to evaluate the response to individual agents and clonal progression.
OUTLINE: This is a dose-escalation study of revumenib in combination with (fixed-dose) venetoclax and azacitadine. Patients are assigned to 1 of 3 arms.
ARM I: Patients receive lower dose revumenib orally (PO) twice per day (BID) on days 1-29, venetoclax PO once per day (QD) on days 2-14 on cycle 1 and days 1-14 on all subsequent cycles, and azacitidine intravenously (IV), over 10-40 minutes, on days 1-7 of each cycle. Cycles repeat every 29 days in the absence of disease progression, unacceptable toxicity or receipt of hematopoietic cell transplant (HCT). Patients may receive methotrexate intrathecally (IT), hydrocortisone IT or cytarabine IT if IT chemotherapy was not given prior to cycle 1 or at the discretion of the treating physician. Patients with central nervous system disease receive IT methotrexate, hydrocortisone and cytarabine weekly, starting on cycle 1 day 8, until the cerebrospinal fluid is cleared of disease. Patients undergo echocardiography and lumbar puncture during screening, and bone marrow aspiration and biopsy and blood sample collection throughout the study.
ARM II: Patients receive lower dose revumenib PO BID on days 1-29, venetoclax PO QD on days 2-21 on cycle 1 and days 1-21 on all subsequent cycles, and azacitidine IV, over 10-40 minutes, on days 1-7 of each cycle. Cycles repeat every 29 days in the absence of disease progression, unacceptable toxicity or receipt of HCT. Patients may receive methotrexate IT, hydrocortisone IT or cytarabine IT if IT chemotherapy was not given prior to cycle 1 or at the discretion of the treating physician. Patients with central nervous system disease receive IT methotrexate, hydrocortisone and cytarabine weekly, starting on cycle 1 day 8, until the cerebrospinal fluid is cleared of disease. Patients undergo echocardiography and lumbar puncture during screening, and bone marrow aspiration and biopsy and blood sample collection throughout the study.
ARM III: Patients receive higher dose revumenib PO BID on days 1-29, venetoclax PO QD on days 2-21 on cycle 1 and days 1-21 on all subsequent cycles, and azacitidine IV, over 10-40 minutes, on days 1-7 of each cycle. Cycles repeat every 29 days in the absence of disease progression, unacceptable toxicity or receipt of HCT. Patients may receive methotrexate IT, hydrocortisone IT or cytarabine IT if IT chemotherapy was not given prior to cycle 1 or at the discretion of the treating physician. Patients with central nervous system disease receive IT methotrexate, hydrocortisone and cytarabine weekly, starting on cycle 1 day 8, until the cerebrospinal fluid is cleared of disease. Patients undergo echocardiography and lumbar puncture during screening, and bone marrow aspiration and biopsy and blood sample collection throughout the study.
After completion of study treatment, patients are followed up according to the investigator’s discretion or every 30 days until any toxicities resolve.
Trial PhasePhase I
Trial Typetreatment
Lead OrganizationSaint Jude Children's Research Hospital
