Study of Revumenib, Azacitidine, and Venetoclax in Pediatric and Young Adult Patients With Refractory or Relapsed Acute Myeloid Leukemia
- Conditions
- Relapsed Acute Myeloid LeukemiaRefractory Acute Myeloid LeukemiaAcute Leukemia of Ambiguous Lineage
- Interventions
- Drug: intrathecal (IT) chemotherapy
- Registration Number
- NCT06177067
- Lead Sponsor
- St. Jude Children's Research Hospital
- Brief 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).
- Detailed 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.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 24
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 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
- Adequate organ function, defined as total bilirubin < 1.5 × 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, calculated creatinine clearance ≥60 mL/min/1.73 m^2, and left ventricular ejection fraction ≥ 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 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 HCT, there can be no evidence of GVHD and 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.
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.
- 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.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description All Eligible Participants intrathecal (IT) chemotherapy All eligible patients receive the following intervention: Revumenib, Venetoclax, Azacitidine, Intrathecal chemotherapy All Eligible Participants Venetoclax All eligible patients receive the following intervention: Revumenib, Venetoclax, Azacitidine, Intrathecal chemotherapy All Eligible Participants Revumenib All eligible patients receive the following intervention: Revumenib, Venetoclax, Azacitidine, Intrathecal chemotherapy All Eligible Participants Azacitidine All eligible patients receive the following intervention: Revumenib, Venetoclax, Azacitidine, Intrathecal chemotherapy All Eligible Participants Methotrexate All eligible patients receive the following intervention: Revumenib, Venetoclax, Azacitidine, Intrathecal chemotherapy All Eligible Participants Cytarabine All eligible patients receive the following intervention: Revumenib, Venetoclax, Azacitidine, Intrathecal chemotherapy
- Primary Outcome Measures
Name Time Method The safety and tolerability of revumenib + azacitidine + venetoclax in pediatric patients with relapsed or refractory AML or ALAL 43 days from the start of therapy. The primary endpoint is the recommended phase 2 dose (RP2D) of revumenib + azacitidine + venetoclax.
- Secondary Outcome Measures
Name Time Method The overall survival of patients treated at the RP2D. 1 year Kaplan-Meier estimates with 95% confidence intervals will be used to describe overall survival.
The rates of complete remission (CR) 43 days from the start of therapy CR is defined as bone marrow with \< 5% blasts confirmed by flow cytometry, ANC ≥500/μL and platelets ≥50,000/μL without transfusions, and no evidence of extramedullary disease.
The rates of complete remission with incomplete count recovery (CRi) 43 days from the start of therapy CRi is defined as bone marrow with \<5% blasts confirmed by flow cytometry and ANC \<500/μL or platelets \<50,000/μL without transfusions
Trial Locations
- Locations (5)
Children's Mercy Hospital of Kansas City
🇺🇸Kansas City, Missouri, United States
Memorial Sloan- Kettering Cancer Center
🇺🇸New York, New York, United States
Cincinnati Children's Hospital Medical Center
🇺🇸Cincinnati, Ohio, United States
UT Southwestern/Simmons Cancer Center
🇺🇸Dallas, Texas, United States
St. Jude Children's Research Hospital
🇺🇸Memphis, Tennessee, United States