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

Study Overview
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Brief Summary
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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 RP2D.

Detailed Description
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Patients will receive revumenib + azacitidine + venetoclax in a dose-escalation fashion. The doses of revumenib and azacitidine will remain constant, while the duration of exposure to venetoclax will be escalated or de-escalated. Patients may continue to receive therapy if there is clinical benefit and no unacceptable toxicity. Patients who achieve complete response (CR) or Complete remission with incomplete blood count recovery (CRi) and subsequently undergo HCT may remain on study. Revumenib, with or without azacitidine and venetoclax, may be resumed after transplant if the patient is at least 60 days post-transplant, remains in CR or CRi, has engrafted, and does not have Grade ≥2 acute graft versus host disease. In the absence of toxicity, revumenib may be continued for a maximum of 12 months. Patients are followed for 30 days after completion of study treatment.

Official Title
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A Phase 1 Study of Revumenib, Azacitidine, and Venetoclax in Pediatric and Young Adult Patients With Refractory or Relapsed Acute Myeloid Leukemia

Conditions
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Refractory Acute Myeloid Leukemia, Relapsed Acute Myeloid Leukemia, Acute Leukemia of Ambiguous Lineage

Intervention / Treatment
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* Drug: Revumenib
* Drug: Venetoclax
* Drug: Azacitidine
* Drug: intrathecal (IT) chemotherapy
* Drug: Cytarabine
* Drug: Methotrexate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants must have a diagnosis of AML or ALAL and meet the criteria below: Refractory leukemia, defined as persistent leukemia (≥1% blasts confirmed by flow cytometry or molecular testing) after at least two courses of induction chemotherapy, or relapsed leukemia, defined as the re-appearance of leukemia (≥1% blasts confirmed by flow cytometry or molecular testing) after the achievement of remission 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 direct bilirubin ≤ 1.5 x institutional upper limit of normal, normal creatinine for age, and left ventricular ejection fraction ≥ 40% QTcF < 480 msec 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 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). 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. 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.

Ages Eligible for Study
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Minimum Age: 1 Year
Maximum Age: 30 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: Participants with relapsed or refractory acute myeloid leukemia (AML) or acute leukemia of ambiguous lineage (ALAL) who meet the eligibility criteria.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: All Eligible Participants<br>All eligible patients receive the following intervention: Revumenib, Venetoclax, Azacitidine, Intrathecal chemotherapy | Drug: Revumenib<br>* Given by mouth (capsule or liquid solution) or liquid solution by Nasogastric tube (NG) or Gastrostomy tube (G-tube)<br>* Other names: SNDX-5613;Drug: Venetoclax<br>* Given by mouth (tablet)<br>* Other names: Venclextra®;Drug: Azacitidine<br>* Given intravenously (IV) infusion<br>* Other names: 5-azacitidine;Drug: intrathecal (IT) chemotherapy<br>* Given intrathecal (IT)<br>* Other names: methotrexate/hydrocortisone/cytarabine;Drug: Cytarabine<br>* Given intrathecal (IT) as part of intrathecal (IT) chemotherapy.<br>* Other names: Cytosar®;Drug: Methotrexate<br>* Given intrathecal (IT) as part of intrathecal (IT) chemotherapy.<br>* Other names: Trexall®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The safety and tolerability of revumenib + azacitidine + venetoclax in pediatric patients with relapsed or refractory AML or ALAL | The primary endpoint is the recommended phase 2 dose (RP2D) of revumenib + azacitidine + venetoclax. | 43 days from the start of therapy. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The rates of complete remission (CR) | 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. | 43 days from the start of therapy | 
| The rates of complete remission with incomplete count recovery (CRi) | CRi is defined as bone marrow with <5% blasts confirmed by flow cytometry and ANC <500/μL or platelets <50,000/μL without transfusions | 43 days from the start of therapy | 
| The overall survival of patients treated at the RP2D. | Kaplan-Meier estimates with 95% confidence intervals will be used to describe overall survival. | 1 year |