Revumenib Treatment in Combination with FLA Chemotherapy in Paediatric Refractory/Relapsed KMT2A-r, NUP98-r or NPM1-mut Acute Myeloid Leukemia (AML)

Prior treatment

• Patients who are currently receiving another investigational drug.
• Patients who are receiving cyclosporine, tacrolimus or other agents to prevent either graft-versus-host disease post bone marrow transplant or organ rejection post-transplant. Patients with active GVHD (other than Grade 1 skin GVHD).
• Patients who are receiving any strong CYP3A4 inhibitors other than itraconazole, ketoconazole, posaconazole, or voriconazole.
• Patients who are receiving any strong or moderate CYP3A4 inducers while on study or within 14 days of starting revumenib.
• Patients known to have one of the following concomitant genetic syndromes: Bloom syndrome, ataxia-telangiectasia, Fanconi anemia, Kostmann syndrome, Shwachman syndrome or any other known bone marrow failure syndrome.
• Patients who have ever used revumenib or any other menin inhibitor.
• Patients with gastrointestinal issues of the upper gastrointestinal tract that might affect oral drug absorption.

Other illness

• Patients with isolated extramedullary disease.
• Hypersensitivity or allergy to the active substance or other excipients contained in the investigational medical product listed in the Summary of Product Characteristics (SmPC) or Investigators Brochure (IB).
• Patients with documented active, uncontrolled infection at the time of study entry.
• Patients with Down Syndrome.
• Patients with a secondary KMT2A-R, NPM1 or NUP98-r leukemia that developed after treatment of prior malignancy with cytotoxic chemotherapy.

Lab values

• Patients who are receiving medications known to prolong the QT/QTc interval (exception of drugs with low risk of QT/QTc prolongation that are used as standard supportive therapies, e.g, diphenhydramine, famotidine, granisetron).
• Patients with a history of congenital prolonged QT syndrome, congestive heart failure or uncontrolled arrhythmia in the past 6 months prior to study enrolment.

Other

• Female patients who are pregnant or breastfeeding.
• Female and male subjects with child bearing potential who avoid using highly effective anticonceptive measure(ment)s.
• Patients whose baseline QTcF >450ms.
• Patients with known partial duplication of KMT2A (MLL-PTD).
• Patients with known Mixed Lineage Leukemia.

• Patients must be > 30 days and ≤ 18 years of age at time of enrollment.
• Patients must have a performance status ≥50% Lansky or Karnofsky score.
• Patients may have status of CNS1, CNS2, CNS3 disease without clinical signs or neurologic symptoms suggestive of CNS leukemia, such as facial nerve palsy, brain/eye involvement or hypothalamic syndrome.
• Patients must have fully recovered from the acute toxic effects of all prior anti-cancer therapy.
• Patients must have adequate renal, liver and cardiac function
• Patients must have R/R KMT2A-translocation (KMT2A-r), NUP98-rearrangement (NUP98-r) or NPM1-mutation (NPM1-mut AML). History of known KMT2A-r, NUP98-r or NPM1-mut is sufficient. Definition of refractory/relapsed disease (patient must have one of the following): primary refractory disease (≥ 5% leukemic blasts) after 2 cycles of induction, or first recurrent disease (≥ 5% leukemic blasts) after having achieved remission (ped-morph-CR).
• ≥21 days must have elapsed since the patient’s last prior anti-cancer therapy (e.g., chemotherapy), except for protocol-defined pre-phase treatment, which is permitted regardless of the timing.
• ≥ 84 days since allogeneic (non-autologous) bone marrow or stem cell transplant (with or without TBI) or boost infusion (any stem cell product; not including DLI); No evidence of graft versus host disease (GVHD) with the exception of Grade 1 skin GVHD being treated by topical treatment.
• Cellular Therapy: ≥ 28 days after the completion of DLI (donor lymphocyte infusion) or any type of cellular therapy (e.g. modified T cells, NK cells, dendritic cells, etc.).
• Understand and voluntarily provide written permission of parental/legal representative(s) to the ICF prior to conducting any trial related assessments/procedures, also concerning data and biomaterial transfer according to ICH/GCP and national/local regulations.
• Able to adhere to the trial visit schedule and other protocol requirements.
• Negative serum pregnancy tests for females of child-bearing potential within 10 days prior to treatment.
• White Blood Cell (WBC): Count must be < 25.000/µL prior to enrolment. Patients may receive cytoreduction with hydroxyurea or low-dose cytarabine (max. 100mg/m² per day) prior to enrollment.