Ziftomenib in Combination With Chemotherapy for Children With Relapsed/Refractory Acute Leukemia

Inclusion Criteria:

• Age: 0-21 years (and at least 5 kg body weight), with a minimum of 80% ofparticipants under 18 years of age.

• Diagnosis: KMT2A-r, NPM1-m, or NUP98-r acute leukemia in first or greater relapse orrefractory to standard (re-) induction treatment (including HSCT). Please note thatgenetic alteration must be confirmed by the central laboratory, or the participantwill discontinue protocol therapy.

• Eligible participants also must fulfill one of the following conditions:

1. Bone marrow relapse is defined as:
2. A single bone marrow sample showing ≥ 5% leukemic blasts by flowcytometry, fluorescence in situ hybridization (FISH) testing, or othermolecular method.

• a single bone marrow sample with at least two tests showing ≥ 1%leukemic blasts, examples of tests (confirmed by central lab)include: Flow cytometry showing leukemia ≥ 1% by multiparameter flowcytometry (MFC) confirmed by central lab.
• Karyotypic abnormality as confirmed by central cytogenetic review.
• FISH abnormality identical to one present at diagnosis (must be abovelevel of sensitivity of specific FISH probe; central cytogeneticreview required).
• Polymerase chain reaction (PCR) or next generation sequencing (NGS)-based demonstration of validated leukemogenic lesion (e.g.,fusion, mutation) in a Clinical Laboratory Improvement Amendments (CLIA)-approved laboratory that matches initial diagnosis and isquantifiable as ≥1% confirmed by central lab.

2. Participants with combined extramedullary and bone marrow relapse (definedas above) are eligible.

3. Participants with isolated extramedullary disease (EMD) are not eligible.EMD relapse is defined as biopsy-proven extramedullary disease withoutbone marrow disease after documented complete response (CR) followinginitial therapy. Participants with isolated central nervous system (CNS)relapse are not eligible. Participants with a combinedmedullary/extramedullary relapse, including CNS disease, are eligible.

4. Participants with asymptomatic CNS3 disease are eligible if they do nothave isolated CNS3 extramedullary relapse.

5. For participants unable to undergo bone marrow assessment, a peripheralblood absolute blast count ≥ 1,000 cell/microliter is sufficient todiagnose relapsed or refractory disease and facilitate confirmation ofrequired genetic alterations for protocol therapy.

6. Refractory disease/induction failure:

7. Acute myeloid leukemia (AML): The bone marrow contains ≥ 1% leukemicblasts by MFC at the end of 2 cycles of induction therapy.

8. Acute lymphoblastic leukemia (ALL)/mixed-phenotype acute leukemia (MPAL)/acute undifferentiated leukemia (AUL): The bone marrow contains ≥ 1% leukemic blasts by MFC at the end of induction and consolidation, orpersistent MRD prior HSCT (defined as > 0.01%).

9. For participants unable to have bone marrow assessed, a peripheral bloodabsolute blast count ≥ 1,000 cell/microliter is sufficient to diagnoserelapsed or refractory disease.

10. Molecular refractory disease in infant ALL, defined as MRD >0.05% after primaryinduction and consolidation therapy measured by MFC or PCR.

• Performance status: Participants must have a performance status corresponding toEastern Cooperative Oncology Group (ECOG) scores of 0, 1 or 2 (≥ 50% Lansky orKarnofsky score). Use ECOG for adult participants (≥18 to 21 years), Karnofsky forparticipants ≥16 to 18 years of age, and Lansky for participants < 16 years of age.Participants who are unable to walk because of paralysis, but who are up in awheelchair, will be considered ambulatory for the purpose of assessing theperformance score.

• Adequate organ function:

1. Renal function defined as: Creatinine clearance (CrCl) ≥60 mL/min (as measuredby a nuclear glomerular filtration rate [GFR] scan or calculated by theSchwartz formula and normalized to a body surface area of 1.73 m^2).

2. Liver function defined as:

3. Direct bilirubin < 3 x upper limit of normal (ULN) and Serum glutamicpyruvic transaminase (SGPT) (alanine transaminase [ALT]) ≤ 5 x ULN.

4. If liver abnormality is due to radiographically identifiable leukemiainfiltrate, the participant will remain eligible.

5. Cardiac function defined as: Pre-treatment left ventricular function onechocardiography: Fractional shortening (FS) ≥ 25% or ejection fraction (EF) ≥ 40%, and no signs of congestive heart failure within 4 weeks before start ofscreening.

• Prior therapy: Participants must have recovered from the acute toxic effects of allprior anti-cancer therapy (excluding Grade 2 toxicities that are not considered asafety risk or medically significant toxicity deemed irreversible by theInvestigator) and must meet the following minimum duration from prior anti-cancerdirected therapy prior to enrollment.

1. Cytotoxic chemotherapy: Must not have received within 14 days or within 5 drughalf-lives (whichever is longer), of entry onto this study, except forhydroxyurea or corticosteroids. Use of steroids and hydroxyurea for otherpurposes such as differentiation syndrome, or to premedication to preventallergic reaction or during anesthesia is allowed.

2. Intrathecal cytotoxic therapy: No washout or waiting period is required forparticipants having received any combination of intrathecal cytarabine,methotrexate, and/or hydrocortisone.

3. Antibodies: ≥ 21 days must have elapsed from infusion of last dose of anantibody-drug conjugate. For unmodified antibodies or T cell engagingantibodies, 2 half-lives must have elapsed before enrollment. Any toxicityrelated to prior antibody therapy must be recovered back to baseline.

4. Interleukins, interferons and cytokines (other than hematopoietic growthfactors): ≥ 21 days after the completion of interleukins, interferon orcytokines (other than hematopoietic growth factors).

5. Hematopoietic growth factors: ≥ 14 days after the last dose of a long-actinggrowth factor (e.g., peg-filgrastim) or 7 days for short-acting growth factor.

6. Radiation therapy (RT): 14 days have elapsed for local palliative RT (smallport); ≥ 84 days must have elapsed if prior craniospinal RT or if ≥ 50%radiation of pelvis; ≥ 42 days must have elapsed if other substantial bonemarrow (BM) radiation.

7. Stem cell infusions:

8. Participants who have relapsed after allogeneic (non-autologous) BM orstem cell transplant (with or without total body irradiation [TBI]) orboost infusion (any stem cell product; not including donor lymphocyteinfusion [DLI]) must be at least 84 days post HSCT and without evidence ofgraft versus host disease (GVHD) of any severity except: the use oftopical steroids for cutaneous GVHD is allowed and stable steroid dosesless than or equal to 10 mg of prednisone daily is permitted. Prednisonedose must be adjusted for body surface area (BSA) in young children.Physiologic doses of hydrocortisone for participants with adrenalinsufficiency is allowed.

9. Participants who after relapse and continue to receive cyclosporine,tacrolimus or other agents to treat or prevent either GVHD post BMtransplant or organ rejection post-transplant are not eligible for thistrial. In the relapse setting, participants must be off medications totreat or prevent either GVHD post BM transplant or organ rejectionpost-transplant for at least 14 days prior to enrollment. A stable steroiddose as mentioned above is allowed.

10. Cellular therapy: ≥ 30 days after the completion of DLI or any type of cellularTherapy (e.g., modified T cells, NK cells, dendritic cells, etc.).

11. Prior exposure to a different menin inhibitor: Participants who receivedprevious treatment with a different menin inhibitor are allowed to enrol in thestudy with the exception of those who experienced a severe adverse eventattributable to the strong anti-proliferative/pro-differentiation effects ofother menin inhibitors (such as severe differentiation syndrome). Participantswho experienced a severe adverse event, which can directly be attributed tospecific effects (e.g., long QT syndrome) observed with other menin inhibitorscan participate in the study if they fulfill the inclusion criteria.

• Informed consent: Written, signed and dated informed consent and pediatric assent (if applicable) according to local law and legislation should be collected beforestart of any study procedures.

• Female participants of childbearing potential must have a negative urine or serumpregnancy test confirmed prior to enrollment.

• Female participants with infants must agree not to breastfeed their infants while onthis study.

• Contraception:

1. Participants of reproductive potential, starting from menarche and onwards, maynot participate unless they have agreed to use a highly effective contraceptivemethod per Clinical Trial Facilitation Group (CTFG) guidelines for the durationof study therapy and for 6 months after the completion of all study therapy.For further guidance please review the CTFG website.

2. Male participants must use a condom during intercourse and agree not to fathera child or donate sperm during therapy and for the duration of study therapyand for 4 months after the completion of all study therapy.

• Enrollment APAL2020SC trial (US and Canada only): Participants in the US and Canadamust have enrolled in the APAL2020SC trial prior to enrollment in the APAL2020Ktrial.

Exclusion Criteria:

• Participants who in the opinion of the investigator may not be able to comply withthe study requirements of the study.

• Participants with Down syndrome.

• Participants with EMD are not eligible. EMD relapse is defined as biopsy provenextramedullary disease without bone marrow disease after documented CR followinginitial therapy.

• Participants with isolated CNS relapse are not eligible, as well as symptomatic CNS3disease.

• Participants with acute promyelocytic leukemia (APL) or juvenile myelomonocyticleukemia (JMML).

• Participants with malabsorption syndrome or any other condition that precludesenteral administration of a menin inhibitor.

• Concomitant therapy: Gastric pH has great influence on absorption of ziftomenib;therefore, the use of proton pump inhibitors is prohibited, if necessary H2 Blockersmay provide an alternative treatment option.

• Participants who are currently receiving another investigational drug.

• Participants with any known congenital bone marrow failure syndrome.

• Participants with known prior allergy to any of the medications used in protocoltherapy.

• Participants with documented active, uncontrolled infection at the time of studyentry.

• Active/uncontrolled known human immunodeficiency virus (HIV) infection, hepatitis Bvirus (HBV) and hepatitis C virus (HCV). Note: HIV testing does not need to beconducted at screening unless it is required per local guidelines or institutionalstandard.

• Post menarche female participants with positive pregnancy test, and a lactatingfemale participant.

• Participant has a pre-existing disorder predisposing the participant to a serious orlife-threatening infection (e.g., cystic fibrosis, congenital or acquiredimmunodeficiency, bleeding disorder, or cytopenia not related to the leukemia or itstreatment).

• Participants must not be receiving other investigational medications (defined asmedicinal products not yet approved for any indications, includingalternative/herbal therapies) within 30 days of first dose of study drug or while onstudy.

• Significant congenital cardiovascular disease including, but not limited toconditions such as long QT syndrome, fundamental uncorrected cardiac defect (e.g.,coarctation of the aorta) that poses a significant risk to the participant (ventricular septal defect or atrial septal defect are considered non-significant).

• Underlying medical condition that, in the Principal Investigator's opinion, willmake the administration of study treatment hazardous or obscure the interpretationof toxicity determination or AEs.

• For fludarabine and cytarabine: Hypersensitivity to the active substance or to anyof the excipients.

• Recent live vaccinations for at least 6 months.