A Phase 2 Study of SNDX-5613 in Combination with Chemotherapy for Patients with Relapsed or Refractory KMT2A-Rearranged Infant Leukemia.

Inclusion Criteria

- Patients must be 1 month to < 6 years old at the time of study enrollment and must

have had initial diagnosis of leukemia at < 2 years old.

- Patients must have KMT2A-rearranged acute lymphoblastic leukemia (ALL), acute leukemia

of ambiguous lineage (ALAL), or mixed phenotype acute leukemia (MPAL), which is

determined to be refractory or in first marrow relapse. All patients must undergo

cytogenetics and fluorescence in situ hybridization (FISH) testing of a

relapsed/refractory blast sample at a Children's Oncology Group (COG)-approved

laboratory for KMT2A-R status determination and the presence of a KMT2A- rearrangement

must be confirmed by central review. Cytogenetics results must be submitted for

central review by Day 10 of protocol therapy, for confirmation of KMT2A-R status.

Patients enrolled with refractory disease may utilize initial diagnostic cytogenetics

for eligibility and submission for central review if testing was performed at a COG

approved laboratory. Patients will be eligible to remain on protocol therapy if

KMT2A-R is confirmed by central review. Additional methods of assessing for KMT2A-R

may be considered if FISH does not detect the rearrangement.

- Disease status at time of enrollment must be one of the following:

- First relapse: Any recurrence of marrow disease, with or without other

extramedullary sites(s), at any point after achieving remission. ("Remission-1",

per definition below) meeting one of these criteria:

- Relapse M1: M1 morphology (< 5% blasts) + at least 2 confirmatory tests

showing >= 1% blasts (testing includes flow, cytogenetics, polymerase chain

reaction [PCR]/next-generation sequencing [NGS] of immunoglobulin

[Ig]/T-cell receptor [TCR] rearrangement, and/or PCR or NGS of fusion gene

identical to diagnosis), OR

- Relapse M2: M2 morphology (5-25% blasts) + 1 confirmatory test showing > 1%

blasts, OR

- Relapse M3: M3 morphology (> 25% blasts)

- Refractory, or failure to achieve Remission-1: Remission-1 is defined as < 1%

marrow blasts by flow minimal residual disease (MRD) and resolution of

extramedullary disease by the end of Consolidation, or 2 courses of frontline

chemotherapy.

- Central Nervous System (CNS) disease: Patients must have CNS1 or CNS2 status and no

clinical signs or neurologic symptoms suggestive of CNS leukemia, such as cranial

palsy.

- Patients with CNS3 disease may receive antecedent intrathecal chemotherapy to

achieve CNS1 or CNS2 status prior to enrollment.

- Patients with a history of CNS chloromatous disease are required to have no

radiographic evidence of CNS disease prior to enrollment.

- White blood cell (WBC) must be < 50,000/uL at the time of study enrollment. Patients

can receive cytoreduction with hydroxyurea and/or corticosteroids for up to 7 days

prior to enrollment.

- Patients >= 12 months of age must have a performance status by Lansky Scale of >= 50%.

- Patients must be able to take enteral medications. Acceptable routes of administration

for SNDX-5613 include: oral (PO), nasogastric (NG) tube, nasojejunal (NJ) tube,

nasoduodenal (ND), and gastrostomy tube (G-tube).

- Patients must have fully recovered from the acute toxic effects of all prior

chemotherapy, immunotherapy, or radiotherapy prior to entering this study

- Cytotoxic chemotherapy or other anti-cancer agents known to be myelosuppressive:

- >= 14 days must have elapsed after the completion of other cytotoxic

therapy, including patients who relapse during pre-Maintenance upfront

therapy, with these specific exceptions: cytoreduction with hydroxyurea

and/or corticosteroids, and intrathecal chemotherapy, which have no required

washout periods. For patients who relapse during upfront Maintenance

therapy, >= 7 days must have elapsed after the last dose of chemotherapy.

Additionally, patients must have fully recovered from all acute toxic

effects of prior therapy.

- NOTE: Cytoreduction with hydroxyurea and/or corticosteroids is

permitted prior to enrollment for patients with WBC >= 50,000/uL, and

by provider discretion regardless of WBC, to reduce potential risk of

differentiation syndrome with SNDX-5613 initiation. Hydroxyurea and/or

corticosteroids may be given for up to 7 days, with no wash-out

required.

- NOTE: No waiting period is required for patients having received

intrathecal cytarabine, methotrexate, and/or hydrocortisone.

Intrathecal chemotherapy that is given up to 7 days prior to the

initiation of protocol therapy counts as protocol therapy and not prior

anti-cancer therapy. Intrathecal chemotherapy given > 7 days prior does

not count as protocol therapy.

- NOTE: Prior exposure to fludarabine and cytarabine (FLA) is permitted.

- Anti-cancer agents not known to be myelosuppressive (e.g., not associated with

reduced platelet or absolute neutrophil count [ANC] counts): >= 7 days after the

last dose of agent.

- Antibodies: >= 21 days must have elapsed from infusion of last dose of antibody,

and toxicity related to prior antibody therapy must be recovered to grade =< 1.

There is an exception for blinatumomab infusions, for which patients must have

been off for at least 3 days and all drug related toxicity must have resolved to

grade 2 or lower as outlined in the inclusion/exclusion criteria.

- Hematopoietic growth factors: >= 14 days after the last dose of a long-acting

growth factor (e.g., pegfilgrastim) or >= 7 days for short-acting growth factor.

For agents that have known adverse events occurring beyond 7 days after

administration, this period must be extended beyond the time during which adverse

events are known to occur. The duration of this interval must be discussed with

the study chair and the study-assigned Research Coordinator.

- Interleukins, Interferons and Cytokines (other than hematopoietic growth

factors): >= 21 days after the completion of interleukins, interferon, or

cytokines

- Stem cell infusions (with or without total body irradiation (TBI):

- Allogeneic (non-autologous) bone marrow or stem cell transplant, or stem

cell boost: >= 84 days after infusion

- Donor leukocyte infusion: >= 28 days

- Cellular Therapy: >= 28 days after the completion of any type of cellular therapy

(e.g., modified T cells, natural killer [NK] cells, dendritic cells, etc.)

- Radiation Therapy (XRT)/External Beam Irradiation including protons: >= 14 days

after local XRT; >= 84 days after TBI, craniospinal XRT or if radiation to >= 50%

of the pelvis; >= 42 days if other substantial bone marrow radiation.

- A serum creatinine based on age as follows:

- Age 1 month to < 6 months: maximum serum creatinine 0.4 mg/dL

- Age 6 months to < 1 year: maximum serum creatinine 0.5 mg/dL

- Age 1 to < 2 years: maximum serum creatinine 0.6 mg/dL

- Age 2 to < 6 years: maximum serum creatinine 0.8 mg/dL OR

- a 24-hour urine Creatinine clearance >= 70 mL/min/1.73 m^2 OR

- a glomerular filtration rate (GFR) >= 70 mL/min/1.73 m^2. GFR must be

performed using direct measurement with a nuclear blood sampling method OR

direct small molecule clearance method (iothalamate or other molecule per

institutional standard).

- NOTE: Estimated GFR (eGFR) from serum creatinine, cystatin C or other estimates

are not acceptable for determining eligibility.

- A direct bilirubin =< 1.5 x upper limit of normal (ULN) for age, unless disease

related

- Serum glutamic-pyruvic transaminase (SGPT) (alanine aminotransferase [ALT]) =< 135 U/L

(3 x ULN) unless disease related.

- Note: For the purpose of eligibility, the ULN for SGPT (ALT) has been set to the

value of 45 U/L

- Shortening fraction of >= 27% by echocardiogram, or ejection fraction of >= 50% by

radionuclide angiogram.

- Corrected QT interval using Fridericia formula (QTcF) of < 450 msec (using the average

of triplicate measurements)

- NOTE: There are no specific electrolyte parameters for eligibility. However, it should

be noted that, to limit QTc prolongation risk, patients must maintain adequate

potassium and magnesium levels to initiate and continue SNDX-5613 on protocol therapy.

- Patients must be able to comply with the safety monitoring requirements of the study,

in the opinion of the treating investigator.

Exclusion Criteria

- Patients with isolated extramedullary leukemia.

- Patients diagnosed with Down syndrome.

- Patients known to have one of the following syndromes:

- Bloom syndrome, ataxia-telangiectasia, Fanconi anemia, Kostmann syndrome,

Shwachman syndrome, or any other known bone marrow failure syndrome.

- Patients with a secondary KMT2A-R leukemia that developed after treatment of prior

malignancy with cytotoxic chemotherapy.

- Patients with a history of congenital prolonged QT syndrome, congestive heart failure

or uncontrolled arrhythmia in the past 6 months prior to study enrollment.

- Patients with an active, uncontrolled infection, further defined below:

- Positive bacterial blood culture within 48 hours of study enrollment

- Fever above 38.2 degrees Celsius (C) within 48 hours of study enrollment with

clinical signs of infection. Fever that is determined to be due to tumor burden

is allowed if patients have documented negative blood cultures for at least 48

hours prior to enrollment and no concurrent signs or symptoms of active infection

or hemodynamic instability

- A positive fungal culture within 30 days of study enrollment or active therapy

for presumed invasive fungal infection

- Patients may be receiving IV or oral antibiotics to complete a course of therapy

for a prior documented infection as long as cultures have been negative for at

least 48 hours and signs or symptoms of active infection have resolved. For

patients with Clostridium (C.) difficile diarrhea, at least 72 hours of

antibacterial therapy must have elapsed and stools must have normalized to

baseline

- Active viral or protozoal infection requiring IV treatment

- Human immunodeficiency virus (HIV)-infected patients are eligible if on effective

anti-retroviral therapy that does not interact with planned study agents and with

undetectable viral load within 6 months of enrollment.

- Patients with active acute graft-versus-host disease (GVHD) > grade 0 (unless skin

only), or chronic GVHD > mild (unless skin only) are not eligible. Patients with acute

or chronic skin GVHD that is =< grade 1, or chronic skin GVHD that is graded as mild

are eligible.

- Patients who have received a prior solid organ transplantation.

- Patients with known Charcot-Marie-Tooth disease, if treating on Regimen A (with

vincristine).

- CYP3A4 Inhibitors or Inducers: Patients who require concomitant therapy with moderate

or strong CYP3A4 inhibitors or inducers, as these are prohibited during the

chemotherapy combination cycles. These agents should be discontinued at least 5

half-lives prior to starting protocol therapy. Concomitant use of strong CYP3A4

inhibitor -azole antifungals are permitted during the SNDX-5613 monotherapy cycles,

with appropriate SNDX-5613 dose modification.

- P-glycoprotein (P-gp) inhibitors or inducers: Vincristine is a substrate for P-gp.

Concomitant use of P-gp inhibitors or inducers with vincristine (patients receiving

Regimen A Cycle 1) should be avoided.

- Investigational Drugs: Patients who are currently receiving another investigational

drug.

- Anti-cancer Agents: Patients who are currently receiving other anti-cancer agents

(exceptions: hydroxyurea and corticosteroids, which may be used as cytoreduction prior

to enrollment).

- Anti-GVHD Agents: Patients who are receiving cyclosporine, tacrolimus, or other

systemic agents to treat graft-versus-host disease post bone marrow transplant.

Patients should discontinue anti-GVHD agents > 7 days prior to enrollment and have no

evidence of worsening GVHD. Topical steroids are permitted.

- Patients who have previously been treated with SNDX-5613. Prior exposure to other

menin inhibitors is permitted.

- All patients and/or their parents or legal guardians must sign a written informed

consent.

- All institutional, Food and Drug Administration (FDA), and National Cancer Institute

(NCI) requirements for human studies must be met.