Eflornithine (DFMO) and AMXT 1501 for Neuroblastoma, CNS Tumors, and Sarcomas

Inclusion Criteria:

1. Age: All participants : Must be a maximum of 26 years of age at diagnosis Age at enrollment by Phase:

2. Safety Run-in (Dose level 1)-The first three (3) participants enrolled will be ≥ 12 years of age at enrollment. Once evaluated for safety by DSMB, we willmove on to the next three (3) participants enrolled who will be ≥6 years of ageat enrollment. Once evaluated for safety by DSMB, we will move on to the Phase I.

3. Phase I and II: ≤ 26 years of age at diagnosis.

4. Pathology All participants must have a confirmed pathologic diagnosis of tumor type (exceptfor DIPG):

• Relapsed/refractory Neuroblastoma (NB)

• Relapsed/refractory Embryonal tumor with multilayer rosettes (ETMR)

• Relapsed/refractory Atypical teratoid rhabdoid tumor (ATRT)

• Newly diagnosed Diffuse Intrinsic Pontine Glioma (DIPG)- radiologic diagnosisacceptable

• Relapsed/refractory Ewing Sarcoma (EWS)

• Relapsed/refractory Osteosarcoma (OST)

3. Tumor assessment: Disease staging must be performed at baseline during the 28 day screening periodprior to first dose of study drug.

4. Disease Status: Relapsed or Refractory Neuroblastoma Relapsed disease defined as: High-riskneuroblastoma that was previously in remission after standard therapy (at least 4cycles of aggressive multi-drug induction chemotherapy, with or without radiation,surgery, and immunotherapy, or according to a standard high-risktreatment/neuroblastoma protocol). Refractory disease defined as: High-risk neuroblastoma that 1) failed to achieve CRafter at least 4 cycles of aggressive multi-drug induction chemotherapy with orwithout radiation and surgery, followed by immunotherapy, or according to a standardhigh-risk treatment/neuroblastoma protocol, or 2) progression during upfront therapyor 3) with disease remaining after standard immunotherapy. Eligible NB participants may have active disease or no active disease. NB participants with no active disease need to meet the following criteria: Timing from prior therapy: Enrollment (first dose of study drug) no later than 60days from most recent therapy. NB participants with active disease need to meet the following criteria:

• Received at least one recent treatment for their relapse/refractory disease andis stable (SD) or better on this treatment.

• Participants must not have disease in any organs (including lungs, liver, orbrain). Relapsed or refractory ETMR/ATRT Participants that have relapsed following standardof care therapy or having progressed during standard of care therapy andnon-responsive/progressive to accepted curative therapy, including up-frontchemotherapy and radiation and/or high-dose chemotherapy with stem cell rescue. ETMR/ATRT participants with no active disease need to meet the following criteria: Timing from prior therapy: Enrollment (first dose of study drug) no later than 60days from most recent therapy. ETMR/ATRT participants with active disease need to meet the following criteria:

• Received at least one recent treatment for their relapse/refractory disease and isstable (SD) or better on this treatment. Newly Diagnosed Diffuse Intrinsic Pontine Glioma (DIPG) Participants with DIPG tostart greater than 30 days, and no longer than 60 days, after standard of careradiation therapy. Participants with newly-diagnosed typical DIPG, defined as tumors with a pontineepicenter and diffuse involvement of the pons on at least 1 axial T2-weighted image,are eligible. No histologic confirmation is required. Participants with metastaticdisease are not eligible. Participants with a biopsy and no evidence of H3K27mmutations are eligible as long as they meet radiographic criteria. Participants withH3K27m altered DMG outside of the brainstem are not eligible. Participants withprogression or recurrence after initial standard of care radiation are ineligible. Relapsed or refractory Ewing sarcoma and osteosarcoma Participants that haverelapsed following standard of care therapy or having progressed during standard ofcare therapy. Standard of care therapy for Ewing sarcoma and osteosarcoma includesmulti-agent chemotherapy with local control consisting of either surgery orradiation therapy. EWS/OST Participants with no active disease need to meet the following criteria: Timing from prior therapy: Enrollment (first dose of study drug) no later than 60days from most recent therapy. EWS/OST Participants with active disease need to meet the following criteria:

• Received at least one recent treatment for their relapse/refractory disease and isstable (SD) or better on this treatment.

5. Participants must be able to swallow capsules.

6. Participants with CNS disease currently taking steroids must have been on a stabledose of steroids for at least one week and must not have progressive hydrocephalusat enrollment.

7. Participants must have fully recovered from the acute toxic effects of all prioranti- cancer chemotherapy and be within the following timelines:

8. Myelosuppressive chemotherapy: Must not have received within 2 weeks ofenrollment onto this study (6 weeks if prior nitrosourea).

9. Small Molecule Inhibitor (anti-neoplastic agent): At least 7 days since thecompletion of therapy with a small molecule inhibitor. For agents that haveknown adverse events occurring beyond 7 days after administration, this periodmust be extended beyond the time during which adverse events are known tooccur. The duration of this interval must be discussed with the Study Chair.

10. Immunotherapy: At least 4 weeks since the completion of any type ofimmunotherapy, e.g. tumor vaccines, CAR-T cells except for anti-GD2 Monoclonalantibodies (ex. naxitamab, dinutuximab, etc.) which should be at least 2 weekssince prior treatment with a monoclonal antibody.

11. XRT: At least 14 days since the last treatment except for radiation deliveredwith palliative intent to a non-target site. Note: Participants with DIPG will be required to have had up front standard ofcare radiation. As above, participants with DIPG must be between 30-60 dayspost initial up- front radiation therapy.

12. Stem Cell Transplant:

13. Allogeneic: No evidence of active graft vs. host disease

14. Allo/Auto: ≥ 45 days must have elapsed since transplant.

15. MIBG Therapy: At least 6 weeks since treatment with MIBG therapy.

16. Participants must have a Lansky or Karnofsky Performance Scale score of >/= 60

17. Participants must have adequate organ function at the time of enrollment:

• Hematological: Hematological recovery as defined by ANC ≥750/μL (unsupported- >24 hrs off G-CSF and 7 days off neulasta)

• Liver: Adequate liver function as defined by AST and ALT <10x upper limit ofnormal

• Cardiac: all participants must have:

1. Normal serum Cardiac Troponin Concentration
2. Normal BNP (B-type natriuretic peptide) Level
3. A QTcF ≤ 470 msec (or EKG with no significant findings)
4. Normal ECHO defined as: i. Shortening fraction of ≥ 27% by echocardiogram, or ii. Ejection fraction of ≥ 50% by echocardiogram or radionuclide angiogram

• Renal: Participants must have adequate renal function defined as:

1. For participants < 17 years old: estimated Glomerular Filtration rate (eGFR) as calculated from the Bedside Schwartz equation (in units ofmL/min/1.73 m2) or via radioisotope GFR of ≥ 70 mL/min/1.73 m2. TheBedside Schwartz equation is: [(0.413) X (Height in cm)] / SCr

2. For participants ≥17 years old: estimated Glomerular Filtration rate (eGFR) as calculated from the Cockcroft and Gault formula (in units ofmL/min/1.73 m2) or via radioisotope GFR of ≥ 70 mL/min/1.73 m2. TheCockcroft and Gault formula is: [(140-age) x (Wt in kg) x (0.85 iffemale)] / (72 x SCr)

3. Participants of childbearing potential must have a negative pregnancy test.Participants of childbearing potential must agree to use an effective birth controlmethod. Participants who are lactating must agree to stop breast-feeding.

4. Written informed consent in accordance with institutional and FDA guidelines must beobtained from all participants (or participants' legal representative).

Exclusion Criteria:

1. BSA of <0.25 m2

2. Investigational Drugs: Participants who are currently receiving anotherinvestigational drug are excluded from participation.

3. Anti-cancer Agents: Participants who are currently receiving other anticancer agentsare not eligible. Participants must have fully recovered from the hematological andbone marrow suppression effects of prior chemotherapy.

4. Infection: Participants who have an uncontrolled infection are not eligible untilthe infection is judged to be well controlled in the opinion of the investigator.

5. Participants who, in the opinion of the investigator, may not be able to comply withthe safety monitoring requirements of the study, or in whom compliance is likely tobe suboptimal, should be excluded.