Eflornithine (DFMO) for Ewing Sarcoma and Osteosarcoma

Cohort 1: Inclusion Criteria: 1. Participants must be ≤50 years of age at enrollment. 2. Histologically confirmed Ewing sarcoma that is refractory or in first or subsequent relapse. Histological confirmation either at initial diagnosis or disease progression. * Relapsed: Participants that have achieved CR at any point and then relapsed following/during standard of care therapy. * Refractory: Participants that failed to achieve CR after standard of care therapy or having progressed during standard of care therapy. * Note: Standard of care therapy for Ewing sarcoma includes multi-agent chemotherapy with local control consisting of either surgery and/or radiation therapy. 3. Extent of disease is judged by treating team to be amenable to the delivery of definitive local control (either definitive radiation, surgery, or a combination of these) at the time of study enrollment (to be completed after protocol defined Cycle 2). 4. Participants may enroll anytime during Cycle 1 or 2, prior to local control, as long as they received the same treatment during Cycle 1 and 2 as prescribed in this protocol. 5. Relapsed or refractory disease, including at least one of the following: * Tumor by CT or MRI * FDG-PET that is positive for disease * Bone Marrow biopsy/aspirate that is positive for disease Organ Function Requirements: 6. Participants must have adequate renal function as defined as: * For participants \< 17 years old: estimated Glomerular Filtration rate (eGFR) as calculated from the Bedside Schwartz equation (in units of mL/min/1.73 m2) or via radioisotope GFR of ≥ 70 mL/min/1.73 m2. The Bedside Schwartz equation is: \[(0.413) X (Height in cm)\] / SCr * For participants ≥17 years old: estimated Glomerular Filtration rate (eGFR) as calculated from the Cockcroft and Gault formula (in units of mL/min/1.73 m2) or via radioisotope GFR of ≥ 70 mL/min/1.73 m2. The Cockcroft and Gault formula is: \[(140-age) x (Wt in kg) x (0.85 if female)\] / (72 x SCr) * OR a 24 hour urine Creatinine clearance ≥ 70 mL/min/1.73 m2 7. Adequate liver function defined as: 1. Total bilirubin ≤1.5 x upper limit of normal (ULN) for age, and 2. SGPT (ALT \<3 x upper limit of normal (ULN) for age (except for participants with liver metastasis who may enroll if ALT \< 5 times ULN for age). 8. Adequate cardiac function defined as: 1. Shortening fraction of ≥27% or 2. Ejection fraction of ≥50% 9. Participants must have fully recovered from the hematological and bone marrow suppression effects of prior chemotherapy. 10. Participants must have a Lansky Play Scale or Karnofsky Performance Scale score of ≥ 60. 11. Participants of childbearing potential must have a negative pregnancy test and agree to use an effective birth control method. Participants who are lactating must agree to stop breast-feeding. 12. Written informed consent in accordance with institutional and FDA guidelines must be obtained from all participants (or participants' legal representative). Exclusion Criteria: 1. BSA of \<0.25 m2 2. Participants with current CNS disease. 3. Investigational Drugs: Participants who are currently receiving another investigational drug are excluded from participation. 4. Anti-cancer Agents: Participants who are currently receiving other anticancer agents are not eligible. 5. Infection: Participants who have an uncontrolled infection are not eligible until the infection is judged to be well controlled in the opinion of the investigator. 6. Participants who, in the opinion of the investigator, may not be able to comply with the safety monitoring requirements of the study, or in whom compliance is likely to be suboptimal, should be excluded. Cohort 2: Inclusion Criteria: * Age 1. Participants must be ≤50 years of age at enrollment. Note: • Infants and small children are eligible for this study, however, the treating physicians and family must be prepared to deliver adequate local control as required in this study (see BCC Surgical and Imaging Guidelines). Diagnosis 2. Participants with histologic diagnosis (by institutional pathologist) of newly diagnosed Ewing sarcoma or peripheral primitive neuroectodermal tumor (PNET) arising from bone or soft tissue and with metastatic disease involving lung, bone, bone marrow, or other metastatic site. For the purpose of this study, metastatic disease is defined as one or more of the following: * Lesions which are discontinuous from the primary tumor, are not regional lymph nodes, and do not share a bone or body cavity with the primary tumor. Skip lesions in the same bone as the primary tumor do not constitute metastatic disease. Skip lesions in an adjacent bone are considered bone metastases. If there is any doubt whether lesions are metastatic, a biopsy of those lesions should be performed. * Contralateral pleural effusion and/or contralateral pleural nodules. * Distant lymph node involvement. * Participants with pulmonary nodules are considered to have metastatic disease if the participant has: * Solitary nodule ≥0.5 cm or multiple nodules of ≥0.3 cm unless lesion is biopsied and negative for tumor; * Participants with solitary nodule \<0.5 cm or multiple nodules \<0.3 cm are not considered to have lung metastasis unless biopsy documents tumor. * Bone marrow metastatic disease is based on morphologic evidence of Ewing sarcoma based on H\&E stains. In the absence of morphologic evidence of marrow involvement on H\&E, participants with bone marrow involvement detected ONLY by flow cytometry, RT PCR, FISH, or immunohistochemistry will NOT be considered to have clinical bone marrow involvement for the purposes of this study. For participants that have a positive FDG-PET scan at study enrollment, a bilateral bone marrow biopsy will be required at study entry. If a bone marrow is required, the suggested approach for participants with large pelvic tumors in which a posteri