• Patients in all cohorts must have relapsed or refractory disease after standard therapy.

• Patients must have:

⁃ Evaluable or measurable disease; and

⁃ Histologic diagnosis of sarcoma

⁃ EWS cohort: Patients must have:

∙ RECIST measurable disease at study entry;

‣ Histologic diagnosis consistent with Ewing sarcoma; and

‣ Molecular evidence of a FET-ETS family translocation including but not limited to any of the following:

⁃ EWSR1::FLI1, EWSR1::ERG, EWSR1::ETV1, EWSR1::ETV4, EWSR1::FEV, FUS::FLI1, FUS::ERG

⁃ DSRCT cohort: Patients must have:

∙ RECIST measurable disease at study entry;

‣ Histologic diagnosis consistent with DSRCT; and

‣ Molecular evidence of an EWSR1::WT1 fusion

⁃ Other sarcoma cohort: Patients must have:

∙ RECIST evaluable or measurable disease; and

‣ Histologic diagnosis of sarcoma. Patients with EWS or DSRCT with evaluable but not measurable disease may participate in this cohort.

‣ Slots in this cohort will include three dedicated slots for patients with rhabdomyosarcoma, three dedicated slots for patients with osteosarcoma and three dedicated slots for patients with other translocation-associated round cell sarcomas.

⁃ Age: ≥ 12 years and ≤ 49 years.

⁃ Weight: Patients must be ≥ 40 kg.

⁃ Performance Status: Karnofsky ≥ 50% for patients \>16 year of age and Lansky ≥ 50% for patients ≤ 16 years of age. (see Appendix A for definitions of Lansky and Karnofsky Performance Status).

⁃ Participants must meet the following organ and marrow function as defined below: Adequate Bone Marrow Function:

∙ Hematologic Requirements for Subjects without Bone Marrow Involvement by

‣ Disease:

⁃ Absolute neutrophil count (ANC) ≥ 1,000/uL

⁃ Platelet count ≥100,000/uL (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment)

‣ -Hematologic Requirements for Subjects with Bone Marrow Involvement by Disease:

⁃ ANC ≥750 /uL

⁃ Platelets ≥50,000 /uL (may receive platelet transfusions) Not known to be refractory to red cell and/or platelet transfusions.

‣ -Adequate Renal Function: Creatinine clearance or radioisotope GFR ≥70ml/min/1.73 m2 or A serum creatinine based on age/sex as follows:

⁃ Age: 12 to \< 13 years, Maximum Serum Creatinine (mg/dL): Male 1.2, Female 1.2

‣ --≥ 16 years, Maximum Serum Creatinine (mg/dL): Male 1.7, Female 1.4

‣ -Adequate Liver Function:

⁃ Bilirubin (sum of conjugated + unconjugated) ≤ 1.5 x upper limit of normal (ULN) for age

⁃ SGPT (ALT) ≤110 U/L. For the purpose of this study, the ULN for SGPT is 45 U/L.

∙ Adequate Cardiac Function: QTc \< 480 msec

• Patients must have fully recovered from the acute toxic effects of all prior anti-cancer therapy except organ function as noted above. Patients must meet the following minimum washout periods prior to enrollment:

‣ Myelosuppressive chemotherapy: At least 14 days after the last dose of myelosuppressive chemotherapy

‣ Radiotherapy:

⁃ At least 14 days after local XRT (small port, including cranial radiation);

⁃ At least 90 days must have elapsed after prior TBI, craniospinal XRT or if \>50% radiation of pelvis;

⁃ At least 42 days must have elapsed if other substantial BM radiation.

∙ Small molecule biologic therapy: At least 7 days following the last dose of a biologic agent.

‣ Monoclonal antibody: At least 21 days must have elapsed after the last dose of antibody.

‣ Myeloid and platelet growth factors: At least 14 days following the last dose of long-acting myeloid growth factor (e.g. Neulasta) or 7 days following short-acting myeloid or platelet growth factor.

‣ Autologous hematopoietic stem cell transplant and stem cell boost: Patients must be at least 60 days from day 0 of an autologous stem cell transplant or stem cell boost.

‣ Cellular Therapies (e.g., CART, NK-cell based therapy): The patient must be and at least 42 days from cellular therapy administration.

‣ Major Surgery: At least 2 weeks from prior major surgical procedure. Note: Biopsy, CNS shunt placement/revision, and central line placement/removal are not considered major.

‣ Irinotecan, liposomal irinotecan, and/or temozolomide: Patients may have received prior irinotecan, liposomal irinotecan, and/or temozolomide. NOTE: Patients who have had progressive disease while receiving irinotecan and temozolomide in combination will be excluded from the Phase 2 EWS and DSRCT cohorts only.

• For patients with metastatic disease to the CNS enrolling to the phase 1 portion of the trial or the other sarcoma cohort, any baseline neurologic deficits (including seizure) must be stable for at least one week prior to study enrollment. Patients with CNS metastatic disease receiving corticosteroids must be on a stable or decreasing dose at time of study entry.

‣ Patients with CNS metastatic disease will not be eligible for the phase 2 EWS and DSRCT cohorts.

⁃ Participants with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial.

• The effects of PEEL-224 in combination with temozolomide and vincristine on the developing human fetus are unknown. For this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of PEEL-224 administration.

• Ability to understand and/or the willingness of the patient (or parent or legally authorized representative, if minor) to provide informed consent, using an institutionally approved informed consent procedure.

• Any participant must obtain prior approval from insurance to reimburse oral temozolomide for the duration of the study or agree to self-pay for oral temozolomide.