TK216 in Patients With Relapsed or Refractory Ewing Sarcoma

1\. Major Inclusion Criteria (for all Study Parts or protocol versions unless specifically noted): Patients who meet the following inclusion criteria will be eligible to participate in this study: 1. Willing and able to provide written IRB/IEC-approved Informed Consent. For patients \< 18 years of age, their parent or legal guardian must sign a written informed consent. Assent, when appropriate, will be obtained according to institutional guidelines. 2. Have histologically or cytologically confirmed diagnosis of Ewing sarcoma (including ESFT) with relapsed or refractory disease 1. who have failed standard therapy and for whom no known curative therapy exists (For Parts 1-3), OR 2. patients with metastatic disease who had standard chemotherapy at the time of diagnosis (For Part 4) (NOTE: as of Protocol version 7, pathology reports and slides or blocks should be available for review or additional testing. If not available, site must discuss with Sponsor.) 3. Measurable disease according to RECIST version 1.1. Measurable disease can be verified from a previously documented CT scan or MRI as long as no anti-cancer treatments have been administered in the interim. 4. Must have a central venous catheter in place prior to initiating infusion of study drug. 5. Prior cancer therapy: 1. Patients may have received any number of prior therapy regimens (For Parts 1-3) OR 2. Patients may have received no more than 5 prior systemic regimens. At the time of treatment initiation, at least 2 weeks or 5 half-lives, whichever is longer, must have elapsed since prior cytotoxic chemotherapy. At least 7 days must have elapsed since completion of any prior non-cytotoxic cancer therapy (For Part 4). 6. Prior radiotherapy is allowed 1. If ≥ 2 weeks have elapsed for local palliative XRT (small port); ≥ 6 months must have elapsed if prior total body irradiation, craniospinal XRT or if \> 50% radiation of the pelvis; \> 6 weeks must have elapsed if other substantial bone marrow radiation. Patients who have received brain irradiation must have completed whole brain radiotherapy and/or gamma knife at least 4 weeks prior to enrollment (For Parts 1-3) OR 2. If ≥ 4 weeks has elapsed for radiation therapy (RT); ≥ 6 months must have elapsed if prior total body irradiation, craniospinal RT or if \> 50% radiation of the pelvis; \> 6 weeks must have elapsed if other substantial bone marrow radiation. Patients who have received brain irradiation must have completed whole brain radiotherapy and/or gamma knife at least 4 weeks prior to enrollment (For Part 4). 7. Stem Cell Transplant or Rescue without TBI: No evidence of active graft vs. host disease and ≥ 3 months must have elapsed since transplant. 8. Patients with controlled asymptomatic CNS involvement are allowed. 9. Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 2 in patients ≥17 years old; or Karnofsky/Lansky \>50 in patients \<16 years old. 10. Age: a. Cohort 1: Patient's age \>18 years old. b. Cohorts 2-6: Patients must be \> 12 years old. c. Cohorts 7-10: Patients must be ≥ 10 years old. d. Cohort 11: Patient's age ≥ 8 years (For Part 4) 11. Life expectancy of at least 3 months. 12. Adequate organ function as measured by baseline laboratory values. 13. Cardiac ejection fraction \> 50% or shortening fraction \> 28%. 14. Females of child-bearing potential must have a negative pregnancy test (within 7-days of starting treatment) during screening and subjects must be willing to use effective contraception. be neither breastfeeding nor intending to become pregnant during study participation. Females of childbearing potential must agree to avoid pregnancy during the study and commit to abstinence from heterosexual intercourse or agree to use two methods of birth control (one highly effective method and one additional effective method) at least 4 weeks before the start of protocol therapy, for the duration of study participation, and for 6 months after the last dose of TK216. 15. Males with partner(s) of childbearing potential must take appropriate precautions to avoid fathering a child from the screening period until 90 days after receiving the last dose of TK216. They must commit to abstinence from heterosexual intercourse or agree to use appropriate barrier contraception. 16\. Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests and other study procedures. Major Exclusion Criteria: Patients will not be enrolled if they meet any one of the following exclusion criteria: 1. Current participation in another therapeutic clinical trial. 2. Symptomatic brain metastases. 3. History of previous cancer (non ES), except squamous cell or basal-cell carcinoma of the skin or any in situ carcinoma that has been completely resected, which required therapy within the previous 3 years. 4. Any of the following in the past 6 months: symptomatic congestive heart failure, cerebrovascular accident or transient ischemic attack, pulmonary embolism, deep vein thrombosis, symptomatic bradycardia, requirement for antiarrhythmic medication. 5. History of prolonged QTc interval (e.g., repeated demonstration of a QTc interval \> 450 milliseconds, unless associated with the use of medications known to prolong the QTc interval). (NOTE: For Part 4, repeated demonstration of a QTc interval \> 470 milliseconds) 6. History of additional risk factors for torsade de pointes (e.g., heart failure, family history of long QT syndrome 7\. Use of concomitant medications that increase or possibly increase the risk to prolong the QTc interval and/or induce torsades de pointes ventricular arrhythmia. 8\. Females who are breastfeeding/lactating. 9. Known active infections (bacterial, fungal, viral including hepatitis and HIV positivity). 10. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study drug administration or may interfere with the interpretation of study results and, in the judgment of the Investigator, would make the patient inappropriate for entry into this study or could compromise protocol objectives in the opinion of the Investigator and/or the Sponsor.