‣ Subjects must meet all the following inclusion criteria to be eligible for enrollment:

‣ Informed Consent/Assent Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.

‣ Age ≥12 years at the time of screening

‣ Type of Subject and Disease Characteristics

• Subjects may be male or female and must be equal to or greater than 12 years of age. No large studies have evaluated the use of vactosertib in younger pediatric subjects, for this reason, children younger than 12 years of age are excluded from this study.

• Subjects must have histologic verification of Osteosarcoma (OS)

• Subjects must have measurable disease per RECIST 1.1 (Appendix C), documented by clinical, radiographic and histologic criteria, and have progressed, relapsed or become refractory to conventional therapy.

• Subjects must have recovered from the acute toxic effects with ≤ Grade 1 as defined by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 5.0 of all prior chemotherapy and immunotherapy with the exception of alopecia, anorexia, bone pain, and tumor pain prior to entering this study.

• Myelosuppressive chemotherapy: Must have adequate recovery of counts from previous treatment prior to entry onto this study.

• Inclusion criteria include adequate renal function, ECOG performance status 0-2, and either Lansky performance status of 50-100% (\<16 years old), or Karnofsky performance status 50-100% (≥16 years old). Subjects who are unable to walk because of paralysis, but who are up in a wheelchair will be considered ambulatory for the purpose of assessing the performance score.

• Subjects must have normal organ and marrow function as defined below:

• a. Adequate bone marrow function defined as: i. Peripheral absolute neutrophil count (ANC) ≥ 750/mcL ii. Platelet count ≥ 75,000/mcL (transfusion independent) iii. Hemoglobin ≥ 8.0 g/dL (may receive packed red blood cell transfusions) b. Adequate liver function defined as: i. Total bilirubin ≤ 1.5 times the upper limit of normal for age ii. AST (SGOT) and ALT (SGPT) 2.5 X institutional upper limit of normal iii. Albumin (serum or plasma) \> 2 g/dL c. Adequate cardiac function defined as: i. Ejection fraction of ≥ 50% by echocardiogram or MUGA

• Subjects must have the ability to understand and the willingness to sign a written informed consent document if ≥ 18 years of age and an assent document if \< 18 years of age (per country).

• Renal laboratory inclusion:

⁃ Relapsed osteosarcoma (first, second, third or any relapse, subject who have recovered from chemotherapy and any other investigational drug/agent treatment, radiotherapy or surgical procedure), with histological confirmed diagnosis of osteosarcoma at original presentation, and progressive disease documented by imaging within 3 months of entry into the trial.