Glembatumumab Vedotin in Treating Patients With Recurrent or Refractory Osteosarcoma

Inclusion Criteria:

* Patients must have had histologic verification of osteosarcoma at original diagnosis or relapse
* Patients must have measurable disease according to RECIST 1.1, and have relapsed or become refractory to conventional therapy
* Patient must have archival tumor specimen available for submission
* Patients must have a performance status corresponding to Eastern Cooperative Oncology Group (ECOG) scores of 0, 1 or 2; use Karnofsky for patients \> 16 years of age and Lansky for patients =\< 16 years of age
* Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study

  * Myelosuppressive chemotherapy: must not have received within 2 weeks of entry onto this study (4 weeks if prior nitrosourea)
  * Biologic (anti-neoplastic agent): at least 7 days since the completion of therapy with a biologic agent
  * Radiation therapy (RT): \>= 2 weeks for local palliative RT (small port); \>= 6 months must have elapsed if prior craniospinal RT or if \>= 50% radiation of pelvis; \>= 6 weeks must have elapsed if other substantial bone marrow (BM) radiation
  * Monoclonal antibodies: must not have received any monoclonal based therapies within 4 weeks, and all other immunotherapy (tumor vaccine, cytokine, or growth factor given to control the cancer) within 2 weeks, prior to study enrollment
* Peripheral absolute neutrophil count (ANC) \>= 1000/uL
* Platelet count \>= 75,000/uL (transfusion independent)
* Hemoglobin \>= 8.0 g/dL (may receive red blood cell \[RBC\] transfusions)
* Creatinine clearance or radioisotope glomerular filtration rate (GFR) \>= 70 mL/min/1.73 m\^2 or a serum creatinine based on age/gender as follows:

  * Age 1 to \< 2 years (male and female: 0.6 mg/dL)
  * Age 2 to \< 6 years (male and female: 0.8 mg/dL)
  * Age 6 to \< 10 years (male and female: 1 mg/dL)
  * Age 10 to \< 13 years (male and female: 1.2 mg/dL)
  * Age 13 to \< 16 years (male: 1.5 mg/dL and female: 1.4 mg/dL)
  * Age \>= 16 (male: 1.7 mg/dL and female: 1.4 mg/dL)
* Total bilirubin =\< 1.5 x upper limit of normal (ULN) for age
* Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase \[AST\]) or serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase \[ALT\]) \< 110 U/L; for the purposes of this study the ULN for SGPT is defined as 45 U/L
* Serum albumin \> 2 g/dL
* Shortening fraction of \>= 27% by echocardiogram, or
* Ejection fraction of \>= 50% by radionuclide angiogram
* All patients and/or their parents or legal guardians must sign a written informed consent
* All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met

Exclusion Criteria:

* Patients with \> grade 2 neuropathy according to the Modified ("Balis") Pediatric Scale of Peripheral Neuropathies will be excluded except in cases in which neuropathy is secondary to prior surgery
* Patients who have previously received CDX-011 (CR011-vc monomethyl auristatin E \[MMAE\]; CDX-011) or other MMAE-containing agents
* Patients who have received other investigational drugs within 2 weeks or 5 half-lives (whichever is longer) prior to study enrollment
* Patients with a history of allergic reactions attributed to compounds of similar composition to dolastatin or auristatin; compounds of similar composition include auristatin PHE as an anti-fungal agent, auristatin PE (TZT-1027, Soblidotin, NSC-654663) as an anti-tumor agent and symplostatin 1 as an anti-tumor agent
* Patients with known central nervous system metastasis are not eligible
* Patients who have had major surgery within 2 weeks prior to enrollment are not eligible; procedures such as placement of a central vascular catheter, or limited tumor biopsy, are not considered major surgery
* Female patients who are pregnant are ineligible
* Lactating females are not eligible unless they have agreed not to breastfeed their infants
* Female patients of childbearing potential are not eligible unless a negative pregnancy test result has been obtained
* Sexually active patients of reproductive potential are not eligible unless they have agreed to use an effective contraceptive method for the duration of their study participation and for 2 months after the end of study treatment