Denosumab in Treating Patients With Recurrent or Refractory Osteosarcoma

This phase II trial studies how well denosumab works in treating patients with osteosarcoma that has come back (recurrent) or does not respond to treatment (refractory). Immunotherapy with monoclonal antibodies, such as denosumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread.

PRIMARY OBJECTIVES:

I. To determine whether denosumab therapy either increases the disease control rate at 4 months in patients with recurrent measurable osteosarcoma as compared to historical Children's Oncology Group (COG) experience or denosumab therapy produces an objective response rate greater than 5% (Cohort 1).

II. To determine whether denosumab therapy increases the disease control rate at 12 months in patients with recurrent resected osteosarcoma as compared to historical COG experience (Cohort 2).

SECONDARY OBJECTIVES:

I. To investigate the pharmacokinetics (PK) and pharmacodynamics (PD) of denosumab in subjects with recurrent osteosarcoma.

II. To describe the tolerability of denosumab in subjects with recurrent osteosarcoma.

III. To report the disease control rate and objective response rate for patients with recurrent osteosarcoma limited to bone.

IV. To investigate biological markers potentially associated with response to denosumab in patients with recurrent osteosarcoma.

OUTLINE:

Patients receive denosumab subcutaneously (SC) on day 1 (days 1, 8, and 15 of course 1 only). Treatment repeats every 4 weeks (28 days) for up to 24 months or 26 courses, whichever occurs first, in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up monthly for 1 year.

Eligibility Criteria:
Inclusion Criteria:

* Female patients must have a bone age of equal to or greater than 12 years of age as determined by local read of appropriate radiographic imaging
* Male patients must have a bone age of equal to or greater than 14 years of age as determined by local read of appropriate radiographic imaging
* Patients must have relapsed or become refractory to conventional therapy, with a regimen including some combination of high dose methotrexate, doxorubicin, cisplatin, ifosfamide and etoposide; and have had histologic verification of osteosarcoma at original diagnosis or at the time of recurrence
* Cohort 1 patients must have measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
* Cohort 2 patients must have had a complete resection of all sites of metastatic disease within 30 days prior to enrollment

  * Patients will only be eligible after they have undergone complete surgical resection of suspected metastatic disease that is histopathologically confirmed to be osteosarcoma prior to enrollment

    * Note: the definition of complete resections is: gross resection of all disease as per the operating surgeon; post-operative imaging is not required for confirmation of complete resection
  * Patients must undergo resection of any lung lesion meeting criteria for likely metastatic disease, defined as:

    * 3 or more lesions \> 5 mm in diameter OR a single lesion \> 1 cm
  * Patients with lung as the only site of resected metastatic disease must have refused participation in protocol AOST1421

    * Note: This applies if AOST1421 is open to enrollment at the enrolling institution on the day the patient consents
* Patient must have adequate 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
* 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: 11 to \< 13 years old; 1.2 (male, female) maximum serum creatinine (mg/dL)
  * Age: 13 to \< 16 years old; 1.5 (male), 1.4 (female) maximum serum creatinine (mg/dL)
  * Age: \>= 16 years old; 1.7 (male), 1.4 (female) maximum serum creatinine (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 \[ALT\]) \< 2.5 x ULN for age
* Serum calcium or albumin-adjusted serum calcium \>= 2.0 mmol/L (8.0 mg/dL) and =\< 2.9 mmol/L (11.5 mg/dL)

Exclusion Criteria:

* Patients with known sensitivity to any of the products to be administered during the study (eg, mammalian derived products, calcium or vitamin D)
* Patients who are receiving other cancer directed therapy at the time of enrollment
* Patients who have previously received denosumab
* Patients who have previously received mithramycin, strontium-89, samarium-153 or rhenium
* Patients receiving bisphosphonates
* Pre-existing conditions

  * Disorders associated with abnormal bone metabolism
  * Hypocalcemia that is not corrected with oral calcium supplementation
  * Vitamin D \< 20 mg/mL
  * Paget's disease
  * Prior history or current evidence of osteonecrosis of the jaw
  * Any dental or oral condition likely to result in disruption of mucosal integrity during denosumab therapy including: active dental or jaw condition requiring oral surgery or tooth extraction; non-healed dental or oral surgery or planned invasive dental procedures during the anticipated course of study therapy
  * Unstable systemic disease, excluding osteosarcoma, such as unstable proximal renal tubule dysfunction (Fanconi syndrome) or congestive heart failure
* Pregnancy and breast feeding

  * Female patients who are pregnant; a pregnancy test is required for female patients of childbearing potential
  * Lactating females who plan to breastfeed their infants while on study therapy and through 5 months after completion of study therapy
  * Sexually active patients of reproductive potential who have not agreed to use an effective contraceptive method for the duration of their study participation and for 5 months after the end of study treatment
* 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