Denosumab in Treating Patients With Recurrent or Refractory Osteosarcoma

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.

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

- Note: patients in Cohort 1 will be stratified as follows:

- Stratum 1: Patients >= 11 years of age but < 18 years

- Stratum 2: Patients >= 11 years of age but < 50 years

- 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