Dinutuximab in Combination With Sargramostim in Treating Patients With Recurrent Osteosarcoma

PRIMARY OBJECTIVES:

I. To determine the disease control rate in patients with completely resected recurrent
osteosarcoma treated with ch14.18 (dinutuximab) in combination with sargramostim
(granulocyte-macrophage colony-stimulating factor [GM-CSF]) as compared to historical
Children's Oncology Group (COG) experience.

SECONDARY OBJECTIVES:

I. To characterize the pharmacokinetics of ch14.18 (dinutuximab) in patients with recurrent
osteosarcoma.

II. To determine the occurrence of unacceptable toxicity (UT) in patients with recurrent
osteosarcoma treated with ch14.18 (dinutuximab) in combination with sargramostim.

III. To assess the relationship between probability of disease control and tumor ganglioside
GD2 (GD2) expression.

TERTIARY OBJECTIVES:

I. To assess the relationship between probability of disease control and tumor GD2
expression.

II. To assess KIR and Fcgamma receptor (FcgammaR) genotypes, NKp30 isoforms and its
circulating ligand, B7-H6, and their relationships to the probability of disease control.

III. To attempt banking of tumor samples for future research studies from patients enrolled
on study who undergo biopsy or resection of suspected metastatic disease recurrence while on
protocol therapy or during the evaluation period.

IV. To determine a descriptive profile of human anti-chimeric antibody (HACA) during
immunotherapy.

V. To bank serial plasma samples for future studies of circulating tumor deoxyribonucleic
acid (ctDNA) detection as a marker of disease progression and response.

OUTLINE:

Patients receive sargramostim subcutaneously (SC) once daily (QD) on days 1-14 and
dinutuximab intravenously (IV) over 10 hours on days 4-7 (dinutuximab infusion may be
extended up to a total of 20 hours per day for anticipated toxicities). Treatment repeats
every 28 days for up to 5 courses in the absence of disease progression or unacceptable
toxicity.

After completion of study treatment, patients are followed up at 8 and 12 months.

Inclusion Criteria:

- Patients must have histologic diagnosis of osteosarcoma at original diagnosis

- Patients must have had at least one episode of disease recurrence in the lungs without
limitation on number of episodes of recurrence as long as they meet the following
criteria:

- Surgical resection of all possible sites of suspected pulmonary metastases in
order to achieve a complete remission within 4 weeks prior to study enrollment**

- Pathologic confirmation of metastases from at least one of the resected sites

- For patients with bilateral pulmonary metastases, resection must be
performed from both lungs and the study enrollment must be within 4 weeks
from date of the last lung surgery

- Note: If surgery related changes such as atelectasis are seen on the
post-operative computed tomography (CT) scan, patients will remain eligible to
enroll as long as the operating surgeon believes that all sites of metastases
were resected; patients with positive microscopic margins will be eligible to
enroll

- 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

- Patients must have fully recovered from the acute toxic effects of all prior
chemotherapy, immunotherapy, or radiotherapy prior to entering this study

- Myelosuppressive anti-cancer therapy: must not have been received within 2 weeks
of study entry (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 radiation therapy (RT)
(small port); >= 6 weeks 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

- Surgery: >= 2 weeks from last major surgery, including pulmonary metastasectomy,
with the exclusion of a central line placement and core needle or small open
biopsies

- Patient must not have received pegfilgrastim within 14 days of enrollment

- Patient must not have received filgrastim (G-CSF, Neupogen) within 7 days of
enrollment

- Patient must not have received immune suppressants: corticosteroids (for other than
allergic reactions and anaphylaxis), cyclosporine or tacrolimus within 7 days of
enrollment

- Note: the use of topical and/or inhalational steroids is allowed

- Total absolute phagocyte count (APC = [%neutrophils + %monocytes) x white blood cells
[WBC]) is at least 1000/uL

- Platelet count >= 50,000/uL

- 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:

- 1 month to < 6 months: 0.4 (male) 0.4 (female)

- 6 months to < 1 year: 0.5 (male), 0.5 (female)

- 1 to < 2 years: 0.6 (male), 0.6 (female)

- 2 to < 6 years: 0.8 (male), 0.8 (female)

- 6 to < 10 years: 1 (male), 1 (female)

- 10 to < 13 years: 1.2 (male), 1.2 (female)

- 13 to < 16 years: 1.5 (male), 1.4 (female)

- >= 16 years: 1.7 (male), 1.4 (female)

- Total bilirubin =< 1.5 x upper limit of normal (ULN) for age

- Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 110
U/L (for the purpose of this study, the ULN for SGPT is 45 U/L)

- Serum albumin >= 2 g/dL

- Baseline electrocardiogram (EKG) shows normal corrected QT interval (QTc) interval of
=< 470 milliseconds (ms)

- Shortening fraction of >= 27% by echocardiogram, or

- Ejection fraction of >= 50% by radionuclide angiogram or echocardiogram

- No evidence of dyspnea at rest, no history of exercise intolerance, and a pulse
oximetry > 94%

- Patient has no known history of seizure disorder

- Central nervous system (CNS) toxicity including peripheral neuropathy =< grade 2

Exclusion Criteria:

- Patients with distant bone metastases at original diagnosis or relapse (patients with
only skip lesions will be eligible)

- Patients with concurrent local and pulmonary recurrence at the time of enrollment;
note: patients who had local recurrence previously that has been treated and now
present with an isolated pulmonary recurrence and meet the surgical resection criteria
stated above will be eligible

- Patients with primary refractory disease with progression of the primary tumor on
initial therapy

- Patients with CNS disease or other sites of extra-pulmonary metastases at the time of
most recent episode of disease recurrence preceding enrollment

- Patients with a prior hypersensitivity reaction to sargramostim

- Patients who have received prior anti-GD2 therapy, including chimeric antigen receptor
(CAR) T cells directed against GD2 antigen

- 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; patients should maintain adequate contraception for a minimum of 2
months after the last dose of ch14.18 (dinutuximab)