A Study of Pre-Operative Treatment of Newly-Diagnosed, Surgically-Resectable Osteosarcoma With Doxorubicin, Ifosfamide, Etoposide, and Cisplatin With Early Metabolic Assessment of Response

This is a pilot study that will allow investigators to collect data related to early and
potentially more accurate response assessments using a chemotherapy protocol that eliminates
methotrexate to maximize the dose intensity of doxorubicin. The pilot data will be used to
seek funding to more fully address the hypotheses in a multi-institutional, Phase II or
Phase III trial. The primary and secondary objectives are as follows:

Primary:

1. To evaluate the feasibility and potential usefulness of measuring early changes in
tumor metabolic activity, assessed by Fludeoxyglucose-Positron Emission Tomography
(FDG-PET) imaging and alkaline phosphatase activity, as early predictors of
histological response rate at 12 weeks in osteosarcoma patients.

2. To explore whether histological response can be assessed by a computer algorithm using
virtual microscopic images of pathology material, and whether quantifying necrosis in
this way correlates with microscope slide-based review.

Secondary:

1. To gather pilot data on the histological response rate, 3-year event-free survival, and
toxicity when children and young adults with resectable osteosarcoma are treated using a
chemotherapy regimen of alternating courses of doxorubicin/cisplatin (DC) and
doxorubicin/ifosfamide/etoposide (IDE).

All patients will receive 4 courses of preoperative chemotherapy courses. With the
exception of high-dose methotrexate, which is given weekly, preoperative and postoperative
chemotherapy courses are planned to begin every 21 days.

Patients with good histological response (those patients with > 90% tumor necrosis at time
of definitive resection) will receive three postoperative chemotherapy courses. The 1st
will consist of doxorubicin, dexrazoxane, cisplatin and Granulocyte-Colony Stimulating
Factor (G-CSF)(or Polyethylene Glycol filgrastim). The 2nd course will consist of
doxorubicin, dexrazoxane, ifosfamide, MESNA, etoposide, G-CSF (or PEG-filgrastim). The 3rd
course will consist of ifosfamide, MESNA, etoposide, G-CSF (or PEG-filgrastrim). The total
doxorubicin dose will be 450 mg/m2.

Patients with poor response (those patients with < 90% tumor necrosis found on pathology at
time of definitive resection) will receive five postoperative chemotherapy courses. High
Dose-Methotrexate will be administered during the 1st and 3rd postoperative chemotherapy
courses as 4-weekly and 2-weekly doses, respectively. The 2nd course will consist of
doxorubicin, dexrazoxane, cisplatin and G-CSF (or PEG-filgrastim). The 4th course will
consist of doxorubicin, dexrazoxane, ifosfamide, Mesna, etoposide, G-CSF (or
PEG-filgrastim). The 5th cycle will consist of ifosfamide, Mesna, etoposide, G-CSF (or
PEG-filgrastrim). The total doxorubicin dose will be 450 mg/m2.