Combination Chemotherapy, PEG-Interferon Alfa-2b, and Surgery in Treating Patients With Osteosarcoma

PRIMARY OBJECTIVES:

I. Compare whether adjuvant maintenance therapy comprising doxorubicin, cisplatin, and
high-dose methotrexate (MAP) alone vs MAP combined with ifosfamide and etoposide improves
event-free survival of patients with resectable high-grade osteosarcoma who achieve a poor
histological response (HR) to neoadjuvant induction therapy comprising MAP.

II. Compare whether adjuvant maintenance therapy comprising MAP alone vs MAP and
PEG-interferon alfa-2b improves event-free survival of patients with resectable high-grade
osteosarcoma who achieve a good HR to neoadjuvant induction therapy comprising MAP.

SECONDARY OBJECTIVES:

I. Compare overall survival of patients treated with these regimens. II. Compare short- and
long-term toxicity of these regimens in these patients. III. Compare quality of life of
patients treated with these regimens. IV. Compare event-free survival and overall survival of
patients with localized osteosarcoma treated with these regimens.

V. Correlate biological or clinical changes with histological response and outcomes in
patients treated with these regimens.

VI. Determine outcomes of patients treated with these regimens.

OUTLINE: This is a randomized, controlled, multicenter study.

INDUCTION THERAPY: (MAP; weeks 1-10) Patients receive doxorubicin IV continuously over 48
hours on days 1-2 and cisplatin IV over 4 hours on days 1 and 2 in weeks 1 and 6. Patients
also receive high-dose methotrexate (MTX)* IV over 4 hours on day 1 in weeks 4, 5, 9, and 10.
Patients then proceed to surgery.

NOTE: *Patients must receive >= 2 but =< 6 doses of high-dose MTX.

SURGERY: Patients undergo amputation or limb salvage surgery in week 11. Tumor tissue is
evaluated for histological response to induction therapy. Patients whose tumor is not
amenable to macroscopically complete surgical resection undergo radiotherapy and/or other
investigational therapy off study. Patients who undergo macroscopically complete surgical
resection of the primary tumor or metastases AND who have no disease progression or
unacceptable toxicity proceed to maintenance therapy.

MAINTENANCE THERAPY: Patients are assigned to 1 of 2 groups according to histological
response (good [< 10% viable tumor] vs poor [? 10% viable tumor]). Patients in each group are
stratified according to site of primary tumor and presence of metastases.

GROUP 1: (good histological response) Patient are randomized to 1 of 2 treatment arms within
35 days after surgery.

ARM I: (MAP; weeks 12-29) Patients receive doxorubicin IV continuously over 48 hours on days
1-2 in weeks 12, 17, 22, and 26 and cisplatin IV over 4 hours on days 1 and 2 in weeks 12 and
17. Patients also receive high-dose MTX IV over 4 hours on day 1 in weeks 15, 16, 20, 21, 24,
25, 28, and 29.

ARM II: (MAPifn; weeks 12-104) Patients receive doxorubicin, cisplatin, and high-dose MTX as
in arm I. Patients than receive PEG-interferon alfa-2b subcutaneously once daily on day 1 in
weeks 30-104.

GROUP 2: (poor histological response) Patients are randomized to 1 of 2 treatment arms within
35 days after surgery.

ARM I: (MAP; weeks 12-29) Patients receive doxorubicin, cisplatin, and high-dose MTX as in
group 1 arm I.

ARM II: (MAPIE; weeks 12-40) Patients receive doxorubicin IV continuously over 48 hours on
days 1-2 in weeks 12, 20, 28, and 36 and cisplatin IV over 4 hours on days 1 and 2 in weeks
12 and 28. Patients also receive high-dose MTX IV over 4 hours on day 1 in weeks 15, 19, 23,
27, 31, 35, 39, and 40. Patients receive ifosfamide IV over 4 hours on days 1-5 in weeks 16,
24, and 32 and on days 1-3 in weeks 20 and 36 and etoposide IV over 1 hour on days 1-5 in
weeks 16, 24, and 32.

In both groups, treatment continues in the absence of disease progression or unacceptable
toxicity. Quality of life is assessed periodically.

After completion of study treatment, patients are followed every 1?-3 months for 2 years,
every 2-4 months for 2 years, every 6 months for 6 years, and then every 6-12 months
thereafter. Peer Reviewed and Funded or Endorsed by Cancer Research UK

Inclusion Criteria:

- Histologically confirmed high-grade osteosarcoma, including second malignancies

- Localized or metastatic disease

- The primary tumor must be located in the limbs or axial skeleton, including any
of the following sites*:

- Long bone of upper limb

- Short bone of upper limb

- Long bone of lower limb

- Short bone of lower limb

- Vertebral column

- Ribs, sternum, clavicle, or scapula

- Pelvic bones, sacrum, or coccyx

- Tumor (primary, metastatic, or both) resectable OR is expected to become resectable
after neoadjuvant induction chemotherapy

- Suitable for neoadjuvant chemotherapy

- Performance status - Lansky 50-100% (for patients under 16 years of age)

- Performance status - Karnofsky 50-100%*

- Performance status - WHO or ECOG 0-2*

- Platelet count ? 100,000/mm?

- Neutrophil count ? 1,500/mm?

- WBC ? 3,000/mm?

- Bilirubin ? 1.5 times upper limit of normal

- Creatinine clearance ? 70 mL/min

- Creatinine based on age as follows:

- No greater than 1.0 mg/dL (for patients 5 to 10 years of age)

- No greater than 1.2 mg/dL (for patients 11 to 15 years of age)

- No greater than 1.5 mg/dL (for patients over 15 years of age)

- Ejection fraction ? 50% by radionuclide angiogram

- Shortening fraction ? 28% by echocardiogram

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception

- No known HIV positivity

- No prior chemotherapy for any disease

- Prior radiotherapy for another malignancy allowed

- No prior treatment for osteosarcoma