Trial Information

Feasibility and Dose Discovery Analysis of Zoledronic Acid With Concurrent Chemotherapy in the Treatment of Newly Diagnosed Metastatic Osteosarcoma

OBJECTIVES:

Primary

- To assess the feasibility and safety of zoledronic acid when administered in
combination with standard chemotherapy in patients with newly diagnosed metastatic
osteosarcoma.

- To determine the maximum tolerated dose of zoledronic acid when administered in
combination with standard chemotherapy in these patients.

Secondary

- To compare the histologic response and event-free survival of patients treated with
this regimen versus patients treated on INT-0133 or CCG-7943.

OUTLINE: This is a multicenter, dose-escalation study of zoledronic acid.

- Induction therapy (weeks 1-11): Patients receive dexrazoxane hydrochloride IV slowly
over 5-15 minutes, doxorubicin hydrochloride IV over 15 minutes, and cisplatin IV over
1 hour on days 1 and 2 of weeks 1 and 6; zoledronic acid IV over 30 minutes on day 4 of
weeks 1 and 6; high-dose methotrexate IV over 4 hours on day 1 of weeks 4, 5, 9, and
10; leucovorin calcium IV or orally every 6 hours on day 2 of weeks 4, 5, 9, and 10;
and filgrastim (G-CSF) subcutaneously (SC) once daily beginning on day 3 of weeks 1 and
6 and continuing until blood counts recover.

- Surgery (week 12): Patients undergo definitive surgery (limb-salvage surgery or
amputation) of the primary tumor in week 12.

- Maintenance therapy course 1 (weeks 13-25): Patients receive etoposide IV over 1 hour
and ifosfamide IV over 4 hours on days 1-5 of weeks 13 and 21; zoledronic acid IV over
30 minutes on day 4 of week 17 and on day 7 of weeks 13 and 21; high-dose methotrexate
IV over 4 hours on day 1 of weeks 16, 20, and 24; leucovorin calcium IV or orally every
6 hours on day 2 of weeks 16, 20, and 24; dexrazoxane hydrochloride IV slowly over 5-15
minutes, doxorubicin hydrochloride IV over 15 minutes, and cisplatin IV over 1 hour on
days 1 and 2 of week 17; and G-CSF SC once daily beginning on day 6 of weeks 13, 17,
and 21 and continuing until blood counts recover.

- Surgery (week 26): Patients may undergo surgical resection of primary metastases in
week 26.

- Maintenance therapy course 2 (weeks 27-36): Patients receive dexrazoxane hydrochloride
IV slowly over 5-15 minutes and doxorubicin hydrochloride IV over 15 minutes on days 1
and 2 of weeks 27 and 31; cisplatin IV over 1 hour on days 1 and 2 of week 27;
zoledronic acid IV over 30 minutes on day 4 of week 27 and on day 7 of weeks 31 and 36;
high-dose methotrexate IV over 4 hours on day 1 of weeks 30, 34, and 35; leucovorin
calcium IV or orally every 6 hours on day 2 of weeks 30, 34, and 35; etoposide IV over
1 hour on days 1-5 of week 36; low-dose ifosfamide IV over 1 hour on days 1-5 of week
31; standard-dose ifosfamide IV over 4 hours on days 1-5 of week 36; and G-CSF SC once
daily beginning on day 3 of weeks 27, 31, and 36 and continuing until blood counts
recover.

After completion of study treatment, patients are followed periodically for up to 5 years.