Trial Information

A Groupwide Phase II Study of Trastuzumab (Herceptin) in Metastatic Osteosarcoma Patients With Tumors That Overexpress HER2

PRIMARY OBJECTIVES:

I. Determine the feasibility and safety of trastuzumab (Herceptin) and chemotherapy in
patients with HER2-overexpressing (2+ level of expression) metastatic osteosarcoma.

II. Determine the response rate and 3-year event-free survival of patients treated with this
regimen.

III. Determine the cardiac toxicity and late effects of this regimen in these patients.

IV. Determine the response rate and 3-year event-free survival of poor-risk patients with
HER2-negative tumors treated with chemotherapy without the addition of trastuzumab.

OUTLINE: This is a multicenter study. Patients are stratified according to tumor HER2 status
(positive vs negative).

Patients receive induction therapy comprising doxorubicin IV over 20 minutes followed by
cisplatin IV over 4 hours on days 1 and 2 of weeks 1 and 6, and methotrexate IV over 4 hours
on day 1 of weeks 4, 5, 9, and 10. Patients also receive leucovorin calcium IV or orally
every 6 hours beginning 24 hours after each methotrexate dose and continuing for at least 10
doses until methotrexate levels sufficiently decrease. Within 24-36 hours after completion
of induction therapy, patients receive filgrastim (G-CSF) daily until blood counts recover.

Patients undergo resection of any remaining primary tumor and/or metastatic lesions during
week 11. Patients who are unable to undergo resection receive radiotherapy between weeks 11
and 17.

Patients receive post-induction therapy comprising doxorubicin IV over 20 minutes on days 1
and 2 of weeks 17, 25, and 29; cisplatin IV over 4 hours on days 1 and 2 of weeks 17 and 25;
methotrexate IV over 4 hours on day 1 of weeks 16, 20, 24, 28, 32, and 33; etoposide IV over
1 hour on days 1-5 of weeks 13, 21, and 34; and ifosfamide IV over 4 hours on days 1-5 of
weeks 13, 21, 29, and 34. Patients also receive leucovorin calcium and G-CSF as in induction
therapy. Patients whose tumors are found to over express HER2 (2+ level of expression) also
receive trastuzumab IV over 30-90 minutes once a week for a total of 34 weeks in addition to
the chemotherapy regimen.

Patients are followed monthly for 1 year, every 2 months for 1 year, every 6 months for 2
years, and then annually thereafter.

PROJECTED ACCRUAL: A total of 80 patients (40 patients per stratum) will be accrued for this
study within 2.5 years.