Trial Information

A Phase II Window Study of Trimetrexate With Simultaneous Leucovorin Protection in the Treatment of Newly Diagnosed Patients With Metastatic Osteosarcoma

OBJECTIVES: I. Determine the efficacy of oral trimetrexate glucuronate with simultaneous
leucovorin calcium protection in patients with newly diagnosed metastatic osteogenic
sarcoma. II. Evaluate the toxicity of this regimen when administered prior to and following
standard chemotherapy in patients with osteogenic sarcoma. III. Correlate response with in
vitro determinants of chemotherapy resistance in tumor samples obtained from these patients.

OUTLINE: Patients receive induction therapy of oral trimetrexate glucuronate (TMTX) and
leucovorin calcium every 12 hours for 21 days (weeks 0-2). Patients receive leucovorin
calcium for 3 additional days after the last dose of TMTX. If age prevents compliance with
oral administration, patients receive TMTX IV and leucovorin calcium IV. Patients undergo
definitive surgery 7-10 days after the induction therapy (week 4). Patients undergo surgery
for metastatic disease, if indicated, as soon as possible following recovery from definitive
surgery. Patients then receive maintenance therapy every 3 weeks for 8-9 months according to
the following schedule: Patients receive ifosfamide IV over 1 hour 4 times daily on days 1-4
plus doxorubicin IV over 48 hours on days 1-2 in weeks 6, 14, and 22, and ifosfamide alone
in week 30. Patients receive cisplatin IV over 4 hours for 1 day, plus doxorubicin IV over
48 hours for 2 days beginning on the same day as the first dose of cisplatin, in weeks 10,
18, and 26. Patients receive cisplatin alone in week 34. Patients receive filgrastim
subcutaneously daily for 2 weeks starting 24 hours after the completion of each course of
ifosfamide and cisplatin therapy. Patients receive methotrexate IV over 4 hours for 1 day,
plus oral leucovorin calcium every 6 hours for at least 10 doses beginning 20 hours after
the last dose of methotrexate, in weeks 9, 13, 17, 21, 25, 29, 33, and 37. In severe cases,
patients receive leucovorin calcium IV over 24 hours. Patients who respond to induction
therapy receive a second course of the same therapy in weeks 38-40. Patients are followed
every 4 months for 1 year, then every 6 months for 2 years.

PROJECTED ACCRUAL: A total of 18-33 patients will be accrued for this study over 2-3 years.