Methotrexate, Trimetrexate Glucuronate, and Leucovorin in Treating Patients With Refractory or Recurrent Osteosarcoma

OBJECTIVES:

Primary

• Determine the maximum tolerated dose of trimetrexate glucuronate when administered with high-dose methotrexate and leucovorin calcium in patients with refractory or recurrent high-grade osteosarcoma.

Secondary

• Determine the dose-limiting toxic effects of this regimen in these patients.
• Determine, preliminarily, the antitumor activity of this regimen in these patients.

OUTLINE: This is a dose-escalation study of trimetrexate glucuronate.

Patients receive high-dose methotrexate IV over 4 hours on days 1 and 8 and oral trimetrexate glucuronate twice daily on days 2-6 and 9-13. Patients also receive leucovorin calcium IV continuously over 24 hours or orally 2 or 4 times daily on days 9-14. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of trimetrexate glucuronate until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity.

PROJECTED ACCRUAL: A maximum of 18 patients will be accrued for this study within 2 years.

DISEASE CHARACTERISTICS:

• Histologically confirmed malignant osteosarcoma

• High-grade disease
• Recurrent or refractory disease after prior standard chemotherapy comprising methotrexate, doxorubicin, cisplatin, and ifosfamide
• No low-grade osteosarcoma
• No parosteal or periosteal sarcoma
• No osteosarcoma arising in premalignant bony lesions (e.g., Paget's disease) OR in a prior radiotherapy field
• No symptomatic or known brain or leptomeningeal involvement

PATIENT CHARACTERISTICS:

Age

• 1 to 35

Performance status

• Karnofsky 70-100% (for patients > 16 years of age)
• Lansky 70-100% (for patients ≤ 16 years of age)

Life expectancy

• At least 3 months

Hematopoietic

• Absolute neutrophil count ≥ 1,000/mm^3
• Platelet count ≥ 75,000/mm^3

Hepatic

• Bilirubin ≤ 1.5 times normal
• AST and ALT ≤ 5 times normal
• Albumin ≥ 2 g/dL
• No clinically significant liver disease

Renal

• Creatinine ≤ 1.5 times normal OR
• Creatinine clearance or radioisotope glomerular filtration rate ≥ lower limit of normal

Cardiovascular

• Shortening fraction ≥ 27% by echocardiogram OR
• Ejection fraction ≥ 50% by gated radionuclide study
• No congestive heart failure
• No angina pectoris
• No myocardial infarction within the past year
• No uncontrolled arterial hypertension
• No uncontrolled arrhythmias

Other

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• No history of significant neurological or psychiatric disorder
• No active infection
• No symptomatic peripheral neuropathy ≥ grade 2
• No other serious illness or medical condition

PRIOR CONCURRENT THERAPY:

Biologic therapy

• At least 7 days since prior biologic therapy
• At least 6 months since prior allogeneic stem cell transplantation AND no evidence of active graft-versus-host disease
• No concurrent sargramostim (GM-CSF)

Chemotherapy

• See Disease Characteristics
• More than 2 weeks since prior myelosuppressive chemotherapy (4 weeks for nitrosoureas)

Endocrine therapy

• Not specified

Radiotherapy

• See Disease Characteristics
• At least 2 weeks since prior local palliative radiotherapy (small port)
• At least 6 months since prior craniospinal radiotherapy
• At least 6 months since prior radiotherapy to ≥ 50% of the pelvis
• At least 6 weeks since prior substantial radiotherapy to the bone marrow

Surgery

• Not specified

Other

• Recovered from prior therapy
• More than 30 days since prior and no other concurrent investigational drugs
• More than 30 days since prior and no concurrent participation in another clinical trial
• No concurrent medications that may interact with study drugs