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

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy, such as methotrexate, trimetrexate glucuronate, and leucovorin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) may kill more tumor cells. PURPOSE: This phase I trial is studying the side effects and best dose of trimetrexate glucuronate when given together with methotrexate and leucovorin in treating patients with refractory or recurrent osteosarcoma.

Detailed Description
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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.

Official Title
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Phase I Study of High Dose Methotrexate With Simultaneous Trimetrexate and Leucovorin in Patients With Recurrent Osteosarcoma

Conditions
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Sarcoma

Intervention / Treatment
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* Drug: leucovorin calcium
* Drug: methotrexate
* Drug: trimetrexate glucuronate


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 1 Year
Maximum Age: 35 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment


Arms and Interventions

| Intervention/Treatment |
| --- |
|Drug: leucovorin calcium|nan|
|Drug: methotrexate|nan|
|Drug: trimetrexate glucuronate|nan|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerated dose (MTD) after 1 course of treatment |  |  | 
| Dose-limiting toxicities as assessed by hematology and biochemistry testing on days 1, 8, and 28 of each course |  |  | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Antitumor activity as measured by radiographic response using RECIST criteria after every 2 courses of treatment |  |  | 
| Antitumor activity as measured by pathologic response using the Huvos grading system to evaluate post-treatment tumor necrosis at time of tumor resection after completion of study treatment |  |  | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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recurrent osteosarcoma