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

This study has been completed.
Information provided by:
Memorial Sloan-Kettering Cancer Center Identifier:
First received: July 12, 2005
Last updated: January 15, 2013
Last verified: January 2013

July 12, 2005
January 15, 2013
April 2005
April 2007   (final data collection date for primary outcome measure)
  • Maximum tolerated dose (MTD) after 1 course of treatment [ Designated as safety issue: Yes ]
  • Dose-limiting toxicities as assessed by hematology and biochemistry testing on days 1, 8, and 28 of each course [ Designated as safety issue: Yes ]
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Complete list of historical versions of study NCT00119301 on Archive Site
  • Antitumor activity as measured by radiographic response using RECIST criteria after every 2 courses of treatment [ Designated as safety issue: No ]
  • 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 [ Designated as safety issue: No ]
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Methotrexate, Trimetrexate Glucuronate, and Leucovorin in Treating Patients With Refractory or Recurrent Osteosarcoma
Phase I Study of High Dose Methotrexate With Simultaneous Trimetrexate and Leucovorin in Patients With Recurrent Osteosarcoma

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.



  • 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.


  • 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.

Phase 1
Primary Purpose: Treatment
  • Drug: leucovorin calcium
  • Drug: methotrexate
  • Drug: trimetrexate glucuronate
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*   Includes publications given by the data provider as well as publications identified by Identifier (NCT Number) in Medline.
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April 2007   (final data collection date for primary outcome measure)


  • 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



  • 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


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


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


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


  • 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


  • 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


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)


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

Endocrine therapy

  • Not specified


  • 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


  • Not specified


  • 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
1 Year to 35 Years
Contact information is only displayed when the study is recruiting subjects
United States
05-028, MSKCC-IRB-05028
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Memorial Sloan-Kettering Cancer Center
National Cancer Institute (NCI)
Study Chair: Paul A. Meyers, MD Memorial Sloan-Kettering Cancer Center
Memorial Sloan-Kettering Cancer Center
January 2013

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP