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

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ClinicalTrials.gov Identifier: NCT00119301
Recruitment Status : Completed
First Posted : July 13, 2005
Last Update Posted : January 17, 2013
National Cancer Institute (NCI)
Information provided by:
Memorial Sloan Kettering Cancer Center

Brief Summary:

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.

Condition or disease Intervention/treatment Phase
Sarcoma Drug: leucovorin calcium Drug: methotrexate Drug: trimetrexate glucuronate Phase 1

Detailed Description:



  • 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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 18 participants
Primary Purpose: Treatment
Official Title: Phase I Study of High Dose Methotrexate With Simultaneous Trimetrexate and Leucovorin in Patients With Recurrent Osteosarcoma
Study Start Date : April 2005
Actual Primary Completion Date : April 2007

Primary Outcome Measures :
  1. Maximum tolerated dose (MTD) after 1 course of treatment
  2. Dose-limiting toxicities as assessed by hematology and biochemistry testing on days 1, 8, and 28 of each course

Secondary Outcome Measures :
  1. Antitumor activity as measured by radiographic response using RECIST criteria after every 2 courses of treatment
  2. 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

Information from the National Library of Medicine

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Ages Eligible for Study:   1 Year to 35 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No


  • 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00119301

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United States, New York
Memorial Sloan-Kettering Cancer Center
New York, New York, United States, 10021
Sponsors and Collaborators
Memorial Sloan Kettering Cancer Center
National Cancer Institute (NCI)
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Study Chair: Paul A. Meyers, MD Memorial Sloan Kettering Cancer Center
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ClinicalTrials.gov Identifier: NCT00119301    
Other Study ID Numbers: 05-028
First Posted: July 13, 2005    Key Record Dates
Last Update Posted: January 17, 2013
Last Verified: January 2013
Keywords provided by Memorial Sloan Kettering Cancer Center:
recurrent osteosarcoma
Additional relevant MeSH terms:
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Neoplasms, Connective and Soft Tissue
Neoplasms by Histologic Type
Neoplasms, Bone Tissue
Neoplasms, Connective Tissue
Calcium-Regulating Hormones and Agents
Physiological Effects of Drugs
Abortifacient Agents, Nonsteroidal
Abortifacient Agents
Reproductive Control Agents
Antimetabolites, Antineoplastic
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Dermatologic Agents
Enzyme Inhibitors
Folic Acid Antagonists
Immunosuppressive Agents
Immunologic Factors
Antirheumatic Agents
Nucleic Acid Synthesis Inhibitors
Protective Agents