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

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

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 Intervention Phase
Drug: leucovorin calcium
Drug: methotrexate
Drug: trimetrexate glucuronate
Phase 1

Study Type: Interventional
Study Design: Primary Purpose: Treatment
Official Title: Phase I Study of High Dose Methotrexate With Simultaneous Trimetrexate and Leucovorin in Patients With Recurrent Osteosarcoma

Resource links provided by NLM:

Further study details as provided by Memorial Sloan Kettering Cancer Center:

Primary Outcome Measures:
  • 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 ]

Secondary Outcome Measures:
  • 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 ]

Estimated Enrollment: 18
Study Start Date: April 2005
Primary Completion Date: April 2007 (Final data collection date for primary outcome measure)
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.


Ages Eligible for Study:   1 Year to 35 Years
Genders Eligible for Study:   Both
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
  Contacts and Locations
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Please refer to this study by its identifier: NCT00119301

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)
Study Chair: Paul A. Meyers, MD Memorial Sloan Kettering Cancer Center
  More Information

Additional Information:
No publications provided Identifier: NCT00119301     History of Changes
Other Study ID Numbers: 05-028, MSKCC-IRB-05028
Study First Received: July 12, 2005
Last Updated: January 15, 2013
Health Authority: United States: Federal Government

Keywords provided by Memorial Sloan Kettering Cancer Center:
recurrent osteosarcoma

Additional relevant MeSH terms:
Neoplasms by Histologic Type
Neoplasms, Bone Tissue
Neoplasms, Connective Tissue
Neoplasms, Connective and Soft Tissue
Abortifacient Agents
Abortifacient Agents, Nonsteroidal
Anti-Infective Agents
Antifungal Agents
Antimetabolites, Antineoplastic
Antineoplastic Agents
Antirheumatic Agents
Dermatologic Agents
Enzyme Inhibitors
Folic Acid Antagonists
Immunologic Factors
Immunosuppressive Agents
Molecular Mechanisms of Pharmacological Action
Nucleic Acid Synthesis Inhibitors
Pharmacologic Actions
Physiological Effects of Drugs
Protective Agents
Reproductive Control Agents processed this record on November 27, 2015