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Methotrexate, Trimetrexate Glucuronate, and Leucovorin in Treating Patients With Refractory or Recurrent Osteosarcoma
This study has been completed.
First Received: July 12, 2005   Last Updated: July 23, 2008   History of Changes
Sponsors and Collaborators: Memorial Sloan-Kettering Cancer Center
National Cancer Institute (NCI)
Information provided by: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT00119301
  Purpose

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
Sarcoma
Drug: leucovorin calcium
Drug: methotrexate
Drug: trimetrexate glucuronate
Phase I

MedlinePlus related topics: Cancer Soft Tissue Sarcoma
Drug Information available for: Leucovorin Methotrexate Citrovorum factor Trimetrexate Trimetrexate glucuronate Leucovorin Calcium Folinic acid calcium salt pentahydrate
U.S. FDA Resources
Study Type: Interventional
Study Design: Treatment
Official Title: Phase I Study of High Dose Methotrexate With Simultaneous Trimetrexate and Leucovorin in Patients With Recurrent Osteosarcoma

Further study details as provided by National Cancer Institute (NCI):

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
Detailed Description:

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.

  Eligibility

Ages Eligible for Study:   1 Year to 35 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00119301

Locations
United States, New York
Memorial Sloan-Kettering Cancer Center
New York, New York, United States, 10021
Sponsors and Collaborators
Memorial Sloan-Kettering Cancer Center
Investigators
Study Chair: Paul A. Meyers, MD Memorial Sloan-Kettering Cancer Center
  More Information

Additional Information:
No publications provided

Study ID Numbers: CDR0000434483, MSKCC-IRB-05028
Study First Received: July 12, 2005
Last Updated: July 23, 2008
ClinicalTrials.gov Identifier: NCT00119301     History of Changes
Health Authority: United States: Federal Government

Keywords provided by National Cancer Institute (NCI):
recurrent osteosarcoma

Study placed in the following topic categories:
Antimetabolites
Immunologic Factors
Clotrimazole
Miconazole
Leucovorin
Neoplasms, Connective and Soft Tissue
Soft Tissue Sarcomas
Vitamins
Antifungal Agents
Methotrexate
Osteogenic Sarcoma
Micronutrients
Trimetrexate
Vitamin B Complex
Tioconazole
Osteosarcoma
Trace Elements
Folic Acid Antagonists
Immunosuppressive Agents
Recurrence
Folic Acid
Calcium, Dietary
Malignant Mesenchymal Tumor
Sarcoma
Antirheumatic Agents

Additional relevant MeSH terms:
Antimetabolites
Anti-Infective Agents
Antimetabolites, Antineoplastic
Immunologic Factors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Physiological Effects of Drugs
Leucovorin
Reproductive Control Agents
Neoplasms, Connective and Soft Tissue
Antifungal Agents
Vitamins
Therapeutic Uses
Abortifacient Agents
Methotrexate
Micronutrients
Dermatologic Agents
Nucleic Acid Synthesis Inhibitors
Trimetrexate
Vitamin B Complex
Neoplasms by Histologic Type
Growth Substances
Osteosarcoma
Enzyme Inhibitors
Folic Acid Antagonists
Abortifacient Agents, Nonsteroidal
Immunosuppressive Agents
Pharmacologic Actions
Neoplasms
Neoplasms, Bone Tissue

ClinicalTrials.gov processed this record on May 07, 2009