Combination Chemotherapy and Surgery in Treating Patients With Newly Diagnosed Metastatic Osteosarcoma

A Phase II Window Study of Trimetrexate With Simultaneous Leucovorin Protection in the Treatment of Newly Diagnosed Patients With Metastatic Osteosarcoma

RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Combining more than one drug or combining chemotherapy with surgery may kill more tumor cells.

PURPOSE: Phase II trial to study the effectiveness of combination chemotherapy and surgery in treating patients who have newly diagnosed metastatic osteosarcoma.

Study Overview

• Status: Completed
• Conditions: Sarcoma
• Intervention / Treatment: Drug: leucovorin calcium; Drug: methotrexate; Drug: cisplatin; Drug: doxorubicin hydrochloride; Biological: filgrastim; Drug: ifosfamide; Procedure: surgical procedure; Drug: trimetrexate glucuronate

Detailed Description

OBJECTIVES: I. Determine the efficacy of oral trimetrexate glucuronate with simultaneous leucovorin calcium protection in patients with newly diagnosed metastatic osteogenic sarcoma. II. Evaluate the toxicity of this regimen when administered prior to and following standard chemotherapy in patients with osteogenic sarcoma. III. Correlate response with in vitro determinants of chemotherapy resistance in tumor samples obtained from these patients.

OUTLINE: Patients receive induction therapy of oral trimetrexate glucuronate (TMTX) and leucovorin calcium every 12 hours for 21 days (weeks 0-2). Patients receive leucovorin calcium for 3 additional days after the last dose of TMTX. If age prevents compliance with oral administration, patients receive TMTX IV and leucovorin calcium IV. Patients undergo definitive surgery 7-10 days after the induction therapy (week 4). Patients undergo surgery for metastatic disease, if indicated, as soon as possible following recovery from definitive surgery. Patients then receive maintenance therapy every 3 weeks for 8-9 months according to the following schedule: Patients receive ifosfamide IV over 1 hour 4 times daily on days 1-4 plus doxorubicin IV over 48 hours on days 1-2 in weeks 6, 14, and 22, and ifosfamide alone in week 30. Patients receive cisplatin IV over 4 hours for 1 day, plus doxorubicin IV over 48 hours for 2 days beginning on the same day as the first dose of cisplatin, in weeks 10, 18, and 26. Patients receive cisplatin alone in week 34. Patients receive filgrastim subcutaneously daily for 2 weeks starting 24 hours after the completion of each course of ifosfamide and cisplatin therapy. Patients receive methotrexate IV over 4 hours for 1 day, plus oral leucovorin calcium every 6 hours for at least 10 doses beginning 20 hours after the last dose of methotrexate, in weeks 9, 13, 17, 21, 25, 29, 33, and 37. In severe cases, patients receive leucovorin calcium IV over 24 hours. Patients who respond to induction therapy receive a second course of the same therapy in weeks 38-40. Patients are followed every 4 months for 1 year, then every 6 months for 2 years.

PROJECTED ACCRUAL: A total of 18-33 patients will be accrued for this study over 2-3 years.

• Study Type: Interventional
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • New York
    • New York, New York, United States, 10021
      • Memorial Sloan-Kettering Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 30 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

DISEASE CHARACTERISTICS: Histologically confirmed, newly diagnosed (within one month of biopsy) malignant high grade osteosarcoma Must have pulmonary metastases (two or more nodules) and/or disease involving other bones or organs Must be an intent to resect at least one primary and/or metastatic site following preoperative chemotherapy Must have at least 1 evaluable site of disease No radiation induced sarcoma No osteosarcoma arising in premalignant bony lesions (e.g. Paget's disease)

PATIENT CHARACTERISTICS: Age: 30 and under Performance status: Not specified Life expectancy: Not specified Hematopoietic: Not specified Hepatic: Bilirubin less than 3.0 times normal SGOT and/or SGPT less than 3.0 times normal Renal: Creatinine no greater than 1.5 times normal OR Creatinine clearance or radioisotope GFR greater than 70 mL/min Cardiovascular: Shortening fraction greater than 28% by echocardiogram OR Ejection fraction greater than 50% by radionuclide angiogram No history of pericarditis or myocarditis

PRIOR CONCURRENT THERAPY: Biologic therapy: No concurrent immunomodulating agents except steroids Chemotherapy: No prior chemotherapy No other concurrent chemotherapy Endocrine therapy: No concurrent immunomodulating agents except steroids Radiotherapy: No prior or concurrent radiotherapy Surgery: Prior biopsy only of primary or metastatic area No prior resection Other: No prior therapy for any other malignancy No concurrent co-trimoxazole

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment

Collaborators and Investigators

• Sponsor: Memorial Sloan Kettering Cancer Center
• Collaborators: National Cancer Institute (NCI)
• Investigators: Study Chair: Richard Gorlick, MD, Memorial Sloan Kettering Cancer Center

Study record dates

Study Major Dates

• Study Start: December 1, 1998
• Primary Completion (Actual): March 1, 2000
• Study Completion (Actual): March 1, 2000

Study Registration Dates

• First Submitted: November 1, 1999
• First Submitted That Met QC Criteria: August 17, 2004
• First Posted (Estimate): August 18, 2004

Study Record Updates

• Last Update Posted (Estimate): June 21, 2013
• Last Update Submitted That Met QC Criteria: June 20, 2013
• Last Verified: June 1, 2013

More Information

Terms related to this study

• Keywords: metastatic osteosarcoma
• Additional Relevant MeSH Terms: Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Bone Tissue; Neoplasms, Connective Tissue; Sarcoma; Osteosarcoma; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Protective Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Dermatologic Agents; Micronutrients; Antibiotics, Antineoplastic; Vitamins; Antifungal Agents; Reproductive Control Agents; Antidotes; Vitamin B Complex; Abortifacient Agents, Nonsteroidal; Abortifacient Agents; Folic Acid Antagonists; Ifosfamide; Leucovorin; Levoleucovorin; Doxorubicin; Liposomal doxorubicin; Methotrexate; Trimetrexate
• Other Study ID Numbers: 98-102; CDR0000066905 (Registry Identifier: PDQ (Physician Data Query)); NCI-G99-1507