Chemotherapy With or Without Trastuzumab in Treating Patients With Metastatic Osteosarcoma

National Cancer Institute (NCI)

Status and phase: Completed; Phase 2

Conditions: Metastatic Osteosarcoma

Treatments: Other: laboratory biomarker analysis; Drug: etoposide; Procedure: therapeutic conventional surgery; Biological: filgrastim; Biological: trastuzumab; Radiation: radiation therapy; Drug: doxorubicin hydrochloride; Drug: methotrexate; Drug: leucovorin calcium; Drug: cisplatin; Drug: ifosfamide

Study type: Interventional

Funder types: NIH

Identifiers

NCT00023998

NCI-2012-01863

U10CA098543 (U.S. NIH Grant/Contract)

AOST0121

CDR0000068882 (Registry Identifier)

Details and patient eligibility

About

Drugs used in chemotherapy work in different ways to stop tumor cells from dividing so they stop growing or die. Monoclonal antibodies such as trastuzumab can locate tumor cells and kill them without harming normal cells. Combining monoclonal antibody therapy with chemotherapy may kill more tumor cells. Phase II trial to study the effectiveness of chemotherapy with or without trastuzumab in treating patients who have metastatic osteosarcoma

Full description

PRIMARY OBJECTIVES:

I. Determine the feasibility and safety of trastuzumab (Herceptin) and chemotherapy in patients with HER2-overexpressing (2+ level of expression) metastatic osteosarcoma.

II. Determine the response rate and 3-year event-free survival of patients treated with this regimen.

III. Determine the cardiac toxicity and late effects of this regimen in these patients.

IV. Determine the response rate and 3-year event-free survival of poor-risk patients with HER2-negative tumors treated with chemotherapy without the addition of trastuzumab.

OUTLINE: This is a multicenter study. Patients are stratified according to tumor HER2 status (positive vs negative).

Patients receive induction therapy comprising doxorubicin IV over 20 minutes followed by cisplatin IV over 4 hours on days 1 and 2 of weeks 1 and 6, and methotrexate IV over 4 hours on day 1 of weeks 4, 5, 9, and 10. Patients also receive leucovorin calcium IV or orally every 6 hours beginning 24 hours after each methotrexate dose and continuing for at least 10 doses until methotrexate levels sufficiently decrease. Within 24-36 hours after completion of induction therapy, patients receive filgrastim (G-CSF) daily until blood counts recover.

Patients undergo resection of any remaining primary tumor and/or metastatic lesions during week 11. Patients who are unable to undergo resection receive radiotherapy between weeks 11 and 17.

Patients receive post-induction therapy comprising doxorubicin IV over 20 minutes on days 1 and 2 of weeks 17, 25, and 29; cisplatin IV over 4 hours on days 1 and 2 of weeks 17 and 25; methotrexate IV over 4 hours on day 1 of weeks 16, 20, 24, 28, 32, and 33; etoposide IV over 1 hour on days 1-5 of weeks 13, 21, and 34; and ifosfamide IV over 4 hours on days 1-5 of weeks 13, 21, 29, and 34. Patients also receive leucovorin calcium and G-CSF as in induction therapy. Patients whose tumors are found to over express HER2 (2+ level of expression) also receive trastuzumab IV over 30-90 minutes once a week for a total of 34 weeks in addition to the chemotherapy regimen.

Patients are followed monthly for 1 year, every 2 months for 1 year, every 6 months for 2 years, and then annually thereafter.

PROJECTED ACCRUAL: A total of 80 patients (40 patients per stratum) will be accrued for this study within 2.5 years.

Enrollment: 80 patients

Sex: All

Ages: Under 30 years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

Inclusion Criteria:

• Histologically confirmed high-grade osteosarcoma

  • Metastatic
  • Newly diagnosed

• No osteosarcoma arising in areas of Paget's disease or radiotherapy-induced sarcoma

• Presenting with at least 1 of the following:

  • Bone metastases with or without lung metastases
  • Bilateral lung metastases (any number of nodules)
  • Unilateral lung metastases with at least 4 nodules

• Planned resection of either the primary site or a metastatic site of disease after completion of induction therapy

• Must be currently enrolled on the tumor biology study COG-P9851

• Performance status - ECOG 0-2

• Performance status - Karnofsky 50-100% (over age 10)

• Performance status - Lansky 50-100% (age 10 and under)

• Absolute neutrophil count > 1,000/mm^3

• Platelet count > 100,000/mm^3

• Bilirubin ≤ 1.5 times normal

• SGPT ≤ 3 times normal

• Creatinine ≤ 1.5 times normal

• Creatinine clearance or glomerular filtration rate ≥ 70 mL/min

• Shortening fraction ≥ 28% by echocardiogram

• Ejection fraction ≥ 50% by echocardiogram or MUGA

• No history of pericarditis, myocarditis, symptomatic arrhythmia, or conduction disturbances

• Normal organ function

• HIV negative

• Not pregnant or nursing

• Fertile patients must use effective contraception

• No prior chemotherapy

• No prior radiotherapy

• See Disease Characteristics

Trial design

Primary purpose: Treatment

Allocation: N/A

Interventional model: Single Group Assignment

Masking: None (Open label)

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80 participants in 1 patient group

Treatment (combination chemotherapy)

Experimental group

Description:

See detailed description.

Treatment:

Drug: ifosfamide

Procedure: therapeutic conventional surgery

Other: laboratory biomarker analysis

Drug: cisplatin

Drug: leucovorin calcium

Radiation: radiation therapy

Drug: methotrexate

Drug: doxorubicin hydrochloride

Biological: trastuzumab

Biological: filgrastim

Drug: etoposide