NCT00134030

Combination Chemotherapy, PEG-Interferon Alfa-2b, and Surgery in Treating Patients With Osteosarcoma

A Randomized Trial of the European and American Osteosarcoma Study Group to Optimize Treatment Strategies for Resectable Osteosarcoma Based on Histological Response to Pre-operative Chemotherapy

• Status: Completed
• Phase: Phase 3
• Study type: Interventional
• Enrollment: 1,334 (actual)
• Sponsor: Children's Oncology Group · Network
• Sex: All
• Age: 5 Years – 40 Years
• Healthy volunteers: Not accepted

Summary

This randomized phase III trial is studying combination chemotherapy followed by surgery and two different combination chemotherapy regimens with or without PEG-interferon alfa-2b to compare how well they work in treating patients with osteosarcoma. Drugs used in chemotherapy 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. Biological therapies, such as PEG-interferon alfa-2b, may interfere with the growth of tumor cells. Giving combination chemotherapy before surgery may shrink the tumor so it can be removed. Giving combination chemotherapy together with PEG-interferon alfa-2b after surgery may kill any remaining tumor cells. It is not yet known whether giving combination therapy together with PEG-interferon alfa-2b is more effective than two different combination chemotherapy regimens alone after surgery in treating osteosarcoma.

Detailed description

PRIMARY OBJECTIVES: I. Compare whether adjuvant maintenance therapy comprising doxorubicin, cisplatin, and high-dose methotrexate (MAP) alone vs MAP combined with ifosfamide and etoposide improves event-free survival of patients with resectable high-grade osteosarcoma who achieve a poor histological response (HR) to neoadjuvant induction therapy comprising MAP. II. Compare whether adjuvant maintenance therapy comprising MAP alone vs MAP and PEG-interferon alfa-2b improves event-free survival of patients with resectable high-grade osteosarcoma who achieve a good HR to neoadjuvant induction therapy comprising MAP. SECONDARY OBJECTIVES: I. Compare overall survival of patients treated with these regimens. II. Compare short- and long-term toxicity of these regimens in these patients. III. Compare quality of life of patients treated with these regimens. IV. Compare event-free survival and overall survival of patients with localized osteosarcoma treated with these regimens. V. Correlate biological or clinical changes with histological response and outcomes in patients treated with these regimens. VI. Determine outcomes of patients treated with these regimens. OUTLINE: This is a randomized, controlled, multicenter study. INDUCTION THERAPY: (MAP; weeks 1-10) Patients receive doxorubicin IV continuously over 48 hours on days 1-2 and cisplatin IV over 4 hours on days 1 and 2 in weeks 1 and 6. Patients also receive high-dose methotrexate (MTX)\* IV over 4 hours on day 1 in weeks 4, 5, 9, and 10. Patients then proceed to surgery. NOTE: \*Patients must receive \>= 2 but =\< 6 doses of high-dose MTX. SURGERY: Patients undergo amputation or limb salvage surgery in week 11. Tumor tissue is evaluated for histological response to induction therapy. Patients whose tumor is not amenable to macroscopically complete surgical resection undergo radiotherapy and/or other investigational therapy off study. Patients who undergo macroscopically complete surgical resection of the primary tumor or metastases AND who have no disease progression or unacceptable toxicity proceed to maintenance therapy. MAINTENANCE THERAPY: Patients are assigned to 1 of 2 groups according to histological response (good \[\< 10% viable tumor\] vs poor \[≥ 10% viable tumor\]). Patients in each group are stratified according to site of primary tumor and presence of metastases. GROUP 1: (good histological response) Patient are randomized to 1 of 2 treatment arms within 35 days after surgery. ARM I: (MAP; weeks 12-29) Patients receive doxorubicin IV continuously over 48 hours on days 1-2 in weeks 12, 17, 22, and 26 and cisplatin IV over 4 hours on days 1 and 2 in weeks 12 and 17. Patients also receive high-dose MTX IV over 4 hours on day 1 in weeks 15, 16, 20, 21, 24, 25, 28, and 29. ARM II: (MAPifn; weeks 12-104) Patients receive doxorubicin, cisplatin, and high-dose MTX as in arm I. Patients than receive PEG-interferon alfa-2b subcutaneously once daily on day 1 in weeks 30-104. GROUP 2: (poor histological response) Patients are randomized to 1 of 2 treatment arms within 35 days after surgery. ARM I: (MAP; weeks 12-29) Patients receive doxorubicin, cisplatin, and high-dose MTX as in group 1 arm I. ARM II: (MAPIE; weeks 12-40) Patients receive doxorubicin IV continuously over 48 hours on days 1-2 in weeks 12, 20, 28, and 36 and cisplatin IV over 4 hours on days 1 and 2 in weeks 12 and 28. Patients also receive high-dose MTX IV over 4 hours on day 1 in weeks 15, 19, 23, 27, 31, 35, 39, and 40. Patients receive ifosfamide IV over 4 hours on days 1-5 in weeks 16, 24, and 32 and on days 1-3 in weeks 20 and 36 and etoposide IV over 1 hour on days 1-5 in weeks 16, 24, and 32. In both groups, treatment continues in the absence of disease progression or unacceptable toxicity. Quality of life is assessed periodically. After completion of study treatment, patients are followed every 1½-3 months for 2 years, every 2-4 months for 2 years, every 6 months for 6 years, and then every 6-12 months thereafter. Peer Reviewed and Funded or Endorsed by Cancer Research UK

Conditions

• Localized Osteosarcoma
• Metastatic Osteosarcoma

Interventions

Type	Name	Description
DRUG	Cisplatin	Given IV
DRUG	Doxorubicin Hydrochloride	Given IV
DRUG	Etoposide	Given IV
DRUG	Ifosfamide	Given IV
DRUG	Methotrexate	Given IV
BIOLOGICAL	Peginterferon Alfa-2b	Given subcutaneously
OTHER	Quality-of-Life Assessment	Ancillary studies
OTHER	Questionnaire Administration	Ancillary studies
PROCEDURE	Therapeutic Conventional Surgery	Undergo amputation or limb salvage surgery

Timeline

• Start date: 2005-11-14
• Primary completion: 2015-01-31
• Completion: 2022-09-30
• First posted: 2005-08-24
• Last updated: 2023-06-07
• Results posted: 2023-06-07

Locations

218 sites across 6 countries: United States, Australia, Canada, New Zealand, Puerto Rico, Switzerland