Overview

This trial is active, not recruiting.

Conditions localized osteosarcoma, metastatic osteosarcoma
Treatments doxorubicin hydrochloride, cisplatin, methotrexate, therapeutic conventional surgery, peginterferon alfa-2b, ifosfamide, etoposide, quality-of-life assessment, questionnaire administration
Phase phase 3
Sponsor Children's Oncology Group
Collaborator National Cancer Institute (NCI)
Start date November 2005
End date January 2017
Trial size 1164 participants
Trial identifier NCT00134030, AOST0331, CDR0000438714, COG-AOST0331, EU-20530, EUDRACT-2004-000242-20, ISRCTN67613327, MRC-BO08, MRC-EURAMOS1, NCI-2009-01066, U10CA098543

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.

United States No locations recruiting
Other Countries No locations recruiting

Study Design

Allocation randomized
Endpoint classification efficacy study
Intervention model parallel assignment
Masking open label
Primary purpose treatment
Arm
(Active Comparator)
Patient undergoes definitive surgery (therapeutic conventional surgery). Patients receive doxorubicin hydrochloride 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 methotrexate (MTX) IV over 4 hours on day 1 in weeks 15, 16, 20, 21, 24, 25, 28, and 29. Quality-of-life assessment, prior to start of Cycle 2, after recovery from the doxorubicin of Week 22 Cycle 5, Week 24/Cycle 5, week 72 (18 months after the start of treatment), week 144 (3 years after the start of treatment)
doxorubicin hydrochloride ADM
Given IV
cisplatin CACP
Given IV
methotrexate amethopterin
Given IV
therapeutic conventional surgery
Undergo amputation or limb salvage surgery
quality-of-life assessment quality of life assessment
Ancillary studies
questionnaire administration
Ancillary studies
(Experimental)
Patient undergoes definitive surgery (therapeutic conventional surgery). Patients receive doxorubicin hydrochloride, cisplatin, and high-dose methotrexate (MTX) as in arm I. Patients than receive PEG-interferon alfa-2b subcutaneously once daily on day 1 in weeks 30-104. Quality-of-life assessment, prior to start of Cycle 2, after recovery from the doxorubicin of Week 22 Cycle 5, Week 24/Cycle 5, week 72 (18 months after the start of treatment), week 144 (3 years after the start of treatment)
doxorubicin hydrochloride ADM
Given IV
cisplatin CACP
Given IV
methotrexate amethopterin
Given IV
therapeutic conventional surgery
Undergo amputation or limb salvage surgery
peginterferon alfa-2b PEG-IFN alfa-2b
Given subcutaneously
quality-of-life assessment quality of life assessment
Ancillary studies
questionnaire administration
Ancillary studies
(Active Comparator)
Patient undergoes definitive surgery (therapeutic conventional surgery). Patients receive doxorubicin hydrochloride, cisplatin, and high-dose methotrexate (MTX) as in group 1 arm I. Quality-of-life assessment, prior to start of Cycle 2, after recovery from the doxorubicin of Week 22 Cycle 5, Week 24/Cycle 5, week 72 (18 months after the start of treatment), week 144 (3 years after the start of treatment)
doxorubicin hydrochloride ADM
Given IV
cisplatin CACP
Given IV
methotrexate amethopterin
Given IV
therapeutic conventional surgery
Undergo amputation or limb salvage surgery
quality-of-life assessment quality of life assessment
Ancillary studies
questionnaire administration
Ancillary studies
(Experimental)
Patient undergoes definitive surgery (therapeutic conventional surgery). Patients receive doxorubicin hydrochloride 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 methotrexate (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. Quality-of-life assessment, prior to start of Cycle 2, after recovery from the doxorubicin of Week 22 Cycle 5, Week 24/Cycle 5, week 72 (18 months after the start of treatment), week 144 (3 years after the start of treatment)
doxorubicin hydrochloride ADM
Given IV
cisplatin CACP
Given IV
methotrexate amethopterin
Given IV
therapeutic conventional surgery
Undergo amputation or limb salvage surgery
ifosfamide Cyfos
Given IV
etoposide EPEG
Given IV
quality-of-life assessment quality of life assessment
Ancillary studies
questionnaire administration
Ancillary studies

Primary Outcomes

Measure
Event-free survival
time frame: From date of randomization to date of the event, assessed up to 10 years

Secondary Outcomes

Measure
Overall survival
time frame: From date of randomization to date of death, assessed up to 10 years
Toxicity as measured by CTCAE v3.0
time frame: Up to 10 years
Quality of life
time frame: Up to 3 years

Eligibility Criteria

Male or female participants from 5 years up to 40 years old.

Inclusion Criteria: - Histologically confirmed high-grade osteosarcoma, including second malignancies - Localized or metastatic disease - The primary tumor must be located in the limbs or axial skeleton, including any of the following sites*: - Long bone of upper limb - Short bone of upper limb - Long bone of lower limb - Short bone of lower limb - Vertebral column - Ribs, sternum, clavicle, or scapula - Pelvic bones, sacrum, or coccyx - Tumor (primary, metastatic, or both) resectable OR is expected to become resectable after neoadjuvant induction chemotherapy - Suitable for neoadjuvant chemotherapy - Performance status - Lansky 50-100% (for patients under 16 years of age) - Performance status - Karnofsky 50-100%* - Performance status - WHO or ECOG 0-2* - Platelet count ≥ 100,000/mm³ - Neutrophil count ≥ 1,500/mm³ - WBC ≥ 3,000/mm³ - Bilirubin ≤ 1.5 times upper limit of normal - Creatinine clearance ≥ 70 mL/min - Creatinine based on age as follows: - No greater than 1.0 mg/dL (for patients 5 to 10 years of age) - No greater than 1.2 mg/dL (for patients 11 to 15 years of age) - No greater than 1.5 mg/dL (for patients over 15 years of age) - Ejection fraction ≥ 50% by radionuclide angiogram - Shortening fraction ≥ 28% by echocardiogram - Not pregnant or nursing - Negative pregnancy test - Fertile patients must use effective contraception - No known HIV positivity - No prior chemotherapy for any disease - Prior radiotherapy for another malignancy allowed - No prior treatment for osteosarcoma

Additional Information

Official title 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 (IND# 12697)
Principal investigator Neyssa Marina, MD
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
Trial information was received from ClinicalTrials.gov and was last updated in November 2016.
Information provided to ClinicalTrials.gov by Children's Oncology Group.