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

Study Overview
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Brief Summary
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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
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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

Official Title
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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

Conditions
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Localized Osteosarcoma, Metastatic Osteosarcoma

Intervention / Treatment
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* Drug: Cisplatin
* Drug: Doxorubicin Hydrochloride
* Drug: Etoposide
* Drug: Ifosfamide
* Drug: Methotrexate
* Biological: Peginterferon Alfa-2b
* Other: Quality-of-Life Assessment
* Other: Questionnaire Administration
* Procedure: Therapeutic Conventional Surgery


Participation Criteria
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Eligibility Criteria
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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 No patients with any of the following: Craniofacial osteosarcoma

Ages Eligible for Study
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Minimum Age: 5 Years
Maximum Age: 40 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Maintenance therapy group 1 arm I<br>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. | Drug: Cisplatin<br>* Given IV<br>* Other names: Platosin;Drug: Doxorubicin Hydrochloride<br>* Given IV<br>* Other names: Rubex;Drug: Methotrexate<br>* Given IV<br>* Other names: WR-19039;Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Other: Questionnaire Administration<br>* Ancillary studies<br>Procedure: Therapeutic Conventional Surgery<br>* Undergo amputation or limb salvage surgery<br>|
| Experimental: Maintenance therapy group 1 arm II<br>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. | Drug: Cisplatin<br>* Given IV<br>* Other names: Platosin;Drug: Doxorubicin Hydrochloride<br>* Given IV<br>* Other names: Rubex;Drug: Methotrexate<br>* Given IV<br>* Other names: WR-19039;Biological: Peginterferon Alfa-2b<br>* Given subcutaneously<br>* Other names: Sylatron;Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Other: Questionnaire Administration<br>* Ancillary studies<br>Procedure: Therapeutic Conventional Surgery<br>* Undergo amputation or limb salvage surgery<br>|
| Active Comparator: Maintenance therapy group 2 arm I<br>Patients receive doxorubicin, cisplatin, and high-dose MTX as in group 1 arm I. | Drug: Cisplatin<br>* Given IV<br>* Other names: Platosin;Drug: Doxorubicin Hydrochloride<br>* Given IV<br>* Other names: Rubex;Drug: Methotrexate<br>* Given IV<br>* Other names: WR-19039;Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Other: Questionnaire Administration<br>* Ancillary studies<br>Procedure: Therapeutic Conventional Surgery<br>* Undergo amputation or limb salvage surgery<br>|
| Experimental: Maintenance therapy group 2 arm II<br>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. | Drug: Cisplatin<br>* Given IV<br>* Other names: Platosin;Drug: Doxorubicin Hydrochloride<br>* Given IV<br>* Other names: Rubex;Drug: Etoposide<br>* Given IV<br>* Other names: VP16;Drug: Ifosfamide<br>* Given IV<br>* Other names: Z-4942;Drug: Methotrexate<br>* Given IV<br>* Other names: WR-19039;Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Other: Questionnaire Administration<br>* Ancillary studies<br>Procedure: Therapeutic Conventional Surgery<br>* Undergo amputation or limb salvage surgery<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event-free Survival (EFS) | EFS is defined as time from randomisation to the first of: death, detection of local recurrence or metastasis, progression of metastatic disease, or detection of a secondary malignancy. EFS will be assessed using the logrank test and expressed using hazard ratios with appropriate confidence intervals. Follow up per participant will be assessed for up to 10 years. The 3 year EFS is provided as a summary. | From date of randomization to date of the event. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Patients With Overall Survival | Overall survival is time from randomization until death from any cause. Will be assessed using the logrank test and expressed using hazard ratios with appropriate confidence intervals. Participants will be assessed for up to 10 years. 5 year overall survival is provided as a summary. | From date of randomization to date of death. | 
| Toxicity as Measured by Common Terminology Criteria for Adverse Events (CTCAE) v3.0 | Percentages of patients experiencing grade 3 and 4 adverse events. These will be compared using chi-square tests or Fisher's exact tests where appropriate. | Adverse events are assessed for up to 10 years per participant. |