Inhaled Sargramostim in Treating Patients With First Pulmonary (Lung) Recurrence of Osteosarcoma

Study Overview
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Brief Summary
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RATIONALE: Inhaling aerosolized sargramostim before and after surgery may interfere with the growth of tumor cells and shrink the tumor so that it can be removed during surgery. Sargramostim may then kill any tumor cells remaining after surgery. This may be an effective treatment for osteosarcoma that has spread to the lung. PURPOSE: This phase II trial is studying how well inhaled sargramostim works in treating patients who are undergoing surgery for the first recurrence of osteosarcoma that has spread to the lung.

Detailed Description
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OBJECTIVES: Primary Assess the histological findings from patients with first pulmonary recurrence of osteosarcoma who undergo resection of pulmonary metastases after treatment with 2 courses of aerosolized sargramostim (GM-CSF). Determine the event-free survival of patients treated with this drug. Determine whether the maximum tolerated dose in the trial of inhaled GM-CSF in adult patients with melanoma is tolerable in pediatric patients. Secondary Determine the effect of specific thoracic surgical management on outcome in patients treated with this drug. OUTLINE: This is a multicenter, dose escalation study. Patients are assigned to 1 of 2 groups according to the extent of pulmonary recurrence (unilateral or bilateral). Group I (unilateral recurrence): Initial inhalation therapy: Patients receive inhaled sargramostim (GM-CSF) twice daily on days 1-7. Treatment repeats every other week every 14 days for a total of 2 courses. Thoracotomy: Patients undergo thoracotomy on day 22. Post-thoracotomy inhalation therapy: Beginning on day 29, or as soon as possible thereafter, patients resume inhalation therapy as above for up to 12 additional courses. Group II (bilateral recurrence): Patients may be enrolled on study either before or after the first thoracotomy. First thoracotomy: Patients undergo unilateral thoracotomy. Initial inhalation therapy: Patients receive inhaled GM-CSF, as soon as possible after recovery from first thoracotomy, twice daily on days 1-7. Treatment repeats every other week every 14 days for a total of 2 courses. Contralateral thoracotomy: Patients undergo contralateral thoracotomy on day 22. Post-thoracotomy inhalation therapy: Beginning on day 29, or as soon as possible, patients resume inhalation therapy as above for up to 12 additional courses. Treatment in both groups continues in the absence of disease progression or unacceptable toxicity. Patients are followed every 2 months for 1 year, every 4 months for 1 year, every 6 months for 3 years, and then annually thereafter. PROJECTED ACCRUAL: A total of 40 patients will be accrued for this study within 1.6-2 years.

Official Title
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A Phase II Study of Aerosolized GM-CSF (NSC# 613795, IND# 11042) in Patients With First Pulmonary Recurrence of Osteosarcoma

Conditions
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Metastatic Cancer, Sarcoma

Intervention / Treatment
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* Biological: sargramostim
* Procedure: conventional surgery


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed osteosarcoma at primary diagnosis Lesions detected in at least 1 lung that are consistent with metastatic disease and approachable with thoracotomy No prior recurrence of osteosarcoma No other sites of metastases Resectable pulmonary nodule(s), defined as nodule(s) that are removable without performing a pneumonectomy (e.g., nodules immediately adjacent to the main stem bronchus or main pulmonary vessels) Prior thoracotomy allowed in patients with imaging consistent with metastatic involvement in both lungs provided the lung on which the thoracotomy was performed is disease-free No pleural effusion or pleural based nodules PATIENT CHARACTERISTICS: Age 39 and under Performance status Karnofsky 50-100% (patients over 16 years of age) Lansky 50-100% (patients 16 years of age and under) Life expectancy At least 8 weeks Hematopoietic Not specified Hepatic Not specified Renal Not specified Pulmonary No evidence of dyspnea at rest No exercise intolerance Pulse oximetry at least 94% Baseline Forced expiratory volume in 1 second (FEV_1) at least 80% of predicted No history of asthma No history of reactive airway disease No history of bronchospasm Other Willing and able to perform inhalation therapy No medical contraindication to surgical excision Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception PRIOR CONCURRENT THERAPY: Biologic therapy No other concurrent immunotherapy No other concurrent immunomodulating agents Chemotherapy No concurrent anticancer chemotherapy Endocrine therapy No concurrent steroids by any route Radiotherapy Not specified Surgery See Disease Characteristics No concurrent thoracoscopy or video-assisted thoracic surgery Other No more than 1 prior treatment regimen for osteosarcoma No concurrent participation in another COG therapeutic study

Ages Eligible for Study
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Maximum Age: 39 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: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1 (unilateral recurrence) - Sargramostim and thoractomy<br>Patients receive initial inhalation therapy inhaled sargramostim (GM-CSF) twice daily on days 1-7. Treatment repeats every other week every 14 days for a total of 2 courses. Patients undergo surgical procedure thoracotomy on day 22. Beginning on day 29, or as soon as possible thereafter, patients begin post-thoracotomy inhalation therapy for up to 12 additional courses. Treatment continues in the absence of disease progression or unacceptable toxicity. Patients are followed every 2 months for 1 year, every 4 months for 1 year, every 6 months for 3 years, and then annually thereafter. | Biological: sargramostim<br>* given by inhalation, dosage escalation Level 1 Dose: 240 micrograms, Level 2 Dose: 1,000 micrograms, and Level 3 Dose: 1,750 micrograms.<br>* Other names: NSC#613795;Procedure: conventional surgery<br>* thoracotomy<br>|
| Experimental: Group 2 (bilateral recurrence) - Sargramostim and thoractomy<br>Patients may be enrolled on study either before or after the first thoracotomy procedure. For the first thoracotomy, patients undergo surgical procedure unilateral thoracotomy. Patients receive initial inhalation therapy inhaled GM-CSF, as soon as possible after recovery from first thoracotomy, twice daily on days 1-7. Treatment repeats every other week every 14 days for a total of 2 courses. Patients undergo surgical procedure contralateral thoracotomy on day 22. Beginning on day 29, or as soon as possible, patients begin post-thoracotomy inhalation therapy as above for up to 12 additional courses. Treatment continues in the absence of disease progression or unacceptable toxicity. Patients are followed every 2 months for 1 year, every 4 months for 1 year, every 6 months for 3 years, and then annually thereafter. | Biological: sargramostim<br>* given by inhalation, dosage escalation Level 1 Dose: 240 micrograms, Level 2 Dose: 1,000 micrograms, and Level 3 Dose: 1,750 micrograms.<br>* Other names: NSC#613795;Procedure: conventional surgery<br>* thoracotomy<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Status of FAS Ligand in Pre-chemotherapy Sample | FAS ligand (FASL) is a homotrimeric type II transmembrane protein expressed on cytotoxic T lymphocytes. The Cluster of Differentiation 1a (CD1a) status is measured in Immunohistochemistry (IHC) categories. | 29 days after start of protocol therapy | 
| Presence of FAS in Pre-chemotherapy Sample | FAS/APO-1 is a transmembrane receptor. The presence is measured in Immunohistochemistry (IHC) categories. | 29 days after start of protocol therapy | 
| FAS Ligand in Post Chemotherapy Sample | FAS ligand or FASL is a homotrimeric type II transmembrane protein expressed on cytotoxic T lymphocytes. The presence is measured in Immunohistochemistry (IHC) categories. | 29 days after start of protocol therapy | 
| FAS Status in Post Chemotherapy Sample | FAS/APO-1 is a transmembrane receptor. The presence is measured in Immunohistochemistry (IHC) categories. | 29 days after start of protocol therapy | 
| CD1a Status in Pre Chemotherapy Sample | CD1a (Cluster of Differentiation 1a) is a human protein encoded by the CD1A gene, presence is measured by positivity. | 29 days after start of protocol therapy | 
| CD1a Status in Post Chemotherapy Sample | CD1a (Cluster of Differentiation 1a) is a human protein encoded by the CD1A gene, presence is measured by positivity. | 29 days after start of protocol therapy | 
| S100 Status in Pre Chemotherapy Sample | The S-100 proteins are a family of low-molecular-weight proteins characterized by two calcium-binding sites that have helix-loop-helix (EF-hand type) conformation. | 29 days after start of protocol therapy | 
| S100 Status in Post Chemotherapy Sample | The S-100 proteins are a family of low-molecular-weight proteins characterized by two calcium-binding sites that have helix-loop-helix (EF-hand type) conformation. | 29 days after start of protocol therapy | 
| Clusterin Status in Pre Chemotherapy Sample | The protein encoded by this gene can under some stress conditions also be found in the cell cytosol. It has been suggested to be involved in several basic biological events such as cell death, tumor progression, and neurodegenerative disorders. | 29 days after start of protocol therapy | 
| Clusterin Status in Post Chemotherapy Sample |  | 29 days after start of protocol therapy | 
| Event Free Survival (EFS) | EFS defined as the time from enrollment on the study until disease progression, occurrence of a second malignant neoplasm (SMN), death or last contact, whichever comes first. Disease progression, occurrence of a SMN or death will be considered an analytic even. In all other cases, the patient will be considered censored at last contact. | Time of enrollment to Event or 5 years from enrollment, whichever occurs first | 
| Feasibility Success | Feasibility success defined as received 21 days of protocol therapy, did not experience grade III or grade IV toxicity according to Common Toxicity Criteria for Adverse Events (CTCAE) version 3 and rendered surgically free of disease in the lungs. | Enrollment through 21 days of protocol therapy | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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metastatic osteosarcoma, recurrent osteosarcoma, lung metastases