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

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

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.

Study Overview

• Status: Completed
• Conditions: Sarcoma; Metastatic Cancer
• Intervention / Treatment: Biological: sargramostim; Procedure: conventional surgery

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 49
• Phase: Phase 2

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Westmead, New South Wales, Australia, 2145
      • Westmead Institute for Cancer Research at Westmead Hospital
  • Western Australia
    • Perth, Western Australia, Australia, 6001
      • Princess Margaret Hospital for Children
• Canada
  • Quebec, Canada, G1V 4G2
    • Centre Hospitalier Universitaire de Quebec
  • Manitoba
    • Winnipeg, Manitoba, Canada, R3E 0V9
      • CancerCare Manitoba
  • Nova Scotia
    • Halifax, Nova Scotia, Canada, B3K 6R8
      • IWK Health Centre
  • Ontario
    • Hamilton, Ontario, Canada, L8N 3Z5
      • McMaster Children's Hospital at Hamilton Health Sciences
  • Quebec
    • Montreal, Quebec, Canada, H3H 1P3
      • Montreal Children's Hospital at McGill University Health Center
    • Montreal, Quebec, Canada, H3T 1C5
      • Hopital Sainte Justine
  • Saskatchewan
    • Saskatoon, Saskatchewan, Canada, S7N 4H4
      • Saskatoon Cancer Centre at the University of Saskatchewan
• Puerto Rico
  • Santurce, Puerto Rico, 00912
    • San Jorge Children's Hospital
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • Lurleen Wallace Comprehensive Cancer at University of Alabama - Birmingham
  • Arizona
    • Phoenix, Arizona, United States, 85016-7710
      • Phoenix Children's Hospital
    • Tucson, Arizona, United States, 85724-5024
      • Arizona Cancer Center at University of Arizona Health Sciences Center
  • Arkansas
    • Little Rock, Arkansas, United States, 72205
      • Arkansas Cancer Research Center at University of Arkansas for Medical Sciences
  • California
    • Downey, California, United States, 90242-2814
      • Southern California Permanente Medical Group
    • Loma Linda, California, United States, 92354
      • Loma Linda University Cancer Institute at Loma Linda University Medical Center
    • Long Beach, California, United States, 90801
      • Jonathan Jaques Children's Cancer Center at Miller Children's Hospital
    • Oakland, California, United States, 94609
      • Children's Hospital and Research Center Oakland
    • Sacramento, California, United States, 95817
      • University of California Davis Cancer Center
    • San Francisco, California, United States, 94115
      • UCSF Helen Diller Family Comprehensive Cancer Center
    • Stanford, California, United States, 94305-5824
      • Stanford Cancer Center
  • Delaware
    • Wilmington, Delaware, United States, 19803
      • Alfred I. DuPont Hospital for Children
  • District of Columbia
    • Washington, District of Columbia, United States, 20010-2970
      • Children's National Medical Center
    • Washington, District of Columbia, United States, 20007
      • Lombardi Comprehensive Cancer Center at Georgetown University Medical Center
  • Florida
    • Fort Myers, Florida, United States, 33901
      • Lee Cancer Care of Lee Memorial Health System
    • Gainesville, Florida, United States, 32610-0232
      • University of Florida Shands Cancer Center
    • Jacksonville, Florida, United States, 32207
      • Nemours Children's Clinic
    • Miami, Florida, United States, 33136
      • University of Miami Sylvester Comprehensive Cancer Center - Miami
    • Miami, Florida, United States, 33155
      • Miami Children's Hospital
    • Miami, Florida, United States, 33176
      • Baptist-South Miami Regional Cancer Program
    • Orlando, Florida, United States, 32806
      • Nemours Children's Clinic - Orlando
    • Pensacola, Florida, United States, 32504
      • Sacred Heart Cancer Center at Sacred Heart Hospital
    • St. Petersburg, Florida, United States, 33701
      • All Children's Hospital
    • Tampa, Florida, United States, 33607
      • St. Joseph's Cancer Institute at St. Joseph's Hospital
    • West Palm Beach, Florida, United States, 33407
      • Kaplan Cancer Center at St. Mary's Medical Center
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Winship Cancer Institute of Emory University
    • Savannah, Georgia, United States, 31403-3089
      • Curtis and Elizabeth Anderson Cancer Institute at Memorial Health University Medical Center
  • Idaho
    • Boise, Idaho, United States, 83712-6297
      • Mountain States Tumor Institute at St. Luke's Regional Medical Center
  • Illinois
    • Chicago, Illinois, United States, 60614
      • Children's Memorial Hospital - Chicago
    • Springfield, Illinois, United States, 62794-9677
      • Simmons Cooper Cancer Institute
  • Indiana
    • Indianapolis, Indiana, United States, 46202-5289
      • Indiana University Melvin and Bren Simon Cancer Center
  • Kansas
    • Kansas City, Kansas, United States, 66160-7357
      • Kansas Masonic Cancer Research Institute at the University of Kansas Medical Center
  • Kentucky
    • Lexington, Kentucky, United States, 40536-0093
      • Lucille P. Markey Cancer Center at University of Kentucky
    • Louisville, Kentucky, United States, 40232
      • Kosair Children's Hospital
  • Maryland
    • Baltimore, Maryland, United States, 21231-2410
      • Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
    • Baltimore, Maryland, United States, 21215
      • Alvin and Lois Lapidus Cancer Institute at Sinai Hospital
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Dana-Farber/Harvard Cancer Center at Dana Farber Cancer Institute
  • Michigan
    • Detroit, Michigan, United States, 48201-1379
      • Barbara Ann Karmanos Cancer Institute
    • Flint, Michigan, United States, 48503
      • Hurley Medical Center
    • Grand Rapids, Michigan, United States, 49503-2560
      • Butterworth Hospital at Spectrum Health
    • Grosse Pointe Woods, Michigan, United States, 48236
      • Van Elslander Cancer Center at St. John Hospital and Medical Center
    • Lansing, Michigan, United States, 48910
      • Breslin Cancer Center at Ingham Regional Medical Center
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic Cancer Center
  • Mississippi
    • Jackson, Mississippi, United States, 39216-4505
      • University of Mississippi Cancer Clinic
  • Missouri
    • Kansas City, Missouri, United States, 64108
      • Children's Mercy Hospital
  • New Jersey
    • Hackensack, New Jersey, United States, 07601
      • Hackensack University Medical Center Cancer Center
    • New Brunswick, New Jersey, United States, 08903
      • Cancer Institute of New Jersey at UMDNJ - Robert Wood Johnson Medical School
    • Newark, New Jersey, United States, 07112
      • Newark Beth Israel Medical Center
  • New Mexico
    • Albuquerque, New Mexico, United States, 87131-5636
      • University of New Mexico Cancer Center
  • New York
    • Buffalo, New York, United States, 14263-0001
      • Roswell Park Cancer Institute
    • New York, New York, United States, 10032
      • Herbert Irving Comprehensive Cancer Center at Columbia University Medical Center
    • Rochester, New York, United States, 14642
      • James P. Wilmot Cancer Center at University of Rochester Medical Center
    • Syracuse, New York, United States, 13210
      • SUNY Upstate Medical University Hospital
  • North Carolina
    • Charlotte, North Carolina, United States, 28232-2861
      • Blumenthal Cancer Center at Carolinas Medical Center
    • Durham, North Carolina, United States, 27710
      • Duke Comprehensive Cancer Center
  • Ohio
    • Akron, Ohio, United States, 44308-1062
      • Akron Children's Hospital
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic Taussig Cancer Center
    • Columbus, Ohio, United States, 43205-2696
      • Nationwide Children's Hospital
    • Dayton, Ohio, United States, 45404-1815
      • Children's Medical Center - Dayton
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • Oklahoma University Cancer Institute
  • Oregon
    • Portland, Oregon, United States, 97227
      • Legacy Emanuel Hospital and Health Center and Children's Hospital
    • Portland, Oregon, United States, 97239-3098
      • Oregon Health and Science University Cancer Institute
  • Pennsylvania
    • Bethlehem, Pennsylvania, United States, 18107
      • Lehigh Valley Hospital - Muhlenberg
    • Hershey, Pennsylvania, United States, 17033-0850
      • Penn State Cancer Institute at Milton S. Hershey Medical Center
    • Philadelphia, Pennsylvania, United States, 19134-1095
      • St. Christopher's Hospital for Children
    • Philadelphia, Pennsylvania, United States, 19104-9786
      • Children's Hospital of Philadelphia
    • Pittsburgh, Pennsylvania, United States, 15213
      • Children's Hospital of Pittsburgh
  • South Carolina
    • Columbia, South Carolina, United States, 29203
      • Palmetto Health South Carolina Cancer Center
    • Greenville, South Carolina, United States, 29605
      • Greenville Hospital Cancer Center
  • Tennessee
    • Knoxville, Tennessee, United States, 37901
      • East Tennessee Children's Hospital
  • Texas
    • Dallas, Texas, United States, 75390
      • Simmons Comprehensive Cancer Center at University of Texas Southwestern Medical Center - Dallas
    • Fort Worth, Texas, United States, 76104
      • Cook Children's Medical Center - Fort Worth
    • Houston, Texas, United States, 77030-4009
      • M. D. Anderson Cancer Center at University of Texas
    • Lubbock, Texas, United States, 79410
      • Covenant Children's Hospital
    • San Antonio, Texas, United States, 78207
      • University of Texas Health Science Center at San Antonio
    • Temple, Texas, United States, 76508
      • CCOP - Scott and White Hospital
  • Vermont
    • Burlington, Vermont, United States, 05401
      • Fletcher Allen Health Care - University Health Center Campus
  • Washington
    • Seattle, Washington, United States, 98105
      • Children's Hospital and Regional Medical Center - Seattle
    • Spokane, Washington, United States, 99220-2555
      • Providence Cancer Center at Sacred Heart Medical Center
  • Wisconsin
    • Green Bay, Wisconsin, United States, 54307-3508
      • St. Vincent Hospital Regional Cancer Center
    • Madison, Wisconsin, United States, 53792-6164
      • University of Wisconsin Paul P. Carbone Comprehensive Cancer Center
    • Marshfield, Wisconsin, United States, 54449
      • Marshfield Clinic - Marshfield Center
    • Milwaukee, Wisconsin, United States, 53226
      • Midwest Children's Cancer Center at Children's Hospital of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 39 years (ADULT, CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NON_RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Group 1 (unilateral recurrence) - Sargramostim and thoractomy; 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; given by inhalation, dosage escalation Level 1 Dose: 240 micrograms, Level 2 Dose: 1,000 micrograms, and Level 3 Dose: 1,750 micrograms.; Other Names: GM-CSF; Granulocyte Macrophage Colony Stimulating Factor; rhu GM-CSF; rGM-CSF; Leukine®; aerosol sargramostim; inhaled GM-CSF; Prokine®; Interberin®; NSC#613795; Procedure: conventional surgery; thoracotomy
Experimental: Group 2 (bilateral recurrence) - Sargramostim and thoractomy; 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; given by inhalation, dosage escalation Level 1 Dose: 240 micrograms, Level 2 Dose: 1,000 micrograms, and Level 3 Dose: 1,750 micrograms.; Other Names: GM-CSF; Granulocyte Macrophage Colony Stimulating Factor; rhu GM-CSF; rGM-CSF; Leukine®; aerosol sargramostim; inhaled GM-CSF; Prokine®; Interberin®; NSC#613795; Procedure: conventional surgery; thoracotomy

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Children's Oncology Group
• Collaborators: National Cancer Institute (NCI)
• Investigators: Study Chair: Carola A. Arndt, MD, Mayo Clinic

Publications and helpful links

General Publications

• Arndt CA, Koshkina NV, Inwards CY, Hawkins DS, Krailo MD, Villaluna D, Anderson PM, Goorin AM, Blakely ML, Bernstein M, Bell SA, Ray K, Grendahl DC, Marina N, Kleinerman ES. Inhaled granulocyte-macrophage colony stimulating factor for first pulmonary recurrence of osteosarcoma: effects on disease-free survival and immunomodulation. a report from the Children's Oncology Group. Clin Cancer Res. 2010 Aug 1;16(15):4024-30. doi: 10.1158/1078-0432.CCR-10-0662. Epub 2010 Jun 24.

Study record dates

Study Major Dates

• Study Start: July 1, 2004
• Primary Completion (Actual): July 1, 2010
• Study Completion (Actual): December 1, 2013

Study Registration Dates

• First Submitted: August 6, 2003
• First Submitted That Met QC Criteria: August 6, 2003
• First Posted (Estimate): August 7, 2003

Study Record Updates

• Last Update Posted (Estimate): March 30, 2015
• Last Update Submitted That Met QC Criteria: March 17, 2015
• Last Verified: March 1, 2015

More Information

Terms related to this study

• Keywords: metastatic osteosarcoma; recurrent osteosarcoma; lung metastases
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Disease Attributes; Neoplasms, Bone Tissue; Neoplasms, Connective Tissue; Sarcoma; Recurrence; Osteosarcoma; Physiological Effects of Drugs; Antineoplastic Agents; Immunologic Factors; Sargramostim; Molgramostim
• Other Study ID Numbers: AOST0221; U10CA098543 (U.S. NIH Grant/Contract); CDR0000315540 (Other Identifier: Clinical Trials.gov); COG-AOST0221 (Other Identifier: Children's Oncology Group); NCI-2012-02543 (Other Identifier: NCI)