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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT00134030
Recruitment Status : Unknown
Verified June 2018 by Children's Oncology Group.
Recruitment status was:  Active, not recruiting
First Posted : August 24, 2005
Last Update Posted : June 8, 2018
Sponsor:
Collaborators:
National Cancer Institute (NCI)
University College London Hospitals
Information provided by (Responsible Party):
Children's Oncology Group

Tracking Information
First Submitted Date  ICMJE August 22, 2005
First Posted Date  ICMJE August 24, 2005
Last Update Posted Date June 8, 2018
Actual Study Start Date  ICMJE November 14, 2005
Actual Primary Completion Date January 31, 2015   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 12, 2013)
Event-free survival [ Time Frame: From date of randomization to date of the event, assessed up to 10 years ]
Will be assessed using the logrank test and expressed using hazard ratios with appropriate confidence intervals.
Original Primary Outcome Measures  ICMJE Not Provided
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: June 12, 2013)
  • Overall survival [ Time Frame: From date of randomization to date of death, assessed up to 10 years ]
    Will be assessed using the logrank test and expressed using hazard ratios with appropriate confidence intervals.
  • Toxicity as measured by CTCAE v3.0 [ Time Frame: Up to 10 years ]
    Proportions of patients experiencing grade 3 and 4 toxicities will be compared using chi-square tests or Fisher's exact tests where appropriate.
  • Quality of life [ Time Frame: Up to 3 years ]
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Combination Chemotherapy, PEG-Interferon Alfa-2b, and Surgery in Treating Patients With Osteosarcoma
Official Title  ICMJE 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
Brief 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 1?-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

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Localized Osteosarcoma
  • Metastatic Osteosarcoma
Intervention  ICMJE
  • Drug: Cisplatin
    Given IV
    Other Names:
    • Abiplatin
    • Blastolem
    • Briplatin
    • CDDP
    • Cis-diammine-dichloroplatinum
    • Cis-diamminedichloridoplatinum
    • Cis-diamminedichloro Platinum (II)
    • Cis-diamminedichloroplatinum
    • Cis-dichloroammine Platinum (II)
    • Cis-platinous Diamine Dichloride
    • Cis-platinum
    • Cis-platinum II
    • Cis-platinum II Diamine Dichloride
    • Cismaplat
    • Cisplatina
    • Cisplatinum
    • Cisplatyl
    • Citoplatino
    • Citosin
    • Cysplatyna
    • DDP
    • Lederplatin
    • Metaplatin
    • Neoplatin
    • Peyrone's Chloride
    • Peyrone's Salt
    • Placis
    • Plastistil
    • Platamine
    • Platiblastin
    • Platiblastin-S
    • Platinex
    • Platinol
    • Platinol- AQ
    • Platinol-AQ
    • Platinol-AQ VHA Plus
    • Platinoxan
    • Platinum
    • Platinum Diamminodichloride
    • Platiran
    • Platistin
    • Platosin
  • Drug: Doxorubicin Hydrochloride
    Given IV
    Other Names:
    • 5,12-Naphthacenedione, 10-[(3-amino-2,3,6-trideoxy-alpha-L-lyxo-hexopyranosyl)oxy]-7,8, 9,10-tetrahydro-6,8,11-trihydroxy-8-(hydroxyacetyl)-1-methoxy-, hydrochloride, (8S-cis)- (9CI)
    • ADM
    • Adriacin
    • Adriamycin
    • Adriamycin Hydrochloride
    • Adriamycin PFS
    • Adriamycin RDF
    • ADRIAMYCIN, HYDROCHLORIDE
    • Adriamycine
    • Adriblastina
    • Adriblastine
    • Adrimedac
    • Chloridrato de Doxorrubicina
    • DOX
    • DOXO-CELL
    • Doxolem
    • Doxorubicin.HCl
    • Doxorubin
    • Farmiblastina
    • FI 106
    • FI-106
    • hydroxydaunorubicin
    • Rubex
  • Drug: Etoposide
    Given IV
    Other Names:
    • Demethyl Epipodophyllotoxin Ethylidine Glucoside
    • EPEG
    • Lastet
    • Toposar
    • Vepesid
    • VP 16-213
    • VP-16
    • VP-16-213
  • Drug: Ifosfamide
    Given IV
    Other Names:
    • Asta Z 4942
    • Asta Z-4942
    • Cyfos
    • Holoxan
    • Holoxane
    • Ifex
    • IFO
    • IFO-Cell
    • Ifolem
    • Ifomida
    • Ifomide
    • Ifosfamidum
    • Ifoxan
    • IFX
    • Iphosphamid
    • Iphosphamide
    • Iso-Endoxan
    • Isoendoxan
    • Isophosphamide
    • Mitoxana
    • MJF 9325
    • MJF-9325
    • Naxamide
    • Seromida
    • Tronoxal
    • Z 4942
    • Z-4942
  • Drug: Methotrexate
    Given IV
    Other Names:
    • Abitrexate
    • Alpha-Methopterin
    • Amethopterin
    • Brimexate
    • CL 14377
    • CL-14377
    • Emtexate
    • Emthexat
    • Emthexate
    • Farmitrexat
    • Fauldexato
    • Folex
    • Folex PFS
    • Lantarel
    • Ledertrexate
    • Lumexon
    • Maxtrex
    • Medsatrexate
    • Metex
    • Methoblastin
    • Methotrexate LPF
    • Methotrexate Methylaminopterin
    • Methotrexatum
    • Metotrexato
    • Metrotex
    • Mexate
    • Mexate-AQ
    • MTX
    • Novatrex
    • Rheumatrex
    • Texate
    • Tremetex
    • Trexeron
    • Trixilem
    • WR-19039
  • Biological: Peginterferon Alfa-2b
    Given subcutaneously
    Other Names:
    • PEG Interferon Alpha-2b
    • PEG Intron
    • PEG-IFN Alfa-2b
    • PEG-IFN-a 2b
    • PEG-interferon alfa-2b
    • PEG-Intron
    • Pegylated Interferon Alpha-2b
    • Polyethylene Glycol IFN-A2b
    • Polyethylene Glycol Interferon Alfa-2b
    • SCH 54031
    • Sylatron
  • Other: Quality-of-Life Assessment
    Ancillary studies
    Other Name: Quality of Life Assessment
  • Other: Questionnaire Administration
    Ancillary studies
  • Procedure: Therapeutic Conventional Surgery
    Undergo amputation or limb salvage surgery
Study Arms  ICMJE
  • Active Comparator: Maintenance therapy group 1 arm I
    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.
    Interventions:
    • Drug: Cisplatin
    • Drug: Doxorubicin Hydrochloride
    • Drug: Methotrexate
    • Other: Quality-of-Life Assessment
    • Other: Questionnaire Administration
    • Procedure: Therapeutic Conventional Surgery
  • Experimental: Maintenance therapy group 1 arm II
    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.
    Interventions:
    • Drug: Cisplatin
    • Drug: Doxorubicin Hydrochloride
    • Drug: Methotrexate
    • Biological: Peginterferon Alfa-2b
    • Other: Quality-of-Life Assessment
    • Other: Questionnaire Administration
    • Procedure: Therapeutic Conventional Surgery
  • Active Comparator: Maintenance therapy group 2 arm I
    Patients receive doxorubicin, cisplatin, and high-dose MTX as in group 1 arm I.
    Interventions:
    • Drug: Cisplatin
    • Drug: Doxorubicin Hydrochloride
    • Drug: Methotrexate
    • Other: Quality-of-Life Assessment
    • Other: Questionnaire Administration
    • Procedure: Therapeutic Conventional Surgery
  • Experimental: Maintenance therapy group 2 arm II
    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.
    Interventions:
    • Drug: Cisplatin
    • Drug: Doxorubicin Hydrochloride
    • Drug: Etoposide
    • Drug: Ifosfamide
    • Drug: Methotrexate
    • Other: Quality-of-Life Assessment
    • Other: Questionnaire Administration
    • Procedure: Therapeutic Conventional Surgery
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Unknown status
Actual Enrollment  ICMJE
 (submitted: June 12, 2013)
1164
Original Enrollment  ICMJE Not Provided
Study Completion Date  ICMJE Not Provided
Actual Primary Completion Date January 31, 2015   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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/mm?
  • Neutrophil count ? 1,500/mm?
  • WBC ? 3,000/mm?
  • 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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 5 Years to 40 Years   (Child, Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Australia,   Canada,   New Zealand,   Puerto Rico,   Switzerland,   United States
Removed Location Countries Germany,   Norway,   United Kingdom
 
Administrative Information
NCT Number  ICMJE NCT00134030
Other Study ID Numbers  ICMJE AOST0331
NCI-2009-01066 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
EUDRACT-2004-000242-20
MRC-EURAMOS1
EU-20530
ISRCTN67613327
MRC-BO08
06-93
CDR0000438714
COG-AOST0331
AOST0331 ( Other Identifier: Childrens Oncology Group )
AOST0331 ( Other Identifier: CTEP )
U10CA180886 ( U.S. NIH Grant/Contract )
U10CA098543 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Current Responsible Party Children's Oncology Group
Original Responsible Party Not Provided
Current Study Sponsor  ICMJE Children's Oncology Group
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE
  • National Cancer Institute (NCI)
  • University College London Hospitals
Investigators  ICMJE
Principal Investigator: Neyssa Marina Children's Oncology Group
PRS Account Children's Oncology Group
Verification Date June 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP