Combination Chemotherapy, PEG-Interferon Alfa-2b, and Surgery in Treating Patients With Osteosarcoma (EURAMOS-1)

• ClinicalTrials.gov Identifier: NCT00134030
• Recruitment Status: Completed
• First Posted: August 24, 2005
• Results First Posted: June 7, 2023
• Last Update Posted: June 7, 2023
• Sponsor: Children's Oncology Group
• Collaborators: National Cancer Institute (NCI); University College, London; Medical Research Council
• Information provided by (Responsible Party): Babasola (Sola) Popoola, University College, London

Tracking Information

• First Submitted Date: August 22, 2005
• First Posted Date: August 24, 2005
• Results First Submitted Date: November 21, 2022
• Results First Posted Date: June 7, 2023
• Last Update Posted Date: June 7, 2023
• Actual Study Start Date: November 14, 2005
• Actual Primary Completion Date: January 31, 2015 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 10, 2023)

Event-free Survival (EFS) [ Time Frame: From date of randomization to date of the event. ]

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.

• Original Primary Outcome Measures: Not Provided

Current Secondary Outcome Measures (submitted: May 10, 2023)

• Percentage of Patients With Overall Survival [ Time Frame: From date of randomization to date of death. ]
  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.
• Toxicity as Measured by Common Terminology Criteria for Adverse Events (CTCAE) v3.0 [ Time Frame: Adverse events are assessed for up to 10 years per participant. ]
  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.

• Original Secondary Outcome Measures: Not Provided
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

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

• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Localized Osteosarcoma
• Metastatic Osteosarcoma

Intervention

• 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
  • 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
  • VP 16-213
  • VP-16
  • VP-16-213
  • VP16
• 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

• 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 *

• Hazewinkel AD, Lancia C, Anninga J, van de Sande M, Whelan J, Gelderblom H, Fiocco M. Disease progression in osteosarcoma: a multistate model for the EURAMOS-1 (European and American Osteosarcoma Study) randomised clinical trial. BMJ Open. 2022 Mar 4;12(3):e053083. doi: 10.1136/bmjopen-2021-053083.
• Hattinger CM, Patrizio MP, Magagnoli F, Luppi S, Serra M. An update on emerging drugs in osteosarcoma: towards tailored therapies? Expert Opin Emerg Drugs. 2019 Sep;24(3):153-171. doi: 10.1080/14728214.2019.1654455. Epub 2019 Aug 14.
• Marina NM, Smeland S, Bielack SS, Bernstein M, Jovic G, Krailo MD, Hook JM, Arndt C, van den Berg H, Brennan B, Brichard B, Brown KLB, Butterfass-Bahloul T, Calaminus G, Daldrup-Link HE, Eriksson M, Gebhardt MC, Gelderblom H, Gerss J, Goldsby R, Goorin A, Gorlick R, Grier HE, Hale JP, Hall KS, Hardes J, Hawkins DS, Helmke K, Hogendoorn PCW, Isakoff MS, Janeway KA, Jurgens H, Kager L, Kuhne T, Lau CC, Leavey PJ, Lessnick SL, Mascarenhas L, Meyers PA, Mottl H, Nathrath M, Papai Z, Randall RL, Reichardt P, Renard M, Safwat AA, Schwartz CL, Stevens MCG, Strauss SJ, Teot L, Werner M, Sydes MR, Whelan JS. Comparison of MAPIE versus MAP in patients with a poor response to preoperative chemotherapy for newly diagnosed high-grade osteosarcoma (EURAMOS-1): an open-label, international, randomised controlled trial. Lancet Oncol. 2016 Oct;17(10):1396-1408. doi: 10.1016/S1470-2045(16)30214-5. Epub 2016 Aug 25.
• Whelan JS, Bielack SS, Marina N, Smeland S, Jovic G, Hook JM, Krailo M, Anninga J, Butterfass-Bahloul T, Bohling T, Calaminus G, Capra M, Deffenbaugh C, Dhooge C, Eriksson M, Flanagan AM, Gelderblom H, Goorin A, Gorlick R, Gosheger G, Grimer RJ, Hall KS, Helmke K, Hogendoorn PC, Jundt G, Kager L, Kuehne T, Lau CC, Letson GD, Meyer J, Meyers PA, Morris C, Mottl H, Nadel H, Nagarajan R, Randall RL, Schomberg P, Schwarz R, Teot LA, Sydes MR, Bernstein M; EURAMOS collaborators. EURAMOS-1, an international randomised study for osteosarcoma: results from pre-randomisation treatment. Ann Oncol. 2015 Feb;26(2):407-14. doi: 10.1093/annonc/mdu526. Epub 2014 Nov 24.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: May 10, 2023): 1334
• Original Enrollment: Not Provided
• Actual Study Completion Date: September 30, 2022
• Actual Primary Completion Date: January 31, 2015 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 5 Years to 40 Years (Child, Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, Canada, New Zealand, Puerto Rico, Switzerland, United States
• Removed Location Countries: Germany, Norway, United Kingdom

Administrative Information

• NCT Number: NCT00134030
• Other Study ID Numbers: AOST0331/ EURAMOS-1; NCI-2009-01066 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); ISRCTN67613327 ( Registry Identifier: ISRCTN ); MRC-BO08 ( Other Identifier: MRC CTU ); MRC-EURAMOS1 ( Other Identifier: MRC CTU ); 06-93 ( Other Identifier: Children's Oncology Group ); CDR0000438714 ( Other Identifier: TBC ); COG-AOST0331 ( Other Identifier: Children's Oncology Group ); EU-20530 ( Other Identifier: TBC ); 2004-000242-20 ( EudraCT Number ); AOST0331 ( Other Identifier: Children's 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: Not Provided
• Current Responsible Party: Babasola (Sola) Popoola, University College, London
• Original Responsible Party: Not Provided
• Current Study Sponsor: Children's Oncology Group
• Original Study Sponsor: Same as current

Collaborators

• National Cancer Institute (NCI)
• University College, London
• Medical Research Council

Investigators

• Principal Investigator: Neyssa M Marina; Children's Oncology Group

• PRS Account: Children's Oncology Group
• Verification Date: May 2023