Combined Chemotherapy With or Without Zoledronic Acid for Patients With Osteosarcoma (OS2006)

OS2006 : Protocole de Traitement Des ostéosarcomes de l'Enfant, de l'Adolescent et de l'Adulte Comportant

RATIONALE: 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. Zoledronic acid may stop the growth of tumor cells in bone. Giving chemotherapy with or without zoledronic acid before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed. Giving these treatments after surgery may kill any tumor cells that remain after surgery. It is not yet known whether giving combination chemotherapy together with zoledronic acid is more effective than combination chemotherapy alone in treating osteosarcoma.

PURPOSE: This randomized phase III trial is studying combination chemotherapy and zoledronic acid to see how well they work compared with combination chemotherapy alone in treating patients with osteosarcoma.

Study Overview

• Status: Active, not recruiting
• Conditions: Sarcoma
• Intervention / Treatment: Drug: etoposide; Drug: methotrexate; Drug: cisplatin; Drug: doxorubicin hydrochloride; Procedure: conventional surgery; Drug: zoledronic acid; Drug: ifosfamide

Detailed Description

OBJECTIVES:

Primary

• Compare the progression-free survival of patients with osteosarcoma treated with combination chemotherapy with or without zoledronic acid.

Secondary

• Compare the overall survival of patients treated with these regimens.
• Compare the percentage of patients with a good histologic response.
• Compare the long and short term toxicity of these regimens in these patients.
• Compare the quality of life of patients treated with these regimens.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to age (< 18 years vs 18-25 years vs > 25 years), risk group (nonmetastatic or resectable vs metastatic or unresectable), and treatment center. Patients receive either methotrexate-based chemotherapy or doxorubicin hydrochloride-based chemotherapy according to age.

• Methotrexate-based chemotherapy (patients ≤ 25 years of age): Patients are randomized to 1 of 2 treatment arms.

  • Arm I: Patients receive methotrexate IV in weeks 1-3, 7, 8, 12, and 13 and etoposide IV and ifosfamide IV in weeks 4 and 9.
  • Arm II: Patients receive methotrexate, etoposide, and ifosfamide as in arm I. Patients also receive zoledronic acid IV in weeks 1, 5, 9, and 13.

All patients undergo surgery in week 14. After surgery, patients are assigned to 1 of 2 groups for further treatment, based on histological response.

• Good responders (< 10% viable cells): Patients are randomized to 1 of 2 treatment arms.

  • Arm I: Patients receive methotrexate IV in weeks 1-3, 7-9, 13-15, and 19-21 and etoposide IV in weeks 4 and 10. Patients also receive ifosfamide IV in weeks 4, 10, and 16.
  • Arm II: Patients receive methotrexate, etoposide, and ifosfamide as in arm I. Patients also receive zoledronic acid IV in weeks 3, 7, 11, 15, 19, and 23.

• Bad responders (> 10% viable cells): Patients are randomized to 1 of 2 treatment arms.

  • Arm I: Patients receive methotrexate IV in weeks 1, 5, 9, 13, and 17 and doxorubicin hydrochloride IV and cisplatin IV in weeks 2, 6, 10, 14, and 18.

  • Arm II: Patients receive methotrexate, doxorubicin hydrochloride, and cisplatin as in arm I. Patients also receive zoledronic acid IV as in arm II (good responders).

    • Doxorubicin hydrochloride-based chemotherapy (patients ≥ 18 years of age): Patients are randomized to 1 of 2 treatment arms.
• Arm I: Patients receive doxorubicin hydrochloride IV and ifosfamide hydrochloride IV in weeks 1, 4, 7, 10, and 13 and cisplatin IV in weeks 1, 7, and 13.
• Arm II: Patients receive doxorubicin hydrochloride, ifosfamide, and cisplatin as in arm I. Patients also receive zoledronic acid IV in weeks 1, 5, 9, and 13.

All patients undergo surgery in week 16. After surgery, patients are assigned to 1 of 2 groups for further treatment, based on histological response.

• Good responders (< 10% viable cells): Patients are randomized to 1 of 2 treatment arms.

  • Arm I: Patients receive doxorubicin hydrochloride IV in weeks 1 and 7 and ifosfamide IV in weeks 1, 4, 7, and 10.
  • Arm II: Patients receive doxorubicin hydrochloride and ifosfamide as in arm I. Patients also receive zoledronic acid IV in weeks 1, 5, 9, 13, 17, and 21.

• Bad responders (> 10% viable cells):

  • Arm I: Patients receive etoposide IV and ifosfamide IV in weeks 1, 4, 7, 10, and 13.
  • Arm II: Patients receive etoposide and ifosfamide as in arm I. Patients also receive zoledronic acid as in arm II (good responders).

PROJECTED ACCRUAL: A total of 440 patients will be accrued for this study.

• Study Type: Interventional
• Enrollment (Actual): 318
• Phase: Phase 3

Contacts and Locations

Study Locations

• France
  • Angers, France, 49036
    • Centre Paul Papin
  • Angers, France, 49036
    • Institut Gustave Roussy
  • Besancon, France, 25030
    • Centre Hospitalier Regional de Besancon - Hopital Jean Minjoz
  • Besancon, France, 25030
    • CHR de Besancon - Hopital Saint-Jacques
  • Bordeaux, France, 33076
    • Institut Bergonie
  • Brest, France, 29609
    • CHU Hopital A. Morvan
  • Caen, France, 14076
    • Centre Regional Francois Baclesse
  • Caen, France, 14033
    • CHU de Caen
  • Clermont-Ferrand, France, 63011
    • Centre Jean Perrin
  • Clermont-Ferrand, France, 63003
    • CHR Clermont Ferrand, Hotel Dieu
  • Dijon, France, 21079
    • Centre Hospitalier Universitaire De Dijon
  • Dijon, France, 21079
    • Centre de Lutte Contre le Cancer Georges-Francois Leclerc
  • Grenoble, France, 38043
    • CHU de Grenoble - Hôpital Michallon
  • Lille, France, 59020
    • Centre Oscar Lambret
  • Lyon, France, 69437
    • Hopital Edouard Herriot - Lyon
  • Lyon, France, 69373
    • Centre Léon Bérard
  • Marseille, France, 13385
    • CHU de la Timone
  • Marseille, France, 13915
    • CHU Nord
  • Marseille, France, 13273
    • Marseille Institute of Cancer - Institut J. Paoli and I. Calmettes
  • Marseille, France, 13385
    • Hôpital d'Enfants de la Timone
  • Montpellier, France, 34298
    • Centre Regional de Lutte Contre le Cancer - Centre Val d'Aurelle
  • Montpellier, France, 34295
    • Hopital Arnaud de Villeneuve
  • Nice, France, F-06202
    • Hopital de l'Archet CHU de Nice
  • Nice, France, 06189
    • Centre Antoine Lacassagne
  • Paris, France, 75248
    • Institut Curie Hopital
  • Poitiers, France, 86021
    • Hopital Jean Bernard
  • Rennes, France, 35042
    • Centre Eugène Marquis
  • Rouen, France, 76038
    • Centre Henri Becquerel
  • Rouen, France, 76031
    • Hopital Charles Nicolle
  • Saint Priest en Jarez, France, 42270
    • Institut de Cancerologie de La Loire
  • Saint-Herblain, France, 44805
    • Centre Regional Rene Gauducheau
  • Strasbourg, France, 67098
    • Hopital Universitaire Hautepierre
  • Strasbourg, France, 67091
    • Hopitaux Universitaire de Strasbourg
  • Toulouse, France, 31059
    • Hopital des Enfants
  • Tours, France, 3700
    • C.H. Bastien de Clocheville
  • Tours, France, 37044
    • CHRU de Tours - Hopital Trousseau
  • Vandoeuvre-les-Nancy, France, 54511
    • Centre Alexis Vautrin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 5 years to 50 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria

• Histologically confirmed high-grade osteosarcoma
• Bilirubin ≤ 2 times upper limit of normal
• No medical condition that would preclude study treatment
• Not pregnant or nursing
• Fertile patients must use effective contraception
• Shortening fraction ≥ 28%
• LVEF ≥ 50%
• Glomerular filtration rate ≥ 70mL/min
• No recent dental problem, including infection, traumatization, or surgery

Exclusion Criteria

• Low-grade osteosarcoma
• Small cell osteosarcoma
• Maxillary osteosarcoma
• Primary resected osteosarcoma
• Osteosarcoma with multiple metastases for which complete removal is not feasible even after shrinkage with chemotherapy
• Extra-osseous osteosarcoma
• Any prior osteonecrosis of the maxilla
• No prior chemotherapy or radiotherapy

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Chemotherapy + zoledronic acid	Drug: etoposide; Drug: methotrexate; Drug: cisplatin; Drug: doxorubicin hydrochloride; Procedure: conventional surgery; Drug: zoledronic acid; Drug: ifosfamide
Active Comparator: chemotherapy	Drug: etoposide; Drug: methotrexate; Drug: cisplatin; Drug: doxorubicin hydrochloride; Procedure: conventional surgery; Drug: ifosfamide

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Event-free survival	3 years

Secondary Outcome Measures

Outcome Measure	Time Frame
Overall survival	10 years
Percentage of good responders	at the time of the surgery
Short term and long term toxicity	10 years

Collaborators and Investigators

• Sponsor: UNICANCER
• Collaborators: Novartis; National Cancer Institute, France; Chugai Pharmaceutical; Ligue contre le cancer, France; SFCE
• Investigators: Study Chair: Laurence Brugieres, MD, Gustave Roussy, Cancer Campus, Grand Paris

Publications and helpful links

General Publications

• 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.
• Lui G, Treluyer JM, Fresneau B, Piperno-Neumann S, Gaspar N, Corradini N, Gentet JC, Marec Berard P, Laurence V, Schneider P, Entz-Werle N, Pacquement H, Millot F, Taque S, Freycon C, Lervat C, Le Deley MC, Mahier Ait Oukhatar C, Brugieres L, Le Teuff G, Bouazza N; Sarcoma Group of UNICANCER. A Pharmacokinetic and Pharmacogenetic Analysis of Osteosarcoma Patients Treated With High-Dose Methotrexate: Data From the OS2006/Sarcoma-09 Trial. J Clin Pharmacol. 2018 Dec;58(12):1541-1549. doi: 10.1002/jcph.1252. Epub 2018 May 23.
• Tabone MD, Brugieres L, Piperno-Neumann S, Selva MA, Marec-Berard P, Pacquement H, Lervat C, Corradini N, Gentet JC, Couderc R, Chevance A, Mahier-Ait Oukhatar C, Entz-Werle N, Blay JY, Le Deley MC. Prognostic impact of blood and urinary angiogenic factor levels at diagnosis and during treatment in patients with osteosarcoma: a prospective study. BMC Cancer. 2017 Jun 15;17(1):419. doi: 10.1186/s12885-017-3409-z.
• Piperno-Neumann S, Le Deley MC, Redini F, Pacquement H, Marec-Berard P, Petit P, Brisse H, Lervat C, Gentet JC, Entz-Werle N, Italiano A, Corradini N, Bompas E, Penel N, Tabone MD, Gomez-Brouchet A, Guinebretiere JM, Mascard E, Gouin F, Chevance A, Bonnet N, Blay JY, Brugieres L; Sarcoma Group of UNICANCER; French Society of Pediatric Oncology (SFCE); French Sarcoma Group (GSF-GETO). Zoledronate in combination with chemotherapy and surgery to treat osteosarcoma (OS2006): a randomised, multicentre, open-label, phase 3 trial. Lancet Oncol. 2016 Aug;17(8):1070-1080. doi: 10.1016/S1470-2045(16)30096-1. Epub 2016 Jun 17.

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2007
• Primary Completion (Actual): December 1, 2015
• Study Completion (Estimated): December 1, 2026

Study Registration Dates

• First Submitted: May 3, 2007
• First Submitted That Met QC Criteria: May 3, 2007
• First Posted (Estimated): May 7, 2007

Study Record Updates

• Last Update Posted (Actual): June 8, 2025
• Last Update Submitted That Met QC Criteria: June 4, 2025
• Last Verified: May 1, 2025

More Information

Terms related to this study

• Keywords: localized osteosarcoma; metastatic osteosarcoma
• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Histologic Type; Sarcoma; Neoplasms, Connective and Soft Tissue; Neoplasms, Bone Tissue; Neoplasms, Connective Tissue; Osteosarcoma; Antibiotics, Antineoplastic; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antirheumatic Agents; Abortifacient Agents, Nonsteroidal; Abortifacient Agents; Reproductive Control Agents; Antimetabolites, Antineoplastic; Antimetabolites; Dermatologic Agents; Folic Acid Antagonists; Nucleic Acid Synthesis Inhibitors; Bone Density Conservation Agents; Topoisomerase Inhibitors; Antineoplastic Agents, Alkylating; Alkylating Agents; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Zoledronic Acid; Methotrexate; Etoposide; Doxorubicin; Liposomal doxorubicin; Ifosfamide
• Other Study ID Numbers: Sarcome 09/0603; UNICANCER-SARCOME-09-0603 (Other Identifier: UNICANCER); 2006-003377-27 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: IPD will not be shared at an individual level, they will be part of the study database including all enrolled patients.