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

• ClinicalTrials.gov Identifier: NCT00470223
• Recruitment Status: Active, not recruiting
• First Posted: May 7, 2007
• Last Update Posted: April 18, 2024
• Sponsor: UNICANCER
• Collaborators: Novartis; Chugai Pharmaceutical; National Cancer Institute, France; SFCE; Ligue contre le cancer, France
• Information provided by (Responsible Party): UNICANCER

Tracking Information

• First Submitted Date: May 3, 2007
• First Posted Date: May 7, 2007
• Last Update Posted Date: April 18, 2024
• Actual Study Start Date: March 2007
• Actual Primary Completion Date: December 2015 (Final data collection date for primary outcome measure)
• Current Primary Outcome Measures (submitted: June 21, 2016): Event-free survival [ Time Frame: 3 years ]
• Original Primary Outcome Measures (submitted: May 3, 2007): Progression-free survival

Current Secondary Outcome Measures (submitted: October 17, 2019)

• Overall survival [ Time Frame: 10 years ]
• Percentage of good responders [ Time Frame: at the time of the surgery ]
• Short term and long term toxicity [ Time Frame: 10 years ]

Original Secondary Outcome Measures (submitted: May 3, 2007)

• Overall survival
• Percentage of good responders
• Short term and long term toxicity
• Quality of life

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

Descriptive Information

• Brief Title: Combined Chemotherapy With or Without Zoledronic Acid for Patients With Osteosarcoma
• Official Title: OS2006 : Protocole de Traitement Des ostéosarcomes de l'Enfant, de l'Adolescent et de l'Adulte Comportant

Brief Summary

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.

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

Intervention

• Drug: cisplatin
• Drug: doxorubicin hydrochloride
• Drug: etoposide
• Drug: ifosfamide
• Drug: methotrexate
• Drug: zoledronic acid
• Procedure: conventional surgery

Study Arms

• Experimental: Chemotherapy + zoledronic acid
  Interventions:

  • Drug: cisplatin
  • Drug: doxorubicin hydrochloride
  • Drug: etoposide
  • Drug: ifosfamide
  • Drug: methotrexate
  • Drug: zoledronic acid
  • Procedure: conventional surgery
• Active Comparator: chemotherapy
  Interventions:

  • Drug: cisplatin
  • Drug: doxorubicin hydrochloride
  • Drug: etoposide
  • Drug: ifosfamide
  • Drug: methotrexate
  • Procedure: conventional surgery

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.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: January 3, 2016): 318
• Original Enrollment (submitted: May 3, 2007): 440
• Estimated Study Completion Date: December 2026
• Actual Primary Completion Date: December 2015 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 5 Years to 50 Years (Child, Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: France

Administrative Information

• NCT Number: NCT00470223
• Other Study ID Numbers: Sarcome 09/0603; UNICANCER-SARCOME-09-0603 ( Other Identifier: UNICANCER ); 2006-003377-27 ( EudraCT Number )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided

IPD Sharing Statement

• Plan to Share IPD: No
• Plan Description: IPD will not be shared at an individual level, they will be part of the study database including all enrolled patients.

• Current Responsible Party: UNICANCER
• Original Responsible Party: Not Provided
• Current Study Sponsor: UNICANCER
• Original Study Sponsor: Same as current

Collaborators

• Novartis
• Chugai Pharmaceutical
• National Cancer Institute, France
• SFCE
• Ligue contre le cancer, France

Investigators

• Study Chair: Laurence Brugieres, MD; Gustave Roussy, Cancer Campus, Grand Paris

• PRS Account: UNICANCER
• Verification Date: April 2024