Clinical trial NCT00470223: 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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Sarcoma
Keywords: localized osteosarcoma
metastatic osteosarcoma
Lead sponsor: UNICANCER
Sponsor class: OTHER
Collaborators: name: Novartis
name: Chugai Pharmaceutical
name: National Cancer Institute, France
name: SFCE
name: Ligue contre le cancer, France
First posted: 2007-05-07
Enrollment: 318
Sex: ALL
Minimum age (years): 5
Maximum age (years): 50
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Event-free survival
timeFrame: 3 years
Secondary outcomes:
measure: Overall survival
timeFrame: 10 years
measure: Percentage of good responders
timeFrame: at the time of the surgery
measure: Short term and long term toxicity
timeFrame: 10 years
Other outcomes:
Locations:
city: Angers
country: France
facility: Centre Paul Papin
city: Angers
country: France
facility: Institut Gustave Roussy
city: Besancon
country: France
facility: Centre Hospitalier Regional de Besancon - Hopital Jean Minjoz
city: Besancon
country: France
facility: CHR de Besancon - Hopital Saint-Jacques
city: Bordeaux
country: France
facility: Institut Bergonie
city: Brest
country: France
facility: CHU Hopital A. Morvan
city: Caen
country: France
facility: CHU de Caen
city: Caen
country: France
facility: Centre Regional Francois Baclesse
city: Clermont-Ferrand
country: France
facility: CHR Clermont Ferrand, Hotel Dieu
city: Clermont-Ferrand
country: France
facility: Centre Jean Perrin
city: Dijon
country: France
facility: Centre de Lutte Contre le Cancer Georges-Francois Leclerc
city: Dijon
country: France
facility: Centre Hospitalier Universitaire de Dijon
city: Grenoble
country: France
facility: CHU de Grenoble - Hopital Michallon
city: Lille
country: France
facility: Centre Oscar Lambret
city: Lyon
country: France
facility: Centre Leon Berard
city: Lyon
country: France
facility: Hopital Edouard Herriot - Lyon
city: Marseille
country: France
facility: Marseille Institute of Cancer - Institut J. Paoli and I. Calmettes
city: Marseille
country: France
facility: CHU de la Timone
city: Marseille
country: France
facility: Hopital d'Enfants de la Timone
city: Marseille
country: France
facility: CHU Nord
city: Montpellier
country: France
facility: Hopital Arnaud de Villeneuve
city: Montpellier
country: France
facility: Centre Regional de Lutte Contre le Cancer - Centre Val d'Aurelle
city: Nice
country: France
facility: Centre Antoine Lacassagne
city: Nice
country: France
facility: Hopital de l'Archet CHU de Nice
city: Paris
country: France
facility: Institut Curie Hopital
city: Poitiers
country: France
facility: Hopital Jean Bernard
city: Rennes
country: France
facility: Centre Eugene Marquis
city: Rouen
country: France
facility: Hopital Charles Nicolle
city: Rouen
country: France
facility: Centre Henri Becquerel
city: Saint Priest en Jarez
country: France
facility: Institut de Cancerologie de la Loire
city: Saint-Herblain
country: France
facility: Centre Regional Rene Gauducheau
city: Strasbourg
country: France
facility: Hopitaux Universitaire de Strasbourg
city: Strasbourg
country: France
facility: Hopital Universitaire Hautepierre
city: Toulouse
country: France
facility: Hopital des Enfants
city: Tours
country: France
facility: C.H. Bastien de Clocheville
city: Tours
country: France
facility: CHRU de Tours - Hopital Trousseau
city: Vandoeuvre-les-Nancy
country: France
facility: Centre Alexis Vautrin
Study officials:
affiliation: Gustave Roussy, Cancer Campus, Grand Paris
name: Laurence Brugieres, MD
role: STUDY_CHAIR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.