ABCB1/P-glycoprotein Expression Influence on Non-metastatic Osteosarcoma of the Extremities

Prospective Observational Study of the Expression of ABCB1 / P-glycoprotein as a Factor for the Biological Stratification of Non-metastatic Osteosarcoma of the Extremities

Post-authorization, observational, multicenter and prospective study in patients between 2 and 30 years old diagnosed with non-metastatic high-grade osteosarcoma of the extremities.

All patients included in the study will receive the initial neoadjuvant treatment prescribed by the doctor of each center, according to standard practice (involving methotrexate, cisplatin, and adriamycin). This initial treatment precedes surgical treatment.

After surgical treatment, the histological response to neoadjuvant chemotherapy will be evaluated. The histological response to primary chemotherapy will be expressed as a percentage of tumor necrosis. In the case of tumor necrosis above 90% the patient is defined as a "good responder" in case of a lower percentage as a "poor responder".

As an adjuvant treatment, the following options may be given according to standard practice in each center:

1. - If there is overexpression of ABCB1 / P-glycoprotein and poor response to induction treatment, in many sites ifosfamide at high doses and MTP-PE, is incorporated in addition to adriamycin.
2. - If there is overexpression of ABCB1 / P-glycoprotein and a good response to induction treatment, in many centers the option of additional administration of methotrexate, CDDP and adriamycin will be chosen.
3. - If there is no overexpression of ABCB1 / P-glycoprotein, the administration of methotrexate, adriamycin and cisplatin will be chosen in many sites.

In some sites they will consider the non-administration of MTP-PE or the non-administration of high doses of ifosfamide. And, in some hospitals, they will consider administering MTP-PE to all patients.

Study Overview

• Status: Completed
• Conditions: Osteosarcoma

Detailed Description

The Primary objective is:

- Disease-free survival measured as a 5-year rate in patients with localized osteosarcoma treated, according to standard practice, with all the drugs currently registered for the treatment of non-metastatic osteosarcoma (methotrexate, cisplatin, adriamycin, ifosfamide, MTP-PE), according to ABCB1 / P-glycoprotein expression.

The Secondary objectives are:

• Evaluate overall survival in a homogeneous population of patients with non-metastatic osteosarcoma.
• Disease-free survival at 2 and 3 years.

• Study Type: Observational
• Enrollment (Actual): 115

Contacts and Locations

Study Locations

• Spain
  • Baracaldo, Spain
    • Hospital Universitario Cruces
  • Barcelona, Spain
    • Hospital Universitari Vall d'Hebron
  • Barcelona, Spain
    • Hospital De La Santa Creu I Sant Pau
  • La Laguna, Spain
    • Hospital Universitario de Canarias
  • Madrid, Spain
    • Hospital General Universitario Gregorio Marañon
  • Madrid, Spain
    • Hospital Universitario La Paz
  • Madrid, Spain
    • Hospital Universitario Ramon y Cajal
  • Madrid, Spain
    • Hospital Universitario Infantil Nino Jesus
  • Málaga, Spain
    • Hospital Regional Universitario de Malaga
  • Palma De Mallorca, Spain
    • Hospital Universitari Son Espases
  • Sevilla, Spain
    • Hospital Universitario Virgen del Rocio
  • Valencia, Spain
    • Hospital Universitari i Politecnic La Fe
  • Zaragoza, Spain
    • Hospital Universitario Miguel Servet
  • A Coruña
    • Santiago De Compostela, A Coruña, Spain
      • Complejo Hospitalario Universitario de Santiago
  • Asturias
    • Oviedo, Asturias, Spain, 33011
      • Hospital Universitario Central de Asturias
  • Madrid
    • Majadahonda, Madrid, Spain
      • Hospital Universitario Puerta de Hierro
  • Murcia
    • El Palmar, Murcia, Spain
      • Hospital Universitario Virgen de la Arrixaca

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years to 30 years (Child, Adult)
• Accepts Healthy Volunteers: N/A
• Genders Eligible for Study: All

• Sampling Method: Probability Sample

Study Population

Patients from 2 to 30 years old diagnosed with non-metastatic high-grade osteosarcoma of the extremities.

Description

Inclusion Criteria:

1. Confirmed histological diagnosis of high-grade osteosarcoma of the extremities.
2. Age: from 2 to 30 years old.
3. Localized disease (metastasis skip accepted).
4. Normal liver, kidney and spinal function.
5. Ventricular ejection fraction of 50%.
6. Absence of previous surgical treatments or chemotherapy for osteosarcoma.
7. Interval between histological diagnosis and initiation of chemotherapy not exceeding 4 weeks.
8. Signing of the consent form to participate in the study.

Exclusion Criteria:

1. Presence of lung metastases on chest CT or in other locations.
2. Parosteal, periosteal, or secondary osteosarcoma.
3. Contraindications of the medications prescribed in the protocol.
4. Pregnant or lactating.
5. Mental or social conditions that do not guarantee adequate adherence to the protocol.
6. Not having an adequate understanding of study participation.

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort
Overexpression of ABCB1 / P-glycoprotein. Poor response; If there is overexpression of ABCB1 / P-glycoprotein and poor response to induction treatment, in many sites ifosfamide at high doses and MTP-PE (Muramyl tripeptide phosphatidylethanolamine), is incorporated in addition to adriamycin. BEFORE SURGERY TREATMENT: Methotrexate: 12g/m2 (3 cycles) Cisplatinum: 120mg/m2 (3 cycles) Doxorubicin: ADM (Adriamycin) 75mg/m2 (3 cycles) AFTER SURGERY TREATMENT for poor responder patients with positive P-GLYCOPROTEIN Methotrexate 12g/m2; Cisplatinum 120mg/m2; Doxorubicin 90mg/m2 ifosfamide 15g/m2 MEPACT 2 mg/m2 twice a week for the first 3 months the weekly for the next 6 months (total length treatment 44 weeks) All the product are used as commercial formulation Other Names: Methotrexate Cisplatinum doxorubicin ifosfamide mifamurtide
Overexpression of ABCB1 / P-glycoprotein. Good response; If there is overexpression of ABCB1 / P-glycoprotein and a good response to induction treatment, in many centers the option of additional administration of methotrexate, CDDP (Cisplatinum) and adriamycin will be chosen. BEFORE SURGERY TREATMENT: Methotrexate: 12g/m2 (3 cycles) Cisplatinum: 120mg/m2 (3 cycles) Doxorubicin: ADM 75mg/m2 (3 cycles) AFTER SURGERY TREATMENT for good responder patients with positive P-GLYCOPROTEIN Methotrexate 12g/m2 (10 Cycles) Cisplatinum 120mg/m2; Doxorubicin 90mg/m2 MEPACT 2 mg/m2 twice a week for the first 3 months the weekly for the next 6 months (total length treatment 44 weeks) All the product are used as commercial formulation Other Names: Methotrexate Cisplatinum doxorubicin ifosfamide mifamurtide
No overexpression of ABCB1 / P-glycoprotein; If there is no overexpression of ABCB1 / P-glycoprotein, the administration of methotrexate, adriamycin and cisplatin will be chosen in many sites. BEFORE SURGERY TREATMENT: Methotrexate: 12g/m2 (3 cycles) Cisplatinum: 120mg/m2 (3 cycles) Doxorubicin: ADM 75mg/m2 (3 cycles) AFTER SURGERY TREATMENT: Methotrexate 12g/m2 (10 cycles) Cisplatinum 120mg/m2; Doxorubicin 90mg/m2 Total length 34 weeks All the product are used as commercial formulation Other Names: methotrexate cisplatin doxorubicine

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival	The Overall Survival will be evaluated at the end of the study period (5 enrollment years and 2 years - minimum- follow-up from the last enrolled patient)	The patients will be followed in term of Overall Survival, for all the study period (expected average: 7 years)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Events free survival	The events free survival will be evaluated by means of interim analysis after 2 and 3 years from the start of study. A further evaluation will be performed at the end of enrollment and after 2 years form the last enrolled patient.	After 2 and 3 years from the start of study

Collaborators and Investigators

• Sponsor: Grupo Espanol de Investigacion en Sarcomas
• Investigators: Principal Investigator: Óscar Gallego, Dr., Fundació Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau; Principal Investigator: Luis Gros, Dr., Hospital Vall d'Hebron

Study record dates

Study Major Dates

• Study Start (Actual): July 2, 2014
• Primary Completion (Actual): October 17, 2020
• Study Completion (Actual): October 17, 2020

Study Registration Dates

• First Submitted: May 7, 2020
• First Submitted That Met QC Criteria: May 7, 2020
• First Posted (Actual): May 12, 2020

Study Record Updates

• Last Update Posted (Actual): August 4, 2021
• Last Update Submitted That Met QC Criteria: August 3, 2021
• Last Verified: August 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Bone Tissue; Neoplasms, Connective Tissue; Sarcoma; Osteosarcoma
• Other Study ID Numbers: GEIS-33

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No