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Study of Intensive Chemotherapy, Surgery and Radiotherapy to Treat Ewing's Sarcoma in Children and Young Adults

Primary Purpose

Ewing's Sarcoma

Status
Completed
Phase
Phase 2
Locations
Spain
Study Type
Interventional
Intervention
Chemotherapy
Surgery
Radiotherapy
Sponsored by
Grupo Espanol de Investigacion en Sarcomas
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Ewing's Sarcoma focused on measuring Ewing's Sarcoma, P6 protocol MSKCC, Gemcitabine, Docetaxel

Eligibility Criteria

undefined - 40 Years (Child, Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Patients with Ewing's Sarcoma in which the molecular analysis has been performed in one of the 2 reference laboratories of the study and the EWS gene rearrangement has been confirmed by RT-PCR in the Hospital Sant Joan de Déu de Barcelona, or by fluorescence in situ hybridization (FISH) in the Cancer Research Center of Salamanca.
  • High-risk patients will be those patients with metastases, patients with primary tumor in pelvis or axial bones and patients with (micro) metastases in bone marrow detected by the molecular study. The remaining patients will be considered as standard risk. Lung nodules identified by CT-scan with diameter > 5 mm will be considered metastatic. Nodules ≤ 5 mm will be biopsied.
  • Age ≤ 40 years.
  • Adequate renal and hepatic function , defined as calculated creatinine clearance > 60 ml/min, creatinine, total bilirubin, AST and/or ALT < 1,5 times the upper limit of normal (ULN).
  • Normal cardiac function defined by echocardiography, or ejection fraction ≥ 55%.
  • ECOG performance status 0 - 1 (Appendix VIII).
  • Informed consent form signed by parents, guardians or the patient (if over 18 years), prior to the start of treatment.
  • Patients of childbearing age (both men and women) must use effective contraceptive methods before study entry and during the realization of it. Effective contraceptive methods for both women and men should be extended to 6 months after stopping the treatment under study. Pregnancy must be excluded by urine test (negative pregnancy test) prior to the inclusion in the study.

Exclusion Criteria:

  • Pregnancy or breastfeeding.
  • Active infection or other severe concomitant diseases.
  • Severe psychiatric conditions that make impossible to obtain the signed informed consent form or limit the treatment compliance.
  • Concurrent treatment with other experimental drugs within 30 days prior to study entry.
  • History of previous cancer diagnosed or treated in the past 5 years except basal cell carcinoma, cervical carcinoma in situ or superficial bladder cancer.

Sites / Locations

  • Hospital Clínic de Barcelona
  • Hospital de la Santa Creu i Sant Pau
  • Hospital Vall d'Hebron
  • Hospital Sant Joan de Déu
  • Institut Català d'Oncologia l'Hospitalet
  • Hospital Universitario de Canarias
  • Hospital Ramón y Cajal
  • Hospital Son Espases
  • Hospital Universitario Miguel Servet

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Chemotherapy + Surgery + Radiotherapy

Arm Description

Standard risk patients: MP6 Treatment: CHEMOTHERAPY: 2 cycles of vincristine-doxorubicin + dexrazoxane-cyclophosphamide, 1 cycle of ifosfamide-etoposide. SURGERY: Ideally within 21 days after chemotherapy. CHEMOTHERAPY: 1 cycle of vincristine-doxorubicin + dexrazoxane-cyclophosphamide, 1 cycle of ifosfamide-etoposide. RADIOTHERAPY: On the primary tumor bed in case of unresectable tumors, resected tumors with inadequate margins, or those with histologic response <90%. High risk patients: CHEMOTHERAPY: Window phase with 2 cycles of gemcitabine + docetaxel. MP6 TREATMENT. CHEMOTHERAPY: Maintenance therapy for 1 year with gemcitabine + docetaxel.

Outcomes

Primary Outcome Measures

Progression Free Survival
Assessment of the progression free survival in all the patients enrolled in the study 3 years after the completion of the treatment under study.

Secondary Outcome Measures

Objective response rate (ORR)
To assess the objective response rate to treatment (ORR) defined following EMEA criteria (CPMP/EWP/205/95/Rev.3/Corr.2) in high risk patients with Ewing's sarcoma treated with an early window phase of Gemcitabine + docetaxel (G + D).
Assessment of disease progression
To assess the disease progression, aiming to reach an index of disease progression < 20% for high risk patients during the maintenance phase with Gemcitabine + Docetaxel.
evaluate the toxicity and tolerance to the treatment Gemcitabine + Docetaxel in high risk patients, and toxicity and tolerance of mP6 treatment in all patients.
To evaluate the toxicity and tolerance to the treatment Gemcitabine + Docetaxel in high risk patients, and toxicity and tolerance of mP6 treatment in all patients.
Assessment of bone marrow condition.
Molecular diagnosis and extension study of bone marrow in all patients included in the trial. Assessment of prognostic significance of the type of translocation and the molecular effect in the bone marrow.
Study the impact of patients treated with Cardioxane in cardioprotection
Creation of a cohort of patients treated with anthracyclines at high doses and early cardioprotection with dexrazoxane (Cardioxane). Long-term study of cardioprotection in these patients compared with historical series from the P6 protocol that did not received cardioprotection.

Full Information

First Posted
June 30, 2011
Last Updated
July 31, 2018
Sponsor
Grupo Espanol de Investigacion en Sarcomas
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1. Study Identification

Unique Protocol Identification Number
NCT01696669
Brief Title
Study of Intensive Chemotherapy, Surgery and Radiotherapy to Treat Ewing's Sarcoma in Children and Young Adults
Official Title
Phase 2, Open-label, Uncontrolled, Multicenter and Prospective Study of Intensive Chemotherapy, Surgery and Radiotherapy to Treat Ewing's Sarcoma in Children and Young Adults
Study Type
Interventional

2. Study Status

Record Verification Date
July 2018
Overall Recruitment Status
Completed
Study Start Date
March 30, 2010 (Actual)
Primary Completion Date
December 20, 2017 (Actual)
Study Completion Date
January 18, 2018 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Grupo Espanol de Investigacion en Sarcomas

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Tumors of the Ewing sarcoma family (ES) affect children, adolescents and young adults. The reported incidence is 0.6 cases per million inhabitants every year. The peak incidence occurs between 10 and 20 years and it is rarely diagnosed beyond 30. The ES is a severe disease with a progression-free survival after 5 years of 60% in cases without metastasis and deadly in the majority of patients presenting metastasis. The ES is considered a systemic disease because, despite receiving an adequate local treatment, over 90% of patients deaths occur due to disseminated disease. Combined therapy of surgery, radiotherapy and chemotherapy has led to an improvement in the prognosis, achieving a survival of about 60% in most series The MSKCC P6 protocol was developed for the treatment of high risk ES. In 2003, Kolb et al. reported the MSKCC experience after a 4-years follow-up of 68 patients who had been included from 1990 to 2001. Following the MSKCC P6 protocol, a survival rate of 82% was achieved in patients without metastasis, superior to the achieved with less intensive protocols. Following the guidelines of the MSKCC P6 protocol, in 2002 we modified the treatment schedule to create the modified P6 protocol (MP6). GEIS intends to develop MP6 as a clinical trial, which could provide the following potential advantages about current treatments: Lower total dose of alkylating agents. Early cardioprotection with dexrazoxane. Radiotherapy adjusted to the initial response. Pilot trial with the combination of Gemcitabine + Docetaxel for high-risk patients.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Ewing's Sarcoma
Keywords
Ewing's Sarcoma, P6 protocol MSKCC, Gemcitabine, Docetaxel

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
43 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Chemotherapy + Surgery + Radiotherapy
Arm Type
Experimental
Arm Description
Standard risk patients: MP6 Treatment: CHEMOTHERAPY: 2 cycles of vincristine-doxorubicin + dexrazoxane-cyclophosphamide, 1 cycle of ifosfamide-etoposide. SURGERY: Ideally within 21 days after chemotherapy. CHEMOTHERAPY: 1 cycle of vincristine-doxorubicin + dexrazoxane-cyclophosphamide, 1 cycle of ifosfamide-etoposide. RADIOTHERAPY: On the primary tumor bed in case of unresectable tumors, resected tumors with inadequate margins, or those with histologic response <90%. High risk patients: CHEMOTHERAPY: Window phase with 2 cycles of gemcitabine + docetaxel. MP6 TREATMENT. CHEMOTHERAPY: Maintenance therapy for 1 year with gemcitabine + docetaxel.
Intervention Type
Drug
Intervention Name(s)
Chemotherapy
Intervention Description
Vincristine, 2 mg/m^2 IV bolus, day 1. Doxorubicin: 75 mg/m^2 per cycle, or 25 mg/m^2/day x 3 days, IV infusion, 1 hour (after dexrazoxane administration at the dose of 10:1). Dexrazoxane: administered at a dose of 10:1, before doxorubicin only in adults. Cyclophosphamide: 2100 mg/m^2 IV infusion, 6 hours, with MESNA protection, days 1 and 2. MESNA: used with cyclophosphamide and ifosfamide. The total daily dose of MESNA is equivalent to at least 60% of the daily dose of cyclophosphamide or ifosfamide. G-CSF: 5 micrograms/kg/day SC. It starts 24 hours after the last dose of chemotherapy and continues until the absolute neutrophil count is ≥ 750 mm^3/L. Ifosfamide: 1800 mg/m^2/day IV infusion, 1 hour, days 1-5 of each cycle (9,000 mg/m^2 total maximum dose). Window phase in high-risk patients (21-days cycle): Gemcitabine: 1000 mg/m^2 IV, 90 minutes on day 1 and 8. Docetaxel 100 mg/m^2, 2-3 hour infusion on day 8.
Intervention Type
Procedure
Intervention Name(s)
Surgery
Intervention Description
Surgical intervention aiming to completely resect the tumor with negative margins.
Intervention Type
Radiation
Intervention Name(s)
Radiotherapy
Intervention Description
On the primary tumor bed in case of unresectable tumors, resected tumors with inadequate margins, or those with histologic response <90%. Patients will receive radiotherapy 21 days after the completion of chemotherapy.
Primary Outcome Measure Information:
Title
Progression Free Survival
Description
Assessment of the progression free survival in all the patients enrolled in the study 3 years after the completion of the treatment under study.
Time Frame
Assessment of the progression free survival in all the patients enrolled in the study 3 years after the completion of the treatment under study.
Secondary Outcome Measure Information:
Title
Objective response rate (ORR)
Description
To assess the objective response rate to treatment (ORR) defined following EMEA criteria (CPMP/EWP/205/95/Rev.3/Corr.2) in high risk patients with Ewing's sarcoma treated with an early window phase of Gemcitabine + docetaxel (G + D).
Time Frame
two months
Title
Assessment of disease progression
Description
To assess the disease progression, aiming to reach an index of disease progression < 20% for high risk patients during the maintenance phase with Gemcitabine + Docetaxel.
Time Frame
to reach an index of disease progression < 20% for high risk patients during the maintenance phase with Gemcitabine + Docetaxel.
Title
evaluate the toxicity and tolerance to the treatment Gemcitabine + Docetaxel in high risk patients, and toxicity and tolerance of mP6 treatment in all patients.
Description
To evaluate the toxicity and tolerance to the treatment Gemcitabine + Docetaxel in high risk patients, and toxicity and tolerance of mP6 treatment in all patients.
Time Frame
12 months
Title
Assessment of bone marrow condition.
Description
Molecular diagnosis and extension study of bone marrow in all patients included in the trial. Assessment of prognostic significance of the type of translocation and the molecular effect in the bone marrow.
Time Frame
24 months
Title
Study the impact of patients treated with Cardioxane in cardioprotection
Description
Creation of a cohort of patients treated with anthracyclines at high doses and early cardioprotection with dexrazoxane (Cardioxane). Long-term study of cardioprotection in these patients compared with historical series from the P6 protocol that did not received cardioprotection.
Time Frame
6 months

10. Eligibility

Sex
All
Maximum Age & Unit of Time
40 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Patients with Ewing's Sarcoma in which the molecular analysis has been performed in one of the 2 reference laboratories of the study and the EWS gene rearrangement has been confirmed by RT-PCR in the Hospital Sant Joan de Déu de Barcelona, or by fluorescence in situ hybridization (FISH) in the Cancer Research Center of Salamanca. High-risk patients will be those patients with metastases, patients with primary tumor in pelvis or axial bones and patients with (micro) metastases in bone marrow detected by the molecular study. The remaining patients will be considered as standard risk. Lung nodules identified by CT-scan with diameter > 5 mm will be considered metastatic. Nodules ≤ 5 mm will be biopsied. Age ≤ 40 years. Adequate renal and hepatic function , defined as calculated creatinine clearance > 60 ml/min, creatinine, total bilirubin, AST and/or ALT < 1,5 times the upper limit of normal (ULN). Normal cardiac function defined by echocardiography, or ejection fraction ≥ 55%. ECOG performance status 0 - 1 (Appendix VIII). Informed consent form signed by parents, guardians or the patient (if over 18 years), prior to the start of treatment. Patients of childbearing age (both men and women) must use effective contraceptive methods before study entry and during the realization of it. Effective contraceptive methods for both women and men should be extended to 6 months after stopping the treatment under study. Pregnancy must be excluded by urine test (negative pregnancy test) prior to the inclusion in the study. Exclusion Criteria: Pregnancy or breastfeeding. Active infection or other severe concomitant diseases. Severe psychiatric conditions that make impossible to obtain the signed informed consent form or limit the treatment compliance. Concurrent treatment with other experimental drugs within 30 days prior to study entry. History of previous cancer diagnosed or treated in the past 5 years except basal cell carcinoma, cervical carcinoma in situ or superficial bladder cancer.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Jaume Mora Graupera, MD
Organizational Affiliation
GEIS
Official's Role
Study Chair
Facility Information:
Facility Name
Hospital Clínic de Barcelona
City
Barcelona
Country
Spain
Facility Name
Hospital de la Santa Creu i Sant Pau
City
Barcelona
Country
Spain
Facility Name
Hospital Vall d'Hebron
City
Barcelona
Country
Spain
Facility Name
Hospital Sant Joan de Déu
City
Esplugues de Llobregat
Country
Spain
Facility Name
Institut Català d'Oncologia l'Hospitalet
City
Hospitalet de Llobregat
Country
Spain
Facility Name
Hospital Universitario de Canarias
City
La Laguna
Country
Spain
Facility Name
Hospital Ramón y Cajal
City
Madrid
ZIP/Postal Code
28034
Country
Spain
Facility Name
Hospital Son Espases
City
Palma de Mallorca
Country
Spain
Facility Name
Hospital Universitario Miguel Servet
City
Zaragoza
Country
Spain

12. IPD Sharing Statement

Learn more about this trial

Study of Intensive Chemotherapy, Surgery and Radiotherapy to Treat Ewing's Sarcoma in Children and Young Adults

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