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

This study is currently recruiting participants. (see Contacts and Locations)
Verified February 2014 by Grupo Espanol de Investigacion en Sarcomas
Sponsor:
Information provided by (Responsible Party):
Mariló de Carrillo, Grupo Espanol de Investigacion en Sarcomas
ClinicalTrials.gov Identifier:
NCT01696669
First received: June 30, 2011
Last updated: August 26, 2014
Last verified: February 2014
  Purpose

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:

  1. Lower total dose of alkylating agents.
  2. Early cardioprotection with dexrazoxane.
  3. Radiotherapy adjusted to the initial response.
  4. Pilot trial with the combination of Gemcitabine + Docetaxel for high-risk patients.

Condition Intervention Phase
Ewing's Sarcoma
Drug: Chemotherapy
Procedure: Surgery
Radiation: Radiotherapy
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by Grupo Espanol de Investigacion en Sarcomas:

Primary Outcome Measures:
  • Progression Free Survival [ 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. ] [ Designated as safety issue: No ]
    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) [ Time Frame: two months ] [ Designated as safety issue: No ]
    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 [ Time Frame: to reach an index of disease progression < 20% for high risk patients during the maintenance phase with Gemcitabine + Docetaxel. ] [ Designated as safety issue: No ]
    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. [ Time Frame: 12 months ] [ Designated as safety issue: Yes ]
    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. [ Time Frame: 24 months ] [ Designated as safety issue: No ]
    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 [ Time Frame: 6 months ] [ Designated as safety issue: Yes ]
    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.


Estimated Enrollment: 43
Study Start Date: April 2010
Estimated Study Completion Date: December 2015
Estimated Primary Completion Date: December 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Chemotherapy + Surgery + Radiotherapy

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.

Drug: Chemotherapy
  • 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.
Procedure: Surgery
Surgical intervention aiming to completely resect the tumor with negative margins.
Radiation: Radiotherapy
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.

  Eligibility

Ages Eligible for Study:   up to 40 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01696669

Contacts
Contact: Jaume Mora Graupera, MD +34 934344412 secretaria@grupogeis.org

Locations
Spain
Hospital Clínic de Barcelona Recruiting
Barcelona, Spain
Principal Investigator: Maurel, MD         
Hospital de la Santa Creu i Sant Pau Recruiting
Barcelona, Spain
Principal Investigator: López Pousa, MD         
Hospital Vall d'Hebron Recruiting
Barcelona, Spain
Principal Investigator: Valverde, MD         
Hospital Sant Joan de Déu Recruiting
Esplugues de Llobregat, Spain
Principal Investigator: Mora, Md         
Institut Català d'Oncologia l'Hospitalet Recruiting
Hospitalet de Llobregat, Spain
Principal Investigator: García del Muro, MD         
Hospital Universitario de Canarias Recruiting
La Laguna, Spain
Principal Investigator: Cruz, MD         
Hospital Ramón y Cajal Recruiting
Madrid, Spain, 28034
Principal Investigator: Vaz, MD         
Hospital Son Espases Recruiting
Palma de Mallorca, Spain
Principal Investigator: Martín Broto, MD         
Hospital Universitario Miguel Servet Recruiting
Zaragoza, Spain
Principal Investigator: Martínez Trufero, MD         
Sponsors and Collaborators
Grupo Espanol de Investigacion en Sarcomas
Investigators
Study Chair: Jaume Mora Graupera, MD GEIS
  More Information

No publications provided

Responsible Party: Mariló de Carrillo, Jaume Mora, Grupo Espanol de Investigacion en Sarcomas
ClinicalTrials.gov Identifier: NCT01696669     History of Changes
Other Study ID Numbers: GEIS-21, 2009-016027-62
Study First Received: June 30, 2011
Last Updated: August 26, 2014
Health Authority: Spain: Agencia Española de Medicamentos y Productos Sanitarios
Spain: Comité Ético de Investigación Clínica

Keywords provided by Grupo Espanol de Investigacion en Sarcomas:
Ewing's Sarcoma
P6 protocol MSKCC
Gemcitabine
Docetaxel

Additional relevant MeSH terms:
Sarcoma
Sarcoma, Ewing
Neoplasms, Connective and Soft Tissue
Neoplasms by Histologic Type
Neoplasms
Osteosarcoma
Neoplasms, Bone Tissue
Neoplasms, Connective Tissue
Gemcitabine
Cyclophosphamide
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antineoplastic Agents
Therapeutic Uses
Antiviral Agents
Anti-Infective Agents
Enzyme Inhibitors
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Radiation-Sensitizing Agents
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Myeloablative Agonists

ClinicalTrials.gov processed this record on October 01, 2014