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

NCT ID: NCT01696669

Last Updated: 2018-08-01

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 43 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2010-03-30
• Study Completion Date: 2018-01-18

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:

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.

Conditions

Ewing's Sarcoma

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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.

Group Type: EXPERIMENTAL

Chemotherapy

Intervention Type: DRUG

• 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.

Surgery

Intervention Type: PROCEDURE

Surgical intervention aiming to completely resect the tumor with negative margins.

Radiotherapy

Intervention Type: RADIATION

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.

Interventions

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.

Intervention Type: DRUG

Surgery

Surgical intervention aiming to completely resect the tumor with negative margins.

Intervention Type: PROCEDURE

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.

Intervention Type: RADIATION

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.

• Maximum Eligible Age: 40 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Grupo Espanol de Investigacion en Sarcomas

OTHER

Sponsor Role: lead

Responsible Party

Mariló de Carrillo

Jaume Mora

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Jaume Mora Graupera, MD

Role: STUDY_CHAIR

GEIS

Locations

Hospital Clínic de Barcelona

Barcelona, , Spain

Hospital de la Santa Creu i Sant Pau

Barcelona, , Spain

Hospital Vall d'Hebron

Barcelona, , Spain

Hospital Sant Joan de Déu

Esplugues de Llobregat, , Spain

Institut Català d'Oncologia l'Hospitalet

L'Hospitalet de Llobregat, , Spain

Hospital Ramón y Cajal

Madrid, , Spain

Hospital Son Espases

Palma de Mallorca, , Spain

Hospital Universitario de Canarias

San Cristóbal de La Laguna, , Spain

Hospital Universitario Miguel Servet

Zaragoza, , Spain

Countries

Spain

Other Identifiers

2009-016027-62

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

GEIS-21

Identifier Type: -

Identifier Source: org_study_id