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

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

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.

Study Overview

• Status: Completed
• Conditions: Ewing's Sarcoma
• Intervention / Treatment: Drug: Chemotherapy; Procedure: Surgery; Radiation: Radiotherapy

• Study Type: Interventional
• Enrollment (Actual): 43
• Phase: Phase 2

Contacts and Locations

Study Locations

• Spain
  • Barcelona, Spain
    • Hospital Clínic de Barcelona
  • Barcelona, Spain
    • Hospital de la Santa Creu i Sant Pau
  • Barcelona, Spain
    • Hospital Vall d'Hebron
  • Esplugues de Llobregat, Spain
    • Hospital Sant Joan De Deu
  • Hospitalet de Llobregat, Spain
    • Institut Catala d'Oncologia L'Hospitalet
  • La Laguna, Spain
    • Hospital Universitario de Canarias
  • Madrid, Spain, 28034
    • Hospital Ramón y Cajal
  • Palma de Mallorca, Spain
    • Hospital Son Espases
  • Zaragoza, Spain
    • Hospital Universitario Miguel Servet

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 38 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	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

Outcome Measure	Measure Description	Time Frame
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).	two months
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.	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.	12 months
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.	24 months
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.	6 months

Collaborators and Investigators

• Sponsor: Grupo Espanol de Investigacion en Sarcomas
• Investigators: Study Chair: Jaume Mora Graupera, MD, GEIS

Study record dates

Study Major Dates

• Study Start (Actual): March 30, 2010
• Primary Completion (Actual): December 20, 2017
• Study Completion (Actual): January 18, 2018

Study Registration Dates

• First Submitted: June 30, 2011
• First Submitted That Met QC Criteria: September 26, 2012
• First Posted (Estimate): October 1, 2012

Study Record Updates

• Last Update Posted (Actual): August 1, 2018
• Last Update Submitted That Met QC Criteria: July 31, 2018
• Last Verified: July 1, 2018

More Information

Terms related to this study

• Keywords: Gemcitabine; Docetaxel; Ewing's Sarcoma; P6 protocol MSKCC
• Additional Relevant MeSH Terms: Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Osteosarcoma; Neoplasms, Bone Tissue; Neoplasms, Connective Tissue; Sarcoma; Sarcoma, Ewing
• Other Study ID Numbers: GEIS-21; 2009-016027-62 (EudraCT Number)