Efficacy of Dose Intensification in Patients With Non-metastatic Ewing Sarcoma

NCT ID: NCT02063022

Last Updated: 2022-09-19

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 278 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2009-01-22
• Study Completion Date: 2022-04-14

Brief Summary

Controlled, randomized phase III study, with the intent of optimizing the treatment of not metastatic Ewing Sarcoma. The patients will be randomized into 2 arms: standard treatment vs intensive treatment. Both arms will receive an induction treatment followed by surgery (wherever is possible) and/or radiotherapy. The maintenance treatment will be different on the basis of the response to the induction treatment (good or poor)

Detailed Description

Eligible patients with non metastatic Ewing's Sarcoma will be randomized into 2 different arms: standard treatment arm A (based on the ISG/SSG III protocol) or into the experimental arm B(chemotherapy with dose intensification and shorter length of treatment).

Both arm will receive an induction treatment with higher dose intensity of doxorubicin and ifosfamide in Arm B.

After the induction treatment all the patient will undergo to local treatment (surgery and/or radiotherapy)that will be followed by a maintenance therapy.

The maintenance therapy will be different for both arms and, within each arm, on the basis of the response (histologically evaluated) of the pre-local treatment therapy.

Maintenance for Arm A: Poor responders will undergo to stem cells apheresis and their reinfusion after treatment with high doses of Busulfan and Melphalan 25 weeks.

Good responders will receive a 6 drugs maintenance treatment for 37 weeks (as per standard ISG/SSG III protocol)

Maintenance for Arm B: Poor responders will undergo to stem cells apheresis and their reinfusion after an intensified treatment with high doses of Busulfan and Melphalan (25 weeks).

Good responders will receive a maintenance treatment for 25 weeks

The primary aim of the study is to assess the Event Free Survival (EFS) that is expected to be similar in both arms

The secondary objectives are:

To assess if the induction treatment in Arm B is able to increase the percentage of good responders compared to those who receive standard treatment.

To assess the toxicity and the Quality of Life related to the chemotherapy treatment

Conditions

Ewing's Sarcoma

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Standard treatment (as per ISG SSG III protocol)

Standard treatment for non metastatic Ewing's Sarcoma (as defined by the ISG/SSG III protocol).

It is based on a 6 drugs pre-local treatment (Vincristin, dactinomycin, cyclophosphamide,ifosfamide,etoposide and doxorubicin) followed by local treatment (surgery and/or radiotherapy)and by a maintenance treatment based on induction response

Group Type: ACTIVE_COMPARATOR

Standard treatment (as per protocol ISG SSG III)

Intervention Type: DRUG

Induction treatment with: 4 cycle of Vincristine (9mg/,2), Dactinomycin (6mg/m2), Doxorubicin (160mg/m2), Cyclophosphamide (2.4g/m2), Ifosfamide (18g/M2) and Etoposide (450mg/m2) given every 3 weeks Maintenance treatment for poor responder (25 weeks): Vincristine (12mg/m2), Dactinomycin (1.5mg/m2), Doxorubicin (320mg/m2), Ifosfamide (27g/m2), Cyclophosphamide (8.8g/m2), Etoposide (1.5g/m2) and peripheral Cells Steam Transplant after Busulfan and Melphalan treatment Maintenance treatment (37 week) for good responder: Vincristine (18mg/m2), Dactinomycin (6mg/m2), Doxorubicin (400mg/m2), Ifosfamide (72g/m2), Cyclosphosphamide(6g/m2), Etoposide (1.8 g/m2)

Intensified treatment

Dose intense treatment for non metastatic Ewing's Sarcoma It is based on a 3 drug pre-local treatment (Vincristin, ifosfamide and doxorubicin)followed by local treatment (surgery and/or radiotherapy)and by a maintenance treatment based on induction response

Group Type: EXPERIMENTAL

Intensified chemotherapy

Intervention Type: DRUG

• Induction treatment with: 4 cycle of Vincristine (10.5 mg/m2), Doxorubicin (320 mg/m2) and Ifosfamide (36 mg/m2) given every 3 weeks
• Maintenance treatment for poor responder (25 weeks): Vincristine (12mg/m2), Doxorubicin (400mg/m2), Ifosfamide (63g/m2), Cyclophosphamide (4g/m2), Etoposide (1.5g/m2) and Cells Steam Transplant after Busulfan and Melphalan treatment
• Maintenance treatment (25 week) for good responder: Vincristine (12mg/m2), Doxorubicin (400mg/m2), Ifosfamide (72g/m2), Etoposide (1.8g/m2)

Interventions

Standard treatment (as per protocol ISG SSG III)

Induction treatment with: 4 cycle of Vincristine (9mg/,2), Dactinomycin (6mg/m2), Doxorubicin (160mg/m2), Cyclophosphamide (2.4g/m2), Ifosfamide (18g/M2) and Etoposide (450mg/m2) given every 3 weeks Maintenance treatment for poor responder (25 weeks): Vincristine (12mg/m2), Dactinomycin (1.5mg/m2), Doxorubicin (320mg/m2), Ifosfamide (27g/m2), Cyclophosphamide (8.8g/m2), Etoposide (1.5g/m2) and peripheral Cells Steam Transplant after Busulfan and Melphalan treatment Maintenance treatment (37 week) for good responder: Vincristine (18mg/m2), Dactinomycin (6mg/m2), Doxorubicin (400mg/m2), Ifosfamide (72g/m2), Cyclosphosphamide(6g/m2), Etoposide (1.8 g/m2)

Intervention Type: DRUG

Intensified chemotherapy

• Induction treatment with: 4 cycle of Vincristine (10.5 mg/m2), Doxorubicin (320 mg/m2) and Ifosfamide (36 mg/m2) given every 3 weeks
• Maintenance treatment for poor responder (25 weeks): Vincristine (12mg/m2), Doxorubicin (400mg/m2), Ifosfamide (63g/m2), Cyclophosphamide (4g/m2), Etoposide (1.5g/m2) and Cells Steam Transplant after Busulfan and Melphalan treatment
• Maintenance treatment (25 week) for good responder: Vincristine (12mg/m2), Doxorubicin (400mg/m2), Ifosfamide (72g/m2), Etoposide (1.8g/m2)

Intervention Type: DRUG

Other Intervention Names

Vincristine; Dactinomycin; Doxorubicin; Ifosfamide; Cyclophosphamide; Etoposide; Busulfan; Melphalan; Vincristine,; Doxorubicin; Ifosfamide; Cyclophosphamide; Etoposide; Busulfan; Melphalan

Eligibility Criteria

Inclusion Criteria

• Ewing Sarcoma or PNET diagnosis centrally confirmed
• Age ≤ 40 years
• Absence of evident metastasis or lung met < 0.5 cm Presence of skip metastasis in the bone compartment of the primary tumor is to be considered as local disease and not metastatic.
• Adeguate bone marrow, hepatic and renal function
• Left Ventricular Ejection Fraction > 50%
• No primary Ewing Sarcoma treatments (both chemotherapy and/or radiotherapy)
• Voluntarily signed an informed consent form
• Radiological and histological documentation available for central review.

Exclusion Criteria

• Presence of lung or extra-pulmonary lesions
• Bone Marrow involvement
• In case of chest disease: presence of plural effusion
• Elapsed time between histological diagnosis and chemotherapy start, more than 4 weeks
• Any medical contraindication to the use of the study drugs
• Any psychological or social conditions that can compromise the protocol compliance and/or follow-up
• Previous malignancies (excluded in situ cervix carcinoma)

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

Sponsors

Italian Sarcoma Group

NETWORK

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Roberto Luksch, MD

Role: PRINCIPAL_INVESTIGATOR

Italian Sarcoma Group

Locations

Centro di Riferimento Oncologico - Unit of Medical Oncology

Aviano, Pordenone, Italy

I.R.C.C. - Unit of Medical Oncology

Candiolo, Torino, Italy

IRCCS materno infantile Burlo Garofolo

Trieste, T, Italy

Azienda Ospedaliero Universitaria Consorziale Policlinico - Bari

Bari, , Italy

Istituto Ortopedico Rizzoli

Bologna, , Italy

A.O. Universitaria Meyer

Florence, , Italy

Istituto Giannina Gaslini

Genova, , Italy

FONDAZIONE IRCCS Istituto Nazionale dei Tumori

Milan, , Italy

Azienda Ospedaliera Universitaria "Federico Ii" .

Napoli, , Italy

Azienda Ospedaliera di Padova

Padua, , Italy

Azienda Ospedaliero Universitaria Pisana

Pisa, , Italy

Istituto Nazionale Tumori Regina Elena - Unit of Medical Oncology I

Roma, , Italy

Ospedale Pediatrico Bambin Gesu'

Roma, , Italy

Ospedale Infantile Regina Margherita - Unit of Paediatric Oncoematology

Torino, , Italy

Countries

Italy

References

S. Ferrari, T. Alvegard, R. Luksch, A. Tienghi, K. S. Hall, G. Bernini, A. Brach del Prever, P. Picci, G. Bacci, S. Smeland Non-metastatic Ewing's family tumors: High-dose chemotherapy with stem cell rescue in poor responder patients. Preliminary results of the Italian/Scandinavian ISG/SSG III protocol. J Clini Oncol, 2007 ASCO Annual Meeting Proceedings Vol 25 (June 20 Suppl), 2007: 10014

Reference Type: BACKGROUND

Luksch R, Palmerini E, Milano GM, Paioli A, Asaftei S, Barretta F, Puma N, Cesari M, Tirtei E, Podda M, Pierobon M, Manzitti C, Ferraresi V, Tamburini A, Bertulli R, Di Pinto D, Mascarin M, Grignani G, Coccoli L, Rabusin M, De Leonardis F, Gambarotti M, Parafioriti A, Cammelli S, Vennarini S, Ferrari S, Donati DM, Bastoni S, Massimino M, Fagioli F, Ibrahim T. Intensified Induction Therapy for Newly Diagnosed, Localized Skeletal Ewing Sarcoma (ISG/AIEOP EW-1): A Randomized, Open-Label, Phase 3, Non-Inferiority Trial. Pediatr Blood Cancer. 2025 Apr;72(4):e31551. doi: 10.1002/pbc.31551. Epub 2025 Jan 20.

Reference Type: DERIVED

PMID: 39833645 (View on PubMed)

Other Identifiers

ISG/AIEOP EW-1

Identifier Type: -

Identifier Source: org_study_id