Localized High-Risk Soft Tissue Sarcomas Of The Extremities And Trunk Wall In Adults: An Integrating Approach Comprising Standard Vs Histotype-Tailored Neoadjuvant Chemotherapy

Summary

This is a randomized Phase III clinical trial in the setting of localized high-risk soft tissue sarcomas (STS). This study will compare a standard neoadjuvant chemotherapy with epirubicin plus ifosfamide versus a histology-driven chemotherapy, i.e. a chemotherapy tailored to the specific histology within the family of adult STS. Chemotherapy will be administered for 3 cycles. There will be five histological groups (representing 80% of STS), as follows: leiomyosarcoma, myxoid liposarcoma with hypercellularity (round cell MLPS), synovial sarcoma, malignant peripheral nerve sheath tumor (MPNST) and undifferentiated pleomorphic sarcoma. The histology-driven chemotherapy for these groups will be, respectively, gemcitabine plus dacarbazine, trabectedin, high-dose ifosfamide, ifosfamide plus etoposide, gemcitabine plus docetaxel. Other histological groups will also be included and registered, but treated only by standard chemotherapy. Patients who have already undergone definitive surgery will receive treatment post-operatively and patients needing a re-excision after inadequate surgery will be treated as patients in the two groups, but of course will not be evaluable for response. A centralized pathological review will be performed. Radiological response will be evaluated according to RECIST and to Choi criteria. Pathological response will also be recorded.

The endpoint will be disease-free survival (DFS) and, secondarily, overall survival (OS) of patients receiving standard chemotherapy versus those receiving histotype-tailored chemotherapy. Additional aims will be to compare the probability of response of standard vs histotype-tailored chemotherapy and to determine the radiological and pathological response with standard chemotherapy vs tailored chemotherapy in each different histological group. Another aim will be to validate the response (both radiological and pathological) to preoperative chemotherapy as a surrogate endpoint for DFS and OS.

Three hundred patients will be randomized over a 3-years period, from a pool of 400-450 registered patients.

Translational research will be performed. Areas of research will include identification and validation of the potential predictive markers for each histological subgroups.

The study is designed to verify the statistical hypothesis that histotype-tailored approach is associated, overall, with a 30% reduction in the hazard of relapse. However, in each different histological group, the effect of histotype-tailored chemotherapy, as compared to standard chemotherapy, can be different. To address this weakness an orthogonal study of response to chemotherapy as a surrogate of DFS and OS has been introduced into the trial. This study intends to extensively investigate the response (radiological and pathological) to preoperative chemotherapy and to validate it as a surrogate endpoint by showing that it correlates with disease free survival and overall survival.

Conditions

• Localized High-risk Soft Tissue Sarcomas of the Extremities and Trunk Wall in Adults

Interventions

DRUG

epirubicin 60 mg/m2/day (days 1, 2) and ifosfamide 3 g/m2/day (days 1, 2, 3)

DRUG

gemcitabine 900 mg/m2 (days 1 and 8) and docetaxel 75 mg/m2 (day 8)

DRUG

trabectedin 1.3 mg/m2

DRUG

high-dose ifosfamide 14 g/m2, given in in 14 days

DRUG

etoposide 150 mg/m2/day (days 1, 2, 3) and ifosfamide 3g/m2/day (days 1, 2, 3)

DRUG

gemcitabine 1800 mg/m2 (day 1) and dacarbazine 500 mg/m2 (day 1)

Sponsors & Collaborators

• French Sarcoma Group

  collaborator OTHER

• Grupo Espanol de Investigacion en Sarcomas

  collaborator OTHER

• Italian Sarcoma Group

  lead NETWORK

Study Design

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Model

PARALLEL

Eligibility

Min Age

18 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2011-06-01

Primary Completion

2024-06-30

Completion

2024-06-30

Countries

• Italy
• Spain

Study Locations