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

This study is currently recruiting participants.
See Contacts and Locations
Verified March 2016 by Italian Sarcoma Group
Sponsor:
Collaborators:
GROUPE SARCOMES FRANÇAIS
Grupo Espanol de Investigacion en Sarcomas
Information provided by (Responsible Party):
Italian Sarcoma Group
ClinicalTrials.gov Identifier:
NCT01710176
First received: October 17, 2012
Last updated: March 1, 2017
Last verified: March 2016
  Purpose

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.


Condition Intervention Phase
Localized High-risk Soft Tissue Sarcomas of the Extremities and Trunk Wall in Adults 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) Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: No masking
Primary Purpose: Treatment
Official Title: Localized High-Risk Soft Tissue Sarcomas Of The Extremities And Trunk Wall In Adults: An Integrating Approach Comprising Standard Vs Histotype-Tailored Neoadjuvant Chemotherapy

Resource links provided by NLM:


Further study details as provided by Italian Sarcoma Group:

Primary Outcome Measures:
  • To compare the effect on disease-free survival of full-dose standard chemotherapy with histotype-tailored chemotherapy within the context of an integrated strategy for high risk soft tissue sarcomas typical of the adult. [ Time Frame: 5 years ]

Secondary Outcome Measures:
  • 1:overall survival 2:response in the whole population 3:response by RECIST and Choi in each different histotype 4:pathological response 5:feasibility of integration of preoperative chemotherapy with preoperative local-regional treatments 6:PET re [ Time Frame: 5 years ]

Other Outcome Measures:
  • To validate the response to preoperative chemotherapy (both radiological and pathological) as a surrogate endpoint by showing that disease free survival and overall survival depend on response status and are independent of the treatment arm. [ Time Frame: 5 years ]

Estimated Enrollment: 350
Actual Study Start Date: June 1, 2011
Estimated Study Completion Date: January 2021
Estimated Primary Completion Date: January 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: standard chemotherapy with full-dose epirubicin + ifosfamide
Standard arm foresees 3 cycles of preoperative chemotherapy, each cycle will be repeated every 21 days and includes: epirubicin 60 mg/m2/day, short infusion, days 1 and 2; ifosfamide 3 g/m2/day, days 1, 2, 3
Drug: epirubicin 60 mg/m2/day (days 1, 2) and ifosfamide 3 g/m2/day (days 1, 2, 3)
Experimental: histotype-tailored chemotherapy according to the histotype
gemcitabine+docetaxel for undifferentiated pleomorphic sarcoma, trabectedin for myxoid liposarcoma with hypercellularity, ifosfamide for synovial sarcoma, ifosfamide+etoposide for malignant peripheral nerve sheath tumor, gemcitabine+dacarbazine for leiomyosarcoma
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)

  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Soft tissue sarcoma of adults, primary or locally recurrent, with spindle-cell or pleomorphic histology, belonging to one of the following for the randomization (Group1):

    myxoid-Round Cell liposarcoma (cellular component >5 %), leiomyosarcoma, synovial sarcoma, malignant peripheral nerve sheat tumor, undifferentiated pleomorphic sarcoma (ex Malignant fibrous histiocytoma)

    Or belonging to one of the following for the registration (Group 2):

    myxofibrosarcoma, unclassified Spindle Cell, pleomorphic liposarcoma, pleomorphic rabdomiosarcoma Or belonging to either group but not being evaluable for response (re-excision after previous inadequate resection or primary definitive surgery) (Group3).

    The histological diagnosis must be made according to the WHO criteria and will have to be centrally reviewed before randomization.

  2. High malignancy grade: grade 3 of 3, according to Coindre, or grade 2 at biopsy with a radiological evidence of more than 50% of necrosis in the tumor mass.
  3. Deep seated extremities, girdles and/or superficial trunk (thoracic or abdominal wall)lesion.
  4. Size of primary tumor (visible or previously inadequately resected) >5 cm at instrumental staging (CT, MRI), or locally recurrent of any size.
  5. Age > 18 years.
  6. ECOG performance status <1.
  7. Adequate bone marrow function:

    WBC >3.500/mm3 neutrophil >1.500/mm3 platelets >150.000/mm3 hemoglobin >11 g%.

  8. Adequate renal (creatinine <1.3 mg%), and hepatic function (bilirubin <1.5 mg% and transaminases <2 x n.v. If ALP > 2.5 x ULN, ALP LF and/or GGT < ULN).
  9. Adequate cardiac function (FE >50%).
  10. Signed informed consent.
  11. Complete compliance of the participating center with the protocol requirements.

Exclusion Criteria:

  1. Pregnancy or lactation.
  2. Distant metastasis.
  3. Other malignancies within past 5 years, with the exception of carcinoma in situ of cervix and basocellular skin cancers treated with eradicating intent.
  4. Sarcoma histotypes other than those mentioned in the inclusion criteria.
  5. Prior CT and/or RT.
  6. Serious psychiatric disease that precludes informed consent or limits compliance.
  7. Medical disease limiting survival to less than two years, limiting compliance or which in the physician's opinion might interfere significantly with the toxicity of the treatments.
  8. Cardiovascular diseases resulting in a New York Heart Association Functional Status > 2.
  9. Uncontrolled bacterial, viral or fungal infection.
  10. Impossibility of ensuring adequate follow-up.
  11. Failure to comply with the requirements of the present protocol leading to exclusion of the participating center.
  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: NCT01710176

Contacts
Contact: Alessandro Gronchi, MD +390223903714 alessandro.gronchi@istitutotumori.mi.it

Locations
Italy
Irccs Centro Di Riferimento Oncologico (Cro) - Recruiting
Aviano (pn), Italy
Irccs Istituto Ortopedico Rizzoli (Ior) - Recruiting
Bologna (bo), Italy
Pres.Ospedal.Spedali Civili Brescia - Recruiting
Brescia (bs), Italy
Fondazione Del Piemonte Per L'Oncologia Ircc Di Candiolo - Recruiting
Candiolo (to), Italy
Irst - Istituto Scientifico Romagnolo Per Lo Studio E La Cura Dei Tumori - Recruiting
Meldola (fc), Italy
Irccs Istituto Europeo Di Oncologia (Ieo) - Recruiting
Milano (mi), Italy
Irccs Istituto Nazionale Dei Tumori (Int) Recruiting
Milano (mi), Italy
Irccs Istituto Nazionale Tumori Fondazione Pascale - Not yet recruiting
Napoli (na), Italy
Irccs Istituto Oncologico Veneto (Iov) Recruiting
Padova, Italy
Irccs Istituto Regina Elena (Ifo) Recruiting
Roma (rm), Italy
Irccs Istituto Clinico Humanitas - Recruiting
Rozzano (mi), Italy
Presidio Sanitario Gradenigo Di Torino Not yet recruiting
Torino (to), Italy
Spain
Hospital Vall D'Hebron Recruiting
Barcelona, Spain
Hospital Clínico de Malaga Recruiting
Malaga, Spain
Hospital Son Espases Recruiting
Palma de Mallorca, Spain
Sponsors and Collaborators
Italian Sarcoma Group
GROUPE SARCOMES FRANÇAIS
Grupo Espanol de Investigacion en Sarcomas
  More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Italian Sarcoma Group
ClinicalTrials.gov Identifier: NCT01710176     History of Changes
Other Study ID Numbers: ISG-STS 10-01
Study First Received: October 17, 2012
Last Updated: March 1, 2017

Additional relevant MeSH terms:
Sarcoma
Neoplasms, Connective and Soft Tissue
Neoplasms by Histologic Type
Neoplasms
Gemcitabine
Etoposide
Epirubicin
Docetaxel
Etoposide phosphate
Isophosphamide mustard
Trabectedin
Ifosfamide
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Antiviral Agents
Anti-Infective Agents
Enzyme Inhibitors
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Antineoplastic Agents, Phytogenic
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Antibiotics, Antineoplastic
Antineoplastic Agents, Alkylating

ClinicalTrials.gov processed this record on June 23, 2017