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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

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ClinicalTrials.gov Identifier: NCT01710176
Recruitment Status : Active, not recruiting
First Posted : October 19, 2012
Last Update Posted : September 13, 2023
Sponsor:
Collaborators:
French Sarcoma Group
Grupo Espanol de Investigacion en Sarcomas
Information provided by (Responsible Party):
Italian Sarcoma Group

Study Description
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Brief 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.


Condition or disease Intervention/treatment 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 Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 550 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
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
Actual Study Start Date : June 1, 2011
Estimated Primary Completion Date : June 30, 2024
Estimated Study Completion Date : June 30, 2024

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
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)


Outcome Measures
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Primary Outcome Measures :
  1. 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. 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:
  1. 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 ]

Eligibility Criteria
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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
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
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01710176


Locations
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Italy
Fondazione Del Piemonte Per L'Oncologia Ircc Di Candiolo -
Candiolo, TO, Italy
Irccs Centro Di Riferimento Oncologico (Cro) -
Aviano (pn), Italy
Irccs Istituto Ortopedico Rizzoli (Ior) -
Bologna, Italy
Pres.Ospedal.Spedali Civili Brescia -
Brescia, Italy
Irst - Istituto Scientifico Romagnolo Per Lo Studio E La Cura Dei Tumori -
Meldola (fc), Italy
Irccs Istituto Europeo Di Oncologia (Ieo) -
Milano, Italy
Irccs Istituto Nazionale Dei Tumori (Int)
Milano, Italy
Irccs Istituto Nazionale Tumori Fondazione Pascale -
Napoli, Italy
Irccs Istituto Oncologico Veneto (Iov)
Padova, Italy
Irccs Istituto Regina Elena (Ifo)
Roma, Italy
Irccs Istituto Clinico Humanitas -
Rozzano (mi), Italy
Presidio Sanitario Gradenigo Di Torino
Torino, Italy
Spain
Hospital Vall D'Hebron
Barcelona, Spain
Hospital Clínico de Malaga
Malaga, Spain
Hospital Son Espases
Palma de Mallorca, Spain
Sponsors and Collaborators
Italian Sarcoma Group
French Sarcoma Group
Grupo Espanol de Investigacion en Sarcomas
More Information
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Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: Italian Sarcoma Group
ClinicalTrials.gov Identifier: NCT01710176    
Other Study ID Numbers: ISG-STS 10-01
First Posted: October 19, 2012    Key Record Dates
Last Update Posted: September 13, 2023
Last Verified: September 2023
Additional relevant MeSH terms:
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Sarcoma
Neoplasms, Connective and Soft Tissue
Neoplasms by Histologic Type
Neoplasms
Gemcitabine
Docetaxel
Etoposide
Epirubicin
Ifosfamide
Isophosphamide mustard
Dacarbazine
Trabectedin
Antimetabolites, Antineoplastic
 Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Antineoplastic Agents, Phytogenic
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Antibiotics, Antineoplastic
Antineoplastic Agents, Alkylating
Alkylating Agents