Benefit of Intensified Peri-operative Chemotherapy Within High-risk CINSARC Patients With Resectable Soft-tissue Sarcomas

Official title

Phase III Trial Investigating the Potential Benefit of Intensified Peri-operative Chemotherapy With in High-risk CINSARC Patients With Resectable Soft-tissue SARComas

Overview

The primary objective of this trial is to investigate whether the addition of 3 additional neo-adjuvant cycles of chemotherapy (doxorubicin based chemotherapy) to standard management according to the ISG-STS 10-01 study (3 cycles of neoadjuvant doxorubicin based chemotherapy + surgery +/- radiotherapy) improves the outcome of high-risk CINSARC patients with resectable soft-tissue sarcoma (STS). Primary endpoint is metastatic progression-free survival (M-PFS, after 3 years of follow-up).

Detailed description

For high-risk CINSARC patients, this is a multicenter randomized two-arm phase III trial, with a ratio 1:1:

* Arm A: standard management (3 cycles of neoadjuvant doxorubicin based chemotherapy + surgery +/- radiotherapy) * Arm B: experimental arm (6 cycles of neoadjuvant doxorubicin based chemotherapy + surgery +/- radiotherapy)

For low-risk CINSARC patients, this a multicenter prospective cohort with treatment at the discretion of the investigator.

Interventions

• Drug Doxorubicin
  A treatment cycle consists of 3 weeks. Doxorubicin will be administered from day 1 to day 3 (60 or 75mg/m² day or 20 or 25 mg/m² per day), repeated every 3 weeks, up to 3 cycles.
• Drug Ifosfamide or dacarbazine
  A treatment cycle consists of 3 weeks. Treatment may continue up to 3 cycles. Ifosfamide will be administered from day 1 to day 3 (7,5-9 g/m² over 3 days with mesna and G-CSF) or dacarbazine (100 mg/m² 1 day or 450 mg/m² 2 days) as per local practices, repeated every 3 weeks, up to 3 cycles.
• Drug Doxorubicin
  A treatment cycle consists of 3 weeks. Doxorubicin will be administered from day 1 to day 3 (60 or 75mg/m² day or 20 or 25 mg/m² per day), repeated every 3 weeks, up to 6 cycles.
• Drug Ifosfamide or dacarbazine
  A treatment cycle consists of 3 weeks. Ifosfamide will be administered from day 1 to day 3 (7,5-9 g/m² over 3 days with mesna and G-CSF) or dacarbazine (100 mg/m² 1 day or 450 mg/m² 2 days) as per local practices, repeated every 3 weeks, up to 6 cycles.
• Drug At the discretion of the investigator
  Drug at the discretion of the investigator.

Primary outcome measures

• Metastasis progression-free survival in High-risk CINSARC patients [Time frame: 3 years]

Secondary outcome measures (10)

• Loco-regional relapse-free survival in High-risk CINSARC patients [Time frame: 3 years]
• Progression-free survival in High-risk CINSARC patients [Time frame: 3 years]
• Overall survival in High-risk CINSARC patients [Time frame: 3 years]
• Best overall response in High-risk CINSARC patients [Time frame: Throughout the treatment period, an average of 6 months]
• Histological response in High-risk CINSARC patients [Time frame: An average of 6 months]
• Safety profile in High-risk CINSARC patients [Time frame: Throughout the treatment period, an average of 6 months]
• Progression-free survival in Low-risk CINSARC patients [Time frame: 3 years]
• Metastasis progression-free survival in Low-risk CINSARC patients [Time frame: 3 years]
• Loco-regional progression-free survival in Low-risk CINSARC patients [Time frame: 3 years]
• Overall survival in Low-risk CINSARC patients [Time frame: 3 years]

Eligibility criteria

Inclusion criteria

• Histologically confirmed soft-tissue sarcoma by the RRePS (Réseau de Référence en Pathologie des Sarcomes et des Viscères) network, as recommended by the French NCI,
• Grade 2 or 3 according to the FNCLCC grading system,
• Available archived tumour sample for research purpose,
• Non-metastatic and resectable disease,
• No prior treatment for the disease under study,
• Age ≥ 18 years,
• Life expectancy ≥ 3 months,
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 1,
• Patients must have measurable disease (lesion in previously irradiated field can be considered as measurable if progressive at inclusion according to RECIST 1.1) defined as per RECIST v1.1 with at least one lesion that can be measured in at least one dimension (longest diameter to be recorded) as ≥ 10 mm or ≥ 15mm in case of adenopathy,
• Women of childbearing potential must have a negative serum pregnancy test before study entry. Both women and men must agree to use a medically acceptable method of contraception throughout the treatment period and for one year after discontinuation of treatment. Acceptable methods of contraception include intrauterine device (IUD), oral contraceptive, subdermal implant and double barrier. Subjects of childbearing potential are those who have not been surgically sterilized (e.g., vasectomy for males and hysterectomy for females) or have not been free from menses for ≥ 1 year,
• Voluntarily signed and dated written informed consents prior to any study specific procedure,
• Patients with a social security in compliance with the French law.

Exclusion criteria

• Soft-tissue sarcoma with the following histological subtypes: well-differentiated liposarcoma, alveolar soft-part sarcoma, dermatofibrosarcoma protuberans, clearcell sarcoma, embryonal and alveolar rhabdomyosarcoma,
• Prior or concurrent malignant disease diagnosed or treated in the last 2 years except for adequately treated in situ carcinoma of the cervix, basal or squamous skin cell carcinoma, or in situ transitional bladder cell carcinoma,
• Any other contraindication to anthracycline, ifosfamide or dacarbazine chemotherapy,
• Participation to a study involving a medical or therapeutic intervention in the last 28 days,
• Known infection with HIV, hepatitis B, or hepatitis C,
• Females who are pregnant or breast-feeding,
• Other medical conditions may interfere with the conduct of the study and, in the judgment of the investigator, would make the patient inappropriate for entry into this study,
• Individuals deprived of liberty or placed under legal guardianship,
• Unwillingness or inability to comply with the study protocol for any reason.

Additional criteria for randomization :

• High-risk CINSARC signature,
• No more than two cycle of neo-adjuvant anthracycline-based chemotherapy before randomization.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

France · 10 centers

• Institut Bergonie — Bordeaux
• Centre Georges François Leclerc — Dijon
• CHU Dupuytren — Limoges
• Centre Léon Bérard — Lyon
• Institut Paoli Calmettes — Marseille
• Insitut du Cancer — Montpellier
• Institut de Cancérologie de l'Ouest - Site René Gauducheau — Saint-Herblain
• CHRU Strasbourg — Strasbourg
• … and 2 more centers

Identifiers

NCT: NCT03805022 · IB 2017-04 · 2018-000186-36

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗