Background
CINSARC signature
Research hypothesis
Methods and design
Trial objectives
Primary objective
Secondary objectives
Trial design
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Patients classified as HR by CINSARC signature (HR-CINSARC) will be randomized between standard of care (surgical excision +/− external radiotherapy) and the experimental arm (standard of care with chemotherapy)
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Patients classified as LR by CINSARC signature (LR-CINSARC) will be treated at the discretion of the clinicians and data will be collected prospectively.
Clinical study endpoints
Primary endpoint
Secondary endpoints
Screening and randomization
Inclusion Criteria | Non Inclusion criteria |
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- The regional platform will transmit the CINSARC status to the sponsor and will be provided to the investigator.According to FNCLCC grading system, grade 2 and grade 1 tumors - Resectable and localized disease after appropriate extension work-up (including at least a chest-CT) - Available archived FFPE tumor sample in sufficient quantity to allow CINSARC qualification - Age ≥ 18 years - Eastern Cooperative Oncology Group (ECOG) performance status ≤2 - Life expectancy of at least 12 weeks after the start of the treatment - Women should be post-menopaused or willing to accept the use an effective contraceptive regimen during the treatment period and at least 12 months after the end of the treatment period. All non-menopaused women should have a negative pregnancy test within 72 h prior to registration. Men should accept to use an effective contraception during treatment period and at least 3 months (Ifosfamide treatment) or 6 months (Dacarbazine treatment) after the end of the study treatment - Signed written informed consent - Patient affiliated to a Social Health Insurance in France Additional criteria: Randomized Part - High-risk CINSARC signature -External radiotherapy not initiated before randomization (if applicable). -Acceptable hematologic function (within 72 h prior randomization): Absolute neutrophil count (ANC) ≥ 1.5 G/L, Platelet count ≥100 G/L and Hemoglobin > 9 g/dL -Acceptable renal function within 72 h prior randomization: Serum creatinine ≤1.5 x ULN or calculated creatinine clearance ≥60 mL/min (by the Cockcroft and Gault formula) -Acceptable liver function: Bilirubin ≤1.5 x upper limit of normal (ULN), AST (SGOT) and ALT (SGPT) ≤ 2.5 x ULN -Normal LVEF (> 50%) measured by echocardiography or isotopic ventriculography | - Soft-tissue sarcoma with the following histological subtypes: well-differentiated liposarcomas, alveolar soft-part sarcoma, dermatofibrosarcoma protuberans, clear-cell sarcoma, epithelioid sarcoma, alveolar or embryonal rhabdomyosarcoma - Primitive cutaneous, retroperitoneal, uterus or visceral STS - Metastatic disease - Previous or ongoing treatment for the sarcoma (with the exception of a surgery for diagnosis intend) - Contra-indication for Doxorubicin, Ifosfamide and Dacarbazine treatments - Prior therapy with ifosfamide or cyclophosphamide or other nitrogen mustards, and prior therapy with anthracyclines - Prior mediastinal/cardiac radiotherapy - History or presence of clinically relevant cardiovascular abnormalities such as uncontrolled hypertension, congestive heart failure NYHA classification of 3, unstable angina or poorly controlled arrhythmia, myocardial infarction within 6 months prior to study entry - 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 - Active, uncontrolled bacterial, viral, or fungal infections, requiring systemic therapy - Known infection with HIV, hepatitis B, or hepatitis C - Women who are breastfeeding, pregnant or who plan to become pregnant while in the trial - Concomitant disease or condition that could interfere with the conduct of the study, or that would, in the opinion of the investigator, pose an unacceptable risk to the subject in this study - Patient who has forfeited his/her freedom by administrative or legal award or who is under legal protection (curatorship and guardianship, protection of justice) - Patient unable to comply with the protocol for any reason. |
CINSARC analysis
Treatment
Standard of care
Experimental treatment
Follow-up
Main statistical analysis
HR-CINSARC patients: randomized part
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50% of expected events (51 events):
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◦ discontinuation for futility if one-sided p-value is > 0.282 (Hazard Ratio > 0.851)
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◦ discontinuation for efficacy if one-sided p-value is < 0.002 (Hazard Ratio < 0.438)
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◦ otherwise continue
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100% of expected events (101 events):
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◦ claim success if one-sided p-value is < 0.024 (Hazard Ratio < 0.676)
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CINSARC prognostic value
Discussion
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To determine the effectiveness of chemotherapy in grade ½ STS patients with HR-CINSARC;
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To prospectively validate the prognostic value of the CINSARC signature in grade ½ STS.