Clinical trial NCT04307277: Interest of Peri Operative CHemotherapy In Patients With CINSARC High-risk Localized Soft Tissue Sarcoma
Official title: Interest of Peri Operative CHemotherapy In Patients With CINSARC High-risk Localized Soft Tissue Sarcoma
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Soft Tissue Sarcoma
Keywords: Soft Tissue Sarcoma
CINSARC signature
Chemotherapy
Lead sponsor: Institut Claudius Regaud
Sponsor class: OTHER
First posted: 2020-03-13
Enrollment: 600
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Phase III, multicenter, randomized open-label and comparative study designed to demonstrate whether adding 4 cycles of peri-operative doxorubicin-based chemotherapy improves metastasis-free survival as compared with standard management in patients with resectable STS, considered as high-risk according to CINSARC (Complexity Index in SARComas) signature.

After signed informed consent, patients considered as eligible to CHIC-STS study by the investigator will be enrolled in the study and a molecular screening will be performed (600 patients will be screened).

Patients considered as low-risk according to CINSARC signature will be treated at the discretion of the clinicians (prospective cohort).

Patients considered as high-risk according to CINSARC signature will be randomized in the open-label multicenter phase III trial and assigned in one of the two following treatments arms:

* Arm A (control arm): Standard of care (surgical excision +/- external radiotherapy).
* Arm B (experimental arm): Standard of care + 4 cycles of intravenous chemotherapy during 12 weeks.

A total of 250 patients will have to be randomized with 125 patients in each arm.


Eligibility criteria: Inclusion Criteria:

1. Diagnosis of soft-tissue sarcoma, histologically confirmed by RRePS (Réseau de Référence en Pathologie des Sarcomes et des Viscères) network
2. According to FNCLCC grading system, grade 1, 2 or 3 tumors
3. Resectable and localized disease after appropriate extension work-up (including at least a chest-CT)
4. 6 weeks or less between surgical excision and inclusion (if performed before inclusion)
5. Available archived FFPE tumor sample in sufficient quantity to allow CINSARC qualification
6. Age ≥ 18 years
7. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2
8. Life expectancy of at least 12 weeks after the start of the treatment
9. Women should be post-menopaused or willing to accept the use of an effective contraceptive regimen during the treatment period and at least 12 months (ifosfamide treatment) or 6 months (dacarbazine treatment) after the end of the treatment period. All non-menopaused women should have a negative pregnancy test within 72 hours prior to registration. Men should accept to use an effective contraception during treatment period and at least 3 months after the end of the study treatment.
10. Signed written informed consent
11. Patient affiliated to a Social Health Insurance in France.

Exclusion Criteria:

1. 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
2. Primitive cutaneous, retroperitoneal, uterus or visceral STS
3. Metastatic disease
4. Previous or ongoing treatment for the sarcoma (with the exception of surgical excision)
5. Contra-indication for Doxorubicin, Ifosfamide and Dacarbazine treatments
6. Prior therapy with ifosfamide or cyclophosphamide or other nitrogen mustards, and prior therapy with anthracyclines
7. Prior mediastinal/cardiac radiotherapy
8. 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
9. 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
10. Active, uncontrolled bacterial, viral, or fungal infections, requiring systemic therapy
11. Known infection with HIV, hepatitis B, or hepatitis C
12. Women who are breastfeeding, pregnant or who plan to become pregnant while in the trial
13. 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
14. Patient who has forfeited his/her freedom by administrative or legal award or who is under legal protection (curatorship and guardianship, protection of justice)
15. Patient unable to comply with the protocol for any reason.

ADDITIONAL CRITERIA FOR THE RANDOMIZED PHASE III STUDY

1. High-risk CINSARC signature
2. Acceptable hematologic function (within 72 hours prior randomization): Absolute neutrophil count (ANC) ≥ 1.5 G/L, Platelet count ≥ 100 G/L and Hemoglobin \> 9g/dL
3. Acceptable renal function within 72 hours prior randomization: Serum creatinine ≤ 1.5 x ULN or calculated creatinine clearance ≥ 60 mL/min (by the Cockcroft and Gault formula)
4. Acceptable liver function: Bilirubin ≤ 1.5 x upper limit of normal (ULN), AST (SGOT) and ALT (SGPT) ≤ 2.5 x ULN
5. Normal LVEF (\>50%) measured by echocardiography or isotopic ventriculography

Primary outcomes:
measure: Metastasis-free survival defined by the delay between randomization and the appearance of metastatic.
timeFrame: 5 years for each patient
Secondary outcomes:
measure: Disease-free survival defined by the delay between randomization and first relapse (local, regional, or distant) or death from any cause.
timeFrame: 5 years for each patient
measure: Safety assessed by the toxicity grading of the National Cancer Institute (NCI-CTCAE v5.0).
timeFrame: 4 months for each patient
measure: Overall survival defined by the delay between randomization and death from any cause.
timeFrame: 5 years for each patient
Other outcomes:
Locations:
city: Besançon
country: France
facility: CHRU Besançon
city: Bordeaux
country: France
facility: Institut Bergonié
city: Caen
country: France
facility: Centre François Baclesse
city: Clermont-Ferrand
country: France
facility: Centre Jean Perrin
city: Dijon
country: France
facility: Centre Georges-François Leclerc
city: Grenoble
country: France
facility: CHU Grenoble
city: Limoges
country: France
facility: CHU Limoges
city: Lyon
country: France
facility: Centre Léon Bérard
city: Marseille
country: France
facility: Institut Paoli-Calmettes
city: Marseille
country: France
facility: CHU Marseille
city: Montpellier
country: France
facility: Institut de Cancérologie de Montpellier
city: Nice
country: France
facility: Centre Antoine Lacassagne
city: Paris
country: France
facility: Hôpital Cochin
city: Poitiers
country: France
facility: CHU Poitiers
city: Reims
country: France
facility: Institut Godinot
city: Rennes
country: France
facility: Centre Eugène Marquis
city: Rouen
country: France
facility: Centre Henri Becquerel
city: Saint-Herblain
country: France
facility: Institut de Cancérologie de l'Ouest
city: Saint-Étienne
country: France
facility: CHU de SAINT ETIENNE
city: Strasbourg
country: France
facility: Institut de Cancérologie Strasbourg Europe
city: Toulouse
country: France
facility: Institut Universitaire du Cancer Toulouse Oncopole
city: Vandœuvre-lès-Nancy
country: France
facility: Institut de Cancérologie de Lorraine - Centre Alexis Vautrin
Study officials:
References:
citation: Filleron T, Le Guellec S, Chevreau C, Cabarrou B, Lesluyes T, Lodin S, Massoubre A, Mounier M, Poublanc M, Chibon F, Valentin T. Value of peri-operative chemotherapy in patients with CINSARC high-risk localized grade 1 or 2 soft tissue sarcoma: study protocol of the target selection phase III CHIC-STS trial. BMC Cancer. 2020 Jul 31;20(1):716. doi: 10.1186/s12885-020-07207-3.