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

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

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).

Study Overview

• Status: Recruiting
• Conditions: Resectable; Non-metastatic Soft-tissue Sarcoma
• Intervention / Treatment: Drug: Doxorubicin; Drug: Ifosfamide or dacarbazine; Drug: Doxorubicin; Drug: Ifosfamide or dacarbazine; Drug: At the discretion of the investigator

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.

• Study Type: Interventional
• Enrollment (Anticipated): 351
• Phase: Phase 3

Contacts and Locations

Study Locations

• France
  • Bordeaux, France, 33076
    • Recruiting
    • Institut Bergonié
  • Dijon, France, 21079
    • Recruiting
    • Centre Georges François Leclerc
  • Limoges, France, 87042
    • Recruiting
    • CHU Dupuytren
  • Lyon Cedex 08, France, 69373
    • Recruiting
    • Centre Leon Berard
  • Marseille, France, 13273
    • Recruiting
    • Institut Paoli Calmettes
  • Montpellier, France, 34298
    • Recruiting
    • Insitut du Cancer
  • Saint-Herblain, France, 44805
    • Recruiting
    • Institut de Cancérologie de l'Ouest - Site René Gauducheau
  • Strasbourg, France, 67200
    • Recruiting
    • CHRU Strasbourg
  • Toulouse, France, 31052
    • Recruiting
    • Institut Claudius Regaud
  • Villejuif, France, 94800
    • Not yet recruiting
    • Institut Gustave Roussy

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria :

1. 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,
2. Grade 2 or 3 according to the FNCLCC grading system,
3. Available archived tumour sample for research purpose,
4. Non-metastatic and resectable disease,
5. No prior treatment for the disease under study,
6. Age ≥ 18 years,
7. Life expectancy ≥ 3 months,
8. Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 1,
9. 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,
10. 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,
11. Voluntarily signed and dated written informed consents prior to any study specific procedure,
12. Patients with a social security in compliance with the French law.

Exclusion Criteria :

1. Soft-tissue sarcoma with the following histological subtypes: well-differentiated liposarcoma, alveolar soft-part sarcoma, dermatofibrosarcoma protuberans, clearcell sarcoma, embryonal and alveolar rhabdomyosarcoma,
2. 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,
3. Any other contraindication to anthracycline, ifosfamide or dacarbazine chemotherapy,
4. Participation to a study involving a medical or therapeutic intervention in the last 28 days,
5. Known infection with HIV, hepatitis B, or hepatitis C,
6. Females who are pregnant or breast-feeding,
7. 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,
8. Individuals deprived of liberty or placed under legal guardianship,
9. Unwillingness or inability to comply with the study protocol for any reason.

Additional criteria for randomization :

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm A; Control-Arm phase III high-risk CINSARC: Patients will be treated by doxorubicin (60 or 75mg/m² day or 20- or 25 mg/m² per day from day1 to day 3) + ifosfamide (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 of a 21-days cycle for up to 3 cycles in neoadjuvant setting Neoadjuvant chemotherapy will be followed by surgery. If indicated, radiotherapy could be prescribed at the discretion of the investigator (in neoadjuvant or adjuvant setting).	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.
Experimental: Arm B; Experimental-Arm phase III high-risk CINSARC: Patients will be treated by doxorubicin (60 or 75mg/m² day or 20 or 25 mg/m² per day from day1 to day 3) + ifosfamide (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 of a 21-days cycle for up to 6 cycles in neoadjuvant setting Neoadjuvant chemotherapy will be followed by surgery. If indicated, radiotherapy could be prescribed at the discretion of the investigator (in neoadjuvant or adjuvant setting).	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.
Experimental: Prospective cohort; Patients will be treated at the discretion of the investigator	Drug: At the discretion of the investigator; Drug at the discretion of the investigator.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Metastasis progression-free survival in High-risk CINSARC patients	Metastasis progression-free survival (M-PFS) defined as the time interval between the date of randomization and the date of death or distant progression.	3 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Loco-regional relapse-free survival in High-risk CINSARC patients	Loco-regional relapse-free survival (LR-RFS) defined as the time interval between the randomization date and the date of death or loco-regional progression.	3 years
Progression-free survival in High-risk CINSARC patients	Progression-free survival (PFS) defined as the time interval between the randomization date and the date of death or progression (as per RECIST v1.1).	3 years
Overall survival in High-risk CINSARC patients	Overall survival (OS) defined as the time interval between the randomization date and the date of death.	3 years
Best overall response in High-risk CINSARC patients	Best overall response under treatment as per RECIST v1.1.	Throughout the treatment period, an average of 6 months
Histological response in High-risk CINSARC patients	Histological response defined as the proportion of recognizable cells on the tumor sample.	An average of 6 months
Safety profile in High-risk CINSARC patients	Toxicity graded using the common toxicity criteria from the NCI v5.	Throughout the treatment period, an average of 6 months
Progression-free survival in Low-risk CINSARC patients	Progression-free survival defined as the time interval between the randomization date and the date of death or progression (as per RECIST v1.1).	3 years
Metastasis progression-free survival in Low-risk CINSARC patients	Metastasis progression-free survival defined as the time interval between the inclusion date and the date of death or distant progression.	3 years
Loco-regional progression-free survival in Low-risk CINSARC patients	Description of the treatment efficacy in terms of 3-years loco-regional progression-free survival defined as the time interval between the randomization date and the date of death or loco-regional progression.	3 years
Overall survival in Low-risk CINSARC patients	Overall survival defined as the time interval between the inclusion date and the date of death.	3 years

Collaborators and Investigators

• Sponsor: Institut Bergonié
• Collaborators: Novartis; Chugai Pharma France

Study record dates

Study Major Dates

• Study Start (Actual): February 14, 2019
• Primary Completion (Anticipated): February 1, 2025
• Study Completion (Anticipated): February 1, 2025

Study Registration Dates

• First Submitted: January 10, 2019
• First Submitted That Met QC Criteria: January 14, 2019
• First Posted (Actual): January 15, 2019

Study Record Updates

• Last Update Posted (Actual): March 1, 2023
• Last Update Submitted That Met QC Criteria: February 28, 2023
• Last Verified: February 1, 2023

More Information

Terms related to this study

• Keywords: Resectable; Solid tumor; Soft-tissue sarcoma; Non-metastatic; Phase III trial
• Additional Relevant MeSH Terms: Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Sarcoma; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Antibiotics, Antineoplastic; Ifosfamide; Isophosphamide mustard; Doxorubicin; Liposomal doxorubicin; Dacarbazine
• Other Study ID Numbers: IB 2017-04; 2018-000186-36 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No