Interest of Post-operative Chemotherapy in Patients With Localised Uterine Leiomyosarcoma Suspected of Having a High Risk of Recurrence Based on a Biological Test Performed on the Tumour

Phase 2

Recruiting

• Conditions: Leiomyosarcoma Uterus
• Interventions: Drug: Doxorubicin; Drug: Trabectedin

• Registration Number: NCT06524583
• Lead Sponsor: UNICANCER

Brief Summary

Addition of postoperative chemotherapy to prevent or delay recurrence in patients newly diagnosed with localized uterine leiomyosarcoma and who have undergone complete tumor surgery.

Detailed Description

This is a biological driven study comprising:

* a multicenter, randomized and comparative phase II trial designed to demonstrate whether adding 4 cycles of post-operative chemotherapy improves relapse-free survival as compared with follow-up (standard management) in patients with resected FIGO stage I uterine leiomyosarcoma, considered at high-risk according to CINSARC NanoCind® signature.

* a prospective cohort for patients with resected FIGO stage I uterine leiomyosarcoma, considered at low-risk according to CINSARC NanoCind® signature.

HIGH-RISK (HR) CINSARC patients will be randomized post-operatively between the two arms of treatment, i.e. standard treatment (active post-surgical surveillance) or chemotherapy, with a 1:1 randomization on one factor: morcellation versus no morcellation of uterine tumor.

LOW-RISK (LR) CINSARC patients' data will be prospectively collected

Study Timeline

• Study First Submitted: 2024-07-23
• Study First Submitted QC: 2024-07-23
• Study First Posted: 2024-07-29
• Study Start: 2025-01-27
• Status Verified: 2025-03
• Last Update Submitted: 2025-03-25
• Last Update Posted: 2025-03-30
• Primary Completion: 2029-12
• Study Completion: 2030-12

Recruitment & Eligibility

• Status: RECRUITING
• Sex: Female
• Target Recruitment: 198

Inclusion Criteria

1. Patient must have a histologically confirmed diagnosis of uterine leiomyosarcoma obtained less than 8 weeks from the surgery

2. Eastern cooperative oncology group (ECOG) performance status (PS) 0 or 1

3. Patient was previously untreated with chemotherapy for a sarcoma, and did not receive anthracyclines and/or trabectedin for another cancer

4. Available Formalin Fixed Paraffin Embedded (FFPE) tumor blocks in sufficient quantity and quality to allow CINSARC NanoCind® qualification (low-risk or high-risk)

5. Age ≥ 18 years and ≤ 75 years

6. FIGO 2018 classification stage I (IA and IB), with complete resection (total hysterectomy and optional bilateral oophorectomy; possible ovarian preservation is feasible in selected cases)

7. No measurable disease, as assessed by the investigator: normal post-operative thoracic, abdominal and pelvic CT-scan or normal MRI of abdomen and pelvis + normal chest CT performed within 4 weeks prior to inclusion or randomization in the study

8. Signed informed consent form prior to any trial specific procedures consistent with international conference on harmonisation - good clinical practice (ICH-GCP) and local legislation

9. Patient must be affiliated to a social security system or in possession of equivalent private health insurance (according to local regulations for participation in clinical trials).

   Additional inclusion criteria for randomization

10. Inclusion criteria checked at study entry are all still met at the time of randomization

11. High-risk CINSARC signature

12. Patient must have a diagnosis of uterine leiomyosarcoma confirmed by a local sarcoma expert pathologist from RRePS (Sarcoma Pathology Reference Network from NETSARC +) locally or by the study central RRePS expert pathologist.

13. Adequate hematologic organ function:

    • absolute neutrophil count ≥ 1.5 Giga/ L
    • hemoglobin ≥ 9 g/dL
    • platelets ≥ 100 Giga/L

14. Adequate renal function: serum creatinine ≤ 1.5 mg/dL (≤ 132.6 µmol/L) or calculated creatinine clearance ≥60 mL/min (by the Cockcroft and Gault formula)

15. Adequate liver function: total bilirubin ≤ upper limit of normal (ULN), transaminases ≤ 2.5 x ULN, alkaline phosphatases ≤ 1.5 x ULN

16. Adequate cardiac function: cardiac ultrasound and/or isotopic ventriculography, shortening fraction (SF) > 30%, Left Ventricular Ejection Fraction (LVEF) (per ultrasound or scintigraphy) > 50%

17. Creatine phosphokinase (CPK) ≤ 2,5 x ULN

18. Albumin ≥ 25 g/L

19. Signed informed consent form for the randomized phase, consistent with ICH-GCP and local legislation.

Exclusion Criteria

• Exclusion criteria:

  1. All other histology types of uterine sarcoma (adenosarcoma, endometrial sarcoma, undifferentiated uterine sarcoma)
  2. Prior or concurrent malignant disease diagnosed or treated in the last 5 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. Planned pelvic post-operative radiation therapy
  4. Metastatic or measurable disease on CT-Scan
  5. Known hypersensitivity to doxorubicin or trabectedin or to any of the excipients
  6. Any contra-indication for the use of doxorubicin and/or trabectedin treatment
  7. Participation in another therapeutic trial within the 30 days prior to inclusion in the study
  8. Active viral hepatitis B or C or known human immunodeficiency virus (HIV) infection.
  9. Prior anticancer therapy, including radiotherapy, endocrine therapy, immunotherapy, chemotherapy (CT) or other investigational agents within the last 4 weeks (6 weeks for nitrosoureas and mitomycin C)
  10. Cardiovascular dysfunction:

• Congestive heart failure (New York Heart Association [NYHA]) ≥ 2)

• Myocardial infarction <6 months before study

• Poorly controlled cardiac arrhythmias

• Uncontrolled hypertension

• Unstable (angina symptoms at rest) or new-onset angina (begun within the last 3 months) 11. Ongoing infection > Grade 2 according to NCI-CTCAE v5.0 12. Breastfeeding woman 13. Patients unwilling or unable to comply with the medical procedures and follow-up required by the trial because of geographic, familial, social, or psychological reasons 14. Persons deprived of their liberty or under protective custody or guardianship.

Additional exclusion criteria for randomization 15. At least one of the exclusion criteria check at study entry is met at the time of randomization 16. Unknown risk for CINSARC signature 17. For patients who require a pathological review by the study central pathologist, failure to obtain a confirmed diagnosis at randomization 18. More than 13 weeks have elapsed since the surgery procedure. 19. Patient receiving phenytoin within 88 hours prior to randomisation and or live attenuated vaccines within 14 days prior to randomisation and or CYP3A4 inhibitors (e.g. oral ketoconazole, fluconazole, ritonavir, clarithromycin or aprepitant) and or strong CYP3A4 inducers (e.g. rifampicin, phenobarbital, St John's wort).

Criteria for continuing in the prospective cohort :

1. Patient must have a diagnosis of uterine leiomyosarcoma confirmed by a sarcoma expert pathologist or by the study central pathologist
2. Patients with a low-risk CINSARC signature

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm B	Doxorubicin	Experimental treatment: 4 cycle of Doxorubicine + trabectedin
Arm B	Trabectedin	Experimental treatment: 4 cycle of Doxorubicine + trabectedin

Primary Outcome Measures

Name	Time	Method
Relapse-free survival	From randomization or enrollment to disease recurrence or death, up to 5 years	The relapse-free survival is defined as the time from the date of randomization assignment (or the date of enrollment for patients in the prospective cohort) to the date of first disease recurrence/relapse (local/regional recurrence and/or distant metastasis) or death from any cause whichever comes first.

Secondary Outcome Measures

Name	Time	Method
Incidence of adverse events	Throughout study completion, up to 5 years	The National Cancer Institute-Common Terminology Criteria for Adverse Events version 5 (NCI-CTCAE v5) is widely accepted in the community of oncology research as the leading rating scale for adverse events. This scale, divided into 5 grades (1 = "mild", 2 = "moderate", 3 = "severe", 4 = "life-threatening", and 5 = "death") determined by the investigator, will make it possible to assess the severity of the disorders.; Safety and tolerability (NCI-CTCAE v5.0) will be assessed through the incidence of adverse events, treatment-related adverse events, serious adverse events (SAEs); and death.
Overall survival	From randomization or enrollment to death, up to 5 years	The overall survival is the length of time from randomization (or enrollment for patients in the prospective cohort) that patients enrolled in the study are still alive.
Metastases-free survival	From randomization or enrollment to metastases onset or death, up to 5 years	The metastases-free survival is the length of time during and after the treatment for cancer that a patient is still alive and the cancer has not spread to other parts of the body.
Quality of life questionnaire - Core 30 (QLQ-C30)	At baseline, end of treatment (up to week 12), 4 months, 6 months, 1 year and 2 years	Developed by the EORTC, this self-reported questionnaire assesses the health-related quality of life of cancer patients in clinical trials.; The questionnaire includes five functional scales (physical, everyday activity, cognitive, emotional, and social), three symptom scales (fatigue, pain, nausea and vomiting), a health/quality of life overall scale, and a number of additional elements assessing common symptoms (including dyspnea, loss of appetite, insomnia, constipation, and diarrhea), as well as, the perceived financial impact of the disease.; All of the scales and single-item measures range in score from 0 to 100. A high scale score represents a higher response level.

Trial Locations

Locations (25)

Centre Léon Berard; 🇫🇷 Lyon, France

Institut Paoli Calmettes; 🇫🇷 Marseille, France

La Timone University Hospital; 🇫🇷 Marseille, France

Centre Antoine Lacassagne; 🇫🇷 Nice, France

Hopital Saint Louis; 🇫🇷 Paris, France

Hôpital Cochin; 🇫🇷 Paris, France

Groupe Hospitalier Diaconesses Croix St Simon; 🇫🇷 Paris, France

Hopital Tenon; 🇫🇷 Paris, France

Institut Curie; 🇫🇷 Paris, France

Chu de Poitiers; 🇫🇷 Poitiers, France

Centre Eugene Marquis; 🇫🇷 Rennes, France

Centre Henri Becquerel; 🇫🇷 Rouen, France

Institut de cancerologie de l'ouest site Rene Gauducheau; 🇫🇷 Saint Herblain, France

Institut de Cancerologie Strasbourg Europe (Icans); 🇫🇷 Strasbourg, France

Institut Claudius Regaud; 🇫🇷 Toulouse, France

CHU Bretonneau; 🇫🇷 Tours, France

Centre Alexis Vautrin; 🇫🇷 Vandoeuvre-les-nancy, France

Gustave Roussy; 🇫🇷 Villejuif, France

Institut de Cancerologie de L'Ouest (Ico); 🇫🇷 Angers, France

Hopital Jean Minjoz; 🇫🇷 Besancon, France

Institut Bergonie; 🇫🇷 Bordeaux, France

Centre Francois Baclesse; 🇫🇷 Caen, France

Centre Jean Perrin; 🇫🇷 Clermont-Ferrand, France

Centre Georges Francois Leclerc; 🇫🇷 Dijon, France

Chu Limoges; 🇫🇷 Limoges, France