Clinical trial NCT06524583: 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
Official title: Interest of Adjuvant Chemotherapy in Patients With CINSARC High-risk Localized Resected Uterine Leiomyosarcoma - Sarcome 15
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Leiomyosarcoma Uterus
Lead sponsor: UNICANCER
Sponsor class: OTHER
Collaborators: name: PharmaMar
name: Ligue contre le cancer, France
name: National Research Agency, France
name: University Hospital, Marseille
name: Institut Claudius Regaud
name: Institut Bergonié
name: Oncopole
First posted: 2024-07-29
Enrollment: 198
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Multicenter, randomized and comparative phase II trial and prospective cohort
Primary purpose: PREVENTION

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

Eligibility criteria: 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

Primary outcomes:
measure: Relapse-free survival
timeFrame: From randomization or enrollment to disease recurrence or death, up to 5 years
Secondary outcomes:
measure: Overall survival
timeFrame: From randomization or enrollment to death, up to 5 years
measure: Metastases-free survival
timeFrame: From randomization or enrollment to metastases onset or death, up to 5 years
measure: Incidence of adverse events
timeFrame: Throughout study completion, up to 5 years
measure: Quality of life questionnaire - Core 30 (QLQ-C30)
timeFrame: At baseline, end of treatment (up to week 12), 4 months, 6 months, 1 year and 2 years
Other outcomes:
Locations:
city: Angers
country: France
facility: Institut de Cancerologie de L'Ouest (Ico)
city: Besancon
country: France
facility: Hopital Jean Minjoz
city: Bordeaux
country: France
facility: Institut Bergonie
city: Caen
country: France
facility: Centre Francois Baclesse
city: Clermont-Ferrand
country: France
facility: Centre Jean Perrin
city: Dijon
country: France
facility: Centre Georges Francois Leclerc
city: Limoges
country: France
facility: Chu Limoges
city: Lyon
country: France
facility: Centre Léon Berard
city: Marseille
country: France
facility: Institut Paoli Calmettes
city: Marseille
country: France
facility: La Timone University Hospital
city: Nice
country: France
facility: Centre Antoine Lacassagne
city: Paris
country: France
facility: Hopital Saint Louis
city: Paris
country: France
facility: Hôpital Cochin
city: Paris
country: France
facility: Groupe Hospitalier Diaconesses Croix St Simon
city: Paris
country: France
facility: Hopital Tenon
city: Paris
country: France
facility: Institut Curie
city: Poitiers
country: France
facility: Chu de Poitiers
city: Rennes
country: France
facility: Centre Eugene Marquis
city: Rouen
country: France
facility: Centre Henri Becquerel
city: Saint Herblain
country: France
facility: Institut de cancerologie de l'ouest site Rene Gauducheau
city: Strasbourg
country: France
facility: Institut de Cancerologie Strasbourg Europe (Icans)
city: Toulouse
country: France
facility: Institut Claudius Regaud
city: Tours
country: France
facility: CHU Bretonneau
city: Vandoeuvre-les-nancy
country: France
facility: Centre Alexis Vautrin
city: Villejuif
country: France
facility: Gustave Roussy
Study officials:
affiliation: La TIMONE University Hospital
name: Florence DUFFAUD, MD
role: PRINCIPAL_INVESTIGATOR
References: