Interest of post-operative chemotherapy in patients with localized uterine leiomyosarcoma suspected to have a high-risk of relapse based on a biologic test performed on the tumor.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Unicancer

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

6 Jan 2025 → ongoing

Decision date (initial)

2024-07-26

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

No

Funding sources

Pharmamar · Ligue contre le cancer · PHRC

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy

To demonstrate that adding 4 cycles of adjuvant post-operative doxorubicin+trabectedin chemotherapy improves relapse-free survival (RFS) as compared with standard management (observation) in patients with resected FIGO stage I uLMS, considered as HR according to CINSARC NanoCind® signature.

Secondary objectives 7

1. In HR CINSARC patients with resected FIGO stage I uLMS : Overall Survival (OS)
2. In HR CINSARC patients with resected FIGO stage I uLMS : Metastases-Free Survival (MFS)
3. In HR CINSARC patients with resected FIGO stage I uLMS : Self-reported Quality of Life (QoL) of patients
4. In resected FIGO stage I ULMS managed as per standard of care (Arm A patients and prospective cohort patients) : RFS
5. In resected FIGO stage I ULMS managed as per standard of care (Arm A patients and prospective cohort patients): OS
6. In resected FIGO stage I ULMS managed as per standard of care (Arm A patients and prospective cohort patients): MFS
7. Assessment of safety and tolerability profile in HR CINSARC patients.

Conditions and MedDRA coding

Localized, resected, FIGO stage I (2018 classification), uterine leiomyosarcoma

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 19

1. Patient must have a histologically confirmed diagnosis of uterine leiomyosarcoma obtained less than 8 weeks from the surgery
2. 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) (1 block)
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 ICHGCP 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).
10. For randomization : Inclusion criteria checked at study entry are all still met at the time of randomization
11. For randomization : High-risk CINSARC signature
12. For randomization : Patient must have a diagnosis of uterine leiomyosarcoma confirmed by a local sarcoma expert pathologist from RRePS (Sarcoma Pathology Refernce Netword from NETSARC +) locally or by the study central RRePS expert pathologist.
13. For randomization : Adequate hematologic organ function: - absolute neutrophil count ≥ 1.5 Giga/ L - hemoglobin ≥ 9 g/dL - platelets ≥ 100 Giga/L
14. For randomization : 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. For randomization : Adequate liver function: total bilirubin ≤ ULN, transaminases ≤ 2.5 x ULN, alkaline phosphatases ≤ 1.5 x ULN
16. For randomization : Adequate cardiac function: cardiac ultrasound and/or isotopic ventriculography, shortening fraction (SF) > 30%, Left Ventricular Ejection Fraction (LVEF) (per ultrasound or scintigraphy) > 50%
17. For randomization : Creatine phosphokinase (CPK) ≤ 2,5 x ULN
18. For randomization : Albumin ≥ 25 g/L
19. For randomization : Signed informed consent form for the randomized phase, consistent with ICH-GCP and local legislation.

Exclusion criteria 19

1. All other histology types of uterine sarcoma (adenosarcoma, endometrial sarcoma, undifferentiated uterine sarcoma)
2. 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)
3. Ongoing infection > Grade 2 according to NCI-CTCAE v5.0
4. Breastfeeding woman
5. 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
6. Persons deprived of their liberty or under protective custody or guardianship.
7. For randomization : At least one of the exclusion criteria check at study entry is met at the time of randomization
8. For randomization : Unknown risk for CINSARC signature
9. For randomization : For patients who require a pathological review by the study central pathologist, failure to obtain a confirmed diagnosis at randomization
10. For randomization : More than 13 weeks have elapsed since the surgery procedure.
11. 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
12. Planned pelvic post-operative radiation therapy
13. Metastatic or measurable disease on CT-Scan
14. Known hypersensitivity to doxorubicin or trabectedin or to any of the excipients
15. Any contra-indication for the use of doxorubicin and/or trabectedin treatment
16. Participation in another therapeutic trial within the 30 days prior to inclusion in the study
17. Active viral hepatitis B or C or known human immunodeficiency virus (HIV) infection.
18. 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)
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).

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The primary endpoint is the RFS, which is defined as the time from the date of randomization assignment to the date of first disease recurrence/relapse (local/regional recurrence and/or distant metastasis) or death from any cause whichever comes first. Patients still alive at the time of analysis (including lost to follow-up) without appearance of relapse or recurrence will be censored at the last disease assessment date.

Secondary endpoints 7

1. Randomized part : Overall survival (OS) is defined by the time between randomization and death from any cause. Patients still alive at the time of analysis (including lost to follow-up) will be censored at the last known alive date.
2. Randomized part : Metastases-free survival (MFS) is defined by the time between randomization and the appearance of metastatic disease or death from any cause. In case of initial loco-regional relapse, patients will be censored at the date of appearance. Patients still alive at the time of analysis (including lost to follow-up) without appearance of metastatic disease will be censored at the last disease assessment date.
3. Randomized part : 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.
4. Randomized part : Quality of life (QoL) will be assessed by the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 questionnaire. A deterioration of scores for five-targeted dimensions: pain, physical and emotional functioning, fatigue, and appetite will be compared between the two treatment arms, while other dimensions will be regarded as exploratory.
5. Prognostic value : The RFS is defined as the time from the date of inclusion assignment to the date of first disease recurrence/relapse (local/regional recurrence and/or distant metastasis) or death from any cause, whichever comes first. Patients still alive at the time of analysis (including lost to followup) without appearance of relapse or recurrence will be censored at the last disease assessment date.
6. Prognostic value : Overall survival (OS) is defined by the time between inclusion and death from any cause. Patients still alive at the time of analysis (including lost to follow-up) will be censored at the last known alive date.
7. Prognostic value : Metastases-free survival (MFS) is defined by the time between inclusion and the appearance of metastatic disease or death from any cause. In case of initial loco-regional relapse, patients will be censored at the date of appearance. Patients still alive at the time of analysis (including lost to follow-up) without appearance of metastatic disease will be censored at the last disease assessment date.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Unicancer

Sponsor organisation

Unicancer

Address

101 Rue De Tolbiac

City

Paris Cedex 13

Postcode

75654

Country

France

Scientific contact point

Organisation

Unicancer

Contact name

Nourredine AIT RAHMOUNE

Public contact point

Organisation

Unicancer

Contact name

Nourredine AIT RAHMOUNE

Locations

1 EU/EEA country · 29 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 11 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

4 submissions — initial application plus substantial / non-substantial modifications