Evaluation of Adjuvant Doxorubicin and Trabectedin Chemotherapy in High-Risk Localized Resected Uterine Leiomyosarcoma
- Trial ID
- 2023-506350-21-00
- Protocol
- UC-SAR-2212_L-UteCIN
- Sponsor
- Unicancer
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the efficacy of adding four cycles of adjuvant post-operative **doxorubicin** and **trabectedin** chemotherapy in improving **relapse-free survival (RFS)** compared to standard management, which involves observation, in patients with resected FIGO stage I uterine leiomyosarcoma (uLMS) identified as high-risk (HR) according to the CINSARC NanoCind® signature. This is clinically relevant as it aims to enhance the management of localized, resected uterine leiomyosarcoma, potentially reducing the risk of relapse and improving patient outcomes.
Secondary objectives include: - Assessing **overall survival (OS)** in HR CINSARC patients with resected FIGO stage I uLMS. - Evaluating **metastases-free survival (MFS)** in the same patient group. - Measuring self-reported **quality of life (QoL)** of these patients. - Determining **RFS** in resected FIGO stage I uLMS patients managed as per standard of care. - Evaluating **OS** and **MFS** in the same cohort. - Assessing the safety and tolerability profile in HR CINSARC patients.
Participants
The clinical trial focuses on a specific population of **female** patients diagnosed with **uterine leiomyosarcoma**, specifically localized, resected, FIGO stage I (2018 classification). The study population comprises individuals aged between 18 and 75 years. Participants are required to have a histologically confirmed diagnosis of uterine leiomyosarcoma obtained within eight weeks post-surgery. The trial does not include male subjects or vulnerable populations. The selection criteria emphasize adequate hematologic, renal, liver, and cardiac function, as well as an ECOG performance status of 0 or 1. Participants must not have been previously treated with chemotherapy for sarcoma or received anthracyclines and/or trabectedin for another cancer. The trial requires participants to have undergone complete resection, with no measurable disease as assessed by imaging. The sponsor has not provided information regarding the total number of participants in the study.
Plans and Procedures
The clinical trial is designed to evaluate the efficacy of adjuvant chemotherapy in patients with **uterine leiomyosarcoma** who are at high risk of relapse. This is a randomized, double-blind, controlled trial with an estimated duration extending until September 2030. The trial involves the administration of a combination of **doxorubicin hydrochloride** and **trabectedin** over a maximum treatment period of 12 months. Participants will be randomly assigned to receive either the chemotherapy regimen or standard management, which involves observation. The primary endpoint is relapse-free survival (RFS), defined as the time from randomization to the first occurrence of disease recurrence or death from any cause.
The trial will commence with a screening visit to confirm eligibility, including a histologically confirmed diagnosis of uterine leiomyosarcoma obtained within eight weeks of surgery. Participants must meet specific inclusion criteria, such as adequate hematologic, renal, liver, and cardiac function, and must not have received prior chemotherapy for sarcoma. Following the screening, eligible participants will be randomized and begin the treatment phase. Study visits will be scheduled to monitor the safety and efficacy of the treatment, assess adverse events, and evaluate quality of life using the EORTC QLQ-C30 questionnaire.
Follow-up visits will occur at regular intervals to assess the primary and secondary endpoints, including overall survival, metastases-free survival, and safety and tolerability. The end-of-study visit will mark the conclusion of the participant's involvement, which is expected to last up to 12 months, depending on the treatment arm and individual response. Participants may be withdrawn from the study early if they experience unacceptable toxicity, withdraw consent, or if the investigator deems it in their best interest. The trial aims to provide valuable insights into the potential benefits of adjuvant chemotherapy in improving outcomes for patients with high-risk uterine leiomyosarcoma.
Treatment
The clinical trial involves the administration of **doxorubicin hydrochloride**, marketed under the name DOXORUBICINE ARROW 2 mg/ml, solution for infusion. This experimental medication is provided in the form of a **solution for infusion** and is intended for intravenous administration. The dosing regimen specifies a maximum daily dose of 60 mg/m², with a total maximum dose of 240 mg/m² over the treatment period. The treatment is scheduled to be administered over a maximum period of 12 weeks. The active substance, doxorubicin hydrochloride, is of chemical origin and is classified under the ATC code L01DB01. The pharmaceutical product is manufactured by EUGIA PHARMA (MALTA) LTD and holds the marketing authorization number NL41267 in France.
The second experimental medication used in the trial is **trabectedin**, marketed as Yondelis 1 mg powder for concentrate for solution for infusion. This medication is also administered intravenously as a **solution for infusion**. The dosing schedule allows for a maximum daily dose of 1.1 mg/m², with a total maximum dose of 3.3 mg/m² over the course of the treatment. Similar to doxorubicin, the treatment period for trabectedin is capped at 12 weeks. Trabectedin is a chemically derived active substance, classified under the ATC code L01CX01. The product is manufactured by PHARMA MAR, S.A. and is authorized for use in the European Union under the marketing authorization number EU/1/07/417/002.
In this clinical trial, the experimental treatment regimen consists of four cycles of adjuvant post-operative chemotherapy combining doxorubicin and trabectedin. The objective is to evaluate the improvement in relapse-free survival (RFS) in patients with resected FIGO stage I uterine leiomyosarcoma, identified as high-risk according to the CINSARC NanoCind® signature. The trial does not include any non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatment. Participant compliance with the dosing schedule will be monitored throughout the study to ensure adherence to the treatment protocol.
Efficacy
Efficacy in this clinical trial will be assessed primarily through **relapse-free survival (RFS)**. RFS is defined as the time from the date of randomization to the date of first disease recurrence or relapse, which includes local or regional recurrence and/or distant metastasis, or death from any cause, whichever occurs first. Patients who are still alive at the time of analysis without any signs of relapse or recurrence will be censored at the last disease assessment date.
Secondary endpoints include overall survival (OS), metastases-free survival (MFS), safety and tolerability, and quality of life (QoL). OS is defined as the time between randomization and death from any cause, with patients still alive at the time of analysis being censored at the last known alive date. MFS is defined as the time between randomization and the appearance of metastatic disease or death from any cause, with patients censored at the date of appearance in case of initial loco-regional relapse. Safety and tolerability will be assessed using the NCI-CTCAE v5.0 criteria, focusing on the incidence of adverse events, treatment-related adverse events, serious adverse events, and death. QoL will be evaluated using the EORTC QLQ-C30 questionnaire, comparing deterioration in scores for pain, physical and emotional functioning, fatigue, and appetite between the two treatment arms.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Patient must have a histologically confirmed diagnosis of uterine leiomyosarcoma obtained less than 8 weeks from the surgery
- ECOG performance status (PS) 0 or 1
- Patient was previously untreated with chemotherapy for a sarcoma, and did not receive anthracyclines and/or trabectedin for another cancer
- 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)
- Age ≥ 18 years and ≤ 75 years
- 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)
- 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
- Signed informed consent form prior to any trial specific procedures consistent with ICHGCP and local legislation
- 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).
- For randomization : Inclusion criteria checked at study entry are all still met at the time of randomization
- For randomization : High-risk CINSARC signature
- 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.
- For randomization : Adequate hematologic organ function: - absolute neutrophil count ≥ 1.5 Giga/ L - hemoglobin ≥ 9 g/dL - platelets ≥ 100 Giga/L
- 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)
- For randomization : Adequate liver function: total bilirubin ≤ ULN, transaminases ≤ 2.5 x ULN, alkaline phosphatases ≤ 1.5 x ULN
- 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%
- For randomization : Creatine phosphokinase (CPK) ≤ 2,5 x ULN
- For randomization : Albumin ≥ 25 g/L
- For randomization : Signed informed consent form for the randomized phase, consistent with ICH-GCP and local legislation.
Exclusion Criteria
- All other histology types of uterine sarcoma (adenosarcoma, endometrial sarcoma, undifferentiated uterine sarcoma)
- 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)
- Ongoing infection > Grade 2 according to NCI-CTCAE v5.0
- Breastfeeding woman
- 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
- Persons deprived of their liberty or under protective custody or guardianship.
- For randomization : At least one of the exclusion criteria check at study entry is met at the time of randomization
- For randomization : Unknown risk for CINSARC signature
- For randomization : For patients who require a pathological review by the study central pathologist, failure to obtain a confirmed diagnosis at randomization
- For randomization : More than 13 weeks have elapsed since the surgery procedure.
- 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
- Planned pelvic post-operative radiation therapy
- Metastatic or measurable disease on CT-Scan
- Known hypersensitivity to doxorubicin or trabectedin or to any of the excipients
- Any contra-indication for the use of doxorubicin and/or trabectedin treatment
- Participation in another therapeutic trial within the 30 days prior to inclusion in the study
- Active viral hepatitis B or C or known human immunodeficiency virus (HIV) infection.
- 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)
- 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).
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Recruiting | 02 Sept 2024 | 198 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
DOXORUBICINE ARROW 2 mg/ml, solution pour perfusion | Test | SOLUTION POUR PERFUSION | CONCENTRATE FOR SOLUTION FOR INFUSION | 60 | 12 | PRD10159655 |
Yondelis 1 mg powder for concentrate for solution for infusion | Test | POWDER FOR CONCENTRATE FOR SOLUTION FOR INFUSION | SOLUTION FOR INFUSION | 1.1 | 12 | PRD343315 |