Phase IIb/III Randomized Controlled Study of Lurbinectedin Plus Doxorubicin Versus Doxorubicin Monotherapy in Metastatic Leiomyosarcoma Patients

The primary objective of this Phase IIb/III study is to evaluate whether the combination of **lurbinectedin** plus doxorubicin, administered as a first-line treatment for metastatic leiomyosarcoma, prolongs progression-free survival (PFS) as assessed by an Independent Review Committee (IRC) compared to doxorubicin administered as a single agent. This is clinically relevant as it may offer a more effective treatment option for patients with this aggressive cancer type, potentially improving their prognosis and quality of life.

The secondary objectives include:

• Phase IIb: To select the optimal lurbinectedin plus doxorubicin combination schedule for the Phase III part.
• Phase IIb and III: To determine differences between the combination therapy and doxorubicin alone in terms of overall survival (OS), progression-free survival by Investigator Assessment (IA), overall response rate (ORR) according to RECIST v.1.1 by IRC and IA, duration of response (DoR) by IRC and IA, clinical benefit rate (CBR) by IRC and IA, and progression-free survival on next-line therapy (PFS2) by IA.
• To evaluate the treatment safety profile according to NCI-CTCAE v.5, patient-reported outcomes (PRO), subgroup analyses, pharmacokinetics (PK) of lurbinectedin and/or doxorubicin and its metabolite doxorubicinol, PK/pharmacodynamic (PD) correlations, and to conduct an exploratory pharmacogenomic (PGx) analysis to identify potential biomarkers of response and/or resistance.

The clinical trial involves a total of **130 participants** diagnosed with **metastatic leiomyosarcoma**. The study population includes both male and female subjects aged 18 years and older. Participants were selected based on specific criteria, including a histologically confirmed diagnosis of metastatic leiomyosarcoma, and they must not be candidates for curative resection. The trial population is characterized by an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, indicating that participants are in relatively good health with adequate hematological, renal, metabolic, and hepatic function. Lifestyle considerations such as diet and physical activity are not specified, but participants must adhere to wash-out periods following any prior treatments. The trial includes individuals who have not received previous systemic therapy for metastatic disease and excludes those with prior anthracycline treatment. Both genders are represented, and the study includes vulnerable populations, ensuring a comprehensive evaluation of the treatment's efficacy across diverse demographic groups.

The clinical trial is designed as a **randomized**, controlled, open-label, Phase IIb/III study to evaluate the efficacy of **lurbinectedin** in combination with **doxorubicin** versus doxorubicin alone as a first-line treatment in patients with metastatic **leiomyosarcoma**. The primary objective is to assess whether the combination therapy prolongs progression-free survival (PFS) compared to doxorubicin alone. The trial is expected to commence recruitment on December 15, 2023, and conclude by April 30, 2029.

Participants will be randomly assigned to receive either the combination of lurbinectedin and doxorubicin or doxorubicin alone. The trial will involve multiple study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, diagnosis, and adequate organ function. Follow-up visits will be scheduled to monitor treatment response, adverse events, and overall health status. The end-of-study visit will occur after the completion of the treatment period or upon early termination.

The expected duration of participant involvement is contingent upon the treatment arm and individual response, with a maximum treatment period of 54 weeks for doxorubicin. Conditions that may lead to early termination from the study include disease progression, unacceptable toxicity, or withdrawal of consent. The trial will adhere to rigorous safety monitoring, with adverse events graded according to the NCI-CTCAE v.5 and analyzed for treatment-related dose delays or reductions.

Primary and secondary endpoints will be evaluated, including PFS by Independent Review Committee (IRC), overall response rate (ORR), duration of response (DoR), and overall survival (OS). The trial will also assess the safety profile, patient-reported outcomes, and pharmacokinetics of the investigational drugs. Subgroup analyses will be conducted to explore efficacy and safety profiles across different patient populations. The trial's design ensures a comprehensive evaluation of the investigational treatment's potential benefits and risks in the target patient population.

The clinical trial involves the administration of **lurbinectedin**, an experimental medication provided in the form of a **powder for concentrate for solution for infusion**. The active substance, lurbinectedin, is of chemical origin and is manufactured by Pharma Mar S.A. The medication is administered intravenously at a dosage of 3.2 mg/m², with a maximum treatment period of 30 days. The administration schedule is designed to ensure optimal therapeutic outcomes while monitoring participant compliance closely.

**Doxorubicin hydrochloride** is used as a comparator treatment in this study. It is provided as a concentrate for solution for infusion and is administered intravenously. The dosage is set at 75 mg/m², with a maximum total dose of 450 mg/m² over a treatment period of 18 days. This medication is also of chemical origin and is utilized to evaluate its efficacy against the experimental treatment.

**Filgrastim** is included as an auxiliary treatment to support participants during the trial. It is available as a solution for injection/infusion and is administered intravenously. The dosage is 5 µg/kg, with a maximum treatment period of 30 days. Filgrastim is a protein-based substance and is used to mitigate potential side effects associated with the primary treatments.

**Dexamethasone sodium phosphate** is another auxiliary treatment used in the study. It is provided as a solution for injection/infusion and administered intravenously. The dosage is 8 mg per day, with a treatment period of up to 30 days. This medication is a mixture and serves to manage inflammation and other related symptoms during the trial.

**Ondansetron hydrochloride dihydrate** is administered as an auxiliary treatment to control nausea and vomiting. It is available as a solution for injection/infusion and is given intravenously at a dosage of 8 mg per day, with a treatment period of 30 days. This chemical entity is included to enhance participant comfort and compliance.

Throughout the trial, participant compliance is monitored through regular assessments and adherence checks to ensure the accurate administration of all medications. The study design incorporates these treatments to evaluate the efficacy and safety of the experimental medication in comparison to standard-of-care therapies for metastatic leiomyosarcoma.

The efficacy of the clinical trial will be assessed primarily through the evaluation of **progression-free survival (PFS)** by an Independent Review Committee (IRC). PFS is defined as the time from the date of randomization to the date of documented progression per RECIST v.1.1 or death, regardless of the cause of death. Secondary endpoints include PFS by Investigator Assessment (IA), overall response rate (ORR) by IRC and IA, duration of response (DoR) by IRC and IA, clinical benefit rate (CBR) by IRC and IA, PFS on next-line therapy (PFS2) by IA, and overall survival (OS). The safety profile will also be evaluated, including adverse events (AEs), serious adverse events (SAEs), and laboratory abnormalities coded by the Medical Dictionary for Regulatory Activities (MedDRA) and graded according to the NCI-CTCAE v.5.

Patient-reported outcomes (PRO) will be measured using the EORTC QLQ-C30 questionnaire to assess the quality of life. Subgroup analyses of efficacy and safety profiles will be conducted, and plasma pharmacokinetics (PK) of lurbinectedin, doxorubicin, and its metabolite doxorubicinol will be evaluated using a sparse sampling scheme. Pharmacogenomics (PGx) will be analyzed to assess the mutational status and expression levels of potential predictive factors of response and/or resistance to the treatments. These assessments will be conducted at various timepoints throughout the trial, with specific details provided in separate analysis plans and reports.