Phase IIb/III study, randomized, controlled, open-label, aimed at evaluating lurbinectedin in combination with doxorubicin compared to doxorubicin monotherapy as first-line treatment in patients with metastatic leiomyosarcoma.

Criteria for participation in trial
1) Written, voluntarily signed and dated informed consent from the patient prior to any study-related procedure. 2) Age ≥ 18 years. 3) Confirmed diagnosis of metastatic LMS by histological examination in patients who are not candidates for curative resection. 4) Measurable disease by radiological examination according to RECIST criteria v.1.1. 5) No prior systemic treatment for metastatic disease (i.e., first-line treatment) and no prior administration of anthracyclines. Note: prior chemotherapy (without anthracycline) as part of adjuvant or induction treatment is allowed. 6) ECOG performance status (Eastern Cooperative Oncology Group) ≤ 1. 7) Adequate hematological, renal, metabolic, and hepatic function: a) Hemoglobin ≥ 9.0 g/dl [patients may have already received a red blood cell transfusion]; absolute neutrophil count (ANC) ≥ 2.0 x 10^9/l and platelet count ≥ 100 x 10^9/l. b) Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 x upper limit of normal (ULN). c) Total bilirubin ≤ ULN or direct bilirubin ≤ ULN if total bilirubin is > ULN. d) Albumin ≥ 3.0 g/dl. e) Calculated creatinine clearance (CrCl) ≥ 30 ml/min (according to the Cockcroft-Gault equation). f) Left ventricular ejection fraction (LVEF) > 50% assessed by isotopic ventriculography (MUGA) or echocardiogram (ECHO). 8) Washout period a) At least three weeks after the last systemic treatment. b) At least three weeks after the last major surgical intervention and one week after the last minor surgical intervention. c) At least two weeks after the last radiotherapy. 9) Evidence of non-procreation in women of childbearing potential (WOCBP). WOCBP must agree to use a highly effective contraceptive method for up to seven months after stopping treatment. Valid methods to determine procreation potential, adequate contraception, and applicable requirements for partners of WOCBP are described in APPENDIX 2. Fertile male patients with a partner of childbearing potential must use condoms during treatment and for four months following the administration of the last dose of the investigational drug (ID). (BASEC)

Exclusion criteria
1) Prior treatment with anthracyclines, lurbinectedin, or trabectedin. 2) Known low-grade leiomyosarcoma (i.e., grade I). 3) Known hypersensitivity to any component of the intravenous formulation of lurbinectedin or doxorubicin. 4) Concomitant diseases/conditions: a) History of heart disease: myocardial infarction or angina; or symptomatic arrhythmia despite ongoing treatment. b) Patients with any immune deficiency, including those known to be infected with the human immunodeficiency virus (HIV). c) Known active chronic hepatitis or cirrhosis. For hepatitis B, this includes positive tests for both hepatitis B surface antigen and quantitative polymerase chain reaction (PCR) for hepatitis B. For hepatitis C, this includes positive tests for both anti-hepatitis C antibodies and quantitative PCR for hepatitis C. d) Uncontrolled active infection. e) Any other major illness (including serious cardiovascular diseases) or risk factors that, in the investigator's judgment, would substantially increase the risk associated with the patient's participation in this study. 5) Use of strong inducers of CYP3A4 activity in the two weeks prior to the first infusion of lurbinectedin. 6) Prior irradiation if only one target lesion (i.e., measurable) is available, unless lesion progression has been confirmed. 7) Known myopathy. 8) History of another neoplastic disease, except for curatively treated basal cell carcinoma or squamous cell carcinoma of the skin, curatively treated cervical or breast carcinoma in situ, or successfully and curatively treated superficial bladder tumors (Ta, Tis, or T1) without signs of recurrence or residual disease in the three years prior to randomization. In case of prior malignancy, the investigator must ensure, based on histological or clinical information, that the metastatic sites are sarcomas and not a recurrence of the initial malignancy. 9) Limitation of the patient's ability to comply with treatment or follow the protocol. 10) Pregnant or breastfeeding women and fertile patients (male and female) who do not use a highly effective contraceptive method. 11) Patients requiring rapid tumor shrinkage (e.g., when a tumor is close to a critical structure). * Women of childbearing potential (WOCBP) must agree to use a highly effective contraceptive method to avoid pregnancy during the study duration (and for at least seven months after the last infusion). Fertile male patients must commit to not causing a pregnancy or donating sperm during the study and for four months following the last infusion. Valid methods to determine procreation potential, adequate contraception, and applicable requirements for partners of WOCBP are described in APPENDIX 2. (BASEC)