Study of Lurbinectedin in Combination With Doxorubicin Versus Doxorubicin Alone as First-line Treatment in Participants With Metastatic Leiomyosarcoma

The primary objective of this phase IIb/III study is to evaluate whether the combination of lurbinectedin plus doxorubicin given as first line treatment for metastatic leiomyosarcoma (LMS) prolongs the progression-free survival (PFS) by Independent Review Committee (IRC) when compared to doxorubicin administered as a single agent.


Eligibility Criteria:
Inclusion Criteria:

1. Participant signed and dated written informed consent of the patient obtained before any study-specific procedure.
2. Age ≥ 18 years.
3. Histologically confirmed diagnosis of metastatic LMS.
4. Radiologically measurable disease according to the RECIST v.1.1.
5. No previous systemic therapy for metastatic disease (i.e., first-line setting) and no previous anthracyclines. Note: prior chemotherapy (without anthracycline) in the context of adjuvant or neoadjuvant therapy is allowed.
6. Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 1
7. Adequate hematological, renal, metabolic and hepatic function:

   1. Hemoglobin ≥ 9.0 g/dL (patients may have received prior red blood cell \[RBC\] transfusion); absolute neutrophil count (ANC) ≥ 2.0 x 10\^9/L, and platelet count

      ≥ 100 x 109/L.
   2. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3.0 x upper limit of normal (ULN).
   3. Total bilirubin ≤ 1.5 x ULN or direct bilirubin ≤ ULN if total bilirubin is \> ULN.
   4. Albumin ≥ 3.0 g/dL.
   5. Calculated creatinine clearance (CrCL) ≥ 30 mL/min (using Cockcroft and Gault's formula).
   6. Left ventricular ejection fraction (LVEF) \> 50% assessed by multiple-gated acquisition scan (MUGA) or echocardiography (ECHO).
8. Wash-out periods:

   1. At least three weeks since last prior systemic treatment.
   2. At least three weeks since last prior major surgery and one week since last prior minor surgery.
   3. At least two weeks since last prior radiotherapy.
9. Evidence of non-childbearing status for women of childbearing potential (WOCBP).

Exclusion Criteria:

1. Prior treatment with anthracyclines, lurbinectedin or trabectedin.
2. Known low grade leiomyosarcoma (i.e., grade I).
3. Known hypersensitivity to any of the components of the i.v. formulation of lurbinectedin or doxorubicin.
4. Concomitant diseases/conditions:

   1. History of cardiac disease: myocardial infarction or unstable angina within the year prior to enrollment; or symptomatic or uncontrolled arrhythmia despite ongoing treatment.
   2. Patients with any immunodeficiency, including those known to be infected by human immunodeficiency virus (HIV).
   3. Known chronic active hepatitis or cirrhosis. For Hepatitis B, this includes positive tests for both Hepatitis B surface antigen and quantitative Hepatitis B polymerase chain reaction (PCR). For Hepatitis C, this includes positive tests for both Hepatitis C antibody and quantitative Hepatitis C PCR.
   4. Active uncontrolled infection.
   5. Any other major illness that, in the Investigator's judgment, will substantially increase the risk associated with the patient's participation in this study.
5. Use of strong or moderate inhibitors or strong inducers of CYP3A4 activity within two weeks prior to the first infusion of lurbinectedin.
6. Prior irradiation if only one target lesion (i.e., measurable) is available, unless progression of the lesion has been confirmed.
7. Known myopathy.
8. History of another neoplastic disease except for curatively treated basal cell carcinoma, squamous cell carcinoma of the skin, properly treated carcinoma in situ of the uterine cervix or breast or superficial bladder tumors (Ta, Tis, or T1) that have been successfully and curatively treated with no evidence of recurrent or residual disease within three years prior to randomization. In case of prior malignancy, theInvestigator should ensure, based on histology or clinical information, that the metastatic sites are sarcoma and not recurrence of the original malignancy.
9. Limitation of the patient's ability to comply with the treatment or to follow-up the protocol.
10. Women who are pregnant or breast feeding and fertile patients (men and women) who are not using a highly effective method of contraception.