Clinical Trial of Lurbinectedin As Single-agent or in Combination with Irinotecan Versus Topotecan or Irinotecan in Patients with Relapsed Small-cell Lung Cancer (LAGOON)

Inclusion Criteria:

1. Voluntary written informed consent of the patient obtained before any study-specificprocedure

2. Age≥18 years

3. Histologically or cytologically confirmed diagnosis of SCLC.

4. One prior line of platinum-containing chemotherapy with/without anti-PD-1 oranti-PD-L1 (Note: at least 70% of patients included in the study have to bepretreated with anti-PD-1 or anti-PD-L1)

5. Chemotherapy-free interval (CTFI, time from the last dose of first-lineplatinum-containing chemotherapy to the occurrence of progressive disease) ≥ 30 days (independent of the immunotherapy maintenance, if applicable)

6. Patients with history of Central Nervous System (CNS) metastases can participateprovided they are pretreated and radiologically stable (i.e., without evidence ofprogression) for at least 4 weeks by repeated imaging (note: repeated imaging shouldbe performed during study screening), asymptomatic, and without requirement ofsteroid treatment for at least 7 days before the first dose of study treatment

7. Eastern Cooperative Oncology Group (ECOG) PS ≤ 2

8. Adequate hematological, renal, metabolic and hepatic function:

9. Hemoglobin ≥ 9.0 g/dL [patients may have received prior red blood cell (RBC)transfusion, if clinically indicated]; absolute neutrophil count (ANC) ≥ 2.0 x 10^9/L, and platelet count ≥ 100 x 10^9/L.

10. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3.0 xupper limit of normal (ULN).

11. Total bilirubin ≤ 1.5 x ULN or direct bilirubin ≤ ULN.

12. Albumin ≥ 3.0 g/dL.

13. Calculated creatinine clearance (CrCL) ≥ 30 mL/min (using Cockcroft and Gault'sformula).

14. At least three weeks since last prior antineoplastic treatment and recovery to grade ≤ 1 from any adverse event (AE) related to previous anticancer treatment (excludingsensory neuropathy, immune-related hypothyroidism, anemia, asthenia and alopecia,all grade ≤ 2) according to the National Cancer InstituteCommon Terminology Criteriafor Adverse Events (NCICTCAE) v.5.

15. Prior radiotherapy (RT): At least two weeks since completion of prophylactic cranialirradiation (PCI), and to any other site not previously specified.

16. Evidence of non-childbearing status for women of childbearing potential (WOCBP).WOCBP must agree to use a highly effective contraceptive measure up to seven monthsafter treatment discontinuation. Fertile male patients with WOCBP partners shoulduse condoms during treatment and for four months following the last investigationalmedicinal product (IMP) dose.

Exclusion Criteria:

1. Platinum-naïve patients or patients pretreated with more than one prior chemotherapyregimen (including patients re-challenged with same initial regimen).

2. Prior treatment with lurbinectedin, trabectedin, PM14, or topoisomerase I inhibitors (irinotecan, topotecan, etc.).

3. Active or untreated CNS metastases and/or carcinomatous meningitis.

4. Patients with limited-stage disease who are candidates for local or regionaltherapy, including PCI, thoracic RT or both, must have been offered that option andcompleted treatment or refused it prior to randomization.

5. Concomitant diseases/conditions:

6. History or presence of unstable angina, myocardial infarction, congestive heartfailure, or clinically significant valvular heart disease within last year.

7. Symptomatic arrhythmia or any uncontrolled arrhythmia requiring ongoingtreatment.

8. Ongoing chronic alcohol consumption or cirrhosis with Child-Pugh score B or C.

9. Known Gilbert's disease.

10. Active uncontrolled infection. Serious non-healing wound, ulcer or bonefracture. Presence of external drainages.

11. Ongoing, treatment-requiring, non-neoplastic chronic liver disease of anyorigin. For Hepatitis B, this includes positive tests for both Hepatitis Bsurface antigen (HBsAg) and quantitative Hepatitis B polymerase chain reaction (PCR). For Hepatitis C, this includes positive tests for both Hepatitis Cantibody and quantitative Hepatitis C PCR. Subjects taking hepatitis relatedantiviral therapy within six months prior to the first dose of study drugs willalso be excluded.

12. Intermittent or continuous oxygen requirement within two weeks prior torandomization. Patients with confirmed or suspected diagnosis of diffuseinterstitial lung disease or pulmonary fibrosis.

13. Patients with a second invasive malignancy treated with chemotherapy and/or RT.Patients with a previous malignancy that was completely resected with curativeintention three or more years prior to randomization, except treated in situcarcinoma of the cervix, basal or squamous cell skin carcinoma, and in situtransitional cell bladder carcinoma and who has been continuously in remissionsince then will be permitted.

14. Limitation of the patient's ability to comply with the treatment or to followthe protocol.

15. Documented or suspected invasive fungal infections requiring systemic treatmentwithin 12 weeks of randomization.

16. Known human immunodeficiency virus (HIV) infection.

17. Any past or present chronic inflammatory colon and/or liver disease, pastintestinal obstruction, pseudo or subocclusion or paralysis.

18. Evident symptomatic pleural or cardiac effusion rapidly increasing and/ornecessitating prompt local treatment within seven days.

19. Any other major illness that, in the Investigator's judgment, willsubstantially increase the risk associated with the patient's participation inthis study (e.g.; COVID-19 disease).

20. RT in more than 35% of the bone marrow.

21. History of previous bone marrow and/or stem cell transplantation and allogenictransplant.

22. Patient has received a live or live-attenuated vaccine within 30 days before thefirst dose of study intervention. Administration of inactivated vaccines is allowed.

23. Impending need for RT (e.g., painful bone metastasis and/or risk of spinal cordcompression).

24. History of allergy or hypersensitivity to any of the study drugs or any of theirexcipients.

25. Women who are pregnant or breast feeding and fertile patients (men and women) whoare not able to use a highly effective method of contraception