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)

• ClinicalTrials.gov Identifier: NCT05153239
• Recruitment Status: Recruiting
• First Posted: December 10, 2021
• Last Update Posted: May 1, 2024
• Sponsor: PharmaMar
• Information provided by (Responsible Party): PharmaMar

Tracking Information

• First Submitted Date: November 29, 2021
• First Posted Date: December 10, 2021
• Last Update Posted Date: May 1, 2024
• Actual Study Start Date: July 22, 2022
• Estimated Primary Completion Date: April 2026 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: November 29, 2021)

Overall survival [ Time Frame: From the date of randomization to the date of death or last contact, up to 39 months ]

Overall survival (OS) will be calculated from the date of randomization to the date of death or last contact (in this case, survival will be censored on that date).

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: February 28, 2024)

• Progression-free survival by IRC (Independent Review Committee) [ Time Frame: From the date of randomization to the date of progressive disease, death or last tumor assessment or further anticancer treatment, up to 39 months ]
  Progression-free survival (PFS) will be calculated from the date of randomization to the date of documented progression per RECIST v.1.1 (Progressive disease is declared when there is an increase in sum of target disease ≥ 20%) or death (regardless of the cause of death). If the patient receives further antitumor therapy, withdraws from the study, or is lost to follow-up before progressive disease (PD), PFS will be censored at the date of last evaluable tumor assessment before the date of subsequent antitumor therapy.
• Progression-free survival by IA (Investigator Assessment) [ Time Frame: From the date of randomization to the date of progressive disease, death or last tumor assessment or further anticancer treatment, up to 39 months ]
  Progression-free survival (PFS) will be calculated from the date of randomization to the date of documented progression per RECIST v.1.1 (Progressive disease is declared when there is an increase in sum of target disease ≥ 20%) or death (regardless of the cause of death). If the patient receives further antitumor therapy, withdraws from the study, or is lost to follow-up before progressive disease (PD), PFS will be censored at the date of last evaluable tumor assessment before the date of subsequent antitumor therapy.
• Overall response rate by IRC [ Time Frame: From the date of randomization to the date of death or last contact, up to 39 months ]
  Overall response rate (ORR) will be the percentage of patients with complete or partial response as the best response obtained in any evaluation according to RECIST v.1.1. Progressive disease is declared when there is an increase in sum of target disease ≥ 20%, stable disease when the change is > -30% and ≤ 20%, partial response when there is a decrease in sum of target disease ≥ 30%, and complete response when all lesions have disappeared or all lesions have disappeared and all nodal disease is < 10 mm each.
• Overall response rate by IA [ Time Frame: From the date of randomization to the date of death or last contact, up to 39 months ]
  Overall response rate (ORR) will be the percentage of patients with complete or partial response as the best response obtained in any evaluation according to RECIST v.1.1. Progressive disease is declared when there is an increase in sum of target disease ≥ 20%, stable disease when the change is > -30% and ≤ 20%, partial response when there is a decrease in sum of target disease ≥ 30%, and complete response when all lesions have disappeared or all lesions have disappeared and all nodal disease is < 10 mm each.
• Overall survival rate at 12 months [ Time Frame: At 12 months ]
  Overall survival rate at 12 months is defined as the percentage of people who are still alive at 12 months after randomization.
• Overall survival rate at 24 months [ Time Frame: At 24 months ]
  Overall survival rate at 24 months is defined as the percentage of people who are still alive at 24 months after randomization.
• Progression-free survival rate at 6 months by IRC [ Time Frame: At 6 months ]
  Progression-free survival rate at 6 months is defined as the percentage of people who remain free from progression at 6 months after randomization
• Progression-free survival rate at 6 months by IA [ Time Frame: At 6 months ]
  Progression-free survival rate at 6 months is defined as the percentage of people who remain free from progression at 6 months after randomization
• Progression-free survival rate at 12 months by IRC [ Time Frame: At 12 months ]
  Progression-free survival rate at 12 months is defined as the percentage of people who remain free from progression at 12 months after randomization
• Progression-free survival rate at 12 months by IA [ Time Frame: At 12 months ]
  Progression-free survival rate at 12 months is defined as the percentage of people who remain free from progression at 12 months after randomization
• Duration of response by IRC [ Time Frame: From the date of first documentation of complete or partial response to the date of documented progression disease, death or last contact, up to 39 months ]
  Duration of response (DoR) will be calculated from the date of first documentation of response per RECIST v.1.1 (complete or partial response, whichever occurs first) to the date of documented PD or death. Progressive disease is declared when there is an increase in sum of target disease ≥ 20%, stable disease when the change is > -30% and ≤ 20%, partial response when there is a decrease in sum of target disease ≥ 30%, and complete response when all lesions have disappeared or all lesions have disappeared and all nodal disease is < 10 mm each.
• Duration of response by IA [ Time Frame: From the date of first documentation of complete or partial response to the date of documented progression disease, death or last contact, up to 39 months ]
  Duration of response (DoR) will be calculated from the date of first documentation of response per RECIST v.1.1 (complete or partial response, whichever occurs first) to the date of documented PD or death. Progressive disease is declared when there is an increase in sum of target disease ≥ 20%, stable disease when the change is > -30% and ≤ 20%, partial response when there is a decrease in sum of target disease ≥ 30%, and complete response when all lesions have disappeared or all lesions have disappeared and all nodal disease is < 10 mm each.
• Patient-reported outcomes [ Time Frame: At baseline and every six weeks (± one week) until end of treatment, up to 39 months ]
  To measure the quality of life of patients, the Lung Cancer Symptom Scale (LCSS) questionnaire will be analyzed.

Original Secondary Outcome Measures (submitted: November 29, 2021)

• Progression-free survival [ Time Frame: From the date of randomization to the date of progressive disease, death or last tumor assessment or further anticancer treatment, up to 39 months ]
  Progression-free survival (PFS) will be calculated from the date of randomization to the date of documented progression per RECIST v.1.1 (Progressive disease is declared when there is an increase in sum of target disease ≥ 20%) or death (regardless of the cause of death). If the patient receives further antitumor therapy, withdraws from the study, or is lost to follow-up before progressive disease (PD), PFS will be censored at the date of last evaluable tumor assessment before the date of subsequent antitumor therapy.
• Overall response rate [ Time Frame: From the date of randomization to the date of death or last contact, up to 39 months ]
  Overall response rate (ORR) will be the best response obtained in any evaluation according to RECIST v.1.1. Progressive disease is declared when there is an increase in sum of target disease ≥ 20%, stable disease when the change is > -30% and ≤ 20%, partial response when there is a decrease in sum of target disease ≥ 30%, and complete response when all lesions have disappeared or all lesions have disappeared and all nodal disease is < 10 mm each.
• Overall survival rate at 12 months [ Time Frame: At 12 months ]
  Overall survival rate at 12 months is defined as the percentage of people who are still alive at 12 months after randomization.
• Overall survival rate at 24 months [ Time Frame: At 24 months ]
  Overall survival rate at 24 months is defined as the percentage of people who are still alive at 24 months after randomization.
• Progression-free survival rate at 6 months [ Time Frame: At 6 months ]
  Progression-free survival rate at 6 months is defined as the percentage of people who remain free from progression at 6 months after randomization
• Progression-free survival rate at 12 months [ Time Frame: At 12 months ]
  Progression-free survival rate at 12 months is defined as the percentage of people who remain free from progression at 12 months after randomization
• Duration of response [ Time Frame: From the date of first documentation of complete or partial response to the date of documented progression disease, death or last contact, up to 39 months ]
  Duration of response (DoR) will be calculated from the date of first documentation of response per RECIST v.1.1 (complete or partial response, whichever occurs first) to the date of documented PD or death. Progressive disease is declared when there is an increase in sum of target disease ≥ 20%, stable disease when the change is > -30% and ≤ 20%, partial response when there is a decrease in sum of target disease ≥ 30%, and complete response when all lesions have disappeared or all lesions have disappeared and all nodal disease is < 10 mm each.
• Patient-reported outcomes [ Time Frame: At baseline and every six weeks (± one week) until end of treatment, up to 39 months ]
  To measure the quality of life of patients, the Lung Cancer Symptom Scale (LCSS) questionnaire will be analyzed.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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)
• Official Title: A Randomized, Multicenter, Open-label, Phase III Study of Lurbinectedin Single-Agent or Lurbinectedin in Combination With Irinotecan Versus Investigator's Choice (Topotecan or Irinotecan) in Relapsed Small Cell Lung Cancer Patients (LAGOON Trial)
• Brief Summary: Multicenter, open-label, randomized, controlled phase III clinical trial to evaluate and compare the activity and safety of two experimental arms consisting of lurbinectedin as single agent (Group A) or the combination of lurbinectedin with irinotecan (Group B) versus Investigator's Choice (topotecan or irinotecan) as control arm (Group C), in Small-cell Lung Cancer (SCLC) patients who failed one prior platinum-containing line.

Detailed Description

Approximately 705 Adult SCLC patients with Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 2 who have failed one prior platinum-containing line with CTFI ≥ 30 days and controlled asymptomatic and pretreated Central Nervous System metastases will be enrolled and assigned to each treatment arm.

Central randomization will be implemented; patients will be assigned to each treatment arm at a 1:1:1 ratio.

An Independent Data Monitoring Committee (IDMC) will oversee the conduct of the study. The IDMC should have access to unblinded efficacy and safety data throughout the trial to enable timely and informed judgments about risks and benefits.

• Study Type: Interventional
• Study Phase: Phase 3

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

Multicenter, open-label, randomized, controlled

Masking: None (Open Label)
Primary Purpose: Treatment

• Condition: Relapsed Small Cell Lung Cancer

Intervention

• Drug: Irinotecan
  Irinotecan 75 mg/m² intravenously Days 1 & 8 q3wk
• Drug: Lurbinectedin
  Lurbinectedin 3.2 mg/m² will be administered intravenously on Day 1 q3wk
  Other Name: PM01183
• Drug: Irinotecan
  For patients aged <70 years: irinotecan 350 mg/m² intravenously Day 1 q3wk For patients aged ≥70 years: irinotecan 300 mg/m² intravenously Day 1 q3wk
• Drug: Topotecan
  Topotecan 2.3 mg/m² oral or 1.5 mg/m² intravenously Days 1-5 q3wk
• Drug: Lurbinectedin
  Lurbinectedin 2.0 mg/m² will be administered intravenously on Day 1 q3wk
  Other Name: PM01183

Study Arms

• Experimental: Lurbinectedin
  Patients will consecutively receive lurbinectedin on Day 1 q3wk (every three weeks = one treatment cycle)
  Intervention: Drug: Lurbinectedin
• Experimental: Lurbinectedin plus Irinotecan

  Patients will consecutively receive the following q3wk (every three weeks = one treatment cycle):

  • Irinotecan (Day 1 and Day 8)
  • Lurbinectedin (Day 1)
  Interventions:

  • Drug: Irinotecan
  • Drug: Lurbinectedin
• Active Comparator: Control arm

  Best Investigator's choice prior to randomization between:

  • Irinotecan on Day 1 q3wk
  • Topotecan on Days 1-5 q3wk
  Interventions:

  • Drug: Irinotecan
  • Drug: Topotecan

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: November 29, 2021): 705
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: April 2026
• Estimated Primary Completion Date: April 2026 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Voluntary written informed consent of the patient obtained before any study-specific procedure
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 or anti-PD-L1 (Note: at least 70% of patients included in the study have to be pretreated with anti-PD-1 or anti-PD-L1)
5. Chemotherapy-free interval (CTFI, time from the last dose of first-line platinum-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 participate provided they are pretreated and radiologically stable (i.e., without evidence of progression) for at least 4 weeks by repeated imaging (note: repeated imaging should be performed during study screening), asymptomatic, and without requirement of steroid 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:

   1. 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.
   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.
   4. Albumin ≥ 3.0 g/dL.
   5. Calculated creatinine clearance (CrCL) ≥ 30 mL/min (using Cockcroft and Gault's formula).
9. At least three weeks since last prior antineoplastic treatment and recovery to grade ≤ 1 from any adverse event (AE) related to previous anticancer treatment (excluding sensory neuropathy, anemia, asthenia and alopecia, all grade ≤ 2) according to the National Cancer InstituteCommon Terminology Criteria for Adverse Events (NCICTCAE) v.5.
10. Prior radiotherapy (RT): At least two weeks since completion of prophylactic cranial irradiation (PCI), and to any other site not previously specified.
11. Evidence of non-childbearing status for women of childbearing potential (WOCBP). WOCBP must agree to use a highly effective contraceptive measure up to seven months after treatment discontinuation. Fertile male patients with WOCBP partners should use condoms during treatment and for four months following the last investigational medicinal product (IMP) dose.

Exclusion Criteria:

1. Platinum-naïve patients or patients pretreated with more than one prior chemotherapy regimen (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 regional therapy, including PCI, thoracic RT or both, must have been offered that option and completed treatment or refused it prior to randomization.

5. Concomitant diseases/conditions:

   1. History or presence of unstable angina, myocardial infarction, congestive heart failure, or clinically significant valvular heart disease within last year.
   2. Symptomatic arrhythmia or any uncontrolled arrhythmia requiring ongoing treatment.
   3. Ongoing chronic alcohol consumption or cirrhosis with Child-Pugh score B or C.
   4. Known Gilbert's disease.
   5. Active uncontrolled infection. Serious non-healing wound, ulcer or bone fracture. Presence of external drainages.
   6. Ongoing, treatment-requiring, non-neoplastic chronic liver disease of any origin. For Hepatitis B, this includes positive tests for both Hepatitis B surface antigen (HBsAg) 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. Subjects taking hepatitis related antiviral therapy within six months prior to the first dose of study drugs will also be excluded.
   7. Intermittent or continuous oxygen requirement within two weeks prior to randomization. Patients with confirmed or suspected diagnosis of diffuse interstitial lung disease or pulmonary fibrosis.
   8. Patients with a second invasive malignancy treated with chemotherapy and/or RT. Patients with a previous malignancy that was completely resected with curative intention three or more years prior to randomization, except treated in situ carcinoma of the cervix, basal or squamous cell skin carcinoma, and in situ transitional cell bladder carcinoma and who has been continuously in remission since then will be permitted.
   9. Limitation of the patient's ability to comply with the treatment or to follow the protocol.
   10. Documented or suspected invasive fungal infections requiring systemic treatment within 12 weeks of randomization.
   11. Known human immunodeficiency virus (HIV) infection.
   12. Any past or present chronic inflammatory colon and/or liver disease, past intestinal obstruction, pseudo or subocclusion or paralysis.
   13. Evident symptomatic pleural or cardiac effusion rapidly increasing and/or necessitating prompt local treatment within seven days.
   14. Any other major illness that, in the Investigator's judgment, will substantially increase the risk associated with the patient's participation in this study (e.g.; COVID-19 disease).
6. RT in more than 35% of the bone marrow.
7. History of previous bone marrow and/or stem cell transplantation and allogenic transplant.
8. Patient has received a live or live-attenuated vaccine within 30 days before the first dose of study intervention. Administration of inactivated vaccines is allowed.
9. Impending need for RT (e.g., painful bone metastasis and/or risk of spinal cord compression).
10. History of allergy or hypersensitivity to any of the study drugs or any of their excipients.
11. Women who are pregnant or breast feeding and fertile patients (men and women) who are not able to use a highly effective method of contraception

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: José Antonio Lopez-Vilariño, MD; 0034 91 823 4564; jalopez-vilarino@pharmamar.com

• Listed Location Countries: Australia, Austria, Belgium, Brazil, Bulgaria, Canada, Chile, Denmark, France, Georgia, Germany, Hungary, Israel, Italy, Japan, Korea, Republic of, Poland, Romania, Spain, Switzerland, Taiwan, Turkey, United Kingdom, United States

Administrative Information

• NCT Number: NCT05153239
• Other Study ID Numbers: PM1183-C-008-21
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: PharmaMar
• Original Responsible Party: Same as current
• Current Study Sponsor: PharmaMar
• Original Study Sponsor: Same as current
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: PharmaMar
• Verification Date: April 2024