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)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Pharma Mar S.A.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

19 Jul 2022 → 11 Apr 2026

Decision date (initial)

2024-07-09

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Pharma Mar S.A.

External identifiers

EU CT number

2024-513559-34-00

EudraCT number

2021-004471-13

ClinicalTrials.gov

NCT05153239

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacodynamic, Pharmacogenomic, Dose response, Pharmacokinetic, Therapy, Efficacy, Safety

To determine whether there is a difference in terms of overall survival (OS) between lurbinectedin as single agent (Group A) or the combination of lurbinectedin with irinotecan (Group B) versus Investigator’s Choice (topotecan or irinotecan) (Group C) in patients with relapsed SCLC after failure of one prior platinum-containing chemotherapy line.

Secondary objectives 9

1. To determine whether there is a difference between lurbinectedin as single agent (Group A) or the combination of lurbinectedin with irinotecan (Group B) versus Investigator’s Choice (topotecan or irinotecan) (Group C) in patients with relapsed SCLC after failure of one prior platinum-containing chemotherapy line in terms of: o Progression-free survival (PFS). o Overall response rate (ORR) according to the Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1. o Duration of response (DoR).
2. To explore the antitumor activity (PFS, ORR and DoR) according to sensitive (CTFI≥90 days) and resistant (CTFI<90 days) disease.
3. To evaluate the safety profile in each study arm.
4. To evaluate patient-reported outcomes (PRO).
5. To explore the efficacy and safety/tolerability between each lurbinectedin arm versus each control arm subset (topotecan or irinotecan).
6. To explore the efficacy and safety/tolerability between lurbinectedin arms in case both arms are significantly better than the control arm in the primary endpoint.
7. To evaluate pharmacokinetics (PK) in patients treated with lurbinectedin and/or irinotecan in the experimental and control arms.
8. To evaluate PK/pharmacodynamic (PD) correlations in patients treated with lurbinectedin and/or irinotecan in the experimental arms and control arms, if any.
9. To conduct an exploratory PGx analysis in tumor and blood samples from patients who consented to be included in a substudy to identify potential biomarkers of response and/or resistance to lurbinectedin single-agent or lurbinectedin in combination with irinotecan.

Conditions and MedDRA coding

Small Cell Lung Cancer (SCLC)

Study design 3 periods

Regulatory references

Scientific advice from competent authorities

Food And Drug Administration, Medicines And Healthcare Products Regulatory Agency

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 11

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 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: a) 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. b) Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3.0 x ULN. c) Total bilirubin ≤ 1.5 x ULN or direct bilirubin ≤ ULN. d) Albumin ≥ 3.0 g/dL. e) 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, immune-related hypothyroidism, anemia, asthenia and alopecia, all grade ≤ 2) according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) 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 11

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: a) History or presence of unstable angina, myocardial infarction, congestive heart failure, or clinically significant valvular heart disease within last year. b) Symptomatic arrhythmia or any uncontrolled arrhythmia requiring ongoing treatment. c) Ongoing chronic alcohol consumption or cirrhosis with Child-Pugh score B or C. d) Known Gilbert´s disease. e) Active uncontrolled infection. Serious non-healing wound, ulcer or bone fracture. Presence of external drainages. f) 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. g) 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. h) 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. i) Limitation of the patient’s ability to comply with the treatment or to follow the protocol. j) Documented or suspected invasive fungal infections requiring systemic treatment within 12 weeks of randomization. k) Known human immunodeficiency virus (HIV) infection. l) Any past or present chronic inflammatory colon and/or liver disease, past intestinal obstruction, pseudo or sub-occlusion or paralysis. m) Evident symptomatic pleural or cardiac effusion rapidly increasing and/or necessitating prompt local treatment within seven days. n) 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 using a highly effective method of contraception (see inclusion criterion No.11).

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Overall survival (OS)

Secondary endpoints 10

1. Progression-free survival (PFS) by Independent Review Committee (IRC)/Investigator's Assessment (IA)
2. Overall response rate (ORR) by IRC/IA
3. OS rate at 12 and 24 months and PFS rate at 6 and 12 months by IRC/IA
4. Duration of response (DoR) by IRC/IA
5. Treatment safety profile
6. Patient-reported outcomes (PRO)
7. Subgroup analyses: Subgroup analyses of efficacy and safety
8. Plasma pharmacokinetics (PK) of lurbinectedin, irinotecan and its metabolite SN-38
9. PK/PD correlation
10. Pharmacogenomics (PGx)

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Comparator 4

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Pharma Mar S.A.

Sponsor organisation

Pharma Mar S.A.

Address

Avenida De Los Reyes 1, Poligono Industrial La Mina Poligono Industrial La Mina

City

Colmenar Viejo

Postcode

28770

Country

Spain

Scientific contact point

Organisation

Pharma Mar S.A.

Contact name

Clinical Development Oncology Unit

Public contact point

Organisation

Pharma Mar S.A.

Contact name

Clinical Development Oncology Unit

Third parties 9

Locations

11 EU/EEA countries · 98 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Serious breaches 2 · Art. 52 CTR

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 115 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

11 submissions — initial application plus substantial / non-substantial modifications