Phase III Randomized Study of Lurbinectedin Alone or with Irinotecan Versus Topotecan or Irinotecan in Relapsed Small Cell Lung Cancer Patients
- Trial ID
- 2024-513559-34-00
- Protocol
- PM1183-C-008-21
- Sponsor
- Pharma Mar S.A.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the difference in **overall survival** (OS) between **lurbinectedin** as a single agent (Group A) or in combination with **irinotecan** (Group B) versus the investigator's choice of treatment (topotecan or irinotecan) (Group C) in patients with relapsed **small cell lung cancer** (SCLC) following the failure of one prior platinum-containing chemotherapy line. This objective is clinically relevant as it aims to determine the most effective treatment option for improving survival outcomes in this patient population.
The secondary objectives include:
- Determining differences in progression-free survival (PFS), overall response rate (ORR) according to the Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1, and duration of response (DoR) between the treatment groups.
- Exploring antitumor activity based on disease sensitivity and resistance.
- Evaluating the safety profile in each study arm.
- Assessing patient-reported outcomes (PRO).
- Exploring efficacy and safety/tolerability between each lurbinectedin arm versus each control arm subset (topotecan or irinotecan).
- Exploring efficacy and safety/tolerability between lurbinectedin arms if both arms are significantly better than the control arm in the primary endpoint.
- Evaluating pharmacokinetics (PK) in patients treated with lurbinectedin and/or irinotecan.
- Evaluating PK/pharmacodynamic (PD) correlations, if any.
- Conducting an exploratory pharmacogenomic (PGx) analysis to identify potential biomarkers of response and/or resistance to lurbinectedin, either as a single agent or in combination with irinotecan.
Participants
The clinical trial involves a total of **181 participants** diagnosed with **Small Cell Lung Cancer (SCLC)**. The study population includes both male and female subjects, aged 18 years and older, who have experienced a relapse after one prior line of platinum-containing chemotherapy. Participants were selected based on specific inclusion criteria, including a histologically or cytologically confirmed diagnosis of SCLC, an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less, and adequate hematological, renal, metabolic, and hepatic function. The trial also considers lifestyle factors such as the requirement for non-childbearing status in women of childbearing potential and the use of effective contraceptive measures. Participants with a history of CNS metastases are eligible if they are pretreated and radiologically stable. The trial population includes individuals who are part of a vulnerable population, ensuring comprehensive representation in the study. The selection process ensures that participants have recovered from any adverse events related to previous anticancer treatments to a grade of 1 or less, with specific exceptions for certain conditions. The trial does not specify any particular dietary or physical activity requirements for participants.
Plans and Procedures
The clinical trial is a **randomized**, multicenter, open-label, Phase III study designed to evaluate the efficacy of **lurbinectedin** as a single agent or in combination with **irinotecan** compared to the investigator's choice of **topotecan** or irinotecan in patients with relapsed **small cell lung cancer** (SCLC). The primary objective is to assess overall survival (OS) among the different treatment groups. Secondary endpoints include progression-free survival (PFS), overall response rate (ORR), duration of response (DoR), treatment safety profile, and patient-reported outcomes (PRO). The trial is expected to conclude by April 2026, with recruitment having commenced in July 2022.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, prior treatment history, and health status. Following randomization, participants will receive treatment according to their assigned group. Regular follow-up visits will be scheduled to monitor treatment response, safety, and any adverse events. These visits will include assessments such as imaging studies, laboratory tests, and clinical evaluations. The end-of-study visit will occur after the completion of the treatment period or upon early termination, which may be due to disease progression, unacceptable toxicity, or withdrawal of consent.
The expected duration of participant involvement in the study is approximately one year, although this may vary depending on individual response to treatment and other factors. Conditions that may lead to early termination from the study include significant adverse events, non-compliance with study procedures, or the participant's decision to withdraw. The study aims to provide valuable insights into the treatment of relapsed SCLC, potentially improving therapeutic strategies for this challenging condition.
Treatment
The clinical trial involves the administration of **lurbinectedin**, an experimental medication provided in the form of a **powder for concentrate for solution for infusion**. The active substance, lurbinectedin, is of chemical origin and is manufactured by Pharma Mar S.A. The medication is administered via **intravenous use** at a maximum daily dose of 3.2 mg/m². The treatment period is limited to one cycle, with the dosing schedule and participant compliance being closely monitored throughout the trial. Lurbinectedin is designated as an orphan drug, and its role in the trial is as a test product.
**Irinotecan** is used as a comparator treatment in the study. It is provided as a **concentrate for solution for infusion** and is also administered intravenously. The active substance, irinotecan hydrochloride, is of chemical origin. The maximum daily dose for irinotecan is set at 350 mg/m², with a treatment period of one cycle. The product is relabeled with a clinical trial label to ensure compliance with trial protocols.
**Topotecan** is another comparator treatment used in the trial, available in two pharmaceutical forms: **powder for concentrate for solution for infusion** and **capsule, hard**. Both forms are administered intravenously, with the powder form having a maximum daily dose of 1.5 mg/m² and the capsule form having a maximum daily dose of 2.3 mg/m². The active substance, topotecan, is of chemical origin, and the treatment period is limited to one cycle. Similar to irinotecan, topotecan is relabeled with a clinical trial label to ensure adherence to study requirements.
Efficacy
The efficacy of the clinical trial will be assessed using several primary and secondary endpoints. The primary endpoint is **Overall Survival (OS)**, which will be measured to determine the difference in survival rates between the treatment groups. Secondary endpoints include Progression-Free Survival (PFS) as assessed by an Independent Review Committee (IRC) or Investigator's Assessment (IA), Overall Response Rate (ORR) by IRC/IA, OS rate at 12 and 24 months, and PFS rate at 6 and 12 months by IRC/IA. Additionally, the Duration of Response (DoR) by IRC/IA, treatment safety profile, and patient-reported outcomes (PRO) will be evaluated.
Subgroup analyses will be conducted to assess efficacy and safety across different patient demographics. Plasma pharmacokinetics (PK) of lurbinectedin, irinotecan, and its metabolite SN-38 will be analyzed, along with PK/PD correlation and pharmacogenomics (PGx) studies. These endpoints will be measured and collected at specified timepoints throughout the trial, with data analysis conducted using validated scales and laboratory tests to ensure accuracy and reliability of the results.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Voluntary written informed consent of the patient obtained before any study-specific procedure.
- Age ≥ 18 years.
- Histologically or cytologically confirmed diagnosis of SCLC.
- 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).
- 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).
- 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.
- Eastern Cooperative Oncology Group (ECOG) PS ≤ 2.
- 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).
- 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.
- Prior radiotherapy (RT): At least two weeks since completion of prophylactic cranial irradiation (PCI), and to any other site not previously specified.
- 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
- Platinum-naïve patients or patients pretreated with more than one prior chemotherapy regimen (including patients re-challenged with same initial regimen).
- Prior treatment with lurbinectedin, trabectedin, PM14, or topoisomerase I inhibitors (irinotecan, topotecan, etc.).
- Active or untreated CNS metastases and/or carcinomatous meningitis.
- 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.
- 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).
- RT in more than 35% of the bone marrow.
- History of previous bone marrow and/or stem cell transplantation and allogenic transplant.
- 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.
- Impending need for RT (e.g., painful bone metastasis and/or risk of spinal cord compression).
- History of allergy or hypersensitivity to any of the study drugs or any of their excipients.
- 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).
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Austria | Not Recruiting | 22 Jul 2022 | 8 |
 Belgium | Not Recruiting | 22 Jul 2022 | 56 |
 Bulgaria | Not Recruiting | 22 Jul 2022 | 5 |
 Denmark | Not Recruiting | 22 Jul 2022 | 15 |
 France | Not Recruiting | 22 Jul 2022 | 36 |
 Germany | Not Recruiting | 22 Jul 2022 | 40 |
 Hungary | Not Recruiting | 22 Jul 2022 | 18 |
 Italy | Not Recruiting | 22 Jul 2022 | 92 |
 Poland | Not Recruiting | 22 Jul 2022 | 22 |
 Romania | Not Recruiting | 22 Jul 2022 | 20 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
TOPOTECAN | Comparator | — | INTRAVENOUS USE | 2.3 | 1 | SUB11191MIG |
TOPOTECAN | Comparator | — | INTRAVENOUS USE | 2.3 | 1 | SUB11191MIG |
IRINOTECAN | Test | — | INTRAVENOUS USE | 350 | 1 | SUB08295MIG |
TOPOTECAN | Comparator | — | INTRAVENOUS USE | 1.5 | 1 | SUB11191MIG |
lurbinectedin | Test | POWDER FOR CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS USE | 3.2 | 1 | PRD162831 |
TOPOTECAN | Comparator | — | INTRAVENOUS USE | 1.5 | 1 | SUB11191MIG |