| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Small Cell Lung Cancer (SCLC) |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10041067 |
| E.1.2 | Term | Small cell lung cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| 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 platinumcontaining chemotherapy line. |
|
| E.2.2 | Secondary objectives of the trial |
To determine whether there is a difference between lurbinectedin as single agent or the combination of lurbinectedin with irinotecan versus Investigator's Choice (topotecan or irinotecan) in patients with relapsed SCLC after failure of one prior platinum-containing chemotherapy line in terms of:
o PFS
o ORR according to the RECIST v.1.1.
o DoR.
- To explore the antitumor activity (PFS, ORR and DoR) according to sensitive chemotherapy–free interval [CTFI]≥90 days) and resistant (CTFI<90 days) disease.
- To evaluate the safety profile in each study arm.
- To evaluate patient-reported outcomes.
- To explore the efficacy and safety/tolerability between each lurbinectedin arm versus each control arm subset (topotecan or irinotecan).
- To explore the efficacy and safety/tolerability between lurbinectedin arms.
- To evaluate PK in patients treated with lurbinectedin and/or irinotecan.
- To evaluate PK/PD correlations.
- To conduct an exploratory PGx analysis (sub-study). |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
PHARMACOGENOMIC (PGx) SUB-STUDY
The objective is to conduct an exploratory PGx analysis in tumor and blood samples from patients who consented to be included in a sub-study to identify potential biomarkers of response and/or resistance to lurbinectedin single-agent or lurbinectedin in combination with irinotecan.
Only those patients that voluntarily signed and dated ICF for the PGx sub-study will participate. Refusal to participate in the PGx sub-study will not affect patient participation in the clinical trial PM1183-C-008-21. |
|
| E.3 | Principal 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 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), symptomatic, 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 upper limit of normal (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, anemia, asthenia and alopecia, all grade ≤ 2) according to the National Cancer Institute Common 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. Valid methods to determine the childbearing potential, adequate
contraception and requirements for WOCBP partners are described in APPENDIX 2. Fertile male patients with WOCBP partners should use condoms during treatment and for four months following the last investigational medicinal product (IMP) dose. |
|
| E.4 | Principal 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:
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 hepatitisrelated 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 subocclusion 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.
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 (see inclusion criterion No.11). |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| -from the date of randomization to the date of death or last contact |
|
| E.5.2 | Secondary end point(s) |
Progression-free survival (PFS) by Independent Review Committee (IRC)/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
Duration of response (DoR) by IRC/IA
Treatment safety profile
Patient-reported outcomes (PRO)
Subgroup analyses: Subgroup analyses of efficacy and safety
Plasma pharmacokinetics (PK) of lurbinectedin, irinotecan and its metabolite SN-38
PK/PD correlation
Pharmacogenomics (PGx) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
-PFS by IRC/IA from the random. date to the date of documented progression per RECIST 1.1 or death
-ORR by IRC/IA will be the % of patients with complete or partial
response as the best response obtained in any evaluation according to RECIST 1.1
-OS rate at 12 and 24 months and PFS rate at 6 and 12 months by IRC/IA will be calculated using Kaplan-Meier estimates
-DoR by IRC/IA - from the date of first documentation of response per RECIST 1.1 to the date of documented PD or death
-Treatment safety: AEs, SAEs and laboratory abnormalities-trough all study
-PRO: at baseline and every 6±1 weeks until EOT
-PK/PD correlation due to analysis plans, results will be presented in separate reports
-PGx, correlation with the clinical response and outcome will be
assessed after treatment |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| Investigator's Choice of Topotecan oral, Topotecan i.v. or Irinotecan i.v. |
|
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 112 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Chile |
| Switzerland |
| Taiwan |
| Australia |
| Brazil |
| Canada |
| Georgia |
| Israel |
| Japan |
| Korea, Republic of |
| United Kingdom |
| United States |
| Austria |
| Belgium |
| Bulgaria |
| Denmark |
| France |
| Germany |
| Hungary |
| Italy |
| Poland |
| Romania |
| Spain |
| Türkiye |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
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