| 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 |
| Small-Cell Lung Cancer (SCLC) |
|
| 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 | 19.0 |
| 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 a difference in PFS by an Independent Review Committee (IRC) between lurbinectedin (PM01183)/DOX and a control arm consisting of best Investigator’s choice between CTX, DOX and VCR (CAV) or topotecan, as treatment in SCLC patients after failure of one prior platinum-containing line |
|
| E.2.2 | Secondary objectives of the trial |
-Overall survival (OS).
-Mid- and long-term survival (OS at 12, 18 and 24 months, respectively).
-Efficacy and safety profiles in the subgroups of the PM01183/DOX arm vs. CAV or topotecan
-PFS by Investigator’s Assessment (IA).
-Antitumor activity according to the Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1.
-Safety profile.
-Patient-reported outcomes (PRO).
-Pharmacokinetics (PK) of the combination in patients treated in the experimental arm (PM01183/DOX)
-PK/pharmacodynamic (PDy) correlations in the Experimental Arm, if any.
-Pharmacogenetics of known polymorphisms in patients treated in the experimental Arm. |
|
| 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 |
Pharmacogenetic sub-study:
To explore factors that may help to explain individual variability in main pharmacokinetic parameters, the presence or absence of germline mutations or polymorphisms will be analyzed in leukocyte DNA extracted from a blood sample obtained at any time during the study in the experimental Arm
|
|
| E.3 | Principal inclusion criteria |
1) Voluntary written informed consent of the patient obtained before any study-specific procedure.
2) Adult patients aged ≥ 18 years.
3) Histologically or cytologically confirmed diagnosis of limited or extensive stage SCLC which failed one prior platinum-containing regimen and with a chemotherapy-free interval (CTFI, time from the last dose of first-line chemotherapy to the occurrence of progressive disease) ≥ 30 days. Small-cell carcinoma of unknown primary site with or without neuroendocrine features confirmed in
histology test(s) performed on metastatic lesion(s) are eligible, if Ki-67/MIB-1 is expressed in >50% of tumor cells.
4) ECOG PS ≤ 2.
5) Adequate hematological, renal, metabolic and hepatic function in an assessment performed within 7 days (+ 3 day window) of randomization:
a) Hemoglobin ≥ 9.0 g/dl [patients may have received priorred 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/minute (using Cockcroft and Gault’s formula).
f) Left ventricular ejection fraction (LVEF) by echocardiogram (ECHO) or multiple-gated acquisition (MUGA) scan within normal range (according to institutional standards).
g) Creatine phosphokinase (CPK) ≤ 2.5 x ULN (≤ 5.0 x ULN is acceptable if elevation is disease-related).
6) At least three weeks since last prior anticancer 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 (NCI-CTCAE,
v.4).
7) Prior radiotherapy (RT): At least four weeks since completion of whole-brain RT (WBRT), at least two weeks since completion of prophylactic cranial irradiation (PCI), and to any other site not previously specified.
8) Evidence of non-childbearing status for women of childbearing potential (WOCBP). WOCBP must agree to use a highly effective contraceptive measure up to six weeks after treatment discontinuation. Valid methods to determine the childbearing potential, adequate contraception and requirements for WOCBP partners are described in the Appendix 2 of the protocol. 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) More than one prior CHT-containing regimen (including patients re-challenged with same initial regimen).
2) Patients who never received any platinum-containing regimen for SCLC treatment.
3) Prior treatment with PM01183, topotecan or anthracyclines.
4) Limited-stage patients 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) Impending need for palliative RT or surgery for pathological fractures and/or for medullary compression within four weeks prior to randomization.
6) Symptomatic, or steroid-requiring, or progressing CNSdisease involvement during at least four weeks prior to randomization (asymptomatic, non-progressing patients taking steroids in the process of already being tapered within two weeks prior to randomization are allowed).
7) Concomitant diseases/conditions:
a) History (within one year prior to randomization) or presence of unstable angina, myocardial infarction, congestive heart failure or clinically significant valvular heart disease.
b) Symptomatic or uncontrolled arrhythmia despite ongoing treatment.
c) Patients with any immunodeficiency, including those known to be or have been infected by human immunodeficiency virus (HIV).
d) 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.
e) Active infection or increased risk due to external drainages.
f) Intermittent or continuous oxygen requirement within two weeks prior to randomization. Patients with confirmed or suspected diagnosis of diffuse interstitial lung disease (ILD) or pulmonary fibrosis.
g) Patients with a second invasive malignancy treated with CHT and/or RT. Patients with a previous malignancy that was completely resected with curative intention three or more years prior to randomization, and who has been continuously in remission since then will be permitted.
h) Limitation of the patient’s ability to comply with the treatment or to follow the protocol.
i) Documented or suspected invasive fungal infections requiring systemic treatment within 12 weeks of randomization.
8) Pregnant or breast feeding women. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Progression-free survival (PFS) by IRC defined as the time from the date of randomization to the date of documented progression per RECIST v.1.1 or death (regardless of the cause of death). If the patient receives further antitumor therapy or is lost to follow-up before PD, PFS will be censored at the date of last tumor assessment before the date of subsequent antitumor therapy. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
-Overall survival (OS) calculated from the date of randomization to the date of death (death event) or last contact.
-OS at 12/18/24 months
-Subgroup analyses
- Progression-free survival (PFS)
- Best antitumor response by Independent Review Committee (IRC)/ Investigator's Assessment (IA)
- Duration of response (DR) by IRC/IA
- Treatment safety profile
- Patient-reported outcomes (PRO)
- Plasma pharmacokinetics (PK) of PM01183 and DOX
- PK/PDy correlation
- Pharmacogenetics |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| 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 | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 106 |
| 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 |
| Argentina |
| Austria |
| Belgium |
| Brazil |
| Bulgaria |
| Canada |
| Czech Republic |
| France |
| Germany |
| Greece |
| Hungary |
| Italy |
| Lebanon |
| Netherlands |
| Poland |
| Portugal |
| Romania |
| Spain |
| United Kingdom |
| United States |
|
| 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
|
| 18 months after the last patient is randomized |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 11 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 11 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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