An Open-Label, Multicenter Study to Assess the Potential Effects of Bosentan (a Moderate CYP3A4 Inducer) on the Pharmacokinetics of Lurbinectedin (PM01183) in Patients With Advanced Solid Tumors
Phase: PHASE1
Conditions: Advanced Solid Tumor
Sponsor: PharmaMar

                                                          
 
                            
 
 
 
 
 
 
 
 
 
 
 
 
PM1183-A-019-20  
 
An Open-Label, Multicenter Study to Assess the Potential Effects of 
Bosentan (a Moderate CYP3A4 Inducer) on the Pharmacokinetics of 
Lurbinectedin in Patients with Advanced Solid Tumors 
 
CLINICAL TRIAL PROTOCOL 
 
 
 
 
 
INVESTIGATIONAL MEDICINAL PRODUCTS: Lurbinectedin and Bosentan. 
Protocol No.: PM1183-A-019-20 
EudraCT No.: 2020-002595-12 
NCT Code: NCT05072106 
 
 
 
 
Version: v3.0  
Date: including substantial amendments #1 dated 9 July 2020 and #2 dated 15 March 
2021, and also non-substantial amendments #1 dated 10 February 2021 and #2 dated 25 
February 2021 
 
 
 
-Confidential-  
 

SPONSOR
Pharma Mar, S.A.
Avda de los Reyes, 1
Polígono Industrial “La Mina”
28770 Colmenar Viejo (Madrid) Spain
Phone: + 34 91 846 6000 
Fax:+ 34 91 846 6003
CLINICAL TRIAL PROTOCOL
PM1183-A-019-20
An Open-Label, Multicenter Study to Assess the Potential Effects of Bosentan (a 
Moderate CYP3A4 Inducer) on the Pharmacokinetics of Lurbinectedin in Patients 
with Advanced Solid Tumors
INVESTIGATIONAL MEDICINAL PRODUCT: Lurbinectedin and Bosentan
Protocol Code: PM1183-A-019-20
EudraCT No: 2020-002595-12
Protocol version 3.0, including substantial amendments #1 dated 9 July 2020 and 
#2 dated 15 March 2021, and also non-substantial amendments #1 dated 10 
February 2021 and #2 dated 25 February 2021.
This study will be conducted in compliance with the protocol, Good Clinical Practice (GCP) 
and the applicable regulatory requirements.
Confidentiality statement
Information and data included in this protocol contain trade secrets and privileged or 
confidential information which is the property of the Sponsor. No person is authorized to make 
it public without written permission of the Sponsor. These restrictions on disclosure will apply 
equally to all future information supplied to you which is indicated as privileged or confidential. 
This material may be disclosed to and used by your staff and associates as it may be necessary 
to conduct the clinical study.

PRINCIPAL INVESTIGATORS
A full list of Investigators will be available as a separate document. 

TABLE OF CONTENTS 
STUDY CONTACTS .................................................................................................................................2
TABLE OF CONTENTS...........................................................................................................................5
LIST OF TABLES.......................................................................................................................................7
LIST OF FIGURES.....................................................................................................................................7
SYNOPSIS ..................................................................................................................................................8
SCHEMATIC OF TRIAL DESIGN.......................................................................................................22
SCHEDULE OF ASSESSMENTS AND PROCEDURES....................................................................23
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS..........................................................29
1.
INTRODUCTION ...........................................................................................................................32
1.1
INFORMATION ON THE STUDY DRUG: LURBINECTEDIN........................................................32
1.1.1
Name and Chemical Information .......................................................................................32
1.1.2
Non-clinical Data ................................................................................................................33
1.1.3
Clinical Data........................................................................................................................35
1.1.3.1
Phase I Trials.............................................................................................................................. 35
1.1.3.2
Human Mass Balance Study....................................................................................................... 38
1.1.3.3
Phase II Trials ............................................................................................................................ 39
1.1.3.4
Phase III Program....................................................................................................................... 40
1.1.3.5
Population Pharmacokinetic and Pharmacodynamic (PKPD) Modeling.................................... 40
1.2
OVERALL STUDY RATIONALE .................................................................................................41
1.3
PHARMACOGENETIC SUB-STUDY RATIONALE........................................................................41
2.
STUDY OBJECTIVES ...................................................................................................................42
2.1
PRIMARY OBJECTIVE...............................................................................................................42
2.2
SECONDARY OBJECTIVES ........................................................................................................42
3.
OVERALL STUDY DESIGN.........................................................................................................42
3.1
STUDY DESIGN..........................................................................................................................42
3.2
STUDY DESIGN RATIONALE.....................................................................................................45
3.3
PRIMARY ENDPOINT ................................................................................................................46
3.3.1
Plasma exposure to lurbinectedin.......................................................................................46
3.4
SECONDARY ENDPOINTS..........................................................................................................46
3.4.1
Secondary PK parameters ...................................................................................................46
3.4.2
Safety Profile........................................................................................................................46
3.4.3
Pharmacogenetics................................................................................................................46
4.
SELECTION OF PATIENTS.........................................................................................................47
4.1
INCLUSION CRITERIA...............................................................................................................47
4.2
EXCLUSION CRITERIA..............................................................................................................48
4.3
PATIENTS FOR THE PHARMACOGENETICS SUB-STUDY...........................................................48
5.
PLAN OF THE STUDY..................................................................................................................48
5.1
PLANNED STUDY PERIODS (FOR THE WHOLE STUDY)............................................................48
5.2
PLANNED STUDY PERIODS (INDIVIDUALLY PER PATIENT).....................................................49
5.2.1
Discontinuations..................................................................................................................49
5.2.1.1
Treatment Discontinuation......................................................................................................... 49
5.2.1.2
Reasons for Treatment Discontinuation ..................................................................................... 50
5.2.1.3
Study Discontinuation................................................................................................................ 50
5.2.2
Protocol Deviations..............................................................................................................50
5.3
REPLACEMENT OF PATIENTS...................................................................................................51
6.
STUDY ASSESSMENTS AND PROCEDURES ..........................................................................51
6.1
ELIGIBILITY ASSESSMENTS .....................................................................................................51
6.2
PATIENT REGISTRATION..........................................................................................................53

6.3
PATIENT RANDOMIZATION......................................................................................................54
6.4
EVALUATIONS DURING TREATMENT ......................................................................................54
6.5
EVALUATIONS AT THE END OF TREATMENT.........................................................................56
6.6
FOLLOW-UP AFTER END-OF-TREATMENT VISIT...................................................................57
7.
TREATMENT .................................................................................................................................57
7.1
DESCRIPTION OF TREATMENT.................................................................................................57
7.1.1
Drug Formulation and Supply............................................................................................57
7.1.2
Storage Conditions...............................................................................................................58
7.2
ADMINISTRATION OF THE STUDY MEDICATION .....................................................................58
7.3
PROPHYLACTIC MEDICATION .................................................................................................59
7.4
CRITERIA FOR TREATMENT CONTINUATION..........................................................................59
7.5
DOSE REDUCTION ....................................................................................................................61
7.6
CONCOMITANT MEDICATION..................................................................................................61
7.6.1
Allowed Medications/Therapies ..........................................................................................62
7.6.2
Prohibited Medications/Therapies ......................................................................................62
7.6.3
Drug-Drug Interactions.......................................................................................................62
7.7
DRUG ACCOUNTABILITY..........................................................................................................63
7.8
TREATMENT COMPLIANCE......................................................................................................63
8.
STUDY EVALUATIONS ...............................................................................................................63
8.1
PHARMACOKINETIC EVALUATIONS ........................................................................................63
8.1.1
Pharmacokinetic Sample Collection and Handling ...........................................................63
8.1.2
Analytical Procedures..........................................................................................................64
8.1.3
Pharmacokinetic Parameters ..............................................................................................65
8.2
PHARMACOGENETICS ..............................................................................................................65
8.3
SAFETY .....................................................................................................................................65
8.4
ADVERSE EVENT DEFINITIONS................................................................................................66
8.4.1
Adverse Event ......................................................................................................................66
8.4.2
Serious Adverse Event.........................................................................................................66
8.4.3
Death....................................................................................................................................67
8.4.4
Life Threatening Event........................................................................................................67
8.4.5
Hospitalization/Prolongation of Hospitalization................................................................67
8.4.6
Unexpected/Unlisted Adverse Event ...................................................................................68
8.4.7
Adverse Reaction .................................................................................................................68
8.4.8
Adverse Events Related to the Study Drug..........................................................................68
8.4.9
Expedited Reporting ............................................................................................................68
8.4.10
Assessment of Causal Relationship to the Study Drug ..................................................68
8.5
ADVERSE EVENT REPORTING PROCEDURES...........................................................................68
8.5.1
Reporting of Adverse Events ...............................................................................................68
8.5.2
Reporting of Serious Adverse Events..................................................................................69
8.5.3
Reporting of Pregnancy Cases Occurring During the Clinical Study...............................70
8.6
ADVERSE EVENTS MONITORING .............................................................................................71
8.7
EFFICACY .................................................................................................................................71
9.
STATISTICAL METHODS...........................................................................................................71
9.1
ANALYSIS POPULATIONS .........................................................................................................71
9.2
SAMPLE SIZE ............................................................................................................................71
9.3
STATISTICAL ANALYSIS...........................................................................................................72
9.3.1
Demographics......................................................................................................................72
9.3.2
Safety....................................................................................................................................72
9.3.3
Efficacy ................................................................................................................................72
9.3.4
Pharmacokinetics ................................................................................................................72
9.3.5
Pharmacogenetics................................................................................................................73
10.
ADMINISTRATIVE SECTION................................................................................................73
10.1
ETHICS......................................................................................................................................73
10.2
MONITORING, AUDITING AND INSPECTING .............................................................................74
10.3
PATIENT INFORMED CONSENT ................................................................................................74

10.4
CONFIDENTIALITY/ PATIENTS IDENTIFICATION.....................................................................75
10.5
ELECTRONIC CASE REPORT FORMS .......................................................................................75
10.6
INSURANCE ...............................................................................................................................75
10.7
RETENTION OF RECORDS.........................................................................................................76
10.8
USE OF INFORMATION AND PUBLICATION ..............................................................................76
11.
REFERENCES............................................................................................................................77
12.
APPENDICES .............................................................................................................................79
APPENDIX 1: ECOG PERFORMANCE STATUS ASSESSMENT SCALE....................................................79
APPENDIX 2: CONTRACEPTION AND PREGNANCY TESTING................................................................80
APPENDIX 3: LIST OF CYP1/CYP2/CYP3 INHIBITORS, INDUCERS AND SUBSTRATES..........................82
APPENDIX 4: FORMULAS.......................................................................................................................85
APPENDIX 5: DECLARATION OF HELSINKI ..........................................................................................86
LIST OF TABLES
Table 1. Completed single-agent lurbinectedin phase I trials in solid tumor patients................................36
Table 2. Phase I combination lurbinectedin trials in solid tumor patients. ................................................37
Table 3. Phase II lurbinectedin trials in solid tumor patients.....................................................................39
Table 4. Screening period assessments......................................................................................................52
Table 5. Evaluations during treatment.......................................................................................................54
Table 6. Composition of lurbinectedin Drug Product reconstituted solution.............................................58
Table 7. Criteria for lurbinectedin treatment continuation.........................................................................60
Table 8. Levels of (intra-patient) lurbinectedin dose reduction in subsequent cycles. ..............................61
Table 9. Lurbinectedin and bosentan blood sampling schedule and aliquot collection. ............................64
LIST OF FIGURES
Figure 1. Structural formula of lurbinectedin. ...........................................................................................33
Figure 2. Study design...............................................................................................................................43

SYNOPSIS
TITLE
An Open-Label, Multicenter Study to Assess the Potential Effects of 
Bosentan (a moderate CYP3A4 inducer) on the Pharmacokinetics of 
Lurbinectedin in Patients with Advanced Solid Tumors. 
PROTOCOL 
CODE
PM1183-A-019-20
INVESTIGATORS
A full list of investigators will be available as a separate document. 
NUMBER OF
SITES/ TRIAL 
LOCATION
Approximately two sites in Spain are expected to participate in this 
study.
STUDY
OBJECTIVES 
Primary:

To assess the effect of bosentan on lurbinectedin total plasma 
exposure in patients with advanced solid tumors. 
Secondary:

To assess the effect of bosentan on lurbinectedin unbound 
plasma exposure.

To assess the effect of bosentan on lurbinectedin major 
metabolites (i.e., M1 and M4).

To assess the effect of bosentan on the safety profile of 
lurbinectedin.

To collect and store a blood sample for germline DNA 
extraction for future pharmacogenetic (PGt) analysis of 
variations on genes that may influence exposure and response 
(i.e., disposition, metabolism and safety) to lurbinectedin.
STUDY DESIGN
Prospective, open-label, two-way crossover, phase Ib drug-drug 
interaction study in patients with advanced solid tumors.
The study will include a pre-treatment (screening) phase followed by 
a treatment phase consisting of two lurbinectedin cycles, one cycle in 
combination with bosentan and one cycle as single agent (in different 
order depending on the study sequence), and one additional third 
cycle of lurbinectedin as a single agent for patients who meet the 
continuation criteria and obtain a clinical benefit after the first two 
cycles, and then follow-up of adverse events if any.
Patients who meet the continuation criteria and obtain a clinical 
benefit after the first two cycles according to the Investigator’s 
criteria will have the opportunity to continue treatment under a 
Compassionate Use Agreement after the completion of the optional 
third study cycle. Patients will be treated as outpatients. At the 
discretion of the Investigator, patients may be admitted to the study 
center on Day –1 or Day 1 and monitored, at least, until completion of 
the Day 1 pharmacokinetic (PK) blood sample collections. 
All patients will receive a maximum of three cycles: two consecutive 
cycles of lurbinectedin, one cycle with and one cycle without 

bosentan co-administration (in different order depending on the study 
Sequence 1 or Sequence 2 of treatment), followed by a third cycle 
with lurbinectedin alone (this last optional for patients with clinical 
benefit). Lurbinectedin will be administered as a 1-hour (-5/+20 min)
intravenous (i.v.) infusion every three weeks (q3wk) via a central or 
peripheral vein. The dose of lurbinectedin will be 3.2 mg/m² for all 
patients when administered with and without bosentan. If toxicity 
occurs, the appropriate intra-patient dose level (DL) reductions will 
be implemented in the subsequent cycle. This DL reduction will be 
according to Table S3. 
Patients will be randomized in a 1:1 ratio (Figure S1) to Sequence 1 
(TR: Test-Reference; lurbinectedin + bosentan in Cycle 1) or 
Sequence 2 (RT: Reference-Test; lurbinectedin + bosentan in Cycle 
2). 
Figure S1. Study design.
BOS, bosentan; LRB, lurbinectedin; TR, test-reference; R; randomized; RT, reference-test.
The enrollment of the patients will be simultaneous. However, if once 
the first three patients enrolled have completed Cycle 1 and Cycle 2, 
total lurbinectedin exposure does not allow an adequate PK 
assessment and if no unacceptable or life-threatening toxicities have 
occurred, the dose of lurbinectedin to be co-administered with 
bosentan in the remaining five patients can be adjusted accordingly.
This decision will be made by the Sponsor and the
study 
Investigators. Therefore, the planned dose of lurbinectedin, when 
given with bosentan for the remaining five patients, will be based on 
the acceptability of the PK and safety results from the first three 
patients. If the initial three patients do not experience adverse events 
(AEs) which might require a dose-reduction, the dose of lurbinectedin 
may still be adjusted (based on the assumption of dose-proportional 
pharmacokinetics) to produce plasma lurbinectedin area under the 
curve (AUC) values that are comparable to those when lurbinectedin 
is given in the absence of bosentan. However, if toxicity occurs in the 
initial three patients, the appropriate dose-reduction of lurbinectedin 
will be implemented in the remaining five patients accordingly.
Patients will receive lurbinectedin until disease progression, 
unacceptable toxicity, consent withdrawal or while it is considered to 
be in their best interest, and for a maximum of three cycles.
Treatment with lurbinectedin outside this study could be continued
under a Compassionate Use Agreement after the completion of the 
optional third study cycle.
STUDY 
POPULATION
Inclusion criteria
All patients must fulfill the following inclusion criteria to be enrolled 
in the study: 
1) Voluntary signed and dated written informed consent prior to any 
specific study procedure. 

2) Male or female with age ≥ 18 years.
3) Eastern Cooperative Oncology Group (ECOG) performance status 
(PS) ≤ 1 (Appendix 1).
4) Life expectancy > 3 months.
5) Pathologically confirmed diagnosis of advanced solid tumors 
[except for primary central nervous system (CNS) tumors], for 
which no approved therapy exists. 
6) Recovery to grade ≤ 1 from drug-related adverse events (AEs) of 
previous treatments, excluding alopecia and grade ≤2 asthenia or 
fatigue, according to the National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI-CTCAE v.5). 
7) Laboratory values within fourteen days prior to registration: 
a)
Absolute neutrophil count (ANC) > 2.0 x 109/L, platelet count 
> 120 x 109/L and hemoglobin > 9.0 g/dL (patients may be 
transfused as clinically indicated prior to study entry).
b) Alanine 
aminotransferase 
(ALT) 
and 
aspartate 
aminotransferase (AST) ≤ 2.5 x upper limit of normal (ULN).
c) Serum total bilirubin ≤ 1.0 x ULN. 
If total bilirubin is > 1.0 x ULN, but ≤ 1.5 x ULN, direct 
bilirubin must be ≤ 1.0 x ULN.
d) Albumin ≥ 3.5 g/dL.
e)
Creatinine clearance (CLcr) > 30 mL/min (using Cockcroft 
and Gault’s formula) (Appendix 4).
f)
Creatine phosphokinase (CPK) ≤ 2.5 x ULN.
8) Left ventricular ejection fraction (LVEF) by echocardiography 
(ECHO) or multiple-gated acquisition (MUGA) within normal 
range (according to institutional standards).
9) Evidence of non-childbearing status for women of childbearing 
potential (WOCBP). WOCBP must agree to use a highly effective 
contraceptive measure up to six months after treatment 
discontinuation. Valid methods to determine the childbearing 
potential, adequate contraception and requirements for WOCBP 
partners are described in Appendix 2. As bosentan may render 
hormonal contraceptives ineffective, and taking into account the 
teratogenic effects observed in animals, hormonal contraceptives 
cannot be the sole method of contraception during treatment with 
bosentan. 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
All patients who meet any of the following criteria will be excluded 
from participating in the study:
1) Concomitant diseases/conditions:
a)
History or presence of unstable angina, myocardial infarction, 
congestive heart failure, or clinically significant valvular 
disease within last year.
b)
Symptomatic arrhythmia or any uncontrolled arrhythmia 
requiring ongoing treatment.

c)
Known cirrhosis, alcohol induced steatosis, or chronic active 
hepatitis. For hepatitis B, this includes positive test for both 
Hepatitis B surface antigen (HBsAg) and quantitative Hepatitis 
B polymerase chain reaction (PCR or HVB-DNA+). For 
hepatitis C, this includes positive test for both Hepatitis C 
antibody and quantitative Hepatitis C by PCR (or HVC-
RNA+). 
d)
History of obstructive cholestatic liver disease (suitable for 
stenting procedure) or biliary sepsis in the past 2 months.
e)
Active COVID-19 disease (this includes positive test for 
SARS-CoV-2 in nasopharyngeal/oropharyngeal swabs or nasal 
swabs by PCR).
2) Symptomatic, 
progressive 
or 
corticosteroids-requiring 
documented 
brain 
metastases 
or 
leptomeningeal 
disease 
involvement. Patients with asymptomatic documented stable brain 
metastases not requiring corticosteroids during the last four weeks 
are allowed.
3) Use of (strong or moderate) inhibitors or inducers of CYP3A4 
activity within three weeks prior to Day 1 of Cycle 1 (Appendix 
3).
4) Use of CYP3A4 substrates for which concomitant administration 
with moderate CYP3A4 inductor is contraindicated (Appendix 3).
5) Treatment with any investigational product within the 30 days 
before Day 1 of Cycle 1.
6) Women who are pregnant or breast-feeding and fertile patients 
(men and women) who are not using an effective method of 
contraception (Appendix 2).
7) Psychiatric illness/social situations that would limit compliance 
with study requirements.
PATIENTS FOR 
THE 
PHARMACOGE-
NETIC 
EVALUATIONS
Only patients who voluntarily sign the written ICF for the 
pharmacogenetic sub-study will participate in it. Refusal to participate 
in this sub-study will not affect patient participation in the clinical 
study PM1183-A-019-20.
EXPECTED 
NUMBER OF 
PATIENTS
Eight patients will be enrolled. Additional patient(s) may be enrolled if 
any patient(s) does not complete the required assessments, including 
the PK blood sample collections of the first and second cycles.
REPLACEMENT 
OF PATIENTS
Patients must be replaced if they are not evaluable for the assessment 
of the primary endpoint (e.g., if they have not sufficient and 
interpretable PK parameters).
All replaced patients who received the study treatment will be included 
in the general safety analysis. 

STUDY DRUGS 
FORMULATION
Bosentan:
Commercially available bosentan film-coated tablets (with strengths of 
125 mg) will be provided by the Sponsor. 
Lurbinectedin:
Lurbinectedin 4 mg drug product (DP) is presented as a lyophilized 
powder for concentrate for solution for infusion in 30 mL vials and 
will be supplied by the Sponsor for the purposes of this study.
Before use, the 4 mg DP should be reconstituted with 8 mL of water 
for injection to give a solution containing 0.5 mg/mL of lurbinectedin. 
For administration to patients as an i.v. infusion, reconstituted vials are 
diluted with glucose 50 mg/mL (5%) solution for infusion or sodium 
chloride 9 mg/mL (0.9%) solution for infusion. The full composition of 
the lurbinectedin 4 mg DP and the reconstituted solution per mL is 
shown in Table S1.
Table S1. Composition of lurbinectedin (PM01183) vials.
Component
Concentration/vial
Concentration/vial 
after reconstitution
Lurbinectedin
4.0 mg
0.5 mg/mL
Sucrose
800 mg
100 mg/mL
Lactic acid
22.08 mg
2.76 mg/mL
Sodium hydroxide
5.12 mg
0.64 mg/mL
TREATMENT 
SCHEDULE AND 
ADMINISTRA-
TION ROUTE
Patients will receive lurbinectedin as a 1-hour (-5/+20 min) i.v. 
infusion on Day 1 every three weeks (q3wk), over a minimum of 100 
mL dilution on 5% glucose or 0.9% sodium chloride via a central line 
(or a minimum of 250 mL dilution if a peripheral line is used).
Patients will receive a maximum of three cycles: two consecutive 
cycles of lurbinectedin, one cycle with and one cycle without bosentan 
co-administration followed by a third cycle with lurbinectedin alone 
(this last optional for patients with clinical benefit).
In the co-administration cycles, bosentan will be administered orally 
twice daily in the morning and evening during five consecutive days,
self-administered at home from Day -5 to Day -1 (i.e., five days before 
lurbinectedin infusion), and once daily on Day 1 (i.e., the day of 
lurbinectedin infusion), following recommendations at the Summary of 
Product Characteristics (SmPC). On Day 1 (i.e., day of lurbinectedin 
infusion), bosentan will be given immediately prior to the start of the 
lurbinectedin infusion. In fact, bosentan should be administered after 
obtaining the bosentan pharmacokinetic (PK) sample #1 and before the 
start of lurbinectedin infusion (-15 min to -1 min).
In case of lurbinectedin delay (≤2 days), bosentan could be 
administered twice daily during a maximum of seven consecutive days 
before lurbinectedin infusion, and supplied at the study center once 
daily on Day 1 (before lurbinectedin infusion).
All patients will be randomly assigned to the corresponding sequences:
Sequence 1 (TR):

Cycle 1: Bosentan + lurbinectedin

Cycle 2: Lurbinectedin alone

Cycle 3: Lurbinectedin alone (optional)

Sequence 2 (RT):

Cycle 1: Lurbinectedin alone

Cycle 2: Bosentan + lurbinectedin

Cycle 3: Lurbinectedin alone (optional)
DOSE
Bosentan co-administration cycle:

Bosentan: 125 mg (one film-coated tablet of 125 mg) orally (p.o.) 
twice daily in the morning and in the evening during the prior five
consecutive days before the day of lurbinectedin infusion (Day 1), 
and once daily on Day 1 (before lurbinectedin infusion).

Lurbinectedin: 3.2 mg/m² as a 1-hour (-5/+20 min) i.v. infusion on 
Day 1 in first three patients. Dose for remaining five patients will 
depend on PK and safety outcomes in first three patients.
Single agent lurbinectedin cycle: 
3.2 mg/m² as a 1-hour (-5/+20 min) i.v. infusion on Day 1. 
PROPHYLACTIC 
MEDICATION
All patients, will receive standard antiemetic prophylaxis before each 
treatment
infusion
(i.e., 30
± 5 minutes before lurbinectedin 
administration), i.v. as follows:

Corticosteroids i.v. (according to institutional standard antiemetic 
doses, at least dexamethasone i.v. 8 mg, or equivalent, maximum 
20 mg/day of dexamethasone or equivalent). If feasible, the 
medication and dose administered in Cycle 1 should be 
maintained in Cycle 2.

Serotonin (5-HT3) antagonists (ondansetron at least 8 mg i.v. and 
no more than 16 mg of ondansetron).
If necessary, in addition to the above, the duration of treatment with 5-
HT3 antagonists and/or dexamethasone could be extended orally (if 
needed) (i.e., 4-8 mg/day for three consecutive days) and/or 10 mg of 
metoclopramide orally every eight hours could be added.
Aprepitant or any other NK-1 antagonist or related Substance P-
antagonists (except for rolapitant)
are forbidden while on 
lurbinectedin treatment.
ALLOWED 
MEDICATIONS/
THERAPIES

Therapies for pre-existing and treatment-emergent medical 
conditions, including pain management and local management of 
mucositis/stomatitis.

Blood products and transfusions, as clinically indicated.

Bisphosphonates.

In case of nausea or vomiting, extended symptomatic treatment 
for emesis will be allowed (with the exception of aprepitant and 
equivalent agents)

Erythropoietin treatment according to the American Society of 
Clinical Oncology (ASCO) guidelines.

Low-molecular weight heparin (LMWH) and/or any other 
anticoagulants, as clinically indicated. Oral anticoagulants must 
be carefully monitored.

Treatment or secondary prophylaxis with granulocyte colony-
stimulating factors (G-CSF) according to ASCO guidelines.


CNS irradiation if required, and/or limited field bone radiotherapy
for pain control outside the thoracic wall.

Megestrol acetate for appetite stimulation.

Contraceptives. As bosentan may render hormonal contraceptives 
ineffective, and taking into account the teratogenic effects 
observed in animals, hormonal contraceptives cannot be the sole 
method of contraception during treatment with bosentan.
PROHIBITED 
MEDICATIONS/
THERAPIES

Concomitant administration of any other antineoplastic therapy. 

Any other investigational agents.

Immunosuppressive therapies other than corticosteroids for 
antiemetic prophylaxis or pain control, or low-dose replacement 
in patients requiring this approach. 

Aprepitant or any other NK-1 antagonist or related Substance P-
antagonists (except for rolapitant).

Primary G-CSF prophylaxis.

CYP3A4 
inhibitors 
such 
as 
ketoconazole, 
fluconazole, 
voriconazole, 
telithromycin, 
clarithromycin, 
erythromycin, 
nafcillin, 
aprepitant, 
fosaprepitant, 
verapamil, 
modafinil, 
nefazodone, or grapefruit juice.

CYP3A
enzyme inducers and/or inhibitors (unless strictly 
necessary and when there is no therapeutic alternative treatments) 
(see Appendix 3).

Use of any prescription or non-prescription herbal and/or dietary 
supplements within 14 days prior to the first dose of study 
medication and until 31 days after the last administration of 
lurbinectedin, unless the Investigators, with the Sponsor 
agreement, consider it will not interfere with study procedures of 
patient safety. 
DRUG-DRUG 
INTERACTIONS
In vitro studies with human microsomes have shown that CYP3A4 is 
the major CYP isoform involved in the metabolism of lurbinectedin. 
The estimated contribution of the other CYP isoenzymes to the 
lurbinectedin metabolism is considered to be negligible. Therefore, 
concomitant drugs which induce or inhibit any of these cytochromes, 
especially CYP3A4, should be carefully monitored or avoided, 
whenever is possible.
A potentially significant interaction with aprepitant is suggested by 
available phase II data from ovarian cancer patients and phase I data 
from a combination trial (PM1183-A-008-13) with lurbinectedin and 
cisplatin. Lurbinectedin clearance was reduced by around 30%, 
approximately, in the presence of aprepitant. Although all patients 
eventually recovered, the use of aprepitant is currently forbidden in 
all phase II/III lurbinectedin studies.
EVALUABILITY 
OF PATIENTS
An evaluable patient for the main objective of the study (e.g., 
assessment of lurbinectedin PK) should have provided sufficient and 
interpretable PK parameters (e.g., AUC0-t should cover at least 80% 
of AUC0-∞) of Cycle 1 and 2. Evaluable patients should have received

the first two complete cycles regardless dose delays or reductions.
The compliance of bosentan will be confirmed based on a patient’s 
diary, the drug accountability and the expected individual plasma 
concentration at the steady state.
EVALUATION 
CRITERIA
Primary endpoint
Plasma exposure to lurbinectedin: Plasma dose-normalized Cmax
and AUC0-∞of lurbinectedin will be compared between Cycle 1 and 
Cycle 2. Pharmacokinetic analyses will be evaluated in plasma by 
standard non-compartmental methods, or population methods, if 
necessary. 
Secondary 
endpoints

Secondary PK parameters:
o Differences in dose-normalized total AUC0-t and Cmax and in Cl, 
Vss and T1/2 of lurbinectedin between Cycle 1 and Cycle 2 will 
be explored.
o Differences in dose-normalized unbound AUCu,0-∞, AUCu,0-t and 
Cu,max and in CLu, Vss,u and T1/2,u of lurbinectedin between Cycle 
1 and Cycle 2 will be explored.
o Differences in ratios between total AUC0-∞, AUC0-t and Cmax, of 
main lurbinectedin metabolites relative to parent drug between 
Cycle 1 and Cycle 2 will be explored. Additional PK parameters 
will be calculated if deemed appropriate.

Safety: patients will be evaluable for safety if they have received 
at least one partial or complete infusion of lurbinectedin. AEs, 
serious adverse events (SAEs) and laboratory abnormalities will 
be graded according to the NCI-CTCAE v.5. Additionally, 
treatment compliance, in particular dose reductions requirements 
and/or treatment delays due to AEs, and reasons for treatment 
discontinuation will also be described.

Pharmacogenetics:
the 
presence 
or 
absence 
of 
PGt 
polymorphisms in genes relevant for lurbinectedin disposition 
(distribution, metabolism and excretion) from a single blood 
sample collected at any time during the trial (but preferably at the 
same time as the pre-treatments PK sample on Day 1 of Cycle 1), 
which will be stored to explain individual variability in main PK 
parameters in future analyses.
CRITERIA FOR 
TREATMENT 
CONTINUATION
Patients may continue treatment with lurbinectedin as long as no 
unacceptable toxicity and/or progression of the disease occurred, and 
for a maximum of three cycles. Thereafter, treatment with 
lurbinectedin can continue under a Compassionate Use Agreement.

Patients assigned to Sequence 1 (TR) (lurbinectedin + bosentan 
in Cycle 1), after Cycle 1 the administration of a new cycle should 
be delayed if the criteria in Table S2 are not met on the 
corresponding Day 1. Re-assessments will be performed 
periodically at intervals of at least 72 hours but not more than one 
week. Lurbinectedin administration should be delayed until 
recovery of these parameters. A maximum delay of 14 days from 
the theoretical due date will be allowed for recovery from 
treatment-related adverse events. If recovery has not occurred 

after that period, the patient should discontinue the treatment, 
except in case of obvious patient benefit at the criteria of the 
Investigator and upon agreement with the Sponsor. 

Patients assigned to Sequence 2 (RT) (lurbinectedin + bosentan 
in Cycle 2), criteria for treatment continuation should be 
investigated on Day 15 of Cycle 1 in order to confirm bosentan 
administration start on Day -5 of Cycle 2, assuring that the 
continuation criteria will be finally met on Day 1 of Cycle 2 
assessment. In case of detected abnormalities on Day 15 in 
sequence RT, these assessments should be repeated every 48-72 
hours until recovery to retreatment criteria. Initiation of bosentan
will be delayed for a maximum of 14 days to ensure that pre-
treatment with bosentan is fulfilled. If recovery has not occurred 
after that period, the patient should discontinue the treatment, 
except in case of obvious patient benefit at the criteria of the 
Investigator and upon agreement with the Sponsor.
Re-treatment criteria for lurbinectedin administration should be 
met on Day 1 of Cycle 2. If they were not met, treatment will be 
delayed for a maximum of 2 days to evaluate continuation of 
lurbinectedin administration, with re-treatment criteria being 
checked every 24 hours. During this time the patient will continue 
receiving bosentan. If after 2 days of delay the patient does not 
meet the criteria for treatment continuation, bosentan will be 
stopped and the patient will be considered not evaluable for the 
trial.
Table S2. Criteria for lurbinectedin treatment continuation.
Variable
Day 1
ECOG PS
≤ 1
ANC
1.5 x 109/l
Platelets
100 x 109/l
Hemoglobin a
8.0 g/dl
Total bilirubin
≤ 1.0 x ULN. If it is > 1.0 x ULN 
but ≤ 1.5 x ULN, direct bilirubin 
must be ≤ 1.0 x ULN
Albumin
3 g/dl
AST / ALT
< 3.0 x ULN
CPK
≤ 2.5 x ULN (≤ 5.0 x ULN is 
acceptable if elevation is disease-
related)
Serum Creatinine levels/ Calculated CLcr
(Cockcroft and Gault’s formula)
Serum creatinine levels ≤ ULN or 
calculated CLcr ≥ 30 mL/min, if 
abnormal (>ULN) serum 
creatinine levels
Other non-hematological drug-related AEs 
(except isolated increased GGT and/or AP; or 
grade 2 alopecia, asthenia, peripheral neuropathy 
and not optimally treated nausea and/or vomiting) 
Grade ≤ 1
a Patients may receive PRBC transfusion and/or EPO treatment if clinically indicated to 
increase/maintain adequate hemoglobin levels.
Sequence 1 (TR):
If a patient does not meet the requirements for treatment continuation on Day 1 of further cycles, 
treatment will be withheld until recovery for a maximum of 14 days after the theoretical treatment 
date. If recovery has not occurred after a delay of > 14 days, discontinue treatment (except in case 
of obvious patient benefit at the criteria of the Investigator and upon agreement with the Sponsor).

Sequence 2 (RT):
If a patient does not meet the requirements for treatment continuation on Day 15 of Cycle 1, 
treatment with bosentan will be withheld until recovery for a maximum of 14 days after the 
theoretical treatment date. If recovery has not occurred after a delay of > 14 days, discontinue 
treatment (except in case of obvious patient benefit at the criteria of the Investigator and upon 
agreement with the Sponsor).
If a patient does not meet the requirements for treatment continuation on Day 1 of Cycle 2, 
treatment with lurbinectedin will be withheld until recovery for a maximum of 2 days after the 
theoretical treatment date. During this time, the patient will continue receiving bosentan. If 
recovery has not occurred after a delay of > 2 days, bosentan will be stopped and the patient will 
be considered not evaluable for the trial.
AEs, adverse events; ALT, alanine aminotransferase; ANC, absolute neutrophil count; AP, 
alkaline phosphatase; AST, aspartate aminotransferase; CLcr, creatinine clearance; CPK, creatine 
phosphokinase; ECOG PS, Eastern Cooperative Oncology Group Performance Status; EPO, 
erythropoietin; GGT, gamma glutamyltransferase; PRBC, packed red blood cells; ULN, upper 
limit of normal.
DOSE 
REDUCTION
Patients may continue in the study treatment at a lurbinectedin 
reduced dose if they present any of the following:

Grade 4 thrombocytopenia or grade 3 thrombocytopenia 
concomitantly with grade ≥3 bleeding.

Two dose delays or prolonged (> one week) dose delay due to 
treatment-related adverse events.

Grade ≥
3 treatment related non-hematological toxicity. 
Exceptions are: grade ≥3 nausea and/or vomiting not optimally 
treated, grade 3 fatigue lasting < two days, grade 3 diarrhea lasting 
< one day or non-optimally treated, isolated grade 3 transient 
ALT/AST elevations which are rapidly reversible and not leading 
to subsequent delays,
and non-clinically relevant isolated 
biochemical abnormalities.

Grade 4 neutropenia or any grade febrile neutropenia.
Up to two lurbinectedin dose reductions are allowed per patient. 
Patients who continue to experience treatment-related toxicity and/or 
dose delays after two dose reductions must be withdrawn from the 
study. Once the dose has been reduced for an individual patient, it 
will not be re-escalated under any circumstances. Lurbinectedin dose 
reduction levels are shown in Table S3.
Table S3. Levels of (intra-patient) lurbinectedin dose reduction in 
subsequent cycles.
Dose reduction 
Lurbinectedin (q3wk)
(mg/m2)
Lurbinectedin alone
Bosentan co-administration 
cycle
1 (starting dose)
3.2
3.2
-1
2.6
2.6
-2
2.0
-
Lurbinectedin total doses in mg will be rounded to the first decimal, if necessary.
q3wk, every three weeks.
Patients who experience grade 3/4 hypersensitivity reactions and/or 
extravasation reactions will be withdrawn from the study treatment.
PHARMACOKI-
NETIC 
EVALUATIONS
The plasma PK of lurbinectedin will be evaluated during the first two 
cycles with a schedule of 11 samples (see Table S4) in all patients. 
The plasma PK of bosentan will be evaluated during the bosentan co-
administration cycle with a schedule of four samples (see Table S4) in 

all patients.
Table S4. Lurbinectedin and bosentan blood sampling schedule and 
aliquot collection.
Sample 
No.
Day Time (h) c
Sampling 
Time d
Lurbinectedin  
Bosentan e
Time 
window
Total Unbound 
(fu)
Metabo-
lites
#1 a, b
1
0
Preinfusion f
●
●
●
●
-15 to -1 min 
before SOI g
#2
1
0.917 
5 min before 
EOI
●
●
●
-
±4 min
#3
1
1.5
30 min after 
EOI
●
-
●
-
± 5 min
#4
1
2
1 h after EOI
●
-
●
●
± 10 min
#5
1
3
2 h after EOI
●
-
●
-
± 10 min
#6
1
5
4 h after EOI
●
-
●
●
± 30 min
#7
1
7
6 h after EOI
●
-
●
-
± 30 min
#8
2
25
24 h after EOI
●
-
●
●
±2 h
#9
3
49
48 h after EOI
●
-
-
-
±2 h
#10
5
97
96 h after EOI
●
-
-
-
±24 h
#11
8
169
168 h after EOI
●
-
-
-
±48 h h
a Additional sample for AAG and IL-6.
b Additional sample for PGt, once only, if written IC given.
c Time relative to infusion start. 
d Time relative to lurbinectedin end of infusion (except PK #1).
e Sampling for bosentan only applies in cycle with bosentan co-administration.
f 5 min before start of infusion. 
g Bosentan should be administered after bosentan PK sample #1 and before the start of lurbinectedin 
infusion (-15 min to -1 min).
h If the scheduled sampling time for this sample should be modified within the allowed time 
window, there must be a difference of at least 20 hours between the collection times of samples 
PK#10 and PK#11.
AAG, alpha 1-acid glycoprotein; EOI, end of infusion; fu, unbound fraction; h, hour; IC, informed 
consent; IL-6, Interleukin 6; EOI, end of infusion; min, minute; PGt, pharmacogenetic; PK, 
pharmacokinetic; SOI, start of infusion.
Pharmacokinetic 
parameters 
will 
be 
calculated 
using 
non-
compartmental analysis (NCA). 
UNBOUND 
FRACTION 
EVALUATION
On Day 1, plasma samples will be taken along with sample #1 
(preinfusion) and sample #2 (5 min. before EOI) for the evaluation of 
lurbinectedin unbound fraction (fu).
PHARMACOGE-
NETICS
In order to explore factors that may help explain individual variability 
in the main PK 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, 
but preferably before infusion start along with PK sample #1 on Day 
1 of Cycle 1. 
STATISTICAL 
METHODS
This clinical pharmacology study is designed to assess the impact of 
bosentan
co-administration 
on 
lurbinectedin 
PK 
parameters 
administered alone.
Analysis populations: 
The PK population will include all patients enrolled who have 
sufficient and interpretable PK parameters to calculate the non-
compartmental PK parameters. Only the patients who have completed 
the two cycles and have sufficient and interpretable PK assessments 
will be included in the statistical comparison to assess the effect of 

bosentan on the PK of lurbinectedin.
The safety population will include all patients who received at least 
one dose of lurbinectedin. Patients who have received at least one 
dose of bosentan but who did not receive any dose of lurbinectedin 
will be excluded from the safety population. The analysis of data 
from these patients will be performed separately (e.g., by means of 
narratives). The safety population will be used for all safety 
evaluations.
Sample size:
A block randomization (1:1 ratio) will be performed. At least 8 
patients are expected to complete all study procedures, including the 
collection of sufficient and interpretable PK assessments. Although at 
least 8 patients will be enrolled in this study; it is estimated that 
complete data from eight patients will be sufficient to estimate the 
drug-drug interaction of bosentan on the PK of lurbinectedin. In case 
of patient replacement, a new patient number will be provided and 
he/she will be assigned to the same sequence as the patient being 
replaced.
This study was designed to assess the potential effects of bosentan on 
the PK of lurbinectedin in patients with advanced malignancies. A 
sample size of eight patients was based on feasibility and clinical 
considerations. Based on previous studies, the intra-subject 
coefficient of variation (CV) of lurbinectedin PK parameters is 
estimated to be more than 30%. The precision (half-width) of the 90% 
CI for [(lurbinectedin + bosentan) / lurbinectedin alone] comparison 
on the log-scale will extend 0.389 from the observed differences in 
means, assuming that the intra-subject CV around 40%. This half-
width corresponds to a 90% CI in the range of 70% and 147% 
assuming the ratio of the means equal to unity for each PK parameter. 
This 90% CI will be used to help with the interpretation of the results. 
Plasma exposure to lurbinectedin:
Only patients who completed the study with sufficient and 
interpretable PK parameters will be included in the statistical 
comparison of plasma exposure to lurbinectedin. Descriptive statistics 
will be used to summarize pharmacokinetic data.
The primary parameter of interest for the statistical analysis will be 
plasma dose-adjusted AUC(0-∞) (if data do not permit so, AUC(0-t) will 
be used) of lurbinectedin. The analysis will compare the log-
transformed AUC for lurbinectedin administered in combination with 
bosentan (Test) to the lurbinectedin alone (Reference). 
A mixed-effects model will be fit to the data with log-transformed 
AUC as the dependent variable, treatment (Test or Reference), period 
and sequence as fixed effects, and patient (sequence) as a random 
effect. The estimated least square means and intrasubject variability 
from the mixed-effects model will be used to construct 90% CIs for 
the difference in means on the log scale between treatments (Test or 
Reference). The adjusted mean differences and the 90% CIs will be 
exponentiated to obtain estimates of the ratio of adjusted geometric
means (Test/Reference) and 90% CIs for the ratios.
A large difference (e.g. two-fold difference shown from CIs and least 
square means) will be considered to show evidence on whether 
bosentan co-administration has a clinically relevant effect on 
lurbinectedin exposure.

Secondary PK parameters:
Similar models used for the primary endpoint will be fit to the data 
with dose-normalized AUC(0-t) and Cmax and in Cl, Vss and T1/2 of 
lurbinectedin or metabolite to parent exposure PK parameters ratio, as 
the dependent variable. Results will also be assessed graphically.
Plasma protein binding:
A similar model used for the primary endpoint will be fit to the data 
with dose-normalized AUCu as the dependent variable.
Safety:
Descriptive statistics will be used to characterize the profiles of drug-
related AEs, drug-related deaths, SAEs, clinical laboratory data, drug-
related delays and/or treatment discontinuations.  All AEs will be 
graded according to NCI-CTCAE v.5. Tables will be displayed by 
sequence and treatment (Test or Reference).
Pharmacogenetics:
Descriptive statistics will be used to summarize pharmacogenetic data 
at the time of planned analysis.
PLANNED TRIAL 
PERIODS
(individually per 
patient)
Patients will be evaluated at scheduled visits in three study periods:

Pre-treatment (screening): from signature of the ICF to the day 
of first administration of the study treatment (bosentan or 
lurbinectedin).

Treatment: from first administration of the study treatment 
(bosentan or lurbinectedin) to the last dose of lurbinectedin plus 
31 days (end-of-treatment, EOT) (maximum of three cycles).

Follow-up: after EOT, patients with treatment-related toxicities > 
grade 2 will be followed  every four weeks until recovery to at 
least grade 1 or stabilization of all treatment-emergent AEs, or 
until the start of a new antitumor therapy, until the continuation of 
treatment outside this study under a Compassionate Use 
Agreement or death, whichever occurs first.
Patients will be considered to be on-study from the signature of the 
ICF to the end of the follow-up period. Patients will be considered to 
be on-treatment for the duration of their treatment and until the day 
of EOT, immediately before the start of the follow-up period. 
An end-of-treatment (EOT) visit will be performed within 31 days 
(±10 days) after administration of the last dose of lurbinectedin, 
unless the patient dies or starts any new antitumor therapy outside this 
clinical study, in which case the EOT visit should be performed 
immediately before the start of the new therapy (ideally the day 
before or the same day).

PLANNED TRIAL 
PERIODS (for the 
whole study)
The total duration of the study will be approximately 22 months, 
including approximately an 18-month enrollment period. 
Planned start date (first patient on study): 4Q2020.
Planned enrollment period: approximately 18 months.
Planned end-of-study date (clinical cutoff): 31 (±10) days after the 
date of the last lurbinectedin administration for last patient /last cycle, 
or when confirmation of evaluability of at least eight patients, 
whichever occurs last. 
Patients who meet the continuation criteria and obtain a clear clinical 
benefit with lurbinectedin after the completion of the first two study 
cycles, according to the Investigator’s criteria may continue treatment 
outside this study under a Compassionate Use Agreement after the 
completion of the optional third study cycle. Should the patient 
continue under a Compassionate Use Agreement, the treating center 
must request authorization to the relevant Health Authorities and 
notify the Sponsor in due time.

SCHEMATIC OF TRIAL DESIGN
Note: Please, be aware that in Sequence 2 (RT) the Day 15 (D15) of Cycle 1 and Day -6 (D-6) of Cycle 2 represents the same day/visit in absence of delays.

SCHEDULE OF ASSESSMENTS AND PROCEDURES
SEQUENCE 1 (TR):
Study Period►
Screening
(days prior 
to 
registration) 
Cycle 1
Cycle 2
Cycle 3
End of 
Treatment
Follow-up 
AEs
Cycle Day►
-6
-5
-4
-3
-2
-1
1*
2
3
5
8
15
1
2
3
5
8
15
1
31 (±10)
Written IC
(Before any 
study 
procedure)
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Demographic data
-14
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Medical history/Baseline condition
-14
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Primary diagnosis/Prior treatment(s)
-14
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Complete physical examination, including 
weight, height and BSA a
-14
-
-
-
-
-
-
X
-
-
-
-
-
X
-
-
-
-
-
X
X
-
ECOG PS a
-14
-
-
-
-
-
-
X
-
-
-
-
-
X
-
-
-
-
-
X
X
-
Vital signs (HR, BP, Tª) a
-14
-
-
-
-
-
-
X
-
-
-
X
-
X
-
-
-
X
-
X
-
-
Hematology b
-14
-
-
-
-
-
-
X
-
-
-
X
X
X
-
-
-
X
X
X
X
-
Coagulation (INR) c
-14
-
-
-
-
-
-
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Biochemistry-A b
-14
-
-
-
-
-
-
X
-
-
-
X
X
X
-
-
-
X
X
X
X
-
Biochemistry-B b
-14
-
-
-
-
-
-
X
-
-
-
-
-
X
-
-
-
-
-
X
X
-
Calculated CLcr (Cockcroft and Gault´s 
formula) b, d
-14
-
-
-
-
-
-
X
-
-
-
X
X
X
-
-
-
X
X
X
X
-
Detection of SARS-CoV-2 (COVID-19) by 
PCR
-14
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Pregnancy test (serum β-hCG ) (only if the 
patient is a WOCBP)
-14
-
-
-
-
-
-
X
-
-
-
-
-
X
-
-
-
-
-
X
X
-
ECG e
-14
-
-
-
-
-
-
X
-
-
-
-
-
X
-
-
-
-
-
-
X
-
LVEF (by ECHO or MUGA) f
-14
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
X
-
Randomization g
-14
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Bosentan delivery and patient’s diary h
-
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Prophylactic medication i
-
-
-
-
-
-
-
X
-
-
-
-
-
X
-
-
-
-
-
X
-
-
Lurbinectedin 1h  (-5/+20 min) infusion
-
-
-
-
-
-
-
X
-
-
-
-
-
X
-
-
-
-
-
X
-
-
Bosentan oral administration
-
-
X
X
X
X
X
X j
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Contact to patients (via telephone or other) k
-
-
X
X
X
X
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
AAG blood sample collection
-
-
-
-
-
-
-
X
-
-
-
-
-
X
-
-
-
-
-
-
-
-
IL6 blood sample collection
-
-
-
-
-
-
-
X
-
-
-
-
-
X
-
-
-
-
-
-
-
-

Study Period►
Screening
(days prior 
to 
registration) 
Cycle 1
Cycle 2
Cycle 3
End of 
Treatment
Follow-up 
AEs
Cycle Day►
-6
-5
-4
-3
-2
-1
1*
2
3
5
8
15
1
2
3
5
8
15
1
31 (±10)
PGt blood sample collection (only if written 
IC given) l
-
-
-
-
-
-
-
One blood sample collected at any time during the study, but preferably just before 
lurbinectedin treatment start in Cycle 1
-
-
Lurbinectedin PK blood sample collection m
-
-
-
-
-
-
-
X
X
X
X
X
-
X
X
X
X
X
-
-
-
-
Bosentan PK blood sample collection m
-
-
-
-
-
-
-
X
X
-
-
-
-
-
-
-
-
-
-
-
-
-
AEs n
Continuous o
X p
Intercurrent events, concomitant disease and 
therapies
Continuous
-
Registration = confirmation of eligibility and inclusion; Day 1 = the day of lurbinectedin administration (with infusion start) of cycle 1 or 2; Day 8 = seven days after the lurbinectedin 
administration of cycle 1 or 2 (±2 days); Day 15 = fourteen days after the lurbinectedin administration of cycle 1 or 2 (±2 days).
* Permitted windows for assessments before Day 1 of Cycle 1:
If physical examination, ECOG PS, vital signs, Hematology, Biochemistry-A, Biochemistry-B, CLcr (provided only if serum creatinine levels are above ULN) and Coagulation were assessed >10 
days before Day 1 of Cycle 1, the tests must be repeated the day before or the Day 1 (always prior to lurbinectedin infusion).
If pregnancy test was done >7 days before Day 1 of Cycle 1, the test must be repeated the day before or the Day 1 (always prior to lurbinectedin infusion). 
A patient should only be treated if eligibility criteria are still met according to assessments performed closest to treatment start.
Permitted windows for assessments after Day 1 of Cycle 1:
A ± 2-day time window will be allowed for Hematology, Biochemistry-A and CLcr (provided only if serum creatinine levels are above ULN) on Day 8 and Day 15, and for vital signs on Day 8 of 
Cycle 1.
A -1 day window will be allowed for physical examination, ECOG PS, vital signs, Hematology, Biochemistry-A, and Biochemistry-B, CLcr (provided only if serum creatinine levels are above ULN) 
and Pregnancy test on Day 1 of Cycle 2 and further cycles (always prior to lurbinectedin infusion).
A + 2 days window for Day 1 lurbinectedin administration of Cycle 3.
If a drug administration is delayed beyond the permitted protocol window, assessments planned for the original administration day must be repeated on the day the dose is finally administered.
a Should treatment be administered more than ten days after the screening tests, repeat these tests prior to the first infusion and if clinically indicated. Height needs to be measured at baseline only. 
BSA will not be reported at the EOT. BSA calculated according to DuBois formula (see Appendix 4).
b Any patient having any grade ≥ 3 laboratory abnormalities and/or treatment-related AEs is suggested to have the relevant tests re-assessed at intervals of at least 72 hours but not more than one week
until recovery to at least grade 2 has been documented.
c Repeat during treatment period and at EOT if clinically indicated.
d
  Calculated CLcr [Cockcroft and Gault’s formula] should be provided only if serum creatinine levels are above ULN.
e ECG should be done in triplicate (at screening, Day 1 and EOT visit) and allow rhythm definition (at least 30 seconds of duration), PR interval and QT interval (raw and corrected by HR using 
Bazett’s formula). On Day 1, 5 minutes before SOI (-25 to -1 min before preinfusion PK samples collection) and 1 hour after EOI (-15 to -1 min before the PK sample collection), both will be done in 
triplicate. 
f A previous LVEF assessment could be used if was made within 28 days prior to screening and will be repeated if clinically indicated, and EOT.
g Randomization apply for all patients.
h Bosentan for self-administration and the patient’s diary should be given to the patient on Day -6 with a -2/+1 day time window (i.e., from Day -8 to Day -5). 
i Corticosteroids i.v. (according to institutional standard antiemetic doses, minimum dose of 8 mg/day and maximum dose of 20 mg/day of dexamethasone sodium phosphate or equivalent); If 
feasible, anti-emetic medication and dose administered in Cycle 1 should be maintained in Cycle 2. Serotonin (5-HT3) antagonists (ondansetron at least 8 mg i.v. and no more than 16 mg of 
ondansetron) (i.e., 30 ± 5 minutes before lurbinectedin administration).
j If patient does not fulfill inclusion criteria (Cycle 1 in TR sequence) in Day 1 assessments and lurbinectedin administration is postponed no more than two days, bosentan should not be discontinued.

Study Period►
Screening
(days prior 
to 
registration) 
Cycle 1
Cycle 2
Cycle 3
End of 
Treatment
Follow-up 
AEs
Cycle Day►
-6
-5
-4
-3
-2
-1
1*
2
3
5
8
15
1
2
3
5
8
15
1
31 (±10)
k The study center will contact the patients (via telephone or other methods) to remind them or confirm that they have taken the morning and evening dose of bosentan when they are not at the study 
center.
l Blood sample for genotyping will be collected at any time during the study but preferably just before infusion start in Cycle 1, only if written IC for the pharmacogenetic sub-study is given.
m Serial peripheral venous blood samples for determination of lurbinectedin (total and unbound), lurbinectedin metabolites (i.e., M1 and M4) and bosentan plasma concentrations will be collected at 
the time points indicated in Section 8.1.1, Table 9.
n Clinical assessment of the patient’s signs and symptoms (including nurses’ assessment and patient-reported issues) should continue on an ongoing basis throughout the study and be reported at least 
every cycle as AEs. Only information on SAEs that occurred after signature of the informed consent and up to Day -5 is required before treatment start. Grading should be as per the NCI-CTCAE v.5. 
Signs and symptoms will be assessed by the Sponsor as all the events ongoing during the screening period, except for prior history conditions, which should be reported in the medical history form. 
Ongoing events during the screening period are those present at any time between the informed consent date and the first drug administration, regardless of if they may be resolved or not at the date of 
Cycle 1 Day 1.
o The “AE form” will be used only for events that occur after the first drug infusion or any event related to a study procedure within the study period (according to ICH guidelines); and to report 
‘ongoing’ baseline conditions in case of any significant change (improvement or worsening) during the study.
p Patients will be followed every four weeks until recovery to at least grade 1 or stabilization of all treatment-emergent AEs, or until the start of a new antitumor therapy, until the continuation of 
treatment outside this study under a Compassionate Use Agreement or death, whichever occurs first. 
Hematology: Differential WBC (including neutrophils, monocytes and lymphocytes), erythrocytes, hemoglobin, hematocrit and platelets.
Coagulation: INR.
Biochemistry A: AST, ALT, AP, lactate dehydrogenase (LDH), creatinine, glucose, creatine phosphokinase (CPK), CPK-MB fraction (if CPK is elevated above the normal range) and gamma 
glutamyltransferase (GGT) and total bilirubin (direct bilirubin if total bilirubin is above the ULN).
Biochemistry B: Serum electrolytes (Na+, K+, Mg++), total calcium, total proteins, albumin, C-reactive protein (CRP).
AAG, alpha-1 acid glycoprotein; AE, adverse events; ALT, alanine aminotransferase; AP, alkaline phosphatase; AST, aspartate aminotransferase; β-hCG, beta subunit of human chorionic 
gonadotropin; BP, blood pressure; BSA, body surface area; CLcr, Creatinine clearance; CPK, creatine phosphokinase; CPK-MB, creatine phosphokinase-isoenzyme MB; CRP, C-reactive protein; D, 
day; ECG, electrocardiogram; ECHO, echocardiogram; ECOG PS, Eastern Cooperative Oncology Group Performance Status; EOT, end of treatment; GGT, gamma glutamyltransferase; HR, heart 
rate; IC, informed consent; ICF, informed consent form; ICH, International Conference on Harmonization; IL6, interleukin 6; INR, International Normalized Ratio; LDH, lactate dehydrogenase; 
LVEF, left ventricular ejection fraction; min, minutes; MUGA, multiple-gated acquisition scan; NCI-CTCAE, National Cancer Institute Common Toxicity Criteria; PCR, polymerase chain reaction; 
PGt; Pharmacogenetic; PK, pharmacokinetics; TR, test-reference sequence; SAE, serious adverse event; SARS-CoV-2, Severe acute respiratory syndrome coronavirus 2; SOI, start of infusion; Tª, 
temperature; ULN, upper limit of normal; WBC, white blood cells; WOCBP, women of childbearing potential.

SEQUENCE 2 (RT):
Study Period►
Screening
(days prior 
to 
registration)
Cycle 1
Cycle 2
Cycle 3
End of 
Treatment
Follow-up 
AEs
Cycle Day►
1*
2
3
5
8
15
-5
-4
-3
-2
-1
1
2
3
5
8
15
1
31 (±10)
Written IC
(Before any 
study 
procedure)
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Demographic data
-14
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Medical history/Baseline condition
-14
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Primary diagnosis/Prior treatment(s)
-14
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Complete physical examination, including 
weight and BSA a
-14
X
-
-
-
-
-
-
-
-
-
-
X
-
-
-
-
-
X
X
-
ECOG PS a
-14
X
-
-
-
-
-
-
-
-
-
-
X
-
-
-
-
-
X
X
-
Vital signs (HR, BP, Tª) a
-14
X
-
-
-
X
-
-
-
-
-
-
X
-
-
-
X
-
X
-
-
Hematology b
-14
X
-
-
-
X
X
-
-
-
-
-
X
-
-
-
X
X
X
X
-
Coagulation (INR) c
-14
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Biochemistry-A b
-14
X
-
-
-
X
X
-
-
-
-
-
X
-
-
-
X
X
X
X
-
Biochemistry-B b
-14
X
-
-
-
-
-
-
-
-
-
-
X
-
-
-
-
-
X
X
-
Calculated CLcr (Cockcroft and Gault´s 
formula) b, d
-14
X
-
-
-
X
X
-
-
-
-
-
X
-
-
-
X
X
X
X
-
Detection of SARS-CoV-2 (COVID-19) 
by PCR
-14
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Pregnancy test (serum β-hCG) (only if the 
patient is a WOCBP)
-14
X
-
-
-
-
-
-
-
-
-
-
X
-
-
-
-
-
X
X
-
ECG e
-14
X
-
-
-
-
-
-
-
-
-
-
X
-
-
-
-
-
-
X
-
LVEF (by ECHO or MUGA) f
-14
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
X
-
Randomization g
-14
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Bosentan delivery and patient’s diary h
-
-
-
-
-
-
X
-
-
-
-
-
-
-
-
-
-
-
-
-
Prophylactic medication i
-
X
-
-
-
-
-
-
-
-
-
-
X
-
-
-
-
-
X
-
-
Lurbinectedin 1h (-5/+20 min) infusion
-
X
-
-
-
-
-
-
-
-
-
-
X
-
-
-
-
-
X
-
-
Bosentan oral administration
-
-
-
-
-
-
-
X
X
X
X
X
X j
-
-
-
-
-
-
-
-
Contact to patients (via telephone or 
other) k
-
-
-
-
-
-
-
X
X
X
X
X
-
-
-
-
-
-
-
-
-
AAG blood sample collection
-
X
-
-
-
-
-
-
-
-
-
-
X
-
-
-
-
-
-
-
-
IL6 blood sample collection
-
X
-
-
-
-
-
-
-
-
-
-
X
-
-
-
-
-
-
-
-
PGt blood sample collection (only if 
written IC given) l
-
One blood sample collected at any time during the study, but preferably just before lurbinectedin treatment 
start in Cycle 1
-
-

Study Period►
Screening
(days prior 
to 
registration)
Cycle 1
Cycle 2
Cycle 3
End of 
Treatment
Follow-up 
AEs
Cycle Day►
1*
2
3
5
8
15
-5
-4
-3
-2
-1
1
2
3
5
8
15
1
31 (±10)
Lurbinectedin PK blood sample collection 
m
-
X
X
X
X
X
-
-
-
-
-
-
X
X
X
X
X
-
-
-
-
Bosentan PK blood sample collection m
-
-
-
-
-
-
-
-
-
-
-
-
X
-
-
-
-
-
-
-
-
AEs n
Continuous o
X p
Intercurrent events, concomitant disease 
and therapies
Continuous
-
Registration = confirmation of eligibility and inclusion; Day 1 = the day of lurbinectedin administration (with infusion start) of cycle 1 or 2; Day 8 = seven days after the 
lurbinectedin administration of cycle 1 or 2 (±2 days); Day 15 = fourteen days after the lurbinectedin administration of cycle 1 o 2 (±2 days).
* Permitted windows for assessments before Day 1 of Cycle 1:
If physical examination, ECOG PS, vital signs, Hematology, Biochemistry-A, Biochemistry-B, CLcr (provided only if serum creatinine levels are above ULN) and Coagulation were assessed 
>10 days before Day 1 of Cycle 1, the tests must be repeated the day before or the Day 1 (always prior to lurbinectedin infusion).
If pregnancy test was done >7 days before Day 1 of Cycle 1, the test must be repeated the day before or the Day 1 (always prior to lurbinectedin infusion). 
A patient should only be treated if eligibility criteria are still met according to assessments performed closest to treatment start.
Permitted windows for assessments after Day 1 of Cycle 1:
A ± 2-day time window will be allowed for Hematology, Biochemistry-A and CLcr (provided only if serum creatinine levels are above ULN) on Day 8 and Day 15, and for vital signs on Day 8 
of Cycle 1.
A -1 day window will be allowed for physical examination, ECOG PS, vital signs, Hematology, Biochemistry-A, and Biochemistry-B, CLcr (provided only if serum creatinine levels are above 
ULN) and Pregnancy test on Day 1 of Cycle 2 and further cycles (always prior to lurbinectedin infusion).
A + 2 days window for Day 1 lurbinectedin administration of Cycle 3.
If a drug administration is delayed beyond the permitted protocol window, assessments planned for the original administration day must be repeated on the day the dose is finally administered.
a Should treatment be administered more than ten days after the screening tests, repeat these tests prior to the first infusion and if clinically indicated. Height needs to be measured at baseline 
only. BSA will not be reported at the EOT. BSA calculated according to DuBois formula (see Appendix 4).
b In case of detected abnormalities on Day 15 in sequence RT, these assessments should be repeated every 48-72 hours until recovery to retreatment criteria. Initiation of cycle 2 will be delayed 
accordingly in order to ensure that pre-treatment with bosentan is fulfilled.
c Repeat during treatment period and at EOT if clinically indicated.
d
  Calculated CLcr [Cockcroft and Gault’s formula] should be provided only if serum creatinine levels are above ULN.
e ECG should be done in triplicate (at screening, Day 1 and EOT visit) and allow rhythm definition (at least 30 seconds of duration), PR interval and QT interval (raw and corrected by HR 
using Bazett’s formula). On Day 1, 5 minutes before SOI (-25 to -1 min before preinfusion PK samples collection) and 1 hour after EOI (-15 to -1 min before the PK sample collection), both 
will be done in triplicate.
f A previous LVEF assessment could be used if was made within 28 days prior to screening and will be repeated if clinically indicated, and EOT.
g Randomization apply for all patients.
h Bosentan for self-administration and the patient’s diary should be given to the patient on Day 15 of Cycle 1 standing for Day -6 of Cycle 2  with a -2/+1 day time window (i.e., from Day 14 of 
Cycle 1 to Day -5 of Cycle 2 ) in absence of delays.
i Corticosteroids i.v. (according to institutional standard antiemetic doses, minimum dose of 8 mg/day and maximum dose of 20 mg/day of dexamethasone sodium phosphate or equivalent); If 
feasible, anti-emetic medication and dose administered in Cycle 1 should be maintained in Cycle 2. Serotonin (5-HT3) antagonists (ondansetron at least 8 mg i.v. and no more than 16 mg of 
ondansetron) (i.e., 30 ± 5 minutes before lurbinectedin administration).
j If patient does not fulfill re-treatment criteria (Cycle 2 in RT sequence) in Day 1 assessments and lurbinectedin administration is postponed no more than two days, bosentan should not be 

Study Period►
Screening
(days prior 
to 
registration)
Cycle 1
Cycle 2
Cycle 3
End of 
Treatment
Follow-up 
AEs
Cycle Day►
1*
2
3
5
8
15
-5
-4
-3
-2
-1
1
2
3
5
8
15
1
31 (±10)
discontinued.
k The study center will contact the patients (via telephone or other methods) to remind them or confirm that they have taken the morning and evening dose of bosentan when they are not at the 
study center.
l Blood sample for genotyping will be collected at any time during the study but preferably just before infusion start in Cycle 1, only if written IC for the pharmacogenetic sub-study is given.
m Serial peripheral venous blood samples for determination of lurbinectedin (total and unbound), lurbinectedin metabolites (i.e., M1 and M4) and bosentan plasma concentrations will be 
collected at the time points indicated in Section 8.1.1, Table 9.
n Clinical assessment of the patient’s signs and symptoms (including nurses’ assessment and patient-reported issues) should continue on an ongoing basis throughout the study and be reported at 
least every cycle as AEs. Only information on SAEs that occurred after signature of the informed consent and up to Day -1 is required before treatment start. Grading should be as per the NCI-
CTCAE v.5. Signs and symptoms will be assessed by the Sponsor as all the events ongoing during the screening period, except for prior history conditions, which should be reported in the 
medical history form. Ongoing events during the screening period are those present at any time between the informed consent date and the first drug administration, regardless of if they may be 
resolved or not at the date of Cycle 1 Day 1.
o The “AE form” will be used only for events that occur after the first drug infusion or any event related to a study procedure within the study period (according to ICH guidelines); and to report 
‘ongoing’ baseline conditions in case of any significant change (improvement or worsening) during the study.
p Patients will be followed every four weeks until recovery to at least grade 1 or stabilization of all treatment-emergent AEs, or until the start of a new antitumor therapy, until the continuation 
of treatment outside this study under a Compassionate Use Agreement or death, whichever occurs first.
Hematology: Differential WBC (including neutrophils, monocytes and lymphocytes), erythrocytes, hemoglobin, hematocrit and platelets.
Coagulation: INR
Biochemistry A: AST, ALT, AP, lactate dehydrogenase (LDH), creatinine, glucose, creatine phosphokinase (CPK), CPK-MB fraction (if CPK is elevated above the normal range) and gamma 
glutamyltransferase (GGT) and total bilirubin (direct bilirubin if total bilirubin is above the ULN).
Biochemistry B: Serum electrolytes (Na+, K+, Mg++), total calcium, total proteins, albumin, C-reactive protein (CRP).
AAG, alpha-1 acid glycoprotein; AE, adverse events; ALT, alanine aminotransferase; AP, alkaline phosphatase; AST, aspartate aminotransferase; β-hCG, beta subunit of human chorionic 
gonadotropin; BP, blood pressure; BSA, body surface area; CLcr, Creatinine clearance; CPK, creatine phosphokinase; CPK-MB, creatine phosphokinase-isoenzyme MB; CRP, C-reactive 
protein; D, day; ECG, electrocardiogram; ECHO, echocardiogram; ECOG PS, Eastern Cooperative Oncology Group Performance Status; EOT, end of treatment; GGT, gamma 
glutamyltransferase; HR, heart rate; IC, informed consent; ICF, informed consent form; ICH, International Conference on Harmonization; IL6, interleukin 6; INR, International Normalized 
Ratio; LDH, lactate dehydrogenase; LVEF, left ventricular ejection fraction; min, minutes; MUGA, multiple-gated acquisition scan; NCI-CTCAE, National Cancer Institute Common Toxicity 
Criteria; PCR, polymerase chain reaction; PGt; Pharmacogenetic; PK, pharmacokinetics; RT, reference-test sequence; SAE, serious adverse event; SARS-CoV-2, severe acute respiratory 
syndrome coronavirus 2; SOI, start of infusion; Tª, temperature; ULN, upper limit of normal; WBC, white blood cells; WOCBP, women of childbearing potential.

LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
AAG
Alpha 1-acid Glycoprotein
AE(s)
Adverse Event(s)
ADR
Adverse Drug Reaction
ALT
Alanine Aminotransferase
ANC 
Absolute Neutrophil Count
AP
Alkaline Phosphatase
ASCO
American Society of Clinical Oncology
AST
Aspartate Aminotransferase
AUC
Area Under the Concentration-time Curve
AUClast
Area Under the Concentration-time Curve up to the last Measurable Concentration
AUCR
Area Under the Concentration-time Curve Ratio
β-hCG
Beta Subunit of Human Chorionic Gonadotropin
BEV
Bevacizumab
BM
Bone Marrow
BOS
Bosentan
BP
Blood Pressure
BSA
Body Surface Area
14C
Radioactive Carbon
CI
Confidence Interval
CL
Clearance
CLcr
Creatinine Clearance
Cmax
Maximum Plasma Concentration
CNS
Central Nervous System
COPD
Chronic Obstructive Pulmonary Disease
CPK
Creatine Phosphokinase
CPK-MB
Creatine Phosphokinase Isoenzyme MB
CRO
Contract Research Organization
CUP
Carcinoma of Unknown Primary Site
CV
Coefficient of Variation
CYP
Cytochrome P450
D
Day
DDI
Drug-drug Interaction
DOX
Doxorubicin
DP
Drug Product
DSBs
Double-strand Breaks
ECG
Electrocardiogram
ECHO
Echocardiogram 
ECOG PS 
Eastern Cooperative Oncology Group Performance Status 
eCRF
Electronic Case Report Form
EFTs
Ewing’s Family of Tumors
EMA
European Medicines Agency
EOI
End of Infusion
EOT
End-of-treatment
EPO
Erythropoietin
FD
Flat Dose
FDA
Food and Drug Administration
FiH
First-in-Human
GCP
Good Clinical Practice
G-CSF
Granulocyte Colony Stimulating Factor
GCT
Germ Cell Tumor
GDPR
General Data Protection Regulation 
GEM
Gemcitabine
GGT
Gamma-glutamyltransferase
GI
Gastrointestinal
GLP
Good Laboratory Practice
GM-CSF
Granulocyte Macrophage Colony Stimulating Factor
GMT
Greenwich Mean Time
h
Hour(s)

Hb
Hemoglobin
HL
Half-life
HR
Heart Rate; Homologous Recombination
HRD
Homologous Recombination-deficient
5-HT3
Serotonin
IB
Investigator’s Brochure
IC
Informed Consent
IC50
Half Maximal Inhibitory Concentration
ICF
Informed Consent Form
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
IL-6
Interleukin 6
IMP
Investigational Medicinal Product
INR
International Normalized Ratio
IUD
Intra-uterine Contraceptive Device
i.v.
Intravenous
L
Liter
LC-MS/MS
Liquid Chromatography with Tandem Mass Spectrometry
LDH
Lactate Dehydrogenase
LMWH
Low Molecular Weight Heparin
LRB
Lurbinectedin
LVEF
Left Ventricular Ejection Fraction
MBC
Metastatic Breast Cancer
Min
Minutes
Mg
Milligram
mL
Milliliter
MRT
Mean Residence Time
MUGA 
Multiple-gated Acquisition Scan
NA
Not Applicable
NCI-CTCAE
National Cancer Institute Common Toxicity Criteria
NER
Nucleotide Excision Repair
NET
Neuroendocrine Tumor
NHEJ
Non-homologous End Joining
NHP
Non-human Primates
NIHS
National Institute of Health Sciences
NSCLC
Non-small cell Lung Cancer
ORR
Overall Response Rate
OS
Overall Survival
OS6
Overall Survival Rate at Six Months
PBPK
Physiologically Based Pharmacokinetic Models
PCR
Polymerase Chain Reaction
PD
Progressive Disease
PFS
Progression-free Survival
PGt
Pharmacogenetic
PK
Pharmacokinetics
PKPD
Pharmacokinetics and Pharmacodynamics
PLD
Pegylated Liposomal Doxorubicin
PN
Peripheral Neuropathy
PRBC
Packed Red Blood Cells
PS
Performance Status
PVC
Polyvinyl Chloride
q3wk
Every Three Weeks
qd
Daily
R
Randomized
RD
Recommended Dose
RECIST
Response Evaluation Criteria in Solid Tumors
RSI
Reference Safety Information
RT
Reference-Test Sequence
SAE(s)
Serious Adverse Event(s)

SARS-CoV-2
Severe Acute Respiratory Syndrome Coronavirus 2
SCLC
Small Cell Lung Cancer
SD
Stable Disease
SDev
Standard Deviation
SmPC
Summary of Product Characteristics
SOI
Start of Infusion
SUSAR
Suspected Unexpected Serious Adverse Reaction
Tª
Temperature
T1/2
Terminal Half-life
TAM
Tumor-associated Macrophage
Tmax
Time at Which the Maximum Plasma Concentration is Observed
TR
Test-Reference Sequence
UK
Unknown
ULN
Upper Limit of Normal
Vs.
Versus
Vss
Volume of Distribution at Steady State
Vz
Volume of Distribution on the Terminal Phase
WBC
White Blood Cells
wk
Week(s)
WOCBP
Woman of Childbearing Potential.

1.
INTRODUCTION
1.1
INFORMATION ON THE STUDY DRUG: LURBINECTEDIN
Lurbinectedin  is a novel synthetic chemical entity composed of a pentacyclic skeleton 
formed by two fused tetrahydroisoquinoline rings with an additional tetrahydro--
carboline moiety (Figure 1).
Lurbinectedin is an inhibitor of oncogenic transcription. It recognizes specific 
sequences in the minor groove of the DNA where it forms adducts that ultimately lead 
to the generation of double-strand breaks (DSBs). Additionally, it induces the specific 
degradation of transcribing RNA Pol II and the eviction of transcription factors from the 
promoters of actively transactivated genes. It is specifically active in tumors addicted to 
transcription. The generation of DSBs triggers an extended delay in the transition 
through phase S of the cell cycle with an arrest in the phases G2/M, leading to tumor 
cell death by apoptosis.
In vitro, lurbinectedin demonstrated cytotoxic effects against a broad selection of tumor 
types with half maximal inhibitory concentration (IC50) values in the range of 1-10 nM. 
Although selectivity was also seen, a clustering of sensitive tumors has not been 
identified. Lurbinectedin also exhibited antitumor activity against different murine 
models of xenografted human-derived tumor types. Lurbinectedin has been tested as a 
single agent or in combination with different drugs in solid tumors; while antitumor 
activity in hematological tumors was deemed negligible, lurbinectedin has shown 
activity in different solid tumors; some of the most responsive tumor types were breast, 
small cell lung cancer (SCLC), ovarian and endometrial cancer. 
Based on current clinical data, the toxicity of lurbinectedin is predictable, reversible and 
manageable. The most relevant toxicity is reversible myelosuppression with a nadir 
occurring in the middle of the second week after Day 1 infusion in an every-three-week 
cycle; overall, the incidence of febrile neutropenia is below 20% in all ongoing Phase II 
trials.
1.1.1
Name and Chemical Information
Lurbinectedin is produced by chemical synthesis and has the following properties:
Chemical Name
(1'R,6R,6aR,7R,13S,14S,16R)-8,14-dihydroxy-6',9-
dimethoxy-4,10,23-trimethyl-19-oxo-
2',3',4',6,7,9',12,13,14,16-decahydro-6aH-spiro[7,13-
azano-6,16-(epithiopropanooxymethano) 
[1,3]dioxolo[7,8]isoquinolino[3,2-b][3]benzazocine-20,1'-
pyrido[3,4-b]indol]-5-yl acetate
Molecular Formula
C41H44N4O10S
Molecular Weight
784.87g/mol
The structural formula of lurbinectedin is shown in Figure 1.

Figure 1. Structural formula of lurbinectedin.
Chirality/Stereochemistry: lurbinectedin is a single stereoisomer with the (1’R, 6R, 6aR, 
7R, 13S, 14S, 16R) configuration
1.1.2
Non-clinical Data
The pentacyclic skeleton of lurbinectedin is mostly responsible for DNA minor groove 
recognition and binding. Lurbinectedin reacts with exocyclic amino group of guanines 
in the minor groove of DNA forming a covalent bond. Lurbinectedin preferentially 
binds the following triplet of bases: AGC>CGG>TGG>AGG>GGC (the middle 
guanine being the site for covalent adducts formation), in the promoter of actively 
transcribed genes [1].  
From the mechanistic point of view, lurbinectedin is an inhibitor of oncogenic 
transcription, inducing the eviction of oncogenic transcription factors from their binding 
sites within the chromatin and their redistribution within the nucleus [2]. Secondarily, 
Lurbinectedin inhibits active transcription through specific and rapid degradation of 
transcribing RNA Pol II, preventing RNA Pol II elongation and consequently RNA 
synthesis, as observed in several human tumor cell lines [1].
Phosphorylated histone H2AX is detected in lurbinectedin-treated cells extracts after the 
disappearance of RNA Pol II, indicating the presence of DSBs. In the process of 
generation of DSBs, the Nucleotide Excision Repair (NER) machinery has a relevant 
role [1, 3]. The presence of the lurbinectedin-DNA adduct in a DNA strand causes that 
the XPF/ERCC1 nuclease of the NER system, instead of repairing the affected strand, 
generates breaks on the opposite DNA strand generating DSBs [1]. Indeed, 
lurbinectedin is less potent in NER-deficient cells than in NER-proficient cells. 
Resistance to DNA alkylators and platinum treatments is often accompanied by 
increased NER activity, suggesting that these platinum-resistant tumor cells could be 
sensitive to lurbinectedin. In vitro, lurbinectedin showed enhanced and similar activity 
towards two cisplatin-resistant ovarian carcinoma cell lines and oxaliplatin-resistant 
colon carcinoma cell lines [3, 4].
DSBs need to be repaired by the Homologous Recombination (HR) System. The Non-
homologous End Joining (NHEJ) and HR repair pathways have been investigated in 
different cell systems in the activity of lurbinectedin [4, 5]. Lurbinectedin is more active 
against Homologous Recombination-deficient (HRD) cell lines such as BRCA mutated 
cells [4, 6, 7]. HR deficient cells have a sensitive profile, 50 to 100 times higher than 

parental lines, possibly due to the persistence of unrepaired DSB during the S phase and 
the subsequent increase in apoptosis [5].
As a final consequence of its mechanism of action, lurbinectedin induces delayed
transition through the phase S of the cell cycle and a final arrest in the G2/M phases, 
triggering tumor cell death by apoptosis [8].  
Lurbinectedin has demonstrated strong in vitro antineoplastic activity in several human 
cancer cell lines, representative of prostate, pancreas, ovary, non-small cell lung cancer 
(NSCLC) and SCLC, liver, leukemia, lymphoma, kidney, gastric, colon and breast 
tumor cell lines, with 50% inhibitory concentration (IC50) values ranging from 0.3 to 
64.5 nM. Moreover, in a dedicated panel composed of 15 human SCLC cell lines, the 
compound showed compelling cytotoxic activity, with an average IC50 of 0.65 nM. 
The in vivo antitumor activity of lurbinectedin was also demonstrated in a panel of 
different types of human-derived experimental tumors. Statistically significant tumor 
volume reduction has been observed in several xenograft models such as SCLC, 
NSCLC, glioma, breast, gastric, kidney, ovary and pancreas tumors. After treatment, 
molecular analysis of these tumors showed a significant increase of γ-H2AX as well as 
a reduction of tumor-associated macrophages (TAMs) [4]. The antitumor effect of the 
drug has been demonstrated in mice bearing different patient-derived xenografts of 
pancreatic ductal carcinoma and in mice bearing orthotopic tumors (pancreas, ovary and 
Ewing sarcoma): in all these models, the drug caused a significant tumor size reduction 
compared to placebo-treated animals.
Lurbinectedin presents a marked effect on tumor microenvironment by inhibiting 
transcription and secretion of tumor-growth promoting cytokines by TAMs [9]. In vivo, 
synergistic anti-tumor effect was demonstrated for the combination of lurbinectedin and 
immune checkpoint blockade (anti-PD1 antibody and anti-CTLA4 antibody) in a 
murine fibrosarcoma MCA205 model [10].
Liver microsomal fractions from human, as well as from other animal species (i.e. 
mouse, rat, guinea pig, dog and non-human primates [NHP]), were incubated with 
unlabeled or 14C1-lurbinectedin. Results showed that lurbinectedin was stable in the 
liver microsomes from these species in the absence of NADPH-regenerating system, 
indicating that the metabolism of lurbinectedin is NADPH-dependent. After the 
incubation period (10 min), 14C1-lurbinectedin was nearly or completely metabolized in 
liver microsomes from NHP, mouse and human, indicating that lurbinectedin undergoes 
an intense and rapid NADPH-dependent microsome-mediated metabolism. The NHP 
was the preclinical specie that exhibit the most qualitatively and quantitatively human-
similar microsome-mediated metabolism.
Experiments performed with human microsomes (both genders) and selective chemical 
inhibitors and inhibitory monoclonal antibodies directed against CYP1A2, 2A6, 2B6, 
2C8, 2C9, 2C19, 2D6, 2E1, and 3A4 pointed to CYP3A4 as the main CYP isoform 
involved in the phase I metabolism of lurbinectedin. The involvement of other CYPs in 
the microsome-mediated metabolism of lurbinectedin was demonstrated to be negligible
[11, 12].
The interaction of lurbinectedin on several human ATP-binding cassette (ABC) efflux 
transporters, namely BCRP (ABCG2), BSEP (ABCB11) and MDR1 (ABCB1/P-gp), as 
well as several human uptake transporters, namely MATE1 (SLC47A1), OATP1B1 
(SLCO1B1), OATP1B3 (SLCO1B3), OAT1 (SLC22A6), OAT3 (SLC22A8), OCT1 

(SLC22A1) and OCT2 (SLC22A2) were evaluated in in vitro studies. Results have 
shown lurbinectedin is substrate of MDR1 (ABCB1) transporter.
In vitro, the percent of lurbinectedin bound to human plasma proteins was very high 
(>99%) and independent of drug concentration. Lurbinectedin binds to both human 
serum albumin and α-1-acid glycoprotein (AAG), with higher affinity to AAG. In vitro 
binding to AAG is linear and non-saturable at clinically relevant concentrations.
In non-clinical species (rat, dog, and monkey), lurbinectedin exhibits low to moderate 
plasma clearance (from 1 to 10 L/h/kg) and large volume of distribution (from 2 to 56 
L/Kg). The elimination half-life was long (from 9 to 22 h).
In non-clinical toxicity studies, lurbinectedin reversibly affected the hematopoietic 
system, mainly reducing reticulocytes and white blood cells and inducing a slight 
anemia, as well as bone marrow (BM) depletion and atrophy of the lymphoid system. 
Hepatotoxicity was observed mainly in rats and was characterized by markedly 
increased liver function tests, hepatocellular necrosis and biliary damage. 
Hepatotoxicity was less pronounced in dog studies. 
Other target organs, mainly identified in rats, were atrophy of the gastrointestinal (GI) 
mucosa, adrenal gland cortical hypertrophy and kidney cortical tubular vacuolization. In 
summary, the main toxic effects of lurbinectedin – transient BM suppression and 
hepatotoxicity – are rather commonly seen with cytotoxic drugs.
Injection site lesions were also seen in studies regardless of the animal studies used. 
These lesions were characterized by perivascular hemorrhage, inflammation, edema and 
chronic phlebitis, necrosis and ulceration. 
More information is available in the Investigator’s Brochure (IB) of lurbinectedin.
1.1.3
Clinical Data
Up to the cut-off date of 15 January 2020 (date of last IB), a total of 2474 patients had 
been included in PharmaMar clinical studies evaluating lurbinectedin; 975 of them 
(39.4%) were treated with lurbinectedin as single-agent; three phase 1 studies in solid 
and hematological tumors at different regimes [day 1, days 1 and 8, and days 1-3 in 
cycles of 3 weeks (q3wk)], five phase 2 studies in different tumor types [pancreatic, 
ovarian, breast, NSCLC and selected aggressive solid tumors including SCLC] and one 
phase 3 study in ovarian cancer. 
1.1.3.1 Phase I Trials
Currently, this program comprises four single-agent studies, three in solid tumors (one 
ongoing in Japanese patients) (Table 1) and one in acute leukemia patients, six phase Ib
combination studies with gemcitabine (GEM), capecitabine, doxorubicin (DOX), 
cisplatin, paclitaxel with or without bevacizumab (BEV), and irinotecan in patients with 
selected advanced solid tumors. 
The First-in-Human (FiH) study (PM1183-A-001-08) was conducted in patients with 
advanced and refractory solid tumors and evaluated lurbinectedin intravenously (i.v.) 
infused over one hour every three weeks (q3wk). Thirty-three patients were included 
and thirty-one patients were treated. The recommended dose (RD) was stablished at an 
equivalent dose of 4.0 mg/m2/q3wk [13]. Since lurbinectedin clearance was found to be 
unrelated to body surface area (BSA), all patients in the RD expansion cohort were 
treated at a flat dose (FD) of 7.0 mg q3wk (equivalent to 4 mg/m2). However, further 

linear regression showed a strong correlation between neutropenia and its severity with 
the systemic exposure (area under the concentration-time curve – AUC), and for this 
reason, lurbinectedin prescriptions are currently calculated against BSA; moreover, 
phase Ib trials started with a FD and were amended to use a BSA-based dose. In this 
study (and subsequent studies), the median terminal plasma half-life (T1/2) was around 
60 hours, with a plasma clearance (CL) close to 12 L/h though large inter-individual 
variability exists. Urinary excretion of unaltered lurbinectedin was almost negligible 
regardless of dose; the mean percentage of unaltered drug recovered in urine at the 
recommended dose was 0.23% [13].
The most relevant toxicity found in the FiH trial was reversible myelosuppression, 
notably grade 4 non-febrile neutropenia in 40% of patients treated at the RD in Cycle 1. 
Neutropenia was generally predictable and short-lasting and rarely caused treatment 
delays with nadir usually occurring during the second week. No cases of febrile 
neutropenia occurred in this study, although patient selection might have played a role. 
Also, at the RD, treatment was generally well tolerated, with no grade 4 transaminase 
increases observed (in contrast to what occurred above the RD). No unexpected 
toxicities occurred in this study, and there were no signs of cumulative toxicity. All 
patients at this dose level were treated with standard antiemetic prophylaxis to control 
grade 2 nausea and/or vomiting [13].
There was one partial response as per the Response Evaluation Criteria in Solid Tumors 
(RECIST v. 1.0) in pancreatic cancer and three disease stabilizations (SD) at the RD 
lasting ≥ 4 months (two in soft tissue sarcomas, one in melanoma) [13]. 
To explore the feasibility of an alternative schedule (Day 1 and 8, q3wk), a second 
phase I trial (PM1183-A-005-11) was started in advanced non-colorectal cancer patients 
following a prospective FD escalation. The RD was 5 mg FD on Day 1 and 8 q3wk. 
Myelosuppression limited further dose escalation; in contrast to the FiH trial, grade 4 
neutropenia lasted longer and there were more drug-related dose delays/omissions [14]. 
Based on the results from single-agent phase I clinical trials in solid tumors, the Day 1 
q3wk schedule was assessed as more convenient with better compliance, and was  
selected for further clinical trials. 
Table 1. Completed single-agent lurbinectedin phase I trials in solid tumor patients.
PM1183-A-001-08
PM1183-A-005-11
Total
Participant sites and countries
(2): Spain, U.S.
(2): U.S.
Schedule
1-h D1 q3wk
1-h D1, D8 q3wk
Patients included
33
21
54
Treated patients
31
21
52
Evaluated patients
31
21
52
RD
4.0 mg/m2 or 7.0 mg FD
5.0 mg FD
Evaluable patients with DLTs at 
the RD (if applicable)
1 of 15:
Myelosuppression
3 of 13:
Myelosuppression and myelosuppression-
related lack of compliance with treatment 
schedule
Study status
Completed [13]
Completed [14]
C, cycle; D, day 1; DLT, dose-limiting toxicity; FD, flat dose; h, hour; mg, milligrams; q3wk: every three weeks; RD, recommended 
dose; U.S., United States of America. 
Lurbinectedin was also explored in combination with other drugs (DOX, GEM, 
capecitabine, paclitaxel with or without BEV, cisplatin with or without aprepitant, or 
irinotecan) in five clinical trials: PM1183-A-003-10, PM1183-A-004-10, PM1183-A-
006-12, PM1183-A-007-13, PM1183-A-008-13 and PM1183-A-014-15 (Table 2). 

Overall, antitumor activity has been observed in all combinations explored; breast, 
SCLC, ovarian and endometrial cancer were the most responsive tumor types in 
combination studies. 
Table 2. Phase I combination lurbinectedin trials in solid tumor patients.
Study
Participant 
sites and 
countries
Schedule
Treated 
patients
RD
Evaluable patients with 
DLTs at the RD (if 
applicable)
Study status
at cutoff
PM1183-A-
003-10 a
7
Spain
U.K.
PM01183 1-h 
D1 q3wk
+
i.v. DOX D1 
q3wk
120
PM01183 4.0 
mg FD 
+
DOX 50.0 
mg/m2
8 of 60:
Myelosuppression
Completed
PM01183 2.0 
mg/m2
+
DOX 40.0 
mg/m2
1 of 30:
Myelosuppression
PM1183-A-
004-10
3
Spain
U.K.
PM01183 1-h 
D1 and D8 
q3wk 
+
i.v. GEM 30-
min D1, D8 
q3wk
45
PM01183 3.0 
mg FD (1.6 
mg/m2) +
GEM 800 
mg/m2
None of 11
Completed
PM1183-A-
006-12
4
Belgium
Spain
PM01183 1-h 
D1, D8
+ capecitabine 
p.o. b.i.d. D1-
D14 q3wk
15
PM01183 2.0 
mg FD 
+ capecitabine 
1650 mg/m2/D  
b.i.d.
None of 9
Completed
PM01183 1-h 
D1 q3wk 
+ capecitabine 
p.o. b.i.d. D1-
D14 q3wk
66
PM01183 4.0 
mg FD (or 2.2 
mg/m2)
+ capecitabine 
1650 mg/m2/D  
b.i.d.
3 of 36:
Myelosuppression-related 
lack of compliance with 
schedule
PM1183-A-
007-13
3
Spain
Switzerland
U.S.
PM01183 1-h 
D1 
+
paclitaxel 1-h 
D1, D8 q3wk
55
PM01183 4.0 
mg FD/D (or 
2.2 mg/m2) 
+
paclitaxel 80 
mg/m2/week
6 of 34:
Myelosuppression
Completed
PM01183 1-h 
D1 
+
paclitaxel 1-h 
D1, D8 
+
BEV D1 q3wk
12
PM01183 2.2 
mg/m2
+
paclitaxel 80 
mg/m2/week +
BEV 15 mg/kg
3 of 12
Myelosuppression and 
non-hematological (G4 
colon perforation; n=1)
PM1183-A-
008-13
4
Switzerland
U.K.
PM01183 1-h 
D1 
+
cisplatin 90-
min D1 q3wk
24
PM01183 1.4 
mg/m2
+
cisplatin 60 
mg/m2
1 of 3
Fatigue
Completed
PM01183 1-h 
D1 
+
cisplatin 90-
min D1 q3wk 
+
Aprepitant
17
PM01183 1.1 
mg/m2
+
cisplatin 60 
mg/m2
1 of 3
Rhabdomyolysis
PM1183-A-
014-15
3
USA Spain
PM01183 1-h 
D1 
+
Irinotecan  90-
min D1, D8 
q3wk
22
PM01183 1.5 
mg/m2
+
Irinotecan 75 
mg/m2
1 of 4
Febrile neutropenia
Ongoing
PM01183 1-h 
D1 
+
Irinotecan  90-
55
PM01183 
2.0mg/m2
+
Irinotecan 75 
3 of 12
Myelosuppression

Study
Participant 
sites and 
countries
Schedule
Treated 
patients
RD
Evaluable patients with 
DLTs at the RD (if 
applicable)
Study status
at cutoff
min D1, D8 
q3wk
+ G-CSF
mg/m2
PM01183 1-h 
D1 
+
Irinotecan  90-
min D1, D8 
q3wk
(irinotecan 
escalation 
group)
16
RD not defined 
at cutoff
.
Total
327
a Two patients > 75 years were included in study PM1183-A-003-10 before a protocol amendment limited age to a maximum of 75 
years. Data from these two patients have been excluded from safety analyses, but included in efficacy analyses.
BEV, bevacizumab; b.i.d., twice daily; D, day; DLT, dose-limiting toxicities; DOX, doxorubicin; FD, flat dose; G, grade as per 
NCI-CTCAE v.3.0 (in PM1183-A-001-08 study) and v. 4.03 (in all the rest of the studies); GEM, gemcitabine; h, hour; i.v., 
intravenous; NCI-CTCAE, National Cancer Institute Common Terminology Criteria for Adverse Events; MDS, myelodysplastic 
syndrome; min, minute; mg, milligram; PM01183, lurbinectedin; p.o., orally; q3wk, every three weeks; RD, recommended dose; 
U.K., United Kingdom; U.S., United States of America.
With regards to lurbinectedin antitumor activity in hematological tumors, the only 
available information comes from one phase I trial (PM1183-A-002-10), where the 
clinical activity of lurbinectedin was considered negligible from the clinical point of 
view in patients with advanced acute leukemia. For this reason, drug development in 
this hematological disease is not warranted.
1.1.3.2 Human Mass Balance Study
In the human mass balance study (PM1183-A-015-16), near complete recovery of 
administered radioactivity (94.3±8.7%) was achieved within 500-hour post-dose 
following a single mass dose of 4.29±0.23 mg of [14C1]-lurbinectedin (radioactive dose 
of 74.28±8.62 µCi) administered as 1-hour i.v. infusion. The majority of radioactivity 
was excreted in feces (88.7±10.1%) with minimal excretion in urine (5.6±2.0%). Whole 
blood to plasma ratio of parent-related [14C]-radioactivity based upon mean AUC0-last
were found to be 0.68 indicating larger distribution in plasma.
The mean plasma lurbinectedin time to peak (tmax) and plasma [14C]-radioactivity was 
found to be similar (1.2 h). Mean plasma [14C]-radioactivity Cmax, AUC0-last and AUC0-
inf were 1.4, 1.6 and 1.9-fold higher as compared to parent compound. Mean plasma 
[14C]-radioactivity t1/2 (55-hour) was 1.2-fold longer than plasma lurbinectedin t1/2 (47-
hour). Mean plasma clearance and volume of distribution of parent compound were 
found to be 1.7- and 2.1-fold higher than plasma [14C]-radioactivity. According to 
AUC0-last comparison, lurbinectedin constituted approximately 62% of the total [14C]-
radioactivity in plasma, thus suggesting that parent compound is the main circulating 
moiety in plasma.
Among the five known lurbinectedin metabolites (M1 to M5), all were detected but only 
four (M1, M4 (PM030047), M3 (PM01158), and M2 (PM030036)) were quantified in 
plasma. M5 (PM030779) could not be quantified, but its presence in plasma, at low 
levels (around its LLOQ of 0.1 mg/mL), was demonstrated.
Up to 10-hour after the end of infusion, 88.7% of the total [14C]-radioactivity in plasma 
can be attributed to lurbinectedin (70.2%) plus these four metabolites (18.5%). Based on 
these results, M1 and M4 (PM030047) were the major metabolites accounting for 10% 
and 7.3% of circulating radioactivity, respectively, thus representing 14.3% and 10.4% 
of the parent compound in plasma.

Whole blood to plasma ratio of parent-related [14C]-radioactivity based upon mean 
AUC0-last were found to be 0.68 indicating larger distribution in plasma.
1.1.3.3 Phase II Trials
As of 15 January of 2020, five phase II clinical studies had explored the efficacy of 
lurbinectedin in specific solid tumor types and settings (Table 3): PM1183-B-001-10 in 
pancreatic cancer as second-line therapy post GEM-based failure; PM1183-B-002-11 in 
platinum-resistant/refractory ovarian cancer; PM1183-B-003-11 in previously treated 
BRCA1/2-associated metastatic breast cancer (MBC); PM1183-B-004-13 in NSCLC, 
and PM1183-B-005-14 in selected advanced solid tumors.
Four of these studies initially evaluated single-agent lurbinectedin at the RD and 
schedule determined in the FiH study (PM1183-A-001-08), i.e., 7.0 mg FD as a 1-h i.v. 
infusion q3wk. In addition, study PM1183-B-004-13 evaluated lurbinectedin in 
combination with GEM at the RD and schedule defined in a previous phase I study 
(PM1183-A-004-10), i.e., lurbinectedin 3.0 mg FD + GEM 800 mg/m2 both on Day 1 
and Day 8 q3wk. However, protocol amendments were implemented to change the fixed 
dose in these studies to a BSA-based dose, as a conservative approach after knowledge 
of data suggesting BSA-related toxicity. The fifth study (PM1183-B-005-14) evaluated 
lurbinectedin at a BSA-based dose of 3.2 mg/m2 as a 1-h i.v. infusion q3wk. 
Table 3. Phase II lurbinectedin trials in solid tumor patients.
Study
Indication
Participant 
sites and 
countries
Drug dose and 
schedule
Treated 
patients
Primary
endpoint
Results
Study status
at cutoff
Non-randomized trials
PM1183-B-001-10
Second-line metastatic 
pancreatic cancer
8
Spain
U.K.
PM01183
7.0 mg FD 1-h D1 
q3wk
44
OS6 rate
OS6: 33%
Completed
PM1183-B-003-11
BRCA 1/2-associated 
or unselected MBC
11
Spain
U.S.
PM01183
7.0 mg FD or 3.5 
mg/m2 as 1-h 
infusion D1 q3wk
BRCA-
mutated
54
Confirmed 
response as per 
RECIST v 1.1
BRCA-mutated
ORR: 41%
Ongoinga
BRCA-
mutated + 
prior PARPi 
20
BRCA-mutated 
+ prior PARPi
ORR: 5%
BRCA-
unselected
35
BRCA-
unselected
ORR: 9%
PM1183-B-005-14
Selected advanced 
solid tumors b
40
Belgium
France
Italy
Spain
Sweden
Switzerland
U.K.
U.S.
PM01183
3.2 mg/m2 as 1-h  
D1 q3wk
335 c
Confirmed 
response as per 
RECIST v 1.1
SCLC
ORR: 36%
BRCA-mutated 
MBC
ORR: 29%
EFTs
ORR: 16%
Endometrial
ORR: 11%
NETs
ORR: 7%
Biliary tract
ORR: 6%
GCTs
ORR: 5%
Ongoing a
Total
488

Study
Indication
Participant 
sites and 
countries
Drug dose and 
schedule
Treated 
patients
Primary
endpoint
Results
Study status
at cutoff
Randomized trials
PM1183-B-002-11
PRROC
9
France
Spain
PM01183
7.0 mg FD as 1-h 
D1 q3wk
81
PM01183: 52
Topotecan: 29
d
Confirmed 
response as per 
RECIST v 1.1 
and/or Rustin 
criteria
PM01183:
ORR: 23%
Topotecan:
ORR: 0%
Completed
PM1183-B-004-13
Unresectable second-
line NSCLC
14
Belgium
France
Italy
Spain
U.S.
PM01183
7.0 mg FD or 3.2 
mg/m2 as 1-h D1 
q3wk
21
PFS4 rate
PFS4: 16%
Completed
PM01183 3.0 mg 
FD or 1.6 mg/m2
as 1-h 
+
GEM 800 mg/m2
both on D1, D8 
q3wk
25
PFS4: 26%
Docetaxel
75 mg/m2 as 1-h 
D1 q3wk
22
PFS4: 27%
Total
149
Total Phase II trials
637
Total lurbinectedin single-agent
(including 15 patients crossed over from topotecan)
576
a Closed recruitment.
b SCLC, H&N, NETs, biliary tract carcinoma, endometrial carcinoma, BRCA1/2-associated metastatic breast carcinoma, CUP, 
GCTs and EFTs.
c Thirty nine of these patients were also included in the PM1183-B-005-14-QT sub-study, to evaluate the potential effects of 
lurbinectedin on the duration of the QTc interval.
d Fifteen of these patients crossed over to the lurbinectedin arm. CUP, carcinoma of unknown primary site;  D, day; EFTs, Ewing’s 
family of tumors; FD, flat dose; GCT, germ cell tumor; GEM, gemcitabine; h, hour; H&N, head and neck carcinoma; mg, 
milligrams; NET, neuroendocrine tumor; NSCLC, non-small cell lung cancer; ORR, overall response rate; OS6, overall survival rate 
at six months; PD, progressive disease; PFS, progression-free survival; PFS4, progression-free survival rate at four months; 
PM01183, lurbinectedin; PRROC, platinum-resistant/refractory advanced ovarian cancer; q3wk, every three weeks; RECIST, 
Response Evaluation Criteria In Solid Tumors; SCLC, small cell lung cancer; SD, stable disease; U.K., United Kingdom; U.S., 
United States of America.
1.1.3.4 Phase III Program
As of 15 January 2020, one completed phase III study (PM1183-C-004-14, CORAIL) 
had compared the efficacy of lurbinectedin in platinum-resistant ovarian cancer against 
standard topotecan or pegylated liposomal doxorubicin (PLD). No significant 
differences between treatment arms were found for secondary efficacy endpoints of this 
trial. Lurbinectedin showed an improvement in terms of safety profile compared to the 
control arm.
The other
phase III clinical study is currently ongoing (PM1183-C-003-14, 
ATLANTIS). This study had completed recruitment. The aim of this study is to 
compare the combination of lurbinectedin with DOX vs. treating physician choice 
(topotecan or CAV) as a second line in SCLC. 
1.1.3.5 Population Pharmacokinetic and Pharmacodynamic (PKPD) Modeling
A population pharmacokinetic model of lurbinectedin was developed by pooling data 
from all studies (including drug combination studies) and it is regularly updated.
A population pharmacokinetic three-compartment model with linear elimination and 
linear distribution adequately fits the PK data. The model estimated a mean (standard 
deviation [SDev]) CL of 12.3 (7.0) L/h, a half-life (HL) of 47.2 (31.5) hours and a wide 
volume of distribution at steady state (Vss) of 436 (250) L. All these PK parameters 
showed high variability (coefficient of variation [CV] about 50%) among patients. The 
lurbinectedin PK showed linearity among the dose range explored (0.5-4.5 mg/m2).

Baseline covariates affecting lurbinectedin CL are albumin, alpha 1-acid glycoprotein, 
BSA, the presence of strong (voriconazole) or moderate (aprepitant or fluconazole) 
CYP3A4 inhibitors, and cardiac function measured by left ventricular ejection fraction 
(LVEF). The use of strong (voriconazole) or moderate (fluconazole or aprepitant) 
CYP3A4 inhibitors reduced lurbinectedin CL by approximately 40% and 20%, 
respectively. Therefore, the use of CYP3A4 inhibitors should be carefully monitored or 
avoided, whenever possible. 
Renal elimination of lurbinectedin was minor in the FiH trial. In addition, the 
population PK model did not establish any relationship between lurbinectedin CL and 
CLcr or creatinine levels. Age and race were found to have no effect over lurbinectedin 
PK, although the number of elderly patients (>75 years) and non-Caucasian patients was 
small.
Lurbinectedin-induced neutropenia and thrombocytopenia population PKPD models 
showed that baseline ANC and platelet count are by far the covariates with the greatest 
effect on the incidence of neutropenia and thrombocytopenia. With a baseline absolute 
neutrophil count (ANC) value of 2.0 x 109/L (currently the lower limit of ANC for 
inclusion is 1.5 x 109/L), and a platelet count of 135 x 109 (currently the lower limit of 
platelet count for inclusion is 100 x 109/L), the incidence of grade 3/4 neutropenia and 
thrombocytopenia were estimated to be around 69% and 13%, respectively, in the first 
cycle. Simulations performed at 3.2 mg/m2 showed a lower neutropenia and 
thrombocytopenia incidence compared to the previous RD of 7.0 mg FD. The results of 
the simulation also showed that BSA-dosing reduced the variability caused by BSA 
compared to 5.7 mg FD. The presence of ascites or the use of CYP3A4 inhibitors would 
increase the incidence of neutropenia, while the use of granulocyte colony-stimulating 
factor (G-CSF) would decrease it markedly. Additionally, breast cancer patients showed 
less risk of developing thrombocytopenia, while the use of strong CYP3A4 inhibitors, 
ascites or pancreatic cancer increased this risk. The population PK model of 
lurbinectedin showed that CL increases with BSA, and the population PKPD models for 
neutropenia and thrombocytopenia showed myelosuppression would be decreased by 
BSA dosing. Therefore, the use of a BSA-dosing strategy for lurbinectedin has been 
resumed in ongoing and planned trials.
1.2
OVERALL STUDY RATIONALE
Lurbinectedin is extensively metabolized by the cytochrome P450 enzymes, primarily 
CYP3A4. Thus, potent inducers or inhibitors of this enzyme may alter the plasma 
concentrations of lurbinectedin. This study is designed to examine the PK and safety of 
lurbinectedin when co-administered with bosentan, a moderate CYP3A4 inducer, in 
comparison with lurbinectedin alone. The results of this study may be used to support 
future clinical studies in patients and prescribing information in future labeling.
1.3
PHARMACOGENETIC SUB-STUDY RATIONALE
Germline genetic variants may influence exposure and toxicity (i.e. disposition, 
metabolism and safety) to lurbinectedin. In order to explore the potential impact of 
genetic factors that may account for inter individual variability in the main PK 
parameters, blood sample for germline DNA extraction will be collected and stored for 
future pharmacogenetic (PGt) analysis. One blood sample obtained at any time during 
the study, but preferably just before infusion start in Cycle PK sample #1 on Day 1 of 
Cycle 1 will be obtained.

2.
STUDY OBJECTIVES
2.1
PRIMARY OBJECTIVE

To assess the effect of bosentan on lurbinectedin total plasma exposure in 
patients with advanced solid tumors.
2.2
SECONDARY OBJECTIVES

To assess the effect of bosentan on lurbinectedin unbound plasma exposure.

To assess the effect of bosentan on lurbinectedin major metabolites (i.e., M1 
and M4).

To assess the effect of bosentan on the safety profile of lurbinectedin.

To collect and store a blood sample for germline DNA extraction for future 
pharmacogenetic (PGt) analysis of variations on genes that may influence 
exposure and response (i.e., disposition, metabolism and safety) to 
lurbinectedin.
3.
OVERALL STUDY DESIGN
3.1
STUDY DESIGN
This is a prospective, open-label, two-way crossover, phase Ib drug-drug interaction 
study in patients with advanced solid tumors.
The study will include a pre-treatment (screening) phase  followed by a treatment phase 
consisting of two lurbinectedin cycles, one cycle in combination with bosentan and one
cycle of lurbinectedin as single agent (in different order depending on the study 
sequence), and one additional third cycle of lurbinectedin as a single agent for patients 
who meet the continuation criteria and obtain a clinical benefit after the first two cycles, 
and then follow-up of adverse events if any.
Patients who meet the continuation criteria and obtain a clinical benefit after the first 
two cycles according to the Investigator’s criteria will have the opportunity to continue 
treatment under a Compassionate Use Agreement after the completion of the optional 
third study cycle.
Patients will be treated as outpatients. At the discretion of the Investigator, patients may 
be admitted to the study center on Day –1 or Day 1 and monitored, at least, until 
completion of the Day 1 PK blood sample collections.
Patients will receive a maximum of three cycles: two consecutive cycles of 
lurbinectedin, one cycle with and one cycle without bosentan co-administration (in 
different order depending on the study Sequence 1 or Sequence 2 of treatment), 
followed by a third cycle with lurbinectedin alone (this last optional for patients with 
clinical benefit). Lurbinectedin will be administered as a 1-hour (-5/+20 min) i.v. 
infusion q3wk via a central or peripheral vein.
In the co-administration cycles, bosentan will be administered orally twice daily in the 
morning and evening during the prior five consecutive days, self-administered at home 
from Day -5 to Day -1 (i.e., five days before lurbinectedin infusion), and once daily on 

Day 1 (i.e., the day of lurbinectedin infusion), following recommendations at the 
Summary of Product Characteristics (SmPC). On Day 1 (i.e., the day of lurbinectedin 
infusion), bosentan will be given immediately prior to starting the lurbinectedin 
infusion. In fact, bosentan should be administered after obtaining the bosentan 
pharmacokinetic (PK) sample #1 and before the start of lurbinectedin infusion (-15 min 
to -1 min).
In case of lurbinectedin delay (≤ 2 days), bosentan could be administered twice daily 
during a maximum of seven consecutive days before lurbinectedin infusion, and 
supplied at the study center once daily on Day 1 (before lurbinectedin infusion).
All patients will receive a maximum of three cycles: two consecutive cycles of 
lurbinectedin, one cycle with and one cycle without bosentan co-administration (in 
different order depending on the study Sequence 1 or Sequence 2 of treatment), 
followed by a third cycle with lurbinectedin alone (this last optional for patients with 
clinical benefit). Patients will be randomized in a 1:1 ratio (Figure 2) to Sequence 1 
(TR: Test- Reference; lurbinectedin + bosentan in Cycle 1) or Sequence 2 (RT: 
Reference-Test; lurbinectedin + bosentan in Cycle 2). Lurbinectedin will be 
administered as a 1-hour (-5/+20 min) intravenous (i.v.) infusion every three weeks 
(q3wk) via a central or peripheral vein. The dose of lurbinectedin will be 3.2 mg/m² for 
all patients when administered with and without bosentan. If toxicity occurs, the 
appropriate intra-patient dose level (DL) reductions will be implemented in the 
subsequent cycle. This DL reduction will be according to Table 8. 
Figure 2. Study design.
BOS, bosentan; LRB, lurbinectedin; TR, test-reference; R; randomized; RT, reference-test.
The enrollment of the patients will be simultaneous. However, if once the first three 
patients enrolled have completed Cycle 1 and Cycle 2, total lurbinectedin exposure 
does not allow an adequate PK assessment and if no unacceptable or life-threatening 
toxicities have occurred, the dose of lurbinectedin to be co-administered with bosentan 
in the remaining five patients can be adjusted accordingly. 
This decision will be made by the Sponsor and the study Investigators. Therefore, the 
planned dose of lurbinectedin, when given with bosentan for the remaining five 
patients, will be based on the acceptability of the PK and safety results from the first 
three patients. If the initial three patients do not experience adverse events (AEs) 
which might require a dose-reduction, the dose of lurbinectedin may still be adjusted 
(based on the assumption of dose-proportional pharmacokinetics) to produce plasma 
lurbinectedin area under the curve (AUC) values that are comparable to those when 
lurbinectedin is given in the absence of bosentan. However, if toxicity occurs in the 
initial three patients, the appropriate dose-reduction of lurbinectedin will be 
implemented in the remaining five patients accordingly.

Patients will receive lurbinectedin until disease progression, unacceptable toxicity, 
consent withdrawal or while it is considered to be in their best interest, and for a 
maximum of three cycles. Treatment with lurbinectedin outside this study could be 
continued under a Compassionate Use Agreement after the completion of the optional 
third study cycle.
All patients will be randomly assigned to the corresponding sequences:

Sequence 1 (TR):
o
Cycle 1: Bosentan + lurbinectedin
o
Cycle 2: Lurbinectedin alone
o
Cycle 3: Lurbinectedin alone (optional)

Sequence 2 (RT):
o
Cycle 1: Lurbinectedin alone
o
Cycle 2: Bosentan + lurbinectedin
o
Cycle 3: Lurbinectedin alone (optional)
Lurbinectedin will be administered to eight evaluable patients and for a maximum of 
three cycles, while considered to be on the patient’s best interest or until PD, 
unacceptable toxicity, intercurrent illness of sufficient magnitude to preclude safe 
continuation of the study, patient’s refusal and/or non-compliance with study 
requirements, a protocol deviation with an effect on the risk/benefit ratio of the clinical 
study, more than two lurbinectedin dose reduction due to AEs related to lurbinectedin 
(unless clear clinical benefit has been documented and always with the Sponsor’s 
agreement), or any other reason at the physician’s judgment that precludes lurbinectedin 
continuation.
If the patient meets the continuation criteria and shows a clear clinical benefit after the 
first two cycles according to Investigator criteria, treatment with lurbinectedin may 
continue outside this study under a Compassionate Use Agreement at the same dose 
based on Investigator’s decision and upon agreement with the Sponsor. Then, the 
treating center must request authorization to the relevant Health Authorities and notify 
the Sponsor in due time. In order to avoid a treatment discontinuation, during the 
Compassionate Use Agreement authorization an additional third cycle with 
lurbinectedin is allowed.
All adverse events (AEs) will be graded according to the National Cancer Institute 
Common Terminology Criteria for Adverse Events (NCI-CTCAE) v.5. Treatment 
delays, dose reduction requirements and reasons for treatment discontinuation will be 
monitored throughout the study. The safety profile of patients will be monitored 
throughout the treatment and up to 31 days (±10 days) after the last lurbinectedin 
infusion (end of treatment, EOT), until the patient starts a new antitumor therapy or 
until the date of death, whichever occurs first. Any treatment-emergent AEs will be 
followed until recovery to at least grade 1 or stabilization of symptoms or until the start 
of a new antitumor therapy, until the continuation of treatment outside this study under 
a Compassionate Use Agreement or death, whichever occurs first. After treatment 
discontinuation, patients will be followed until resolution or stabilization of all 
toxicities, if any.
Patients will be evaluated at scheduled visits on three study periods: pre-treatment 
(screening), treatment (one cycle of lurbinectedin in combination with bosentan and two

as a single agent and the third cycle optional) and follow-up of adverse events if any 
(see Section Schedule of Assessments and Procedures). 
3.2
STUDY DESIGN RATIONALE
Lurbinectedin is a genotoxic agent and should not be administered to healthy subjects. 
Therefore, this study will enroll patients with locally advanced or metastatic solid 
tumors. The crossover design reduces treatment bias and permits intra-subject 
comparisons and control.
The dose of 3.2 mg/m2 of lurbinectedin administered as a 1-hour (-5/+20 min) infusion 
every 3 weeks will be given to patients when they are not given the bosentan co-
administration. Studies of single-agent lurbinectedin given as same dose regimen have 
shown activity in several tumor types including endometrial cancer, breast cancer, and 
specially SCLC.
In the bosentan co-administration cycle, the twice daily oral administration in the 
morning and evening following recommendations at the SmPC will start with self-
administration at home on Day -5 (five days before lurbinectedin infusion) and until 
Day -1 (the day before lurbinectedin infusion), and supplied at the study center on Day 
1. On Day 1 (day of lurbinectedin infusion), bosentan will be given immediately prior to 
the start of the lurbinectedin infusion. In case of lurbinectedin delay (≤2 days), bosentan 
could be administered during a maximum of 7 and a half days.
The proposed bosentan regimen is expected to produce sustained induction of CYP3A4 
activity over the entire lurbinectedin PK profile. The total daily dose given in a single 
dose (i.e. 125 mg twice daily) on the morning and on the evening during 5 and a half 
days (only morning dose on the day of lurbinectedin infusion start) will produce a 
consistent degree of induction of CYP3A4 activity during the day of lurbinectedin-
bosentan co-administration and beyond, since it takes time for the enzyme’s activity to 
return to normal following the inducer’s removal.
The exposure of lurbinectedin given as a 1-hour i.v. infusion when co-administered with 
bosentan, a moderate CYP3A4 inhibitor, will be assessed. Previously, a dose of 3.2 
mg/m2 administered over 1 hour  without concomitant administration of inhibitors of 
CYP3A4 activity, produced lurbinectedin concentrations in plasma that were 
measurable for at least 160 hours after start of the infusion (Basket study, PM1183-B-
005-14). A 3.2 mg/m2 dose of lurbinectedin co-administered with bosentan is expected 
to produce measurable concentrations in samples collected for at least the initial 80 
hours. 
The PK (and safety) of bosentan will be assessed in the first three patients in order to 
confirm the above statements.
Patients will receive i.v. corticosteroids (according to institutional standard antiemetic 
doses, minimum dose of 8 mg/day and maximum dose of 20 mg/day of dexamethasone 
sodium phosphate or equivalent) 30 ± 5 minutes before the infusion of lurbinectedin 
during Cycles 1 and 2. The optional treatment with additional antiemetic drugs on Day 
1 of Cycles 1 and 2 is allowed, but should be identical across Cycle 1 and 2 for a given 
patient when possible to minimize intra-subject variability in the PK of lurbinectedin. 
Ondansetron is the recommended serotonin (5-HT3) antagonist, since it is metabolized 
by multiple hepatic cytochrome P450 enzymes. Its metabolic clearance is less likely to 

be influenced by the co-administration of bosentan, relative to a serotonin receptor 
antagonist that is predominately metabolized by a single cytochrome P450 enzyme.
A 168-hour blood sample collection period is sufficient to assess the potential effects of 
bosentan on lurbinectedin systemic exposure. In order to confirm the presence of 
measurable bosentan exposure and provide an abbreviated profile of plasma 
concentrations of bosentan, four samples will be collected in the cycle during which 
patients receive bosentan, as detailed in the Schedule of Assessments and Procedures
section. 
3.3
PRIMARY ENDPOINT
3.3.1
Plasma exposure to lurbinectedin
Plasma dose-normalized Cmax and AUC0-∞of lurbinectedin will be compared between 
Cycle 1 and Cycle 2. Pharmacokinetic analyses will be evaluated in plasma by standard 
non-compartmental methods, or population methods, if necessary.
3.4
SECONDARY ENDPOINTS
3.4.1
Secondary PK parameters

Differences in dose-normalized total AUC0-t and Cmax and in Cl, Vss and T1/2 of 
lurbinectedin between Cycle 1 and Cycle 2 will be explored.

Differences in dose-normalized unbound AUCu,0-∞, AUCu,0-t and Cu,max and in CLu, 
Vss,u and T1/2,u of lurbinectedin between Cycle 1 and Cycle 2 will be explored.

Differences in ratios between total AUC0-∞, AUC0-t and Cmax, of main lurbinectedin 
metabolites relative to parent drug between Cycle 1 and Cycle 2 will be explored. 
Additional PK parameters will be calculated if deemed appropriate.
3.4.2
Safety Profile
Treatment safety, including AEs, serious adverse events (SAEs) and laboratory 
abnormalities will be graded according to the NCI-CTCAE v.5. Additionally, 
treatment compliance, in particular dose reductions requirements and/or treatment 
delays due to AEs, and reasons for treatment discontinuation will also be described.
Patients will be evaluable for safety if they have received at least one partial or 
complete infusion of lurbinectedin.
3.4.3
Pharmacogenetics
The presence or absence of PGt polymorphisms in genes relevant for lurbinectedin 
disposition (distribution, metabolism and excretion) from a single blood sample 
collected (only if written IC given) at any time during the trial (but preferably at the 
same time as the pre-treatments PK sample on Day 1 of Cycle 1), which will be stored 
to explain individual variability in main PK parameters in future analyses.

4.
SELECTION OF PATIENTS
4.1
INCLUSION CRITERIA
All patients must fulfill the following inclusion criteria to be enrolled in the study:
1) Voluntary signed and dated written informed consent prior to any specific study 
procedure. 
2) Male or female with age ≥18 years.
3) Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 1 
(Appendix 1).
4) Life expectancy > 3 months.
5) Pathologically confirmed diagnosis of advanced solid tumors [except for primary 
central nervous system (CNS) tumors], for which no approved therapy exists. 
6) Recovery to grade ≤ 1 from drug-related adverse events (AEs) of previous 
treatments, excluding alopecia and grade ≤2 asthenia or fatigue, according to the 
National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-
CTCAE v.5). 
7) Laboratory values within fourteen days prior to registration: 
a) Absolute neutrophil count (ANC) > 2.0 x 109/L, platelet count > 120 x 109/L 
and hemoglobin > 9.0 g/dL (patients may be transfused as clinically indicated 
prior to study entry).
b) Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 x 
upper limit of normal (ULN).
c) Serum total bilirubin ≤ 1.0 x ULN.
If total bilirubin is > 1.0 x ULN, but ≤ 1.5 x ULN, direct bilirubin must be ≤ 1.0 
x ULN.
d) Albumin ≥ 3.5 g/dL.
e) Creatinine clearance (CLcr) > 30 mL/min (using Cockcroft and Gault’s 
formula) (Appendix 4).
f)
Creatine phosphokinase (CPK) ≤ 2.5 x ULN.
8) Left ventricular ejection fraction (LVEF) by echocardiography (ECHO) or 
multiple-gated acquisition (MUGA) within normal range (according to institutional 
standards).
9) Evidence of non-childbearing status for women of childbearing potential 
(WOCBP). WOCBP must agree to use a highly effective contraceptive measure up 
to six months after treatment discontinuation. Valid methods to determine the 
childbearing potential, adequate contraception and requirements for WOCBP 
partners are described in Appendix 2. As bosentan may render hormonal 
contraceptives ineffective, and taking into account the teratogenic effects observed 
in animals, hormonal contraceptives cannot be the sole method of contraception 
during treatment with bosentan. Fertile male patients with WOCBP partners should 
use condoms during treatment and for four months following the last 
investigational medicinal product (IMP) dose.

4.2
EXCLUSION CRITERIA
All patients who meet any of the following criteria will be excluded from participating 
in the study:
1) Concomitant diseases/conditions:
a) History or presence of unstable angina, myocardial infarction, congestive heart 
failure, or clinically significant valvular disease within last year.
b) Symptomatic arrhythmia or any uncontrolled arrhythmia requiring ongoing 
treatment.
c) Known cirrhosis, alcohol induced steatosis, or chronic active hepatitis. For 
hepatitis B, this includes positive test for both Hepatitis B surface antigen 
(HBsAg) and quantitative Hepatitis B polymerase chain reaction (PCR or 
HVB-DNA+). For hepatitis C, this includes positive test for both Hepatitis C 
antibody and quantitative Hepatitis C by PCR (or HVC-RNA+). 
d) History of obstructive cholestatic liver disease (suitable for stenting procedure) 
or biliary sepsis in the past 2 months.
e) Active COVID-19 disease (this includes positive test for SARS-CoV-2 in 
nasopharyngeal/oropharyngeal swabs or nasal swabs by PCR). 
2) Symptomatic, 
progressive 
or 
corticosteroids-requiring 
documented 
brain 
metastases or leptomeningeal disease involvement. Patients with asymptomatic 
documented stable brain metastases not requiring corticosteroids during the last 
four weeks are allowed.
3) Use of (strong or moderate) inhibitors or inducers of CYP3A4 activity within three 
weeks prior to Day 1 of Cycle 1 (Appendix 3).
4) Use of CYP3A4 substrates for which concomitant administration with moderate 
CYP3A4 inductor is contraindicated (Appendix 3).
5) Treatment with any investigational product within the 30 days before Day 1 of 
Cycle 1.
6) Women who are pregnant or breast feeding and fertile patients (men and women) 
who are not using an effective method of contraception (Appendix 2).
7) Psychiatric illness/social situations that would limit compliance with study 
requirements.
4.3
PATIENTS FOR THE PHARMACOGENETICS SUB-STUDY 
Only patients who voluntarily sign the written ICF for the pharmacogenetic sub-study 
will participate in it. Refusal to participate in this sub-study will not affect patient 
participation in the clinical study PM1183-A-019-20.
5.
PLAN OF THE STUDY
5.1
PLANNED STUDY PERIODS (FOR THE WHOLE STUDY)
The total duration of the study will be approximately 22 months, including 
approximately an 18-month enrollment period.


Planned start date (first patient on study): 4Q2020.

Planned enrollment period: approximately 18 months.

Planned end-of-study date (clinical cutoff): 31 (±10) days after the date of the 
last lurbinectedin administration for last patient
/last
cycle,
or when 
confirmation of evaluability of at least eight patients, whichever occurs last.
Patients who meet the continuation criteria and obtain a clear clinical benefit 
with lurbinectedin after the completion of the first two study cycles, according 
to the Investigator’s criteria may continue treatment outside this study under a 
Compassionate Use Agreement after the completion of the optional third study 
cycle. Should the patient continue under a Compassionate Use Agreement, the 
treating center must request authorization to the relevant Health Authorities and 
notify the Sponsor in due time.
5.2
PLANNED STUDY PERIODS (INDIVIDUALLY PER PATIENT)
Patients will be evaluated at scheduled visits in three study periods:

Pre-treatment (screening): from signature of the ICF to the day of first 
administration of the study treatment (bosentan or lurbinectedin).

Treatment: from first administration of the study treatment (bosentan or 
lurbinectedin) to the last dose of lurbinectedin plus 31 days (end-of-treatment, 
EOT) (maximum of three cycles).

Follow-up of adverse events: after EOT, patients with treatment-related 
toxicities > grade 2 will be followed every four weeks until recovery to at least 
grade 1 or stabilization of all treatment-emergent AEs, or until the start of a new 
antitumor therapy, until the continuation of treatment outside this study under a 
Compassionate Use Agreement or death, whichever occurs first. 
Patients will be considered to be on-study from the signature of the ICF to the end of 
the follow-up period. Patients will be considered to be on-treatment for the duration of 
their treatment and until the day of EOT, immediately before the start of the follow-up 
period. 
An end-of-treatment visit will be performed within 31 days (±10 days) after 
administration of the last dose of lurbinectedin, unless the patient dies or starts any new 
antitumor therapy outside this clinical study, in which case the EOT visit should be 
performed immediately before the start of the new therapy (ideally the day before or the 
same day).
5.2.1
Discontinuations
5.2.1.1 Treatment Discontinuation
Treatment discontinuation occurs when an enrolled patient ceases to receive the study 
treatment regardless of the circumstances. By convention, the date of EOT is defined as 
31 days after the day of the last dose of lurbinectedin (treatment discontinuation), the 
start of a new antitumor therapy or death, whichever occurs first, in which case the date 
of administration of this new therapy or the date of death will be considered the date of 
EOT.

The primary reason for any treatment discontinuation will be recorded on the patient’s 
electronic Case Report Form (eCRF).
If a patient discontinues treatment, every effort should be made to complete the 
scheduled assessments as appropriate.
5.2.1.2 Reasons for Treatment Discontinuation
Patients will receive the study medication for a maximum of three cycles and while it is 
considered to be in their best interest. Specifically, treatment will continue for a 
maximum of three cycles until:

Disease progression.

Unacceptable toxicity.

Intercurrent illness of sufficient magnitude to preclude safe continuation of the 
study.

Patient’s refusal and/or non-compliance with study requirements.

A protocol deviation with an effect on the risk/benefit ratio of the clinical 
study.

Delay > 14 days due to treatment-related adverse events (unless clear clinical 
benefit has been documented and always with the Sponsor’s agreement).

More than two lurbinectedin dose reductions due to adverse events related to 
lurbinectedin (unless clear clinical benefit has been documented and always 
with the Sponsor’s agreement).

Any other reason at the physician’s judgment that precludes lurbinectedin 
continuation. 
5.2.1.3 Study Discontinuation
Study discontinuation occurs when an enrolled patient ceases to participate in the study, 
regardless of the circumstances, prior to completion of the study. Patients have the right 
to withdraw consent at any time; if this is the case, no further study procedures should 
be performed. The Investigator must determine the primary reason for discontinuation. 
The date and reason for a patient’s discontinuation from the study will be recorded on 
the eCRF.
5.2.2
Protocol Deviations
A protocol deviation is defined as any departure from what is described in the protocol 
of a clinical study approved by an Independent Ethics Committee (IEC) and a 
Competent Authority. Therefore, it applies to deviations related to patient inclusion and 
clinical procedures (e.g., assessments to be conducted or parameters to be determined), 
and also to other procedures described in the protocol that concern Good Clinical 
Practice (GCP) guidelines or ethical issues (e.g., issues related to obtaining patients’ 
informed consent, data reporting or Investigator’s responsibilities).
Deviations with no effects on the risk/benefit ratio of the clinical study (such as minimal 
delays in assessments or visits) will be distinguished from those that might have an 
effect on this risk/benefit ratio, such as:


Deviations that might affect the clinical study objectives, such as those involving 
relevant inclusion/exclusion criteria (which could mean that the patient is not 
eligible for the study) and those having an effect on patient evaluability.

Deviations that might affect the patient’s well-being and/or safety, such as an 
incorrect dosing of study treatment due to not following dose adjustment 
specifications or an incorrect preparation of the medication.

Deviations related to the following of GCP guidelines as described in the protocol 
and regulations in force, such as deviations when obtaining informed consent or 
not following the terms established for reporting serious adverse events (SAEs), 
etc.
No deviations that may have an effect on the risk/benefit ratio of the clinical study will 
be authorized. All protocol deviations detected during the study will be appropriately 
documented, and those considered particularly relevant (i.e., those related to ethical 
issues, fulfillment of GCP guidelines and with an effect on the risk/benefit ratio) will be 
notified to the pertinent IEC and, if applicable, to the Competent Authorities as 
established by local regulations.
5.3
REPLACEMENT OF PATIENTS
Patients must be replaced if they are not evaluable for the assessment of the primary 
endpoint (e.g., if they have not sufficient and interpretable PK parameters). 
Evaluable patients for the main objective of the study (e.g., assessment of lurbinectedin 
PK) should have provided sufficient and interpretable PK parameters (e.g., AUC0-t
should cover at least 80% of AUC0-∞) of Cycle 1 and 2. Evaluable patients should have 
received the first two complete cycles regardless dose delays or reductions. 
The compliance of bosentan will be confirmed based on a patient’s diary, the drug 
accountability and the expected individual plasma concentration at the steady state.
Any replacement subject during the treatment phase will be given a new subject number 
and assigned to the same sequence as the not-evaluable subject being replaced. All 
replaced patients who received the study treatment will be included in the general 
safety.
6.
STUDY ASSESSMENTS AND PROCEDURES
6.1
ELIGIBILITY ASSESSMENTS  
The patient will be allocated a patient number in the eCRF after signing the ICF and 
screening for eligibility begins. This patient number should be used on all future 
documentation and correspondence referring to this patient. During the screening 
period, the Investigator will assess the patient’s eligibility for inclusion in the study by 
conducting the assessments summarized below (Table 4).

Table 4. Screening period assessments.
ASSESSMENT
TIME
1. Written 
informed 
consents
(general and PGt 
sub-study)
The informed consent process involves an 
explanation and discussion with the patient 
including time for questions and answers, 
and culminates in signing and dating the 
consent form if the patient agrees. 
Document registration in the patient’s 
medical chart as well.
Sub-study participation is optional and 
requires a separate signed consent.-
Sequence 1 (TR) and Sequence 2 (RT):
Before any study-specific procedures.
2. Medical and 
cancer history/ 
clinical 
examination
Demographic data (race/ethnicity [if 
permitted], age, gender).
Primary diagnosis and prior 
treatment(s) (with best response, when 
available).
Medical and cancer history/baseline 
condition.
Complete physical examination, 
including weight, height and calculation of 
BSA (Appendix 4).
ECOG performance status (Appendix 1).
Vital signs: heart rate, blood pressure, 
and body temperature.
Sequence 1 (TR) and Sequence 2 (RT):
Within 14 days prior to day of 
registration. a
3. Laboratory tests
Hematology: Differential WBC 
(including neutrophils, monocytes and 
lymphocytes), erythrocytes, hemoglobin, 
hematocrit and platelets.
Biochemistry-A: AST, AP, ALT, lactate 
dehydrogenase (LDH), creatinine, glucose, 
creatine phosphokinase (CPK), CPK-MB 
fraction (if CPK is elevated above the 
normal range) and gamma 
glutamyltransferase (GGT) and total 
bilirubin (direct bilirubin if total bilirubin is 
above the ULN). 
Biochemistry-B: Serum electrolytes 
(Na+, K+, Mg++), total calcium, total 
proteins, albumin, CRP.
Coagulation: INR.
Calculated CLcr (Cockcroft-Gault 
formula) (Appendix 4). b
Sequence 1 (TR) and Sequence 2 (RT):
Within 14 days prior to day of 
registration. a
4.Detection of 
SARS-CoV-2 
(COVID-19)
PCR for SARS-CoV-2 (COVID-19) in 
nasopharyngeal/oropharyngeal swabs and 
nasal swabs.
Sequence 1 (TR) and Sequence 2 (RT):
Within 14 days prior to day of 
registration. a
5. Pregnancy test 
Assessment of β-hCG (serum) only if the 
patient is a WOCBP (Appendix 2). 
Sequence 1 (TR) and Sequence 2 (RT):
Within 14 days prior to day of 
registration. a
6. Cardiac 
assessment
ECG: Cardiac rhythm will be done in 
triplicate and identified in ECG intervals of
at least 30 seconds of duration, PR interval, 
QT interval (raw and corrected by HR using 
Bazett’s formula)
Sequence 1 (TR) and Sequence 2 (RT):
Within 14 days prior to day of 
registration. a
LVEF: ECHO or MUGA scan.
Sequence 1 (TR) and Sequence 2 (RT):
A previous LVEF assessment could be 
used if was made within 28 days prior to 
screening, if no previous assessment 
available; perform within 14 days prior to 
day of registration. a
7. Bosentan 
delivery and 
patient’s diary
-
Only in Sequence 1 (TR):
Day -6 with a -2/+1 day time window 
(i.e., from Day -8 to Day -5), but after the 
registration.

ASSESSMENT
TIME
8. Intercurrent 
events, 
concomitant 
disease and 
therapies
-
Sequence 1 (TR) and Sequence 2 (RT):
Within 14 days prior to day of
registration. a
9. Adverse events
Clinical assessment of the patient’s signs 
and symptoms. c
Only information on SAEs that occurred 
after signature of the informed consent is 
required before treatment start. Grading 
should be as per the NCI-CTCAE v.5.
Sequence 1 (TR) and Sequence 2 (RT):
Within 14 days prior to day of 
registration. a
Permitted windows for assessments before Day 1 of Cycle 1:
If physical examination, ECOG PS, vital signs, Hematology, Biochemistry-A, Biochemistry-B, CLcr ( provided 
only if serum creatinine levels are above ULN) and Coagulation were assessed >10 days before Day 1 of Cycle 1, 
the tests must be repeated the day before or the Day 1 (always prior to lurbinectedin infusion).
If pregnancy test was done >7 days before Day 1 of Cycle 1, the test must be repeated the day before or the Day 
1 (always prior to lurbinectedin infusion). 
A patient should only be treated if eligibility criteria are still met according to assessments performed closest to 
treatment start.
a Sequence 1 (TR)/ Sequence 2 (RT): day of registration, confirmation of eligibility.
b Calculated CLcr [Cockcroft and Gault’s formula] should be provided only if serum creatinine levels are above 
ULN.
c Signs and symptoms will be assessed by the Sponsor as all the events ongoing during the screening period, 
except for prior history conditions, which should be reported in the medical history form. Ongoing events during 
the screening period are those present at any time between the informed consent date and the first drug 
administration, regardless of if they may be resolved or not at the date of Cycle 1 Day 1.
ALT, alanine aminotransferase; AP, alkaline phosphatase; AST, aspartate aminotransferase; β-hCG, beta subunit 
of human chorionic gonadotropin; BSA, body surface area; CLcr, Creatinine clearance; CPK, creatine 
phosphokinase; CPK-MB, creatine phosphokinase-isoenzyme MB; CRP,
C-reactive protein; ECG, 
electrocardiogram; ECHO, echocardiogram; ECOG PS, Eastern Cooperative Oncology Group Performance 
Status; GGT, gamma glutamyltransferase; INR, International Normalized Ratio; LDH, lactate dehydrogenase; 
LVEF, left ventricular ejection fraction; MUGA, multiple-gated acquisition scan; NCI-CTCAE, National Cancer 
Institute-Common Terminology Criteria for Adverse Events;
PCR, polymerase chain reaction; PGt; 
pharmacogenetic; RT, reference-test; SAE, serious adverse event; SARS-CoV-2, severe acute respiratory 
syndrome coronavirus 2; TR, test-reference sequence; ULN, upper limit of normal; WBC, white blood cells; 
WOCBP, woman of childbearing potential.
6.2
PATIENT REGISTRATION
Eligibility will be checked before registration confirmed by the Sponsor. The patient 
will be a screening failure if not all inclusion criteria are met, if any exclusion criterion 
is met, or if the Sponsor does not approve registration. Regardless of circumstances, 
Investigators will not be allowed to treat any patient before appropriate receipt of the 
Sponsor’s agreement to proceed with registration. A patient should only be treated if 
eligibility criteria are still met according to assessments performed closest to first drug 
administration.
A patient who has been treated without the Sponsor’s agreement may not be considered 
evaluable for the primary endpoint of the study and may need to be replaced (although 
can continue in treatment provided this does not pose a risk to the patient until 
discontinuation for any other reason).
For patients included in the study (all registered patients) but never treated, only the 
applicable forms at baseline and off-study visit modules of the eCRF should be 
completed but serious adverse events (SAEs) occurring during screening period need to 
be reported (using paper SAE forms).

For screen failures (patients who started screening but were not finally registered), only 
the screening form of the eCRF should be completed but SAEs occurring during 
screening need to be reported (using paper SAE forms).
6.3
PATIENT RANDOMIZATION
This is an open-label study; therefore, blinding of treatment will not be performed.
Block randomization will be used to avoid bias in the assignment of patients to 
treatment sequence group, to increase the likelihood that known and unknown subject 
attributes (e.g., demographic and baseline characteristics) are evenly balanced across 
treatment sequence groups, and to enhance the validity of statistical comparisons across 
treatment sequence groups. Randomization will apply for all patients.
6.4
EVALUATIONS DURING TREATMENT
The following assessments will be done while patient is on treatment (Table 5). For a 
more graphic display, please refer to the table Schedule of Assessments and Procedures.
Table 5. Evaluations during treatment.
ASSESSMENT
TIME
1. Clinical 
examination
Complete physical examination, including 
weight and calculation of BSA. a
Sequence 1 (TR) and Sequence 2 (RT):
Day 1 of each cycle (always prior to 
lurbinectedin infusion).
Also repeat on Day 1 of Cycle 1 (prior to 
lurbinectedin infusion) if more than ten 
days have passed since the screening 
assessment.
Vital signs: heart rate, blood pressure and 
body temperature.
Sequence 1 (TR) and Sequence 2 (RT):
Day 1 of each cycle (always prior to 
lurbinectedin infusion), and Day 8 in 
Cycles 1 and 2.
Also repeat on Day 1 of Cycle 1 (prior to 
lurbinectedin infusion) if more than ten 
days have passed since the screening 
assessment.
ECOG performance status (Appendix 1).
Sequence 1 (TR) and Sequence 2 (RT):
Day 1 of each cycle (always prior to 
lurbinectedin infusion).
Also repeat on Day 1 of Cycle 1 (prior to 
lurbinectedin infusion) if more than ten 
days have passed since the screening 
assessment.
2. Laboratory tests b
Hematology: Differential WBC (including 
neutrophils, monocytes and lymphocytes), 
erythrocytes, hemoglobin, hematocrit and 
platelets.
Biochemistry A: AST, AP, ALT, lactate 
dehydrogenase (LDH), creatinine, glucose, 
creatine phosphokinase (CPK), CPK-MB 
fraction (if CPK is elevated above the normal 
range) and gamma glutamyltransferase (GGT) 
and total bilirubin (direct bilirubin if total 
bilirubin is above the ULN).
Sequence 1 (TR) and Sequence 2 (RT):
Cycle 1: Day 8 and Day 15. 
Also repeat on Day 1 of Cycle 1 (prior to 
lurbinectedin infusion) if more than ten 
days have passed since the screening 
assessment.
Cycle 2: Day 1, Day 8 and Day 15. 
Cycle 3: Day 1.
(always prior to lurbinectedin infusion). 
Biochemistry B:
Serum electrolytes (Na+, K+, Mg++), total 
calcium, total proteins, albumin, CRP.
Sequence 1 (TR) and Sequence 2 (RT):
Cycle 2 and Cycle 3: Day 1 of each cycle 
(always prior to lurbinectedin infusion). 
Also repeat on Day 1 of Cycle 1 (prior to 
lurbinectedin infusion) if more than ten 
days have passed since the screening 
assessment.

ASSESSMENT
TIME
Coagulation (INR):
Sequence 1 (TR) and Sequence 2 (RT):
Repeat on Day 1 of Cycle 1 (prior to 
lurbinectedin infusion) if more than ten 
days have passed since the screening 
assessment.
Also repeat if clinically indicated.
Calculated CLcr: Cockcroft and Gault´s 
formula (Appendix 4). c
Sequence 1 (TR) and Sequence 2 (RT):
Cycle 1: Day 8 and Day 15.
Also repeat on Day 1 of Cycle 1 (prior to 
lurbinectedin infusion) if more than ten 
days have passed since the screening 
assessment.
Cycle 2: Day 1, Day 8 and Day 15.
Cycle 3: Day 1.
(always prior to lurbinectedin infusion).
3. Pregnancy test
Only applicable to WOCBP. Assessment of 
β-hCG (in serum).
During the on-treatment period,
testing should be done be every cycle
(always prior to lurbinectedin infusion).
Also repeat on Day 1 of Cycle 1 (prior to 
lurbinectedin infusion) if more than seven 
days have passed since the screening 
assessment.
4. Pharmacokinetics
Cycle 1 and Cycle 2: Eleven blood samples 
each (before lurbinectedin infusion start, 5 min 
before end of lurbinectedin infusion and 30 
min, 1 hour, 2 hours, 4 hours, 6 hours, 24 
hours, 48 hours, 96 hours, 168 hours after the 
end of lurbinectedin infusion) will be collected 
for pharmacokinetic analyses (see details in 
Section 8.1.1).
Sequence 1 (TR) and Sequence 2 (RT):
Cycle 1 and Cycle 2.
PK sampling for bosentan will be done in 
Cycle 1 for patients assigned to Sequence 
1 (TR), and in Cycle 2 for assigned to 
Sequence 2 (RT).
See Table 9.
5. AAG and IL6 
collection
One blood sample per cycle.
Sequence 1 (TR) and Sequence 2 (RT):
On Day 1 of Cycle 1 and Cycle 2 (always 
prior to lurbinectedin infusion).
6. Pharmacogenetics
(only if written 
informed consent 
given) 
One blood sample.
Sequence 1 (TR) and Sequence 2 (RT):
At any time during the study, but 
preferably just before lurbinectedin  
infusion start in Cycle 1.
7. ECG
ECG should be done in triplicate and cardiac 
rhythm will be identified in ECG intervals of 
at least 30 seconds of duration, PR interval, 
QT interval (raw and corrected by HR using 
Bazett’s formula).
Sequence 1 (TR) and Sequence 2 (RT):
On Day 1 of Cycle 1 and Cycle 2, 5 
minutes before SOI (-25 to -1 min before 
preinfusion PK samples collection) and 1 
hour after EOI (-15 to -1 min before the 
PK sample collection).
8.  LVEF
LVEF measured by MUGA or ECHO.
Sequence 1 (TR) and Sequence 2 (RT):
Repeat if clinically indicated. 
9.  Bosentan 
delivery and 
patient’s diary
-
Sequence 2 (RT):
Day -6 of Cycle 2 with a -2/+1 day time 
window (i.e., from Day 14 of Cycle 1 to 
Day -5 of Cycle 2).
10. Contact to 
patients
The study center will contact the patients daily 
(via telephone or other methods) to remind 
them or confirm that they have taken the 
morning and evening dose of bosentan when 
they are not at the study center.
Sequence 1 (TR):
Day -5, -4, -3, -2 and -1 of Cycle 1.
Sequence 2 (RT):
Day -5, -4, -3, -2 and -1 of Cycle 2.
11. Intercurrent 
events, concomitant 
disease and 
therapies
-
Throughout the “on treatment” period. d
12. Adverse events
As per NCI-CTCAE v.5. e
Throughout the “on treatment” period. d
Registration = confirmation of eligibility and inclusion; Day 1 = the day of lurbinectedin administration (with 
infusion start) of cycle 1 or 2; Day 8 = seven days after the lurbinectedin administration of cycle 1 or 2 (±2 
days); Day 15 = fourteen days after the lurbinectedin administration of cycle 1 or 2 (±2 days).

ASSESSMENT
TIME
Permitted windows for assessments before Day 1 of Cycle 1:
If physical examination, ECOG PS, vital signs, Hematology, Biochemistry-A, Biochemistry-B, CLcr (provided only 
if serum creatinine levels are above ULN) and Coagulation were assessed >10 days before Day 1 of Cycle 1, the tests 
must be repeated the day before or the Day 1 (always prior to lurbinectedin infusion).
If pregnancy test was done >7 days before Day 1 of Cycle 1, the test must be repeated the day before or the Day 1 
(always prior to lurbinectedin infusion). 
A patient should only be treated if eligibility criteria are still met according to assessments performed closest to 
treatment start.
Permitted windows for assessments after Day 1 of Cycle 1:
A ± 2-day time window will be allowed for Hematology, Biochemistry-A and CLcr (provided only if serum 
creatinine levels are above ULN) on Day 8 and Day 15, and for vital signs on Day 8 of Cycle 1.
A -1 day window will be allowed for physical examination, ECOG PS, vital signs, Hematology, Biochemistry-A, 
Biochemistry-B, CLcr (provided only if serum creatinine levels are above ULN) and Pregnancy test on Day 1 of 
Cycle 2 and further cycles (always prior to lurbinectedin infusion).
A + 2 days window for Day 1 lurbinectedin administration of Cycle 3.
If a drug administration is delayed beyond the permitted protocol window, assessments planned for the original 
administration day must be repeated on the day the dose is finally administered.
a BSA calculated according to DuBois formula (see Appendix 4).
b Any patient having any grade ≥ 3 laboratory abnormalities and/or treatment-related AEs is suggested to have the 
relevant tests re-assessed at intervals of at least 72 hours but not more than one week (for patients allocated to 
Sequence 1) or at least every 48-72 hours (for patients allocated to Sequence 2) until recovery to at least grade 2 has 
been documented.
c Calculated CLcr [Cockcroft and Gault’s formula] should be provided only if serum creatinine levels are above 
ULN.
d “On treatment period” = from first administration of the study treatment (bosentan or lurbinectedin) to the last 
lurbinectedin administration (and maximum of three cycles) plus 31 days (EOT).  Follow-up period will be extended 
every four weeks until recovery to at least grade 1 or stabilization of all treatment-emergent AEs, or until the start of 
a new antitumor therapy, until the continuation of treatment outside this study under a Compassionate Use Agreement 
or death, whichever occurs first.
e The “AE form” will be used only for events that occur after the first drug infusion or any event related to a study 
procedure within the study period (according to ICH guidelines); and to report ‘ongoing’ baseline conditions in case 
of any significant change (improvement or worsening) during the study.
AAG, alpha 1-acid glycoprotein; AEs, adverse events; ALT, alanine aminotransferase; AP, alkaline phosphatase; 
AST, aspartate aminotransferase; BSA, body surface area; CLcr, creatinine clearance; CPK, creatine phosphokinase; 
CPK-MB, creatine phosphokinase-isoenzyme MB; CRP, C-reactive protein; ECG, electrocardiogram; ECHO, 
echocardiogram; EOI, end of infusion; EOT, end of treatment; GGT, gamma glutamyltransferase; ICH, International 
Conference on Harmonization; IL-6, interleukin 6; INR, International Normalized Ratio; LDH, lactate 
dehydrogenase; LVEF, left ventricular ejection fraction; MUGA, multiple-gated acquisition scan; NCI-CTCAE, 
National Cancer Institute-Common Terminology Criteria for Adverse Events; PK, pharmacokinetics; RT, reference-
test; SOI, start of infusion; TR, test-reference sequence; ULN, upper limit of normal; WBC, white blood cells; 
WOCBP, woman/women of childbearing potential.
6.5
EVALUATIONS AT THE END OF TREATMENT
The end-of-treatment (EOT) visit will be scheduled within 31 days (±10 days) after 
administration of the last dose of lurbinectedin, unless the patient starts a subsequent 
antitumor therapy, in which case the end-of-treatment visit should be performed 
immediately before the start of the new therapy (ideally the day before or the same day).
Patients who meet the continuation criteria and obtain a clear clinical benefit with 
lurbinectedin after the completion of the first two study cycles, may continue treatment 
outside this study under a Compassionate Use Agreement after the completion of the 
optional third study cycle. Should the patient continue under a Compassionate Use 
Agreement, the treating center must request authorization to the relevant Health 
Authorities and notify the Sponsor in due time. Patients, regardless of the reason for 
ending the treatment, will have to undergo at the end of treatment the following 
assessments:


Complete physical examination (BSA and height not needed).

ECOG PS.

Laboratory tests (hematology and biochemistry A and B, and Calculated CLcr).
Calculated CLcr [Cockcroft and Gault’s formula] should be provided only if 
serum creatinine levels are above ULN.

Coagulation (INR) will be repeated only if clinically indicated.

ECG (in triplicate) and LVEF assessment.

Adverse Events.

Intercurrent events, concomitant disease and therapies.

Pregnancy test in WOCBP.
Adverse events must be reported for 31 days after the last study treatment 
administration. All serious adverse events (SAEs) occurring within 31 days of the last 
study treatment administration or until the start of a new antitumor therapy, until the 
continuation of treatment outside this study under a Compassionate Use Agreement or 
death, whichever occurs first, will be reported. Beyond this period of time, only those 
suspected to be treatment-related SAEs will be reported (Section 8.5.2).
The Sponsor will evaluate all safety information that is spontaneously reported by an 
Investigator beyond the time frame specified in the protocol.
6.6
FOLLOW-UP AFTER END-OF-TREATMENT VISIT
After EOT, patients with treatment-related toxicities > grade 2 will be followed  every 
four weeks until recovery to at least grade 1 or stabilization of all treatment-emergent 
AEs, or until the start of a new antitumor therapy, until the continuation of treatment 
outside this study under a Compassionate Use Agreement or death, whichever occurs 
first. 
7.
TREATMENT
7.1
DESCRIPTION OF TREATMENT
All patients will receive two consecutive cycles of lurbinectedin, one cycle with and 
one cycle without bosentan co-administration (in different order depending on the 
study sequence of treatment), followed by a third cycle with lurbinectedin alone (this 
last cycle optional for patients with clinical benefit).
7.1.1 Drug Formulation and Supply
Bosentan
Commercially available bosentan film-coated tablets (with strengths of 125 mg) will be 
provided by the Sponsor.
Lurbinectedin
Lurbinectedin 4 mg drug product (DP) is presented as a lyophilized powder for 
concentrate for solution for infusion in 30 mL vials and will be supplied by the 
Sponsor for the purposes of this study.
Before use, the 4 mg DP should be reconstituted with 8 mL of water for injection to 
give a solution containing 0.5 mg/mL of lurbinectedin. For administration to patients 

as an i.v. infusion, reconstituted vials should be diluted with either glucose 50 mg/mL 
(5%) or sodium chloride 9 mg/mL (0.9%) solution for infusion.
The full composition of the lurbinectedin 4 mg DP and the reconstituted solution per 
mL is shown below:
Table 6. Composition of lurbinectedin Drug Product reconstituted solution.
Component
Concentration/vial
Concentration/vial 
after reconstitution
Lurbinectedin
4.0 mg
0.5 mg/mL
Sucrose
800 mg
100 mg/mL
Lactic acid
22.08 mg
2.76 mg/mL
Sodium hydroxide
5.12 mg
0.64 mg/mL
For detailed instructions on the reconstitution and dilution, refer to the latest 
lurbinectedin IB and the “Preparation Guide for Infusion” document.
7.1.2 Storage Conditions
Bosentan
Bosentan film-coated tablets should be stored following the instructions described in 
the SmPC.
Lurbinectedin 
Until more information is available from ongoing stability studies, lurbinectedin DP 4 
mg should be stored at +5º ± 3ºC.
7.2
ADMINISTRATION OF THE STUDY MEDICATION
Bosentan
Bosentan will be administered orally twice daily as 125 mg film-coated tablets.
In the co-administration cycles, bosentan will be administered orally twice daily in the 
morning and in the evening from Day -5 to Day -1 (i.e., five days before lurbinectedin 
infusion), and once daily on Day 1 (i.e., the day of lurbinectedin infusion), following 
recommendations at the Summary of Product Characteristics (SmPC). On Day 1 (i.e., 
day of lurbinectedin infusion), bosentan will be given immediately prior to the start of 
the lurbinectedin infusion. In fact, bosentan should be administered after obtaining the 
bosentan PK sample #1 and before the start of lurbinectedin infusion (-15 min to -1 
min). In case of lurbinectedin delay (≤2 days), bosentan could be administered twice 
daily during a maximum of seven consecutive days before lurbinectedin infusion, and 
supplied at the study center once daily on Day 1 (before lurbinectedin infusion).
In Sequence 1 (TR), bosentan for self-administration and the patient’s diary should be 
given to the patient on Day -6 with a -2/+1 day time window (i.e., from Day -8 to Day -
5). In Sequence 2 (RT), bosentan and the patient’s diary should be given to the patient 
on Day -6 of Cycle 2 with a -2/+1 day time window (i.e., from Day 14 of Cycle 1 to 
Day -5 of Cycle 2). 
In addition, the study center will contact the patients (via telephone or other methods) 
daily during bosentan intake to remind them or confirm that they have taken the 
morning and evening dose of bosentan when they are not at the study center.

Lurbinectedin 
Lurbinectedin will be administered as a 1-hour (-5/+20 min) i.v. infusion on Day 1 
q3wk, over a minimum of 100 mL dilution on 5% glucose or 0.9% sodium chloride via 
a central line (or a minimum of 250 mL dilution if a peripheral line is used).
Patients will receive a maximum of three cycles: two consecutive cycles of 
lurbinectedin, one cycle with and one cycle without bosentan co-administration (in 
different order depending on the Sequence 1 or Sequence 2 of treatment), followed by 
a third cycle with lurbinectedin alone (this last cycle optional for patients with clinical 
benefit).
The dose of lurbinectedin when given in combination with bosentan will be 3.2 mg/m². 
Lurbinectedin dose will be based on the acceptability of the PK and safety results from 
the first three patients.
In cycles with lurbinectedin as single agent, lurbinectedin will we administered at 3.2 
mg/m2.
7.3
PROPHYLACTIC MEDICATION
All patients will receive standard antiemetic prophylaxis before each treatment infusion 
(i.e., 30 ± 5 minutes before lurbinectedin administration), i.v. as follows:

Corticosteroids i.v. (according to institutional standard antiemetic doses, 
minimum dose of dexamethasone 8 mg/day and maximum dose of 20 mg/day 
of dexamethasone or equivalent). If feasible, the medication and dose 
administered in Cycle 1 should be maintained in Cycle 2.

Serotonin (5-HT3) antagonists (ondansetron at least 8 mg i.v. and no more than 
16 mg of ondansetron).
If necessary, in addition to the above, the duration of treatment with 5-HT3 antagonists 
and/or dexamethasone could be extended orally (if needed) (i.e., 4-8 mg/day for three 
consecutive days) and/or 10 mg of metoclopramide orally every eight hours could be 
added (according to institutional guidelines). 
For the purpose of safety evaluations, optimum prophylaxis is defined as all the 
aforementioned medications at their respective maximum dose.
Aprepitant or any other NK-1 antagonist or related Substance P-antagonists 
(except rolapitant) are forbidden while on lurbinectedin treatment.
7.4
CRITERIA FOR TREATMENT CONTINUATION 
Patients may continue treatment with lurbinectedin as long as no unacceptable toxicity 
and/or PD occurred, and for a maximum of three cycles. Thereafter, treatment with 
lurbinectedin can continue under a Compassionate Use Agreement.

Patients assigned to Sequence 1 (TR) (lurbinectedin + bosentan in Cycle 1), 
after Cycle 1 the administration of a new cycle should be delayed if the criteria 
in Table 7 are not met on the corresponding Day 1. Re-assessments will be 
performed periodically at intervals of at least 72 hours but not more than one 
week. Lurbinectedin administration should be delayed until recovery of these 
parameters. A maximum delay of 14 days from the theoretical due date will be 
allowed for recovery from treatment-related AEs. If recovery has not occurred 

after that period, the patient should discontinue the treatment, except in case of 
obvious patient benefit at the criteria of the Investigator and upon agreement 
with the Sponsor.

Patients assigned to Sequence 2 (RT) (lurbinectedin + bosentan in Cycle 2), 
criteria for treatment continuation should be investigated on Day 15 of Cycle 1 
in order to confirm bosentan administration start on Day -5 of Cycle 2, assuring 
that the continuation criteria will be finally met on Day 1 of Cycle 2 
assessment. In case of detected abnormalities on Day 15 in sequence RT, these 
assessments should be repeated every 48-72 hours until recovery to retreatment 
criteria. Initiation of bosentan will be delayed for a maximum of 14 days to 
ensure that pre-treatment with bosentan is fulfilled. If recovery has not 
occurred after that period, the patient should discontinue the treatment, except 
in case of obvious patient benefit at the criteria of the Investigator and upon 
agreement with the Sponsor.
Re-treatment criteria for lurbinectedin administration should be met on Day 1 
of Cycle 2. If they were not met, treatment will be delayed for a maximum of 2 
days to evaluate continuation of lurbinectedin administration, with re-treatment 
criteria being checked every 24 hours. During this time the patient will 
continue receiving bosentan. If after 2 days of delay the patient does not meet 
the criteria for treatment continuation, bosentan will be stopped and the patient 
will be considered not evaluable for the trial.
If the criteria for treatment continuation are not met as described above, treatment must
be discontinued and the EOT visit performed.
Table 7. Criteria for lurbinectedin treatment continuation.
Variable
Lurbinectedin (Day 1) 
ECOG PS
≤ 1
ANC
1.5 x 109/L
Platelets
100 x 109/L
Hemoglobin a
8.0 g/dL
Total bilirubin
≤ 1.0 x ULN. If it is > 1.0 x ULN but ≤ 1.5 x ULN, direct 
bilirubin must be ≤ 1.0 x ULN
Albumin
3.0 g/dL
AST/ALT
3.0 x ULN
CPK
≤ 2.5 x ULN (≤ 5.0 x ULN is acceptable if elevation is 
disease-related)
Serum Creatinine levels/ Calculated 
CLcr (Cockcroft and Gault’s formula)
Serum creatinine levels ≤ ULN or calculated CLcr ≥ 30 
mL/min, if abnormal (>ULN) serum creatinine levels
Other non-hematological drug-related 
AEs (except isolated increased GGT 
and/or AP; or grade 2 alopecia, asthenia,
peripheral neuropathy and non-optimally 
treated nausea and/or vomiting) 
Grade ≤ 1
a Patients may receive PRBC transfusions and/or EPO treatment if clinically indicated to increase/maintain adequate 
hemoglobin levels.
Sequence 1 (TR):
If a patient does not meet the requirements for treatment continuation on Day 1 of further cycles, treatment will be 
withheld until recovery for a maximum of 14 days after the theoretical treatment date. If recovery has not occurred 
after a delay of > 14 days, discontinue treatment (except in case of obvious patient benefit at the criteria of the 
Investigator and upon agreement with the Sponsor).

Variable
Lurbinectedin (Day 1) 
Sequence 2 (RT):
If a patient does not meet the requirements for treatment continuation on Day 15 of Cycle 1, treatment with bosentan 
will be withheld until recovery for a maximum of 14 days after the theoretical treatment date. If recovery has not 
occurred after a delay of > 14 days, discontinue treatment (except in case of obvious patient benefit at the criteria of 
the Investigator and upon agreement with the Sponsor).
If a patient does not meet the requirements for treatment continuation on Day 1 of Cycle 2, treatment with 
lurbinectedin will be withheld until recovery for a maximum of 2 days after the theoretical treatment date. During this 
time, the patient will continue receiving bosentan. If recovery has not occurred after a delay of > 2 days, bosentan 
will be stopped and the patient will be considered not evaluable for the trial.
AEs, adverse events; ALT, alanine aminotransferase; ANC, absolute neutrophil count; AP, alkaline phosphatase; 
AST, aspartate aminotransferase; CLcr, creatinine clearance; CPK, creatine phosphokinase;  ECOG PS, Eastern 
Cooperative Oncology Group Performance Status; EPO, erythropoietin; GGT, gamma glutamyltransferase; PRBC, 
packed red blood cells; UULN, upper limit of normal.
7.5
DOSE REDUCTION
Patients may continue in the study treatment at a lurbinectedin reduced dose if they 
present any of the following:

Grade 4 thrombocytopenia or grade 3 thrombocytopenia concomitantly with grade ≥
3 bleeding. 

Two dose delays or prolonged (> one week) dose delay due to treatment-related 
adverse events.

Grade ≥3 treatment related non-hematological toxicity. Exceptions are: grade ≥3 
nausea and/or vomiting not optimally treated, grade 3 fatigue lasting < two days, 
grade 3 diarrhea lasting < one day or non-optimally treated, isolated grade 3 
transient ALT/AST elevations which are rapidly reversible and not leading to 
subsequent delays and, non-clinically relevant isolated biochemical abnormalities.

Grade 4 neutropenia or any grade febrile neutropenia. 
Up to two dose reductions are allowed per patient. Patients who continue to experience 
treatment-related toxicity and/or dose delays after two dose reductions must be 
withdrawn from the study. Once the dose has been reduced for an individual patient, it 
will not be re-escalated under any circumstances.
Lurbinectedin dose reduction levels are shown in Table 8.
Table 8. Levels of (intra-patient) lurbinectedin dose reduction in subsequent cycles.
Dose reduction 
Lurbinectedin (q3wk)
(mg/m2)
Lurbinectedin alone
Bosentan co-administration cycle
1 (starting dose)
3.2
3.2
-1
2.6
2.6
-2
2.0
-
Lurbinectedin total doses in mg will be rounded to the first decimal, if necessary.
 q3wk, every three weeks.
Patients who experience any treatment-related grade 3/4 hypersensitivity and/or 
extravasation reactions will permanently discontinue treatment.
7.6
CONCOMITANT MEDICATION
All treatments received by the patient during the on-treatment period of the trial must be 
documented in the eCRF.

7.6.1 Allowed Medications/Therapies

Therapies for pre-existing and treatment-emergent medical conditions, 
including pain management and local management of mucositis/stomatitis.

Blood products and transfusions, as clinically indicated.

Bisphosphonates.

In case of nausea or vomiting, extended symptomatic treatment for emesis will 
be allowed (with the exception of aprepitant equivalent agents).

Erythropoietin treatment according to the ASCO guidelines.

Low-molecular weight heparin (LMWH) and/or any other anticoagulants, as 
clinically indicated. Oral anticoagulants must be carefully monitored.

Treatment or secondary prophylaxis with G-CSF according to ASCO 
guidelines.

CNS irradiation if required, and/or limited field bone radiotherapy for pain 
control outside the thoracic wall.

Megestrol acetate for wasting syndrome.

Contraceptives.
7.6.2 Prohibited Medications/Therapies

Concomitant administration of any other antineoplastic therapy. 

Any other investigational agents.

Immunosuppressive therapies other than corticosteroids for antiemetic 
prophylaxis, pain control, or low-dose replacement in patients requiring this 
approach. 

Aprepitant or any other NK-1 antagonist or related Substance P-antagonists 
(except rolapitant).

Primary G-CSF prophylaxis.

CYP3A4 inhibitors such as ketoconazole, fluconazole, voriconazole, 
telithromycin, clarithromycin, erythromycin, nafcillin, aprepitant, fosaprepitant, 
verapamil, modafinil, nefazodone, or grapefruit juice.

CYP3A enzyme inducers and/or inhibitors (unless strictly necessary and when 
there is no therapeutic alternative treatments) (see Appendix 3).

Use of any prescription or non-prescription herbal and/or dietary supplements 
within 14 days prior to the first dose of study medication and until 31 days after 
the last administration of lurbinectedin, unless the Investigators, with the 
Sponsor agreement, consider it will not interfere with study procedures of 
patient safety.
7.6.3 Drug-Drug Interactions
In vitro studies with human microsomes have shown that CYP3A4 is the major CYP 
isoform involved in the metabolism of lurbinectedin. The estimated contribution of the 
other CYP isoenzymes to the lurbinectedin metabolism is considered to be negligible. 

Therefore, concomitant drugs which induce or inhibit any of these cytochromes, 
especially CYP3A4, should be carefully monitored or avoided, whenever is possible.
A potentially significant interaction with aprepitant is suggested by available phase II 
data from ovarian cancer patients and phase I data from a combination trial with 
lurbinectedin and cisplatin (PM1183-A-008-13). Lurbinectedin clearance was reduced 
by around 30%, approximately, in the presence of aprepitant. Although all patients 
eventually recovered, the use of aprepitant is currently forbidden in all phase II/III 
lurbinectedin studies.
7.7
DRUG ACCOUNTABILITY
The Investigator at each study site (or center) will be the person ultimately responsible 
for drug accountability at the site. The Investigator site will appoint the designee as 
product storage manager and delegate the control of and accountability for the trial 
drugs to him/her. After receipt of the investigational product, he/she will keep records to 
allow a comparison of quantities of drug received and used at each site for monitoring 
purposes.
The investigator or designated study personnel will maintain a log of all bosentan drug 
dispensed and returned. Drug supplies for each subject will be inventoried and 
accounted for throughout the study.
All unused drug supplied by the Sponsor will be properly destroyed at the study site. 
Documentation of this procedure must be provided to the Sponsor (or its designee). If 
the Sponsor (or its designee) agrees, unused drug supplies may be returned to the drug 
repository.
7.8
TREATMENT COMPLIANCE
Lurbinectedin will be administered as an i.v. infusion by qualified staff. The morning 
and evening doses of bosentan should be administered following the SmPC 
specifications. Patients will self-administer the morning and evening daily doses of 
bosentan when not at the study center. The study center will contact the patients (via 
telephone or other methods) to remind them or confirm that they have taken the 
morning and evening dose of bosentan when they are not at the study center. When the 
subject is at the study center, the administration of bosentan is to be supervised and 
documented by the staff. Patients will be requested to keep records of bosentan when 
administered at home. The patients will be given a diary to record the dates and times 
when bosentan was administered at home. Diaries will be reviewed at each study visit 
and recorded in the source data system. The compliance of bosentan will be confirmed 
based on a patient’s diary, the drug accountability and the expected individual plasma 
concentration at the steady state.
8.
STUDY EVALUATIONS
8.1
PHARMACOKINETIC EVALUATIONS
8.1.1 Pharmacokinetic Sample Collection and Handling
Serial peripheral venous blood samples for determination of lurbinectedin (total and 
unbound), lurbinectedin metabolites (i.e., M1 and M4)
and bosentan plasma 

concentrations will be collected at the time points indicated in Table 9 and also in the
Schedule of Assessments and Procedures. The exact dates and times of blood sample 
collection must be recorded in the eCRF.
PK sampling for lurbinectedin will be done always in Cycle 1 and Cycle 2 with a 
schedule of eleven samples in all patients. PK sampling for bosentan will be done in 
Cycle 1 of Sequence 1 (TR), and in Cycle 2 of Sequence 2 (RT) with a schedule of four 
samples in all patients (Table 9).
Plasma samples for PK analysis of lurbinectedin and bosentan will be obtained through 
a peripheral vein located in the contra-lateral side to that of the administration of 
lurbinectedin. In any case, the sampling vein has to be different to that in which drugs 
are being administered. Even the last sample must never be collected from the catheter 
used for the drug administration. 
If the blood sample is obtained from a catheter, the first milliliter (mL) of blood will be 
discarded to avoid the dilution of the sample with the solution used to keep it clean. 
Heparin (10 U/mL in normal saline solution) or a slow drip of normal saline solution 
(10 mL/h) can be used to keep the catheter permeable between extractions.
The laboratory manual provides further information regarding handling and shipment of 
plasma samples. Samples will be stored at –80 (±10) ºC. 
Table 9. Lurbinectedin and bosentan blood sampling schedule and aliquot collection.
Sample 
No.
Day
Time (h)c
Sampling Time d
Lurbinectedin  
Bosentane
Time window
Total
Unbound (fu)
Metabolites
#1 a, b
1
0
Preinfusion f
●
●
●
●
-15 to -1 min 
before SOI g
#2
1
0.917 
5 min before EOI
●
●
●
-
±4 min
#3
1
1.5
30 min after EOI
●
-
●
-
± 5 min
#4
1
2
1 h after EOI
●
-
●
●
± 10 min
#5
1
3
2 h after EOI
●
-
●
-
± 10 min
#6
1
5
4 h after EOI
●
-
●
●
± 30 min
#7
1
7
6 h after EOI
●
-
●
-
± 30 min
#8
2
25
24 h after EOI
●
-
●
●
±2 h
#9
3
49
48 h after EOI
●
-
-
-
±2 h
#10
5
97
96 h after EOI
●
-
-
-
±24 h
#11
8
169
168 h after EOI
●
-
-
-
±48 h h
a Additional sample for AAG and IL-6.
b Additional sample for PGt, once only, if written IC given.
c Time relative to infusion start.
d Time relative to lurbinectedin end of infusion (except PK #1).
e Sampling for bosentan only applies in cycle with bosentan co-administration.
f 5 min before start of infusion.
g Bosentan should be administered after bosentan PK sample #1 and before the start of lurbinectedin infusion (-15 min to -1 min).
h If the scheduled sampling time for this sample should be modified within the allowed time window, there must be a difference of 
at least 20 hours between the collection times of samples PK#10 and PK#11.
AAG, alpha 1-acid glycoprotein; EOI, end of infusion; fu, unbound fraction; h, hour; IC, informed consent; IL-6, Interleukin 6; EOI, 
end of infusion; min, minute; PGt, pharmacogenetic; PK, pharmacokinetic; SOI, start of infusion.
8.1.2 Analytical Procedures
HPLC-MS/MS determinations of total, unbound plasma concentrations of lurbinectedin 
and total plasma concentration of its main metabolites (i.e., M1 and M4) will be 
performed using validated assays. 
A validated bioanalytical method will be used to measure the bosentan plasma 
concentrations.

8.1.3 Pharmacokinetic Parameters
The time course of metabolite concentration –relative to parent drug, and if possible, 
absolute– will be elucidated up to the maximum possible extent, to obtain the best 
available estimate for metabolite exposure. 
Total and unbound plasma concentration time course of the lurbinectedin and its main 
metabolites will be analyzed by standard non-compartmental methods. Bosentan total 
plasma concentration time course also will be analyzed by standard non-compartmental 
methods. The area under the concentration-time curve (AUC) will be calculated using 
the linear-log trapezoidal rule with extrapolation to infinity. The maximum plasma 
concentration (Cmax) will be obtained directly from the experimental data. Terminal 
half-life (T1/2) will be obtained from the terminal rate constant calculated by linear 
regression using at least 3 observations. Other parameters will be calculated including: 
Mean residence time extrapolated to infinity (MRT) corrected by the infusion time. 
It is calculated by dividing the area under the moment curve extrapolated to infinity by 
the area under the curve extrapolated to infinity and subtracting half the duration of drug 
infusion.
Total body clearance (CL), calculated by dividing the administered dose by the AUC 
with extrapolation to infinity.
Volume of distribution (both at steady state and based on the terminal phase) (Vss and 
Vz, respectively): Vss is an estimate that equals mean residence time times total body 
clearance. Vz, calculated dividing the administered dose by the product of the AUC with 
extrapolation to infinity by the terminal rate constant.
The same analysis will be applied to the metabolites for which the obtained 
experimental data allow it. The potential relevance of the identified metabolites will be 
explored by additional preclinical experiments that will be decided on the basis of the 
results and, if possible, by opportunistic observations based on the study data. 
8.2
PHARMACOGENETICS
Patients will be evaluable for pharmacogenetics if they have signed the ICF and a valid 
9-mL blood sample will be taken for genetic analysis at any time during the study, but 
preferably before infusion start along with PK sample #1 on Day 1 of Cycle 1. 
A genotype evaluation in genes relevant for lurbinectedin metabolism and transport will 
be investigated and reported in an independent report in order to determine whether the 
observed differences between patients in PK parameters are related to these genetic 
features.
8.3
SAFETY
Patients will be evaluable for safety if they have received at least part of one 
lurbinectedin infusion. AEs will be graded according to the NCI-CTCAE v. 5.
Treatment compliance, i.e., dose delays, dose reductions and reasons for treatment 
discontinuation, will be monitored throughout the study. 
The safety profile of patients will be monitored throughout the treatment and up to 31 
days (±10 days) after the last treatment infusion (EOT), or until the patient starts a new 
antitumor therapy, until the continuation of treatment outside this study under a 
Compassionate Use Agreement or until the date of death, whichever occurs first.

Any treatment-emergent AEs will be followed until recovery to at least grade 1 or 
stabilization of symptoms or until the start of a new antitumor therapy, until the 
continuation of treatment outside this study under a Compassionate Use Agreement or 
death, whichever occurs first. After treatment discontinuation, patients will be followed 
until resolution or stabilization of all toxicities, if any. Patients having any treatment-
related grade ≥ 3 AEs should have relevant tests re-assessed at intervals of at least 72 
hours but not more than one week (for patients allocated to Sequence 1) or at least every 
48-72 hours (for patients allocated to Sequence 2) until recovery to at least grade 2.
8.4
ADVERSE EVENT DEFINITIONS
8.4.1 Adverse Event
An AE is any untoward medical occurrence in a patient or clinical investigation patient 
administered a pharmaceutical product which does not necessarily have a causal 
relationship with this treatment. 
An AE can therefore be any unfavorable and unintended sign, (e.g., an abnormal 
laboratory finding), or a disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product.
Illnesses with onset during the study or exacerbations of pre-existing illnesses, including
but not limited to clinically significant changes in physical examination findings and 
abnormal objective tests/procedures findings (e.g., X-ray, ECG) should be recorded. 
The criteria for determining whether an abnormal objective test finding should be 
reported as an AE are as follows:

The test result is associated with clinically significant symptoms, and/or

The test result leads to a change in the study dosing or discontinuation from the 
clinical trial, significant additional concomitant drug treatment or other therapy, 
and/or

The test result leads to any of the outcomes included in the definition of a SAE 
(see definition below), and/or

The test result is considered to be clinically relevant by the Investigator.
For the purpose of this protocol, PD or worsening of the underlying malignancy should 
not be reported as AEs.
8.4.2 Serious Adverse Event 
A SAE is defined as any adverse experience occurring at any dose that:

results in death (is fatal),

is life-threatening,

requires or prolongs inpatient hospitalization,

results in persistent or significant disability or incapacity,

is a congenital anomaly or birth defect, or

is medically significant.

Any suspected transmission via a medicinal product of an infectious agent.

Medical and scientific judgment should be exercised in deciding whether expedited 
reporting is appropriate in other situations, such as an important medical event that may 
not be immediately life-threatening or result in hospitalization but may jeopardize the 
patient or may require intervention to prevent one of the outcomes listed in the above 
definition.
Tumor progression (including associated signs and symptoms) or appearance of new 
tumor lesions cannot be reported as a SAE.
8.4.3 Death
Death as such is the outcome of a SAE and should not be used as the SAE term itself. 
The cause of death should be recorded as the SAE term instead. When available, the 
autopsy report will be provided to the Sponsor.
8.4.4 Life Threatening Event
A life threatening event is defined as any event in which the subject is at risk of death at 
the time of the event; it does not refer to an event which hypothetically might have 
caused death if it were more severe.
8.4.5 Hospitalization/Prolongation of Hospitalization
Any event requiring hospitalization (or prolongation of hospitalization) that occurs or 
worsens during the course of a patient’s participation in a clinical study must be 
reported as a SAE unless exempted from SAE reporting. Prolongation of hospitalization 
is defined as any extension of an inpatient hospitalization beyond the stay 
anticipated/required for the initial admission, as determined by the Investigator or 
treating physician.
Hospitalizations that do not meet criteria for SAE reporting are: 

Reasons described in the protocol (e.g., investigational medicinal product 
[IMP] administration, protocol-required investigations). However, events 
requiring hospitalization or prolongation of hospitalization as a result of a 
complication of therapy administration or clinical study procedure will be 
reported as a SAE.

Hospitalization or prolonged hospitalization for technical, practical or social 
reasons, in the absence of an AE. 

Pre-planned hospitalizations: Any pre-planned surgery or procedure must be 
documented in the source documentation. Only if the pre-planned surgery 
needs to be performed earlier due to a worsening of the condition, should this 
event (worsened condition) be reported as a SAE.
Other situations that MUST NOT be considered as hospitalizations are:

An emergency visit due to an accident where the patient is treated and 
discharged.

When the patient is held 24 h for observation and is finally not admitted.

Planned treatments at sites not associated to a hospital and generally considered 
as minor surgical procedures (i.e. laser eye surgery, arthroscopy, etc…).

8.4.6 Unexpected/Unlisted Adverse Event
An AE is considered unexpected/unlisted when the nature or severity of which is not 
consistent with the applicable reference safety information. The Sponsor will use as the 
reference safety information (RSI) for the evaluation of listedness/expectedness the RSI 
of the most updated IB for lurbinectedin, and the SmPC for commercially-available 
bosentan.
8.4.7 Adverse Reaction
All untoward and unintended response to an IMP related to any dose administered. This 
definition also covers medication errors and uses outside what is foreseen in the 
protocol, including overdose, misuse and abuse of the product. 
8.4.8 Adverse Events Related to the Study Drug
An AE is considered related to a study drug/IMP if the Investigator and/or the Sponsor’s
assessment of causal relationship to the IMP(s) is “Y (yes)” (see Section 8.4.10). The 
Investigator will assess the causal relationship of the IMP(s) to the SAE. The Sponsor 
will consider related to the study drug(s)/IMP(s) those events for which the Investigator 
and/or the Sponsor assesses the causal relationship with the IMP(s) as “Uk (unknown)” 
when it cannot rule out a role of the IMP(s) in the event.
8.4.9 Expedited Reporting
The Sponsor is responsible for appropriate expedited reporting to the Competent 
Authorities, the Investigators and the IEC according to current legislation.
8.4.10 Assessment of Causal Relationship to the Study Drug
The Investigator must provide an assessment of causality for the IMP according to the 
following criteria:

Y (yes): there is a reasonable possibility that the IMP(s) caused the SAE.

N (not): there is NO a reasonable possibility that the IMP(s) caused the SAE 
and other causes are more probable.

UK (Unknown): only to be used in special situations where the Investigator has 
insufficient information (i.e., the patient was not seen at his/her center). If none 
of the above can be used. 
8.5
ADVERSE EVENT REPORTING PROCEDURES
8.5.1 Reporting of Adverse Events
The Sponsor will collect AEs until 31-day (±10 days) after administration of the last 
dose of lurbinectedin or until the start of a new antitumor therapy, until the continuation 
of treatment outside this study under a Compassionate Use Agreement or until the date 
of death, whichever occurs first. All AEs suspected to be related to the study 
drug(s)/IMP(s) must be followed-up after the time of therapy discontinuation until the 
event or its sequelae resolve or stabilize at an acceptable level to the Investigator and 
the Sponsor.
All AEs, including medication errors and uses outside what is foreseen in the protocol, 
must be recorded in English using medical terminology in the source document and the 

eCRF. Whenever possible, the Investigator will record the main diagnosis instead of the 
signs and symptoms normally included in the diagnoses. 
Investigators must assess severity (grade) of the event following the NCI-CTCAE v.5 
and assign a relationship to each study drug(s)/IMP(s); and pursue and obtain 
information adequate both to determine the outcome and to assess whether it meets the 
criteria for classification as a SAE requiring immediate notification to the Sponsor or its 
designated representative. The Investigator must provide any relevant information as 
requested by the Sponsor in addition to that on the eCRF.
Abnormal laboratory tests occurring during the study must only be recorded in the AE 
section of the eCRF if the disorder:

Is associated with clinically significant symptoms, and/or

Leads to a change in study dosing (omission, delay or reduction) or discontinuation 
from the study, significant additional concomitant drug treatment or other therapy, 
and/or

Leads to any of the outcomes included in the definition of a SAE.
Otherwise, laboratory results should be reported in the corresponding section of the 
eCRF (e.g. biochemistry, hematology).
Signs and symptoms: The Sponsor will consider signs and symptoms all the events 
ongoing during the screening period, except for prior history conditions, which should 
be reported in the medical history form. Ongoing events during the screening period are 
those present at any time between the informed consent date and the first drug 
administration, regardless of if they may be resolved or not at the date of Cycle 1 Day 1.
The “Adverse event form” will be used only for events that occur after the first drug 
infusion or any event related to a study procedure within the study period (according to 
ICH guidelines); and to report ‘ongoing’ baseline conditions in case of any significant 
change (improvement or worsening) during the study.
8.5.2 Reporting of Serious Adverse Events
The Sponsor will collect SAEs from the time of signing of the ICF and until 31 (±10) 
days after administration of the last dose of lurbinectedin or until the start of a new 
antitumor therapy, until the continuation of treatment outside this study under a 
Compassionate Use Agreement or death, whichever occurred first. Beyond this period 
of time, only those SAEs suspected to be related to the IMPs will be collected. 
Nonetheless, the Sponsor must evaluate any safety information related to the clinical 
study that is spontaneously reported by an Investigator beyond the time frame specified 
in the protocol.
All SAEs (as defined above) that have occurred after patient registration, regardless of 
relationship to the study drug(s)/IMP(s), must be reported immediately, and always 
within 24 hours to the Pharma Mar S.A. Pharmacovigilance Department electronically 
by completing the applicable eCRF section. Only in situations of electronic system 
failure or pregnancy exposure during the clinical trial, can SAEs be reported using paper 
on 
a 
“SAE 
form 
by 
fax 
(+34 
91 
846 
6004), 
e-mail 
(AEincoming@pharmamar.comphv@pharmamar.com) or telephone (+34 91 823 4562). 
Out of office hours [Greenwich Meridian Time (GMT)], assistance on SAE reporting 
can be obtained by calling the Pharmacovigilance Department at +34 681 263 592. In 
case of electronic system failure or pregnancy exposure during the clinical trial, SAEs 

initially reported by alternative methods (not electronically), must be followed by a 
completed electronic SAE reporting on eCRF from the investigational staff within one 
working day.
SAEs occurring during the screening phase (from ICF signature to the first study drug 
administration) and after off-study will be reported using a paper “SAE form” that must 
be forwarded as mentioned above always within 24 hours to the Pharma Mar S.A. 
Pharmacovigilance Department by fax or email.
All SAEs suspected to be related to the study drug must be followed until the event or 
its sequelae resolves or stabilizes to at least grade 1, or to an acceptable level according 
to the Investigator and the Sponsor or his/her designated representative.
8.5.3 Reporting of Pregnancy Cases Occurring During the Clinical Study
National regulations require that the Sponsor collect information on pregnancies 
occurring during clinical trials, in which exposure to the study drug at any time during 
pregnancy, via either maternal or paternal exposure, is suspected. 
Therefore, pregnancy and suspected pregnancy (including a positive pregnancy test 
regardless of age or disease state) of a female patient or the female partner of a male 
patient occurring while the patient is on study drug, or within 31 days of the patient’s 
discontinuation visit, are considered an immediately reportable events. 
The investigator will report the following events immediately and always within 24 
hours from first knowledge:

Any occurrence of a pregnancy where any kind of exposure to the study drug is 
suspected.

Possible exposure of a pregnant woman.

All reports of elevated/questionable or indeterminate beta human chorionic 
gonadotropins (β-hCGs).
Immediately after detecting a case of suspected pregnancy in a female clinical trial 
patient, the decision on her continued participation in the clinical trial will be jointly 
taken by the trial patient, the Investigator and the Sponsor with the patient’s best interest 
in mind. A decision to continue the pregnancy will require immediate withdrawal from 
the trial.
Any pregnancy, suspected pregnancy, or positive pregnancy test must be reported to the 
Pharmacovigilance Department at PharmaMar immediately by facsimile using the 
Pregnancy Report Form.
The Investigator will follow the pregnancy until completion/termination, and must 
notify the outcome of the pregnancy to the Pharmacovigilance Department at 
PharmaMar within 24 hours of first knowledge as a follow-up to the initial Pregnancy 
report.
For any event during the pregnancy which meets a seriousness criterion (including fetal 
or neonatal death or congenital anomaly), the Investigator will also follow the 
procedures for reporting SAEs (complete and send the SAE form to Sponsor,  
Pharmacovigilance by facsimile within 24 h of the Investigator’s knowledge of the 
event).

All neonatal deaths that occur within 30 days of birth should be reported, regardless of 
causality, as SAEs. In addition, any infant death at any time thereafter that the 
Investigator suspects as related to the in utero exposure to the study drug should also be 
reported to the Pharmacovigilance Department at PharmaMar by facsimile within 24 h 
of the Investigators’ knowledge of the event. 
8.6
ADVERSE EVENTS MONITORING
Safety review will be performed at Pharma Mar, S.A. once the SAE forms have been 
received and the eCRFs have been completed by the Investigator. 
Periodic safety review of clinical data will be performed; however, no formal Data 
Safety Monitoring Board has been appointed for this trial. AEs will be monitored by the 
Investigators and by the study team at Pharma Mar, S.A. The personnel in charge of this 
process are defined in the section “Study Contacts” of this protocol. In general, a 
clinical oncologist, together with a member of the Pharma Mar, S.A. Pharmacovigilance 
Department will review the safety data of this trial on an ongoing basis. 

SAEs will be collected, assessed and reported as per the applicable Regulations 
by the Pharmacovigilance Department. 
Non-serious AEs will be checked for accuracy against the eCRF during monitoring 
visits by the monitor. 
8.7
EFFICACY
Not applicable.
9.
STATISTICAL METHODS
This clinical pharmacology study is designed to assess the impact of bosentan co-
administration on lurbinectedin PK parameters administered alone.
9.1
ANALYSIS POPULATIONS
The PK population will include all patients enrolled who have sufficient and 
interpretable PK parameters to calculate the non-compartmental PK parameters. Only 
the patients who have completed the two cycles and have sufficient and interpretable
PK assessments will be included in the statistical comparison to assess the effect of 
bosentan on the PK of lurbinectedin.
The safety population will include all patients who received at least one dose of 
lurbinectedin. Patients who have received at least one dose of bosentan but who did not 
receive any dose of lurbinectedin will be excluded from the safety population. The 
analysis of data from these patients will be performed separately (e.g., by means of 
narratives). The safety population will be used for all safety evaluations.
9.2
SAMPLE SIZE
A block randomization (1:1 ratio) will be performed. At least 8 patients are expected to 
complete all study procedures, including the collection of sufficient and interpretable 
PK assessments. Although at least 8 patients will be enrolled in this study; it is 
estimated that complete data from eight patients will be sufficient to estimate the drug-

drug interaction of bosentan on the PK of lurbinectedin. In case of patient replacement, 
a new patient number will be provided and he/she will be assigned to the same sequence 
as the patient being replaced.
This study was designed to assess the potential effects of bosentan on the PK of 
lurbinectedin in patients with advanced malignancies. The 90% CI will be used to help 
with the interpretation of the results. A sample size of eight patients was based on 
feasibility and clinical considerations. Based on previous studies, the intra-subject 
coefficient of variation (CV) of lurbinectedin PK parameters is estimated to be more 
than 30%. The precision (half-width) of the 90% CI for [(lurbinectedin + bosentan) / 
lurbinectedin alone] comparison on the log-scale will extend 0.389 from the observed 
differences in means, assuming that the intra-subject CV around 40%. This half-width 
corresponds to a 90% CI in the range of 70% and 147% assuming the ratio of the means 
equal to unity for each PK parameter. This 90% CI will be used to help with the 
interpretation of the results.
9.3
STATISTICAL ANALYSIS
Descriptive statistics (arithmetic and geometric means, median, SDev, CV% and 95% 
confidence interval [CI], range of value, frequencies and percentages) will be used to 
summarize the data.
9.3.1 Demographics
Descriptive statistics will be used to summarize the patients’ baseline characteristics.
9.3.2 Safety
All AEs will be graded according to NCI-CTCAE v.5. 
Treatment-emergent adverse events (TEAEs) are any adverse event aggravated in 
severity from baseline or having their onset between the first dose of the study drug and 
31-day (±10 days) after the last treatment dose, death or date of further therapy, 
whichever came first. AEs related to the study treatment or with unknown relationship 
occurring more than 31 days after the last dose were also taken into account as TEAEs.
Descriptive statistics will be used to characterize the profiles of drug-related AEs, drug-
related deaths, SAEs, clinical laboratory data, drug-related delays and/or treatment 
discontinuations. Tables will be displayed by sequence and treatment (Test or 
Reference).
9.3.3 Efficacy
Not applicable.
9.3.4 Pharmacokinetics
Plasma exposure to lurbinectedin
Only patients who completed the study with sufficient and interpretable PK parameters 
will be included in the statistical comparison of plasma exposure to lurbinectedin.
Descriptive statistics will be used to summarize pharmacokinetic data.
The primary parameter of interest for the statistical analysis will be plasma dose-
adjusted AUC(0-∞) (if data do not permit so, AUC(0-t) will be used) of lurbinectedin. The 

analysis will compare the log-transformed AUC for lurbinectedin administered in 
combination with bosentan (Test) to the lurbinectedin alone (Reference). 
A mixed-effects model will be fit to the data with log-transformed AUC as the 
dependent variable, treatment (Test or Reference), period and sequence as fixed effects, 
and patient (sequence) as a random effect. The estimated least square means and 
intrasubject variability from the mixed-effects model will be used to construct 90% CIs 
for the difference in means on the log scale between treatments (Test or Reference). The 
adjusted mean differences and the 90% CIs will be exponentiated to obtain estimates of 
the ratio of adjusted geometric means (Test/Reference) and 90% CIs for the ratios.
A large difference (e.g. two-fold difference shown from CIs and least square means) 
will be considered to show evidence on whether bosentan co-administration has a 
clinically relevant effect on lurbinectedin exposure.
Secondary PK parameters
Similar models used for the primary endpoint will be fit to the data with dose-
normalized AUC(0-t) and Cmax and in Cl, Vss and T1/2 of lurbinectedin or metabolite to 
parent exposure PK parameters ratio, as the dependent variable. Results will also be 
assessed graphically.
Plasma protein binding
A similar model used for the primary endpoint will be fit to the data with dose-
normalized AUCu as the dependent variable.
9.3.5 Pharmacogenetics
Descriptive statistics will be used to summarize pharmacogenetic data in a separate 
report.
10. ADMINISTRATIVE SECTION
10.1 ETHICS 
This study will be conducted in accordance with the ethical principles that have their 
origin in the Declaration of Helsinki (Appendix 5) and will be consistent with GCP and 
other applicable regulatory requirements.
The study personnel involved in conducting this study will be qualified by education, 
training and experience to perform their respective task(s).
The study will be conducted in compliance with the protocol. The protocol, any 
amendments, the patient’s diary and the patient ICF will receive IEC approval/favorable 
opinion prior to initiation. The decision of the IEC concerning the conduct of the study 
will be made in writing to the Investigator and a copy of this decision will be provided 
to the Sponsor before commencement of the study.
The Investigator and/or the Sponsor is/are responsible for keeping the IEC informed of 
significant new information about the study drug.
All protocol amendments will be agreed upon by the Sponsor and the Investigator.
Administrative changes of the protocol are minor corrections and/or clarifications that 
have no impact on the way the study is to be conducted.

10.2 MONITORING, AUDITING AND INSPECTING
The study will be monitored by regular site visits and telephone calls to the Investigator 
by the clinical study monitor designated by Pharma Mar, S.A. Source document 
verification may be performed remotely, if required.
During site visits, the study monitor should review original patient records, drug 
accountability records and document retention (study file). Additionally, the monitor 
should observe study procedures and will discuss any problem with the Investigator.
Adequate time for these visits should be allocated by the Investigator. The Investigator 
should also ensure that the monitor is given direct access (as per International 
Conference on Harmonization [ICH] Topic E6 Guideline for Good Clinical Practice, 
GCP) to source documents (i.e., hospital or private charts, original laboratory records, 
appointment books, etc.) of the patient which support data entered in the case report 
forms, as defined in the ICH-GCP.
Systems and procedures will be implemented to ensure the quality of every aspect of the 
study.
At any time during the course or at the end of the study, the Clinical Quality Assurance 
Department of PharmaMar or external auditors contracted by the Sponsor may conduct 
an onsite or remote audit visit to the centers (ICH-GCP).
Participation in this study implies acceptance of potential onsite or remote inspections 
by national or foreign Competent Authorities.
10.3 PATIENT INFORMED CONSENT
The rights, safety and well-being of the trial patients are the most important 
considerations and should prevail over interests of science and society.
The ICF will include all elements required by ICH, GCP and applicable regulatory 
requirements.
Prior to inclusion into the trial, the Investigator or a person designated by the 
Investigator, must provide the patient with one copy of the Informed Consent Form 
(ICF). This copy must provide written full information about the clinical trial, in a 
language that is non-technical and easily understood. The Investigator should allow the 
necessary time for the patient or his/her legally acceptable representative to inquire 
about the details of the clinical study; then, the ICF must be freely signed and personally 
dated by the patient and by the person who conducted the Informed Consent discussion 
before the beginning of the study. The patient should receive a copy of the signed ICFs 
and any other written information provided to study patients prior to participation in the 
trial.
Participation in the pharmacogenetic sub-study is optional and will need an additional 
ICF signed by the patient. Should the patient decide not to participate in the 
pharmacogenetic sub-study, this will not affect his/her rights to participate in the current 
study.
During a patient's participation in the trial, any updates to the consent forms and any 
updates to the written information will be provided to him/her.
If there is a need to obtain new consent from the patients, the Investigator or a person 
designated by the Investigator should inform the patients of any new information 

relevant to the patients’ willingness to continue participation in the study, before 
obtaining the written consent.
10.4 CONFIDENTIALITY/ PATIENTS IDENTIFICATION
The collection and processing of personal data from patients enrolled in this study will 
be limited to data that are necessary to investigate the efficacy, safety, quality, and 
usefulness of the IMP(s) used in this study. It is the Investigator’s responsibility that 
sufficient information pertaining to the patient’s identity be retained. 
The study monitor, the Sponsor’s auditor, the IEC and the Competent Authorities 
should have direct access to all requested study-related records and agree to keep the 
identity of the study patients confidential.
The data must be collected and processed with adequate precautions to ensure 
confidentiality and compliance with applicable data privacy protection laws and 
regulations.
Explicit consent for the processing of personal data will be obtained from the 
participating patient before data collection, if applicable, and this consent should also 
address the transfer of the data to other entities and countries.
The Sponsor will comply with General Data Protection Regulation (GDPR) (EU) 
2016/679 effective from 25 May 2018 (repealing Directive 95/46/EC of the European 
Parliament and of the Council of 24 October 1995), and applicable regulations on the 
protection of individuals with regards to the processing of personal data and on the free 
movement of such data. 
10.5 ELECTRONIC CASE REPORT FORMS
Electronic case report forms (eCRFs) will be used to record all data for each patient. It 
is the responsibility of the Investigator to ensure that the eCRFs are properly and fully 
completed in English. ECRFs must be completed for all patients who have given 
informed consent and have been enrolled into the study.
A patient’s source documentation comprises all medical records (including but not 
limited to physician/hospital notes, nurses notes, IMP preparation records including 
reconstitution and dilution, IMP administration records) and any original document, and 
as such they should be maintained at the study site.
The data collected in the eCRF will be entered into the Sponsor’s databases which 
comply with GDPR (EU) 2016/679 effective from 25 May 2018 (repealing Directive 
95/46/EC of the European Parliament and of the Council of 24 October 1995) on the 
protection of individuals with regard to the processing of personal data and on the free 
movement of such data.
10.6 INSURANCE
The Sponsor will provide insurance or indemnity in accordance with the applicable 
regulatory requirements.

10.7 RETENTION OF RECORDS
The Investigator/Institution should maintain study documents according to ICH 
Guideline for Good Clinical Practice and as required by applicable regulatory 
requirements.
Essential documents should be retained as per the aforementioned ICH guideline or for 
a longer period of time, if required by the applicable regulations. 
10.8 USE OF INFORMATION AND PUBLICATION
Before the investigators of this study submit a paper or abstract for publication or 
otherwise publicly disclose information concerning the study drug or products, Pharma 
Mar, S.A. must be provided with at least 60 days to revise and approve the proposed 
publication or disclosure to ensure that confidential and proprietary data are protected.
If Pharma Mar, S.A. determines that patentable patient matter is disclosed in the 
proposed publication or disclosure, the publication or disclosure will be withheld for a 
period of time considered convenient. If the study is part of a multicenter study, the first 
publication of the study shall be made in conjunction with the presentation of a joint, 
multicenter publication of the study results with the investigators and the institutions 
from all appropriate sites that are contributing data, analysis and comments. However, if 
such a multicenter publication is not submitted within 12 months after conclusion, 
abandonment or termination of the study at all sites, the present study may be published 
individually in accordance with the procedure established above.
The order of the coauthors will reflect the relative contribution of each one to study 
development and analysis. Relevant Sponsor personnel who have fully participated in 
the study must be considered for co-authorship of the publication. In general, the order 
of the investigator will reflect who recruits the highest number of patients with 
information finally available for data analysis. 

11. REFERENCES
1.
Santamaria Nunez G, Robles CM, Giraudon C, Martinez-Leal JF, Compe E, 
Coin F, Aviles P, Galmarini CM and Egly JM. Lurbinectedin specifically 
triggers the degradation of phosphorylated RNA polymerase II and the 
formation of DNA breaks in cancer cells. Mol Cancer Ther 2016; 15 (10): 1-14.
2.
Harlow ML, Maloney N, Roland J, Guillen Navarro MJ, Easton MK, Kitchen-
Goosen SM, Boguslawski EA, Madaj ZB, Johnson BK, Bowman MJ, D'incalci 
M, Winn ME, Turner L, Hostetter G, Galmarini CM, Aviles PM and Grohar PJ. 
Lurbinectedin inactivates the Ewing sarcoma oncoprotein EWS-FLI1 by 
redistributing it within the nucleus. Cancer Res 2016; 76 (22): 6657-68.
3.
Soares D, Rocca C, Machado M, Poindessous V, Ouaret D, Sarasin A, 
Galmarini C, Henriques J, Escargueil A and Larsen A. PM01183, a marine-
derived product, shows activity toward platinum-resistant cells and attenuates 
nucleotide excision repair [abstract #5431]. in 102nd Annual Meeting of the 
American Association for Cancer Research.Orlando, Florida.
4.
Romano M, Frapolli R, Zangarini M, Bello E, Porcu L, Galmarini CM, Garcia-
Fernandez LF, Cuevas C, Allavena P, Erba E and D'incalci M. Comparison of in 
vitro and in vivo biological effects of trabectedin, lurbinectedin (PM01183) and 
Zalypsis(R) (PM00104). Int J Cancer 2013; 133 (9): 2024-33.
5.
Lima M, Bouzid H, Soares DG, Selle F, Morel C, Galmarini CM, Henriques JA, 
Larsen AK and Escargueil AE. Dual inhibition of ATR and ATM potentiates the 
activity of trabectedin and lurbinectedin by perturbing the DNA damage 
response and homologous recombination repair. Oncotarget 2016; 7 (18): 
25885-901.
6.
Cruz C, Vivancos A, Caratu G, Ibrahim Y, Serra V and Balmaña J. Analysis  of  
secondary  mutations  in  BRCA1/2  genes  as  a  mechanism  of resistance to 
PM01183 in BRCA-mutation carriers. Mol Cancer Ther 2013; 12 (11 Suppl): 
B117.
7.
Cruz C, Ibrahim Y, Morancho B, Anton P, Grueso J, Cozar P, Guzman M, 
Aviles PM, Guillen MJ, Galmarini C, Arribas J, Baselga J, Balmaña J and Serra 
V. Development of xenoimplants from germline BRCA1/2 mutant breast cancer 
(BC) for the identification of predictive biomarkers, mechanisms of resistance 
against poly(ADP-ribose) polymerase (PARP) inhibitors and evaluation of novel 
therapies. Eur J Cancer 2014; 50 (Suppl. 6): 82.
8.
Leal JF, Martinez-Diez M, Garcia-Hernandez V, Moneo V, Domingo A, 
Bueren-Calabuig JA, Negri A, Gago F, Guillen-Navarro MJ, Aviles P, Cuevas 
C, Garcia-Fernandez LF and Galmarini CM. PM01183, a new DNA minor 
groove covalent binder with potent in vitro and in vivo anti-tumour activity. Br J 
Pharmacol 2010; 161 (5): 1099-110.
9.
Belgiovine C, Bello E, Liguori M, Craparotta I, Mannarino L, Paracchini L, 
Beltrame L, Marchini S, Galmarini CM, Mantovani A, Frapolli R, Allavena P 
and D'incalci M. Lurbinectedin reduces tumour-associated macrophages and the 

inflammatory tumour microenvironment in preclinical models. Br J Cancer 
2017; 117 (5): 628-38.
10.
Xie W, Forveille S, Iribarren K, Sauvat A, Senovilla L, Wang Y, Humeau J, 
Perez-Lanzon M, Zhou H, Martinez-Leal JF, Kroemer G and Kepp O. 
Lurbinectedin synergizes with immune checkpoint blockade to generate 
anticancer immunity. Oncoimmunology 2019; 8 (11): e1656502.
11.
Pernice T. The in vitro metabolism of PM01183 in liver microsomes of mouse, 
rat, dog, NHP (Cynomolgus), mini-pig and human. PMar14-NC032.  
(PharmaMar, Colmenar Viejo, Spain., 2016).
12.
Altares R. Chemical and enzymatic inhibition of PM01183 when incubated in 
human liver microsomes (HLM). PMAR15-NC015.  (PharmaMar, Colmenar 
Viejo, Spain, 2018).
13.
Elez ME, Tabernero J, Geary D, Macarulla T, Kang SP, Kahatt C, Pita AS, 
Teruel CF, Siguero M, Cullell-Young M, Szyldergemajn S and Ratain MJ. First-
in-human phase I study of Lurbinectedin (PM01183) in patients with advanced 
solid tumors. Clin Cancer Res 2014; 20 (8): 2205-14.
14.
Ratain MJ, Gore M, Szyldergemajn S, Diamond J, Geary D, Fernandez Teruel 
C, Soto-Matos A, Sharma M and Jimeno A. Phase I study of lurbinectedin 
(PM01183) administered on days (D) 1 & 8 every 3 weeks (q3wk) in patients 
(pts) with solid tumors. Eur J Cancer 2014; 50 (Suppl. 6): 13-4.

12. APPENDICES
APPENDIX 1: ECOG PERFORMANCE STATUS ASSESSMENT SCALE
Grade
ECOG PS*
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light house work, office work
2
Ambulatory and capable of all self-care but unable to carry out any work 
activities. Up and about more than 50% of waking hours
3
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours
4
Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair
5
Dead
*As published in Am. J. Clin. Oncol 5:649-655, 1982: Oken, M.M., Creech, R.H., Tormey, D.C., Horton, 
J., Davis, T.E., McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern 
Cooperative Oncology Group. 

APPENDIX 2: CONTRACEPTION AND PREGNANCY TESTING 
This document is based on the Heads of Medicines Agencies’ Recommendations Related 
to Contraception and Pregnancy Testing in Clinical Trials, published by the Clinical 
Trial Facilitation Group (CTFG) on 21 September 2020
and available at 
http://www.hma.eu/ctfg.html (accessed 5 January 2021). 
A woman is considered of childbearing potential (WOCBP) following menarche and 
until becoming post-menopausal unless permanently sterile. Permanent sterilization 
methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. A 
postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal 
range may be used to confirm a post-menopausal state in women not using hormonal 
contraception or hormonal replacement therapy. However, in the absence of 12 months 
of amenorrhea, a single FSH measurement is insufficient. Immediately after detecting a 
case of suspected pregnancy in a patient, the decision on her continued participation in 
the clinical trial will be jointly taken by the patient, the Investigator and the Sponsor, 
with the patient’s best interest in mind. A decision to continue the pregnancy will 
require immediate discontinuation any investigational medicinal product (IMP). 
A man is considered fertile after puberty unless permanently sterile by bilateral 
orchidectomy. Fertile male patients included in this study should refrain from fathering 
a child or donating sperm during the study and for four months following the last IMP 
dose. If they have WOCBP partners the male subject should use condom during 
treatment and for four months following the last IMP dose. 
Highly effective birth control methods are:
1. Combined (estrogen and progestogen containing) hormonal contraception 
associated with inhibition of ovulation 1:
a.
oral 
b. intravaginal 
c.
transdermal 
2. Progestogen-only hormonal contraception associated with inhibition of 
ovulation 1: 
a.
oral 
b. injectable
c.
implantable 2
3. Intrauterine device (IUD) 2
4. Intrauterine hormone-releasing system (IUS) 2
5. Bilateral tubal occlusion 2
6. Vasectomized partner 2,3
7. Sexual abstinence 4
8. A combination of male condom with either cap, diaphragm or sponge with 
spermicide (double barrier methods) are also considered acceptable, but not 
highly effective, birth control methods.
1 Hormonal contraception may be susceptible to interaction with the IMP, which may 
reduce the efficacy of the contraception method (see below).
2 Contraception methods that are considered to have low user dependency. 

3 Vasectomized partner is a highly effective birth control method provided that partner is the 
sole sexual partner of the WOCBP trial participant and that the vasectomized partner has 
received medical assessment of the surgical success. 
4 Sexual abstinence is considered a highly effective method only if defined as refraining 
from heterosexual intercourse during the entire period of risk associated with the study 
treatments. The reliability of sexual abstinence needs to be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the subject. Periodic 
abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus 
interruptus), spermicides only, and lactational amenorrhea method (LAM) are not 
acceptable methods of contraception. Female condom and male condom should not be used 
together.
Contraception methods with low user dependency should preferably be used, in 
particular when contraception is introduced as a result of participation in this trial. It 
cannot be excluded that the IMP bosentan may reduce exposure to substrates of CYP3A 
through enzyme induction; the efficacy of hormonal contraceptives may be reduced if 
co-administered with this drug.

APPENDIX 3: LIST OF CYP1/CYP2/CYP3 INHIBITORS, INDUCERS AND SUBSTRATES
Table 1. Classification of in vivo inhibitors of CYP Enzymes (1).
CYP 
enzymes
Strong Inhibitors (2)  
≥ 5-fold increase in 
AUC
or > 80% decrease in 
CL
Moderate inhibitors (3)  
≥ 2 but < 5-fold increase in AUC 
or 50-80% decrease in CL
Weak inhibitors (4)  
≥ 1.25 but < 2-fold increase in 
AUC or 20-50% decrease in CL
CYP1A2
ciprofloxacin, enoxacin, 
fluvoxamine(a)
methoxsalen, mexiletine ,oral 
contraceptives
acyclovir, allopurinol, cimetidine, 
peginterferon alpha-2a, piperine, 
zileuton
CYP2B6
-
-
clopidogrel(b), tenofovir, 
ticlopidine(c), voriconazole(d)
CYP2C8
gemfibrozil(e)
clopidogrel(b), deferasirox, 
teriflunomide
trimethoprim
CYP2C9
-
amiodarone, fluconazole(f), 
miconazole, piperine
diosmin, disulfiram, fluvastatin, 
fluvoxamine(a), voriconazole
CYP2C19
fluconazole(f), 
fluoxetine(g), 
fluvoxamine(a), 
ticlopidine
felbamate
omeprazole, voriconazole
CYP2D6
bupropion, fluoxetine(g), 
paroxetine, quinidine(h), 
terbinafine
abiraterone, cinacalcet, duloxetine, 
lorcaserin, mirabegron
amiodarone, celecoxib, cimetidine, 
clobazam, cobicistat, 
escitalopram, fluvoxamine(a), 
labetalol, ritonavir(h,i,j), sertraline, 
vemurafenib
CYP3A
boceprevir, 
clarithromycin(h), 
cobicistat(h), danoprevir 
and ritonavir(j), 
elvitegravir and 
ritonavir(j), grapefruit 
juice(k), idelalisib, 
indinavir and ritonavir(j), 
itraconazole(h), 
ketoconazole, lopinavir 
and ritonavir(h,j), 
nefazodone, nelfinavir(h), 
paritaprevir and ritonavir 
and (ombitasvir and/or 
dasabuvir)(j), 
posaconazole, 
ritonavir(h,j), saquinavir 
and ritonavir(h,j), 
telaprevir(h), tipranavir 
and ritonavir(h,j), 
telithromycin, 
troleandomycin, 
voriconazole
aprepitant, ciprofloxacin, conivaptan(l),
crizotinib, cyclosporine, diltiazem(m), 
dronedarone(h), erythromycin, 
fluconazole(f), fluvoxamine(a), 
imatinib, tofisopam, verapamil(h)
chlorzoxazone, cilostazol, 
cimetidine, clotrimazole, 
fosaprepitant, istradefylline, 
ivacaftor(h), lomitapide, ranitidine, 
ranolazine(h), ticagrelor(h)
1.
Please note: For an updated list, see the following link: https://www.fda.gov/drugs/drug-interactions-
labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers#table3-2
2.
A strong inhibitor for a specific CYP is defined as an inhibitor that increases the AUC of a substrate for that 
CYP by equal or more than 5-fold.
3.
A moderate inhibitor for a specific CYP is defined as an inhibitor that increases the AUC of a sensitive 
substrate for that CYP by less than 5-fold but equal to or more than 2-fold.
4.
A weak inhibitor for a specific CYP is defined as an inhibitor that increases the AUC of a sensitive 
substrate for that CYP by less than 2-fold but equal to or more than 5-fold.
(a) Strong inhibitor of CYP1A2 and CYP2C19. Moderate inhibitor of CYP3A and Weak inhibitor of CYP2D6.

(b) Moderate inhibitor of CYP2C8 and weak inhibitor of CYP2B6.
(c) Strong inhibitor of CYP2C19 and weak inhibitor of CYP2B6.
(d) Strong inhibitor of CYP2C19 and CYP3A, and weak inhibitor of CYP2B6.
(e) Strong inhibitor of CYP2C8 and inhibitor of OATP1B1 and OAT3.
(f) Strong inhibitor of CYP2C19 and moderate inhibitor of CYP2C9 and CYP3A. 
(g) Strong inhibitors of CYP2C19 and CYP2D6.
(h) Inhibitor of P-gp (defined as those increasing AUC of digoxin to ≥1.25-fold).
(i) Strong inhibitors of CYP3A and weak inhibitor of CYP2D6.
(j) Ritonavir is usually given in combination with other anti-HIV or anti-HCV drugs in clinical practice. Caution 
should be used when extrapolating the observed effect of ritonavir alone to the effect of combination 
regimens on CYP3A activities.
(k) The effect of grapefruit juice varies widely among brands and is concentration-, dose-, and preparation-
dependent. Studies have shown that it can be classified as a “strong CYP3A inhibitor” when a certain 
preparation was used (e.g., high dose, double strength) or as a “moderate CYP3A inhibitor” when another 
preparation was used (e.g., low dose, single strength).
(l) The classification is based on studies conducted with intravenously administered conivaptan.
(m) Diltiazem increased AUC of certain sensitive CYP3A substrates (e.g., buspirone) more than 5-fold.
Table 2. Classification of in vivo inducers of CYP Enzymes (1).
CYP
enzymes
Strong Inducers
≥ 80% decrease in AUC
Moderate Inducers
50-80% decrease in AUC
Weak Inducers
20-50% decrease in AUC
CYP1A2
-
phenytoin(a) rifampin(b), 
ritonavir(c,d), smoking, 
teriflunomide
-
CYP2B6
carbamazepine(e)
efavirenz(e), rifampin(a)
nevirapine, ritonavir(c, d)
CYP2C8
-
rifampin(a)
-
CYP2C9
-
enzalutamide(g), rifampin(a)
apalutamide, aprepitant, 
carbamazepine(e), ritonavir(c, d)
CYP2C19
rifampin(a)
apalutamide, efavirenz(e,f), 
enzalutamide(g), phenytoin(b)
ritonavir(c, d)
CYP3A
apalutamide, 
carbamazepine(e), 
enzalutamide(g), mitotane, 
phenytoin(b), rifampin(a), St. 
John’s wort(h)
bosentan, efavirenz(f), etravirine, 
phenobarbital, primidone
armodafinil, modafinil(i), 
rufinamide
1.
Please note: 
For an updated list, see the following link: https://www.fda.gov/drugs/drug-interactions-
labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers#table3-3.
(a) Strong inducer of CYP3A and moderate inducer of CYP1A2, CYP2C19.
(b) Strong inducer of CYP2C19, CYP3A, and moderate inducer of CYP1A2, CYP2B6, CYP2C8, CYP2C9.
(c) Moderate inducer of CYP1A2 with dose of 800 mg/day ritonavir (not with other anti-HIV drugs). Effect on 
CYP1A2 at lower doses of ritonavir is unknown.
(d) Weak inducer of CYP2B6, CYP2C9, and CYP2C19. Classification is based on studies conducted with 
ritonavir itself (not with other anti-HIV drugs) at doses of 100-200 mg/day, although larger effects have 
been reported in literature for high doses of ritonavir.
(e) Strong inducer of CYP2B6, CYP3A, and weak inducer of CYP2C9.
(f) Moderate inducer of CYP2B6, CYP2C19 and CYP3A.
(g) Strong inducer of CYP3A and moderate inducer of CYP2C9, and CYP2C19.
(h) The effect of St. John’s wort varies widely and is preparation-dependent.
(i) Based on effect of 200 mg/day modafinil. A higher dose (400 mg/day) modafinil had larger induction effect 
on CYP3A.

Table 3. Examples (1) of sensitive and moderate sensitive in vivo CYP substrates.
CYP
enzymes
Sensitive substrates (2)
Moderate sensitive substrates (3)
CYP1A2
alosetron, caffeine, duloxetine, melatonin, 
ramelteon, tasimelteon, tizanidine
clozapine, pirfenidone, ramosetron, theophylline
CYP2B6
bupropion(a)
efavirenz(a)
CYP2C8
repaglinide(b)
montelukast, pioglitazone, rosiglitazone
CYP2C9
celecoxib(c)
glimepiride, phenytoin, tolbutamide, warfarin
CYP2C19
S-mephenytoin, omeprazole
diazepam, lansoprazole(d), rabeprazole, 
voriconazole
CYP2D6
atomoxetine, desipramine, dextromethorphan , 
eliglustat(e), nebivolol, nortriptyline, perphenazine, 
tolterodine, R-venlafaxine
encainide, imipramine, metoprolol, propafenone, 
propranolol, tramadol, trimipramine, S-
venlafaxine
CYP3A (4)
alfentanil, avanafil, buspirone, conivaptan, 
darifenacin, darunavir(f), ebastine, everolimus, 
ibrutinib, lomitapide, lovastatin(g), midazolam, 
naloxegol, nisoldipine, saquinavir(f), simvastatin(g), 
sirolimus, tacrolimus, tipranavir(f), triazolam, 
vardenafil
alprazolam, aprepitant, atorvastatin(c), colchicine, 
eliglustat(e), pimozide, rilpivirine, rivaroxaban, 
tadalafil
budesonide, dasatinib, dronedarone, eletriptan, 
eplerenone, felodipine, indinavir(f), lurasidone, 
maraviroc, quetiapine, sildenafil, ticagrelor, 
tolvaptan
1.
Please note: For an updated list, see the following link: https://www.fda.gov/drugs/drug-interactions-
labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers#table3-1.
2.
Sensitive CYP substrates refer to drugs whose plasma AUC values have been shown to increase 5-fold or 
higher when co-administered with a known CYP inhibitor.
3.
Moderate sensitive substrates are drugs that demonstrate an increase in AUC of ≥2 to <5-fold with strong 
index inhibitors of a given metabolic pathway in clinical DDI studies.
4.
Sensitive substrates of CYP3A with ≥10-fold increase in AUC by co-administration of strong index 
inhibitors are shown above the dashed line.
(a) Listed based on an in vivo induction study and the observed effect might be partly attributable to induction of 
other pathway(s).
(b) OATP1B1 substrate.
(c) Listed based on pharmacogenetic studies.
(d) S-lansoprazole is a sensitive substrate in CYP2C19 EM subjects.
(e) Sensitive substrate of CYP2D6 and moderate sensitive substrate of CYP3A.
(f) Usually administered to patients in combination with ritonavir, a strong CYP3A inhibitor.
(g) Acid form is an OATP1B1 substrate.

APPENDIX 4: FORMULAS
Cockcroft-Gault Formula for Calculated Creatinine Clearance
CLcr (mL/min) = (140 −Age) × Weight (kg)
72 × Creatinine !"(mg dL
⁄
) × 0.85 if female
Cockcroft D.W., Gault M.H. Prediction of Creatinine Clearance from Serum Creatinine. Nephron 
1976;16:31–41 (DOI:10.1159/000180580)
DuBois Formula for Body Surface Area
Body Surface Area (m2) ＝Weight (kg)0.425 × Height (cm)0.725 × 0.007184.
DuBois D, DuBois EF. A formula to estimate the approximate surface area if height and weight be 
known. Arch Intern Medicine. 1916; 17:863-71.

APPENDIX 5: DECLARATION OF HELSINKI
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI
Ethical Principles for Medical Research Involving Human Subjects
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964
and amended by the:
29th WMA General Assembly, Tokyo, Japan, October 1975
35th WMA General Assembly, Venice, Italy, October 1983
41st WMA General Assembly, Hong Kong, September 1989
48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996
52nd WMA General Assembly, Edinburgh, Scotland, October 2000
53rd WMA General Assembly, Washington DC, USA, October 2002 (Note of 
Clarification added)
55th WMA General Assembly, Tokyo, Japan, October 2004 (Note of Clarification 
added)
59th WMA General Assembly, Seoul, Republic of Korea, October 2008
64th WMA General Assembly, Fortaleza, Brazil, October 2013
Preamble
1.
The World Medical Association (WMA) has developed the Declaration of 
Helsinki as a statement of ethical principles for medical research involving 
human subjects, including research on identifiable human material and data.
The Declaration is intended to be read as a whole and each of its constituent 
paragraphs should be applied with consideration of all other relevant paragraphs.
2.
Consistent with the mandate of the WMA, the Declaration is addressed primarily 
to physicians. The WMA encourages others who are involved in medical 
research involving human subjects to adopt these principles.
General Principles
3.
The Declaration of Geneva of the WMA binds the physician with the words, 
“The health of my patient will be my first consideration,” and the International 
Code of Medical Ethics declares that, “A physician shall act in the patient's best 
interest when providing medical care.”
4.
It is the duty of the physician to promote and safeguard the health, well-being 
and rights of patients, including those who are involved in medical research. The 
physician's knowledge and conscience are dedicated to the fulfilment of this 
duty.
5.
Medical progress is based on research that ultimately must include studies 
involving human subjects.

6.
The primary purpose of medical research involving human subjects is to 
understand the causes, development and effects of diseases and improve 
preventive, diagnostic and therapeutic interventions (methods, procedures and 
treatments). Even the best proven interventions must be evaluated continually 
through research for their safety, effectiveness, efficiency, accessibility and 
quality.
7.
Medical research is subject to ethical standards that promote and ensure respect 
for all human subjects and protect their health and rights.
8.
While the primary purpose of medical research is to generate new knowledge, 
this goal can never take precedence over the rights and interests of individual 
research subjects.
9.
It is the duty of physicians who are involved in medical research to protect the 
life, health, dignity, integrity, right to self-determination, privacy, and 
confidentiality of personal information of research subjects. The responsibility 
for the protection of research subjects must always rest with the physician or 
other health care professionals and never with the research subjects, even though 
they have given consent.
10.
Physicians must consider the ethical, legal and regulatory norms and standards 
for research involving human subjects in their own countries as well as 
applicable international norms and standards. No national or international 
ethical, legal or regulatory requirement should reduce or eliminate any of the 
protections for research subjects set forth in this Declaration.
11.
Medical research should be conducted in a manner that minimises possible harm 
to the environment.
12.
Medical research involving human subjects must be conducted only by 
individuals with the appropriate ethics and scientific education, training and 
qualifications. Research on patients or healthy volunteers requires the 
supervision of a competent and appropriately qualified physician or other health 
care professional.
13.
Groups that are underrepresented in medical research should be provided 
appropriate access to participation in research.
14.
Physicians who combine medical research with medical care should involve 
their patients in research only to the extent that this is justified by its potential 
preventive, diagnostic or therapeutic value and if the physician has good reason 
to believe that participation in the research study will not adversely affect the 
health of the patients who serve as research subjects.
15.
Appropriate compensation and treatment for subjects who are harmed as a result 
of participating in research must be ensured.

Risks, Burdens and Benefits
16.
In medical practice and in medical research, most interventions involve risks and 
burdens.
Medical research involving human subjects may only be conducted if the 
importance of the objective outweighs the risks and burdens to the research 
subjects.
17.
All medical research involving human subjects must be preceded by careful 
assessment of predictable risks and burdens to the individuals and groups 
involved in the research in comparison with foreseeable benefits to them and to 
other individuals or groups affected by the condition under investigation.
Measures to minimise the risks must be implemented. The risks must be 
continuously monitored, assessed and documented by the researcher.
18.
Physicians may not be involved in a research study involving human subjects 
unless they are confident that the risks have been adequately assessed and can be 
satisfactorily managed.
When the risks are found to outweigh the potential benefits or when there is 
conclusive proof of definitive outcomes, physicians must assess whether to 
continue, modify or immediately stop the study.
Vulnerable Groups and Individuals
19.
Some groups and individuals are particularly vulnerable and may have an 
increased likelihood of being wronged or of incurring additional harm.
All vulnerable groups and individuals should receive specifically considered 
protection.
20.
Medical research with a vulnerable group is only justified if the research is 
responsive to the health needs or priorities of this group and the research cannot 
be carried out in a non-vulnerable group. In addition, this group should stand to 
benefit from the knowledge, practices or interventions that result from the 
research.
Scientific Requirements and Research Protocols
21.
Medical research involving human subjects must conform to generally accepted 
scientific principles, be based on a thorough knowledge of the scientific 
literature, other relevant sources of information, and adequate laboratory and, as 
appropriate, animal experimentation. The welfare of animals used for research 
must be respected.
22.
The design and performance of each research study involving human subjects 
must be clearly described and justified in a research protocol.

The protocol should contain a statement of the ethical considerations involved 
and should indicate how the principles in this Declaration have been addressed. 
The protocol should include information regarding funding, sponsors, 
institutional affiliations, potential conflicts of interest, incentives for subjects and 
information regarding provisions for treating and/or compensating subjects who
are harmed as a consequence of participation in the research study.
In clinical trials, the protocol must also describe appropriate arrangements for 
post-trial provisions.
Research Ethics Committees
23.
The research protocol must be submitted for consideration, comment, guidance 
and approval to the concerned research ethics committee before the study 
begins. This committee must be transparent in its functioning, must be 
independent of the researcher, the sponsor and any other undue influence and 
must be duly qualified. It must take into consideration the laws and regulations 
of the country or countries in which the research is to be performed as well as 
applicable international norms and standards but these must not be allowed to 
reduce or eliminate any of the protections for research subjects set forth in this 
Declaration.
The committee must have the right to monitor ongoing studies. The researcher 
must provide monitoring information to the committee, especially information 
about any serious adverse events. No amendment to the protocol may be made 
without consideration and approval by the committee. After the end of the study, 
the researchers must submit a final report to the committee containing a 
summary of the study’s findings and conclusions.
Privacy and Confidentiality
24.
Every precaution must be taken to protect the privacy of research subjects and 
the confidentiality of their personal information.
Informed Consent
25.
Participation by individuals capable of giving informed consent as subjects in 
medical research must be voluntary. Although it may be appropriate to consult 
family members or community leaders, no individual capable of giving informed 
consent may be enrolled in a research study unless he or she freely agrees.
26.
In medical research involving human subjects capable of giving informed 
consent, each potential subject must be adequately informed of the aims, 
methods, sources of funding, any possible conflicts of interest, institutional 
affiliations of the researcher, the anticipated benefits and potential risks of the 
study and the discomfort it may entail, post-study provisions and any other 
relevant aspects of the study. The potential subject must be informed of the right 
to refuse to participate in the study or to withdraw consent to participate at any 
time without reprisal. Special attention should be given to the specific 

information needs of individual potential subjects as well as to the methods used 
to deliver the information.
After ensuring that the potential subject has understood the information, the 
physician or another appropriately qualified individual must then seek the 
potential subject’s freely-given informed consent, preferably in writing. If the 
consent cannot be expressed in writing, the non-written consent must be 
formally documented and witnessed.
  
All medical research subjects should be given the option of being informed 
about the general outcome and results of the study.
27.
When seeking informed consent for participation in a research study the 
physician must be particularly cautious if the potential subject is in a dependent 
relationship with the physician or may consent under duress. In such situations 
the informed consent must be sought by an appropriately qualified individual 
who is completely independent of this relationship.
28.
For a potential research subject who is incapable of giving informed consent, the 
physician must seek informed consent from the legally authorised representative. 
These individuals must not be included in a research study that has no likelihood 
of benefit for them unless it is intended to promote the health of the group 
represented by the potential subject, the research cannot instead be performed 
with persons capable of providing informed consent, and the research entails 
only minimal risk and minimal burden.
29.
When a potential research subject who is deemed incapable of giving informed 
consent is able to give assent to decisions about participation in research, the 
physician must seek that assent in addition to the consent of the legally 
authorised representative. The potential subject’s dissent should be respected.
30.
Research involving subjects who are physically or mentally incapable of giving 
consent, for example, unconscious patients, may be done only if the physical or 
mental condition that prevents giving informed consent is a necessary 
characteristic of the research group. In such circumstances the physician must 
seek informed consent from the legally authorised representative. If no such 
representative is available and if the research cannot be delayed, the study may 
proceed without informed consent provided that the specific reasons for 
involving subjects with a condition that renders them unable to give informed 
consent have been stated in the research protocol and the study has been 
approved by a research ethics committee. Consent to remain in the research must 
be obtained as soon as possible from the subject or a legally authorised 
representative.
31.
The physician must fully inform the patient which aspects of their care are 
related to the research. The refusal of a patient to participate in a study or the 
patient’s decision to withdraw from the study must never adversely affect the 
patient-physician relationship.
32.
For medical research using identifiable human material or data, such as research 
on material or data contained in biobanks or similar repositories, physicians 

must seek informed consent for its collection, storage and/or reuse. There may 
be exceptional situations where consent would be impossible or impracticable to 
obtain for such research. In such situations the research may be done only after 
consideration and approval of a research ethics committee.
Use of Placebo
33.
The benefits, risks, burdens and effectiveness of a new intervention must be 
tested against those of the best proven intervention(s), except in the following 
circumstances:
Where no proven intervention exists, the use of placebo, or no intervention, is 
acceptable; or
Where for compelling and scientifically sound methodological reasons the use of 
any intervention less effective than the best proven one, the use of placebo, or no 
intervention is necessary to determine the efficacy or safety of an intervention
and the patients who receive any intervention less effective than the best proven 
one, placebo, or no intervention will not be subject to additional risks of serious 
or irreversible harm as a result of not receiving the best proven intervention.
Extreme care must be taken to avoid abuse of this option.
Post-Trial Provisions
34.
In advance of a clinical trial, sponsors, researchers and host country 
governments should make provisions for post-trial access for all participants 
who still need an intervention identified as beneficial in the trial. This 
information must also be disclosed to participants during the informed consent 
process.
Research Registration and Publication and Dissemination of Results
35.
Every research study involving human subjects must be registered in a publicly 
accessible database before recruitment of the first subject.
36.
Researchers, authors, sponsors, editors and publishers all have ethical 
obligations with regard to the publication and dissemination of the results of 
research. Researchers have a duty to make publicly available the results of their 
research on human subjects and are accountable for the completeness and 
accuracy of their reports. All parties should adhere to accepted guidelines for 
ethical reporting. Negative and inconclusive as well as positive results must be 
published or otherwise made publicly available. Sources of funding, institutional 
affiliations and conflicts of interest must be declared in the publication. Reports 
of research not in accordance with the principles of this Declaration should not 
be accepted for publication.
Unproven Interventions in Clinical Practice
37.
In the treatment of an individual patient, where proven interventions do not exist 
or other known interventions have been ineffective, the physician, after seeking 
expert advice, with informed consent from the patient or a legally authorised 

representative, may use an unproven intervention if in the physician's judgement 
it offers hope of saving life, re-establishing health or alleviating suffering. This 
intervention should subsequently be made the object of research, designed to 
evaluate its safety and efficacy. In all cases, new information must be recorded 
and, where appropriate, made publicly available.
Disclaimer: ©2013 World Medical Association, Inc. All Rights Reserved. All intellectual property rights 
in the Declaration of Helsinki are vested in the World Medical Association. Previous permissions granted 
to publish or reproduce otherwise WMA policy don’t apply to this version of the Declaration of Helsinki 
until January 1st, 2014. For further questions, please contact the WMA secretariat at 
secretariat@wma.net.