Conditions: Advanced Solid Tumors
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 345
Healthy volunteers: no

Brief summary:
Multicenter, open-label, exploratory, phase II clinical trial to evaluate the efficacy and safety of PM01183 in previously treated patients with advanced solid tumors

Detailed description:
Patients with relapsed small cell lung cancer (SCLC), head and neck carcinoma (H\&N), neuroendocrine tumors (NETs), biliary tract carcinoma, endometrial carcinoma, BRCA 1/2-associated metastatic breast carcinoma, carcinoma of unknown primary site, germ cell tumors (GCTs), and Ewing's family of tumors (EFTs) will be enrolled in nine different cohorts. Up to 25 evaluable patients are planned to be enrolled in each cohort (50 in the endometrial carcinoma and 100 in the SCLC cohort).

Arms:
arm 1: lurbinectedin (PM01183) 4 mg vials of powder for concentrate for solution for infusion

Interventions: intervention 1: lurbinectedin (PM01183)
Intervention descriptions: intervention 1: None

Protocol document:
Prot_002.pdf: 


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SPONSORS
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
Pharma Mar USA, Inc.
205 East 42nd Street, suite 15003
New York, New York 10017, USA
Phone: + 1 646 880 4429
Fax : + 1 646 893 5856
CLINICAL TRIAL PROTOCOL
PM1183-B-005-14
A Multicenter Phase II Clinical Trial of Lurbinectedin (PM01183) in 
Selected Advanced Solid Tumors
INVESTIGATIONAL MEDICINAL PRODUCT: Lurbinectedin (PM01183)
Protocol Code: PM1183-B-005-14
EudraCT No: 2014-003773-42
Protocol version 8.0 including substantial amendments #1 dated 13 May 2015, #2 
dated 04 February 2016, #3 dated 22 March 2016, #4 dated 19 July 2016, #5 dated 
08 March 2017, #6 dated 18 July 2018 and #7 dated 5 June 2020.
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.


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


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TABLE OF CONTENTS
STUDY CONTACTS .................................................................................................................................2
PRINCIPAL INVESTIGATORS..............................................................................................................4
SYNOPSIS ..................................................................................................................................................8
SCHEDULE OF ASSESSMENTS AND PROCEDURES....................................................................25
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS..........................................................27
1.
INTRODUCTION ...........................................................................................................................31
1.1
SMALL CELL LUNG CANCER (SCLC).....................................................................................31
1.2
HEAD AND NECK CANCER (H&N)...........................................................................................32
1.3
NEUROENDOCRINE TUMORS (NETS) ......................................................................................33
1.4
BILIARY TRACT CARCINOMA..................................................................................................35
1.5
ENDOMETRIAL CARCINOMA....................................................................................................35
1.6
BRCA 1/2-ASSOCIATED METASTATIC BREAST CANCER.......................................................36
1.7
CARCINOMA OF UNKNOWN PRIMARY SITE ............................................................................37
1.8
GERM CELL TUMORS (GCTS).................................................................................................38
1.9
EWING FAMILY OF TUMORS (EFTS).......................................................................................39
1.10
INFORMATION ON THE STUDY DRUG......................................................................................40
1.10.1
Lurbinectedin (PM01183)...............................................................................................40
1.10.1.1
Name and Chemical Information ............................................................................................... 40
1.10.1.2
Non-clinical Data ....................................................................................................................... 40
1.10.1.3
Clinical Data .............................................................................................................................. 42
1.11
STUDY RATIONALE...................................................................................................................43
1.12
RATIONALE FOR THE DOSE......................................................................................................44
1.13
PHARMACOGENETIC SUB-STUDY RATIONALE........................................................................45
1.14
PHARMACOGENOMICS SUB-STUDY RATIONALE.....................................................................45
2.
STUDY OBJECTIVES ...................................................................................................................46
2.1
PRIMARY ..................................................................................................................................46
2.2
SECONDARY..............................................................................................................................46
3.
OVERALL STUDY DESIGN.........................................................................................................46
3.1
PRIMARY ENDPOINT ................................................................................................................48
3.2
SECONDARY ENDPOINTS..........................................................................................................48
4.
SELECTION OF PATIENTS.........................................................................................................49
4.1
INCLUSION CRITERIA...............................................................................................................49
4.2
EXCLUSION CRITERIA..............................................................................................................50
4.3
PATIENTS FOR THE PHARMACOGENOMIC (PGX) AND PHARMACOGENETIC EVALUATIONS 51
5.
PLAN OF THE STUDY..................................................................................................................51
5.1
PLANNED TRIAL PERIODS (FOR THE WHOLE STUDY) ............................................................51
5.2
PLANNED TRIAL PERIODS (INDIVIDUALLY PER PATIENT)......................................................51
5.2.1
Discontinuations..................................................................................................................53
5.2.1.1
Treatment Discontinuation......................................................................................................... 53
5.2.1.2
Reasons for Treatment Discontinuation ..................................................................................... 53
5.2.1.3
Study Discontinuation................................................................................................................ 53
5.2.2
Protocol Deviations..............................................................................................................53
5.3
REPLACEMENT OF PATIENTS...................................................................................................54
5.4
PRE-TREATMENT ASSESSMENTS..............................................................................................54
5.5
PATIENT REGISTRATION..........................................................................................................56
5.6
PATIENT RANDOMIZATION......................................................................................................56
5.7
EVALUATIONS DURING TREATMENT.......................................................................................56
5.8
EVALUATIONS AT END OF TREATMENT ..................................................................................58
5.9
FOLLOW-UP AFTER END-OF-TREATMENT VISIT....................................................................58


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6.
TREATMENT .................................................................................................................................59
6.1
DESCRIPTION OF TREATMENT.................................................................................................59
6.1.1
Drug Formulation and Supply............................................................................................59
6.2
ADMINISTRATION OF THE STUDY MEDICATION .....................................................................59
6.3
STARTING DOSES AND SCHEDULE ...........................................................................................60
6.4
PROPHYLACTIC MEDICATION .................................................................................................60
6.5
CRITERIA FOR TREATMENT CONTINUATION..........................................................................60
6.6
DOSE REDUCTION ....................................................................................................................61
6.7
CONCOMITANT MEDICATION..................................................................................................62
6.7.1
Allowed Medications/Therapies ..........................................................................................62
6.7.2
Prohibited Medications/Therapies ......................................................................................62
6.7.3
Drug-drug Interactions .......................................................................................................62
6.8
DRUG ACCOUNTABILITY..........................................................................................................63
6.9
TREATMENT COMPLIANCE......................................................................................................63
7.
STUDY EVALUATIONS ...............................................................................................................63
7.1
EFFICACY .................................................................................................................................63
7.2
PHARMACOKINETICS ...............................................................................................................64
7.2.1
Blood Sampling....................................................................................................................64
7.2.2
Analytical Procedures..........................................................................................................65
7.2.3
Pharmacokinetic Parameters ..............................................................................................65
7.3
PHARMACOGENETIC EVALUATIONS........................................................................................65
7.4
PHARMACOGENOMIC (PGX) EVALUATIONS...........................................................................65
7.5
SAFETY .....................................................................................................................................66
7.6
ADVERSE EVENTS DEFINITIONS ..............................................................................................66
7.6.1
Adverse Event (AE)..............................................................................................................66
7.6.2
Serious Adverse Event (SAE)..............................................................................................66
7.6.3
Death....................................................................................................................................67
7.6.4
Life-threatening Event.........................................................................................................67
7.6.5
Hospitalization or Prolongation of Hospitalization............................................................67
7.6.6
Unlisted/Unexpected Adverse Event ...................................................................................67
7.6.7
Adverse Reactions................................................................................................................68
7.6.8
Adverse Events Related to the Study Drug..........................................................................68
7.6.9
Expedited Reporting ............................................................................................................68
7.6.10
Assessment of Causal Relationship to the Study Drug ..................................................68
7.7
ADVERSE EVENTS REPORTING PROCEDURES.........................................................................68
7.7.1
Reporting Adverse Events....................................................................................................68
7.7.2
Reporting Serious Adverse Events ......................................................................................69
7.7.3
Reporting Pregnancy Cases Occurred within the Clinical Trial........................................69
7.8
ADVERSE EVENTS MONITORING .............................................................................................70
8.
STATISTICAL METHODS...........................................................................................................71
8.1
SAMPLE SIZE ............................................................................................................................71
8.2
STATISTICAL ANALYSIS...........................................................................................................72
8.2.1
Efficacy Analyses.................................................................................................................72
8.2.2
Pharmacokinetic Analyses ..................................................................................................73
8.2.3
Pharmacogenetic Analyses..................................................................................................73
8.2.4
Pharmacogenomic Analyses................................................................................................73
8.2.5
Safety Analyses ....................................................................................................................73
8.3
INTERIM ANALYSES .................................................................................................................73
9.
ADMINISTRATIVE SECTION ....................................................................................................74
9.1
ETHICS......................................................................................................................................74
9.2
MONITORING, AUDITING AND INSPECTING .............................................................................74
9.3
PATIENT INFORMED CONSENT ................................................................................................75
9.4
CONFIDENTIALITY/PATIENTS IDENTIFICATION......................................................................75
9.5
CASE REPORT FORMS..............................................................................................................76
9.6
INSURANCE ...............................................................................................................................76


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9.7
RETENTION OF RECORDS.........................................................................................................76
9.8
USE OF INFORMATION AND PUBLICATION ..............................................................................76
10.
REFERENCES............................................................................................................................77
11.
APPENDICES .............................................................................................................................85
APPENDIX 1: ECOG PERFORMANCE STATUS ASSESSMENT SCALE .......................................85
APPENDIX 2: CONTRACEPTION AND PREGNANCY TESTING...................................................86
APPENDIX 3: LIST OF CYP1/CYP2/CYP3 INHIBITORS, INDUCERS AND SUBSTRATES.........88
APPENDIX 4: EVALUATION OF RESPONSE. THE RECIST. ..........................................................91
APPENDIX 5: DECLARATION OF HELSINKI.................................................................................100


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SYNOPSIS
TITLE
A Multicenter Phase II Clinical Trial of Lurbinectedin 
(PM01183) in Selected Advanced Solid Tumors.
PROTOCOL CODE
PM1183-B-005-14
NUMBER OF SITES / 
TRIAL LOCATION
This is a multicenter study. 
A full list of investigators will be available as a separate 
document.
STUDY OBJECTIVES 
Primary:

To assess the antitumor activity of lurbinectedin 
(PM01183) in terms of overall response rate (ORR), 
according to the Response Evaluation Criteria in Solid 
Tumors (RECIST) v.1.1, in the following advanced 
solid tumors: small cell lung cancer (SCLC), head and 
neck 
carcinoma 
(H&N), 
neuroendocrine 
tumors 
(NETs), 
biliary 
tract 
carcinoma, 
endometrial 
carcinoma, BRCA 1/2-associated metastatic breast 
carcinoma, carcinoma of unknown primary site, germ 
cell tumors (GCTs), and Ewing’s family of tumors 
(EFTs).
Secondary:

To further characterize the antitumor activity of 
PM01183 in terms of duration of response (DR), 
clinical benefit [ORR or stable disease (SD) lasting 
over four months (SD ≥ 4 months)], progression-free 
survival (PFS) by Investigator’s assessment (IA), and 
overall survival (OS) in each cohort of advanced solid 
tumors.

To further investigate the antitumor activity of 
PM01183 in terms of ORR, DR, clinical benefit (ORR 
or SD ≥ 4 months) and PFS by an Independent Review 
Committee (IRC) in the cohort of SCLC patients.

To characterize the plasma pharmacokinetics (PK) of 
PM01183.

To conduct an exploratory pharmacogenomic (PGx)
and pharmacogenetic analysis.

To evaluate the safety profile of PM01183 in this 
patient population.
STUDY DESIGN
Multicenter, open-label, exploratory, phase II clinical trial to 
evaluate the efficacy and safety of PM01183 in previously 
treated patients with the following advanced solid tumors: 
SCLC, H&N, NETs, biliary tract carcinoma, endometrial 
carcinoma, BRCA 1/2-associated metastatic breast carcinoma, 
carcinoma of unknown primary site, GCTs, and EFTs.
Patients with each of the aforementioned tumors will be 


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enrolled in nine cohorts. Up to 25 evaluable patients are 
planned to be enrolled in each cohort (50 in the endometrial 
carcinoma and 100 in the SCLC cohort). To consider that 
PM01183 has antitumor activity in any of the tumor types 
analyzed, at least two confirmed responses [complete (CR) or 
partial response (PR)] per RECIST v.1.1 out of the 25 patients 
of each cohort are expected. 

If no confirmed responses are observed in the first 15 
evaluable patients of each cohort, the recruitment of the 
corresponding cohort will be stopped.

If one confirmed response is observed in the first 15 
evaluable patients of each cohort, the recruitment of this 
cohort will continue to up to 25 evaluable patients.
o In the cohort of endometrial carcinoma, if ≥2 confirmed 
responses occur in the first 25 evaluable patients, the 
sample size will be doubled to 50 evaluable patients. 
o In the cohort of SCLC, if ≥2 confirmed responses occur 
in the first 25 evaluable patients, the sample size will be 
increased to 100 evaluable patients. 

If two confirmed responses are observed in the first 15 
evaluable patients of each cohort, the recruitment of the 
corresponding cohort can be stopped.
Only in the SCLC cohort, an IRC will determine the best 
patient’s response and assign the date of first documentation 
of response and progression/censoring according to RECIST 
v.1.1. Operational details for the IRC and the algorithm and its 
validation by an expert panel is described in detail in the IRC 
charter.
In addition, for safety reasons:

If two patients have a treatment-related death in a cohort, 
the recruitment of the corresponding cohort will be 
stopped.

If six patients have treatment-related deaths in the whole 
population, the study will be stopped.
Finally,

A determined cohort can be early closed by the Sponsor in 
case of a low recruitment rate.

Once the target of patients included in each cohort is 
reached, recruitment in this cohort will be kept “on hold” 
during the period of patients’ data analysis to assess their
evaluability and the response rate. After this period, if the 
number of evaluable patients does not reach the planned 
target, recruitment will be re-opened and non-evaluable 
patients will be replaced. 
STUDY POPULATION
Previously treated patients with the following advanced solid 
tumors: SCLC, H&N, NETs, biliary tract carcinoma, 
endometrial carcinoma, BRCA 1/2-associated metastatic 
breast carcinoma, carcinoma of unknown primary site, GCTs, 


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and EFTs.
STUDY POPULATION
Inclusion criteria
1)
Age ≥ 18 years. 
2)
Voluntary signed informed consent (IC) of the patient 
before any study-specific procedure.
3)
Pathologically proven diagnosis of any of the following 
malignancies:
a) Small cell lung cancer (SCLC). 
b) Head and neck carcinoma (H&N). Salivary glands 
tumors are excluded.
c) Neuroendocrine tumors (NETs), grade 2 and grade 3
according to World Health Organization (WHO) 
classification.
d) Biliary tract carcinoma. 
e) Endometrial carcinoma. 
f) BRCA 1/2- associated metastatic breast carcinoma
g) Carcinoma of unknown primary site. 
h) Germ cell tumor (GCTs), excluding immature teratoma, 
or teratoma with malignant transformation.
i) Ewing’s family of tumors (EFTs).
4)
Prior treatment. Patients must have received:
a) SCLC: one prior chemotherapy-containing line.
b) H&N: one or two prior chemotherapy-containing lines.
c) NETs: one or two prior chemotherapy-containing lines. 
No more than three prior hormone or biological therapy 
lines.
d) Biliary tract carcinoma: one or two prior chemotherapy-
containing lines.
e) Endometrial carcinoma: one prior chemotherapy-
containing line.
f) BRCA 1/2-associated metastatic breast carcinoma: at least 
one but no more than three prior chemotherapy-containing 
lines.
g) Carcinoma of unknown primary site: one or two prior 
chemotherapy-containing lines.
h) GCTs: no limit of prior therapy (patients with no other 
clinical therapeutic options).
i) EFTs: no more than two prior chemotherapy-containing 
lines in the metastatic/recurrent setting.
5)
Measurable disease as defined by RECIST v.1.1, and 
documented progression before study entry.
6)
Eastern 
Cooperative 
Oncology 
Group 
(ECOG) 
performance status (PS) ≤ 2.
7)
Adequate major organ function:
a) Hemoglobin ≥ 9 g/dl, prior red blood cell (RBC) 
transfusions are allowed if clinically indicated; absolute 


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neutrophil count (ANC) ≥ 2.0 × 109/l; and platelet count 
≥ 100 × 109/l.
b) Alanine 
aminotransferase 
(ALT), 
and 
aspartate 
aminotransferase (AST) 3.0 × upper limit of normal 
(ULN).
c) Total bilirubin 1.5
× ULN, or direct bilirubin 
ULN.
d) Albumin ≥ 3 g/dl.
e) Serum creatinine ≤ 1.5 × ULN or creatinine clearance ≥ 
30 ml/min.
f) Creatine phosphokinase (CPK) ≤ 2.5 × ULN.
8)
Washout periods prior to Day 1 of Cycle 1: 
a) At least three weeks since the last chemotherapy (six 
weeks if therapy contained nitrosureas or systemic 
mitomycin C).
b) At least four weeks since the last monoclonal antibody 
(MAb)-containing therapy, or radiotherapy (RT) > 30 
gray (Gy).
c) At 
least 
two 
weeks 
since 
the 
last 
biological/investigational therapy (excluding MAbs) or 
palliative RT (≤ 10 fractions or ≤ 30 Gy total dose).
9)
Grade ≤ 1 toxicity due to any previous cancer therapy 
according to the National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI-CTCAE, 
v.4). Grade 2 is allowed in case of alopecia and/or 
peripheral sensory neuropathy.
10) Women of childbearing potential must have pregnancy 
excluded by appropriate testing before study entry. Fertile 
women must agree to use a medically acceptable method of 
contraception throughout the treatment period and for at 
least three months after treatment discontinuation. Fertile 
men must agree to refrain from fathering a child or 
donating sperm during the trial and for four months after 
the last infusion.
Exclusion criteria
1) Prior treatment with PM01183 or trabectedin.
2) Prior or concurrent malignant disease unless in complete 
remission for more than five years, except treated in situ
carcinoma of the cervix, basal or squamous cell skin 
carcinoma, and in situ transitional cell bladder carcinoma.
3) Known central nervous system (CNS) involvement. In 
patients with SCLC, brain computed tomography (CT)-scan 
or magnetic resonance imaging (MRI) results must be 
provided at baseline.
4) Relevant diseases or clinical situations which may increase 
the patient’s risk:
a) History within the last year or presence of unstable 
angina, myocardial infarction, congestive heart failure, 
or clinically relevant valvular heart disease or 


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symptomatic 
arrhythmia 
or 
any 
asymptomatic 
ventricular arrhythmia requiring ongoing treatment.
b) Grade ≥ 3 dyspnea or daily intermittent oxygen 
requirement within two weeks prior to the study 
treatment onset.
c) Active infection.
d) Unhealed wounds or presence of any external drainage.
e) Known chronic active hepatitis or cirrhosis.
f) Immunocompromised 
patients, 
including 
known 
infection by human immunodeficiency virus (HIV).
5) Women who are pregnant or breast-feeding, and fertile 
patients (men and women) who are not using an effective 
method of contraception. *
6) Impending need for RT (e.g., painful bone metastasis 
and/or risk of spinal cord compression).
7) Limitation of the patient’s ability to comply with the 
treatment or to follow-up the protocol.
* Women of childbearing potential (WOCBP) must agree to 
use an effective contraception method to avoid pregnancy 
during the course of the trial (and for at least three months after 
the last infusion). Valid methods to determine the childbearing 
potential, adequate contraception and requirements for WOCBP 
partners are described in APPENDIX 2. Fertile men must agree 
to refrain from fathering a child or donating sperm during the 
trial and for four months after the last infusion.
INCLUSION CRITERIA 
FOR THE 
PHARMACOGENOMIC
AND 
PHARMACOGENETIC 
SUB-STUDY
Only patients who voluntarily sign the written informed 
consent 
(IC) 
for 
the 
pharmacogenomic 
(PGx)
and 
pharmacogenetic sub-study will participate. Refusal to 
participate in this
sub-study
will not affect patient 
participation in the clinical study PM1183-B-005-14.
EXPECTED NUMBER 
OF PATIENTS
A minimum of 135 evaluable patients are planned. If response 
rate exceeds the one defined in the stopping rule, the 
recruitment can proceed to up to 350 evaluable patients (see 
Statistical Methods).
REPLACEMENT OF 
PATIENTS
Patients will be replaced if they are not evaluable for the 
primary endpoint of the study (ORR as per RECIST v. 1.1), 
specifically if (any of the following):
They are not eligible.
They have not received the study treatment.
They are not evaluable for ORR as per RECIST v1.1 
and they are not categorized as “treatment failures”. 
Treatment failures will not be replaced and are defined 
as patients who:  
o Discontinue treatment due to any treatment-related 


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toxicity before an appropriate tumor assessment has 
been performed.
o Early death due to malignant disease.
All replaced patients who received study treatment will be 
included in the safety analysis.
STUDY DRUG 
FORMULATION
PM01183 drug product (DP) is presented as a lyophilized 
powder for concentrate for solution for infusion in 4-mg vials, 
which will be supplied by the Sponsor for the purposes of this 
study.
Before use, the 4-mg vials should be reconstituted with 8 ml 
of sterile water for injection to give a solution containing 0.5 
mg/ml of PM01183. 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 PM01183 4-mg vials and the 
reconstituted solution per ml is as shown in Table 1.
Table 1. Composition of PM01183 vials.
Component
Concentration/vial 
Concentration/vial 
after reconstitution
PM01183
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
ROUTE OF 
ADMINISTRATION
PM01183 will be administered over a minimum total volume 
of 100 ml of solution for infusion (either on 5% glucose or 
0.9% sodium chloride), through a central catheter, or over a 
minimum total volume of 250 ml if administered through a 
peripheral line, always over one hour at a fixed infusion rate.
STARTING DOSES AND 
SCHEDULE
Starting dose will be 3.2 mg/m2. Dose will be capped at BSA 
of 2.0 m2 (i.e., dose will not exceed 6.4 mg).
Patients will receive PM01183 i.v. as a one-hour infusion on 
Day 1 every three weeks (q3wk) (three weeks = one treatment 
cycle). 
PROPHYLACTIC 
MEDICATION
All patients will receive standard antiemetic prophylaxis 
before each treatment infusion. The i.v. formulations of these 
agents must be used in this setting:

Corticosteroids (dexamethasone 8 mg or equivalent).

Serotonin (5-HT3) antagonists (ondansetron 8 mg or 
equivalent).

Extended treatment with oral 5-HT3 antagonists and oral 
dexamethasone for two consecutive days. 

If necessary, and in addition to the above, administration
of 10 mg of oral or i.v. metoclopramide (or equivalent) 


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Protocol PM1183-B-005-14
every eight hours. 
Aprepitant and equivalent agents (e.g., fosaprepitant) are 
forbidden in patients treated with PM01183.
CRITERIA FOR 
TREATMENT 
CONTINUATION
Further treatment cycles (i.e., Cycle 2 or subsequent) will be 
administered q3wk (± 48 hours) if the patient fulfills all the re-
treatment criteria defined in Table 2.
Table 2. Criteria for treatment continuation.
Variable 
Re-treatment 
(Day 1)
ECOG PS
2
Hemoglobin*
8.0 g/dl
ANC
1.5 × 109/l
Platelets
100 × 109/l
AST/ALT
3.0 × ULN
Total bilirubin or 
direct bilirubin
1.5 × ULN or
× ULN 
Albumin
3 g/dl
Serum creatinine
1.5 × ULN or creatinine 
clearance ≥ 30 ml/min
CPK
Grade ≤ 1
Other non-hematological drug-related AEs 
(except isolated increased GGT and/or AP; 
grade 2 asthenia, constipation, alopecia, 
peripheral neuropathy, or  non-optimally 
treated nausea and/or vomiting) 
Grade 1
Active infection (including sepsis) and/or 
bleeding (any grade)
Absence
* Patients may receive packed red blood cells (PRBC) transfusion and/or 
erythropoietin (EPO) treatment, if clinically indicated, to increase/maintain adequate 
hemoglobin levels.
AE(s), adverse event(s); ANC, absolute neutrophil count; AP, alkaline phosphatase; 
AST/ALT, aspartate aminotransferase/alanine aminotransferase; CPK, creatinine 
phosphokinase; ECOG, Eastern Cooperative Oncology Group; GGT, gamma-
glutamyltransferase; PS, performance status; ULN, upper limit of normal.
If a patient does not meet the requirements for re-treatment on 
Day 1 of any following cycle, regardless of the reason, re-
assessments will be performed at least every 48-72 hours. 
Treatment will be then withheld, up to a maximum of three 
weeks beyond its due date, until appropriate recovery. 
Patients not meeting re-treatment criteria after a maximum 3-
week delay must be withdrawn from trial. In case of objective 
clinical benefit, the patient could continue receiving the 
treatment (upon the Sponsors’ agreement).
For any delay due to treatment-related adverse events lasting 
for more than one week, a dose reduction must be 
implemented upon recovery, following the rules explained in 
the next section.
DOSE REDUCTION
Patients may continue the study treatment at a reduced dose if 
they present any of the following:
Grade ≥ 3 treatment-related non-hematological toxicity. 
Exceptions are: grade ≥ 3 nausea and/or vomiting not 
optimally treated, grade 3 asthenia lasting ≤ 3 days, grade 
3 diarrhea lasting ≤ 2 days or not optimally treated, grade 


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3 transient ALT/AST elevations which are rapidly 
reversible and not leading to subsequent delays, and non-
clinically relevant biochemical abnormalities.
Grade 4 thrombocytopenia or grade 3 thrombocytopenia 
concomitantly with grade ≥3 bleeding.
Grade 4 neutropenia, any grade febrile neutropenia or 
neutropenia associated with infection/sepsis. 
Frequent or prolonged (>1 week) dose delays due to 
treatment-related adverse events.
Patients who experience grade 3/4 hypersensitivity reactions 
will be discontinued from study treatment.
Dose reduction levels are shown in Table 3.
Table 3. Criteria for dose reduction.
Dose reduction
PM01183  dose*
(mg/m2)
  1 (starting dose)
   3.2**
−1
2.6
−2
2.0
*Dose rounded to the first decimal. 
**Dose will be capped at BSA of 2.0 m2 (i.e., dose will not exceed 6.4 mg).
BSA, body surface area; ECOG, Eastern Cooperative Oncology Group; PS, 
performance status.
Up to two dose reductions are allowed per patient. 
Patients who continue to experience treatment-related toxicity 
and/or frequent dose delays after permitted dose reductions 
must be withdrawn from the study. They can continue 
receiving the study medication if objective clinical benefit is 
adequately documented by the Investigator, and upon 
agreement with the Sponsor. Once the dose has been reduced 
for an individual patient, it will not be re-escalated under any 
circumstances.
ALLOWED 
MEDICATIONS/
THERAPIES

Therapies for pre-existing and treatment-emergent medical 
conditions, including pain management.

Blood products and transfusions, as clinically indicated.

Bisphosphonates.

In case of nausea or vomiting, secondary prophylaxis 
and/or symptomatic treatment for emesis according to the 
American 
Society 
of 
Clinical 
Oncology 
(ASCO) 
guidelines.

Erythropoietin (EPO) treatment according to the ASCO 
guidelines.

Anticoagulation therapy.
PROHIBITED 
MEDICATIONS/
THERAPIES

Any other antineoplastic therapy, except somatostatin 
analogues for NETs. 

Any other investigational agents.

Primary G-CSF prophylaxis.


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Protocol PM1183-B-005-14

Immunosuppressive therapies other than corticosteroids
for antiemetic prophylaxis and/or pain control. 

Medroxyprogesterone (patients with endometrial cancer).

Aprepitant, fosaprepitant or related compounds.

Radiotherapy.
DRUG-DRUG 
INTERACTIONS
In vitro studies have shown PM01183 may inhibit CYP3A4. 
The magnitude of the interaction is unknown at present. 
Therefore, caution should be exercised when PM01183 is 
administered 
concomitantly 
with 
CYP3A4 
substrates. 
Additionally, in vitro studies with human microsomes have 
shown that CYP3A4 is the major CYP isoform involved in the 
metabolism of PM01183, followed by CYP2E1, CYP2D6 and 
CYP2C9. The estimated contribution of the other CYP 
isoenzymes to the PM01183 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 possible.
EFFICACY 
EVALUATIONS
The primary objective of this study is to assess the antitumor 
activity of PM01183 in terms of overall response rate
(ORR), primary endpoint,
supported by the secondary 
endpoint duration of response (DR), both assessed by the IA.
ORR will be assessed using the RECIST v.1.1 on a set of 
measurable lesions identified at baseline as target lesions or as 
non-target lesions (if any), and followed until disease 
progression (PD) by an appropriate method (e.g., helical CT-
scan, MRI). 
Radiological tumor assessment will be performed at baseline, 
and every two cycles from the onset of the study treatment 
until Cycle 6 or evidence of PD. After Cycle 6, tumor 
assessment will be performed every three cycles until 
evidence of PD. If an objective response is observed, 
according to the RECIST v1.1, it must be confirmed by the 
same method at least four weeks after the date of the first 
documentation of response.
ORR is defined as the percentage of evaluable patients with a 
confirmed response, either complete (CR) or partial response 
(PR), from the start of treatment to the date of progression or 
the start of a subsequent therapy or end of patient’s follow-up, 
according to the RECIST (v. 1.1). 
DR will be calculated from the date of first documentation of 
response to the date of first documented PD, recurrence or 
death due to any cause in the responder patients.
The date of response, the date of radiological or clinical PD,
according to the investigator assessment and the independent 
assessment by IRC when applicable (i.e., SCLC cohort), and 
the date of death will be registered and documented, as 
appropriate.
In case of objective tumor response, a copy of CT-scans or 


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MRIs can be requested by the Sponsor.
In SCLC patients, anonymized copies of all the images 
obtained throughout the study must be submitted to the 
Sponsor. These copies of CT scans, MRIs and any other 
documented methods to evaluate tumor response or 
progression in the SCLC cohort should be available for 
external radiological review by an IRC. The IRC will 
determine the patient’s best response and assign the date of 
first documentation of response and progression/censoring 
according to RECIST v.1.1. 
PHARMACOKINETIC 
EVALUATIONS
The plasma PK of PM01183 will be evaluated during Cycle 1 
and 2 in all treated patients. The sampling schedule will be as 
shown in Table 4 and Table 5 for Cycle 1 and Cycle 2, 
respectively.
Table 4. Blood samples for pharmacokinetic evaluations in 
Cycle 1.
Sample No.
Day 
Sampling time
Sampling window
#1
D1
Before infusion start
--
#2 *
D1
5 min before EOI
+/- 4 min
#3
D1
30 min after EOI
+/- 4 min
#4
D1
1 hour after EOI
+/- 10 min
#5
D1
3 hours after EOI
+/- 10 min
#6
D2
24 hours after EOI
+/- 2 hours
#7
D4
72 hours after EOI
+/-  24 hours
#8
D8
168 hours after EOI
+/- 24 hours
* Sample #2 must be collected before EOI.
D, day; EOI, end of infusion.
Table 5. Blood samples for pharmacokinetic evaluations in 
Cycle 2.
Sample No.
Day
Sampling time
Sampling window
#9
D1
Before infusion start
--
#10 *
D1
5 min before EOI
+/- 4 min
#11
D1
30 min after EOI
+/- 4 min
#12
D1
1 hour after EOI
+/- 10 min
#13
D1
3 hours after EOI
+/- 10 min
#14
D8
168 hours after EOI
+/- 24 hours
* Sample #10 must be collected before EOI 
D, day; EOI, end of infusion.
PK parameters will be calculated using non-compartmental 
analysis (NCA) and population methods if appropriate, after 
pooling data from this study with data obtained from other 
studies.
The plasma PK of PM01183 will be evaluated during Cycle 1 
and 2 in all treated patients. The sampling schedule will be as 
shown in Table 4 and Table 5 for Cycle 1 and Cycle 2, 
respectively.


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Table 4. Blood samples for pharmacokinetic evaluations in 
Cycle 1.
Sample No.
Day 
Sampling time
Sampling window
#1
D1
Before infusion start
--
#2 *
D1
5 min before EOI
+/- 4 min
#3
D1
30 min after EOI
+/- 4 min
#4
D1
1 hour after EOI
+/- 10 min
#5
D1
3 hours after EOI
+/- 10 min
#6
D2
24 hours after EOI
+/- 2 hours
#7
D4
72 hours after EOI
+/-  24 hours
#8
D8
168 hours after EOI
+/- 24 hours
* Sample #2 must be collected before EOI.
D, day; EOI, end of infusion.
Table 5. Blood samples for pharmacokinetic evaluations in 
Cycle 2.
Sample No.
Day
Sampling time
Sampling window
#9
D1
Before infusion start
--
#10 *
D1
5 min before EOI
+/- 4 min
#11
D1
30 min after EOI
+/- 4 min
#12
D1
1 hour after EOI
+/- 10 min
#13
D1
3 hours after EOI
+/- 10 min
#14
D8
168 hours after EOI
+/- 24 hours
* Sample #10 must be collected before EOI 
D, day; EOI, end of infusion.
PK parameters will be calculated using non-compartmental 
analysis (NCA) and population methods if appropriate, after 
pooling data from this study with data obtained from other 
studies.
PHARMACOGENETIC 
EVALUATIONS
Pharmacogenetic sub-study: 
To explore factors that may help to explain individual 
variability in main PK parameters, the presence or absence of 
germline mutations or polymorphisms that may be involved in 
the metabolism and/or transport of PM01183 will be analyzed 
in leukocyte DNA extracted from a blood sample obtained at 
any time during the study, but preferably just before treatment 
start in Cycle 1. 
PHARMACOGENOMIC 
EVALUATIONS
Pharmacogenomic sub-study: 
The analysis of potential predictive factors to PM01183 
treatment will be analyzed on prior available paraffin-
embedded tumor tissue samples from consenting patients. 
These factors will include genes involved in DNA repair 
mechanisms (such as nucleotide excision repair, homologous 
recombination repair or mismatch repair) and other factors 
related to the mechanism of action of PM01183 or to the 
pathogenesis of the disease, and their expression will be 
analyzed at the mRNA or protein level by quantitative 
polymerase chain reaction (PCR) and immunohistochemistry 
(IHC), respectively; their polymorphisms and mutations might 
be also analyzed, if relevant. 


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SAFETY 
EVALUATIONS
Patients will be evaluable for safety if they have received any 
partial or complete infusion of PM01183. 
All adverse events (AEs) will be graded according to the NCI-
CTCAE, v.4.
The safety profile of patients will be monitored throughout the 
treatment and up to 30 days after the last PM01183 infusion 
(end of treatment, EOT), or until the patient starts a new 
antitumor therapy or until the date of death, whichever occurs 
first. 
Treatment delays, dose reduction requirements, transfusions, 
and reason for treatment discontinuation will be monitored 
throughout the study.
Any treatment-related AEs will be followed until recovery to 
at least grade 1 or stabilization of symptoms or until the start 
of a new antitumor therapy, whichever occurs first.
STUDY
ENDPOINTS
Primary endpoint:

Overall Response Rate (ORR) in each tumor type. 
ORR is defined as the percentage of patients with a 
confirmed response, either complete (CR) or partial 
(PR), according to the RECIST (v. 1.1). 
Secondary endpoints:
Efficacy (all cohorts):

Duration of Response (DR) by IA, defined as the time 
between the date when the response criteria (PR or CR, 
whichever one is first reached) are fulfilled to the first 
date when PD, recurrence or death is documented.

Clinical Benefit by IA, defined as ORR or stable 
disease lasting over four months (SD ≥ 4 months).

Progression-free Survival (PFS) by IA, defined as the 
period of time from the date of first infusion to the date 
of PD, death (of any cause), or last tumor evaluation. 

PFS4/PFS6 by IA, defined as the Kaplan-Meier 
estimates of the probability of being free from 
progression and death after the first infusion at these 
time points (4 and 6 months).

OS, defined as the period of time from the date of first 
infusion to the date of death or last contact in case of 
patients lost to follow-up or alive at the clinical cut-off 
established for the cohort.

OS6/OS12, defined as the Kaplan-Meier estimates of 
the probability of being alive after the first infusion at 
these time points (6 and 12 months).
Efficacy (only in the SCLC cohort):

ORR, Clinical Benefit, DR, PFS and PFS4/PFS6 by 
IRC. The same definitions detailed for IA will be used.


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Plasma Pharmacokinetics (PK) of PM01183
Non-compartmental (NCA) PK parameters: area under the 
curve (AUC), Cmax, clearance (CL) and half-life (t1/2). 
Population PK parameters of the compartment model to be 
developed (initially based on Volumes and Clearance), and 
PK/PD correlation parameters, if applicable.
Pharmacogenetics
This analysis will be performed in those patients who signed 
the IC for the pharmacogenetic sub-study. The presence or 
absence of known polymorphisms from a single sample 
collected at any time during the study, but preferably just 
before treatment start in Cycle 1, will be assessed to explain 
the individual variability in the main PK parameters.
Pharmacogenomics (PGx):
This exploratory analysis will be performed in those patients 
treated in any arm who signed the IC for the PGx sub-study. 
mRNA or protein expression levels of factors involved in 
DNA repair mechanisms, or related to the mechanism of 
action of lurbinectedin, will be evaluated from prior available 
tumor tissue samples obtained at diagnosis or relapse. Their 
mutational status might be also analyzed. Their correlation 
with the clinical response and outcome after treatment will be 
assessed.
Safety Profile:

Clinical examinations.

Clinical assessment of AEs and serious adverse events 
(SAEs).

Changes in laboratory parameters (hematological and 
biochemical, including liver function tests). 

Reasons for treatment discontinuations.

Reasons for dose reduction and treatment delays.
STATISTICAL 
METHODS
This phase II trial is designed to assess the antitumor activity of 
PM01183 in terms of ORR according to the RECIST v.1.1
assessed by IA in different selected advanced solid tumors: 
SCLC, H&N, NETs, biliary tract carcinoma, endometrial 
carcinoma, BRCA 1/2-associated metastatic breast carcinoma, 
carcinoma of unknown primary site, GCTs, and EFTs. In 
addition, in the SCLC cohort, tumor evaluation will be also 
done by IRC.
Sample Size:
Up to 25 evaluable patients in each tumor type will be recruited 
to test the null hypothesis that 1% or less patients get a response 
(p ≤ 0.01) versus the alternative hypothesis that 10% or more 
patients get a response (p ≥ 0.10). The variance of the 
standardized test is based on the null hypothesis. The type I 
error (alpha) associated with this one-sided test is 0.025 and the 


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type II error (beta) is 0.2 (normal approximation; ~0.3 if exact 
binomial distribution); hence, statistical power is 80% (normal 
approximation; ~70% if exact binomial distribution). With 
these assumptions, if the number of patients who achieve a 
confirmed response is ≥ 2, then this would allow the rejection 
of the null hypothesis.
Endometrial carcinoma:
Up to 50 evaluable patients will be recruited to test the null 
hypothesis that 10% or less patients get a response (p ≤ 0.10) 
versus the alternative hypothesis that 25% or more patients get 
a response (p ≥ 0.25). The variance of the standardized test is 
based on the null hypothesis. The type I error (alpha) associated 
with this one-sided test is 0.025 and the type II error (beta) is 
0.144 (normal approximation; ~0.16 if exact binomial 
distribution); hence, statistical power is ~86% (normal 
approximation; ~84% if exact binomial distribution). With 
these assumptions, if the number of patients who achieve a 
confirmed response is ≥ 10, then this would allow the rejection 
of the null hypothesis.
SCLC: 
Up to 100 evaluable patients will be recruited to test the null 
hypothesis that 15% or less patients get a response (p ≤ 0.15) 
versus the alternative hypothesis that 30% or more patients get 
a response (p ≥ 0.30). The variance of the standardized test is 
based on the null hypothesis. The type I error (alpha) associated 
with this one-sided test is 0.025 and the type II error (beta) is 
0.051 (normal approximation; ~0.05 if exact binomial 
distribution); hence, statistical power is 95% (normal 
approximation; ~95% if exact binomial distribution). With 
these assumptions, if the number of patients who achieve a 
confirmed response is ≥ 23, then this would allow the rejection 
of the null hypothesis. The judgement of patient’s evaluability 
and replacement of non-evaluable patients in each cohort for 
the interim analyses will be guided by the investigator 
assessment. 
Interim Analyses:
An interim analysis to reject H0 (non-binding) or to reject H1 
(futility) in each tumor type is planned after the recruitment of 
15 evaluable patients in each cohort. The Gamma family 
boundary will be used to control the type I error, the parameter 
to reject H0 is fixed as -1 and the parameter to reject H1 is 
fixed as 0. If none of the first 15 evaluable patients in a 
determined cohort has a confirmed response, the alternative 
hypothesis will be rejected, according to boundaries and sample 
size assumptions, and recruitment will be stopped. If the 
number of responding patients is already two or more at the 
interim analysis, then H0 could be rejected and the study will 
have enough power to be stopped. On the contrary, if there is 
one confirmed response, the recruitment will be continued to up 
to 25 evaluable patients.

A phase III trial of PM01183 combined with 


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doxorubicin in SCLC is ongoing. Hence, the sample size 
for the SCLC cohort of this study will be increased to 
100 evaluable patients if the success boundary (≥2 
confirmed responses) is reached in the first 25 evaluable 
patients. The type I/II error will be controlled with a 
Gamma family boundary (-1 to reject Ho, 0 to reject H1)  

A phase I trial of PM01183 combined with doxorubicin 
has shown encouraging antitumor activity in endometrial 
carcinoma. Hence, the sample size for the endometrial 
carcinoma cohort of this study will be doubled to 50 
evaluable patients if the success boundary (≥2 confirmed 
responses) is reached in the first 25 evaluable patients. 
The type I/II error will be controlled with a Gamma 
family boundary (-1 to reject Ho, -3 to reject H1)  
With the sample size of 100 and 50 evaluable patients in each 
indication (SCLC and endometrial), the obtained confidence 
interval will be narrower and its half-width will be confined to 
±15%.
Statistical Analysis
Statistical analysis will be done by the Sponsor or under the 
authority of the Sponsor. The study protocol contains a general 
description; specific details will be provided in the Statistical 
Analysis Plan.
Frequency tables will be prepared for categorical variables, and 
continuous variables will be described by means of summary 
tables, which will include the median, mean, standard 
deviation, minimum, and maximum of each variable. 
Efficacy Analyses: 
Counts and percentages, with their corresponding exact 95% 
confidence intervals, will be calculated for the binomial 
endpoints (e.g., ORR, clinical benefit). 
Time-to-event variables (OS, PFS and DR) and their set time 
estimates (i.e., PFS 4/6 and OS 6/12) will be analyzed 
according to the Kaplan-Meier method. 
In the SCLC cohort, the evaluation of the efficacy endpoints 
evaluated by IA and IRC will be analyzed and compared. The 
rate of concordance between both evaluation methods for best 
response, progression status and progression-free survival will 
be presented with 2-way frequency tables and measures of 
agreement.
Waterfall plots will be used to describe the best variation of the 
sum of target lesions during treatment.
The number of patients recruited in any cohort may differ from 
that pre-specified according to the sample size assumptions.
Therefore, the main efficacy results will be calculated 
according to the planned cohort sample size and, if any cohort 
sample size differs at least 10% from the assumptions, a 
sensitivity analysis using all evaluable patients recruited 
(adjusting the corresponding boundaries to test the null 
hypothesis) will be performed.


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Pharmacokinetic Analyses:
PK data will be listed in the population PK-report for all 
patients with available PM01183 concentrations. PK analysis of 
plasma concentration-time data of PM01183 will be performed 
using 
non-linear 
mixed-effects 
modeling 
and/or 
non-
compartmental analysis. Data may be combined with those of a 
selection of phase I or II studies to support a relevant structural 
model. Available patient characteristics (e.g., demographics, 
laboratory variables, genotypes) will be tested as potential 
covariates affecting PK parameters.
Pharmacogenetic Analyses:
The influence of known polymorphisms on main PK 
parameters will be assessed by Student’s test or Mann-
Whitney’s U test as appropriate.
Pharmacogenomics Analyses: 
Analysis of RNA/protein expression, polymorphisms and 
mutations will be performed blind and with clinical data 
compiled only after all analyses are completed. A Fisher´s exact 
test/logistic regression for categorical variables and log rank 
test/Cox regression for time to event variables will be used to 
test whether a specific profile is associated with clinical 
outcome. The prognosis value of markers will be explored for 
objective response, PFS and OS. In each case, if applicable, a 
multivariate model will be developed by stepwise selection. All 
tests of statistical significance will be two-sided, and 
significance will be set at 0.05.
Safety Analyses: 
AEs, 
SAEs, 
deaths, 
laboratory 
evaluations, 
dose 
delays/reductions and study drug discontinuations due to AEs 
will be tabulated in a descriptive way. Counts and percentages 
will be used for categorical variables, and summary tables will 
be used for continuous variables.
DURATION OF STUDY 
PERIOD (per patient)
Patients will be evaluated at scheduled visits within three study 
periods:

Pre-treatment: from signature of IC to the first infusion 
of the study treatment.

Treatment:
from the first infusion of the study 
treatment to the end of treatment (EOT).

Follow-up: after EOT, patients will be followed-up
every four weeks until resolution or stabilization of all 
drug-related adverse events, if any, or until start a new 
antitumor therapy. Patients will be followed-up for at 
least one year after their first PM01183 infusion. Patients 
who finish treatment without disease progression (PD) 
will be followed-up every two months during the first six 
months and every three months thereafter until PD, start 
of a new antitumor therapy, death or until the end of 
study date (clinical cutoff). After PD is documented or a 
new antitumor therapy is started, each cohort (except 


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SCLC) will be followed-up at least every six months 
and up to 12 months after the last patient enrolled 
received the first PM01183 infusion (a documented 
phone contact will be acceptable). Patients in the SCLC 
cohort, after PD, will be followed-up every six months 
for at least 18 months after the last patient enrolled 
received the first PM01183 infusion (a documented 
phone contact will be acceptable).
Patients will be considered to be on-study from the signature of 
the informed consent form (ICF) until 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. This EOT 
is defined as 30 days after the day of the last PM01183 
infusion, unless the patient starts a new antitumor therapy or 
dies (whichever occurs first). An end-of-treatment visit (EOT 
visit) will be performed within 30 days (± 7 days) after the last 
study treatment administration, unless the patient starts any 
subsequent antitumor therapy, in which case the EOT visit 
should be performed immediately before the start of the new 
therapy.
Patients will receive the study treatment while it is considered 
to be in their best interest. Specifically, treatment will continue 
until:

Disease progression.

Unacceptable toxicity.

Treatment delay > three weeks from the treatment due 
date (except in case of clear clinical benefit, upon 
Sponsors’ approval).

Requirement of > two dose reductions.

Intercurrent illness of sufficient magnitude to preclude 
safe continuation of the study.

A major protocol deviation that may affect the 
risk/benefit ratio for the participating patient.

Investigator’s decision.

Non-compliance with study requirements. 

Patient’s refusal.
PLANNED TRIAL 
PERIODS (for the whole 
study)
The total duration of the study will be approximately 52
months, including approximately a 40-month enrolment period. 
Planned start date (first patient on study): 3Q2015.
Planned enrolment period: 40 months.
Planned end-of-study date (clinical cutoff for each cohort 
except SCLC): when all evaluable patients within each cohort
have at least 12 months of follow-up from the first PM01183 
infusion. Patients in the SCLC cohort will be followed-up for at 
least 18 months after the last patient enrolled received the first 
PM01183 infusion.


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SCHEDULE OF ASSESSMENTS AND PROCEDURES
Assessments and procedures
Screening*
(days)
Treatment
Follow-
up
Cycle 1
Cycle 2
Further 
cycles
End of 
treatment 
(EOT) ‡
D1
D8
D15 D1
D8
D15
D1
Written informed consents
(general and PGx/pharmacogenetic
sub-study)
Before any 
study 
procedure
-
-
-
-
-
-
-
-
Demographic data
-28  to  0
-
-
-
-
-
-
-
-
Primary diagnosis and prior 
treatment(s) 
-28  to  0
(+1 week)
-
-
-
-
-
-
-
-
Medical and cancer 
history/baseline conditions
-14  to  0 
(+1 week)
-
-
-
-
-
-
-
-
Assessment of disease signs and 
symptoms
-7  to  0
(+1 day)
-
-
-
-
-
-
-
-
Complete physical examination,
including weight and height and 
calculation of BSA (1)
-7  to  0   
(+1 day)     

-
-

-
-


-
ECOG PS
-7  to  0
(+1 day)

-
-

-
-


-
Vital signs (heart rate, blood 
pressure, temperature)
-7  to  0
(+1 day)

-
-

-
-


-
Coagulation panel
-7  to  0
-
-
-

-
-


-
Hematology (2, 3) †
-7  to  0

(4)






(5)

-
Biochemistry A (2) †
-7 to  0
-






(5)

-
Biochemistry B †
-7  to  0
-
-
-

-
-


-
Pharmacokinetics and AAGP
-

(6)
-
-

(7)
-
-
-
-
-
Pharmacogenetic sub-study (only if 
written informed consent given)
One blood sample collected at any time during the study, but 
preferably just before treatment start in Cycle 1
-
Pharmacogenomic (PGx) sub-study 
(only if written informed consent 
given)  
Available stored paraffin-embedded tumor tissue samples,
assessed at any time during the study.
-
Pregnancy test (8) †
-7  to  0

-
-

-
-


-
ECG (9)
-7  to  0
(+3 days)
Repeat if clinically indicated
-
LVEF by ECHO or MUGA(9)
-28  to  0
(+3 days)
Repeat if clinically indicated
-
Radiological tumor assessment (10)
-28  to  0
(+1 week)
Every two cycles from the onset of the study treatment
until Cycle 6 and every three cycles thereafter (11)
  (12)
Concomitant therapies
-14  to  0
(+1 week)
Throughout the ”on-treatment period” 
-
Adverse events 
  - §
Throughout the ”on-treatment period” 
(13)
*Screening procedures will have to be repeated in case that the first infusion of the study treatment is given out of the established 
windows. 
† Day 0 is when eligibility is confirmed and a patient is registered: for the purposes of assessment windows, it is assumed that Day 0 
is the calendar day before Day 1 of Cycle 1. If this is not the case and first infusion is administered more than one week after 
screening window, laboratory tests (hematology, biochemistry A, B and pregnancy test if applicable) must be repeated within the 
three days prior to first infusion.
‡ At 30 ±7 days after the last treatment infusion, an EOT visit should be performed. The listed assessments will have to be done if 
no recent data are available (i.e. within last 10 days prior to the EOT visit) or if the last data available show a grade ≥ 2 alteration.
§ Only information on SAEs that occur after signature of informed consent form is required. Grading should be as per NCI-CTCAE 
v. 4.
A 3-day window will be allowed for laboratory procedures and ECG, a 1-week window for radiological tumor assessments 
(helical CT-scan or MRI) and LVEF assessments, a 1-day window for clinical assessments (ECOG PS, physical examination, 
vital signs, weight, BSA), and a 7-day window for the assessments at EOT. 


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1.
Body surface area (BSA) will be recalculated on Day 1 of each treatment cycle. Dose will be adjusted if BSA change is ≥ 10% 
(higher or lower) of the previous value. Height is only required at baseline.
2.
Any patient presenting a grade ≥ 3 treatment-related AE should have all relevant tests re-assessed at least every 48-72 hours 
until recovery to grade ≤ 2.
3.
Any patient having febrile neutropenia of any grade, grade 4 neutropenia, and/or grade 4 thrombocytopenia, should have 
relevant tests repeated daily until recovery to grade ≤3 and up to the next day after fever resolution, if applicable.
4.
Two blood samples (24 hours and 72 hours after the end of PM01183 infusion) will be collected at the same time than PK 
samples #6 and #7 in Cycle 1 for monocyte count.
5.
From Cycle 2 onwards, Hematology and Biochemistry A tests on Days 8 and 15 are to be performed only in patients who 
present biochemical grade ≥3 or hematological grade > 4 treatment-related toxicities, or who required dose adjustments  due to 
hematological or biochemical abnormalities in the preceding cycle. 
6.
Eight blood samples (before PM01183 infusion start, 5 min before the end of PM01183 infusion and 30 min, 1 hour, 3 hours, 
24 hours, 72 hours and 168 hours after the end of PM01183 infusion) will be collected for pharmacokinetic analyses in Cycle 1. 
In addition, one blood sample for the evaluation of AAGP will be collected before PM01183 infusion start.
7.
Six blood samples (before PM01183 infusion start, 5 min before the end of PM01183 infusion and 30 min, 1 hour, 3 hours and 
168 hours after the end of PM01183 infusion) will be collected for pharmacokinetic analyses in Cycle 2. In addition, one blood 
sample for the evaluation of AAGP will be collected before PM01183 infusion start.
8.
Beta subunit-human chorionic gonadotropin (ß-hCG) (urine or serum). In patients of childbearing potential (except germ cell 
tumor patients), if ß-hCG levels are elevated, pregnancy must be clinically discarded by an additional test (i.e., ultrasound) 
before any other study procedure. Pregnancy during treatment or within three months from the patient’s last PM01183 
administration is considered an immediately reportable event.
9.
ECG: cardiac rhythm will be identified in ECG intervals of at least 30 seconds of duration, PR interval, QT interval (raw), heart 
rate (HR) and QRS complex. LVEF: impaired cardiac function is defined as LVEF < 50 % as measured by multiple-gated 
acquisition scan (MUGA) or echocardiography (ECHO).
10. Evaluation by contrast enhanced helical CT-scan or MRI, as clinically indicated, of all measurable sites of disease involvement 
and of all non-measurable sites of disease should be done at baseline. While on treatment, evaluation of all original sites of 
disease involvement at baseline should be done as per RECIST v.1.1. Evaluation should be repeated at end of treatment visit, if 
not previously done, and if the reason for treatment discontinuation is other than PD. The same initial method must be used 
throughout the study. In SCLC patients, brain CT-scan or MRI will be requested at baseline within two weeks before the 
planned treatment onset to rule out CNS involvement. In SCLC patients, anonymized copies of all the images obtained 
throughout the study must be submitted to the Sponsor.
11. Patients showing a response must have a confirmatory assessment at least four weeks later. 
12. Only patients who discontinue treatment without PD will have radiological evaluations. The assessments will be performed 
every two months during the first six months and every three months thereafter until PD, start of a new antitumor therapy, 
death, or until the date of study termination (clinical cutoff for each cohort except SCLC: when all evaluable patients within 
each cohort have at least 12 months of follow-up from the first PM01183 infusion). Patients with SCLC will be followed-up for 
at least 18 months after the last patient enrolled received the first PM01183 infusion (a documented phone contact will be 
acceptable).
13. Patients withdrawn from the study treatment with an ongoing drug-related AE should be followed every four weeks until event 
recovery to at least grade 1 or stabilization or until onset of a new antitumor therapy.
Coagulation: PT/INR and PTT.
Hematology: Hemoglobin, platelet counts, and differential WBC including neutrophils, monocytes and lymphocytes.
Biochemistry A: Serum electrolytes (Na+, K+, Cl−), AST, ALT, AP, GGT, total bilirubin (direct bilirubin to be measured only if 
total bilirubin is >1.5xULN), LDH, creatinine, glucose, and CPK.
Biochemistry B: Albumin, total proteins, total calcium and Mg++. Albumin assessments on Day 1 of every cycle during the study 
are mandatory for all patients. Total proteins, total calcium and Mg++ will be measured at baseline and repeated thereafter only in 
those patients with abnormal baseline values. 
In patients with germ cell tumors, ß-hCG and AFP will be measured at baseline and repeated thereafter in those patients with 
elevated values at baseline.
AAGP, alpha-1 acid glycoprotein; AFP, alpha fetoprotein; AE(s), adverse event(s); ALT, alanine aminotransferase; AP, alkaline 
phosphatase; AST, aspartate aminotransferase; ß-hCG, beta subunit of human chorionic gonadotropin; CNS, central nervous 
system; CPK, creatinine phosphokinase; CPK-MB, creatinine phosphokinase MB isoenzyme; CT, computed tomography; ECG, 
electrocardiogram; ECHO, echocardiogram; ECOG PS, Eastern Cooperative Oncology Group performance status; EOT, end of 
treatment; GGT, gamma glutamyltransferase; HCG, human chorionic gonadotropin; HR, heart rate; ICF, informed consent form; 
INR, international normalized ratio; LDH, lactate dehydrogenase; LDL, low density lipoprotein; LVEF, left ventricular ejection 
fraction; MRI, magnetic resonance imaging; MUGA, multiple gated acquisition scan; NA, not applicable; NCI-CTCAE, National 
Cancer Institute Common Terminology Criteria for Adverse Events; PD, progressive disease; PGx, pharmacogenomics; PK, 
pharmacokinetic(s); PT, pro-thrombin time; PTT, partial thromboplastin time; SCLC, small cell lung cancer; WBC, white blood 
cells.


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
1y-OS
One-year Overall Survival
5-FU
5-Fluorouracil
5-HT3
Serotonin
AAGP
Alpha-1 Acid Glycoprotein
AE(s)
Adverse Event(s)
AFP
Alpha-Fetoprotein
ALT
Alanine Aminotransferase
ANC 
Absolute Neutrophil Count
AP
Alkaline Phosphatase
ASCO
American Society of Clinical Oncology
AST
Aspartate Aminotransferase
β-hCG
Beta Subunit of Human Chorionic Gonadotropin
BEP
Bleomycin, Etoposide and Cisplatin
BSA
Body Surface Area
Cmax
Maximum Plasma Concentration
CAV
Cyclophosphamide, Doxorubicin (Adriamycin) and Vincristine
CNS
Central Nervous System
CPK
Creatine Phosphokinase
CR
Complete Response
CRA
Clinical Research Assistant
CRF
Case Report Form
CSF
Colony-stimulating Factors
CT
Computed Tomography
d/D
Day(s)
DNA
Deoxyribonucleic Acid
DP
Drug Product
DR
Duration of Response
DSB
Double-strand Breaks
ECG
Electrocardiogram
ECHO
Echocardiography
ECOG
Eastern Cooperative Oncology Group
EFTs
Ewing Family of Tumors
EGF
Epidermal Growth Factor
EGFR
Epidermal Growth Factor Receptor
EOI
End of Infusion
EOT
End of Treatment
EPO
Erythropoietin


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EU
European Union
FD
Flat Dose
FDA
Food and Drug Administration
FUP
Follow-up
GCP
Good Clinical Practice
GCTs
Germ Cell Tumors
GDPR
General Data Protection Regulation
GEP-NETs
Gastroenteropancreatic Neuroendocrine Tumors
GGT
Gamma Glutamyltransferase
GMT
Greenwich Meridian Time
Gy
Gray
H&N
Head and Neck Carcinoma (Cancer)
hCG
Human Chorionic Gonadotropin
HER-2
Human Epidermal Growth Factor Receptor 2
HIV
Human Immunodeficiency Virus
HR
Hazard Ratio/Homologous Recombination
IA
Investigator’s Assessment
IB
Investigator’s Brochure
IC
Informed Consent
IC50
Half Maximal Inhibitory Concentration 
ICF
Informed Consent Form
ICH
International Conference on Harmonization
IEC
Independent Ethics Committees
IG50
Concentration that Results in 50% of Cell Growth Inhibition
IHC
Immunohistochemistry
IMP
Investigational Medicinal Product
INR
International Normalized Ratio
IRB
Institutional Review Board
IRC
Independent Review Committee
irPFS
Immune-related PFS
i.v.
Intravenous (ly)
LC-MS/MS
Liquid Chromatography/Mass Spectrometry/Mass Spectrometry 
LDH
Lactate Dehydrogenase
LVEF
Left Ventricular Ejection Fraction
MAb
Monoclonal Antibody
MBC
Metastatic Breast Cancer
mg
Milligram
MRI
Magnetic Resonance Imaging
mTOR
Mammalian Target of Rapamycin


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MUGA
Multiple-gated Acquisition Scan
NCCN
National Comprehensive Cancer Network
NCI
National Cancer Institute
NCI-CTCAE
National Cancer Institute-Common Terminology Criteria for Adverse Events
NER
Nucleotide Excision Repair
NET(s)
Neuroendocrine tumor(s)
NSCLC
Non-small Cell Lung Cancer
ORR
Overall Response Rate
OS
Overall Survival
PARP
Poly (ADP-Ribose) Polymerase
PCR
Polymerase Chain Reaction
PD
Progressive Disease/Disease Progression
PFS
Progression-free Survival
PhV
Pharmacovigilance
PGx
Pharmacogenomics
PK
Pharmacokinetics
PM01183
Lurbinectedin
PNET
Peripheral Neuroectodermic Tumor
PR
Partial Response
PRBC
Packed Red Blood Cells
PRE TT
Pre-treatment
PS
Performance Status
PT
Pro-thrombin Time
PTEN
Phosphatase and Tensin Homolog
PTT
Partial Thromboplastin Time
q3wk
Every Three Weeks
Q7dx3
Three Consecutive Weekly Doses (D-0,7,14)
Qdx5x2
Two Cycles of Five Daily Doses
RBC(s)
Red Blood Cell(s)
RD
Recommended Dose 
RECIST
Response Evaluation Criteria In Solid Tumors
RR
Response Rate
RT
Radiotherapy
SAE(s)
Serious Adverse Event(s)
SCLC
Small Cell Lung Cancer
SD
Stable Disease
SUSAR/SUA
Suspected Unexpected Serious Adverse Reaction
T/C
Treatment/Control
TAP
Cisplatin, Doxorubicin, plus Paclitaxel


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TIP
Paclitaxel, Ifosfamide and Cisplatin
TT
Treatment
TTP
Time to Progression
UK
United Kingdom
ULN
Upper Limit of Normal
US/USA
United States/United States of America
VIP
Etoposide, Ifosfamide and Cisplatin (Vinblastine-based)
WBC
White Blood Cells
WHO
World Health Organization
wk/wks
Week/weeks
WOCBP
Women of Childbearing Potential
WMA
World Medical Association


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1.
INTRODUCTION
This will be a multicenter, phase II clinical trial to evaluate the efficacy and safety of 
lurbinectedin (PM01183) in patients with the following advanced solid tumors.
1.1
SMALL CELL LUNG CANCER (SCLC)
Small cell lung cancer (SCLC) is a particularly aggressive type of lung cancer, related 
to smoking, which comprises approximately 10-15% of all lung cancers. It is 
characterized by rapid growth, early dissemination and acquired resistance to drugs [1]. 
SCLC is classically staged into limited stage or extensive stage disease. Limited stage
disease is potentially curable with aggressive therapy consisting of concurrent 
chemoradiotherapy, prophylactic cranial irradiation, and occasionally, surgery [2, 3]. 
However, despite best management, the 5-year overall survival (OS) in limited stage 
SCLC is still only 15% to 25%. In addition, nearly two-thirds of SCLC patients have 
extensive stage disease at diagnosis. Extensive stage disease is not curable and patients 
are treated with palliative intent, with a median survival of 7 to 11 months and less than 
5% being alive at 2 years [1, 4].
Standard ﬁrst-line chemotherapy consists of a platinum compound, such as cisplatin or 
carboplatin, in combination with etoposide [5]. Most treated patients show disease 
relapse and are eligible for second-line therapy. Selection of second-line chemotherapy 
depends on the duration of the response to the ﬁrst-line one. If the duration of response 
is > 3 months, the disease is considered sensitive, oppositely to resistant, with a duration 
of response of < 3 months, and refractory, which does not respond or progresses on 
initial treatment [6, 7]. Patients with sensitive disease have a much greater likelihood of 
responding to further systemic treatment, and are often re-challenged with the first-line 
regimen. Patients with refractory and resistant disease are usually treated with a
different chemotherapy regimen in second-line. Second-line treatment in refractory or 
resistant disease usually is the combination of cyclophosphamide, doxorubicin and 
vincristine (CAV) or topotecan. Topotecan was approved for use in the second-line 
setting because it demonstrated efﬁcacy similar to CAV: response rate 24.3% vs. 18.3%; 
median time to progression 13.3 weeks vs. 12.3 weeks, and median survival 25 weeks 
vs. 24.7 weeks, and tolerability was better [8-10].  
A phase II study evaluated ipilimumab plus paclitaxel/carboplatin in extensive stage 
disease SCLC. One hundred and thirty chemotherapy-naïve patients were randomized 1: 
1: 1 to receive paclitaxel (175 mg/m2)/carboplatin (area under the curve = 6) with either 
placebo or ipilimumab 10 mg/kg in two alternative regimens: concurrent (ipilimumab 
plus paclitaxel/carboplatin followed by placebo plus paclitaxel/carboplatin) or phased
(placebo 
plus 
paclitaxel/carboplatin 
followed 
by 
ipilimumab 
plus 
paclitaxel/carboplatin). Treatment was administered every 3 weeks (q3wk) for a 
maximum of 18 weeks (induction), followed by maintenance ipilimumab or placebo 
every 12 weeks. Endpoints included progression-free survival (PFS), best overall 
response rate (ORR), OS and safety. Phased ipilimumab, but not concurrent 
ipilimumab, improved immune-related PFS (irPFS) versus control [hazard ratio
(HR)=0.64; p=0.03]. No improvement in PFS (HR=0.93; p=0.37) or OS (HR=0.75; 
p=0.13) was observed. Phased ipilimumab, concurrent ipilimumab and control, 
respectively, were associated with median irPFS of 6.4, 5.7 and 5.3 months, and median 
OS of 12.9, 9.1 and 9.9 months. Overall rates of grade 3/4 adverse events (AEs) were 


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17%, 21% and 9% for phased ipilimumab, concurrent ipilimumab and control, 
respectively [11]. 
Results of the phase III ACT-1 trial showed that amrubicin, a topoisomerase II inhibitor, 
had advantages over topotecan as second-line treatment for SCLC. Both drugs achieved 
similar OS: 7.5 months in the amrubicin arm versus 7.8 months in the topotecan arm, 
but amrubicin improved response rates (31.1% vs. 16.9%) and PFS (4.1 months vs. 3.5 
months) and also improved control of lung cancer-associated symptoms. In addition, 
amrubicin appeared to have some advantage in OS of patients with refractory disease 
(6.2 months vs. 5.7 months) [12]. Amrubicin is approved in Japan for SCLC.
However, patients who respond to second-line treatment will invariably progress and a 
decision will need to be made about further therapy. High quality evidence to guide 
treatment decisions for SCLC in the third-line is scarce; several agents have been tried,
but no drug or combination regimen is approved in this setting [1, 13, 14]. 
There is a critical need for effective therapy in advanced forms of this disease and,
whenever possible, patients should be given the opportunity to participate in clinical 
trials. 
1.2
HEAD AND NECK CANCER (H&N)  
Head and neck cancer (H&N) accounts for approximately 6.6% of all cancers. The vast 
majority of these cancers arise from the epithelium lining the oral cavity, oropharynx, 
hypopharynx and larynx, and are, therefore, epidermoid carcinomas
[15]. 
Environmental contributory factors to the development of H&N include smoking, 
alcohol consumption and human papillomaviruses. Despite advances in the diagnosis 
and treatment of H&N, survival has not improved signiﬁcantly. If detected early, 
surgery is the mainstay treatment for this cancer. However, most patients present with 
advanced disease. The 5-year survival for H&N is 64%. Forty-ﬁve percent of these 
cancers are treated with surgery alone, 26% are treated with surgery and radiation 
therapy, and 30% receive radiation therapy alone [16]. Several clinical trials confirmed 
the superiority in regard to tumor control of altered fractionation schedules as compared 
to standard (conventional) fractionation. However, improvement in patients’ survival 
has not been consistent. Clinical investigations show that improvement in locoregional 
disease control and consistent gain in survival have been achieved with combinations of 
radiotherapy and concurrent chemotherapy in patients with mostly stage IV carcinomas. 
Cisplatin-based chemoradiotherapy is nowadays the standard of care for advanced H&N
patients [17, 18]; nevertheless, disease control occurs at the expense of increased 
morbidity. Consequently, concurrent radiochemotherapy is now preferred for non-
surgical treatment of patients with locally advanced carcinomas, while altered 
fractionation is generally selected for patients with intermediate-stage tumors or who 
are medically unfit to receive chemotherapy [19].
Targeted therapies have also played an important role in the treatment of head and neck 
carcinoma. The epidermal growth factor receptor (EGFR) has a strong influence in 
H&N development, growth, angiogenesis and metastatic spread. The addition of 
cetuximab to radiotherapy significantly increased the 3-year locoregional control rates 
(47% vs. 34%) and OS rates (55% vs. 45%) compared to radiotherapy alone in a trial on 
424 patients
[20]. The combined effect of cetuximab and cisplatin-based 
chemoradiotherapy was also studied in a phase II trial in patients with advanced H&N. 
Although the 3-year OS and locoregional control rates were 76% and 71%, respectively, 
the study was closed due to significant toxicity [21]. 


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Combination therapies with antiangiogenic agents have also been evaluated. A phase II 
clinical trial in patients with advanced H&N that involved bevacizumab and cisplatin-
based chemotherapy combined with intensity-modulated radiotherapy achieved a PFS at 
2 years of 75.9% and an OS rate at 2 years of 88% [22]. 
The latest radiotherapy techniques combined with adjuvant and/or targeted therapies 
succeeded in increasing locoregional control in advanced H&N patients. The downside 
is the increased rate of side effects. Furthermore, OS in this patient group has not 
improved considerably over the last decades. Advanced unresectable H&N are still a 
clinical challenge and their optimal treatment is yet to be established [23].
1.3
NEUROENDOCRINE TUMORS (NETS)
Neuroendocrine tumors (NETs) originate from the neuroendocrine network, which 
comprises the gastrointestinal tract, the lungs, the paraganglia, including the adrenal 
medulla, and the neuroendocrine cells scattered in the skin, thymus, prostate and other 
tissues. NETs are characterized by their ability to secrete a large number of peptide 
hormones that can lead to the development of distinct clinical syndromes. Based on this, 
NETs are broadly subdivided into functional or non-functional tumors. However, the 
functional status of these tumors may change over time or with treatment.
Gastroenteropancreatic neuroendocrine tumors (GEP-NETs), also known as carcinoids 
and islet cell tumors (in pancreas), are derived from neuroendocrine cells that can occur 
anywhere along the gastrointestinal tract and comprise a heterogeneous family of 
neoplasms with a wide spectrum of clinical behavior. These tumors have been 
considered rare diseases, although the most recent data from the US Surveillance 
Epidemiology and End Results show an increase of more than 400% in the incidence of 
this disease over a period of 29 years, from 1.09 per 100000 population in 1973 to 5.25 
per 100000 population in 2004 [24]. This can partially be due to improved detection 
methods.
Surgery is the only potentially curative therapeutic strategy in localized disease. No 
adjuvant therapy is recommended in completely resected, well-differentiated localized 
GEP-NETs. For advanced disease, somatostatin analogues have proven to be effective 
in ameliorating symptoms of hormone overproduction in functional tumors; however, 
options regarding systemic therapy continue to be limited [25].
The role of chemotherapy is controversial. 5-fluorouracil (5-FU), streptozocin, 
capecitabine, temozolamide, dacarbazine, doxorubicin, lomustine, platinum drugs and 
etoposide have been used in various combinations. Pancreatic tumors often respond 
better to chemotherapy than other NETs, while most types of chemotherapy are less 
effective for carcinoid tumors. Streptozocin was approved in 1976 by the US Food and 
Drug Administration (FDA) for pancreatic NETs; however, earlier trials often used 
criteria to measure outcomes that are not accepted today, namely, physical examinations 
were sometimes used to document response to therapy and cross-sectional imaging was 
not uniformly used to measure tumor size. Two retrospective studies of 84 and 45 
patients with advanced pancreatic NETs treated with streptozocin-based chemotherapy 
demonstrated response rates by the Response Evaluation Criteria In Solid Tumors 
(RECIST) or World Health Organization (WHO) criteria of 39% and 36%, respectively, 
but treatment was associated with significant toxicity [26, 27]. Finally, no published 
data have documented improvements in PFS or OS compared with best supportive care
[28, 29]. 


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Other regimens using temozolomide-based chemotherapy have also been studied in 
small prospective studies that included small numbers of NETs, but need confirmation 
in larger studies. A phase II study investigating the combination of temozolomide and 
thalidomide demonstrated an objective response rate of 45% in a subset of 11 patients 
with NETs [30]. A retrospective study of temozolomide with capecitabine in 30 chemo-
naïve patients reported an objective radiological response rate of 70% and a median PFS 
of 18 months [31]. A phase II trial of temozolomide and bevacizumab reported a 
response rate of 33% in a more heavily pretreated subpopulation with advanced NETs
[32]. 
The mammalian target of rapamycin (mTOR) has a role to play in islet cell tumors in 
patients with tuberous sclerosis as well as in sporadic NETs [33]. Thirty-six patients 
with advanced NETs and evidence of progressive disease were treated with the mTOR 
inhibitor, temsirolimus, as a single agent in a phase II study. Disease stabilization 
occurred in 58 cases and partial radiological response in two cases (6%) with median 
time to progression of 6 months. Adverse events such as fatigue, rash and 
hyperglycemia occurred in a number of patients [34]. A phase II study evaluating 
everolimus monotherapy versus everolimus plus octreotide in patients with advanced 
pancreatic NET who had progressed on first-line yielded 80% of stable disease and 
4.4% partial response with a median PFS of 16.7 months in the combined treatment 
arm. In the everolimus monotherapy arm, partial responses were observed in 9.6% and 
stable disease in 67.8%; median PFS was 9.7 months [35]. These promising results led 
to the conduction of two everolimus trials, RADIANT-2 and RADIANT-3. The first one 
was a randomized, double-blind, placebo-controlled, multicenter, phase III study of 
octreotide combined with everolimus or placebo in patients with advanced NETs. It 
showed an improvement in PFS from 11 months in the placebo arm to 16 months in the 
active treatment arm. On central radiologic review, the statistical signiﬁcance of this 
trial was borderline (P = 0.026) [36]. RADIANT-3 was a randomized, double-blind, 
placebo-controlled, multicenter phase III study of everolimus plus best supportive care 
vs. placebo and best supportive care in patients with progressive advanced pancreatic 
NETs. Results from this study demonstrated a statistically and clinically significant PFS 
improvement , with medians of 11.0 months with everolimus compared with 4.6 months 
with placebo [37]. In addition, a phase III study compared sunitinib vs. placebo in 
advanced, progressive well-differentiated pancreatic NETs. The study was stopped at 
interim analysis, after enrollment of 171 patients, due to a significant improvement in 
median PFS from 5.5 months in the placebo arm to 11.4 months in the treatment arm 
(HR 0.418; p=0.0001). Unblinding at the interim analysis allowed the majority of 
placebo patients to cross over to the treatment arm. A trend toward improved OS was 
observed, which did not meet statistical significance. Side effects included 
hypertension, palmar-plantar erythrodysesthesia, fatigue, diarrhea, and cytopenias [38].
Although randomized, placebo-controlled studies have demonstrated statistically 
significant improvements in PFS for everolimus and sunitinib, response rates associated 
with these agents are quite low (5% to 9.3%) and there are no supporting randomized 
trials with active controls. Temozolomide- and streptozocin-based regimens appear to 
yield substantially higher response rates, but these regimens have not been studied in 
randomized clinical trials. At present, no proven predictive factors can help guide 
treatment selection for patients with advanced NET, and the guidelines of the National 
Comprehensive Cancer Network (NCCN) include somatostatin analogs, everolimus, 
sunitinib, cytotoxic chemotherapy, as treatment options, but do not recommend a 


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particular sequence of treatments. Further clinical studies with new therapeutic agents in 
advanced NET are warranted.
1.4
BILIARY TRACT CARCINOMA
Biliary tract carcinoma (mostly adenocarcinoma) is the primary cancer of the epithelial 
cells of the bile ducts arising along the intrahepatic or extra-hepatic biliary tree. It is the 
second-most common primary liver cancer and accounts for an estimated 15% of 
primary liver cancer worldwide. Its incidence varies highly in different areas of the 
world, with 1-2 cases per 100000 population per year in the United Kingdom (UK) and 
the USA, and 5.5 and 7.3 cases per 100000 people per year in Japan and Israel, 
respectively. There is a high incidence of cholangiocarcinoma in Southeast Asian 
countries, due to chronic endemic infestation with different species of trematoda [39].
Most cases occur over 60 years. Risk factors include primary sclerosing cholangitis, 
Crohn's disease, parasitic infestation, industrial chemical and thorium exposure and 
congenital abnormalities of the bile ducts. Hepatitis C, human immunodeficiency virus 
(HIV) infection and diabetes have been recently associated with intrahepatic 
cholangiocarcinoma [40, 41].
Owing to the lack of randomized controlled trials, no standard chemotherapy exists in 
the treatment of advanced biliary tract carcinoma. 5-FU or gemcitabine are
recommended based on small phase II trials. An analysis of all chemotherapy trials 
published from 1985 to July 2006 as well as of the American Society of Clinical 
Oncology (ASCO) abstracts from 1999 to 2006 was done. Response rate (RR), tumor 
control rate, time to progression (TTP), OS and toxicity were studied in 104 trials 
comprising 112 trial arms and 2810 patients (with 634 responders and 1368 patients 
with tumor control). Pooled RR and tumor control rate were 22.6 and 57.3%, 
respectively. Significant correlations of RR and tumor control rate with survival times 
were observed. Subgroup analysis showed superior RRs for gallbladder carcinoma 
compared with cholangiocarcinoma, but shorter OS for the former. Furthermore, 
superior RRs and tumor control rate of gemcitabine and platinum-containing regimens 
were found with higher RR and tumor control rate in the combination subgroup. Based 
on the published results of these phase II trials, gemcitabine combined with platinum 
compounds represents the provisional standard of chemotherapy in advanced biliary 
tract cancer [42].
1.5
ENDOMETRIAL CARCINOMA
Endometrial carcinoma is the most common gynecological malignancy in Europe and 
North America. It is the seventh most common cause of death from cancer in women in 
Western Europe, accounting for 1-2% of all deaths from cancer. In the United States, 
endometrial cancer accounts for 6% of all cancers in women. Median age of occurrence 
is 63 years and more than 90% of women are older than 50-years-old [43, 44]. Risk 
factors for developing endometrial cancer are: obesity, nulliparity, late menopause, 
diabetes mellitus and prolonged exposure to estrogen, tamoxifen and
oral 
contraceptives.
The most common type is endometrioid adenocarcinoma. Clear cell and papillary serous 
endometrial carcinoma are histologically similar to those arising in the ovary and the 
fallopian tube, and their prognosis is worse relative to adenocarcinomas.
Based on histopathology, molecular profile and clinical course, endometrial cancers are 
divided into two categories. Type I include low-grade (I–II) adenocarcinomas that are 


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usually estrogen-related and have a favorable prognosis. Type II endometrial cancer is
not hormone dependent and comprise grade III endometrioid adenocarcinomas, 
papillary serous, clear cell carcinomas and other non-carcinomatous tumor types. They 
are associated with early spread and worse prognosis. Type II endometrial cancers have 
p53 mutations and loss of heterozygosity at several chromosomal loci. Some type II 
tumors may have molecular alterations found in type I such as K-ras, phosphatase and 
tensin homolog (PTEN), β-catenin and microsatellite instability, which indicates that 
type II tumors can arise from dedifferentiation of a pre-existing type I cancer [45, 46]. 
Endometrial carcinoma is generally associated with a good prognosis, largely because 
approximately 75% of patients are diagnosed with stage I disease and 13% of patients 
with stage II disease [47]. For early-stage disease, surgery alone or in combination with 
local therapy is generally curative. For patients with stage III or stage IV disease and for 
those with recurrent endometrial cancer, the prognosis remains poor and the optimal 
adjuvant therapy is yet to be established. Women with advanced stage disease at 
presentation may also be appropriate candidates for systemic and local therapies. 
Treatment choice depends largely on the localization of disease, the patient’s 
performance status and previous treatment history, as well as on the tumor’s hormonal 
receptor status. Radiotherapy is appropriate for isolated vaginal recurrences in patients 
with no previous history of radiation therapy. Patients with recurrent low-grade tumors 
overexpressing estrogen and progesterone receptors may be treated with progestin 
therapy. Systemic therapy with platinum-based chemotherapy is appropriate for patients 
with disseminate recurrences or advanced stage disease at presentation, or for those with 
receptor-negative tumors. The two most commonly used regimens to treat metastatic 
endometrial cancer are carboplatin plus paclitaxel, or the triple drug combination of 
cisplatin, doxorubicin plus paclitaxel (TAP) [48]. Of these, carboplatin and paclitaxel is 
the most used regimen because it has similar activity to TAP in terms of PFS and OS,
but is associated with less toxicity [49].
Women who have disease progression despite first-line chemotherapy have a poor 
prognosis. They are usually treated with supportive care and referred to palliative care 
regardless of whether second-line treatment is administered. For women who desire 
subsequent treatment, the choice of second-line therapy depends on the type of 
treatment administered in the first-line setting. Single agent therapy in second line with 
anthracyclines, taxanes, alkylators or topoisomerase inhibitors has shown responses in 4 
to 27% of the patients [50]. These responses are often short-lived and median OS across 
studies is typically less than one year. New active therapies are urgently needed for this 
group of patients.
1.6
BRCA 1/2-ASSOCIATED METASTATIC BREAST CANCER
Despite of the advances achieved in the treatment of breast cancer, the prognosis for 
patients with metastatic breast cancer (MBC) remains poor [51]. Metastatic disease at 
diagnosis occurs in only 6% of newly diagnosed cases [52], but approximately 30% of 
women with early breast cancer will eventually develop recurrent advanced or 
metastatic disease. MBC remains incurable, with a median survival time between 18 
and 30 months, and there is no single standard of care for these patients, as treatment 
requires an individualized approach based on multiple factors.
It is currently estimated that 5-10% of all breast cancers are hereditary due to germline 
mutations in BRCA 1 and BRCA 2 genes. The BRCA 1 and BRCA 2 proteins 
participate in deoxyribonucleic acid (DNA) repair and homologous recombination as 


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well as other cellular processes [53].  The fact that hormone unresponsive MBC lacking
human epidermal growth factor receptor 2 (HER-2) overexpression, known as triple 
negative (TN) breast cancer, is more common in BRCA-mutated patients suggest a 
worse prognosis for these hereditary breast cancers. In particular, BRCA 1-associated 
hereditary breast cancer may be more aggressive than sporadic breast cancer, with 
medullar or atypical features, p53 mutations and/or high level expression of epidermal 
growth factor (EGF) and Ki-67 [54]. BRCA 2 mutations are heterogeneous and often 
present in relatively high grade tumors [55]. BRCA 1/2-associated breast cancer has 
come into focus due to the development of new molecules able to inhibit the poly 
(ADP-ribose) polymerase (PARP), a nuclear enzyme responsible for signaling in the 
presence of DNA damage facilitating its repair by specific enzymes such as BRCA 1/2 
proteins. Indeed, BRCAness tumors are more sensitive to PARP inhibition than wild 
type tumors, which may escape through alternative pathways; thus, the possibility of 
selectively target these tumors had brought along a lot of interest. Promising response 
rates up to 41% were reported in a phase II trial in advanced breast cancer with a novel 
oral PARP inhibitor, olaparib [56] and several large phase III trials of PARP inhibitors 
have been conducted in relapsed and MBC. Drugs with novel mechanism of action, 
lacking cross-resistance with other commonly used agents, are needed for MBC in 
patients with deleterious BRCA 1/2 mutations [57].  
1.7
CARCINOMA OF UNKNOWN PRIMARY SITE
The site of origin of a histologically documented carcinoma is not identified clinically 
in approximately 3% of patients; this situation is often referred to as carcinoma of 
unknown primary origin or occult primary malignancy. The deﬁnition of carcinoma of 
unknown primary site includes patients who present with histologically conﬁrmed 
metastatic cancer in whom a detailed medical history, complete physical examination 
including pelvic and rectal examination, full blood count and biochemistry, urinalysis 
and stool occult blood testing, histopathological review of biopsy material with the use 
of immunohistochemistry, chest radiography, abdominal and pelvis computed 
tomography and, in certain cases, mammography, fail to identify the primary site. The 
majority of them are adenocarcinomas or undifferentiated tumors, or, less commonly, 
squamous cell carcinoma, melanoma, sarcoma, and neuroendocrine tumors [58]. 
Carcinomas of unknown primary are by definition metastatic; therefore, the prognosis is 
poor. As a group, the median survival is approximately 3 to 4 months, with less than 
25% and 10% of patients alive at 1 and 5 years, respectively. Chemotherapy regimens 
have been explored in over 35 prospective clinical trials, most of them phase II. 
Combination doublets, (usually platinum and taxane-containing) appear to be superior 
to single-agent regimens while triplet combinations do not appear to be better than 
doublets. High-dose regimens do not appear to be superior to regular regimens. One of 
the best outcomes from a phase II trial is from a combination of a platinum/taxane 
doublet with bevacizumab and erlotinib; median OS for this regimen was 12.6 months 
(n=60). A randomized phase II trial in 80 patients showed better efficacy/toxicity ratio 
with the cisplatin/gemcitabine than with the cisplatin/irinotecan regimen [59]. The only 
phase III trial performed in carcinomas of unknown primary site, comparing paclitaxel, 
carboplatin, and etoposide with gemcitabine and irinotecan (n=198), showed no 
statistically significant difference between either arm (median OS 7.4 vs. 8.5 months). 
Overall median OS from chemotherapy combinations yields survival rates of 9 to 13 
months, which parallels the median survival rates of thoracic, gastrointestinal, and 
urothelial malignancies that comprise most of these cancers. It is likely that advances in 


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oncology regimens for difficult-to-treat cancers may improve outcomes in carcinoma of 
unknown primary site [60].
1.8
GERM CELL TUMORS (GCTS)
Testicular germ cell tumors (GCTs) account for between 1% and 1.5% of male 
neoplasms. Germ cell tumors (seminomatous and non-seminomatous) are the most 
common cancers of young adult men, and their incidence is increasing rapidly. Over 
90% of these tumors arise in the testes. Ovarian germ cell malignant tumors are very 
infrequent; they represent less than 2% of all ovarian cancers. Extragonadal primary 
sites also occur, usually in the retroperitoneum, mediastinum, and pineal/suprasellar 
region. Extragonadal tumors commonly metastasize to the regional lymph nodes, lungs, 
and other sites. Undescended testis, contralateral testicular tumor and familial testis 
cancer are risk factors for testicular GCTs. Prognosis is related not only to anatomic 
extent of spread, but also to the primary site (extragonadal or gonadal) and to the extent 
of production of the tumor markers alpha-fetoprotein (AFP), human chorionic 
gonadotropin (hCG), and lactate dehydrogenase (LDH), which may reflect the 
underlying biologic aggressiveness [61]. Serum AFP increase is observed in 40% to 
60% of men with non-seminomas. Seminomas do not produce AFP. Patients with 
elevated serum AFP should be considered to have a mixed GCT. Increase of the beta 
subunit of hCG is found in approximately 14% of the patients with stage I pure 
seminoma and in about half of patients with metastatic seminoma. Approximately 40% 
to 60% of men with non-seminomas have an elevated serum beta-hCG. Serum tumor 
markers are also very useful for monitoring all stages of non-seminomas and for 
monitoring metastatic seminomas because elevated marker levels are often the earliest 
sign of relapse [62].
Patients with localized seminoma can be cured with radical orchiectomy and adjuvant 
radiotherapy. In low risk localized non-seminomatous GCTs, surveillance computed 
tomography scanning at three and 12 months post-surgery is recommended. Serum 
markers should be checked before and after surgery and weekly thereafter until normal. 
Measurement of serum AFP and HCG is essential in the follow up of patients with non-
seminomatous GCTs.
For patients with metastatic disease, the combination of bleomycin, etoposide and 
cisplatin (BEP) is the standard therapy. At first relapse most patients retain platinum 
sensitivity and standard-dose salvage regimens are based on cisplatin and ifosfamide. 
Response rates are generally around 50% with long term disease-free survival rates of 
20-30%. The largest body of evidence for standard-dose salvage therapy is for the 
paclitaxel-based, TIP (paclitaxel, ifosfamide and cisplatin) or vinblastine-based, VIP 
(etoposide, ifosfamide and cisplatin) ones. TIP is being increasingly used although there 
is no randomized comparison between these two regimens.
In patients who relapse after standard-dose salvage therapy,
only high-dose 
chemotherapy offers a chance of cure. For others, further lines of treatment are 
generally considered to be palliative. The choice of third-line therapy will be heavily 
dependent on the patient’s bone marrow reserve, performance status and resolution of 
toxicity from prior regimens. There are a number of single agents and combination 
regimens, containing gemcitabine, oxaliplatin, paclitaxel and epirubicin, none of which 
have been tested in comparative studies. These regimens lead to a low overall response 
rate of 18-24% with short duration of response [63].


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1.9
EWING FAMILY OF TUMORS (EFTS)  
Ewing family of tumors (EFTs) comprises several tumors derived from the same 
primordial bone marrow-derived mesenchymal stem cell,
including bone and 
extraskeletal Ewing’s sarcoma, peripheral neuroectodermic tumor (PNET) and Askin 
tumor (thoracic wall). They have in almost all instances a clonal translocation in the 
long arms of chromosomes 11 and 22, which fuses the EWS gene of chromosome 22 to 
the FLI1 gene of chromosome 11 [64]. 
The incidence of EFTs is approximately three cases per 1 million per year and has 
remained unchanged for 30 years [65].The median age of patients with EFTs is 15 
years, and more than 50% are adolescents. Based on data from 1,426 patients entered 
into the European Intergroup Cooperative Ewing Sarcoma Studies, 59% of patients 
were male and 41% female. For extraosseous sarcoma, the most  common  sites  are  
trunk  (32%),  limbs  (26%),  head  and  neck  (18%), retroperitoneum (16%) and other 
sites (9%) [66]. 
The prognosis of EFTs varies depending on primary tumor site, presence of metastases 
and tumor size. The overall 5-year disease-free survival rate for localized sarcoma 
treated with surgery, radiation and multi-agent chemotherapy is 65-76% [67]. However, 
the 5-year disease-free survival rate drops to 30% if metastases are present at diagnosis.  
Limited improvement of survival rates has been achieved for metastatic Ewing’s 
sarcoma. Similarly, relapsed patients have a poor outcome, with very common failure to 
second-line therapy and low 5-year survival rates (13%) [68]. 
A multidisciplinary approach, including surgery, chemotherapy, and radiotherapy (RT) 
is mandatory. Multi-agent chemotherapy is essential for Ewing’s sarcoma due to the 
high risk of micrometastatic disease. It includes vincristine, doxorubicin, ifosfamide, 
and etoposide. Most protocols use cyclophosphamide as well and some incorporate 
dactinomycin. Duration of primary chemotherapy ranges from six months to one year
[69]. 
In high-risk  cases  of  Ewing’s sarcoma,  myeloablative  chemotherapy  followed  by 
autologous  stem  cell  transplantation  has  been  used  as  consolidation  therapy. 
Although  better  survival  than  expected  was  reported  with  this  approach,  large 
prospective trials are needed to properly evaluate the potential utility of this therapy in 
Ewing’s sarcoma patients [70].  
The management of relapsed or recurrent disease is not standardized and, in most cases, 
consists of different combinations of the same agents used as adjuvant therapy. Patients 
are often treated with more than one regimen to reduce disease burden to the minimum. 
Ifosfamide and etoposide are active in treating Ewing’s tumor of bone and should be 
considered for patients who have not previously received these agents. Combinations 
such as cyclophosphamide plus topotecan and irinotecan plus temozolomide have also 
been active in patients with recurrent or refractory disease [71, 72]. Radiotherapy of 
lung and bone, and surgical removal of metastases are also included in the management 
of these patients.  However,  patients  with  relapsed  disease  have  a  poor  outcome;  
failure  to second-line  therapy  is very  common,  with  5-year  survival  rates  around  
13% [44]. In addition,  the  toxicity,  morbi-mortality,  and  long-term  complications  of  
these  agents (cardiac,  renal,  pulmonary,  gonadal  and  secondary  neoplasias)  are  
considerable. Therefore, there is an urgent need for new therapeutic agents with 
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1.10 INFORMATION ON THE STUDY DRUG
1.10.1 Lurbinectedin (PM01183)
Please refer to the Investigator's Brochure (IB) for full information on lurbinectedin 
(PM01183).
1.10.1.1
Name and Chemical Information
PM01183 is produced by synthesis and has the following chemical properties:
Chemical Name
(1R,6'R,6a'R,7'R,13'S,14'S,16'R)-8',14'-dihydroxy-6,9'-dimethoxy-
4',10',23'-trimethyl-19'-oxo-2,3,4,6',7',9,12',13', 14',16'-decahydro-6a'H-
spiro[ß-carboline-1,20'-
[7,13]epimino[6,16](epithiopropanooxymethano) 
[1,3]dioxolo[7,8]isoquino[3,2-b][3]benzazocin]-5'-yl acetate
Molecular Formula
C41H44N4O10S
Molecular Weight
784.874
The structural and molecular formula of PM01183 are shown in Figure 1. 
Figure 1. Molecular formula of lurbinectedin (PM01183).
1.10.1.2
Non-clinical Data
PM01183 is a new synthetic tetrahydroisoquinoline alkaloid which binds the DNA 
minor groove, causing spatial distortion of DNA and protein complexes and leading to 
the formation of DNA double-strand breaks (DSBs), thus inducing apoptosis and 
delaying progression through the cell cycle S/G2 phase. 
PM01183 has a negative COMPARE analysis when compared against other 98 standard 
anticancer agents in the standard National Cancer Institute (NCI) panel of 36 cell lines. 
Thus, its mechanism of action is likely to differ significantly from all the other drugs. It 
only showed a positive correlation (S-rank > 0.8) with trabectedin [73]. 
In vitro, PM01183 demonstrated cytotoxic effects against a broad selection of tumor-
derived cell lines with half maximal inhibitory concentration (IC50) values in the low to 
very low nanomolar range (approximately median IC50 of 1-10 M). PM01183 also has in 
vivo antitumor activity against different murine models of xenografted human-derived 
tumor types.
The antineoplastic in vitro activity of PM01183 was evaluated in a panel of solid tumor 
cell lines (some of which are shown in Table 1), which were exposed to a range of 


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PM01183 concentrations for 72 hours and then assayed for viability by a MTT short-
term assay [74].
Table 1. Selected in vitro activity of PM01183.
Tumor
Cell line
IG50 (M)
Breast
BT-474
1.3·10-9
MDA-MB-231
3.5·10-9
MCF-7
1.7·10-9
Colon
LoVo
2.0·10-9
HCT 116
6.5·10-8
HT-29
2.4·10-9
Lung
A-549
1.3·10-9
NCI-H460
1.6·10-9
NCI-H23
5.4·10-10
Ovarian
A2780
1.6·10-9
IGROV-1
9.8·10-9
Pancreas
MiaPaca-2
1.1·10-9
PANC-1
2.9·10-9
IG50, concentration that results in 50% of cell growth inhibition.
The antineoplastic in vivo activity of PM01183 was demonstrated in a panel of several 
different human-derived tumor types, i.e., breast, colon, lung, ovarian and prostate 
(Table 2). The resulting tumor susceptibility was analyzed in xenografts grown in 
athymic mice, when unformulated PM01183 was administered at the rodent maximum 
tolerated dose [0.3 mg/kg (0.9 mg/m2)] as single bolus intravenous (i.v.) injection. 
PM01183 demonstrated statistically significant antitumor activity (p<0.05) against 
breast, lung and ovarian xenografts at different time points during the experiment, but 
had a more moderate antitumor profile against bladder, pancreas and prostate [75].
Table 2. Selected in vivo activity of PM01183.
Tumor
Cell line
Schedule
Dose level 
mg/kg/day (mg/m2/day)
T/C 
%
Optimal day
Lung
LXFL 529
Q7dx3
0.18 (0.54)
5
D-28
Bladder
UM-UC-3
Qdx5x2
0.06 (0.18)
58
D-23
Breast
MDA-MB-231
Q7dx3
0.18 (0.54)
40
D-34
MX-1
Q7dx3
0.18 (0.54)
0
D-21
Ovary
A2780
Q7dx3
0.18 (0.54)
34
D-17
Pancreas
Capan-1
Q7dx3
0.18 (0.54)
61
D-61
Prostate
PC-3
Q7dx3
0.18 (0.54)
65
D-27
D, day; Qdx5x2, two cycles of five daily doses; Q7dx3, three consecutive weekly doses (D-0, 7, 14); T/C, 
treatment/control.
Toxicology studies in rats and dogs showed that the main target organs were the bone 
marrow and the liver. The effect of a single bolus injection of PM01183 on 
cardiovascular parameters [arterial blood pressure, heart rate and lead II 
electrocardiogram (ECG)] was evaluated in dogs for six hours [76]. This study showed 
no effects on heart, blood pressure, lead II ECG variables (PR, QT, QTcF and QTcV 
intervals, and QRS duration), ECG gross morphology or rhythm in dogs treated with 
PM01183 at doses up to 0.01 mg/kg (0.2 mg/m2). Additionally, two different studies 
found no electrophysiological alterations in the heart rate and ECGs of dogs following 
single or repeated PM01183 administration at doses up to 0.05 mg/kg (1 mg/m2) [77, 
78].


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The antineoplastic in vitro activity of PM01183 was also evaluated in combination with 
other antineoplastic agents in solid and non-solid tumor cell lines [79, 80]. In solid 
tumor models, two combinations were strongly synergistic: PM01183 combined with 
topotecan (colon HT29, pancreas PANC-1 and glioblastoma U87MG cell lines) and 
PM01183 combined with erlotinib (lung A-549, gastric HGC-27 and prostate PC-3 cell 
lines). Some other standard agents, including platinum agents like oxaliplatin and 
cisplatin, showed synergistic activity in combination with PM01183 in different cell 
lines.
Part of the in vivo antitumor activity of lurbinectedin (PM01183) could be related to 
host-mediated effects that occur in vivo but not in vitro. Recent studies have highlighted 
the ability of trabectedin to modify the tumor microenvironment; particularly the drug 
seems to induce a decrease in the tumor-associated macrophages with significant down-
regulation of cytokines, chemokines and angiogenic factors [81-85]. Although these 
effects have been demonstrated for trabectedin, initial data suggest that some of these 
effects are shared by lurbinectedin (PM01183) (P.Allavena, unpublished data) [86].
1.10.1.3
Clinical Data
Based on the positive preclinical results described above, the clinical development 
program of PM01183 was started in March 2009. Currently, this program comprises 
five phase I single-agent studies (four in solid tumors and one in acute adult leukemia 
patients); six phase Ib combination studies with gemcitabine, capecitabine, doxorubicin, 
cisplatin, irinotecan, or paclitaxel with or without bevacizumab, in patients with selected 
advanced solid tumors; five phase II studies: three studies as single agent in second-line 
pancreatic cancer, in BRCA-mutated or in BRCA-unselected metastatic breast cancer 
patients, and the current basket trial, and two randomized studies in patients with 
platinum-resistant/refractory ovarian cancer (PM01183 single agent vs. topotecan), and 
in combination with gemcitabine as second-line therapy in advanced non-small cell lung 
cancer (NSCLC) (PM01183 plus gemcitabine vs. PM0183 vs. docetaxel); and two phase 
III randomized controlled trials in platinum resistant ovarian carcinoma (PM01183 vs.
PLD or topotecan) and NSCLC (PM01183 plus doxorubicin vs. CAV or topotecan).
One QT evaluation study in patients already participating in the phase II trial PM1183-
B-005-14; and three investigator-sponsored studies (ISTs: one with single-agent 
PM01183 in mesothelioma; one with PM01183 in combination with olaparib in 
advanced solid tumors; and one with PM01183 alone or in combination with 
doxorubicin or gemcitabine in soft tissue sarcoma).As of 15 January 2018, 2060 patients 
have been enrolled in PM01183 clinical studies, and of these 1584 have been treated 
with PM01183 alone or combined therapy: 501 in phase I trials, 543 in phase II trials, 
404 in phase III trials and 136 in investigator sponsored trials.
The two phase I trials which explore single-agent PM01183 schedules in solid tumor 
patients (PM1183-A-001-08 and PM1183-A-005-11) have finished recruitment and a 
recommended dose (RD) was selected for further study in phase II trials. The first-in-
human study (PM1183-A-001-08) explored PM01183 administered as a 1-hour i.v. 
infusion on Day 1 q3wk in patients with solid tumors. The RD was established at 4.0 
mg/m2/q3wk [87]; since PM01183 clearance was found to be unrelated to body surface 
area (BSA), all patients in the RD expansion cohort were treated at an equivalent flat 
dose (FD) of 7.0 mg q3wk. In this and subsequent studies, the median terminal plasma 
half-life was around 60 hours, though inter-individual variability was high. No evidence
of drug accumulation was found. Non-hematological toxicity was generally mild and 
reversible. Standard antiemetic prophylaxis was used at the RD to control grade 2 


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nausea and/or vomiting. Hematological toxicity, particularly grade 4 non-febrile 
neutropenia, was the most relevant toxicity and occurred in 40% of patients at the RD in 
the single-agent phase I studies. Neutropenia was generally predictable and short-
lasting, and rarely caused treatment delays. In the first-in-human study (Day 1, q3wk) 
nadir usually occurred during the second week. One of 15 patients treated at the RD had 
a dose-limiting toxicity (grade 4 thrombocytopenia). No cases of febrile neutropenia 
occurred in this study, although patient selection may have played a role. 
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 (around 40% of patients developed 
grade 4 neutropenia). Severe neutropenia was reversible in all cases, but two patients at 
the RD had grade 4 neutropenia lasting for more than one week. No unexpected 
toxicities were found. The safety profile of this schedule seems similar to that of the 
Day 1 q3wk trial, although neutropenia appeared more prolonged and may require 
additional dose adjustment. 
Based on the results from single-agent phase I clinical trials, the Day 1 q3wk schedule
has a good compliance and is more convenient. Therefore, the Day 1 q3wk schedule 
was selected for further clinical trials.
Antitumor activity has been observed with PM01183 either as single agent or in 
combination with other cytotoxics. Objective responses have been observed in patients 
with ovarian, pancreatic cancer, breast cancer, NSCLC, SCLC, and other tumor types 
(neuroendocrine tumors, endometrial carcinoma, bladder carcinoma, and soft tissue 
sarcoma).
1.11 STUDY RATIONALE
The management of advanced SLCL, H&N, NETs, biliary tract carcinoma, 
endometrial
carcinoma, BRCA 1/2-associated metastatic breast carcinoma, 
carcinoma of unknown primary site, GCTs and EFTs represent an unmet medical 
need. Cytotoxic chemotherapy remains a crucial component of their therapeutic 
armamentarium but there is a need to develop new anticancer agents that broaden 
the clinical benefit. 
PM01183 is a new chemical entity that induces double-strand DNA breaks through 
binding to the DNA minor groove. Results of the COMPARE analysis [88] revealed 
that is unlikely that this drug shares a similar mechanism of action with any of the 
other 98 standard cytotoxic agents compared.
PM01183 has shown antitumor activity in most of the tumor types selected in this 
clinical study. In the combination trial of PM01183 at 4.0 mg FD with 50 mg/m2 of 
doxorubicin q3wk (PM1183-A-003-10), five of 12 evaluable patients with SCLC 
achieved partial response (42.0%), with a median TTP of 2.0 months. In 
endometrial carcinoma, two of three patients treated with the combination 
PM01183 plus doxorubicin at the aforementioned dose and schedule had a complete 
response and a partial response, respectively. The third patient had disease 
stabilization longer than 4 months. The median TTP was 10.1 months. Also with 
this combination, a patient with NET had a partial response with a TTP of 4.5 
months. In a phase II clinical trial of PM01183 as single agent in MBC, one of 54 
patients with germline BRCA 1/2 mutation had a complete response (2%) and 21


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patients had partial response (39%). Twenty-three additional patients had disease 
stabilization (43%). One patient with H&N carcinoma treated with PM01183 as 
single agent at 2.6 mg/m2 q3wk achieved a disease stabilization of 4 months 
duration. Finally, one patient with a carcinoma of unknown primary site treated 
with PM01183 as single agent at 7 mg FD q3wk had disease stabilization for 2.6 
months.
The inclusion of patients with EFTs is based mainly on the similar mechanism of 
action of PM01183 and its related compound trabectedin. In sarcomas associated to 
translocations, such as myxoid liposarcoma, in which the translocation produces a 
fusion protein (FUS-CHOP) that acts as a deregulated transcription factor, 
trabectedin has been shown to interfere with the binding of this protein to specific 
DNA promoters, hence with the synthesis of downstream proteins. Based on the 
structural and functional similarities of these fusion proteins, trabectedin could 
induce on other translocation-related sarcomas similar effects to those described in 
myxoid liposarcoma. In fact, trabectedin has shown efficacy in advanced pretreated 
patients with Ewing’s sarcoma: three partial responses and seven disease 
stabilizations in 20 patients, with a 25% 6-month PFS rate [89]. Since PM01183 has 
a favorable pharmacokinetic (PK) profile in comparison to trabectedin, manifested 
by a tolerated dose four times higher and an exposure 15.3 times that of trabectedin 
at the RD, it has been postulated that its effect on rapidly growing tumors such as 
EFTs would be superior. In addition, an improved therapeutic index of PM01183 
relative to trabectedin, as well as suppression of the EFTs fusion protein EWS/FLI1 
activity by PM01183 at clinically achievable concentrations has been shown [90].
PM01183 activity in aggressive tumors with high proliferation index, such as 
neuroendocrine tumors and SCLC led to the inclusion of GCTs and biliary tract 
carcinoma in this study.
In conclusion, this clinical trial has been designed to establish or confirm the proof 
of concept of PM01183 anticancer activity in several difficult-to-treat tumors for 
their potential further development.
1.12 RATIONALE FOR THE DOSE
Initially, the starting dose for the current phase II trial was 4.0 mg/m2 administered 
intravenously (i.v.) (1-hour infusion) on Day 1 every three weeks (q3wk). This was the 
dose recommended from the first-in-human trial. Use of colony-stimulating factors 
(CSFs) was considered due to the high risk of febrile neutropenia. Furthermore, a dose 
reduction of 25% was established for fragile patients [i.e., those with an ECOG 
performance status (PS) of 2 or aged > 70 years old].
A safety analysis of data from 216 patients treated with PM01183 in phase II trials or at 
the RD in phase I trials comparing different intended dose levels showed that a 
PM01183 dose reduction of 20% (i.e., from 4.0 to 3.2 mg/m2) decreased the incidence 
of life-threatening neutropenia, thrombocytopenia and febrile neutropenia. Thus, grade 
3/4 neutropenia decreased from 70% to 38% (46% reduction), grade 3/4 
thrombocytopenia from 24% to 16% (33% reduction), and febrile neutropenia from 
14% to 6% (57% reduction). Therefore, the dose of 3.2 mg/m2 was considered safe.
Furthermore, in 22 patients with ECOG PS=2 and/or aged > 70 years treated with 
PM01183 at doses equivalent to 4.0 mg/m2, the incidence was 73% (n=16) for grade 3/4 
neutropenia, 18% (n=4) for grade 3/4 thrombocytopenia, and 9% (n=2) for febrile 


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neutropenia. These percentages were similar to those found in the overall population. 
Hence, a PM01183 dose reduction of 20% from the initial recommended dose might 
decrease toxicity in a similar magnitude in this subset of patients, who therefore might 
not require further dose adjustment. 
Based on these findings, the mandatory CSF prophylaxis was removed (see details in 
Amendment No.1, dated 13 May 2015) and the new starting dose of PM01183 for the 
current phase II study was set at 3.2 mg/m2 for all patients included in the trial, without 
differentiation according to PS score or age.
1.13 PHARMACOGENETIC SUB-STUDY RATIONALE
Germline mutations or polymorphisms may be involved in the metabolism and/or 
transport of PM01183. Then, to explore factors that may help to explain individual 
variability in the main pharmacokinetic parameters, the presence or absence of germline 
mutations or polymorphisms will be analyzed in leukocyte DNA extracted from one 
blood sample obtained at any time during the study, but preferably just before treatment 
start in Cycle 1.
1.14 PHARMACOGENOMICS SUB-STUDY RATIONALE
The antitumor activity of PM01183 is associated with the following cell events, as 
described in Leal et al. [91]: 
PM01183 binds to the minor groove of DNA. This binding occurs in preferred GC-
rich trinucleotide sequences, preferably AGC. The binding of PM01183 to the DNA 
produces a stabilization of the DNA duplex. This could account for the need of the 
same DNA repair machinery that usually deals with inter-strand cross-links and 
involves proteins from both homologous recombination (HR) and nucleotide 
excision repair (NER) machineries.
PM01183 induces DNA double-strand breaks (DSBs). In fact, treatment of cells 
with the drug induces the formation of foci of -H2AX, which is indicative of the 
formation of DSBs. In addition, treatment of cells with PM01183 leads to cell cycle 
delay in the S phase, activation of the DNA damage checkpoint, and cell death by 
apoptosis. 
PM01183 interferes with DNA repair. Experimental data reveal that the NER 
system is essential to overcome PM01183-induced DNA damage. When the pattern 
of sensitivity to PM01183 was analyzed in a collection of 5000 haploid deletion 
mutants of the yeast Saccharomyces cerevisiae, Rad13(orthologue of human 
XPG) haploid deletion mutants were found to be more resistant to PM01183 than 
wild-type cells, therefore indicating the dependence of the cytotoxic effect of this 
compound to a functional NER system. XPG is a member of the NER system.
Objective of the Pharmacogenomic Sub-study
The experimental data indicate that PM01183 binds to DNA and interferes with 
NER pathway, inducing DSBs and cell death by apoptosis. Thus, it seems of 
interest to conduct studies correlating the tumor/patient and genes/proteins 
determinant in the efficiency/deficiency of the DNA repair pathways and the 
outcome of patients exposed to PM01183. The ultimate goal is the characterization 
of such patients who shall be prone to respond or show resistance to PM01183, in 
order to implement a customized therapy in the future.


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Initially, the mRNA and/or protein expression levels of genes involved in DNA 
repair mechanisms (such as nucleotide excision repair, homologous recombination 
repair or mismatch repair) and other factors related to the mechanism of action of 
PM01183 or to the pathogenesis of the disease will be determined in paraffin-
embedded tumor tissue blocks from consenting patients. Their polymorphisms and 
mutations might be also analyzed, if relevant.
2.
STUDY OBJECTIVES
2.1
PRIMARY
To assess the antitumor activity of lurbinectedin (PM01183) in terms of ORR, 
according to the RECIST v.1.1, in the following advanced solid tumors: small cell 
lung cancer (SCLC), head and neck carcinoma (H&N), neuroendocrine tumors 
(NETs), biliary tract carcinoma, endometrial carcinoma, BRCA 1/2-associated 
metastatic breast carcinoma, carcinoma of unknown primary site, germ cell tumors 
(GCTs), and Ewing’s family of tumors (EFTs).
2.2
SECONDARY
To further characterize the antitumor activity of PM01183 in terms of duration of 
response (DR), clinical benefit [ORR or stable disease (SD) lasting over four 
months (SD ≥ 4 months)], progression-free survival (PFS) by Investigator’s 
assessment (IA), and overall survival (OS) in each cohort of advanced solid tumors. 
To further investigate the antitumor activity of PM01183 in terms of ORR, DR, 
clinical benefit (ORR or SD ≥ 4 months) and PFS by an Independent Review 
Committee (IRC) in the cohort of SCLC patients.
To characterize the plasma pharmacokinetics (PK) of PM01183.
To conduct an exploratory pharmacogenomic (PGx) and pharmacogenetic analysis.
To evaluate the safety profile of PM01183 in this patient population.
3.
OVERALL STUDY DESIGN
Multicenter, open-label, exploratory, phase II clinical trial to evaluate the efficacy and 
safety of PM01183 in previously treated patients with the following advanced solid 
tumors: SCLC, H&N, NETs, biliary tract carcinoma, endometrial carcinoma, BRCA 
1/2-associated metastatic breast carcinoma, carcinoma of unknown primary site, GCTs, 
and EFTs.
Patients with each of the aforementioned tumors will be enrolled in nine cohorts. Up to 
25 evaluable patients are planned to be enrolled in each cohort (50 in the endometrial 
carcinoma and 100 in the SCLC cohort). To consider that PM01183 has antitumor 
activity in any of the tumor types analyzed, at least two confirmed responses [complete 
(CR) or partial response (PR)] per RECIST v.1.1 out of the 25 patients of each cohort 
are expected.
If no confirmed responses are observed in the first 15 evaluable patients of each 
cohort, the recruitment of the corresponding cohort will be stopped.
If one confirmed response is observed in the first 15 evaluable patients of each 
cohort, the recruitment of this cohort will continue to up to 25 evaluable patients.


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o
In the cohort of endometrial carcinoma, if ≥2 confirmed responses occur in the 
first 25 evaluable patients, the sample size will be doubled to 50 evaluable 
patients. 
o In the cohort of SCLC, if ≥2 confirmed responses occur in the first 25 evaluable 
patients, the sample size will be increased to 100 evaluable patients.
If two confirmed responses are observed in the first 15 evaluable patients of each 
cohort, the recruitment of the corresponding cohort can be stopped.
Only in the SCLC cohort, an IRC will determine the best patient’s response and assign 
the date of first documentation of response and progression/censoring according to 
RECIST v.1.1. Operational details for the IRC and the algorithm and its validation by 
an expert panel is described in detail in the IRC charter.
In addition, for safety reasons:
If two patients have a treatment-related death in a cohort, the recruitment of the 
corresponding cohort will be stopped.
If six patients have treatment-related deaths in the whole population, the study will
be stopped.
Finally,
A determined cohort can be early closed by the Sponsor in case of a low 
recruitment rate.
Once the target of patients included in each cohort is reached, recruitment in this 
cohort will be kept “on hold” during the period of patients’ data analysis to assess 
their evaluability and the response rate. After this period, if the number of evaluable 
patients does not reach the planned target, recruitment will be re-opened and non-
evaluable patients will be replaced.
Patients will receive the study treatment as long as it is considered to be in their best 
interest. Specifically, treatment will continue until disease progression, unacceptable 
toxicity, treatment delay > three weeks from the treatment due date (except in case of 
clear clinical benefit, upon Sponsors’ approval), requirement of > two dose reductions,
intercurrent illness of sufficient magnitude to preclude safe continuation of the study, a
major protocol deviation that may affect the risk/benefit ratio for the participating 
patient, investigator’s decision, non-compliance with study requirements and/or 
patient’s refusal.
All adverse events (AEs) will be graded according to the National Cancer Institute 
Common Terminology Criteria for Adverse Events (NCI-CTCAE) v.4. Treatment 
delays, dose reduction requirements and reason for treatment discontinuation will be 
monitored throughout the study. The safety profile of patients will be monitored 
throughout the treatment and up to 30 days (±7 days) after the last treatment infusion 
(end of treatment, EOT), until the patient starts a new antitumor therapy or until the date 
of death, whichever occurs first. Any treatment-related AEs will be followed until 
recovery to at least grade 1 or stabilization of symptoms or until the start of a new 
antitumor therapy, whichever occurs first.
Patients will be evaluated at scheduled visits on three study periods: Pre-treatment, 
Treatment and Follow-up (see Section 5.2). This clinical trial will finish (clinical cutoff
for each cohort except SCLC) when all evaluable patients within each cohort have at 
least 12 months of follow-up from the first PM01183 infusion. Patients with SCLC will 
be followed-up for at least 18 months after the last patient enrolled received the first 
PM01183 infusion.


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3.1
PRIMARY ENDPOINT
Overall Response Rate (ORR) in each tumor type. ORR is defined as the 
percentage of patients with a confirmed response, either CR or PR, according to the 
RECIST (v. 1.1). 
3.2
SECONDARY ENDPOINTS
Efficacy (all cohorts):

Duration of Response (DR) by IA, defined as the time between the date when 
the response criteria (PR or CR, whichever one is first reached) are fulfilled to the 
first date when disease progression (PD), recurrence or death is documented.

Clinical Benefit by IA, defined as ORR or SD lasting over four months (SD ≥ 4 
months).

Progression-free Survival (PFS) by IA, defined as the period of time from the 
date of first infusion to the date of PD, death (of any cause), or last tumor 
evaluation. 

PFS4/PFS6 by IA, defined as the Kaplan-Meier estimates of the probability of 
being free from progression and death after the first infusion at these time points 
(4 and 6 months).

OS, defined as the period of time from the date of first infusion to the date of 
death or last contact in case of patients lost to follow-up or alive at the clinical 
cut-off established for the cohort.

OS6/OS12, defined as the Kaplan-Meier estimates of the probability of being 
alive after the first infusion at these time points (6 and 12 months).
Efficacy (only in the SCLC cohort): 

ORR, Clinical Benefit, DR, PFS and PFS4/PFS6 by IRC. The same 
definitions detailed for IA will be used.
Plasma Pharmacokinetics (PK) of PM01183 

Non-compartmental (NCA) PK parameters: area under the curve (AUC), 
maximum plasma concentration (Cmax), clearance (CL) and half-life (t1/2). 
Population PK parameters of the compartment model to be developed (initially 
based on Volumes and Clearance), and PK/PD correlation parameters, if 
applicable.
Pharmacogenetics:  

This analysis will be performed in those patients who signed the written informed 
consent (IC) for the pharmacogenetic sub-study. The presence or absence of 
known polymorphisms from a single sample collected at any time during the 
study, but preferably just before treatment start in Cycle 1, will be assessed to 
explain the individual variability in the main PK parameters.
Pharmacogenomics (PGx):

This exploratory analysis will be performed on prior available paraffin-embedded 
tumor tissue samples from consenting patients of any arm. This sub-study will 
include factors involved in DNA repair mechanisms (such as nucleotide excision 
repair, homologous recombination repair and mismatch repair) and other factors 
related to the mechanism of action of PM01183 or to the pathogenesis of the 
disease, and their expression will be analyzed at the mRNA or protein level by 


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quantitative polymerase chain reaction (PCR) and immunohistochemistry (IHC), 
respectively; their polymorphisms and mutations might be also analyzed, if 
relevant. Their correlation with clinical response and outcome after treatment will 
be assessed (see Section 7.4 for evaluation of PGx).
Safety Profile:

Clinical examinations.

Clinical assessment of AEs and serious adverse events (SAEs).

Changes in laboratory parameters (hematological and biochemical, including liver 
function tests). 

Reasons for treatment discontinuations.

Reasons for dose reduction and treatment delays.
4.
SELECTION OF PATIENTS
Patients must fulfill all the following inclusion/exclusion criteria to be eligible to
participate in the study.
4.1
INCLUSION CRITERIA
1) Age ≥ 18 years. 
2) Voluntary signed informed consent (IC) of the patient before any study-specific 
procedure.
3) Pathologically proven diagnosis of any of the following malignancies:
a) Small cell lung cancer (SCLC). 
b) Head and neck carcinoma (H&N). Salivary glands tumors are excluded.
c) Neuroendocrine tumors (NETs), grade 2 and grade 3 according to WHO 
classification [92].
d) Biliary tract carcinoma. 
e) Endometrial carcinoma.
f)
BRCA 1/2-associated metastatic breast carcinoma
g) Carcinoma of unknown primary site. 
h) Germ cell tumor (GCTs), excluding immature teratoma, or teratoma with 
malignant transformation.
i)
Ewing’s family of tumors (EFTs).
4) Prior treatment. Patients must have received:
a) SCLC: one prior chemotherapy-containing line.
b) H&N: one or two prior chemotherapy-containing lines.
c) NETs: one or two prior chemotherapy-containing lines. No more than three prior 
hormone or biological therapy lines.
d) Biliary tract carcinoma: one or two prior chemotherapy-containing lines.
e) Endometrial carcinoma: one prior chemotherapy-containing line.
f)
BRCA 1/2-associated metastatic breast carcinoma: at least one but no more than 
three prior chemotherapy-containing lines.


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g) Carcinoma of unknown primary site: one or two prior chemotherapy-containing 
lines.
h) GCTs: no limit of prior therapy (patients with no other clinical therapeutic 
options).
i)
EFTs: no more than two prior chemotherapy-containing lines
in the 
metastatic/recurrent setting.
5) Measurable disease as defined by the RECIST v.1.1, and documented progression 
before study entry.
6) Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 2 (see 
APPENDIX 1).
7) Adequate major organ function:
a) Hemoglobin ≥ 9 g/dl, prior red blood cell (RBC) transfusions are allowed if 
clinically indicated; absolute neutrophil count (ANC) ≥ 2.0 × 109/l; and platelet 
count ≥ 100 × 109/l.
b) Alanine aminotransferase (ALT), and aspartate aminotransferase (AST) 3.0 ×
upper limit of normal (ULN).
c) Total bilirubin 1.5 × ULN, or direct bilirubin ULN.
d) Albumin ≥ 3 g/dl.
e) Serum creatinine ≤ 1.5 × ULN or creatinine clearance ≥ 30 ml/min.
f)
Creatine phosphokinase (CPK) ≤ 2.5 × ULN.
8) Washout periods prior to Day 1 of Cycle 1: 
a) At least three weeks since the last chemotherapy (six weeks if therapy contained 
nitrosureas or systemic mitomycin C).
b) At least four weeks since the last monoclonal antibody (MAb)-containing 
therapy, or radiotherapy (RT) > 30 gray (Gy).
c) At least two weeks since the last biological/investigational therapy (excluding 
MAbs) or palliative RT (≤ 10 fractions or ≤ 30 Gy total dose).
9) Grade ≤ 1 toxicity due to any previous cancer therapy according to the NCI-
CTCAE, v.4. Grade 2 is allowed in case of alopecia and/or peripheral sensory 
neuropathy.
10) Women of childbearing potential must have pregnancy excluded by appropriate 
testing before study entry. Fertile women must agree to use a medically acceptable 
method of contraception throughout the treatment period and for at least three 
months after treatment discontinuation. Fertile men must agree to refrain from 
fathering a child or donating sperm during the trial and for four months after the last 
infusion.
4.2
EXCLUSION CRITERIA
1) Prior treatment with PM01183 or trabectedin.
2) Prior or concurrent malignant disease unless in complete remission for more than 
five years, except treated in situ carcinoma of the cervix, basal or squamous cell skin 
carcinoma, and in situ transitional cell bladder carcinoma.
3) Known central nervous system (CNS) involvement. In patients with SCLC, brain 
computed tomography (CT)-scan or MRI results must be provided at baseline.
4) Relevant diseases or clinical situations which may increase the patient’s risk:


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a) History within the last year or presence of unstable angina, myocardial 
infarction, congestive heart failure, or clinically relevant valvular heart disease 
or symptomatic arrhythmia or any asymptomatic ventricular arrhythmia 
requiring ongoing treatment.
b) Grade ≥ 3 dyspnea or daily intermittent oxygen requirement within two weeks 
prior to the study treatment onset.
c) Active infection.
d) Unhealed wounds or presence of any external drainage.
e) Known chronic active hepatitis or cirrhosis.
f)
Immunocompromised 
patients, 
including 
known 
infection 
by 
human 
immunodeficiency virus (HIV).
5) Women who are pregnant or breast feeding and fertile patients (men and women) 
who are not using an effective method of contraception. *
6) Impending need for RT (e.g., painful bone metastasis and/or risk of spinal cord 
compression).
7) Limitation of the patient’s ability to comply with the treatment or to follow-up the 
protocol.
* Women of childbearing potential (WOCBP) must agree to use an effective 
contraception method to avoid pregnancy during the course of the trial (and for at least 
three months after the last infusion). Valid methods to determine the childbearing 
potential, adequate contraception and requirements for WOCBP partners are described 
in APPENDIX 2. Fertile men must agree to refrain from fathering a child or donating 
sperm during the trial and for four months after the last infusion.
4.3
PATIENTS FOR THE PHARMACOGENOMIC (PGX)
AND PHARMACOGENETIC 
EVALUATIONS
Only patients who voluntarily sign the IC for the PGx and pharmacogenetic sub-study 
will participate. Refusal to participate in this sub-study will not affect patient 
participation in the clinical study PM1183-B-005-14.
5.
PLAN OF THE STUDY
5.1
PLANNED TRIAL PERIODS (FOR THE WHOLE STUDY)
The total duration of the study will be approximately 52 months, including 
approximately a 40-month enrolment period. 
Planned start date (first patient on study): 3Q2015.
Planned enrolment period: 40 months.
Planned end-of-study date (clinical cutoff for each cohort except SCLC): when all 
evaluable patients within each cohort have at least 12 months of follow-up from the first 
PM01183 infusion. Patients with SCLC will be followed-up for at least 18 months after 
the last patient enrolled received the first PM01183 infusion.
5.2
PLANNED TRIAL PERIODS (INDIVIDUALLY PER PATIENT)
Patients will be evaluated at scheduled visits within three study periods:

Pre-treatment: from signature of IC to the first infusion of study treatment. 


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
Treatment: from the first infusion of the study treatment to end of treatment
(EOT) (see Section 5.2.1.1).

Follow-up: after EOT, patients will be followed-up every four weeks until 
resolution or stabilization of all drug-related toxicities, if any, or until start of a 
new antitumor therapy. Patients will be followed-up for at least one year after 
their first PM01183 infusion. Patients who finish treatment without PD will be 
followed-up every two months during the first six months and every three months 
thereafter until PD, start of a new antitumor therapy, death or until the end of 
study date (clinical cutoff). After PD is documented or a new antitumor therapy is 
started, each cohort (except SCLC) will be followed-up at least every six months 
and up to 12 months after the last patient enrolled received the first PM01183 
infusion (a documented phone contact will be acceptable). Patients in the SCLC 
cohort, after PD, will be followed-up every six months for at least 18 months after 
the last patient enrolled received the first PM01183 infusion (a documented phone 
contact will be acceptable).
Patients will be considered to be on-study from the signature of the informed consent
form (ICF) until 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. This EOT is defined as 30 days after the day of 
the last PM01183 infusion (see Figure 2), unless the patient starts a new antitumor 
therapy or dies (whichever occurs first). An end-of-treatment visit (EOT visit) will be 
performed within 30 days (± 7 days) after the last study treatment administration, unless 
the patient starts any subsequent antitumor therapy, in which case the EOT visit should 
be performed immediately before the start of the new therapy.
Figure 2. Study periods.
FUP, follow-up; ICF, informed consent form; PRE TT, pre-treatment; TT, treatment; wks, weeks.
Patients may withdraw their consent at any time; under this circumstance, no further 
study activities will be conducted on them.


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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 end of treatment is 
defined as 30 days after the day of the last dose of the study treatment (treatment 
discontinuation), 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 
Case Report Form (CRF).
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 treatment while it is considered to be in their best interest. 
Specifically, treatment will continue until:

Disease progression.

Unacceptable toxicity.

Treatment delay > three weeks from the treatment due date (except in case of 
clear clinical benefit, upon Sponsors’ approval).

Requirement of > two dose reductions.

Intercurrent illness of sufficient magnitude to preclude safe continuation of the 
study.

A major protocol deviation that may affect the risk/benefit ratio for the 
participating patient.

Investigator’s decision.

Non-compliance with study requirements.

Patient’s refusal.
Patients who are withdrawn for any reasons must not be re-treated in the context of this 
study at any time. For follow-up activities, please refer to Section 5.9.
5.2.1.3
Study Discontinuation
Study discontinuation occurs when an enrolled patient ceases to participate in the study, 
regardless of the reason (as detailed under “Follow-up” in Section 5.2). Patients have 
the right to withdraw consent at any time; if this is the case, no further study procedures
should be performed.
The date and reason for study discontinuation will be clearly documented on the 
patient’s CRF. 
5.2.2
Protocol Deviations
A protocol deviation is defined as any departure from what is described in the protocol 
of a clinical trial approved by an Independent Ethics Committee (IEC)/Institutional 
Review Board (IRB) and Competent Authorities. 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 the Good Clinical Practice (GCP) guidelines or ethical issues (e.g., issues 


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related to obtaining the patients’ Informed Consent, data reporting or the responsibilities 
of the Investigator).
Deviations with no effects on the risk/benefit ratio of the clinical trial (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 trial objectives, such as those involving 
the inclusion/exclusion criteria (which could mean that the patient is not eligible 
for the trial) 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 the 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 the Informed Consent 
or not following the terms established for reporting Serious Adverse Events, etc.
No deviations that may have an effect on the risk/benefit ratio of the clinical trial 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, to fulfillment of GCP guidelines and with an effect on the risk/benefit ratio) will 
be notified to the pertinent IEC/IRB and, if applicable, to the Competent Authorities as 
established by local regulations.
5.3
REPLACEMENT OF PATIENTS
Patients will be replaced if they are not evaluable for the primary endpoint of the study 
(ORR as per RECIST v. 1.1), specifically if (any of the following):
They are not eligible.
They have not received the study treatment.
They are not evaluable for ORR as per RECIST v1.1 and they are not 
categorized as “treatment failures”. Treatment failures will not be replaced and 
are defined as patients who:  
o Discontinue treatment due to any treatment-related toxicity before an 
appropriate tumor assessment has been performed.
o Early death due to malignant disease.
All replaced patients who received study treatment will be included in the safety 
analysis.
5.4
PRE-TREATMENT ASSESSMENTS
During the pre-treatment period, following signature of the ICF, the Investigator will 
confirm the patient’s eligibility for the study by conducting the assessments summarized 
in Table 3.
Table 3. Screening period: pre-treatment assessments.
ASSESSMENT
TIME
1. Written informed 
consents
(general and 
PGx/pharmacogenetic  
sub-study)
Before any study procedures.


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ASSESSMENT
TIME
2. Medical and cancer 
history/ clinical 
examination
Demographic data (race/ethnicity, age, gender).
Within 28 days prior to registration.
Primary diagnosis and prior treatment(s) (with 
best response and TTP, when available).
Within 
28
days 
prior 
to 
registration.*
Medical and cancer history/baseline condition.
Concomitant therapies.
Within 
14 
days 
prior 
to 
registration.*
Disease-related signs and symptoms.

Complete physical examination, including 
weight, height and calculation of BSA. 
Performance status (ECOG PS).
Vital signs: heart rate, blood pressure and body 
temperature.
Within 
7 
days 
prior 
to 
registration.**
3. Laboratory tests
Coagulation panel: PT/INR and PTT.
Hematology: Hemoglobin, platelet counts, and 
differential WBC counts (including neutrophils, 
monocytes and lymphocytes).
Biochemistry A: Serum electrolytes (Na+, K+, 
Cl−), AST, ALT, AP, GGT, total bilirubin (direct 
bilirubin to be measured only if total bilirubin is 
>1.5xULN), LDH, creatinine, glucose, and CPK.
Biochemistry B: Total proteins, albumin, total 
calcium and Mg++. 
In patients with germ cell tumors, ß-hCG and AFP 
will be also measured.
Within 7 days prior to registration.
4. Pharmacogenetics
(only if written 
informed consent 
given)
One blood sample. ***
At any time during the study, but 
preferably just before treatment 
start in Cycle 1.
5. PGx
Available stored paraffin-embedded tumor tissue 
samples (only if written informed consent given)
At any time during the study.
6. Pregnancy test (if 
women of 
childbearing 
potential)
ß-hCG (urine or serum). In patients of childbearing 
potential (except germ cell tumor patients), if ß-
hCG levels are elevated, pregnancy must be 
clinically discarded by an additional test (i.e., 
ultrasound) before any other study procedure. 
Pregnancy during treatment or within three months
from the patient’s last PM01183 administration is 
considered an immediately reportable event.
Within 7 days prior to registration, 
if applicable.****
7. ECG
Cardiac rhythm will be identified in ECG intervals 
of at least 30 seconds of duration, PR interval, QT 
interval (raw), heart rate and QRS complex.
Within 
7 
days 
prior 
to 
registration.****
8.  LVEF
LVEF measured by MUGA or ECHO.
Within 
28 
days 
prior 
to 
registration.****
9. Radiological tumor 
assessment
In all patients, contrast enhanced helical CT-scan or 
MRI, as clinically indicated. 
Within 
28 
days 
prior 
to 
registration.*
In SCLC patients, brain CT-scan or MRI to rule out 
CNS involvement.
Within 
14 
days 
prior 
to 
registration.*
10. Adverse events
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.4.
-
Day 0 is when eligibility is confirmed and a patient is registered: for the purposes of assessment windows, it is 
assumed that Day 0 is the calendar day before Day 1 of Cycle 1. If this is not the case and first infusion is 
administered more than one week after screening window, laboratory tests (hematology, biochemistry A, B and 
pregnancy test if applicable) must be repeated within the three days prior to first infusion.
*A 1-week window is allowed for primary diagnosis and prior treatment(s), medical and cancer history/baseline 
conditions, concomitant therapies and radiological tumor assessment at screening. 
**A 1-day window is allowed for assessment of disease signs and symptoms, complete physical examination, ECOG 
PS, and vital signs at screening.
***One blood sample will be collected to evaluate the presence or absence of known polymorphisms.
****A 3-day window is allowed for ECG and LVEF assessment at screening.
AFP, alpha fetoprotein; ALT, alanine aminotransferase; AP, alkaline phosphatase; AST, aspartate aminotransferase; 
β-hCG, beta subunit of human chorionic gonadotropin; BSA, body surface area;  CNS, central nervous system;  CPK, 
creatine phosphokinase; CT, computed tomography; ECG, electrocardiogram; ECHO, echocardiography; ECOG, 
Eastern Cooperative Oncology Group; GGT, gamma-glutamyltransferase; INR, international normalized ratio; LDH, 


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ASSESSMENT
TIME
lactate dehydrogenase; LVEF, left ventricular ejection fraction; MRI, magnetic resonance imaging; MUGA, multiple-
gated acquisition scan; NCI-CTCAE, National Cancer Institute Common Terminology Criteria for Adverse Events; 
PGx, pharmacogenomics; PS, performance status; PT, pro-thrombin time; PTT, partial thromboplastin time; ULN, 
upper limit of normal; SAE, serious adverse event; SCLC, small cell lung cancer; TTP, time to progression; WBC, 
white blood cells.
Screening procedures will have to be repeated in case that the first infusion of the study 
treatment is given out of the established windows.  
5.5
PATIENT REGISTRATION
After the patient has signed the ICF and all eligibility criteria have been met, the patient 
will be included into the trial. A patient number will be provided at the time of 
registration. This number should be used in all future documentation and 
correspondence referring to this patient. Investigators are under no circumstances 
allowed to treat any patient before appropriate reception of the patient registration 
number.
5.6
PATIENT RANDOMIZATION
Not applicable.
5.7
EVALUATIONS DURING TREATMENT
The following assessments will be done while the patient is on treatment (Table 4).
Table 4. Evaluations during treatment.
ASSESSMENT
TIME
1. Clinical 
examination
Complete physical examination, including 
weight and calculation of BSA. Dose will be 
adjusted if BSA change is ≥ 10% (higher or 
lower) of the previous value. 
Day 1 of each cycle (always prior to 
PM01183 infusion).*
Performance status (ECOG PS).
Vital signs: heart rate, blood pressure and 
body temperature.
Day 1 of each cycle (always prior to 
PM01183 infusion).*
Concomitant therapies.
Throughout the “on treatment” period.**
2. Laboratory tests
Coagulation panel: PT/INR and PTT.
Day 1 of each cycle (always prior to 
PM01183 infusion).*
Hematology: Hemoglobin, platelet counts, 
and differential WBC counts (including 
neutrophils, monocytes and lymphocytes).
Biochemistry A: Serum electrolytes (Na+, 
K+, Cl−), AST, ALT, AP, GGT, total bilirubin 
(direct bilirubin to be measured only if total 
bilirubin is >1.5xULN), LDH, creatinine, 
glucose, and CPK.
Cycle 1 and 2: 
Day 1, 8 and 15 (always prior to 
PM01183 infusion).*
Two blood samples (24 hours and 72 
hours after the end of PM01183 infusion) 
will be collected at the same time than PK 
samples 6 and 7 in Cycle 1 for 
monocyte count.
Further cycles: 
Day 1 of each cycle (always prior to 
PM01183 infusion). *
From Cycle 2 onwards, Hematology and 
Biochemistry A tests on Days 8 and 15 are 
to be performed only in patients who 
present 
biochemical
grade 
≥3 
or 
hematological grade > 4 treatment-related 
toxicities, 
or 
who 
required 
dose 
adjustments due to hematological or 
biochemical abnormalities in the preceding 
cycle. 
Any patient presenting a grade ≥ 3 
treatment-related AE should have all 
relevant tests re-assessed at least every 48-
72 hours until recovery to grade ≤ 2.
Any patient having febrile neutropenia of 


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ASSESSMENT
TIME
any grade, grade 4 neutropenia, and/or 
grade 4 thrombocytopenia, should have 
relevant tests repeated daily until recovery 
to grade ≤ 3 and up to the next day after 
fever resolution, if applicable.
Biochemistry B:
Albumin, total proteins, total calcium and 
Mg++. 
In patients with germ cell tumors, ß-hCG and 
AFP only in those patients with elevated 
values at baseline.
Albumin: Day 1 of each cycle (always
prior to PM01183 infusion). *
Total proteins, total calcium and Mg++
will be measured only in those patients 
with abnormal baseline values.
Any patient presenting a grade ≥ 3 
treatment-related AE should have all 
relevant tests re-assessed at least every 48-
72 hours until recovery to grade ≤ 2.
3.Pharmacokinetics
Cycle 1: Eight blood samples (before 
PM01183 infusion start, 5 min before end of 
PM01183 infusion and 30 min, 1 hour, 3
hours, 24 hours, 72 hours and 168 hours after 
the end of PM01183 infusion) will be 
collected for pharmacokinetic analyses (see 
details in Section 7.2.1).

Cycle 2: Six
blood samples
(before 
PM01183 infusion start, 5 min before end of 
PM01183 infusion and 30 min, 1 hour, 3 hours 
and 168 hours after the end of PM01183 
infusion) will be collected for pharmacokinetic 
analyses (see details in Section 7.2.1).
Cycle 1 and Cycle 2.
4. AAGP
One blood sample per cycle.
On Day 1 of Cycle 1 and Cycle 2 (always 
prior to PM01183 infusion).
5. Pharmacogenetics
(only if written 
informed consent 
given) 
One blood sample.
At any time during the study, but 
preferably just before treatment start in 
Cycle 1.
6. Pregnancy test (if 
women of 
childbearing 
potential) 
ß-hCG (urine or serum). In patients of 
childbearing potential (except germ cell tumor 
patients), if ß-hCG levels are elevated, 
pregnancy must be clinically discarded by an 
additional test (i.e., ultrasound) before any 
other study procedure. Pregnancy during 
treatment or within three months from the 
patient’s last PM01183 administration is 
considered an immediately reportable event.
Day 1 of each cycle (always prior to 
PM01183 infusion).*
7. ECG
Cardiac rhythm will be identified in ECG 
intervals of at least 30 seconds of duration, PR 
interval, QT interval (raw), heart rate and QRS 
complex.
Repeat if clinically indicated. 
8.  LVEF
LVEF measured by MUGA or ECHO.
Repeat if clinically indicated. 
9. Radiological 
tumor assessment
Contrast enhanced helical CT-scan or MRI, as 
clinically indicated.
Every two cycles from the onset of the 
study treatment until Cycle 6 and every 
three cycles thereafter.* 
Patients showing a response must have a 
confirmatory
assessment at least four 
weeks later. 
10. Adverse events
As per NCI-CTCAE v.4.
Throughout the “on treatment” period.** 
*A 3-day window will be allowed for laboratory procedures and ECG, a 1-week window for radiological tumor 
assessments (helical CT-scan or MRI) and LVEF assessments and a 1-day window for clinical assessments (ECOG 
PS, physical examination, vital signs, weight, BSA). 
** “On treatment period” = from first PM01183 infusion to EOT [30 days after the day of the last PM01183 infusion, 
unless the patient starts a new antitumor therapy or dies (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].
AAGP, alpha-1 acid glycoprotein; AE, adverse event; ALT, alanine aminotransferase; AP, alkaline phosphatase; 


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TIME
AST, aspartate aminotransferase; β-hCG, beta subunit of human chorionic gonadotropin; BSA, body surface area; 
CPK, creatine phosphokinase; CT, computed tomography; ECG, electrocardiogram; ECHO, echocardiography; 
ECOG, Eastern Cooperative Oncology Group; EOT, end of treatment; GGT, gamma-glutamyltransferase; INR, 
international normalized ratio; LDH, lactate dehydrogenase; LVEF, left ventricular ejection fraction; MRI, magnetic 
resonance imaging; MUGA, multiple-gated acquisition scan; NCI-CTCAE, National Cancer Institute Common 
Terminology Criteria for Adverse Events; PK, pharmacokinetic; PS, performance status; PT, pro-thrombin time; 
PTT, partial thromboplastin time; ULN, upper limit of normal; WBC, white blood cells.
5.8
EVALUATIONS AT END OF TREATMENT
The end-of-treatment visit will be scheduled within 30 days (± 7 days) after the last 
PM01183 infusion, 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, regardless of the reason for ending the treatment, will have to undergo at the 
end of treatment the following assessments:

Complete physical examination.

ECOG PS.

Vital signs.

Concomitant therapies.

Laboratory tests (coagulation panel, hematology and biochemistry A and B).

Pregnancy test, ECG or LVEF assessment (if clinically indicated).

Radiological tumor assessment (the evaluation should be repeated at EOT visit, 
if not previously done, and if the reason for treatment discontinuation is other 
than PD).

Adverse events. 
These evaluations will only have to be repeated for those parameters for which no 
measurement is available within 10 days before the EOT visit, or for those parameters 
with values that were out of range in the last assessment (grade ≥2 according to the 
NCI-CTCAE v.4).
Adverse events must be reported for 30 days after the last study treatment
administration. All serious adverse events (SAEs) occurring within 30 days of the last 
study treatment administration or until the start of a new antitumor therapy, whichever 
occurs first, will be reported. Beyond this period of time, only those suspected to be 
treatment-related SAEs will be reported (Section 7.7.2).
The Sponsor will evaluate all safety information that is spontaneously reported by an
Investigator beyond the time frame specified in the protocol.
5.9
FOLLOW-UP AFTER END-OF-TREATMENT VISIT
The date and reason of the study discontinuation will be recorded on the patient’s CRF 
(see Section 5.2.1.1).
Only patients who discontinue treatment without PD will have radiological evaluations 
during follow-up period. The assessments will be performed every two months during 
the first six months and every three months thereafter until PD, start of a new antitumor 
therapy, death, or until the end of study date (clinical cutoff). After PD is documented or 


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a new antitumor therapy is started, each cohort (except SCLC) will be followed-up at 
least every six months and up to 12 months after the last patient enrolled received the 
first PM01183 infusion (a documented phone contact will be acceptable). Patients in the 
SCLC cohort, after PD, will be followed-up every six months for at least 18 months 
after the last patient enrolled received the first PM01183 infusion (a documented phone 
contact will be acceptable).
The end-of-study date (clinical cutoff for each cohort except SCLC) is defined as the 
time point when all evaluable patients within each cohort have at least 12 months of 
follow-up from the first PM01183 infusion. Patients with SCLC will be followed-up for 
at least 18 months after the last patient enrolled received the first PM01183 infusion.
Patients who have withdrawn from the study treatment with an ongoing drug-related AE 
should be followed every four weeks until event recovery to at least grade 1 or 
stabilization or until onset of a new antitumor therapy.
Additional parameters and/or increased frequency of observations should be performed 
at the Investigator’s discretion and according to the nature of the observed AEs. In case 
of death, autopsy data should be provided when available.
6.
TREATMENT
6.1
DESCRIPTION OF TREATMENT
6.1.1 Drug Formulation and Supply
PM01183 drug product (DP) is presented as a lyophilized powder for concentrate for 
solution for infusion in 4-mg vials, which will be supplied by the Sponsor for the 
purposes of this study.
Before use, the 4-mg vials should be reconstituted with 8 ml of sterile water for 
injection to give a solution containing 0.5 mg/ml of PM01183. 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.
For details on reconstitution/dilution, please refer to the IB and Preparation Guide for 
Infusion. PM01183 reconstitution/dilution records will be kept at the site.
The full composition of the PM01183 4-mg vials and the reconstituted solution per ml 
is as shown in Table 5.
Table 5. Composition of lurbinectedin (PM01183) vials.
Component
Concentration/vial
Concentration/vial after 
reconstitution
PM01183
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
6.2
ADMINISTRATION OF THE STUDY MEDICATION
PM01183 will be administered over a minimum total volume of 100 ml of solution for 
infusion (either on 5% glucose or 0.9% sodium chloride), through a central catheter, or 
over a minimum total volume of 250 ml if administered through a peripheral line, 
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6.3
STARTING DOSES AND SCHEDULE
Starting dose will be 3.2 mg/m2. Dose will be capped at BSA of 2.0 m2 (i.e., dose will 
not exceed 6.4 mg). 
Patients will receive PM01183 i.v. as a one-hour infusion on Day 1 every three weeks 
(q3wk) (three weeks = one treatment cycle).
6.4
PROPHYLACTIC MEDICATION
All patients will receive standard antiemetic prophylaxis before each treatment infusion. 
The i.v. formulations of these agents must be used in this setting:

Corticosteroids (dexamethasone 8 mg or equivalent).

Serotonin (5-HT3) antagonists (ondansetron 8 mg or equivalent).

Extended treatment with oral 5-HT3 antagonists and oral dexamethasone for two
consecutive days. 

If necessary, and in addition to the above, administration of 10 mg of oral or i.v. 
metoclopramide (or equivalent) every eight hours. 
Aprepitant and equivalent agents (e.g., fosaprepitant) are forbidden in patients 
treated with PM01183.
For the purpose of safety evaluations, an optimal prophylaxis is defined as all the 
aforementioned allowed medications at their respectively maximum dose.
6.5
CRITERIA FOR TREATMENT CONTINUATION 
Further treatment cycles (i.e., Cycle 2 or subsequent) will be administered every q3wk 
(± 48 hours) if the patient fulfills all the re-treatment criteria defined in Table 6.
Table 6. Criteria for treatment continuation.
Variable 
Re-treatment (Day 1)
ECOG PS
2
Hemoglobin*
8.0 g/dl
ANC
1.5 × 109/l
Platelets
100 × 109/l
AST/ALT
3.0 × ULN
Total bilirubin or 
direct bilirubin
1.5 × ULN or
× ULN 
Albumin
3 g/dl
Serum creatinine
1.5 × ULN or 
creatinine clearance ≥ 
30 ml/min
CPK
Grade ≤ 1
Other non-hematological drug-related AEs (except isolated 
increased GGT and/or AP; grade 2 asthenia, constipation, 
alopecia, peripheral neuropathy, or  non-optimally treated 
nausea and/or vomiting) 
Grade 1
Active infection (including sepsis) and/or bleeding (any grade)
Absence
* Patients may receive packed red blood cells (PRBC) transfusion and/or erythropoietin (EPO) treatment, 
if clinically indicated, to increase/maintain adequate hemoglobin levels.
AE(s), adverse event(s); ANC, absolute neutrophil count; AP, alkaline phosphatase; AST/ALT, aspartate 
aminotransferase/alanine aminotransferase; CPK, creatinine phosphokinase; ECOG, Eastern Cooperative 
Oncology Group; GGT, gamma-glutamyltransferase; PS, performance status; ULN, upper limit of 


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Variable 
Re-treatment (Day 1)
normal.
If a patient does not meet the requirements for re-treatment on Day 1 of any following 
cycle, regardless of the reason, re-assessments will be performed at least every 48-72 
hours. Treatment will be then withheld, up to a maximum of three weeks beyond its due
date, until appropriate recovery. 
Patients not meeting re-treatment criteria after a maximum 3-week delay must be 
withdrawn from trial. In case of objective clinical benefit, the patient could continue 
receiving the treatment (upon the Sponsors’ agreement).
For any delay due to treatment-related adverse events lasting for more than one week, a 
dose reduction must be implemented upon recovery, following the rules explained in the 
next section (Section 6.6).
6.6
DOSE REDUCTION
Patients may continue the study treatment at a reduced dose if they present any of the 
following:
Grade ≥ 3 treatment-related non-hematological toxicity. Exceptions are: grade ≥ 3 
nausea and/or vomiting not optimally treated, grade 3 asthenia lasting ≤ 3 days, 
grade 3 diarrhea lasting ≤ 2 days or not optimally treated, grade 3 transient 
ALT/AST elevations which are rapidly reversible and not leading to subsequent 
delays, and non-clinically relevant biochemical abnormalities.
Grade 4 thrombocytopenia or grade 3 thrombocytopenia concomitantly with 
grade ≥3 bleeding.
Grade 4 neutropenia, any grade febrile neutropenia or neutropenia associated with 
infection/sepsis. 
Frequent or prolonged (>1 week) dose delays due to treatment-related adverse 
events.
Patients who experience grade 3/4 hypersensitivity reactions will be discontinued from 
study treatment.
Dose reduction levels are shown in Table 7.
Table 7. Criteria for dose reduction.
Dose reduction
PM01183  dose (mg/m2) *
  1 (starting dose)
   3.2 **
−1
2.6
−2
2.0
*Dose rounded to the first decimal. 
**Dose will be capped at BSA of 2.0 m2 (i.e., dose will not exceed 6.4 mg).
BSA, body surface area; ECOG, Eastern Cooperative Oncology Group; PS, performance status.
Up to two dose reductions are allowed per patient.
Patients who continue to experience treatment-related toxicity and/or frequent dose 
delays after permitted dose reductions must be withdrawn from the study. They can 
continue receiving the study medication if objective clinical benefit is adequately 
documented by the Investigator, and upon agreement with the Sponsor. Once the dose 
has been reduced for an individual patient, it will not be re-escalated under any 
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6.7
CONCOMITANT MEDICATION
All treatments received by the patient during the “on-treatment” period of the trial must 
be documented in the CRF.
6.7.1
Allowed Medications/Therapies
Therapies for pre-existing and treatment-emergent medical conditions, including 
pain management.
Blood products and transfusions, as clinically indicated.
Bisphosphonates.
In case of nausea or vomiting, secondary prophylaxis and/or symptomatic 
treatment for emesis according to the ASCO guidelines.
Erythropoietin (EPO) treatment according to the ASCO guidelines.
Anticoagulation therapy.
6.7.2
Prohibited Medications/Therapies
Any other antineoplastic therapy, except somatostatin analogues for NETs. 
Any other investigational agents.
Primary G-CSF prophylaxis.
Immunosuppressive therapies other than corticosteroids
for antiemetic 
prophylaxis and/or pain control. 
Medroxyprogesterone (patients with endometrial cancer).
Aprepitant, fosaprepitant or related compounds.
Radiotherapy.
6.7.3
Drug-drug Interactions
In vitro studies using human liver microsomes have shown that PM01183 has the 
potential to inhibit cytochrome CYP2C8, CYP3A4 and, to a minor extent, CYP2B6. 
Moreover, the calculated Ki values were 0.2, 1.4, 8.9 and 1.9 µM for CYP3A4m, 
CYP3A4t, CYP2B6 and CYP2C8, respectively. Additional in vitro studies demonstrated 
that time dependent inhibition or irreversible inhibition for cytochrome CYP3A4 was 
not present. The total mean maximum plasma concentration at the RD (or [I]) (182.2 
µg/L in study PM1183-A-001-08) was ca. 0.23 μM (or ca. 0.005 μM when expressed as 
unbound fraction; 2.2%).
According to the recommendations in the Guideline CPMP/EWP/560/95, the risk of 
inhibition in vivo is evaluated by comparing observed Ki values. If [I]/Ki ≥ 0.02, 
inhibition in vivo cannot be excluded. The estimated [I]/Ki values were 0.023, 0.004, 
0.001 and 0.003 for CYP3A4m, CYP3A4t, CYP2B6 and CYP2C8, respectively. 
Therefore, an inhibitory effect of PM01183 on CYP3A4 cannot be excluded.
The basic model proposed at the FDA guidance for DDI (Draft February 2012) and the 
NISH Drug Interaction Guideline for Drug Development and Provision of Appropriate
Information (Draft 2014), results in a R1 value for CYP3A4m of 2.15, which still 
suggests a potential inhibition for CYP3A4. On the other hand, when applying the 
mechanistic static model, AUCR=1.01 (Ah in FDA guidance or Ch in NIHS guideline 
was 0.98 and fm=0.4), the inhibitory effect of PM01183 on CYP3A4 can be discarded. 
As a conclusion, while and inhibitory effect of PM01183 on CYP2C8 and CYP2B6 
can be ruled out, the effect on CYP3A4 deserves further exploration. Ongoing PBPK 


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models will explore deeply any potential effect of PM01183 as CYP3A4 inhibitor. In 
the meantime, caution should be exercised when PM01183 is administered 
concomitantly with CYP3A4 substrates.
Additionally, in vitro studies with human microsomes have shown that CYP3A4 is the 
major CYP isoform involved in the metabolism of PM01183, followed by CYP2E1, 
CYP2D6 and CYP2C9. The estimated contribution of the other CYP isoenzymes to the 
PM01183 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 possible (see APPENDIX 3).
6.8
DRUG ACCOUNTABILITY
Proper drug accountability will be done by appropriate trained study personnel. Each 
study site will keep records to allow a comparison of quantities of drug received and 
used at each site for monitoring purposes. The Investigator at each study site will be the 
person ultimately responsible for drug accountability at the site.   
All unused drug supplied by the Sponsor will be properly destroyed at the study site. 
Documentation of this procedure must be provided to the clinical trial monitor. If the 
Sponsor agrees, unused drug supplies may be returned to the drug repository.
6.9
TREATMENT COMPLIANCE
The Investigator is ultimately responsible for supervising compliance with the 
instructions described in this study protocol.
7.
STUDY EVALUATIONS
7.1
EFFICACY
The primary objective of this study is to assess the antitumor activity of PM01183 in 
terms of overall response rate (ORR), primary endpoint, supported by the secondary 
endpoint duration of response (DR), both assessed by the IA.
ORR will be assessed using the RECIST v.1.1 (see APPENDIX 4) on a set of 
measurable lesions identified at baseline as target lesions or as non-target lesions (if 
any), and followed until disease progression (PD) by an appropriate method (e.g., 
helical CT-scan, MRI). 
Radiological tumor assessment will be performed at baseline, and every two cycles 
from the onset of the study treatment until Cycle 6 or evidence of PD. After Cycle 6, 
tumor assessment will be performed every three cycles until evidence of PD. If an 
objective response is observed, according to the RECIST v1.1, it must be confirmed by 
the same method at least four weeks after the date of the first documentation of 
response.
ORR is defined as the percentage of evaluable patients with a confirmed response, 
either complete (CR) or partial response (PR), from the start of treatment to the date of 
progression or the start of a subsequent therapy or end of patient’s follow-up, according 
to the RECIST (v. 1.1). 
DR will be calculated from the date of first documentation of response to the date of 
first documented PD, recurrence or death due to any cause in the responder patients.


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The date of response, the date of radiological or clinical PD, according to the 
investigator assessment and the independent assessment by IRC when applicable (i.e., 
SCLC cohort), and the date of death will be registered and documented, as appropriate.
A copy of CT-scans or MRIs can be requested by the Sponsor in selected cases.
In SCLC patients, anonymized copies of all the images obtained throughout the study 
must be submitted to the Sponsor. These copies of CT scans, MRIs and any other 
documented methods to evaluate tumor response or progression in the SCLC cohort 
should be available for external radiological review by an IRC. The IRC will determine 
the patient’s best response and assign the date of first documentation of response and 
progression/censoring according to RECIST v.1.1.
7.2
PHARMACOKINETICS
7.2.1
Blood Sampling
The plasma PK of PM01183 will be evaluated during Cycle 1 and Cycle 2 in all treated 
patients. The sampling schedule for Cycle 1 and Cycle 2 will be as shown in Table 8
and Table 9, respectively.
Table 8. Blood samples for pharmacokinetic evaluations in Cycle 1.
Sample No.
Day 
Sampling time
Sampling window
#1
D1
Before treatment start
--
#2 *
D1
5 min before EOI
+/- 4 min
#3
D1
30 min after EOI
+/- 4 min
#4
D1
1 hour after EOI
+/- 10 min
#5
D1
3 hours after EOI
+/- 10 min
#6
D2
24 hours after EOI
+/- 2 hours
#7
D4
72 hours after EOI
+/-  24 hours
#8
D8
168 hours after EOI
+/- 24 hours
* Sample #2 must be collected before EOI.
D, day; EOI, end of infusion.
Table 9. Blood samples for pharmacokinetic evaluations in Cycle 2.
Sample No.
Day 
Sampling time
Sampling window
#9
D1
Before infusion start
--
#10 *
D1
5 min before EOI
+/- 4 min
#11
D1
30 min after EOI
+/- 4 min
#12
D1
1 hour after EOI
+/- 10 min
#13
D1
3 hours after EOI
+/- 10 min
#14
D8
168 hours after EOI
+/- 24 hours
* Sample #10 must be collected before EOI.
D, day; EOI, end of infusion.
The infusion rate will be predetermined to ensure that the dose of PM01183 is infused 
in 60 min at a constant rate. In order to obtain reliable PK information, the infusion rate 
should not be modified once the infusion begins. If a variation in the infusion time 
eventually occurs, it is very important this to be reflected in the CRF. The accurate 
recording of actual dosing and sampling times is much more important than the strict 
adherence to the scheduled times.


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Blood samples will be obtained into a vacutainer tube by using a peripheral catheter 
placed in a vein of the arm opposite to the side used for drug infusion. Even the last 
sample must never be collected from the catheter used for drug infusion.
A total of 14 samples of about 4 ml each will be collected for the determination of 
plasma concentrations of PM01183 in Cycle 1 and Cycle 2 (about 56 ml of whole 
blood) at the predefined times depicted in the above tables. The Laboratory Manual 
describes in more detail the required procedures. Please read it carefully before PK 
sampling. In short, after collection, each sample will be centrifuged and the resulting 
plasma layer transferred into a new tube for the determination of PM01183 
concentration. The plasma-containing tubes will be stored frozen until their shipment 
with dry ice according to the Laboratory Manual instructions. AAGP samples will be 
shipped together with PK samples. All the material for PK procedures will be provided 
by the Sponsor(s). 
7.2.2
Analytical Procedures
Plasma samples will be analyzed to determine concentrations of PM01183 using a 
validated, specific, and sensitive liquid chromatography/mass spectrometry/mass 
spectrometry (LC-MS/MS) method by or under the supervision of the Sponsor.
7.2.3
Pharmacokinetic Parameters
PK parameters will be calculated using non-compartmental analysis (NCA) and 
population methods if appropriate, after pooling data from this study with data obtained 
from other studies.
7.3
PHARMACOGENETIC EVALUATIONS
To explore factors that may help to explain individual variability in the main PK 
parameters, the presence or absence of germline mutations or polymorphisms that may 
be involved in the metabolism and/or transport of PM01183 will be analyzed in 
leukocyte DNA extracted from one blood sample (8 ml) obtained at any time during the 
study. The collection and management of the polymorphisms samples are quite different 
than those for PK assessment. Please, follow carefully the instructions detailed in the 
Laboratory Manual that will be provided. The assessment of polymorphisms is not 
affected by treatment, but this sample should be collected preferably just before 
treatment start in Cycle 1. Therefore, the Sponsor may require the collection of 
additional polymorphisms samples later on, if the first assessment has not been 
performed accurately.
7.4
PHARMACOGENOMIC (PGX) EVALUATIONS
Provision of samples for PGx analyses will be optional and performed upon patient 
consent by signing the PGx IC. For those patients who consent to participate in the PGx 
study, available tumor tissue blocks obtained at diagnosis of the disease will be 
collected during his/her participation in the associated clinical trial. 
The following analyses will be done in paraffin-embedded tumor tissue from consenting 
patients: 

Quantitation of mRNA expression of selected genes involved in DNA repair 
mechanisms and/or related to the mechanism of action of PM01183 or to the 
pathogenesis of the disease by real-time qRT-PCR.


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
Quantitation of protein expression of selected genes involved in DNA repair 
mechanisms and/or related to the mechanism of action of PM01183 or to the 
pathogenesis of the disease by IHC in tumor tissue microarrays constructed.

Analysis of polymorphisms and mutations of the above mentioned selected 
genes will be analyzed, if relevant, by qRT-PCR and/or DNA sequencing.

Expression levels of the different markers will be correlated with the patient’s 
clinical outcome.
7.5
SAFETY
Patients will be evaluable for safety if they have received any partial or complete 
infusion of PM01183. All AEs will be graded according to the NCI-CTCAE, v.4. 
The safety profile of patients will be monitored throughout the treatment and up to 30 
days after the last PM01183 infusion (end of treatment, EOT), or until the patient starts 
a new antitumor therapy or until the date of death, whichever occurs first.
Treatment delays, dose reduction requirements and reason for treatment discontinuation 
will be monitored throughout the study. Any treatment-related AEs will be followed 
until recovery to at least grade 1 or stabilization of symptoms or until the start of a new 
antitumor therapy, whichever occurs first. 
7.6
ADVERSE EVENTS DEFINITIONS
7.6.1
Adverse Event (AE)
An AE is any untoward medical occurrence in a patient who has received 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.
7.6.2
Serious Adverse Event (SAE)
A SAE is any adverse experience occurring at any dose that:
Results in death (is fatal),
Is life-threatening,
Requires or prolongs inpatient hospitalization,


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Results in persistent or significant disability or incapacity,
Is a congenital anomaly or birth defect, 
Is medically significant, or
Is any suspected transmission of an infectious agent via a medicinal product. 
Medical and scientific judgment should be exercised in deciding whether expedited 
reporting is appropriate in other situations such an important medical events 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.
7.6.3
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.
7.6.4
Life-threatening Event
Any event in which the patient was at risk of death at the time of the event is considered 
life-threatening; it does not refer to an event which hypothetically might have caused 
death if it had been more severe.
7.6.5
Hospitalization or Prolongation of Hospitalization
Any AE requiring hospitalization (or prolongation of hospitalization) that occurs or 
worsens during the course of a patient’s participation in a clinical trial 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: 
a. Reasons described in protocol [e.g., investigational medicinal product (IMP) 
administration, protocol-required intervention/investigations, etc.]. However, 
events requiring hospitalizations or prolongation of hospitalization as a result of a 
complication of therapy administration or clinical trial procedures will be reported 
as SAEs.
b. Hospitalization or prolonged hospitalization for technical, practical or social 
reasons, in absence of an AE.
c. 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 the following:
d. An emergency visit due to an accident where the patient is treated and discharged.
e. When the patient is held 24 hours for observation and finally is not admitted.
f. Planned treatments at sites not associated to a hospital and generally considered as 
minor surgical procedures (e.g., laser eye surgery, arthroscopy).
7.6.6
Unlisted/Unexpected Adverse Event
An AE, the nature or severity of which is not consistent with the applicable reference 
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The Sponsor will use as the reference safety information for the evaluation of 
listedness/expectedness the most updated IB for lurbinectedin (PM01183).
7.6.7
Adverse Reactions
All untoward and unintended responses to an investigational medicinal product related 
to any dose administered. This definition covers also medication errors and uses outside 
what is foreseen in the protocol, including overdose, lack of efficacy, misuse and abuse 
of the product.
7.6.8
Adverse Events Related to the Study Drug
An AE is considered related to a study drug/IMP if the Investigator’s assessment of 
causal relationship to the IMP(s) is “Y (yes)” (see Section 7.6.10). 
The Investigator will assess the causal relationship of the IMP(s) to the SAE.
The Sponsor may also consider related to the study drug(s)/IMP(s) those events for 
which the Investigator 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.
7.6.9
Expedited Reporting
The Sponsor is responsible for the appropriate expedited reporting of serious 
unlisted/unexpected and related adverse events (SUSAR/SUA), including misuse, 
overdose and abuse, to the Competent Authorities. The Sponsor will also report all 
SAEs, including misuse, overdose and abuse, which are unlisted/unexpected and related 
to the study drug(s) [IMP(s)] to the Investigators and to the IECs/IRBs according to the 
current legislation, unless otherwise required and documented by the IECs/IRBs.
7.6.10 Assessment of Causal Relationship to the Study Drug
The Investigator must provide an assessment of the causal relationship of the clinical 
trial IMP(s) to each SAE according to the following scale:
Y
There is a reasonable possibility that the IMP(s) caused the SAE.
N
There is no 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 (e.g., the patient was not seen at his/her 
center) if none of the above can be used.
7.7
ADVERSE EVENTS REPORTING PROCEDURES
7.7.1
Reporting Adverse Events
The Sponsor will collect AEs until 30 days after administration of the last dose of the 
study drug(s)/IMP(s) or until the start of a new antitumor therapy, whichever occurs 
first. All AEs suspected to be related to the study drug/IMP 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 misuse, overdose and abuse, must be recorded in English using 
medical terminology in the source document and the CRF. 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.4 
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 


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criteria for classification as a SAE requiring immediate notification to Pharma Mar or 
its designated representative. The Investigator must provide any relevant information as 
requested by the Sponsor in addition to that on the CRF.
Abnormal laboratory tests occurring during the study should only be recorded in the AE 
section of the CRF if the disorder:
Is associated with clinically significant symptoms, and/or
Leads to a change in study dosing 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 CRF 
(i.e., biochemistry, hematology).
7.7.2
Reporting Serious Adverse Events
The Sponsor will collect SAEs from the time of signing of the informed consent form 
(ICF) until 30 days after administration of the last dose of study drug(s)/IMP(s) or until 
the start of a new antitumor therapy, whichever occurs first. Beyond this period of time, 
only those SAEs suspected to be related to the IMP will be collected. Nonetheless, the 
Sponsor will evaluate any safety information that is spontaneously reported by an 
Investigator beyond the time frame specified in the protocol.
All SAEs (as defined above) 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 as appropriate: electronically (e-CRF), fax (+34 91 846 
6004), e-mail (phv@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. SAEs initially 
reported by phone must be followed by a completed electronic SAE reporting on e-CRF 
from the investigational staff within one working day.
If the SAE occurs after the patient’s registration has been confirmed, this information 
will preferably be reported electronically by completing the applicable eCRF sections. 
Those SAEs occurring during the screening phase (from ICF signature to registration) 
and after off-study will be reported using a paper “SAE form” that must be forwarded as 
mentioned above and always within 24 hours to the Pharmacovigilance Department.
All SAEs suspected to be related to the IMP(s) must be followed until the event or its 
sequelae resolves or stabilizes at an acceptable level by the Investigator and the clinical 
monitor or his/her designated representative.
7.7.3
Reporting Pregnancy Cases Occurred within the Clinical Trial
National regulations require that clinical trial Sponsors collect information on 
pregnancies occurring during clinical trials, in which exposure to the IMP(s) at any time 
during pregnancy, via either maternal or paternal exposure, is suspected.
Therefore, pregnancy (including a positive pregnancy test regardless of age or disease 
state) of a female patient within three months from the patient’s last PM01183 last 
administration, or the female partner of a male patient occurring while the patient is on 
study drugs, or within four months after the last PM01183 administration, are 
considered immediately reportable events.
The Investigator will report the following events immediately and always within 24 
hours from first knowledge:


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Any occurrence of a pregnancy where any kind of exposure to the IMP(s) is 
suspected.
Possible exposure of a pregnant woman.
All reports of elevated/questionable or indeterminate beta human chorionic 
gonadotropins (β-hCGs) and additional tests (ultrasounds).
Immediately after detecting a case of 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 withdrawal from the trial. 
Any pregnancy or positive pregnancy test must be reported to Pharma Mar S.A. 
Pharmacovigilance Department immediately using the Pregnancy Report form.
The Investigator will follow the pregnancy until its outcome, and must notify Pharma 
Mar S.A. Pharmacovigilance Department the outcome of the pregnancy within 24 hours 
of first knowledge as a follow-up to the initial 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 Pharma Mar S.A. 
Pharmacovigilance Department within 24 hours of the Investigator’s knowledge of the 
event). 
All neonatal deaths that occur within 30 days of birth should be reported, without regard 
to causality, as SAEs. In addition, any infant death at any time thereafter that the 
Investigator suspects is related to the exposure to the study drug(s)/IMP(s) should also 
be reported to Pharma Mar S.A. Pharmacovigilance Department within 24 hours of the 
Investigators’ knowledge of the event.
7.8
ADVERSE EVENTS MONITORING
Safety review will be performed at Pharma Mar S.A. once SAE forms have been 
received and the CRFs electronically completed by the Investigator.
At every monitoring visit performed by the designated clinical trial monitor, the 
consistency between the CRF/SAE data reported to the Pharmacovigilance Department 
and the patient's source data will be reviewed. In every case a discrepancy is found 
during the review, data will be amended/updated in the CRF and the SAE 
form/information reported to the Pharmacovigilance Department (when applicable), 
according to source data. An update (follow-up) with changes arisen will be signed by 
the Principal Investigator (or his/her designee) and then reported/provided to the 
Pharmacovigilance Department within 24 hours, with the CRF updated on the same 
dates. 
Periodic safety review of clinical data will be performed. 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. Pharma Mar S.A. 
Pharmacovigilance Department will review the safety data of this trial on an ongoing 
basis. 
SAEs will be continuously collected, assessed and reported throughout all the study as 
per the applicable Regulations by the Pharma Mar S.A. Pharmacovigilance Department. 
Periodic safety reviews of SAE reports are to be conducted and documented by the 
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As per the applicable regulations, Pharma Mar S.A. will report to the IECs/IRBs, 
Investigators and Competent Authorities:

expedited: all serious, related, unlisted/unexpected AEs or critical safety 
findings (including those of special interest) from this and any other clinical trial 
with PM01183 and, 

periodic: all relevant safety information generated in all clinical trials with the 
IMP(s) within the Development Safety Update Report.
Non-serious AEs will be verified during monitoring visits by the monitor, who will 
discuss them with the Investigators, if applicable. 
8.
STATISTICAL METHODS
This phase II trial is designed to assess the antitumor activity of PM01183 in terms of 
ORR according to the RECIST v.1.1 assessed by IA in different selected advanced 
solid tumors: SCLC, H&N, NETs, biliary tract carcinoma, endometrial carcinoma, 
BRCA 1/2-associated metastatic breast carcinoma, carcinoma of unknown primary 
site, GCTs, and EFTs. In addition, in the SCLC cohort, tumor evaluation will be also 
done by IRC.
8.1
SAMPLE SIZE
Up to 25 evaluable patients in each tumor type will be recruited to test the null 
hypothesis that 1% or less patients get a response (p ≤ 0.01) versus the alternative 
hypothesis that 10% or more patients get a response (p ≥ 0.10). The variance of the 
standardized test is based on the null hypothesis. The type I error (alpha) associated 
with this one-sided test is 0.025 and the type II error (beta) is 0.2 (normal 
approximation; ~0.3 if exact binomial distribution); hence, statistical power is 80% 
(normal approximation; ~70% if exact binomial distribution). With these assumptions, 
if the number of patients who achieve a confirmed response is ≥ 2, then this would 
allow the rejection of the null hypothesis.
An interim analysis to reject H0 (non-binding) or to reject H1 (futility) in each tumor 
type is planned after the recruitment of 15 evaluable patients in each cohort. The 
Gamma family boundary will be used to control the type I error, the parameter to reject 
H0 is fixed as -1 and the parameter to reject H1 is fixed as 0. If none of the first 15 
evaluable patients in a determined cohort has a confirmed response, the alternative 
hypothesis will be rejected, according to boundaries and sample size assumptions, and 
recruitment will be stopped. If the number of responding patients is already two or more 
at the interim analysis, then H0 could be rejected and the study will have enough power 
to be stopped. On the contrary, if there is one confirmed response, the recruitment will 
be continued to up to 25 evaluable patients.

A phase III trial of PM01183 combined with doxorubicin in SCLC is ongoing. 
Hence, the sample size for the SCLC cohort of this study will be expanded to 
100 evaluable patients if the success boundary (≥2 confirmed responses) is 
reached in the first 25 evaluable patients.  

Based on the newly available information, additional patients will be recruited to 
test the null hypothesis that 15% or less patients get a response (p ≤ 0.15) versus
the alternative hypothesis that 30% or more patients get a response (p ≥ 0.30). 
The variance of the standardized test is based on the null hypothesis. The type I 
error (alpha) associated with this one-sided test is 0.025 and the type II error 


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(beta) is 0.051 (normal approximation; ~0.05 if exact binomial distribution); 
hence, statistical power is 95% (normal approximation; ~95% if exact binomial 
distribution). With these assumptions, if the number of patients who achieve a 
confirmed response is ≥ 23, then this would allow the rejection of the null 
hypothesis. The judgement of patient’s evaluability and replacement of non-
evaluable patients in each cohort for the interim analyses will be guided by the 
investigator assessment.

A phase I trial of PM01183 combined with doxorubicin has shown encouraging 
antitumor activity in endometrial carcinoma. Hence, the sample size for the 
endometrial carcinoma cohort of this study will be doubled to 50 evaluable 
patients if the success boundary (≥2 confirmed responses) is reached in the first 
25 evaluable patients.
Based on the newly available information, additional patients will be recruited 
to test the null hypothesis that 10% or less patients get a response (p ≤ 0.10) 
versus the alternative hypothesis that 25% or more patients get a response (p ≥ 
0.25). The variance of the standardized test is based on the null hypothesis. The 
type I error (alpha) associated with this one-sided test is 0.025 and the type II 
error (beta) is 0.144 (normal approximation; ~0.16 if exact binomial 
distribution); hence, statistical power is ~86% (normal approximation; ~84% if 
exact binomial distribution). With these assumptions, if the number of patients 
who achieve a confirmed response is ≥ 10, then this would allow the rejection 
of the null hypothesis.
With the sample size of 100 and 50 evaluable patients in each indication (SCLC and 
endometrial), the obtained confidence interval will be narrower and its half-width will 
be confined to ±15%.
8.2
STATISTICAL ANALYSIS
Statistical analysis will be done by the Sponsor or under the authority of the Sponsor. 
The study protocol contains a general description; specific details will be provided in 
the Statistical Analysis Plan.
Frequency tables will be prepared for categorical variables, and continuous variables 
will be described by means of summary tables, which will include the median, mean, 
standard deviation, minimum, and maximum of each variable. 
8.2.1
Efficacy Analyses
Counts and percentages, with their corresponding exact 95% confidence intervals, will 
be calculated for the binomial endpoints (e.g., ORR, clinical benefit). The confidence 
intervals based on the group sequential tests performed for each cohort will also be 
calculated.
Time-to-event variables (OS, PFS and DR) and their set time estimates (i.e., PFS 4/6 
and OS 6/12) will be analyzed according to the Kaplan-Meier method.
In the SCLC cohort, the evaluation of the efficacy endpoints evaluated by IA and IRC 
will be analyzed and compared. The rate of concordance between both evaluation 
methods for best response, progression status and progression-free survival will be 
presented with 2-way frequency tables and measures of agreement.
Waterfall plots will be used to describe the best variation of the sum of target lesions 
during treatment.


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The number of patients recruited in any cohort may differ from that pre-specified 
according to the sample size assumptions. Therefore, the main efficacy results will be 
calculated according to the planned cohort sample size and, if any cohort sample size 
differs at least 10% from the assumptions, a sensitivity analysis using all evaluable 
patients recruited (adjusting the corresponding boundaries to test the null hypothesis) 
will be performed.
8.2.2
Pharmacokinetic Analyses
PK data will be listed in the population PK-report for all patients with available 
PM01183 concentrations. PK analysis of plasma concentration-time data of PM01183 
will be performed using non-linear mixed-effects modeling and/or non-compartmental 
analysis. Data may be combined with those of a selection of phase I or II studies to 
support a relevant structural model. Available patient characteristics (e.g., 
demographics, laboratory variables, genotypes) will be tested as potential covariates 
affecting PK parameters.
8.2.3
Pharmacogenetic Analyses
The influence of known polymorphisms on main PK parameters will be assessed by 
Student’s test or Mann-Whitney’s U test as appropriate.
8.2.4
Pharmacogenomic Analyses
Analysis of RNA/protein expression, polymorphisms and mutations will be performed 
blind and with clinical data compiled only after all analyses are completed. A Fisher´s 
exact test/logistic regression for categorical variables and log rank test/Cox regression 
for time to event variables will be used to test whether a specific profile is associated 
with clinical outcome. The prognostic value of markers will be explored for objective 
response, PFS and OS. In each case, if applicable, a multivariate model will be 
developed by stepwise selection. All tests of statistical significance will be two-sided, 
and significance will be set at 0.05.
8.2.5
Safety Analyses
AEs, SAEs, deaths, laboratory evaluations, dose delays/reductions and study drug 
discontinuations due to AEs will be tabulated in a descriptive way. Counts and 
percentages will be used for categorical variables, and summary tables will be used for 
continuous variables. 
8.3
INTERIM ANALYSES
An interim analysis to reject H0 (non-binding) or to reject H1 (futility) in each tumor 
type is planned after the recruitment of 15 evaluable patients in each cohort. The 
Gamma family boundary will be used to control the type I error, the parameter to reject 
H0 is fixed as -1 and the parameter to reject H1 is fixed as 0. If none of the first 15 
evaluable patients in a determined cohort has a confirmed response, the alternative 
hypothesis will be rejected, according to boundaries and sample size assumptions, and 
recruitment will be stopped. If the number of responding patients is already two or more 
at the interim analysis, then H0 could be rejected and the study will have enough power 
to be stopped. On the contrary, if there is one confirmed response, the recruitment will 
be continued to up to 25 evaluable patients.
In particular, in the SCLC and endometrial carcinoma cohorts, the analysis at 25 
evaluable patients will serve as second interim analysis to decide the continuation of 
recruitment. Two objective responses will be required to expand the accrual up to 100
and 50 evaluable patients respectively. 


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
For the SCLC cohort, the type I/II error will be controlled with a Gamma 
family boundary (-1 to reject Ho, 0 to reject H1)  

For the endometrial carcinoma cohort, the type I/II error will be controlled with
a Gamma family boundary (-1 to reject Ho, -3 to reject H1)  
9.
ADMINISTRATIVE SECTION
9.1
ETHICS
This clinical trial will be conducted in accordance with the ethical principles that have 
their origin in the World Medical Association (WMA) Declaration of Helsinki (see
APPENDIX 5) and will be consistent with GCP guidelines and pertinent regulatory 
requirements.
The study personnel involved in conducting this trial 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 and the patient informed consent will receive Competent Authorities and 
IEC/IRB approval/favorable opinion prior to initiation, according to pertinent 
regulations.
The decision of the Competent Authorities and the IEC/IRB 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 the beginning of the study.
The Investigator and/or the Sponsor is/are responsible for keeping the Competent 
Authorities and the IEC/IRB informed of any 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.
9.2
MONITORING, AUDITING AND INSPECTING
The study will be monitored by regular site visits and telephone calls to the Investigator 
by the clinical trial monitor designated by Pharma Mar S.A.
During site visits, the trial monitor should revise original patient records, drug 
accountability records and document retention (study file). Additionally, the trial 
monitor should observe study procedures and will discuss any problems 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, 
Sections 4.9.7 and 6.10] 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 Topic E6 Guideline for Good Clinical 
Practice, Sections 1.51 and 1.52.
Systems and procedures will be implemented to ensure the quality of every aspect of the 
trial.
During the course of the trial, the Clinical Quality Assurance Department of Pharma 
Mar S.A. or external auditors contracted by the Sponsor may conduct an onsite audit 
visit (ICH Topic E6 Guideline for GCP, Section 1.6).


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Participation in this trial implies acceptance of potential inspection by national or 
foreign Competent Authorities.
9.3
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 ICFs 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 Forms
(ICFs). This copy must provide written full information about the clinical trial, in a 
language that is non-technical and easily understood, as well as on other sub-studies 
(PGx/pharmacogenetic analyses). The Investigator should allow the necessary time for 
the patient or his/her legally acceptable representative to inquire about the details of the 
clinical trial; then, the ICFs 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.
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.
9.4
CONFIDENTIALITY/PATIENTS IDENTIFICATION
The collection and processing of personal data from the patients enrolled in this clinical 
trial will be limited to those data that are necessary to investigate the efficacy, safety, 
quality and usefulness of the study drug used in this trial.
It is the Investigator’s responsibility that sufficient information on the identity of the 
patients will be retained.
The trial monitor, the Sponsor’s auditor, the IECs/IRBs and the Competent Authorities
should have direct access to all requested trial-related records, and agree to keep the 
identity of 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. Patients’ personal data will be collected, processed and transmitted in a 
pseudonymised form.
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 shall comply with General Data Protection Regulation (GDPR) (EU) 
2016/679 effective from 25 May 2018 (repealing Directive 95/46/EC GDPR of 24 
October 1995), and applicable regulations on the protection of individuals with regard 
to the processing of personal data and on the free movement of such data.


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9.5
CASE REPORT FORMS
CRFs will be used to record all data for each patient. It is the responsibility of the 
Investigator to ensure that the CRFs are properly and completely filled in, in English. 
CRFs must be completed for all patients who have given their informed consent.
A patient’s source documentation is the patient’s records (including but not limited to 
physician/hospital notes, nurses notes, IMP preparation records including reconstitution 
and dilution, IMP administration records, etc.) and any original document, and as such 
they should be maintained at the study site.
The data collected in the CRF will be entered into the Sponsor’ databases, which 
comply with General Data Protection Regulation (GDPR) (EU) 2016/679 effective from 
25 May 2018 (repealing Directive 95/46/EC GDPR of 24 October 1995) on the 
protection of individuals with regard to the processing of personal data.
9.6
INSURANCE
The Sponsor will provide insurance or indemnity in accordance with the applicable 
regulatory requirements.
9.7
RETENTION OF RECORDS
The Investigator/Institution should maintain trial documents according to Section 8 of 
the ICH Topic E6 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. 
9.8
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. In general, the first author will be the investigator who 
recruits the highest number of patients with information finally available for data 
analysis. Relevant Pharma Mar S.A. personnel who have fully participated in the study 
must be considered for co-authorship of the publication.


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drugs against human tumor cell lines: development of mean graph and 
COMPARE algorithm. J Natl Cancer Inst 1989;81(14):1088-1092.
89.
Dileo P, Grosso F, Casanova M, Jimeno J, Marsoni S, Sanfilippo R, Podda M, 
Ferrari S, Bertulli R, Casali PG. Trabectedin (T) in metastatic Ewing's family 
tumors (EFT) patients (pts) progressing after standard chemotherapy. J Clin 
Oncol; 2007 ASCO Annual Meeting Proceedings Part I. 2007;25(18s):10040.
90.
Harlow M, Maloney N, Guillen Navarro MJ, D'Incalci M, Galmarini C, Aviles 
Marin PM, Grohar P. PM01183 shows an improved therapeutic index relative to 
trabectedin and suppresses EWS/FLI1 activity at clinically achievable 
concentrations. AACR American Association for Cancer Research; 105th 
Annual Meeting; April 5-9, 2014. San Diego, California 2014.
91.
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, 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):1099-1110.
92.
Bosman FT, Carneiro F, Hruban RH, Theise ND. WHO Classification of 
Tumours of the Digestive System 4th ed: IARC Press, Lyon, France; 2010.


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11. 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. 


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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 15 September 2014
and available at 
http://www.hma.eu/ctfg.html (accessed 30 July 2015). 
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 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. Combinations 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. 


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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 may reduce exposure to substrates of CYP3A through 
enzyme induction; the efficacy of hormonal contraceptives may be reduced if co-
administered with this drug.


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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
Methoxsalen, mexiletine,
oral contraceptives, 
phenylpropanolamine,
thiabendazole, zileuton
Acyclovir, allopurinol, caffeine, 
cimetidine,
Daidzein, (5), disulfiram, Echinacea, 
(5) famotidine, norfloxacin, 
propafenone, propranolol, 
terbinafine, ticlopidine, verapamil
CYP2B6
Clopidogrel, ticlopidine
prasugrel
CYP2C8
Gemfibrozil(6)
Fluvoxamine, ketoconazole, 
trimethoprim
CYP2C9
Amiodarone, fluconazole,
miconazole, oxandrolone
Capecitabine, cotrimoxazole,
etravirine, fluvastatin, fluvoxamine, 
metronidazole, sulfinpyrazone, 
tigecycline,
voriconazole, zafirlukast
CYP2C19
Fluconazole, (7)
Fluvoxamine, (8)
ticlopidine (9)
Esomeprazole, fluoxetine, 
moclobemide,
omeprazole, voriconazole
Allicin (garlic derivative), 
armodafinil, carbamazepine,
cimetidine,
etravirine,
human growth hormone (rhGH),
felbamate,
ketoconazole,
oral contraceptives (10)
CYP3A
Boceprevir,
clarithromycin, 
conivaptan,
grapefruit juice, (11) 
indinavir, itraconazole, 
ketoconazole,
lopinavir/ritonavir,
mibefradil, (12)
nefazodone, nelfinavir,
posaconazole, ritonavir,
saquinavir,
telaprevir,
telithromycin,
voriconazole
Amprenavir, aprepitant,
atazanavir, ciprofloxacin,
darunavir/ritonavir, diltiazem, 
erythromycin, fluconazole, 
fosamprenavir, grapefruit juice, 
(11)
imatinib, verapamil
Alprazolam, amiodarone,
amlodipine, atorvastatin, 
bicalutamide, cilostazol, cimetidine,
cyclosporine, fluoxetine, 
fluvoxamine, ginkgo, (5) goldenseal, 
(5)
isoniazid, nilotinib,
oral contraceptives, ranitidine, 
ranolazine,
tipranavir/ritonavir, zileuton
CYP2D6
Bupropion, fluoxetine,
paroxetine, quinidine
Cinacalcet, duloxetine,
terbinafine
Amiodarone, celecoxib,
cimetidine, desvenlafaxine, 
diltiazem, diphenhydramine, 
Echinacea, (5) escitalopram, 
febuxostat, gefitinib,
hydralazine, hydroxychloroquine,
imatinib, methadone,
oral contraceptives, propafenone, 
ranitidine,
ritonavir, sertraline,
telithromycin, verapamil
1.
Please note the following: This is not an exhaustive list. For an updated list, see the following link: 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/uc
m080499.htm.
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.


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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.
5.
Herbal product.
6.
Gemfibrozil also inhibits OATP1B1.
7.
Fluconazole is listed as a strong CYP2C19 inhibitor based on the AUC ratio of omeprazole, which is also 
metabolized by CYP3A; fluconazole is a moderate CYP3A inhibitor.
8.
Fluvoxamine strongly inhibits CYP1A2 and CYP2C19, but also inhibits CYP2C8/2C9 and CYP3A;
9.
Ticlopidine strongly inhibits CYP2C19, but also inhibits CYP3A, CYP2B6, and CYP1A2.
10. Effect seems to be due to CYP2C19 inhibition by ethinyl estradiol.
11. 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).
12. Withdrawn from the United States market because of safety reasons.
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
Montelukast, phenytoin, 
smokers versus non-smokers (2)
Moricizine, omeprazole, 
phenobarbital,
CYP2B6
Efavirenz, rifampin
Nevirapine
CYP2C8
Rifampin
CYP2C9
Carbamazepine,
rifampin
Aprepitant, bosentan, 
phenobarbital, St. John’s wort 
(3,4)
CYP2C19
Rifampin
Artemisinin
CYP3A
Avasimibe, (5) 
carbamazepine, phenytoin, 
rifampin, St. John’s wort 
(3)
Bosentan, efavirenz, etravirine, 
modafinil, nafcillin
Amprenavir, aprepitant, 
armodafinil, echinacea,(4) 
pioglitazone, prednisone, 
rufinamide
CYP2D6
None known
None known
None known
1.
Please note the following: This is not an exhaustive list. For an updated list, see the following link: 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabelin
g/ucm080499.htm.
2.
For a drug that is a substrate of CYP1A2, the evaluation of the effect of induction of CYP1A2 can be 
carried out by comparative PK studies in smokers vs. non-smokers.  
3.
The effect of St. John’s wort varies widely and is preparation-dependent.
4.
Herbal product.
5.
Not a marketed drug.
Table 3. Examples (1) of Sensitive In Vivo CYP Substrates and CYP Substrates with 
Narrow Therapeutic Range
CYP
enzymes
Sensitive substrates (2)
Substrates with
narrow therapeutic range (3)
CYP1A2
Alosetron, caffeine,
duloxetine, melatonin, ramelteon,
tacrine, tizanidine
Theophylline, tizanidine
CYP2B6 (4)
Bupropion, efavirenz
CYP2C8
Repaglinide (5)
Paclitaxel
CYP2C9
Celecoxib
Warfarin, phenytoin
CYP2C19
Lansoprazole, omeprazole, S-mephenytoin
S-mephenytoin
CYP3A (6)
Alfentanil, aprepitant, budesonide, buspirone, conivaptan, 
darifenacin, darunavir, dasatinib, dronedarone, eletriptan, 
eplerenone, everolimus, felodipine, indinavir, fluticasone, 
lopinavir, lovastatin, lurasidone, maraviroc, midazolam, 
nisoldipine, quetiapine, saquinavir, sildenafil, simvastatin, 
sirolimus, tolvaptan, tipranavir, triazolam, vardenafil
Alfentanil, astemizole, (7) 
cisapride, (7) cyclosporine, 
dihydroergotamine, ergotamine, 
fentanyl, pimozide, quinidine, 
sirolimus, tacrolimus,
terfenadine (7)


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CYP
enzymes
Sensitive substrates (2)
Substrates with
narrow therapeutic range (3)
CYP2D6
Atomoxetine, desipramine,
dextromethorphan, metoprolol,
nebivolol, perphenazine, tolterodine,
venlafaxine
Thioridazine
1.
Note that this is not an exhaustive list.
For an updated list, see the following link: 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabelin
g/ucm080499.htm.
2.
Sensitive CYP substrates refers to drugs whose plasma AUC values have been shown to increase 5-fold or 
higher when co-administered with a known CYP inhibitor.
3.
CYP substrates with narrow therapeutic range refers to drugs whose exposure-response relationship 
indicates that small increases in their exposure levels by the concomitant use of CYP inhibitors may lead to 
serious safety concerns (e.g., Torsades de Pointes).
4.
The AUC of these substrates were not increased by 5-fold or more with a CYP2B6 inhibitor, but they 
represent the most sensitive substrates studied with available inhibitors evaluated to date.
5.
Repaglinide is also a substrate for OATP1B1, and it is only suitable as a CYP2C8 substrate if the inhibition 
of OATP1B1 by the investigational drug has been ruled out.  
6.
Because a number of CYP3A substrates (e.g., darunavir, maraviroc) are also substrates of P-gp, the 
observed increase in exposure could be due to inhibition of both CYP3A and P-gp.
7.
Withdrawn from the United States market because of safety reasons.


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APPENDIX 4: EVALUATION OF RESPONSE. THE RECIST.
This document summarizes the main information contained in RECIST version 1.1. 
Further details can be found in the original article: Eisenhauer EA, Therasse P, 
Bogaerts J, et al.: New response evaluation criteria in solid tumours: revised RECIST 
guideline (version 1.1). Eur J Cancer 2009; 45(2): 228-247.
LIST OF ABBREVIATIONS
CR
Complete Response
CRF
Case Report Form
CT
Computed Tomography
FDG-PET
Fluorodeoxyglucose-Positron Emission Tomography
MRI
Magnetic Resonance Imaging
NE
Not Evaluable
PD
Progressive Disease
PET
Positron Emission Tomography
PFS
Progression-free Survival
PR
Partial Response
PSA
Prostate-specific Antigen
RECIST
Response Evaluation Criteria in Solid Tumors
SD
Stable Disease
TTP
Time to Progression
LIST OF TABLES
Table 1. Time point response: patients with target (+/–non-target) disease.
Table 2. Time point response: patients with non-target disease only.
Table 3.  Best overall response when confirmation of complete response (CR) and 
partial response (PR) is  required.
1. MEASURABILITY OF TUMOR LESIONS AT BASELINE
1.1 Definitions
At baseline, tumor lesions/lymph nodes will be categorized measurable or non-
measurable as follows:
1.1.1 Measurable
Tumor Lesions:
Must be accurately measured in at least one dimension (longest diameter in the plane of 
measurement is to be recorded) with a minimum size of: 

10 mm by computed tomography (CT) scan (irrespective of scanner type) 
and magnetic resonance imaging (MRI) (no less than double the slice 
thickness and a minimum of 10 mm).

10 mm caliper measurement by clinical exam (when superficial). 

20 mm by chest X-ray (if clearly defined and surrounded by aerated lung).


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Malignant Lymph Nodes:
To be considered pathologically enlarged and measurable, a lymph node must be ≥ 15 
mm in short axis when assessed by CT scan (CT scan slice thickness recommended to 
be no greater than 5 mm). At baseline and in follow-up, only the short axis will be
measured and followed (see Schwartz et al. Eur J Cancer. 2009; 45(2):261-267). See 
also notes below on ‘Baseline documentation of target and non-target lesions’ for 
information on lymph node measurement. 
1.1.2 Non-measurable
All other lesions, including small lesions (longest diameter < 10 mm or pathological 
lymph nodes with ≥ 10 to < 15 mm short axis) as well as lesions considered truly non-
measurable. Lesions considered truly non-measurable include: leptomeningeal disease, 
ascites, pleural or pericardial effusion, inflammatory breast disease, lymphangitic 
involvement of skin or lung, and abdominal masses/abdominal organomegaly identified 
by physical exam that is not measurable by reproducible imaging techniques. 
1.1.3 Special Considerations Regarding Lesion Measurability
Bone lesions, cystic lesions, and lesions previously treated with local therapy require 
particular comment:
Bone Lesions:

Bone scan, positron emission tomography (PET) scan or plain films are not 
considered adequate imaging techniques to measure bone lesions. However, 
these techniques can be used to confirm the presence or disappearance of bone 
lesions. 

Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, that can be evaluated by cross sectional imaging techniques such as 
CT or MRI can be considered as measurable lesions if the soft tissue component
meets the definition of measurability described above.

Blastic bone lesions are non-measurable.
Cystic Lesions:

Lesions that meet the criteria for radiographically defined simple cysts should 
not be considered as malignant lesions (neither measurable nor non-measurable) 
since they are, by definition, simple cysts.

‘Cystic lesions’ thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the definition of measurability described above. 
However, if non-cystic lesions are present in the same patient, these are 
preferred for selection as target lesions.
Lesions with Prior Local Treatment:

Tumor lesions situated in a previously irradiated area, or in an area subjected to 
other loco-regional therapy, are usually not considered measurable unless there 
has been demonstrated progression in the lesion. Study protocols should detail 
the conditions under which such lesions would be considered measurable.
1.2. Specifications by Methods of Measurement
1.2.1 Measurement of Lesions
All measurements should be recorded in metric notation, using calipers if clinically 
assessed. All baseline evaluations should be performed as close as possible to the 
treatment start and never more than four weeks before the beginning of the treatment.


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1.2.2 Method of Assessment
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. Imaging based 
evaluation should always be done rather than clinical examination unless the lesion(s) 
being followed cannot be imaged but are assessable by clinical exam.
Clinical Lesions: 
Clinical lesions will only be considered measurable when they are superficial and ≥ 10 
mm diameter as assessed using calipers (e.g., skin nodules). For the case of skin lesions, 
documentation by color photography including a ruler to estimate the size of the lesion 
is suggested. As noted above, when lesions can be evaluated by both clinical exam and 
imaging, imaging evaluation should be undertaken since it is more objective and may 
also be reviewed at the end of the study.
Chest X-Ray: 
Chest CT is preferred over chest X-ray, particularly when progression is an important 
endpoint, since CT is more sensitive than X-ray, particularly in identifying new lesions. 
However, lesions on chest X-ray may be considered measurable if they are clearly 
defined and surrounded by aerated lung. See original article, Appendix II, for more 
details.
Computed Tomography (CT), Magnetic Resonance Imaging (MRI):
CT is the best currently available and reproducible method to measure lesions selected 
for response assessment. This guideline has defined measurability of lesions on CT scan 
based on the assumption that CT slice thickness is 5 mm or less. As is described in 
original article (Appendix II), when CT scans have slice thickness greater than 5 mm, 
the minimum size for a measurable lesion should be twice the slice thickness. MRI is 
also acceptable in certain situations (e.g., for body scans). More details concerning the 
use of both CT and MRI for assessment of objective tumor response evaluation are 
provided in the original article, Appendix II.
Ultrasound:
Ultrasound is not useful in assessment of lesion size and should not be used as a method 
of measurement. Ultrasound examinations cannot be reproduced in their entirety for 
independent review at a later date and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken from one 
assessment to the next (described in greater detail in the original article, Appendix II). If 
new lesions are identified by ultrasound in the course of the study, confirmation by CT 
or MRI is advised. If there is concern about radiation exposure at CT, MRI may be used 
instead of CT in selected instances.
Endoscopy, Laparoscopy: 
The use of these techniques for objective tumor evaluation is not advised. However, 
they can be useful to confirm complete pathological response when biopsies are 
obtained or to determine relapse in trials where recurrence following complete response 
or surgical resection is an endpoint.
2. TUMOR RESPONSE EVALUATION
2.1 Assessment of Overall Tumor Burden and Measurable Disease
To assess objective response or future progression, it is necessary to estimate the overall 
tumor burden at baseline and use this as a comparator for subsequent measurements. 


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Only patients with measurable disease at baseline should be included in protocols where 
objective tumor response is the primary endpoint. Measurable disease is defined by the 
presence of at least one measurable lesion (as detailed above in Section 1. Measurability 
of tumor at baseline). In studies where the primary endpoint is tumor progression (either 
time to progression or proportion with progression at a fixed date), the protocol must 
specify if entry is restricted to those with measurable disease or whether patients having 
non-measurable disease only are also eligible.
2.2 Baseline Documentation of “Target” and “Non-target” Lesions
When more than one measurable lesion is present at baseline, all lesions up to a 
maximum of ﬁve lesions total (and a maximum of two lesions per organ) representative 
of all involved organs should be identiﬁed as target lesions and will be recorded and 
measured at baseline (this means in instances where patients have only one or two organ 
sites involved that a maximum of two and four lesions will be recorded, respectively). 
For evidence to support the selection of only ﬁve target lesions, see analyses on a large 
prospective database in the article by Bogaerts et al. Eur J Cancer 2009;45:248–260. 
Target lesions should be selected on the basis of their size (lesions with the longest 
diameter), be representative of all involved organs, but in addition should be those that 
lend themselves to reproducible repeated measurements. It may be the case that, on 
occasion, the largest lesion does not lend itself to reproducible measurement, in which 
circumstance the next largest lesion which can be measured reproducibly should be 
selected. To illustrate this point see the example in the original article, Figure 3 of 
Appendix II. 
Lymph nodes merit special mention since they are normal anatomical structures which 
may be visible by imaging even if not involved by tumor. As noted in the previous 
section, pathological nodes which are defined as measurable and may be identified as 
target lesions must meet the criterion of a short axis of ≥ 15 mm by CT scan. Only the 
short axis of these nodes will contribute to the baseline sum. The short axis of the node 
is the diameter normally used by radiologists to judge if a node is involved by solid 
tumor. Nodal size is normally reported as two dimensions in the plane in which the 
image is obtained (for CT scan this is almost always the axial plane; for MRI the plane 
of acquisition may be axial, sagittal or coronal). The smaller of these measures is the 
short axis. For example, an abdominal node which is reported as being 20 mm × 30 mm 
has a short axis of 20 mm and qualifies as a malignant, measurable node. In this 
example, 20 mm should be recorded as the node measurement (see also the example in 
the original article, Figure 4 of Appendix II). All other pathological nodes (those with 
short axis ≥ 10 mm but < 15 mm) should be considered non-target lesions. Nodes that 
have a short axis < 10 mm are considered non-pathological and should not be recorded 
or followed. 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for 
all target lesions will be calculated and reported as the baseline sum diameters. If lymph 
nodes are to be included in the sum, then as noted above, only the short axis is added 
into the sum. The baseline sum diameters will be used as reference to further 
characterize any objective tumor regression in the measurable dimension of the disease.
All other lesions (or sites of disease) including pathological lymph nodes should be 
identified as non-target lesions and should also be recorded at baseline. Measurements 
are not required and these lesions should be followed as ‘present’, ‘absent’, or in rare 
cases ‘unequivocal progression’ (more details to follow). In addition, it is possible to 
record multiple non-target lesions involving the same organ as a single item on the case 


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record form (e.g., ‘multiple enlarged pelvic lymph nodes’ or ‘multiple liver 
metastases’).
2.3 Response Criteria
This section provides the definitions of the criteria used to determine objective tumor 
response for target lesions.
2.3.1 Evaluation of Target Lesions
Complete Response (CR):
Disappearance of all target lesions. Any pathological 
lymph nodes   (whether target or non-target) must have 
reduction in short axis to < 10 mm.
Partial Response (PR):
At least a 30% decrease in the sum of diameters of target 
lesions, taking as reference the baseline sum diameters.
Progressive Disease (PD):
At least a 20% increase in the sum of diameters of target 
lesions, taking as reference the smallest sum on study 
(this includes the baseline sum if that is the smallest on 
study). In addition to the relative increase of 20%, the 
sum must also demonstrate an absolute increase of at least 
5 mm. (Note: the appearance of one or more new lesions 
is also considered progression). 
Stable Disease (SD):
Neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD taking as reference 
the smallest sum diameters while on study.
2.3.2 Special Notes on the Assessment of Target Lesions
Lymph Nodes:
Lymph nodes identified as target lesions should always have the actual short axis 
measurement recorded (measured in the same anatomical plane as the baseline 
examination), even if the nodes regress to below 10 mm on study. This means that when 
lymph nodes are included as target lesions, the ‘sum’ of lesions may not be zero even if 
complete response criteria are met, since a normal lymph node is defined as having a 
short axis of < 10 mm. Case report forms (CRFs) or other data collection methods may 
therefore be designed to have target nodal lesions recorded in a separate section where, 
in order to qualify for CR, each node must achieve a short axis < 10 mm. For PR, SD 
and PD, the actual short axis measurement of the nodes is to be included in the sum of 
target lesions.
Target Lesions that Become ‘Too Small to Measure’:
While on study, all lesions (nodal and non-nodal) recorded at baseline should have their 
actual measurements recorded at each subsequent evaluation, even when very small 
(e.g., 2 mm). However, sometimes lesions or lymph nodes which are recorded as target 
lesions at baseline become so faint on CT scan that the radiologist may not feel 
comfortable assigning an exact measure and may report them as being ‘too small to 
measure’. When this occurs it is important that a value be recorded on the CRF. If it is 
the opinion of the radiologist that the lesion has likely disappeared, the measurement 
should be recorded as 0 mm. If the lesion is believed to be present and is faintly seen 
but too small to measure, a default value of 5 mm should be assigned (Note: It is less 
likely that this rule will be used for lymph nodes since they usually have a definable size 
when normal and are frequently surrounded by fat such as in the retroperitoneum; 
however, if a lymph node is believed to be present and is faintly seen but too small to 
measure, a default value of 5 mm should be assigned in this circumstance as well). This 


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default value is derived from the 5 mm CT slice thickness (but should not be changed 
with varying CT slice thickness). The measurement of these lesions is potentially non-
reproducible, therefore providing this default value will prevent false responses or 
progressions based upon measurement error. To reiterate, however, if the radiologist is 
able to provide an actual measure, that should be recorded, even if it is below 5 mm.
Lesions that Split or Coalesce on Treatment:
As noted in the original article, Appendix II, when non-nodal lesions ‘fragment’, the 
longest diameters of the fragmented portions should be added together to calculate the 
target lesion sum. Similarly, as lesions coalesce, a plane between them may be 
maintained that would aid in obtaining maximal diameter measurements of each 
individual lesion. If the lesions have truly coalesced such that they are no longer 
separable, the vector of the longest diameter in this instance should be the maximal 
longest diameter for the ‘coalesced lesion’.
2.3.3 Evaluation of Non-target Lesions
This section provides the definitions of the criteria used to determine the tumor response 
for the group of non-target lesions. While some non-target lesions may actually be 
measurable, they need not be measured and instead should be assessed only 
qualitatively at the time points specified in the protocol.
Complete Response (CR):
Disappearance of all non-target lesions and normalization 
of tumor marker level. All lymph nodes must be non-
pathological in size (< 10 mm short axis).
Non-CR/Non-PD:
Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal 
limits. 
Progressive Disease (PD):
Unequivocal progression (see comments below) of 
existing non-target lesions (Note: the appearance of one or 
more new lesions is also considered progression).
2.3.4 Special Notes on Assessment of Progression of Non-target Disease
The concept of progression of non-target disease requires additional explanation as 
follows:
When the Patient Also Has Measurable Disease:
In this setting, to achieve ‘unequivocal progression’ on the basis of the non-target 
disease, there must be an overall level of substantial worsening in non-target disease 
such that, even in presence of SD or PR in target disease, the overall tumor burden has 
increased sufficiently to merit discontinuation of therapy (see examples in the original 
article, Appendix II and further details below). A modest ‘increase’ in the size of one or 
more non-target lesions is usually not sufficient to quality for unequivocal progression 
status. The designation of overall progression solely on the basis of change in non-target 
disease in the face of SD or PR of target disease will therefore be extremely rare.
When the Patient Has only Non-measurable Disease:
This circumstance arises in some phase III trials when it is not a criterion of study entry 
to have measurable disease. The same general concepts apply here as noted above, 
however, in this instance there is no measurable disease assessment to factor into the 
interpretation of an increase in non-measurable disease burden. Because worsening in 
non-target disease cannot be easily quantified (by definition: if all lesions are truly non-
measurable) a useful test that can be applied when assessing patients for unequivocal 


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progression is to consider if the increase in overall disease burden based on the change 
in non-measurable disease is comparable in magnitude to the increase that would be 
required to declare PD for measurable disease: i.e., an increase in tumor burden 
representing an additional 73% increase in ‘volume’ (which is equivalent to a 20% 
increase diameter in a measurable lesion). Examples include an increase in a pleural 
effusion from ‘trace’ to ‘large’, an increase in lymphangitic disease from localized to 
widespread, or may be described in protocols as ‘sufficient to require a change in 
therapy’. Some illustrative examples are shown in the original article, Figures 5 and 6 of 
Appendix II. If ‘unequivocal progression’ is seen, the patient should be considered to 
have had overall PD at that point. While it would be ideal to have objective criteria to 
apply to non-measurable disease, the very nature of that disease makes it impossible to 
do so, therefore the increase must be substantial.
2.3.5 New Lesions
The appearance of new malignant lesions denotes disease progression; therefore, some 
comments on detection of new lesions are important. There are no speciﬁc criteria for 
the identiﬁcation of new radiographic lesions; however, the ﬁnding of a new lesion 
should be unequivocal: i.e., not attributable to differences in scanning technique, change 
in imaging modality or ﬁndings thought to represent something other than tumor (for 
example, some ‘new’ bone lesions may be simply healing or ﬂare of pre-existing 
lesions). This is particularly important when the patient’s baseline lesions show PR or 
CR. For example, necrosis of a liver lesion may be reported on a CT scan report as a 
‘new’ cystic lesion, which it is not. 
A lesion identiﬁed on a follow-up study in an anatomical location that was not scanned 
at baseline is considered a new lesion and will indicate disease progression. An example 
of this is the patient who has visceral disease at baseline and while on study has a CT or 
MRI brain ordered which reveals metastases. The patient’s brain metastases are 
considered to be evidence of PD even if he/she did not have brain imaging at baseline. 
If a new lesion is equivocal, for example because of its small size, continued therapy 
and follow-up evaluation will clarify if it represents truly new disease. If repeat scans 
conﬁrm there is deﬁnitely a new lesion, then progression should be declared using the 
date of the initial scan. 
2.4 Evaluation of Best Overall Response
The best overall response is the best response recorded from the start of the study 
treatment until the end of treatment taking into account any requirement for 
conﬁrmation. On occasion a response may not be documented until after the end of 
therapy so protocols should be clear if post-treatment assessments are to be considered 
in determination of best overall response. Protocols must specify how any new therapy 
introduced before progression will affect best response designation. The patient’s best 
overall response assignment will depend on the ﬁndings of both target and non-target 
disease and will also take into consideration the appearance of new lesions. 
Furthermore, depending on the nature of the study and the protocol requirements, it may 
also 
require 
conﬁrmatory 
measurement 
(see 
Section 
2.6. 
Confirmatory 
Measurement/Duration of Response). Speciﬁcally, in non-randomized trials where 
response is the primary endpoint, conﬁrmation of PR or CR is needed to deem either 
one the ‘best overall response’. This is described further below.


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2.4.1 Time Point Response 
It is assumed that at each protocol speciﬁed time point, a response assessment occurs. 
Table 1 provides a summary of the overall response status calculation at each time point 
for patients who have measurable disease at baseline. 
Table 1. Time point response: patients with target (+/–non-target) disease.
Target lesions
Non-target lesions
New
lesions
Overall
response
CR
CR
No
CR
CR
Non-CR/non-PD
No
PR
CR
Not evaluated
No
PR
PR
Non-PD or not all evaluated
No
PR
SD
Non-PD or not all evaluated
No
SD
Not all evaluated
Non- PD
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
CR, complete response; NE, inevaluable; PD, progressive disease; PR, partial response; SD, stable disease. 
When patients have non-measurable (therefore non-target) disease only, Table 2 is to be 
used. 
Table 2. Time point response: patients with non-target disease only.
Non-target lesions
New lesions
Overall response
CR
No
CR
Non-CR/non-PD
No
Non-CR/non-PDa
Not all evaluated
No
NE
Unequivocal PD
Yes or No
PD
Any
Yes
PD
CR, complete response, NE, inevaluable; PD, progressive disease. 
a ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is increasingly used as endpoint 
for assessment of efficacy in some trials; so, to assign this category when no lesions can be measured is not advised.
2.4.2 Missing Assessments and Inevaluable Designation
When no imaging/measurement is done at all at a particular time point, the patient is not 
evaluable (NE) at that time point. If only a subset of lesion measurements are made at 
an assessment, usually the case is also considered NE at that time point, unless a 
convincing argument can be made that the contribution of the individual missing 
lesion(s) would not change the assigned time point response. This would be most likely 
to happen in the case of PD. For example, if a patient had a baseline sum of 50 mm with 
three measured lesions and at follow-up only two lesions were assessed, but those gave 
a sum of 80 mm, the patient will have achieved PD status, regardless of the contribution 
of the missing lesion.
2.4.3 Best Overall Response: All Time Points 
The best overall response is determined once all the data for the patient is known.
Best Response Determination in Trials Where Conﬁrmation of Complete or Partial 
Response IS NOT Required: 
Best response in these trials is deﬁned as the best response across all time points (for 
example, a patient who has SD at ﬁrst assessment, PR at second assessment, and PD on 
last assessment has a best overall response of PR). When SD is believed to be best


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response, it must also meet the protocol speciﬁed minimum time from baseline. If the 
minimum time is not met when SD is otherwise the best time point response, the 
patient’s best response depends on the subsequent assessments. For example, a patient 
who has SD at ﬁrst assessment, PD at second and does not meet minimum duration for 
SD, will have a best response of PD. The same patient lost to follow-up after the ﬁrst 
SD assessment would be considered inevaluable. 
Best Response Determination in Trials Where Conﬁrmation of Complete or Partial 
Response IS Required: 
Complete or partial responses may be claimed only if the criteria for each are met at a 
subsequent time point as speciﬁed in the protocol (generally four weeks later). In this 
circumstance, the best overall response can be interpreted as in Table 3. 
Table 3.  Best overall response when confirmation of complete response (CR) and partial 
response (PR) is  required.
Overall response.
First time point
Overall response.
Subsequent time point
BEST overall response
CR
CR
CR
CR
PR
SD, PD or PRa
CR
SD
SD provided minimum criteria for SD duration met, 
otherwise, PD
CR
PD
SD provided minimum criteria for SD duration met, 
otherwise, PD
CR
NE
SD provided minimum criteria for SD duration met, 
otherwise NE
PR
CR
PR
PR
PR
PR
PR
SD
SD
PR
PD
SD provided minimum criteria for SD duration met, 
otherwise, PD
PR
NE
SD provided minimum criteria for SD duration met, 
otherwise NE
NE
NE
NE
CR, complete response; NE, inevaluable; PD, progressive disease; PR, partial response; SD, stable disease. 
a If a CR is truly met at first time point, then any disease seen at a subsequent time point, even disease meeting PR 
criteria relative to baseline, makes the disease PD at that point (since disease must have reappeared after CR). Best 
response would depend on whether minimum duration for SD was met. However, sometimes ‘CR’ may be claimed 
when subsequent scans suggest small lesions were likely still present and in fact the patient had PR, not CR at the 
first time point. Under these circumstances, the original CR should be changed to PR and the best response is PR. 


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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.


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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.


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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.


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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 


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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 


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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 


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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.

SAP_001.pdf: 
 
 
 
 
 
 
 
 
 
 
 
PM1183-B-005-14 
 
 
A Multicenter Phase II Clinical Trial of Lurbinectedin (PM01183) in 
Selected Advanced Solid Tumors 
 
STATISTICAL ANALYSIS PLAN 
 
Protocol Code: PM1183-B-005-14 EudraCT: 2014-003773-42 NCT Code: NCT02454972 
 
 
 
 
 
 
 
  
 
 
 
 
Version: 5.0  
Date: 11Nov2020     


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TABLE OF CONTENTS 
1
STUDY RATIONALE
8
2
STUDY DESIGN
9
3
OBJECTIVES AND ENDPOINTS
10
3.1
Primary Objective
10
3.2
Secondary Objectives
10
3.3
Endpoints
11
4
PATIENTS EVALUABILITY CRITERIA
12
4.1
Included Population
13
4.2
Efficacy Populations
13
4.3
Safety Population
13
5
SAMPLE CONSIDERATIONS
13
5.1
Sample Size
13
6
STATISTICAL METHODOLOGY FOR EFFICACY
14
6.1
Planned Analyses and Definitions
14
6.2
Efficacy Analysis Methods
15
6.2.1
Primary Endpoint
16
6.2.2
Secondary Endpoints
16
7
STATISTICAL METHODOLOGY FOR SAFETY
16
7.1
Toxicity and Adverse Events
16
7.2
Clinical Laboratory Evaluation
17
7.3
Vital Signs, Physical Examination, Left Ventricular Ejection Fraction and Electrocardiogram 
Findings
17
7.4
Deaths and Other Serious Adverse Events
17
8
OTHER ANALYSES
17
8.1
Patient Disposition and Treatment/Study Discontinuation
18
8.2
Protocol Deviations
18
8.3
Baseline and Demographic Data
18
8.4
Treatment Administration
18
8.5
Subsequent Therapy
19
8.6
Pharmacokinetic Analyses
19
8.7
Pharmacogenetics Analyses
19
8.8
Pharmacogenomic Analyses
19
8.9
Imputation of Incomplete Dates
19
8.10
Decimal Places
20
8.11
Subgroup Analyses
20
8.12
Methods for Handling Missing Data
21
8.13
Interim and Group Sequential Analyses
21
8.14
Identification of Fixed or Random Effects Models
21
8.15
Data Analysis Conventions
21
9
STATISTICAL SOFTWARE
22
APPENDIX I
22
10
Study Patients
23
10.1
Patient Disposition
23


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10.2
Reasons for Treatment and Study Discontinuation
24
10.3
Protocol Deviations
25
11
Efficacy Evaluation
26
11.1
Demographic and Other Baseline Characteristics
26
11.1.1
Patient Characteristics at Baseline
26
11.1.2
Disease at Diagnosis and Disease at Study Entry
26
11.1.3
Disease at Diagnosis and Disease at Study Entry: Small Cell Lung Cancer (SCLC)
28
11.1.4
Disease at Diagnosis and Disease at Study Entry: Head and Neck Carcinoma (H&N) 28
11.1.5
Disease at Diagnosis and Disease at Study Entry: Neuroendocrine Tumors (NETs)
28
11.1.6
Disease at Diagnosis and Disease at Study Entry: Biliary Tract Carcinoma
29
11.1.7
Disease at Diagnosis and Disease at Study Entry: Endometrial Carcinoma
29
11.1.8
Disease at Diagnosis and Disease at Study Entry: BRCA 1/2-associated Metastatic 
Breast Carcinoma (MBC)
30
11.1.9
Disease at Diagnosis and Disease at Study Entry:   Carcinoma of Unknown Primary 
Site
31
11.1.10
Disease at Diagnosis and Disease at Study Entry: Germ Cell Tumors (GCTs)
31
11.1.11
Disease at Diagnosis and Current Disease: Ewing's Family of Tumors (EFTs)
31
11.1.12
Prior History
32
11.1.13
Prior Anticancer Therapy
32
11.1.14
Physical Examination and Performance Status at Baseline
34
11.1.15
Vital Signs, Electrocardiogram, LVEF and other tests.
34
11.1.16
Hematological Values at Baseline
36
11.1.17
Biochemical Values at Baseline
36
11.1.18
Coagulation Values at Baseline
37
11.1.19
Adverse Events at Baseline
38
11.1.20
Concomitant Therapy and Procedures at Baseline
38
11.2
Measurements of treatment compliance
39
11.3
Efficacy Analysis
39
11.3.1
Primary Analysis (excluding SCLC cohort)
40
11.3.2
Secondary Analyses (excluding SCLC cohort)
40
11.3.3
SCLC Cohort
41
12
Safety Analysis
51
12.1
Extent of Exposure
51
12.1.1
Treatment Administration
51
12.1.2
Cycle Delays
51
12.1.3
Dose Reductions
53
12.1.4
Temporarily Interrupted Infusions
54
12.1.5
Prophylactic Medication Administration
54
12.2
Adverse Events
54
12.2.1
Treatment Emergent Adverse Events
54
12.2.2
Display of Treatment Emergent Adverse Events
55
12.3
Serious Adverse Events and Deaths.
56
12.3.1
Serious Adverse Events
56
12.3.2
Deaths
57
12.4
Clinical Laboratory Evaluation
57
12.4.1
Hematological Abnormalities during Treatment
57
12.4.2
Biochemical Abnormalities during Treatment
58


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12.4.3
Coagulation Abnormalities during Treatment
58
12.4.4
Laboratory Values over Time
59
12.5
Physical Findings, PS, LVEF, ECG and Other Tests
60
12.5.1
Physical Findings and PS (ECOG)
60
12.5.2
LVEF, ECG and Other Related Tests
61
12.6
Concomitant Therapy / Procedures According to the ATC Classification.
61
12.7
Subsequent therapy.
62
12.8
Subgroup Analyses Related to Safety.
64
13
Figures
66
APPENDIX II
70
14
DB Listings, BIMO and ICH listings
70
15
SAP VERSION HISTORY
76
15.1
SAP version history v1.0
76
15.2
SAP version history v2.0
83
15.3
SAP version history v3.0
136
15.4
SAP version history v4.0
143


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ABBREVIATIONS AND GLOSSARY
AAGP
Alpha-1 Acid Glycoprotein
AE(s)
Adverse Event(s)
AFP
Alpha-Fetoprotein
ALT 
Alanine Aminotransferase
AP
Alkaline Phosphatase
APTT
Activated Partial Thromboplastin Time
AST 
Aspartate Aminotransferase
ATC
Anatomical Therapeutic Chemical
BIMO
Bioresearch Monitoring
BL
Baseline
BRCA1/2
Breast Cancer 1 or Breast Cancer 2 Gene
BSA
Body Surface Area
C
Cycle
CI
Confidence Interval
CPK 
Creatine Phosphokinase
CR
Complete Response
CRF
Case Report Form
CTCAE
Common Terminology Criteria for Adverse Events
CTFI
Chemotherapy Free Interval
DB
Database
DCR
Disease Control Rate
DR
Duration of Response
DNA
Deoxyribonucleic Acid
ECG
Electrocardiogram
ECHO
Echocardiogram
ECOG
Eastern Cooperative Oncology Group
EFTs
Ewing´s Family of Tumors
ER-/+
Estrogen Receptor -/+
FD
Flat Dose
G-CSF
Granulocyte-Colony Stimulating Factor
GCTs
Germ Cell Tumors
GGT
Gamma-glutamyltransferase
H0
Null Hypothesis
H1
Alternative Hypothesis
hCG
Human Chorionic Gonadotropin
HER-2
Human Epidermal Growth Factor receptor 2


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H&N
Head and Neck Carcinoma
IA
Investigator’s Assessment
ICH
International Conference on Harmonization
IB
Investigator’s Brochure
IRC
Independent Review Committee
i.v.
Intravenous(ly)
K
Potassium
LDH
Lactate Dehydrogenase
LVEF
Left Ventricular Ejection Fraction
MBC
Metastatic Breast Carcinoma
MedDRA
Medical Dictionary for Regulatory Activities
MUGA
Multiple-gated Acquisition Scan
NA
Sodium / Not applicable
NCI
National Cancer Institute
NCI-CTC
National Cancer Institute-Common Toxicity Criteria
NCI-CTCAE
National Cancer Institute-Common Terminology Criteria for Adverse Events
NE
Not Evaluable
NETs
Neuroendocrine Tumors
NOS
Not Otherwise Specified
ORR
Overall Response Rate
OS
Overall Survival
OSI
Office of Scientific Investigations
PD
Progressive Disease
PCI
Prophylactic Cranial Irradiation
PFS
Progression-free Survival
PGx
Pharmacogenomics
PK/PD
Pharmacokinetics/Pharmacodynamics
PR
Partial Response
PR-/+
Progesterone Receptor -/+
PS
Performance Status
PT
Prothrombin Time/Preferred Term
PTT
Partial Thromboplastin Time
q3wk
Every Three Weeks
R
Resistant
RBC
Red blood cell
RD
Recommended Dose
RR
Refractory


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RECIST
Response Evaluation Criteria In Solid Tumors
S
Sensitive
SAE(s)
Serious Adverse Event(s)
SCLC
Small Cell Lung Cancer
SD
Stable Disease
SOC
System Organ Class
Std.
Standard deviation
TEAE
Treatment Emergent Adverse Event
TTP
Time to Progression
ULN
Upper Limit of Normal
UK
Unknown
vs.
Versus
VS
Very Sensitive
WBC
White Blood Cells
WHO
World Health Organization
Wk(s)
Week(s)
y
Year


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1
STUDY RATIONALE

The management of advanced small cell lung cancer (SCLC), head and neck (H&N) cancer, 
neuroendocrine tumors (NETs), biliary tract carcinoma, endometrial carcinoma, BRCA1/2-
associated metastatic breast cancer, carcinoma of unknown primary site, germ cell tumors 
(GCTs) and Ewing family of tumors (EFTs) represents an unmet medical need. Cytotoxic 
chemotherapy remains a crucial component of their therapeutic armamentarium but there is a 
need to develop new anticancer agents that broaden the clinical benefit. 

PM01183 is a new chemical entity that induces double-strand DNA breaks through binding to 
the DNA minor groove. Results of the COMPARE analysis revealed that it is unlikely that this 
drug shares a similar mechanism of action with any of the other 98 standard cytotoxic agents 
compared.

PM01183 has shown antitumor activity in most of the tumor types selected in this clinical 
study. In the combination trial of PM01183 at 4.0 mg flat dose (FD) with 50 mg/m2 of 
doxorubicin every three weeks (q3wk) (PM1183-A-003-10), five of 12 evaluable patients with 
SCLC achieved partial response (42.0%), with a median time-to-progression (TTP) of 2.0 
months. In endometrial carcinoma, two of three patients treated with the combination 
PM01183 plus doxorubicin at the aforementioned dose and schedule had a complete response 
and a partial response, respectively. The third patient had disease stabilization longer than 4 
months. The median TTP was 10.1 months. Also with this combination, a patient with NET 
had a partial response with a TTP of 4.5 months. In a phase II clinical trial of PM01183 as 
single agent in MBC, one of 54 patients with germline BRCA 1/2 mutation had a complete 
response (2%) and 21 patients had partial response (39%). Twenty-three additional patients 
had disease stabilization (43%). One patient with H&N carcinoma treated with PM01183 as 
single agent at 2.6 mg/m2 q3wk achieved a disease stabilization of 4 months duration. Finally, 
one patient with a carcinoma of unknown primary site treated with PM01183 as single agent at 
7 mg FD q3wk had disease stabilization for 2.6 months.

The inclusion of patients with EFTs is mainly based on the similar mechanism of action of 
PM01183 and its related compound trabectedin. In sarcomas associated with translocations, 
such as myxoid liposarcoma, in which the translocation produces a fusion protein (FUS-
CHOP) that acts as a deregulated transcription factor, trabectedin has been shown to interfere 
with the binding of this protein to specific DNA promoters, and hence with the synthesis of 
downstream proteins. Based on the structural and functional similarities of these fusion 
proteins, trabectedin could induce on other translocation-related sarcomas similar effects to 
those described in myxoid liposarcoma. In fact, trabectedin has shown efficacy in advanced 
pretreated patients with Ewing’s sarcoma: three partial responses and seven disease 
stabilizations in 20 patients, with a 25% 6-month progression-free survival (PFS) rate. Since 
PM01183 has a favorable pharmacokinetic (PK) profile compared to trabectedin, as shown by 
a tolerated dose four times higher and an exposure 15.3 times higher than that of trabectedin at 
the RD, it has been postulated that its effect on rapidly growing tumors such as EFTs would be 
superior. In addition, an improved therapeutic index of PM01183 relative to trabectedin, as 
well as suppression of the EFTs fusion protein EWS/FLI1 activity by PM01183 at clinically 
achievable concentrations, have been reported.


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
The finding of PM01183 activity in aggressive tumors with high proliferation index, such as 
BRCA germline mutation-positive breast carcinomas, neuroendocrine tumors and SCLC, led 
to the inclusion of GCTs and biliary tract carcinoma in this study.

In conclusion, this clinical trial has been designed to establish or confirm the proof of concept 
of PM01183 anticancer activity in several difficult-to-treat tumors for potential further 
development.
2
STUDY DESIGN
Multicenter, open-label, exploratory, phase II clinical trial to evaluate the efficacy and safety of 
PM01183 in previously treated patients with the following advanced solid tumors: SCLC, H&N, 
NETs, biliary tract carcinoma, endometrial carcinoma, BRCA 1/2-associated MBC, carcinoma of 
unknown primary site, GCTs, and EFTs.
Patients with each of the aforementioned tumors will be enrolled in nine cohorts. Up to 25 evaluable 
patients are planned to be enrolled in each cohort (50 in the endometrial carcinoma and 100 in the 
SCLC cohort). To consider that PM01183 has antitumor activity in any of the tumor types analyzed,
at least two confirmed responses [complete (CR) or partial response (PR)] per RECIST v.1.1 out of 
the 25 patients of each cohort are expected.

If no confirmed responses are observed in the first 15 evaluable patients of each cohort, the 
recruitment of the corresponding cohort will be stopped.

If one confirmed response is observed in the first 15 evaluable patients of each cohort, the 
recruitment of this cohort will continue to up to 25 evaluable patients.
o
In the cohort of endometrial carcinoma, if ≥2 confirmed responses occur in the first 25 
evaluable patients, the sample size will be doubled to 50 evaluable patients. 
o
In the cohort of SCLC, if ≥2 confirmed responses occur in the first 25 evaluable 
patients, the sample size will be increased to 100 evaluable patients. 

If two confirmed responses are observed in the first 15 evaluable patients of each cohort, the 
recruitment of the corresponding cohort can be stopped. 
Only in the SCLC cohort, an IRC will be performed on all images collected and will provide a 
radiographic response at each time point termed. These data and the clinical database information 
will be used to derive the independent review efficacy information following the RECIST v.1.1. 
Operational details for the IRC and the algorithm and its validation by an expert panel is described 
in detail in the IRC charter.
In addition, for safety reasons:

If two patients have a treatment-related death in a cohort, the recruitment of the corresponding 
cohort will be stopped.

If six patients have treatment-related deaths in the whole population, the study will be stopped.
Finally,

A determined cohort can be early closed by the Sponsor in case of a low recruitment rate.


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
Once the target of patients included in each cohort is reached, recruitment in this cohort will be 
kept “on hold” during the period of patients’ data analysis to assess their evaluability and the 
response rate. After this period, if the number of evaluable patients does not reach the planned 
target, recruitment will be re-opened and non-evaluable patients will be replaced. 
Patients will receive the study treatment as long as it is considered to be in their best interest. 
Specifically, treatment will continue until disease progression, unacceptable toxicity, treatment delay 
> three weeks from the treatment due date (except in case of clear clinical benefit, upon Sponsors’ 
approval), requirement of > two dose reductions, intercurrent illness of sufficient magnitude to 
preclude safe continuation of the study, a major protocol deviation that may affect the risk/benefit 
ratio for the participating patient, investigator’s decision, non-compliance with study requirements 
and/or patient’s refusal.
All adverse events (AEs) will be graded according to the National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI-CTCAE) v.4. 
Treatment delays, dose reduction requirements and reason for treatment discontinuation will be 
monitored throughout the study. The safety profile of patients will be monitored throughout the 
treatment and up to 30 days (±7 days) after the last treatment infusion (end of treatment, EOT), until 
the patient starts a new antitumor therapy or until the date of death, whichever occurs first. Any 
treatment-related AEs will be followed until recovery to at least grade 1 or stabilization of symptoms 
or until the start of a new antitumor therapy, whichever occurs first.
Patients will be evaluated at scheduled visits on three study periods: Pre-treatment, Treatment and 
Follow-up. This clinical trial will finish (clinical cut-off for each cohort except SCLC cohort) when all 
evaluable patients within each cohort have at least 12 months of follow-up from the first PM01183 
infusion. Patients with SCLC will be followed-up for at least 18 months after the last patient enrolled 
received the first PM01183 infusion.
3
OBJECTIVES AND ENDPOINTS
3.1
Primary Objective

To assess the antitumor activity of lurbinectedin (PM01183) in terms of overall response rate 
(ORR), 
according 
to 
the RECIST 
v.1.1, 
in 
the 
following 
advanced 
solid 
tumors: SCLC, H&N, NETs, biliary tract carcinoma, endometrial carcinoma, BRCA 1/2-
associated MBC, carcinoma of unknown primary site, GCTs, and EFTs.
3.2
Secondary Objectives

To further characterize the antitumor activity of PM01183 in terms of duration of response 
(DR), clinical benefit [ORR or stable disease (SD) lasting over four months (SD ≥ 4 months)], 
progression-free survival (PFS) by Investigator’s assessment (IA), and overall survival (OS) in 
each cohort of advanced solid tumors.

To further investigate the antitumor activity of PM01183 in terms of ORR, DR, clinical benefit 
[ORR or SD ≥ 4 months] and PFS by an Independent Review Committee (IRC) in the cohort 
of SCLC patients.


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
To characterize the plasma pharmacokinetics (PK) of PM01183.

To conduct an exploratory pharmacogenomic (PGx) and pharmacogenetic analysis.

To evaluate the safety profile of PM01183 in this patient population.
3.3
Endpoints
The following are the endpoints defined in the protocol. See further detail in the efficacy section. 
Primary Endpoint: 

Overall Response Rate (ORR) in each tumor type. ORR is defined as the percentage of 
patients with a confirmed response, either complete (CR) or partial (PR), according to the 
RECIST (v.1.1). 
Secondary Endpoints:
Efficacy (all cohorts):

Duration of Response (DR) by IA, defined as the time between the date when the response 
criteria (PR or CR, whichever one is first reached) are fulfilled to the first date when PD, 
recurrence or death is documented.

Clinical Benefit by IA, defined as response or stable disease lasting over four months (SD ≥ 4 
months).

Progression-free Survival (PFS) by IA, defined as the period of time from the date of first 
infusion to the date of PD, death (of any cause), or last tumor evaluation. 

PFS4/PFS6 by IA, defined as the Kaplan-Meier estimates of the probability of being free from 
progression and death after the first infusion at these time points (4 and 6 months).

OS, defined as the period of time from the date of first infusion to the date of death or last 
contact in case of patients lost to follow-up or alive at the clinical cut-off stablished for the 
cohort.

OS6/OS12, defined as the Kaplan-Meier estimates of the probability of being alive after the 
first infusion at these time points (6 and 12 months).
Efficacy (only in the SCLC cohort): 

ORR, Clinical Benefit, DR, PFS and PFS4/PFS6 by IRC. The same definitions detailed for IA
but following IRC evaluation will be used.
Plasma Pharmacokinetics (PK) of PM01183 

Non-compartmental (NCA) PK parameters: area under the curve (AUC), maximum plasma 
concentration (Cmax), clearance (CL) and half-life (t1/2). Population PK parameters of the 
compartment model to be developed (initially based on Volumes and Clearance), and PK/PD 
correlation parameters, if applicable.
Pharmacogenetics:  

This analysis will be performed in those patients who signed the written informed consent (IC) 
for the pharmacogenetic sub-study. The presence or absence of known polymorphisms from a 


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single sample collected at any time during the study, but preferably just before treatment start 
in Cycle 1, will be assessed to explain the individual variability in the main PK parameters.
Pharmacogenomics (PGx):

This exploratory analysis will be performed on prior available paraffin-embedded tumor tissue 
samples from consenting patients of any arm. This sub-study will include factors involved in 
DNA repair mechanisms (such as nucleotide excision repair, homologous recombination repair 
and mismatch repair) and other factors related to the mechanism of action of PM01183 or to 
the pathogenesis of the disease, and their expression will be analyzed at the mRNA or protein 
level by quantitative polymerase chain reaction (PCR) and immunohistochemistry (IHC), 
respectively; their polymorphisms and mutations might be also analyzed, if relevant. Their 
correlation with clinical response and outcome after treatment will be assessed.
Safety Profile:

Clinical examinations.

Clinical assessment of AEs and serious adverse events (SAEs).

Changes in laboratory parameters (hematological and biochemical, including liver function 
tests). 

Reasons for treatment discontinuations.

Reasons for dose reduction and treatment delays.
4
PATIENTS EVALUABILITY CRITERIA
The study population will include the following analysis sets definitions:

“All Included Patients” analysis set is defined as all patients recorded in the database who have 
been included in the trial, regardless of whether they have received the study drug or not.

“All Treated Patients” analysis set is defined as all included patients who have received any 
partial or complete infusion of PM01183.

“All Evaluable Patients” analysis set is defined as all eligible patients, defined as patients 
accepted by the sponsor to take part in the trial, who have had at least one complete infusion of 
PM01183, and either have had at least one assessment (as per RECIST v1.1) or have been 
categorized as “treatment failures”. Patients who discontinue treatment due to any treatment-
related toxicity before an appropriate tumor assessment has been performed or those who 
experience early death due to malignant disease or those with treatment withdrawn due to
clinical PD/symptomatic deterioration with no tumor assessments will be defined as “treatment 
failures”. These patients will be included as non-evaluable for response in the analysis of 
objective response as per RECIST v1.1, although they will not be replaced as will be 
considered evaluable for efficacy. For the IRC assessment in SCLC patients same definition 
will be followed but based on its assessment.

“All Responding Patients” analysis set is defined as all evaluable patients who have had a 
confirmed CR or PR as overall best response according to the RECIST v1.1. For the IRC 
assessment in SCLC patients same definition will be followed but based on its assessment.


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4.1
Included Population
The “All Included Patients” dataset, defined as all patients accepted by the sponsor to take part in the 
trial, will be used for the descriptive analyses of disposition of patients in each cohort of advanced 
solid tumors.
4.2
Efficacy Populations
In all cohorts but SCLC, the “All Evaluable Patients” analysis set will be used for the primary 
endpoint analysis of ORR and for the secondary endpoints of DR, Clinical benefit (ORR or SD ≥ 4 
months), PFS (including PFS4/PFS6 months), and OS6/OS12 months in each cohort of advanced 
solid tumors. The “All Treated Patients” analysis set will also be used for the sensitivity analyses.
In SCLC cohort, the “All Treated Patients” analysis set will be used for the primary endpoint analysis 
of ORR and for the secondary endpoints of DR, Clinical benefit (ORR or SD ≥ 4 months), PFS 
(including PFS4/PFS6 months), and OS6/OS12 months in each cohort of advanced solid tumors. The 
“All Evaluable Patients” analysis set will also be used for the sensitivity analyses.
The “All Responding Patients” set will be used for the secondary endpoint analysis of DR.
4.3
Safety Population
The safety analysis will be based on the “All Treated Patients” analysis set by cohort of tumor types 
and total population.
5
SAMPLE CONSIDERATIONS
5.1
Sample Size
Up to 25 evaluable patients in each tumor type will be recruited to test the null hypothesis that 1% or 
less patients get a response (p ≤ 0.01) versus the alternative hypothesis that 10% or more patients get a 
response (p ≥ 0.10). The variance of the standardized test is based on the null hypothesis. The type I 
error (alpha) associated with this one-sided test is 0.025 and the type II error (beta) is 0.2 (normal 
approximation; ~0.3 if exact binomial distribution); hence, statistical power is 80% (normal 
approximation; ~70% if exact binomial distribution). With these assumptions, if the number of 
patients who achieve a confirmed response is ≥ 2, then this will allow the rejection of the null 
hypothesis.

A phase III trial of PM01183 combined with doxorubicin in SCLC is ongoing. Hence, the 
sample size for the SCLC cohort of this study will be increased to 100 evaluable patients if the 
success boundary (≥2 confirmed responses) is reached in the first 25 evaluable patients. The 
type I/II error will be controlled with a Gamma family boundary (-1 to reject Ho, 0 to reject 
H1).
Based on the newly available information, additional patients will be recruited to test the null 
hypothesis that 15% or less patients get a response (p ≤ 0.15) versus the alternative hypothesis 
that 30% or more patients get a response (p ≥ 0.30). The variance of the standardized test is 
based on the null hypothesis. The type I error (alpha) associated with this one-sided test is 
0.025 and the type II error (beta) is 0.051 (normal approximation; ~0.05 if exact binomial 
distribution); hence, statistical power is 95% (normal approximation; ~95% if exact binomial 


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distribution). With these assumptions, if the number of patients who achieve a confirmed 
response is ≥ 23, then this would allow the rejection of the null hypothesis. The judgement of 
patient’s evaluability and replacement of non-evaluable patients were guided by the 
investigator assessment.

A phase I trial of PM01183 combined with doxorubicin has shown encouraging antitumor 
activity in endometrial carcinoma. Hence, the sample size for the endometrial carcinoma 
cohort of this study will be doubled to 50 evaluable patients if the success boundary (≥2 
confirmed responses) is reached in the first 25 evaluable patients. The type I/II error will be 
controlled with a Gamma family boundary (-1 to reject Ho, -3 to reject H1).
Based on the newly available information, additional patients will be recruited to test the null 
hypothesis that 10% or less patients get a response (p ≤ 0.10) versus the alternative hypothesis 
that 25% or more patients get a response (p ≥ 0.25). The variance of the standardized test is 
based on the null hypothesis. The type I error (alpha) associated with this one-sided test is 
0.025 and the type II error (beta) is 0.144 (normal approximation; ~0.16 if exact binomial 
distribution); hence, statistical power is ~86% (normal approximation; ~84% if exact binomial 
distribution). With these assumptions, if the number of patients who achieve a confirmed 
response is ≥ 10, then this would allow the rejection of the null hypothesis.
With the sample size of 100 and 50 evaluable patients in each indication (SCLC and endometrial), the 
obtained confidence interval will be narrower and its half-width will be confined to ±15%.
6
STATISTICAL METHODOLOGY FOR EFFICACY
Frequency tables will be prepared for categorical variables, whereas continuous variables will be 
described by means of summary tables that will include the median, mean, standard deviation,
minimum, and maximum of each variable.
6.1
Planned Analyses and Definitions
Primary Endpoint
The primary study analysis except for SCLC cohort will be based on the ORR in the “All Evaluable 
Patients” population set. For SCLC cohort, the primary study analysis will be based on the ORR in the 
“All Treated Patients” population set.
Overall response rate (ORR) is calculated as the number of patients who have had a confirmed CR or 
PR as overall best response according to the RECIST v1.1, divided by the number of patients in the 
“All Evaluable Patients” (“All Treated Patients” in SCLC cohort) population set. 
Secondary Endpoints
The following time-related parameters will be analyzed according to available follow-up data:
Duration of response (DR) is defined as the time from the first observation of response to the date of 
disease progression, recurrence or death. Other cases will be censored. Although the responses have to 
be confirmed according to RECIST v1.1, the first documentation (not the confirmation) will be taken 
into account to calculate DR. Patients who progress or die will be considered to have had an event, 


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except if this event occurs after the start of subsequent antitumor therapy, in which case the patient 
will be censored at the time of last disease assessment prior to or on the first day of the first 
subsequent antitumor therapy.
Clinical benefit rate is calculated as the number of patients who have had a confirmed CR, PR, or SD 
≥ 4 months as overall best response according to the RECIST v1.1, divided by the number of patients 
in the “All Evaluable Patients” (“All Treated Patients” in SCLC cohort) analysis set. 
Progression-free survival (PFS) is defined as the time from the date of start of treatment to the date 
of documented progressive disease (PD) by RECIST v1.1 or death (regardless of the cause of death), 
whichever comes first. Patients who progress or die will be considered to have had an event of 
progression, except if this event occurs after the start of subsequent antitumor therapy, in which case 
the patient will be censored at the time of last disease assessment prior to or on the first day of the first 
subsequent antitumor therapy. If the patient is lost for the assessment of progression during the 
follow-up period, or has more than one missing follow-up between the date of last tumor assessment 
and the date of progression, death or further antitumor therapy, the PFS/DR will be censored at the 
date of last valid disease assessment before the missing evaluations.
The date of response, the date of radiological progression, according to the investigator assessment 
and the independent assessment by IRC when applicable (i.e., SCLC cohort), the date of clinical PD 
and the date of death will be registered and documented, as appropriate.
Overall survival (OS) is defined as the time from the date of start of treatment to the date of death or 
last contact. One year (1y-OS)/6 months overall survival is defined as the Kaplan-Meier estimate of 
the probability of patients being alive at 12/6 months after the date of start of treatment.
A sensitivity analysis for all cohorts but SCLC will be performed for ORR, Clinical Benefit Rate, PFS 
and OS in the “All Treated Patients population”. For the SCLC cohort, the sensitivity analysis will be 
carried out the “All Evaluable Patients”.
6.2
Efficacy Analysis Methods
Counts and percentages, with their corresponding exact 95% confidence intervals, will be calculated 
for the binomial endpoints (e.g., ORR, clinical benefit). The confidence intervals based on the group 
sequential tests performed for each cohort will also be calculated.
Time-to-event variables (OS, PFS and DR) and their set time estimates (i.e., PFS 4/6 and OS 6/12) will 
be analyzed according to the Kaplan-Meier method.
In the SCLC cohort, the evaluation of the efficacy endpoints evaluated by IA and IRC will be shown and 
compared. The rate of concordance between both evaluation methods for best response, progression 
status and progression-free survival will be presented with 2-way frequency tables and measures of 
agreement.
Waterfall plots will be used to describe the best variation of the sum of target lesions during treatment.
The number of patients recruited in any cohort may differ from that pre-specified according to the 
sample size assumptions. Therefore, the main efficacy results will be calculated according to the 
planned cohort sample size and, if any cohort sample size differs at least 10% from the assumptions, a 
sensitivity analysis using all evaluable patients recruited (adjusting the corresponding boundaries to 
test the null hypothesis) will be performed.


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The patient level response will be calculated by means of statistical programming. In the case of a 
Partial Response followed by a time point with a tumor size reduction lower than 30% compared to 
the baseline assessment but an increase in the size of the target lesions not qualifying for disease 
progression (e.g. increase of sum of target lesions compared with the nadir is lower than 20%) then 
the response will be considered maintained following RECIST advice( (“The definition of SD: a 
clarification” http://recist.eortc.org/recist-1-1-2/).
Example: Baseline evaluation: 38 mm, first evaluation: 26 mm (Tumor Size Reduction from baseline 
= 31.6% PR), second evaluation: 28 mm (Reduction from baseline = 26.3%, but increase from nadir = 
7.7%).
The best overall response will be considered as confirmed PR.
6.2.1
Primary Endpoint
Exact binomial estimates with 95% confidence intervals (CIs) in each cohort will be calculated for the 
analysis of the main endpoint (ORR according to RECIST v1.1 by Investigator assessment)
6.2.2
Secondary Endpoints 
Exact binomial estimates with 95% confidence intervals (CIs) will be performed in the SCLC cohort 
for the analysis of the ORR according to RECIST v1.1 by IRC.
Time-to-event endpoints (DR, PFS and OS) and their set time estimates (i.e. PFS4, PFS6 and OS 
6/12) will be analyzed according to the Kaplan-Meier method.
7
STATISTICAL METHODOLOGY FOR SAFETY
The safety analysis for the secondary endpoints will be based on the “All Treated Patients” population 
set in each cohort of advanced solid tumors or the total population (if applicable).
Patients will be evaluable for safety if they received any partial or complete infusion of PM01183.
All AEs/laboratory visits reported as “End of treatment” visit will be mapped to the last cycle visit for 
each patient.
7.1
Toxicity and Adverse Events 
All the adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA).
The toxicity evaluation will be coded with the National Cancer Institute Common Terminology 
Criteria for Adverse Events (NCI-CTCAE) v4.
Treatment-emergent adverse events (TEAE) are defined as any adverse events aggravated in severity 
from baseline or having their onset between the first dose of the study drug and 30 days after the last 
treatment dose, death or date of further therapy (whichever comes first). Adverse Events Related to 
Study Drug or with Unknown relationship occurring more than 30 days after the last dose will also be 
taken into account as TEAEs.
Summary of overall AEs will be done by System Organ Class (SOC) and Preferred Term (PT), by 
severity (worst toxicity grade), by relationship to the study drug and by AE outcome. Tables will be 


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organized by category of events using SOC (i.e. alphabetical order) and PT in descending frequencies 
(i.e., from higher to lower).
A frequency table or listing will be made for the AEs leading to cycle delay, dose reduction or 
withdrawal of study medication. Adverse events with outcome of death will also be presented by
relationship to the study drugs.
7.2
Clinical Laboratory Evaluation
Laboratory results will be classified according to the NCI-CTCAE v4. 
The following hematological values (worst grade per patient and per cycle during treatment) will be 
displayed: white blood cells count (WBC), neutrophils count, lymphocytes count, platelets count and 
hemoglobin.
Overall cross tabulation will be presented for the worst grade during treatment versus the baseline 
severity grading of leukopenia, neutropenia, lymphopenia, thrombocytopenia and anemia.
If a grade ≥3 neutropenia or thrombocytopenia occurs during a cycle of treatment, the first day it 
reaches grade 3 or 4 (counting from the start of the cycle) and the duration of the abnormality (i.e., 
until recovery to grade ≤ 2) will be tabulated.
Similarly, the following biochemical values (worst grade per patient and per cycle during treatment) 
will be displayed: alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin, 
alkaline phosphatase (AP), creatine phosphokinase (CPK), creatinine, gamma-glutamyltransferase 
(GGT), calcium (corrected by albumin levels), potassium, sodium, magnesium, glucose and albumin.
If a grade ≥3 AST or ALT increase occurs during a cycle of treatment, both the day it peaked 
(counting from the start of the cycle) and the duration of the abnormality (i.e., until recovery to grade 
≤ 2) will be tabulated.
Overall cross tabulation will be presented for the worst grade during treatment versus the baseline 
severity grading of biochemical abnormalities.
7.3
Vital Signs, Physical Examination, Left Ventricular Ejection Fraction and 
Electrocardiogram Findings
Tabulation will be made summarizing the performance status, body weight, left ventricular ejection 
fraction (LVEF) and electrocardiogram (ECG) abnormalities at baseline and during the treatment, if 
appropriate, for each cohort and patient.
7.4
Deaths and Other Serious Adverse Events
Deaths and other serious adverse events (SAEs) will be tabulated.
8
OTHER ANALYSES
Continuous variables will be tabulated and presented with summary statistics (i.e., mean, standard 
deviation, median and range). 
Categorical variables will be summarized in frequency tables by means of counts and percentages.
Percentages in the summary tables will be rounded and may therefore not always add up to exactly 
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8.1
Patient Disposition and Treatment/Study Discontinuation
The number of patients included in the study, the number of patients treated and the number of 
patients evaluable for the main endpoint will be shown. Also, accrual by center and country and the 
main dates of the study will be displayed. Reasons for treatment discontinuation and for study 
discontinuation will be tabulated.
8.2
Protocol Deviations
Analysis of inclusion/exclusion criteria deviations, retreatment restrictions, concomitant medication 
and clinically relevant discontinuations, among others, will be done as described in Appendix I.  
8.3
Baseline and Demographic Data
Baseline data such as demographics, cancer history, prior therapy, prior relevant history, signs and 
symptoms, ECG, LVEF, physical examination, vital signs, laboratory values and concomitant 
medication, coded according to the World Health Organization (WHO) Anatomical Therapeutic 
Chemical (ATC) classification system, will be described following standard tables detailed in 
Appendix I. 
Age, baseline weight, height, and body surface area (BSA) will be summarized descriptively. 
Baseline weight and height will be recorded on the case report form (CRF).
Baseline BSA will be calculated using the Dubois & Dubois formula.
Age categories and race will be summarized with frequency counts.
Baseline Eastern Cooperative Oncology Group (ECOG) performance status (PS) will be summarized 
with frequency counts.
For the cancer history: time from initial diagnosis, time from metastatic disease and time from last 
progression before the study entry will be recorded. These time calculations will be shown in months 
and summarized descriptively. Histology and characteristics of the disease at study entry will be 
tabulated.
Previous relevant medical history (other than cancer) will be listed.
A frequency tabulation of the number of patients with and the different types of previous surgery, 
radiotherapy, or therapy (number of lines) will be given.
Adverse events at baseline will be displayed by tabulation of frequencies according to NCI-CTCAE 
v4 toxicity grades. They will also be listed.
In case of pre-treatment characteristics with multiple measurements per patient before the start of 
treatment (e.g. laboratory assessments, vital signs) the baseline measurement will be considered the 
last valid value prior to or on the first day of treatment.
8.4
Treatment Administration
Total cumulative dose, dose intensity and relative dose intensity, time on treatment, cycle delays and 
dose reductions will be described following standard tables detailed in Appendix I.
Total cumulative dose, expressed in mg, will be the sum of all the study drug doses from the first 
cycle until the last cycle, including the dose received in the last cycle.


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Patients will be considered to be on-treatment for the duration of their treatment and for 30 days 
after the last treatment dose. If the patient starts any new antitumor therapy outside this clinical trial or 
dies within 30 days of the last treatment dose, the date of administration of this new therapy or the 
date of death will be considered the date of treatment discontinuation.
However, as a convention, the duration of the last cycle will be considered to be 21 days (instead of 
30 days) for dose intensity calculation purposes. 
Intended dose intensity is the planned dose per cycle divided by the planned number of weeks per 
cycle.
Absolute dose intensity is the actual cumulative dose divided by the number of weeks of treatment. 
Relative dose intensity (%) is the ratio of absolute dose intensity divided by the intended dose 
intensity.
The CRF item «Infusion delayed: yes/no» will be used to calculate the delayed cycles. For those 
cycles considered as delayed by the Investigator, the delay will be calculated as follows:
Delay:  Date of actual drug administration – Date of previous drug administration – 21. 
The infusion of the first cycle will be excluded from all calculations regarding cycle delays and 
modifications.
8.5
Subsequent Therapy
A table summarizing the subsequent therapies received after treatment discontinuation will be shown.
8.6
Pharmacokinetic Analyses
This analysis will be detailed in a separate document.
8.7
Pharmacogenetics Analyses
This analysis will be detailed in a separate document.
8.8
Pharmacogenomic Analyses
This analysis will be detailed in a separate document.
8.9
Imputation of Incomplete Dates
The dates of certain historical or on-study clinical data are key components for statistical analysis. An 
incomplete date results from a missing day, month or year; in that case, the missing figure can be 
imputed, thus allowing the calculation of variables, such as duration and time of a specific event. 
However, when all dates (day, month and year) are missing, no imputation will be done unless 
otherwise specified. Whenever imputations are applicable, it will be clearly specified in 
the corresponding shell table, listing or figure in sections 10-16 of this SAP.
Before Registration
If the day of a month is unknown, then the imputed day will be the 1st. of the month; if the month is 
also unknown, then the imputed date will be the 1st of July. This assumption will only be valid if the 
imputed date occurs earlier than the first dose administration date; otherwise the imputed date will be 
the first day of the month of administration of the first dose (i.e. 01/ month of administration of the 
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Between treatment start and end of treatment
All date variables during treatment where information is needed and is not fully available, for example 
adverse events or concomitant medications, will be subject of imputation by means of SAS 
programming. If the day of a date is unknown then the imputed day will be 1, if the month and/or year 
is also unknown then the imputed date will 1/January (this assumption will be valid if the imputed 
date is later than the treatment start date; otherwise, the imputed date will be the treatment start date).
After End of Treatment
To ensure the most conservative approach for the time-to-event variables (i.e., DR, PFS and OS), 
which can be affected by missing values, the following rules will be implemented: if the day of a date 
is unknown then the imputed day will be the 1st; if the month is also unknown, then the imputed date 
will be the 1st of July. This assumption will be valid if the imputed date occurs later than the last drug 
administration date; otherwise the imputed date will be the date of the last drug administration plus 
the predefined cycle length (i.e., 21 days if PM01183), except if the patient dies before, in which case 
the date of death minus 1 will be used. For OS, if a patient dies the imputation event date should be 
the last date the patient is known to be alive minus one day.
For the determination of treatment emergent AEs with incomplete dates that do not allow to know if 
they occurred during the treatment period, the following imputation rules will apply: 
-
If the start day, month and year are missing, the event will be considered treatment emergent.
-
If the start day and month are missing, no date imputation will be  performed but the event will 
be  considered TEAE, if the reported year is the same or occurs after the infusion year and also 
the reported year is the same or occurs before the EOT year.
-
If the start day is missing, no imputation date will be performed but the event will be 
considered TEAE, if the reported month and year occur after the first infusion date 
(month/year) and before the EOT date (month/year).
-
8.10 Decimal Places
By default, all numeric results will be rounded to one decimal, except when variables are integers; in 
that case, they will be reported without decimals (for example, age in years, number of sites, etc.).
Three decimal places will be used for Hazard Ratios or Odds Ratios. Four decimal places will be used 
for p-values.
8.11 Subgroup Analyses
Specific subgroup efficacy analyses will be done for patients with SCLC. These analyses will be 
performed by IA/IRC and in all evaluable/all treated patient populations, pre-specified analyses are by 
CTFI defined as the time from the last dose of the last platinum containing therapy to the occurrence 
of progressive disease,(< 90 days and ≥ 90 days and/or Refractory (RR) [<30 days], Resistant 
(R)[>=30 and <90 days], Sensitive (S) [>=90 and <180 days] and Very Sensitive (VS)[>=180 days]), 
excluding patients with CTFI<30 days and considering event to clinical progressions although they 


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were not documented by radiological images. Any other exploratory analyses requested by the 
physician at the time of the analysis will be clearly explained, specifying the selected patient 
population and following the same layout detailed for the other subgroup analyses.
If the number of patients recruited in any cohort differs at least 10% from the sample size 
assumptions, a sensitivity analysis for main efficacy endpoints using all evaluable patients will be 
performed.
Pre-specified safety subgroup analyses are: by sex (male vs. female), by age (<65 years-old vs. ≥65 
years-old), by race (white vs. other), by number of prior lines (1 vs. >1 line), by BSA (<1.8 vs. ≥1.8) 
and by geographical area (USA vs. Europe vs. rest of the world).
No differentiation by center is planned.
8.12 Methods for Handling Missing Data
Missing values will be tabulated with their frequency but they will not be included in the calculation 
of percentages.
8.13 Interim and Group Sequential Analyses
An interim analysis to reject H0 (non-binding) or to reject H1 (futility) in each tumor type is planned 
after the recruitment of 15 evaluable patients in each cohort. The Gamma family boundary will be 
used to control the type I error, the parameter to reject H0 is fixed as -1 and the parameter to reject H1 
is fixed as 0. If none of the first 15 evaluable patients in a specific cohort has a confirmed response, 
the alternative hypothesis will be rejected, according to boundaries and sample size assumptions, and 
recruitment will be stopped. If the number of responding patients is already two or more at the interim 
analysis, then H0 could be rejected and the study will have enough power to be stopped. On the 
contrary, if there is one confirmed response, the recruitment will be continued to up to 25 evaluable 
patients.
In particular, in the SCLC and endometrial carcinoma cohorts, the analysis at 25 evaluable patients 
will serve as second interim analysis to decide the continuation of recruitment. Two objective 
responses will be required to expand the accrual up to 100 and 50 evaluable patients respectively. 

For the SCLC cohort, the type I/II error will be controlled with a Gamma family boundary (-1 
to reject Ho, 0 to reject H1)  

For the endometrial carcinoma cohort, the type I/II error will be controlled with a Gamma 
family boundary (-1 to reject Ho, -3 to reject H1)  
8.14 Identification of Fixed or Random Effects Models
Not applicable.
8.15 Data Analysis Conventions
All data analysis conventions, data calculations and grouping needed to perform the statistical analysis 
not included in this SAP will be described in separate document. 


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9
STATISTICAL SOFTWARE
Medidata Rave® EDC will be used for data entry and clinical data management.
EAST v5.4 has been used to calculate sample size. SAS v9.2 or higher will be used for all statistical 
analysis outputs.
APPENDIX I
Statistical output will be displayed by cohort of tumor types and/or total population, and it will be 
clearly identified with labels (also for subgroup analyses).
Each table, listing and figure will have a comprehensive header identifying the tumor type (cohort) or 
the total population (if applicable).
For this reason each SAP Table/Listing/Figure will have different granularity, i.e Table 11.1.1.1.x 
where “x” is a different sublevel of granularity. The following values apply:
Table/Listing/Figure granularity level
Contents
none
Totals all cohort
.b
BRCA 1/2-associated metastatic breast carcinoma
.i
Biliary tract carcinoma
.c
Carcinoma of unknown primary site
.e
Endometrial carcinoma
.w
Ewing’s family of tumors (EFTs)
.g
Germ cell tumor (GCTs)
.h
Head and neck carcinoma (H&N)
.n
Neuroendocrine tumors (NETs)
.s
Small cell lung cancer (SCLC)
.s1
Resistant*
.s2
Sensitive*
(*)For tables to be produced for resistant (.s1) and sensitive (.s2) populations, please see indications in the respective table or figure 
footnote.  
Summary tables will have source data footnotes that will refer to the relevant listings. The tables' 
layout may change to adequately accommodate cohort size as appropriate. 
If the number of categories or items does not yield appropriate tabular or graphic representations, 
detailed listings will be shown instead.


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10 Study Patients
10.1 Patient Disposition 
Main characteristics concerning inclusion in the study, withdrawal from the study and protocol 
deviations will be displayed in this section.
Each table, listing and figure will have a comprehensive header identifying the tumor type (cohort) or 
the total population (if applicable).
Table 10.1.1 Number of patients included, treated and evaluable for the primary endpoint.
N
%
Included patients
Eligible patients*
Treated patients
Evaluable patients for efficacy**
Evaluable patients for efficacy by IRC (SCLC cohort)***
(*) Patients who were considered eligible according to the registration screening form and were accepted to take part in the trial with the 
sponsor’s agreement in the screening reply form. (**) Includes patients treated with early death/or PD not documented by image (early 
PD). (***) For sensitivity analysis.
Listing 10.1.2 Patients who do not meet all the inclusion criteria.
Patient id.
Criterion number(s) and description
Listing 10.1.3 Patients who meet any exclusion criteria.
Patient id.
Criterion number(s) and description
Listing 10.1.4 Non-evaluable patients for efficacy analysis.
Patient id.
Reason
Listing 10.1.5 Non-evaluable patients for efficacy analysis by IRC (SCLC cohort).
Patient id.
Reason
Listing 10.1.6 Non-evaluable patients for safety (Non-treated patients).
Patient id.
Reason
Table 10.1.7 Patients accrual by institution.
N
%
No. of patients included
Country 1
Institution 1
…
Total
…
Institution 1
…


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Total
Total
Institution 1
…
Total
No. of patients treated
Country 1
Institution 1
…
Total
…
Institution 1
…
Total
Total
Institution 1
…
Total
Table 10.1.8 Study dates.
Total
Date of first registration
Date of first dose of the first patient
Date of last registration
Date of first dose of the last patient
Date of last dose
Date of last follow-up*
(*) Last follow-up, examination or procedure before clinical cut-off or study closure.
10.2 Reasons for Treatment and Study Discontinuation
Each table, listing and figure displayed in this section will have a comprehensive header identifying 
the tumor type (cohort) or the total population (if applicable). The reasons for treatment 
discontinuation will be calculated in the treated patient’s population. The rest of tables and listings in 
this section will be calculated in the included patient’s population.
Table 10.2.1 Treatment discontinuation.
Reason
N
%
Progressive disease
Treatment-related adverse event*
Non treatment-related adverse event*
Patient refusal to treatment*
Death**
Investigator’s decision*
Other* 
Ongoing at cutoff
Total
Note: Also for s1 and s2; (*) Specify (see Listing 10.2.2), (**) Cause of Death (See Table 12.3.2.1).
Listing 10.2.2 Reasons for treatment discontinuation other than progressive disease.
Patient id.
CTFI*
Reason
Last cycle
Comments 
(*) Only for SCLC patients (RR, R, S, VS).
Table 10.2.3 Reasons for treatment discontinuation by cycles received.
Reason
Last cycle
1
2
…
Total


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Progressive disease
Treatment-related adverse event*
Non treatment-related adverse event*
Patient refusal to treatment*
Death**
Investigator’s decision*
Other*
Ongoing at cutoff
Total
(*) Specify (see Listing 10.2.2); (**) Cause of Death (See Table 12.3.2.1); 
When the reason for discontinuation is a study treatment-related adverse event or study treatment-
related death, identify patients and describe them in detail here.
Listing 10.2.4 Treatment discontinuation due to adverse events.
Patient id. CTFI*
Last 
cycle
Preferred  
term code
Adverse event 
reported 
(verbatim)
Grade 
Relationship 
Onset 
date
Resolved date Seriousness criteria
(*) Only for SCLC patients (RR, R, S, VS).
Table 10.2.5 Study discontinuation.
Reason
N
%
Never treated*
Study termination (clinical cut-off)
Patient's refusal
Death**
Lost to follow-up
Other ***
Total
Note: Also for s1 and s2; (*) See Listing 10.2.6; (**) Cause of Death (See Table 12.3.2.1); (***) Specify (see listing 10.2.7).
Listing 10.2.6 Patients included but not treated.
Patient id.
Off-study reason
Listing 10.2.7 Study discontinuation due to other reason.
Patient id.
Specify
10.3 Protocol Deviations 
Listing 10.3.1 Protocol deviations.
Patient id.
Deviation type
Description


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11 Efficacy Evaluation
11.1 Demographic and Other Baseline Characteristics
Demographic and Other Baseline Characteristics will be carried out on the “All Treated Patients” 
population and narratives will be used to describe patients who are included but not treated.
Each table, listing and figure displayed in this section will have a comprehensive header identifying 
the tumor type (cohort) or the total population (if applicable).
11.1.1 Patient Characteristics at Baseline
Table 11.1.1.1 Baseline characteristics: Age at treatment registration.
Age
N
%
18-XX
X
XX.X
XX-YY
≥65
Total
Mean, Std., Median, Range
Note: Also for s1 and s2.
Table 11.1.1.2 Baseline characteristics: Gender.
N
%
Male
X
XX.X
Female
Total
Note: Also for s1 and s2.
Table 11.1.1.3 Baseline characteristics: Race.
N
%
American Indian or Alaskan Native
X
XX.X
Asian
Black or African American
Native Hawaiian or Other Pacific Islander
White
Other*
Total
Note: Also for s1 and s2; (*) See Listing 11.1.1.5
Listing 11.1.1.4 Other race, specify.
Patient id.
CTFI*
Specify
(*) Only for SCLC.
11.1.2 Disease at Diagnosis and Disease at Study Entry 
Table 11.1.2.1 Time from first diagnosis to registration and Time from advanced disease to 
registration.
N
Mean
Std.
Median
Min
Max
Time from diagnosis to registration (months)
Time from advanced disease (months)
Note: Also for s1 and s2.


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Table 11.1.2.2 Histology type at diagnosis.
N
%
Small cell lung cancer (SCLC)
X
XX.X
Head and neck carcinoma (H&N)
Neuroendocrine tumors (NETs)
Biliary tract carcinoma
Endometrial carcinoma
BRCA 1/2-associated metastatic breast carcinoma (MBC)
Carcinoma of unknown primary site
Germ cell tumor (GCTs)
Ewing’s family of tumors (EFTs)
Total
Table 11.1.2.3 Stage at diagnosis.
N
%
Early
X
XX.X
Locally advanced
Metastatic
Total
Note: Also for s1 and s2.
Table 11.1.2.4 TNM.
N
%
T3N0M0
X
XX.X
….
Total
Table 11.1.2.5 Time from last progression before the study entry and TTP from last medical therapy.
N
Mean
Std.
Median
Min
Max
Time from last PD  (weeks) 
TTP to last medical therapy (months)
Note: Also for s1 and s2.
Table 11.1.2.6 Sites of disease.
N
%
Primary tumor
X
XX.X
Bone*
Lung
Liver
Pleura
Lymph node**
Other***
Note: Also for s1 and s2; (*) See Table 11.1.2.7; (**) See Table 11.1.2.8; (***) Other sites will be re-coded to specific sites by clinical 
review.
Listing 11.1.2.7 Bone location.
Patient id.
Specify
Table 11.1.2.8 Lymph node location.
N
%
Neck
X
XX.X
Mediastinal
…


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Table 11.1.2.9 Number of sites at baseline.
No. of sites
N
%
1
X
XX.X
2
...
Total
Mean, Standard deviation, Median (Range)
Note: Also for s1 and s2; (*) Sites of disease from cancer history.
Table 11.1.2.10 Sum of target lesions at baseline.
N
%
>50 mm
X
XX.X
>100 mm
Bulky disease*
Note: Also for s1 and s2. (*) One lesion more than 50 mm.
11.1.3 Disease at Diagnosis and Disease at Study Entry: Small Cell Lung Cancer (SCLC)
Table 11.1.3.1 Stage at diagnosis.
N
%
Limited 
X
XX.X
Extended
Total
Note: Also for s1 and s2.
Table 11.1.3.2 History or current presence of CNS involvement.
N
%
Yes
X
XX.X
No
Total
Note: Also for s1 and s2.
11.1.4 Disease at Diagnosis and Disease at Study Entry: Head and Neck Carcinoma (H&N)
Table 11.1.4.1 Anatomical subsite.
N
%
Larynx
X
XX.X
……
Total
11.1.5 Disease at Diagnosis and Disease at Study Entry: Neuroendocrine Tumors (NETs)
Table 11.1.5.1 NET type.
N
%
Gastroenteropancreatic neuroendocrine tumors (GEP NETs for short)
X
XX.X
……
Other*
Total


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(*)  See Listing 11.1.5.2.
Listing 11.1.5.2 Other type.
Patient id.
Specify
Table 11.1.5.3 NET subtype.
N
%
Functioning neuroendocrine tumors (F-NETs)
X
XX.X
Non-Functioning neuroendocrine tumors (NF-NET)
Total
Table 11.1.5.4 KI-67/MIB-1.
N
%
<10%
X
XX.X
>10%
Not done/Unknown
Total
11.1.6 Disease at Diagnosis and Disease at Study Entry: Biliary Tract Carcinoma
Table 11.1.6.1 Primary site.
N
%
Intrahepatic cholangiocarcinoma
X
XX.X
Gallbladder
Ampulla of Vater
…
Total
Table 11.1.6.2 Histology type.
N
%
Adenocarcinoma
X
XX.X
Papillary
Intestinal type
Other*
Total
(*)  See Listing 11.1.6.3.
Listing 11.1.6.3 Other histology type.
Patient id.
Specify
11.1.7 Disease at Diagnosis and Disease at Study Entry: Endometrial Carcinoma
Table 11.1.7.1 Histology type.
N
%
Endometrioid
X
XX.X
Serous/Papillary
Clear cell
…
Other*
Total


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(*)  See Listing 11.1.7.2.
Listing 11.1.7.2 Other histology type.
Patient id.
Specify
11.1.8 Disease at Diagnosis and Disease at Study Entry: BRCA 1/2-associated Metastatic Breast 
Carcinoma (MBC)
Table 11.1.8.1 Primary site.
N
%
Left
X
XX.X
Right
Bilateral
Total
Table 11.1.8.2 Histology type.
N
%
Ductal
X
XX.X
Lobular
…
Other*
Total
(*)  See Listing 11.1.8.3.
Listing 11.1.8.3 Other histology type.
Patient id.
Specify
Table 11.1.8.4 Receptor status. 
Positive
Negative
N
%
N
%
Estrogen receptor
X
XX.X
X
XX.X
Progesterone receptor
HER-2/neu receptor
Table 11.1.8.5 Hormonal status.
N
%
ER and/or PR positive and HER2 negative
X
XX.X
ER and/or PR positive and HER2 positive
ER and/or PR negative and HER2 positive
Triple negative
Total
Note: Triple negative: HER2 negative ER negative and PR negative.
Table 11.1.8.6 BRCA 1/2. 
N
%
BRCA 1
X
XX.X
BRCA 2
Both
Total
Table 11.1.8.7 KI-67/MIB-1.
N
%


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<5%
X
XX.X
5-10%
>10%
Not done/Unknown
Total
11.1.9 Disease at Diagnosis and Disease at Study Entry:   Carcinoma of Unknown Primary Site
Table 11.1.9.1 Histology type.
N
%
Adenocarcinoma
X
XX.X
Carcinoma NOS
Undifferentiated
Total
11.1.10  Disease at Diagnosis and Disease at Study Entry: Germ Cell Tumors (GCTs)
Table 11.1.10.1 Primary site.
N
%
Gonadal
Testicular
X
XX.X
Ovarian
Retroperitoneal
…
Other*
Total
(*)  See Listing 11.1.10.2.
Listing 11.1.10.2 Other primary sites.
Patient id.
Specify
Table 11.1.10.3 Histology type.
N
%
Seminomatous
X
XX.X
Non-seminomatous*
Total
(*) If Non-Seminomatous see Table 11.1.10.4.
Listing 11.1.10.4 Non-seminomatous.
Patient id.
Specify
11.1.11  Disease at Diagnosis and Current Disease: Ewing's Family of Tumors (EFTs)
Table 11.1.11.1 Anatomical subtype.
N
%
Osseous
X
XX.X
Extraosseous - Primitive neuroectodermal tumor
Extraosseous - Askin tumor
*
Total


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(*) Other, in case of none of the others CRF categories apply.
11.1.12  Prior History
Each table, listing and figure displayed in this section will have a comprehensive header identifying 
the tumor type (cohort) or the total population (if applicable).
Table  11.1.12.1 Prior history.
SOC
Preferred term*
N
%
Gastrointestinal disorders
Constipation
Diarrhea NOS
…
…
…
(*) Only terms coded by the applicable dictionary.  
Listing 11.1.12.2 Prior history (Ongoing events).
Patient id.
Description (Literal)
SOC
PT
Onset date
Table  11.1.12.3 Smoker status.
*
N
%
Former/current
X
XX.X
Never
UK                             
Total
(*) Only for SCLC cohort and information obtained from CRF pages of Prior history.
Table  11.1.12.4 Paraneoplastic syndrome.
*
N
%
Yes 
X
XX.X
No                             
Total
(*) Only for SCLC cohort and information obtained from CRF pages AEs at baseline and/or Prior history. 
11.1.13 Prior Anticancer Therapy
Each table, listing and figure displayed in this section will have a comprehensive header identifying 
the tumor type (cohort) or the total population (if applicable).
Table 11.1.13.1 Patients with prior surgery.
N
%
Yes
X
X.X
        Palliative
        Curative
No
Total
Table 11.1.13.2 Patients with prior radiotherapy
N
%
Yes
        Brachytherapy
X
X.X
        External (including IMRT)
X
X.X
        IMRT


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No
Total
Table 11.1.13.3 Number of lines of prior therapy.
No. of systemic lines
N
%
1
X
XX.X
...
Total
Mean, Standard Deviation, Median (Range)
Setting
N
%
Neoadjuvant
X
XX.X
Adjuvant
Neoadjuvant + Adjuvant
Advanced
No. of advanced chemotherapy lines
N
%
1
X
XX.X
...
Total
Mean, Standard Deviation, Median (Range)
Note: Also for s1 and s2.
Table 11.1.13.4 Prior anticancer agents.
Antineoplastic and immunomodulating agents (ATC-class.)
N
%
Antineoplastic agents (L01)
X
XX.X
     Alkylating agents
           Nitrogen mustard analogues
           Alkyl sulphonates
Prior anticancer agents*
Hormones
Prior Immunotherapy
…
Biological agents     
…
….
Note: Also for s1 and s2; (*) Therapies of interest for each tumor type e.g MBC, endometrial carcinoma, hormone, Biological agents 
etc…..
Table 11.1.13.5 PCI.
*
N
%
Yes
X
XX.X
No
Total
Note: Also for s1 and s2; (*) Only for SCLC patients.
  Table 11.1.13.6 CTFI by subgroup.
*
N
%
Mean, Std., Median, 
Range**
CTFI< 90 days
X
XX.X
        RR
        R
CTFI≥ 90 days
        S
        VS
Total
(*) Only for SCLC patients. (**) Units in months.


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Table 11.1.13.7 Best response and TTP to last prior platinum.
*
N
%
CR
X
XX.X
PR
SD
PD
UK/NA
Total
TTP to last previous platinum Mean, Std., Median, Range
(*) Only for SCLC patients. Note: Also for s1 and s2.
11.1.14 Physical Examination and Performance Status at Baseline
Each table, listing and figure displayed in this section will have a comprehensive header identifying 
the tumor type (cohort) or the total (if applicable).
Table 11.1.14.1 Baseline physical examination.
N
%
Normal
X
X.X
Abnormal
Total
Table 11.1.14.2 Baseline physical examination: BSA, Weight and Height.
N
Mean
Std.
Median
Min
Max
BSA (m2)
Weight (Kg)
Height (cm)
Note: Also for s1 and s2.
Table 11.1.14.3 Baseline characteristics: ECOG Performance Status.
PS (ECOG)
N
%
0
X
XX.X
1
2
3
4
Total
Note: Also for s1 and s2.
11.1.15 Vital Signs, Electrocardiogram, LVEF and other tests.
Each table, listing and figure displayed in this section will have a comprehensive header identifying 
the tumor type (cohort) or the total (if applicable).
For vital signs, electrocardiogram, LVEF and other tests, the last examination available before 
treatment will be described in the following tables.
Table 11.1.15.1 Baseline characteristics: vital signs.
Parameter
N
Mean
Std.
Median
Min
Max
Heart rate (beats/min)
Systolic blood pressure (mmHg)
Diastolic blood pressure (mmHg)


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Temperature (ºC)
Table 11.1.15.2 Baseline characteristics: electrocardiogram result.
ECG
N
%
Normal
X
XX.X
Significant abnormalities*
Non-significant abnormalities
(*) See Listing 11.1.15.4.
Table 11.1.15.3 Baseline characteristics: electrocardiogram values.
Parameter
N
Mean
Std.
Median
Min
Max
PR interval (msec)
Heart rate (bpm)
QT interval (msec)
QRS complex (msec)
QTc Bazett’s
Fridericia corrected QT
Listing 11.1.15.4 Patients with abnormal electrocardiogram.
Patient 
id.
Abnormality
Details*
Reason for 
clinically 
indicated 
repeat
PR interval 
(msec)
Heart rate 
(bpm)
QT interval 
(msec)
QRS 
complex 
(msec)
QTc 
Fridericia
QTc 
Bazett’s**
(*)For non-significant abnormalities, for further details see prior medical history or Signs and symptoms; (**) QTc (Bazett’s) = QT 
interval / √(60/Heart rate).
Table 11.1.15.5 Baseline characteristics: left ventricular ejection fraction (LVEF).
LVEF
N
%
Normal
X
XX.X
Abnormal*
Total
(*) See listing 11.1.15.7 for details.
Table 11.1.15.6 Baseline characteristics: LVEF values.
LVEF (%) by Method
N
Mean
Std.
Median
Min
Max
ECHO
MUGA
Both
Listing 11.1.15.7 Patients with abnormal LVEF.
Patient id.
Abnormality
Details*
Reason for 
clinically 
indicated repeat
Method
LVEF (%)
Institution normal 
range
(*) For non-significant abnormalities, for further details see prior medical history or Signs and symptoms.
Table 11.1.15.8 Baseline characteristics: pregnancy test.
Pregnancy test
N
%
Positive
X
XX.X
Negative
NA*
Total
Table 11.1.15.9 Baseline characteristics: adequate contraception.
Adequate birth control
N
%


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Yes
X
XX.X
No
NA*
Total
11.1.16 Hematological Values at Baseline
Each table, listing and figure displayed in this section will have a comprehensive header identifying 
the tumor type (cohort) or the total population (if applicable).
Table 11.1.16.1 Hematological abnormalities at baseline.
Grade 
1
…
Grade 
4
All*
N
%
…
N
%
N
%
Anemia
Leukopenia
Neutropenia 
Lymphopenia
Thrombocytopenia
Note: Also for s1 and s2; (*) Any grade.
Table 11.1.16.2 Hematological values at baseline.
Parameter*
N
Mean
Std.
Median
Min
Max
Hemoglobin (g/dl)
Platelets (x10*9/L)
WBC (x10*9/L)
Neutrophils (x10*9/L)
Lymphocytes (x10*9/L)
Monocytes (x10*9/L)
Listing 11.1.16.3 Hematological tests not assessed at baseline.
Patient id.
Lab. test
Listing 11.1.16.4 Hematological abnormalities at baseline. Grade ≥ 2.
Patient id
Parameter
Value
Units
Grade
11.1.17 Biochemical Values at Baseline
Each table, listing and figure displayed in this section will have a comprehensive header identifying 
the tumor type (cohort) or the total population (if applicable).
Table 11.1.17.1 Biochemical abnormalities at baseline.
Grade 
1
…
Grade 
4
All*
N
%
…
N
%
N
%
AST increased
ALT increased
Total bilirubin increased
AP increased


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…
Hyperglycemia 
Hypoglycemia
…
Note: Also for s1 and s2; (*) Any grade.
Table 11.1.17.2 Biochemical values at baseline.
N
Mean
Std.
Median
Min
Max
AST (xULN)
ALT (xULN)
Direct bilirubin (xULN)
Total bilirubin (xULN)
AP (xULN)
LDH (xULN)
CPK (xULN)
GGT (xULN)
Creatinine (xULN)
…
Listing 11.1.17.3 Biochemical tests not assessed at baseline.
Patient id.
Lab. test
…
Listing 11.1.17.4 Biochemical abnormalities at baseline. Grade ≥ 2.
Patient id
Parameter
Value
Units
Grade
Table 11.1.17.5 AAGP values at baseline.
N
Mean
Std.
Median
Min
Max
AAGP (xULN)
Table 11.1.17.6 Abnormal LDH at baseline.
*
N
%
Yes
X
XX.X
No                             
Total
(*) Only for SCLC cohort. Abnormal LDH: (>ULN).
11.1.18 Coagulation Values at Baseline
Each table, listing and figure displayed in this section will have a comprehensive header identifying 
the tumor type (cohort) or the total population (if applicable).
Table 11.1.18.1 Coagulation abnormalities at baseline.
Grade 
1
…
Grade 
4
All*
N
%
…
N
%
N
%
INR increased
PTT prolonged
(*) Any grade.
Table 11.1.18.2 Coagulation values at baseline.


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N
Mean
Std.
Median
Min
Max
INR 
PT (sec)
PT (ratio)
PTT (sec)
PTT (ratio)
Listing 11.1.18.3 Coagulation tests not assessed at baseline.
Patient id.
Lab. test
…
Listing 11.1.18.4 Coagulation abnormalities at baseline. Grade ≥ 2.
Patient id
Parameter
Value
Units
Grade
11.1.19 Adverse Events at Baseline
Each table, listing and figure displayed in this section will have a comprehensive header identifying 
the tumor type (cohort) or the total population (if applicable).
Table 11.1.19.1 Patients with adverse events at baseline.
No. of adverse events per patient
N
%
0
X
XX.X
1
2
3
Mean, Standard Deviation, Median (Range)
Table 11.1.19.2 Patients with disease-related adverse events at baseline.
No. of disease-related adverse events per patient
N
%
0
X
XX.X
1
2
3
Mean, Standard Deviation, Median (Range)
Table 11.1.19.3 Adverse events at baseline.
SOC
Preferred term
Grade 
1
…
Grade 
4
All*
N
%
…
N
%
N
%
Gastrointestinal disorders
Constipation
Diarrhea NOS
…
…
…
Note: Also for s1 and s2; (*)Any grade.
11.1.20 Concomitant Therapy and Procedures at Baseline
Each table, listing and figure displayed in this section will have a comprehensive header identifying 
the tumor type (cohort) or the total population (if applicable).


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Table 11.1.20.1 Concomitant medication at baseline (ATC1/ATC2/ATC3/ATC4/PN).
Concomitant medication at baseline
N
%
Alimentary tract and metabolism
   Antacids
      Magnesium compounds
          Magnesium adipate
…
Blood and blood forming organs
   Antithrombotic agents
      Vitamin K antagonists
          Acenocoumarol
…
Table 11.1.20.2 Summary of concomitant medication at baseline.
N
%
No. of systems at BL (ATC1 level)
0
1
2
3
Mean, Standard Deviation, Median (Range)
No. of indications at BL (ATC2 level)
0
1
2
3
  Mean, Standard Deviation, Median (Range)
No. of agent families at BL (ATC4 level)
0
1
2
3
Mean, Standard Deviation, Median (Range)
No. of agents at BL (PN level)
      0
1
2
      3
Mean, Standard Deviation, Median (Range)
If there are a relevant number of patients receiving the same concomitant medication, a table 
summarizing this information can be added.
11.2 Measurements of treatment compliance
Compliance of individual patients with the treatment regimen under study will be measured and 
tabulated in section 12.1 and listed in appendix 16.2.5 (ICH listings).
11.3 Efficacy Analysis
Efficacy analysis will be carried out on the “All Evaluable Patients” population. For SCLC patients in 
“All Treated Patients” and in “ All Evaluable Patients” by IA/IRC and in all pre-specified analyses, by 
CTFI (< 90 days and ≥ 90 days and/or Refractory (RR)[<30 days], Resistant (R) [>=30 and <90 days], 
Sensitive (S) [>=90 and <180 days] and Very Sensitive (VS) [>=180 days]), excluding patients with 


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CTFI<30 days and considering event in the clinical progressions although they were not documented 
by radiological images. 
Each table, listing and figure displayed in this section will have a comprehensive header identifying 
the tumor type (cohort), the total population (if applicable) or SCLC patients by CTFI or sensitivity 
analysis if recruitment in any cohort differs at least 10% from the assumptions. Any other exploratory 
analyses will be clearly specified by selected patient population and will be performed following the 
same table layout detailed below.
11.3.1 Primary Analysis (excluding SCLC cohort)
Primary Analysis by IA:
Table 11.3.1.1 Response rate.
Response
N
%
Complete response (CR)
Partial response (PR)
Stable disease SD≥4 months
Stable disease SD<4 months
Progressive disease (PD)
Inevaluable for response*
(*) for example: early death, malignant disease; toxicity; tumor assessments not repeated/incomplete; other (specify)
Table 11.3.1.2 ORR.
Percentage
Lower 95% limit
Upper 95% limit
Response rate*
(*) Confirmed CR + PR. Binomial exact estimator and 95% CI.
11.3.2 Secondary Analyses (excluding SCLC cohort)
Secondary Analyses by IA:
Table 11.3.2.1  Descriptive Duration of response (DR).
N
Mean
Std.Std.
Median
Min
Max
Table 11.3.2.2  DR.
DR
N
Events
Censored
Median DR
DR at 4 months
DR at 6 months
DR at 12 months
Kaplan-Meier plot will also be shown (Figure 11.3.2.2).
Table 11.3.2.3 Clinical benefit rate and Disease control rate.
Percentage
Lower 95% limit
Upper 95% limit
Clinical benefit rate*
Disease control rate**
(*) CR + PR + SD ≥ 4 months. Binomial exact estimator and 95% CI.
(**) CR + PR + SD. Binomial exact estimator and 95% CI.


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Table 11.3.2.4 PFS.
PFS
N
Events
Censored
Median PFS
PFS at 4 months
PFS at 6 months
PFS at 12 months
Kaplan-Meier plot will also be shown (Figure 11.3.2.4).
Table 11.3.2.5  OS.
OS
N
Events
Censored
Median OS
OS at 6 months
OS at 12 months
OS at 24 months
Kaplan-Meier plot will also be shown (Figure 11.3.2.5).
Listing 11.3.2.6 Characteristics of patients with clinical benefit*. 
Baseline Characteristics**
Study treatment characteristics**
Patient id.
PS /
Age/Gender
Histology 
type / 
Histology 
grade
No. of prior 
regimens
Best 
response 
last 
therapy 
TTP last 
therapy 
Cycles 
received
Best 
response
PFS 
(mo)
OS 
(mo)
DR
(mo)
…
(*) CR + PR + SD ≥ 4 months.
(**) Any other clinically relevant variable will be added at the time of the analysis.
Table 11.3.2.7 Median follow-up.
Follow-up*
Median
95% CI/Range
PFS
OS
(*) Calculated using the Kaplan-Meier method reversing the censoring values and also by descriptive methods.
11.3.3 SCLC Cohort
Primary Analysis (ORR):
Table 11.3.3.1 Response rate by IA (All treated patients).
Response
N
%
Complete response (CR)
Partial response (PR)
Stable disease SD≥4 months
Stable disease SD<4 months
Progressive disease (PD)
Inevaluable for response*
(*) for example: early death, malignant disease; toxicity; tumor assessments not repeated/incomplete; other (specify)


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Table 11.3.3.2 ORR by IA (All treated patients).
Percentage
Lower 95% limit
Upper 95% limit
Response rate*
(*) Confirmed CR + PR. Binomial exact estimator and 95% CI.
Secondary and Supportive Analysis for ORR:
Table 11.3.3.3 Response rate by IA (All evaluable patients).
Response
N
%
Complete response (CR)
Partial response (PR)
Stable disease SD≥4 months
Stable disease SD<4 months
Progressive disease (PD)
Inevaluable for response*
(*) for example: early death, malignant disease; toxicity; tumor assessments not repeated/incomplete; other (specify).
Table 11.3.3.4 ORR by IA (All evaluable patients).
Percentage
Lower 95% limit
Upper 95% limit
Response rate*
(*) Confirmed CR + PR. Binomial exact estimator and 95% CI.
Table 11.3.3.5 Response rate by IRC (All treated patients).
Response
N
%
Complete response (CR)
Partial response (PR)
Stable disease SD≥4 months
Stable disease SD<4 months
Progressive disease (PD)
Inevaluable for response*
(*) for example: early death, malignant disease; toxicity; tumor assessments not repeated/incomplete; other (specify).
Table 11.3.3.6 ORR by IRC (All treated patients).
Percentage
Lower 95% limit
Upper 95% limit
Response rate*
(*) Confirmed CR + PR. Binomial exact estimator and 95% CI.
Table 11.3.3.7 Response rate and reliability by IA and IRC (All treated patients).
Response
IA
Complete 
response (CR)
Partial 
response (PR)
Stable 
disease 
SD≥4 
months
Stable 
disease 
SD<4 
months
Progressive 
disease (PD)
Inevaluable for 
response*
N
%
N
%
N
%
N
%
N
%
N
%
IRC
Complete 
response (CR)
Partial response 
(PR)
Stable disease 
SD≥4 months
Stable disease 
SD<4 months
Progressive 
disease (PD)
Inevaluable for 


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response
Test of Symmetry**
Statistic (S)
DF
Pr > S
Kappa statistics**
                                                               Value                                    ASE                                95% Confidence Limits
Simple kappa
Weighted kappa
Test of H0: Weighted Kappa = 0
ASE under H0
Z
One-sided Pr >  Z
Two-sided Pr > |Z|
(*) for example: early death, malignant disease; toxicity; tumor assessments not repeated/incomplete; other (specify).
For discrepancies see Listing 11.3.3.15. Percentage by columns. (**)  Kappa Index for concordance of all response categories according 
to IA or IRC assessment.
Other Secondary Analyses:
Table 11.3.3.8 Descriptive* DR by IA and IRC.
N
Mean
Std.
Median
Min
Max
IA
IRC
(*) Calculated with univariate procedures, not taking into account censoring, instead of Kaplan-Meier estimates.
Table 11.3.3.9 DR by IA and IRC.
IA
IRC
N
Events
Censored
Median DR
DR at 4 months
DR at 6 months 
DR at 12 months 
Kaplan-Meier plots will also be shown (Figure 11.3.3.9.1 DR by IA; Figure 11.3.3.9.2 DR by IRC and Figure 11.3.3.9.3 DR by IA and 
IRC)
Table 11.3.3.10 Clinical benefit rate and Disease control rate by IA and IRC (All treated patients).
Percentage
Lower 95% limit
Upper 95% limit
IA
Clinical benefit rate*
Disease control rate**
IRC
Clinical benefit rate*
Disease control rate**
(*) CR + PR + SD ≥ 4 months. Binomial exact estimator and 95% CI.
(**) CR + PR + SD. Binomial exact estimator and 95% CI.
Table 11.3.3.11 PFS by IA and IRC (All treated patients). 
IA
IRC
N
Events
Censored
Median PFS 
PFS at 4 months 
PFS at 6 months 
PFS at 12 months


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Kaplan-Meier plot will also be shown. (Figure 11.3.3.11.1 PFS by IA (All treated patients), Figure 11.3.3.11.2 PFS by IRC (All treated 
patients) and Figure 11.3.3.11.3 PFS by IA and IRC (All treated patients))
Table 11.3.3.12 OS (All treated patients).
OS
N
Events
Censored
Median OS
OS at 6 months
OS at 12 months
OS at 24 months
Kaplan-Meier plot will also be shown (Figure 11.3.3.12).
Listing 11.3.3.13 Characteristics of patients with clinical benefit* by CTFI by IA and IRC. (All 
treated patients).
Baseline characteristics
Study treatment characteristics
Patient 
id.
CTFI**
PS /
Age/  
Gender
***
No. of 
prior 
regimens
Last prior 
therapy 
Best 
response/TTP 
last therapy 
Cycles 
received
Best response 
IA/IRC
PFS 
(mo)
IA/IRC
DR
(mo) 
IA/IRC
OS 
(mo)
…
(*) CR + PR + SD ≥ 4 months.
(**) RR, R, S, VS.
(***) Any other clinical relevant variable (including sites of disease, limited/extended disease, LDH [normal/abnormal] and alpha-acid 
glycoprotein [xULN]) will be added at the analysis time.
Table 11.3.3.14 Median follow-up by IA and IRC. (All treated patients).
Follow-up*
Median
95% CI/Range
IA
PFS
OS
IRC
PFS
(*) Calculated using the Kaplan-Meier method reversing the censoring values and also by descriptive methods.
Listing 11.3.3.15 Concordance by IA and IRC. (All treated patients).
Patient id.
CTFI*
Study treatment characteristics by IA
Study treatment characteristics by IRC
Best response
PFS (mo)
DR (mo)
Best 
response
PFS (mo)
DR (mo)
(*) RR, R, S, VS.  
Table 11.3.3.16 Progression type by IA and IRC. (All treated patients)
IA
IRC
N
%
N
%
Target lesion
Non-target lesion
New lesions 
                       CNS
                       CNS + Other
                       No CNS


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Death due to malignant disease
Other*
(*)Please specify.
Table 11.3.3.17 Censoring reason by IA and IRC. (All treated patients)
IA
IRC
N
%
N
%
Progression-free at last tumor assessment
   FU completed
   FU ongoing
Subsequent therapy before documented progression
Other*
(*)Please specify.
Subgroup Analysis by CTFI (< 90 days and ≥ 90 days/or Refractory (RR) [<30 days], Resistant (R) 
[>=30 and <90 days], Sensitive (S) [>=90 and <180 days] and Very Sensitive (VS)[>=180 days]):
Table 11.3.3.18 Response rate IA and IRC by CTFI (All treated patients).
Response
CTFI< 90 days
CTFI≥ 90 days
RR
R
Total
S
VS
Total
N
%
N
%
N
%
N
%
N
%
N
%
IA
Complete response (CR)
Partial response (PR)
Stable disease SD≥4 months
Stable disease SD<4 months
Progressive disease (PD)
Inevaluable for response*
IRC
Complete response (CR)
Partial response (PR)
Stable disease SD≥4 months
Stable disease SD<4 months
Progressive disease (PD)
Inevaluable for response*
(*) for example: early death, malignant disease; toxicity; tumor assessments not repeated/incomplete; other (specify).
Table 11.3.3.19 ORR IA and IRC by CTFI (All treated patients).
Response rate*
Percentage
Lower 95% limit
Upper 95% limit
IA
CTFI< 90 days
RR
R
Total
CTFI≥ 90 days
S
VS
Total
IRC
CTFI< 90 days
RR
R
Total
CTFI≥ 90 days
S
VS
Total
(*) Confirmed CR + PR. Binomial exact estimator and 95% CI. 
Table 11.3.3.20 Response rate IA and IRC by CTFI (All treated patients).
Response
IA


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Complete 
response (CR)
Partial 
response (PR)
Stable 
disease 
SD≥4 
months
Stable 
disease 
SD<4 
months
Progressive 
disease (PD)
Inevaluable for 
response*
N
%
N
%
N
%
N
%
N
%
N
%
CTFI< 90 days
IRC
Complete 
response (CR)
Partial response 
(PR)
Stable disease 
SD≥4 months
Stable disease 
SD<4 months
Progressive 
disease (PD)
Inevaluable*
CTFI≥ 90 days
IRC
Complete 
response (CR)
Partial response 
(PR)
Stable disease 
SD≥4 months
Stable disease 
SD<4 months
Progressive 
disease (PD)
Inevaluable for 
response*
(*) for example: early death, malignant disease; toxicity; tumor assessments not repeated/incomplete; other (specify).
For discrepancies see Listing 11.3.3.15; Percentage in columns
Table 11.3.3.21 Descriptive DR IA and IRC by CTFI.
N
Mean
Std.
Median
Min
Max
IA
CTFI< 90 days
RR
R
Total
CTFI≥ 90 days
S
VS
Total
IRC
CTFI< 90 days
RR
R
Total
CTFI≥ 90 days
S
VS
Total
Table 11.3.3.22 DR IA by CTFI.
CTFI< 90 days*
CTFI≥ 90 days*
RR**
R**
Total*
S**
VS**
Total*
N
Events
Censored
Median DR
DR at 4 months
DR at 6 months
DR at 12 months
(*/**) Kaplan-Meier plot will also be shown. (*) Table/Figure 11.3.3.22.1 with the following categories (CTFI< 90 days and CTFI≥ 90 


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days), (**) Table /Figure 11.3.3.22.2 with the following categories RR, R, S and VS.
Table 11.3.3.23 DR IRC by CTFI.
CTFI< 90 days*
CTFI≥ 90 days*
RR**
R**
Total*
S**
VS**
Total*
N
Events
Censored
Median DR
DR at 4 months
DR at 6 months
DR at 12 months
(*/**) Kaplan-Meier plot will also be shown. (*) Table/Figure 11.3.3.23.1 with the following categories (CTFI< 90 days and CTFI≥ 90 
days), (**) Table /Figure 11.3.3.23.2 with the following categories RR, R, S and VS.
Table 11.3.3.24 Clinical benefit rate and Disease control rate IA and IRC by CTFI (All treated 
patients).
Percentage
Lower 95% 
limit
Upper 95% 
limit
Clinical benefit rate*
IA
CTFI< 90 days
RR
R
Total
CTFI≥ 90 days
S
VS
Total
IRC
CTFI< 90 days
RR
R
Total
CTFI≥ 90 days
S
VS
Total
Disease control rate**
IA
CTFI< 90 days
RR
R
Total
CTFI≥ 90 days
S
VS
Total
IRC
CTFI< 90 days
RR
R
Total
CTFI≥ 90 days
S
VS
Total
(*) CR + PR + SD ≥ 4 months. Binomial exact estimator and 95% CI.
(**) CR + PR + SD. Binomial exact estimator and 95% CI.
Table 11.3.3.25 PFS IA by CTFI (All treated patients).
CTFI< 90 days*
CTFI≥ 90 days*
RR**
R**
Total*
S**
VS**
Total*
N
Events
Censored
Median PFS
PFS at 4 months
PFS at 6 months
PFS at 12 months
(*/**) Kaplan-Meier plots will also be shown. (*)Table/Figure 11.3.3.25.1 with the following categories (CTFI< 90 days and CTFI≥ 90 
days), (**) Table/Figure 11.3.3.25.2 with the following categories RR, R, S and VS.


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Table 11.3.3.26 PFS IRC by CTFI (All treated patients).
CTFI< 90 days*
CTFI≥ 90 days*
RR**
R**
Total*
S**
VS**
Total*
N
Events
Censored
Median PFS
PFS at 4 months
PFS at 6 months
PFS at 12 months
(*/**) Kaplan-Meier plots will also be shown. (*)Table/Figure 11.3.3.26.1 with the following categories (CTFI< 90 days and CTFI≥ 90 
days), (**) Table/Figure 11.3.3.26.2 with the following categories RR, R, S and VS.
Table 11.3.3.27 OS by CTFI (All treated patients).
CTFI< 90 days*
CTFI≥ 90 days*
R**
RR**
Total*
S**
VS**
Total*
N
Events
Censored
Median OS
OS at 6 months
OS at 12 months
OS at 24 months
(*/**) Kaplan-Meier plots will also be shown. (*)Table/Figure 11.3.3.27.1 with the following categories (CTFI< 90 days and CTFI≥ 90 
days), (**) Table/Figure 11.3.3.27.2 with the following categories RR, R, S and VS.
Subgroup Analysis excluding CTFI < 30 days:
Table 11.3.3.28 Response rate IA and IRC excluding CTFI<30 (All treated patients).
Response
N
%
IA
Complete response (CR)
Partial response (PR)
Stable disease SD≥4 months
Stable disease SD<4 months
Progressive disease (PD)
Inevaluable for response*
IRC
Complete response (CR)
Partial response (PR)
Stable disease SD≥4 months
Stable disease SD<4 months
Progressive disease (PD)
Inevaluable for response*
(*) for example: early death, malignant disease; toxicity; tumor assessments not repeated/incomplete; other (specify).
Table 11.3.3.29 ORR IA and IRC excluding CTFI<30 (All treated patients).
Response rate*
Percentage
Lower 95% limit
Upper 95% limit
IA
IRC
(*) Confirmed CR + PR. Binomial exact estimator and 95% CI.
Table 11.3.3.30 DR by IA and IRC excluding CTFI<30.
IA
IRC
N
Events
Censored


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Median DR
DR at 4 months
DR at 6 months 
DR at 12 months 
Kaplan-Meier plot will also be shown (Figure 11.3.3.30.1 DR by IA excluding CTFI<30 (All treated patients), Figure 11.3.3.30.2 DR by 
IRC excluding CTFI<30 (All treated patients) and 11.3.3.30.3 DR by IA and IRC excluding CTFI<30 (All treated patients))
Table 11.3.3.31 Clinical benefit rate and Disease control rate by IA and IRC excluding CTFI<30 (All 
treated patients).
Percentage
Lower 95% limit
Upper 95% limit
IA
Clinical benefit rate*
Disease control rate**
IRC
Clinical benefit rate*
Disease control rate**
(*) CR + PR + SD ≥ 4 months. Binomial exact estimator and 95% CI.
(**) CR + PR + SD. Binomial exact estimator and 95% CI.
Table 11.3.3.32 PFS IA and IRC excluding CTFI<30 (All treated patients). 
IA
IRC
N
Events
Censored
Median PFS 
PFS at 4 months 
PFS at 6 months 
PFS at 12 months
Kaplan-Meier plot will also be shown (Figure 11.3.3.32.1 PFS by IA excluding CTFI<30 (All treated patients), Figure 11.3.3.32.2 PFS 
by IRC excluding CTFI<30 (All treated patients) and Figure 11.3.3.32.3 PFS by IA and IRC excluding CTFI<30 (All treated patients))
Table 11.3.3.33 OS excluding CTFI<30 (All treated patients).
OS
N
Events
Censored
Median OS
OS at 6 months
OS at 12 months
OS at 24 months
Kaplan-Meier plot will also be shown (Figure 11.3.3.33).
DR and PFS considering event in the clinical progressions:
Table 11.3.3.34 DR IA giving event in clinical PD (All treated patients).
DR
N
Events
Censored
Median DR
DR at 4 months
DR at 6 months
DR at 12 months
Kaplan-Meier plot will also be shown (Figure 11.3.3.34).


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Table 11.3.3.35 PFS IA giving event in clinical PD (All treated patients).
PFS
N
Events
Censored
Median PFS
PFS at 4 months
PFS at 6 months
PFS at 12 months
Kaplan-Meier plot will also be shown (Figure 11.3.3.35).
Survival in responders:
Table 11.3.3.36 OS in responders by IA and by CTFI (All treated patients).
CTFI< 90 days*
CTFI≥ 90 days*
Total***
R**
RR**
Total*
S**
VS**
Total*
N
Events
Censored
Median OS
OS at 6 months
OS at 12 months
OS at 24 months
(*/**/***) Kaplan-Meier plots will also be shown. (*)Table/Figure 11.3.3.36.1 with the following categories (CTFI< 90 days and 
CTFI≥ 90 days), (**) Table/Figure 11.3.3.36.2 with the following categories RR, R, S and VS. (***) Table/Figure 11.3.3.36.3 for totals.
Table 11.3.3.37 OS in responders by IRC and by CTFI (All treated patients).
CTFI< 90 days*
CTFI≥ 90 days*
Total***
R**
RR**
Total*
S**
VS**
Total*
N
Events
Censored
Median OS
OS at 6 months
OS at 12 months
OS at 24 months
(*/**/***) Kaplan-Meier plots will also be shown. (*)Table/Figure 11.3.3.37.1 with the following categories (CTFI< 90 days and 
CTFI≥ 90 days), (**) Table/Figure 11.3.3.37.2 with the following categories RR, R, S and VS. (***) Table/Figure 11.3.3.37.3 for totals.
Table 11.3.3.38 OS in responders by IA and IRC excluding CTFI<30 (All treated patients).
IA
IRC
N
Events
Censored
Median OS
OS at 6 months
OS at 12 months
OS at 24 months
Kaplan-Meier plot will also be shown (Figure 11.3.3.38.1 OS in responders by IA excluding CTFI<30 (All treated patients), Figure 
11.3.3.38.2 OS in responders by IRC excluding CTFI<30 (All treated patients).


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12 Safety Analysis
Safety analysis will be carried out on the “All Treated Patients” population by cohort of tumor types 
and total population.
Each table, listing and figure displayed in this section will have a comprehensive header identifying 
the tumor type (cohort) or the total population (if applicable).
12.1 Extent of Exposure
12.1.1 Treatment Administration
Table 12.1.1.1  Number of cycles administered and dose intensity.
No. of cycles administered per patient
N
%
1
2
3
…
Mean, Standard Deviation, Median (Range)
Time on treatment* (weeks)
Median 
Range
Mean 
Standard Deviation
PM01183 cumulative dose (mg)
Median
Range
Mean
Standard Deviation
PM01183 dose intensity (mg/m²/wk)
Median
Range
Mean
Standard Deviation
PM01183 relative dose intensity (%) 
Median
Range
Mean
Standard Deviation
Note: Also for s1 and s2; (*) Time on treatment: defined as date of last infusion plus 30 days, or date of death or subsequent therapy 
(whichever comes first) minus date of first infusion. 
12.1.2 Cycle Delays 
The first cycle will be excluded from all calculations.
Listing 12.1.2.1 Delays.
Patient id.
CTFI*
Delayed 
cycle 
Delayed 
cycle start 
date
Previous cycle
Previous cycle 
start date
Dose delay 
calculated. (days)
Reason for 
dose delay
Dose delay, 
spec.
(*) Only for SCLC (RR, R, S, VS).


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Table 12.1.2.2 Number of patients and cycles with dosing delay, any relationship.
N
%
No. of patients treated
No. of patients susceptible of delay
No. of patients with any dose delay
No. of cycles administered
No. of cycles susceptible to be delayed
No. of cycles with dosing delay
No. of patients with 
No cycles delayed
1 cycle delayed 
2 cycles delayed
3 cycles delayed
Note: Also for s1 and s2.
Table 12.1.2.3 Number of patients and cycles with dosing delay, treatment related.
N
%
No. of patients treated
No. of patients with drug related dose delay
No. of cycles administered
No. of cycles susceptible to be delayed
No. of cycles with drug related dose delay
No. of patients with 
No cycles delayed
1 cycle drug related delayed 
…..
Note: Also for s1 and s2.
Table 12.1.2.4 Reasons for dosing delay according to the relationship.
Reasons for delays
N
%
No. of patients with any dose delay
Treatment-related
X
XX.X
Hematological
Non-hematological
Both
Non-treatment-related
No. of cycles with any dose delay
N
%
Treatment-related
X
XX.X
      Hematological
      Non-hematological
      Both
Non-treatment-related
Note: Also for s1 and s2;
Table 12.1.2.5 Length of dosing delay.
Treatment-related**
Non-treatment-related
Total
Length of delay 
Median (range)
Length of delay
N
%
N
%
N
%
<= 7 days
>7 days and <=14 days
> 14 days
Note: Also for s1 and s2.
Listing 12.1.2.6 Cycle delays due to AEs.


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Patient 
id.
CTFI*
Cycle
Preferred  
term code
Adverse 
event 
reported 
(verbatim)
Grade Relationship Onset 
date
Resolved 
date
No. of days 
with delay
Action taken
Significant 
consequences
AEs with action = ‘Dose delayed’ or ‘Reduced and delayed’. (*) Only for SCLC (RR, R, S, VS).
12.1.3 Dose Reductions
The first cycle will be excluded from all calculations.
All dose reductions should be considered and described, specifying the reason for reduction 
(hematological toxicity, non-hematological toxicity or other causes). 
Listing 12.1.3.1 Dose reductions.
Patient id.
CTFI*
Cycle
Day
Cycle start date
Previous dose
Reduced dose
Reason for 
dose 
reduction
Dose 
reduction 
Spec.
(*) Only for SCLC (RR, R, S, VS).
Table 12.1.3.2 Number of patients and cycles with dose reduction, any relationship.
N
%
No. of patients treated
X
XX.X
No. of patients susceptible to have a dose reduction
No. of patients with any dose reduced
No. of patients with:
No PM01183 reduction
1 cycle with PM01183 dose reduced
2 cycles with PM01183 dose reduced
No. of cycles administered
No. of cycles susceptible to have any dose reduced
No. of cycles with PM01183 dose reduced 
Note: Also for s1 and s2.
Table 12.1.3.3 Number of patients and cycles with dose reduction, treatment related.
N
%
No. of patients treated
X
XX.X
No. of patients with any dose reduced (Treatment-related)
No. of patients with:
No PM01183 reduction
1 cycle with PM01183 dose reduced (Treatment-related)
2 cycles with PM01183 dose reduced (Treatment-related)
No. of cycles administered
No. of cycles susceptible to have any dose reduced
No. of cycles with PM01183 dose reduced (Treatment-related)
Note: Also for s1 and s2.
Table 12.1.3.4 Number of patients and cycles with dose reduction according to the relationship.


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Reasons for reductions
N
%
No. patients with reductions
Treatment-related
X
XX.X
Hematological
Non-hematological
Both
Non-treatment-related
No. of cycles patients with reductions
N
%
Treatment-related
X
XX.X
      Hematological
      Non-hematological
      Both
Non-treatment-related
Note: Also for s1 and s2.
Listing  12.1.3.5 Dose reductions due to AEs.
Patient 
id.
CTFI*
Total 
no. of 
cycles
Cycle Preferred  
term code
Adverse 
event 
reported 
(verbatim)
Grade
Relationship
Onset 
date
Resolution date
Action taken
Significant 
consequences
AEs with action = ‘Dose reduced/adjusted’ or ‘Reduced and delayed’. (*) Only for SCLC (RR, R, S, VS).
12.1.4 Temporarily Interrupted Infusions
A listing of the patients who had temporarily interrupted infusions, with the corresponding reasons, 
will be provided.
Listing  12.1.4.1  Interrupted infusions.
Patient id.
Cycle
Reason
12.1.5 Prophylactic Medication Administration 
A listing of the patients who have not received corticosterioids, 5-HT3 antagonists, prokinetics and 
other antiemetics or equivalents with the corresponding reasons will be reported.
Listing  12.1.5.1 Patients and cycles with prophylactic medication not taken per protocol.
Patient id.
Cycle
Prophylactic medication not taken*
Reason
…
(*) Corticosterioids, 5-HT3 antagonists, prokinetics and other antiemetics.
12.2 Adverse Events
12.2.1 Treatment Emergent Adverse Events
Treatment emergent adverse events will be described in this section; treatment-related events (stated 
as related to the study drug or of unknown relationship) will be tabulated. 
Type of toxicity and worst grade or severity by cycle and by patient will be summarized according to 
the Preferred Term coded with MedDRA. Tables will be organized per category of events using 
System Organ Class of MedDRA.


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Each table, listing and figure displayed in this section will have a comprehensive header identifying 
the tumor type (cohort) and the total population (if applicable).
12.2.2 Display of Treatment Emergent Adverse Events
Table 12.2.2.1 Summary of treatment emergent adverse events per patient.
Category**
N
%
Patients with at least one TEAE regardless of relationship
Any treatment-related** AE
Any grade ≥3 TEAE
Any treatment-related grade ≥3 AE
Any Treatment emergent SAE in DB
Any treatment-related SAE 
Any grade ≥3 Treatment emergent SAE 
Any treatment-related grade ≥3 SAE 
TEAEs leading to death
Treatment-related AE leading to death
TEAEs leading to dose delay***
TEAEs leading to dose reduction***
TEAEs leading to treatment discontinuation
Treatment-related AEs leading to treatment discontinuation
Note: Also for s1 and s2; (*) Percentage based on number of treated patients; (**) Treatment related adverse event is every event whose 
relationship is ‘Yes’ or ‘Unknown’. (***) TEAEs leading to dose delay and reduction according to the AE form, with no delay or 
reduction because the patient discontinues treatment and there is no additional cycle administered are not counted here.
Table 12.2.2.2 Treatment-related adverse events. Worst grade by patient.
Table 12.2.2.3 Treatment-related adverse events. Worst grade by cycle.
Table 12.2.2.4 Treatment emergent adverse events regardless of relationship. Worst grade by patient.
Table 12.2.2.5 Treatment emergent adverse events regardless of relationship. Worst grade by cycle.
Tables 12.2.2.2 to 12.2.2.5 will have the following pattern, but depending on the number and severity 
of the adverse events observed, the NCI-CTCAE v4 grades may be grouped as ≥1 and ≥3 categories.
SOC
Preferred term
Grade 
1
…
Grade 
4
Grade 
≥1
Grade 
≥3
N
%
…
N
%
N
%
Blood and lymphatic 
system disorders
Anemia NOS
...
…
Cardiac disorders
Arrhythmia NOS
…
Note: Tables 12.2.2.2 and 12.2.2.4 also for s1 and s2.
Listing 12.2.2.6 Treatment-related grade ≥3 adverse events. Worst grade per patient.
Listing 12.2.2.7 Treatment-related grade ≥3 adverse events. Worst grade by cycle.
Listing 12.2.2.8 Grade ≥3 treatment emergent adverse events regardless of relationship. Worst grade 
per patient. 
Listing 12.2.2.9 Grade ≥3 treatment emergent adverse events regardless of relationship. Worst grade 
by cycle.


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Listings 12.2.2.6 to 12.2.2.9 will have the following pattern:
Patient id.
CTFI**
Cycle*
SOC name
Preferred term
Grade
(*) NA in the per patient summaries; (**) CTFI only for SCLC patients (RR, R, S, VS).
At the time of the analysis, if appropriate, grouping of similar or clinically related AEs will be made.
12.3 Serious Adverse Events and Deaths. 
Each table, listing and figure displayed in this section will have a comprehensive header identifying 
the tumor type (cohort) or the total population (if applicable).
12.3.1 Serious Adverse Events
Listing 12.3.1.1 SAEs.
Patient 
id.
Preferred  
term code Onset cycle
Intended 
Dose of 
onset cycle
(mg/m2)
Adverse 
event 
reported 
(verbatim)
Status Grade Relationship
Onset date
Resolution
date
Action Serious criteria
The Pharmacovigilance Department will provide the narratives of the SAEs from the 
Pharmacovigilance Database (DB).
Table 12.3.1.2 Treatment-related serious adverse events. Worst grade by patient.
Table 12.3.1.3 Treatment-related serious adverse events. Worst grade by cycle.
Table 12.3.1.4 Serious adverse events regardless of relationship. Worst grade by patient.
Table 12.3.1.5 Serious adverse events regardless of relationship. Worst grade by cycle.
Tables 12.3.1.2 to 12.3.1.5 will have the following pattern, but depending on the number and severity 
of the adverse events observed, the NCI-CTCAE v4 grades may be grouped as ≥1 and ≥3 categories.
SOC
Preferred term
Grade 
1
…
Grade
4
Grade 
≥1
Grade 
≥3
N
%
…
N
%
N
%
N
%
Blood and lymphatic 
system disorders
Anemia NOS
...
…
Cardiac disorders
Arrhythmia NOS
…
Note: Tables 12.3.1.2 and 12.3.1.4 also for s1 and s2;
Listing 12.3.1.6 Treatment-related grade ≥3 serious adverse events. Worst grade per patient.
Listing 12.3.1.7 Treatment-related grade ≥3 serious adverse events. Worst grade by cycle.
Listing 12.3.1.8 Grade ≥3 serious adverse events regardless of relationship. Worst grade per patient. 
Listing 12.3.1.9 Grade ≥3 serious adverse events regardless of relationship. Worst grade by cycle.
Listings 12.3.1.6 to 12.3.1.9 will have the following pattern:
Patient id.
CTFI**
Cycle*
SOC name
Preferred term
Grade


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(*)NA in the patient summaries; (**) CTFI only for SCLC patients (RR, R, S, VS).
12.3.2 Deaths
Table 12.3.2.1 Cause of death.
Reason*
N
%
Malignant disease
Study drug-related TEAE
Non-study drug-related TEAE
Other 
Total
Note: Also for s1 and s2; (*) Denominator=Number of patients who died.
Listing 12.3.2.2 Deaths.
Patient 
id.
CTFI***
Death 
date
Cause
No. of cycles 
administered
Last
infusion 
date
Time on 
treatment*
Time from
Last dose **
Comments
Autopsy
(*) Time on treatment: defined as date of last infusion plus 30 days, or date of death or subsequent therapy (whichever comes first) 
minus date of first infusion.  (**) Time from last dose defined as date of death minus date of last infusion. (***) Only for SCLC cohort 
(RR, R, S, VS).
Listing 12.3.2.3 Adverse events with outcome of death.
Patient id. 
Cycle
Preferred  term 
code
Adverse event 
reported 
(verbatim)
Grade
Relationship
Onset 
date 
Date of death
Action
12.4
Clinical Laboratory Evaluation
Each table, listing and figure displayed in this section will have a comprehensive header identifying 
the tumor type (cohort) or the total population (if applicable).
12.4.1 Hematological Abnormalities during Treatment
Hematological toxicities classified according to the NCI-CTCAE will be calculated for all cycles. The 
worst grade reached by each patient during treatment will also be calculated.
Table 12.4.1.1 Hematological abnormalities, worst grade per patient.
Table 12.4.1.2 Hematological abnormalities, worst grade per cycle.
Tables 12.4.1.1 and 12.4.1.2 will have the following pattern but depending on the number and severity 
of the adverse events observed, the NCI-CTCAE v4 grades may be grouped as ≥1 and ≥3 categories.
Grade 
1
…
Grade 
4
Grade 
≥1
Grade 
≥3
N
%
…
N
%
N
%
N
%
Anemia
Leukopenia
Neutropenia 
Lymphopenia
Thrombocytopenia


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Note: Tables 12.4.1.1 and 12.4.1.2 also for s1 and s2.
Listing 12.4.1.3 Grade ≥3 hematological abnormalities. Worst grade per patient.
Patient id.
Test
Grade
Listing 12.4.1.4 Grade ≥3 hematological abnormalities. Worst grade per cycle.
Patient id.
Cycle
Test
Grade
Listing 12.4.1.5 Hematological tests not assessed by patient and cycle.
Patient id.
Total number of cycles
Cycle with missing lab. test
Lab. test
12.4.2 Biochemical Abnormalities during Treatment
Table 12.4.2.1 Biochemical abnormalities, worst grade per patient.
Table 12.4.2.2 Biochemical abnormalities, worst grade per cycle.
Tables 12.4.2.1 and 12.4.2.2 will have the following pattern but depending on the number and severity 
of the adverse events observed, the NCI-CTCAE v4 grades may be grouped as ≥1 and ≥3 categories.
Grade 
1
…
Grade 
4
Grade 
≥1
Grade 
≥3
N
%
…
N
%
N
%
N
%
AST increased
ALT increased
Total bilirubin increased
AP increased
Hyperglycemia
Hypoglycemia
…
Note: Tables 12.4.2.1 and 12.4.2.2 also for s1 and s2.
Listing 12.4.2.3 Grade ≥3 biochemical abnormalities. Worst grade per patient.
Patient id.
Test
Grade
Listing 12.4.2.4 Grade ≥3 biochemical abnormalities. Worst grade per cycle.
Patient id.
Cycle
Test
Grade
Listing 12.4.2.5 Biochemical tests not assessed by patient and cycle.
Patient id.
Total number of cycles
Cycle with missing lab. test
Lab. test
12.4.3 Coagulation Abnormalities during Treatment
Table 12.4.3.1 Coagulation abnormalities, worst grade per patient.
Table 12.4.3.2 Coagulation abnormalities, worst grade per cycle.


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Tables 12.4.3.1 and 12.4.3.2 will have the following pattern but depending on the number and severity 
of the adverse events observed, the NCI-CTCAE v4 grades may be grouped as 1-3 category.
Grade 
1
…
Grade 
3
Grade 
≥1
Grade 
≥3
N
%
…
N
%
N
%
N
%
INR increased
APTT prolonged
Listing 12.4.3.3 Grade 3 coagulation abnormalities. Worst grade per patient.
Patient id.
Test
Grade
Listing 12.4.3.4 Grade 3 coagulation abnormalities. Worst grade per cycle.
Patient id.
Cycle
Test
Grade
Listing 12.4.3.5 Coagulation tests not assessed by patient and cycle.
Patient id.
Total number of cycles
Cycle with missing lab. test
Lab. test
12.4.4 Laboratory Values over Time
Table 12.4.4.1 Evolution of hematological abnormalities from baseline, worst case per patient.
Table 12.4.4.2 Evolution of hematological abnormalities from baseline, worst case in the first cycle 
per patient.
Table 12.4.4.3 Evolution of biochemical abnormalities from baseline, worst case per patient.
Table 12.4.4.4 Evolution of biochemical abnormalities from baseline, worst case in the first cycle per 
patient.
Tables 12.4.4.1 to 12.4.4.4 will have the following pattern:
Baseline grade*
Worst grade per patient
Total
0
1
…
N
%
N
%
N
%
N
%
Baseline
Parameter 1
Grade 0
Grade 1
……
Parameter 2
Grade 0
Grade 1
……
….
Grade 0
Grade 1
……
(*) Defined as the last value recorded before or on the date of first infusion.
Table 12.4.4.5 Platelet count time course pattern (summary).
Table 12.4.4.6 Neutrophil count time course pattern (summary).
Tables 12.4.4.5 and 12.4.4.6 will have the following pattern:


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All cycles
First cycle
N, Mean, Std., Median, 
Range
N, Mean, Std., Median, Range
Grade ≥3* onset day
Nadir (x109/L)
Duration of grade ≥3 (days)
Day of recovery to grade 1/2 or baseline values**
(*) Grade 3 or 4; (**) grade 2 or less.
Table 12.4.4.7 AST time course pattern (summary).
Table 12.4.4.8 ALT time course pattern (summary).
Tables 12.4.4.7 and 12.4.4.8 will have the following pattern:
All cycles
First cycle
N, Mean, Std., Median, 
Range
N, Mean, Std., Median, Range
Grade ≥3* onset day
Peak (xULN)
Duration of grade ≥3 (days)
Day of recovery to grade 1/2 or baseline values**
(*) Grade 3 or 4; (**) grade 2 or less.
12.5 Physical Findings, PS, LVEF, ECG and Other Tests
Each table, listing and figure displayed in this section will have a comprehensive header identifying 
the tumor type (cohort) or the total population (if applicable).
12.5.1 Physical Findings and PS (ECOG)
Listing 12.5.1.1 ECOG performance status during the study.
(*) Worst ECOG PS score of the cycle determinations.
Listing 12.5.1.2 Weight by patient per cycle.
(*) % of changes compared to baseline.
Cycle/ECOG PS*
0
1
2
3
4
…
EOT
Patient id.
…
…
Cycle/Weight
0
(kg)
1*
(%)
2*
(%)
3*
(%)
4*
(%)
…*
(%)
EOT*
(%)
Patient id.
…


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12.5.2 LVEF, ECG and Other Related Tests
Listing 12.5.2.1 Patients with abnormal or clinical indicated LVEF during the study.
Patient 
id.
Assessment 
date
Abnormality
Specify
Reason for 
clinically 
indicated 
Method
LVEF (%)
Institution 
normal range
Listing 12.5.2.2 Patients with abnormal or clinical indicated Electrocardiogram during the study.
Patient 
id.
Assessment 
date
Result
Specify
Reason 
for 
clinically 
indicated 
repeat
PR 
interval 
(msec)
Heart rate 
(bpm)
QT 
interval 
(msec)
QRS 
complex 
(msec)
QTc 
Fridericia
QTc*
(Bazett’s)
(*) QTc (Bazett’s) = QT interval / √(60/Heart rate).
12.6 Concomitant Therapy / Procedures According to the ATC Classification.
Each table, listing and figure displayed in this section will have a comprehensive header identifying 
the tumor type (cohort) or the total population (if applicable).
Table 12.6.1 Concomitant medication during treatment (ATC1/ATC2/ATC3/ATC4/PN).
Concomitant medication 
N
%
Alimentary tract and metabolism
   Antacids
      Magnesium compounds
          Magnesium adipate
…
Blood and blood forming organs
   Antithrombotic agents
      Vitamin K antagonists
          Acenocoumarol
…
Table 12.6.2 Summary of concomitant medication during treatment.
N
%
No. of systems (ATC1 level)
0
1
2
3
Mean, Standard Deviation, Median (Range) 
No. of indications (ATC2 level)
0
1
2
3
Mean, Standard Deviation, Median (Range)
No. of agent families (ATC4 level)
0
1
2
3


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Mean, Standard Deviation, Median (Range)
No. of agents (PN level)
0
1
2
3
Mean, Standard Deviation, Median (Range)
Table 12.6.3 Patients and cycles with any transfusions/GCSF during treatment.
N
%
No. of patients with Platelet transfusions 
No. of cycles with Platelet transfusions
No. of patients with RBC
No. of cycles with RBC
No. of patients with GCSF
Note: Also for s1 and s2.
Listing  12.6.4 Patients with any transfusion during treatment.
Patient id.
Cycle
PM1183 
dose in the 
previous 
cycle
Platelets / 
RB
Date of first 
transfusion
Date of last transfusion
No. of units required*
(*) No. of transfusions for platelets or No. of packed RBC transfusions.
Listing  12.6.5 Patients with GCSF during treatment.
Patient id.
Cycle
Date
Medication
Reason
Specify
12.7 Subsequent therapy.
Table 12.7.1 Any Subsequent medical therapy.
N
%
Type
  Medical therapy
Radiotherapy
Surgery
Number of subsequent medical therapies (Median and range)
0
1
2
…
Subsequent agents of medical therapy (ATC)
  …
   …
Note: Also for s1 and s2.
Table 12.7.2 First Subsequent medical therapy.
N
%
Subsequent chemotherapy agents (ATC)
  …
   …
Note: Also for s1 and s2.
Table 12.7.3 First Subsequent medical therapy. Best response (if available).
Best response
First Subsequent therapy


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CR
PR
SD
PD
NE
PM01183
CR
PR
SD
PD
NE
Note: Also for s1 and s2; (*) If a low number of best responses to the subsequent therapy are available, a listing, instead of this table, 
will be provided. In case of sufficient number of subsequent Immunotherapy, a separate table/listing will be performed for patients 
having immunotherapy as first subsequent therapy.
Table 12.7.4 First Subsequent medical therapy. PFS (if available).
PFS (months)
First Subsequent therapy
<1 month
[1-3) months
[3-6) months
[6-12) months
≥12 months
PM01183
<1 month
[1-3) months
[3-6) months
[6-12) months
≥12 months
Note: Also for s1 and s2;
Any other exploratory analyses will be performed at the analysis time if any relevant variable will be 
considered potentially relevant. Table’s layout will follow the same prior patterns.  


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12.8 Subgroup Analyses Related to Safety.
Table 12.8.1 Worst grade ≥3 by patient in special subgroups (Sex).
Table 12.8.2 Worst grade ≥3 by cycle in special subgroups (Sex).
Table 12.8.3 Worst grade ≥3 by patient in special subgroups (Age*).
Table 12.8.4 Worst grade ≥3 by cycle in special subgroups (Age*).
Table 12.8.5 Worst grade ≥3 by patient in special subgroups (Race).
Table 12.8.6 Worst grade ≥3 by cycle in special subgroups (Race).
Table 12.8.7 Worst grade ≥3 by patient in special subgroups (Number of prior lines*).
Table 12.8.8 Worst grade ≥3 by cycle in special subgroups (Number of prior lines*).
Table 12.8.9 Worst grade ≥3 by patient in special subgroups (BSA*).
Table 12.8.10 Worst grade ≥3 by cycle in special subgroups (BSA*).
Table 12.8.11 Worst grade ≥3 by patient in special subgroups (ECOG).
Table 12.8.12 Worst grade ≥3 by cycle in special subgroups (ECOG).
Table 12.8.13 Worst grade ≥3 by patient in special subgroups (Geographical area*).
Table 12.8.14 Worst grade ≥3 by cycle in special subgroups (Geographical area*).
Table 12.8.15 Worst grade ≥3 by patient in special subgroups (AAGP*).
Table 12.8.16 Worst grade ≥3 by cycle in special subgroups (AAGP*).
Tables 12.8.1 to 12.8.16 will have the following pattern:
Laboratory abnormalities/ drug-
related AEs
Subgroup 1
Subgroup 2
….
No. of 
patients/cycles
evaluated
Grade 
≥3
%
No. of 
patients/cycles
evaluated
Grade 
≥3
%
No. of 
patients/cycles
evaluated
Grade 
≥3
%
Thrombocytopenia
Neutropenia 
AP 
Bilirubin 
AST 


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Laboratory abnormalities/ drug-
related AEs
Subgroup 1
Subgroup 2
….
No. of 
patients/cycles
evaluated
Grade 
≥3
%
No. of 
patients/cycles
evaluated
Grade 
≥3
%
No. of 
patients/cycles
evaluated
Grade 
≥3
%
ALT 
CPK
Nausea
Vomiting
Fatigue
Other**
(*) Categories Age (<65 yrs vs >=65 yrs); Number of prior lines (1 line vs >=2 lines); BSA (=< 1.8 m2 vs. > 1.8 m2) Geographical area 
(Europe vs US); Alpha-glycoprotein (ULN<= vs >ULN). (**)Any drug-related toxicity present in >=5% of patients in any group.


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13 Figures
Figures displayed in this section will have a comprehensive header identifying the tumor type (cohort) 
or the total population (if applicable) and/or any other specific subgroups (e.g: CTFI categorized). See 
examples below, numbering will be updated accordingly.
Figure 13.1.1 Waterfall graph by subgroup.
Waterfall for each tumor type will be also provided. Also SCLC by CTFI (RR, R, S VS).
Figure 13.1.2 Waterfall graph by IRC (SCLC cohort).
Waterfall for SCLC and by CTFI (RR, R, S VS).
NOTE: If the measurements of the first and the second radiologists are the same, the target lesions measurements of the first one will be 
selected. If the measurements of both radiologists are different and an adjudicator is involved, his/her endorsement will be selected. 


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Figure 13.1.3 Pattern of hematological/non-hematological abnormalities per tumor type.
Hematological abnormalities include neutrophils and platelets; non-hematological abnormalities include AST and ALT.
Figure 13.1.4 Best response, PFS and Reasons for discontinuation (SCLC cohort).
Also for s1 and s2. 


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Figure 13.1.5 Last previous TTP vs PFS PM01183 (SCLC cohort).
Note: For PM01183 responders and/or SD (if applicable)
Figure 13.1.6 Last previous Immunotherapy TTP vs PFS PM01183 (SCLC cohort).
Figures described in Section 11.3 Efficacy Analysis will have the following patterns depending on 
the number of groups represented:


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APPENDIX II
14 DB Listings, BIMO and ICH listings
CRF Listings.
Listing 14.1.1: Cover.
Patient id.
Informed Consent Date
Part of QT
substudy?
QT informed
consent
date
Patient
QT inclusion
accepted
by Pharmamar?
PGN/PGx
consent
PGN/PGx
date
Listing 14.1.2: Study registration.
Patient id.
Patient inclusion accepted by Pharmamar?
Eligibility requirements?
Criterion identifier I/E
I/E details
Listing 14.1.3: Demography.
Patient id.
Age at inclusion
Gender
Race
Other Race, specify
Listing 14.1.4: Pregnancy test and adequate contraception.
Pregnancy test
Adequate contraception
Patient id.
Visit
Not
applicable?
Reason
Not 
done?
Sample 
date
Result
Reason 
for 
clinically 
indicated 
repeat
Adequate 
contraception?
Specify
Listing 14.1.5: Prior medical history.
Patient id.
Event/Condition
System
Organ
Class
MedDRA
Preferred
Term
Onset date
End date
Ongoing?
Listing 14.1.6: Cancer history.
Current stage 
At diagnosis
Patient 
id.
Tumor 
type
….*
Date of 
advanced/metastasic 
disease
Date of 
last PD
Sites:Primary
tumor/local relapse
(Not for UPS)
Sites**
Diagnosis 
date
Stage
TNM
(*) For each tumor type CRF has specific categories. e.g: Endometrial patients; (Carcinoma type, Histology type, Other) 
(**)Tumor sites are nested for each patient obtained from Cancer History Form e.g: (Lung/Liver/LN:/Neck LN/Mediastinal LN); 
Listing 14.1.7: Prior surgery.
Patient id.
None?
Site and Procedures
Date
Intention
Listing 14.1.8: Prior radiotherapy.
Patient id.
None?
Type
Intention
Site
Total dose
First dose
Last dose
Listing 14.1.9: Prior medical therapy.
Patient id.
None?
Regimen
Setting
Agent
Agent
Agent Class
Setting
Start Date
Stop Date
Best
Prog. Date
Non PD


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Coded
Resp.
Listing 14.1.10: Hematological laboratory values.
Patient 
id.
Visit
Date
n
Clinically 
indicated 
repeat 
required?
Hemoglobin 
(g/dl)
Platelets 
(x10*9/L)
WBC 
(x10*9/L)
Neutrophils 
(x10*9/L)
Lymphocytes 
(x10*9/L)
Monocytes 
(x10*9/L)
Listing 14.1.11: Biochemical laboratory values.
Patient 
id.
Visit
Date
n
Clinically 
indicated 
repeat 
required?
Total Bilirubin 
(mg/dl)
Direct Bilirubin 
(mg/dl)
AST 
(IU/L)
ALT 
(IU/L)
AP 
(IU/L)
…..*
(*) GGT (IU/L), Glucose (mmol/L), Creatinine (mg/dl), CrCl (mL/min), NA (mmol/L), CL (mmol/L), K (mmol/L), LDH (IU/L), CPK 
(IU/L), Total Proteins (g/dl), Albumin (g/dl), CA (mmol/L), Mg (mg/dl), AFP (ng/m), hCG (IU/L).
Listing 14.1.12: Alpha Glycoprotein.
Patient id.
Visit
Date
n
Alpha-1-acid glycoprotein 
(MG/DL)
Comments 1
Comments 2
Listing 14.1.13: Coagulation laboratory values.
Patient id.
Visit
Date
n
Clinically indicated 
repeat required?
INR (ratio)
PT (sec/ratio)
PTT 
(sec/ratio)
Listing 14.1.14: Physical examination.
Patient id.
Visit
Not done
Date
Abnormalities
Weight
(Kg)
Height
(cm)
BSA
(m2)
Body System
Findings
Clinical Significance
Listing 14.1.15: Performance status.
Patient id.
Not Done 
Visit
ECOG
Listing 14.1.16: Vital signs.
Patient id.
Not done
Visit 
Date
Heart Rate
(BPM)
Systolic
(mmHG)
Diastolic
(mmHG)
Temperature 
(ºC)
Listing 14.1.17: Electrocardiogram.
Patient 
id.
Not 
done
Visit
ECG 
Date
Result
Abnormal, 
specify
PR
Interval(msec)
Heart 
rate 
(bpm)
QT
Interval(msec)
QRS
Interval(msec)
Corrected 
QT
Fridericia
Listing 14.1.18: LVEF.
Patient id.
Not done
Visit
LVEF Date
Type
Value
Range
Result
Abnormal, specify
Reason for clinically indicated
Listing 14.1.19: Prophylactic medication.
Patient 
Visit
Medication
Drug 
...*
Route
Daily 
Units
Start 
End 
Time
Taken per 
Specify


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id.
Type
Dose
date
date
protocol
(*) ATC1, ATC2, ATC3, ATC4.
Listing 14.1.20: Drug administration.
Reductions
Delays
Patient 
id.
Visit
Admin. 
date
Start 
time
End 
time
Intended  
dose
Total 
dose
Adm. 
Volume
Dose  
reduced?
Reason
Dose 
delayed?
Reason
Dose 
interrupted?
Listing 14.1.21: Adverse events (including adverse events at baseline).
Patient 
id.
Adverse 
Event 
Verbatim
NCI-
CTC 
Grade
SAE
Onset 
cycle
Onset 
date
Ongoing
End 
cyc.
End 
date
Ongoing/
Continuing
Relationship 
Specify
Action
taken
Seriousness 
Criteria
Listing 14.1.22: Concomitant therapy/procedures.
Patient id.
Medication  
type
Medication
Reason
…*
Route/Dose(Units)/Time 
interval
Start 
date
End 
date
Indication
AE
Other
(*) ATC1, ATC4
Listing 14.1.23: Tumor assessment.
Target
Non target
New lesions
Patient
id.
…..*
Sum of
Diameters
Var.(%)
….*
Response
…*
Longest diameter
Non-measurable
(*) Visit, Not done, lesion, organ site, date, method. Sort by Visit and then by Start date,
Listing 14.1.24: Evaluation of response by cycle.
Patient id.
Visit
Not done?
Date
Response 
Target lesions
Response 
Non Target 
Lesions
New lesions?
Overall cycle response
Listing 14.1.25: Best study overall response by IA and IRC and End of treatment.
Patient id.
CTFI*
Best Response by 
IA**
Best Response by IRC*
End of treatment 
Reason
End of treatment, Specify
(*) Only for SCLC cohort. (**) Data obtained from radiological assessment of response in the CRF
Listing 14.1.26: Follow up.
Patient 
id.
Follow-
up date
Survival 
status
Previous 
PD 
or 
Therapy
TA 
Done
Reason
Type of 
therapy
Start 
date
End 
date
Treatment*
Best 
response**
Progression date**
(*) Procedure for surgery, localization for radiotherapy or agent for medical therapy.
(**) Only for Medical therapy. Sort by FU date first and then by Start date.
Listing 14.1.27: Off study and Death report form.
Off study
Death report
Patient id.
Off study 
Reason
If other 
Specify
Off study date
Best response
Death 
Date
Cause
Specify
Autopsy?


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Listing 14.1.28: Investigator comments and Investigator comments before end of study.
Patient id.
Page name
Instance
Variable
Comment
To fulfil the Office of Scientific Investigations (OSI) request, the items described in the draft 
Guidance for Industry Standardized Format for Electronic Submission of NDA and BLA Content for 
the Planning of Bioresearch Monitoring (BIMO) Inspections for CDER Submissions (February 2018) 
and the associated Bioresearch Monitoring Technical Conformance Guide Containing Technical 
Specifications will be provided following the recommended standardized formats.
https://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/FormsSubmissionRequirement
s/UCM332466.pdf
https://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/FormsSubmissionRequirement
s/UCM332468.pdf.
Listing 15.1 Site Level Summary.
Site
Patients Screened
Patients Treated
Patients End of 
Treatment
Patients Off Study
Listing 15.2 Consented Subjects by Site.
Site
Patient id.
Informed
Consent date
Screening
failure?
Date of 
Screening failure
Met
Eligibility
Criterion
Identifier
Details
Treated
Date of
First
treatment
Listing 15.3 Treatment Assignment by Site.
Site
Patient id.
DA Start date
First Intended dose
Listings 15.4 Discontinuations by Site.
Site
Patient id.
End of treatment Reason
End of treatment, Specify
Off study 
date
Off study 
Reason
If other 
Specify
Listings 15.5 Study Population by Site.
Site
Patient id.
Included population
Treated population
Reason
Evaluable population
Reason
Listings 15.6 Inclusion and Exclusion Criteria by Site.
Site
Patient id.
Eligibility requirements?
Criterion identifier I/E
I/E details
Listings 15.7 Adverse Events by Site.
Site
Patient 
id.
Adverse 
Event 
Verbatim
NCI-
CTC 
Grade
SAE
Onset 
cycle
Onset 
date
End 
cyc.
End 
date
Relationship 
Specify
Action
taken
Seriousness 
Criteria
Listings 15.8 Protocol Deviations by Site.


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Site
Patient id.
Deviation type
Deviation
Listings 15.9 Efficacy Endpoints by Site.
Site
Patient id.
Best 
response 
by IA
Best 
response 
by IRC
PFS by IA 
(months)
PFS by IRC 
(months)
DOR by IA 
(months)
DOR by IA 
(months)
OS
(months)
Death 
status
Listings 15.10 Concomitant Medications by Site.
Site
Patient 
id.
Medication  
type
Medication
Reason
…*
Route/Dose(Units)/Time 
interval
Start 
date
End 
date
Indication
(*) ATC1, ATC4
Listings 15.11.1 Laboratory measurements by Site.
Site
Patient 
id.
Visit Date Laboratory Hemoglobin 
(g/dl)
Platelets 
(x10*9/L)
WBC 
(x10*9/L)
Neutrophils 
(x10*9/L)
Lymphocytes 
(x10*9/L)
Monocytes 
(x10*9/L)
…..*
(*) Total Bilirubin, Direct Bilirubin in (mg/dl), AST, ALT, AP, GGT in (IU/L), Glucose (mmol/L), Creatinine (mg/dl), CrCl (mL/min), 
NA (mmol/L), CL (mmol/L), K (mmol/L), LDH (IU/L), CPK (IU/L), Total Proteins (g/dl), Albumin (g/dl), CA (mmol/L), Mg (mg/dl),
INR (ratio), PT (sec/ratio), PTT (sec/ratio) AFP (ng/m), hCG (IU/L), AAGP (mg/dl).
Listings 15.11.2 Electrocardiogram by Site.
Site
Patient 
id.
Not 
Done
Visit
Date
Results
Abnormal, 
Specify
PR
interval 
(msec)
Heart rate
(bpm)
QT Interval
(msec)
QRS 
interval
(msec)
Corrected QT 
Fridericia
Listings 15.11.3 LVEF by Site.
Site
Patient 
id.
Not 
Done
Visit
Date
Method
LVEF (%)
Range 
Lowe 
Limit
Abnormality
Specify
Reason for Clinically 
Indicated Repeat
In accordance with ICH E-3 guidelines, the patient listings specified as Section 16.2 will be prepared by 
tumor type and for the total of patients.
Listing 16.2.1 Discontinued Patients.
Patient id.
Institution
Treated
Cycles 
received
First infusion 
date
Last infusion 
date
Reason for end of 
treatment
Comments
Listing 16.2.2 Protocol Deviations.
Patient id.
Type
Description
Listing 16.2.3 Patients Not Included in the Efficacy Analysis.
Patient id.
Non evaluable reason


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Listing 16.2.4 Demographic Data.
Patient 
id.
Tumor 
type
Histology
type*
Stage*
Age/Gender
ECOG
Weight 
(kg)
Height 
(cm)
BSA 
(m2)
Prior 
Radiotherapy
Prior agents for 
the
treatment
(*)At diagnosis.
Listing 16.2.5 Compliance and/or Drug Concentration Data.
Patient id.
Drug
First
Intended 
dose
(mg/m2)
Cycles 
received
Start date 
(First 
cycle)
Start date 
(Last 
cycle)
Total dose 
(mg/m2)
Dose intensity 
per week 
(mg/m2/wk)
Relative 
Dose 
intensity  
(%)
Delays*
Reductions*
(*) Delays/reductions will be nested for each patient (cycle and reasons of delay/reduction). e.g: C1 hematological toxicity/C3 non drug 
related.
Listing 16.2.6 Individual Efficacy Response Data.
Patient id.
Best Response by 
IA
Best Response by 
IRC*
PFS by IA 
(months)
PFS by 
IRC*
(months)
DOR by 
IA 
(months)
DOR by 
IRC*
(months)
OS (months)
(*) Only for SCLC
Listing 16.2.7 Adverse Event Listing.
Patient id.
Literal
Preferred Term
Grade 
Coded 
Value
SAE
Onset date
Resolved 
date
Relationship
Action taken
Serious criteria
Listing 16.2.8 Listing of Individual Laboratory Measurements by Patient.
Hemoglobin
(g/dL)
WBC
(10*9/L)
Neutrophils
(10*9/L)
Lymphocytes
(10*9/L)
…*
Patient id.
Cycle
Examination
date
Laboratory
Std.value
Std.value
Std.value
Std.value
Std.value
(*) Monocytes (x10*9/L), Direct Bilirubin (mg/dl),Total Bilirubin (mg/dl), AST IU/L),  ALT (IU/L)  AP (IU/L), GGT (IU/L), Glucose 
(mmol/L), Creatinine (mg/dl), CrCl (mL/min), NA (mmol/L), CL (mmol/L), K  (mmol/L), LDH (IU/L), CPK (IU/L), Total Proteins 
(g/dl), Albumin (g/dl), CA (mmol/L), Mg (mg/dl), INR (ratio), PT (sec/ratio), PTT (sec/ratio), AFP (ng/m), hCG (IU/L), AAGP (mg/dl).


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15 SAP VERSION HISTORY
15.1
SAP version history v1.0
After the first version of the SAP was approved by the responsible physician, the medical writer and 
the biostatistics manager, a new protocol "substantial amendment No. 4 and No 5" were included; 
therefore the SAP has been updated (highlighted in italic bold) in accordance with the new version 
(version 2) of the protocol as follows:

Cohorts of SCLC and Endometrial carcinoma patients are expanded up to 100 and 50 patients, 
respectively. 

A QT evaluation study in a subset of sites of this clinical trial PM1183-B-005-14 was also 
performed. A specific CSR including its SAP was built to analyse it but some tables and listings 
excluded from the SAP of the QT substudy that are common to the main study were moved and 
will be displayed in the main study PM1183-B-005-14. With regards to the specific QT substudy 
data, if any relevant data differences occurred after the data cut-off date of the QT study and 
main study cut-off, these changes will be displayed in a new Appendix III using the original 
format and numbering specified in the QT substudy SAP.

Some minor changes and corrections have been done in the text and the mock shells to allow a 
clear and unambiguous communication of the science and statistics of the trial.
Summary of proposed changes by section:
Section 2: Study rationale
Original text:

……. In a phase II clinical trial of PM01183 as single agent in MBC, one of 17 patients with 
germline BRCA 1/2 mutation had a complete response (6%) and six had partial response (35%). 
Six additional patients had disease stabilization (35%). One patient with H&N carcinoma treated 
with PM01183 as single agent at 2.6 mg/m2 q3wk achieved disease stabilization for 4 months. 
Changes to:

…….. In a phase II clinical trial of PM01183 as single agent in MBC, two of 54 patients with 
germline BRCA 1/2 mutation had a complete response (3.7%) and 20 patients had partial response 
(37%). Twenty-three additional patients had disease stabilization (43%). One patient with H&N 
carcinoma treated with PM01183 as single agent at 2.6 mg/m2 q3wk achieved a disease 
stabilization of 4 months duration.
Section 2: Study design
Original text:
Patients with each of the aforementioned tumors will be enrolled in nine cohorts. Up to 25 evaluable 
patients are planned to be enrolled in each cohort. To consider that PM01183 has antitumor activity in 


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any of the tumor types analyzed, at least two confirmed responses [complete (CR) or partial response 
(PR)] per RECIST v.1.1 out of the 25 patients of each cohort are expected.

If no confirmed responses are observed in the first 15 evaluable patients of each cohort, the 
recruitment of the corresponding cohort will be stopped.

If one confirmed response is observed in the first 15 evaluable patients of each cohort, the 
recruitment of this cohort will continue to up to 25 evaluable patients.
…..
Changes to:
Patients with each of the aforementioned tumors will be enrolled in nine cohorts. Up to 25 evaluable 
patients are planned to be enrolled in each cohort (50 in the endometrial carcinoma and 100 in the 
SCLC cohort). To consider that PM01183 has antitumor activity in any of the tumor types analyzed, 
at least two confirmed responses [complete (CR) or partial response (PR)] per RECIST v.1.1 out of 
the 25 patients of each cohort are expected.

If no confirmed responses are observed in the first 15 evaluable patients of each cohort, the 
recruitment of the corresponding cohort will be stopped.

If one confirmed response is observed in the first 15 evaluable patients of each cohort, the 
recruitment of this cohort will continue to up to 25 evaluable patients.
o
In the cohort of endometrial carcinoma, if ≥2 confirmed responses occur in the first 
25 evaluable patients, the sample size will be doubled to 50 evaluable patients. 
o
In the cohort of SCLC, if ≥2 confirmed responses occur in the first 25 evaluable 
patients, the sample size will be increased to 100 evaluable patients. 
….
Section 3.2: Secondary objectives
Original text:

To further characterize the antitumor activity of PM01183 in terms of duration of response 
(DR), clinical benefit [ORR or stable disease (SD) lasting over four months (SD ≥ 4 
months)], PFS, and one-year overall survival (1y-OS) in each cohort of advanced solid tumors.
Changes to:

To further characterize the antitumor activity of PM01183 in terms of duration of response 
(DR), clinical benefit [ORR or stable disease (SD) lasting over four months (SD ≥ 4 
months)], PFS, and one-year overall survival (1y-OS) in each cohort of advanced solid tumors 
[overall survival (OS) in the cohort of SCLC patients].
Section 3.3: Endpoints (Secondary endpoints)
Original text:

Clinical Benefit, defined as ORR or stable disease lasting over four months (SD ≥ 4 months).


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
OS6/OS12, defined as the Kaplan-Meier estimates of the probability of being alive after the 
first infusion at these time points (6 and 12 months). 
Changes to:

OS6/OS12, defined as the Kaplan-Meier estimates of the probability of being alive after the 
first infusion at these time points (6 and 12 months) (overall survival in the cohort of SCLC
patients).

Clinical Benefit, defined as ORR response or stable disease lasting over four months (SD ≥ 4 
months).
Section 5.1: Sample size
Original text:
Up to 25 evaluable patients in each tumor type will be recruited to test the null hypothesis that 1% or 
less patients get a response (p ≤ 0.01) versus the alternative hypothesis that 10% or more patients get a 
response (p ≥ 0.10). The variance of the standardized test is based on the null hypothesis. The type I 
error (alpha) associated with this one-sided test is 0.025 and the type II error (beta) is 0.2; hence, 
statistical power is 80%. With these assumptions, if the number of patients who achieve a confirmed 
response is ≥ 2, then this will allow the rejection of the null hypothesis.
An interim analysis to reject H0 (non-binding) or to reject H1 (futility) in each tumor type is planned 
after the recruitment of 15 evaluable patients in each cohort. The Gamma family boundary will be 
used to control the type I error, the parameter to reject H0 is fixed as -1 and the parameter to reject H1 
is fixed as 0. If none of the first 15 evaluable patients in a specific cohort has a confirmed response, 
the alternative hypothesis will be rejected, according to boundaries and sample size assumptions, and 
recruitment will be stopped. If the number of responding patients is already two or more at the interim 
analysis, then H0 could be rejected and the study will have enough power to be stopped. On the 
contrary, if there is one confirmed response, the recruitment will be continued to up to 25 evaluable 
patients.
Changes to:
Up to 25 evaluable patients in each tumor type will be recruited to test the null hypothesis that 1% or 
less patients get a response (p ≤ 0.01) versus the alternative hypothesis that 10% or more patients get a 
response (p ≥ 0.10). The variance of the standardized test is based on the null hypothesis. The type I 
error (alpha) associated with this one-sided test is 0.025 and the type II error (beta) is 0.2 (normal 
approximation; ~0.3 if exact binomial distribution); hence, statistical power is 80% (normal 
approximation; ~70% if exact binomial distribution). With these assumptions, if the number of 
patients who achieve a confirmed response is ≥ 2, then this will allow the rejection of the null 
hypothesis.
An interim analysis to reject H0 (non-binding) or to reject H1 (futility) in each tumor type is planned 
after the recruitment of 15 evaluable patients in each cohort. The Gamma family boundary will be 
used to control the type I error, the parameter to reject H0 is fixed as -1 and the parameter to reject H1 
is fixed as 0. If none of the first 15 evaluable patients in a specific cohort has a confirmed response, 
the alternative hypothesis will be rejected, according to boundaries and sample size assumptions, and 
recruitment will be stopped. If the number of responding patients is already two or more at the interim 


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analysis, then H0 could be rejected and the study will have enough power to be stopped. On the 
contrary, if there is one confirmed response, the recruitment will be continued to up to 25 evaluable 
patients.

A phase III trial of PM01183 combined with doxorubicin in SCLC is ongoing. Hence, the 
sample size for the SCLC cohort of this study will be increased to 100 evaluable patients if 
the success boundary (≥2 confirmed responses) is reached in the first 25 evaluable patients. 
The type I/II error will be controlled with a Gamma family boundary (-1 to reject Ho, 0 to 
reject H1).
Based on the newly available information, additional patients will be recruited to test the 
null hypothesis that 15% or less patients get a response (p ≤ 0.15) versus the alternative 
hypothesis that 30% or more patients get a response (p ≥ 0.30). The variance of the 
standardized test is based on the null hypothesis. The type I error (alpha) associated with 
this one-sided test is 0.025 and the type II error (beta) is 0.051 (normal approximation; 
~0.05 if exact binomial distribution); hence, statistical power is 95% (normal 
approximation; ~95% if exact binomial distribution). With these assumptions, if the number 
of patients who achieve a confirmed response is ≥ 23, then this would allow the rejection of 
the null hypothesis.

A phase I trial of PM01183 combined with doxorubicin has shown encouraging antitumor 
activity in endometrial carcinoma. Hence, the sample size for the endometrial carcinoma 
cohort of this study will be doubled to 50 evaluable patients if the success boundary (≥2 
confirmed responses) is reached in the first 25 evaluable patients. The type I/II error will be 
controlled with a Gamma family boundary (-1 to reject Ho, -3 to reject H1).
Based on the newly available information, additional patients will be recruited to test the 
null hypothesis that 10% or less patients get a response (p ≤ 0.10) versus the alternative 
hypothesis that 25% or more patients get a response (p ≥ 0.25). The variance of the 
standardized test is based on the null hypothesis. The type I error (alpha) associated with 
this one-sided test is 0.025 and the type II error (beta) is 0.144 (normal approximation; 
~0.16 if exact binomial distribution); hence, statistical power is ~86% (normal 
approximation; ~84% if exact binomial distribution). With these assumptions, if the number 
of patients who achieve a confirmed response is ≥ 10, then this would allow the rejection of 
the null hypothesis.
With the sample size of 100 and 50 evaluable patients in each indication (SCLC and endometrial), 
the obtained confidence interval will be narrower and its half-width will be confined to ±15%.
Section 8.11: Subgroup analysis
Original text adds:
Specific subgroup efficacy analysis will be done for all Evaluable patients with SCLC by CTFI (< 
90 days and ≥ 90 days).
Section 8.13: Interim and Group Sequential Analyses


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Original text adds:
In particular, in the SCLC and endometrial carcinoma cohorts, the analysis at 25 evaluable 
patients will serve as second interim analysis to decide the continuation of recruitment. Two 
objective responses will be required to expand the accrual up to 100 and 50 evaluable patients 
respectively. 

For the SCLC cohort, the type I/II error will be controlled with a Gamma family boundary 
(-1 to reject Ho, 0 to reject H1)  

For the endometrial carcinoma cohort, the type I/II error will be controlled with a Gamma 
family boundary (-1 to reject Ho, -3 to reject H1)  
Section 11.3: Efficacy Analysis
Original text:
Efficacy analysis will be carried out on the “All Evaluable Patients” population.
Each table, listing and figure displayed in this section will have a comprehensive header identifying 
the tumor type (cohort) or the total population (if applicable).
Changes to:
Efficacy analysis will be carried out on the “All Evaluable Patients” population and for all 
“Evaluable Patients” with SCLC by CTFI (< 90 days and ≥ 90 days).
Each table, listing and figure displayed in this section will have a comprehensive header identifying 
the tumor type (cohort), the total population (if applicable) or SCLC patients by CTFI.
Section 11.3.2: Secondary Analysis. Add a new table
Table 11.3.2.1 Descriptive Duration of response (DR) by tumor type.
N
Mean
Std. deviation
Median
Min
Max
SCLC*
…..
Total
*Also by CTFI.
Tables 11.3.2.2 Duration of response (DR), Table 11.3.2.4 Progression-free survival (PFS) and table 
11.3.2.4 Overall survival (OS) add the following footnote: Kaplan-Meier plot will also be shown (Figure 
13.1.1). All cohorts and SCLC by CTFI.
Section 12.1.2.1: Number of Patients and Cycles with Dosing Delay, any Relationship
Table 12.1.2.3 is changed.
Table 12.1.2.1.3 Number of patients and cycles with dosing delay according to the relationship.


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Treatment-related**
Non-treatment-related
N
%
N
%
No. of patients with 
1 cycle delayed 
2 cycles delayed
3 cycles delayed
No. of cycles with
dosing delay*
(*) Denominator= Number of cycles susceptible to be delayed. (**) Hematological reason, non-hematological reason or both.
Table 12.1.2.1.3 Number of patients and cycles with dosing delay, treatment related.
N
%
No. of patients treated
No. of patients with drug related dose delay
No. of cycles administered
No. of cycles susceptible to be delayed*
No. of cycles with drug related dosing delay**
No. of patients with 
No cycles delayed
1 cycle drug related delayed 
…..
(*) All cycles excluding first cycle. (**) Denominator= Number of cycles susceptible to be delayed.
Section 12.1.3: Dose reductions
Table 12.1.3.2 Number of patients and cycles with dose reduction, any relationship.
N
%
No. of patients treated
X
XX.X
No. of patients with any dose reduced
No. of patients with:
No PM01183 reduction
1 cycle with PM01183 dose reduced
2 cycles with PM01183 dose reduced
No. of cycles administered
No. of cycles susceptible to have any dose reduced* 
No. of cycles with PM01183 dose reduced **
No. of cycles with PM01183 dose reduced (Treatment related)**
(*) All cycles excluding first cycle. (**) Denominator= Number of cycles susceptible to have a dose reduction.
Table 12.1.3.3 Number of patients and cycles with dose reduction, treatment related.
N
%


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No. of patients treated
X
XX.X
No. of patients with any dose reduced (Treatment related)
No. of patients with:
No PM01183 reduction
1 cycle with PM01183 dose reduced (Treatment-related)
2 cycles with PM01183 dose reduced (Treatment-related)
No. of cycles administered
No. of cycles susceptible to have any dose reduced* 
No. of cycles with PM01183 dose reduced (Treatment-related)**
(*) All cycles excluding first cycle. (**) Denominator= Number of cycles susceptible to have a dose reduction.
Section 12.6: Concomitant therapy/ Procedures According to the ATC Classification. Add a new 
table
Listing 12.6.4 Patients with GCSF during treatment.
Patient
Cycle
Date
Medication
Reason
Specify
Section 13: Figures
Figures 13.1.1 to 13.1.3 add the following footnote:
Kaplan-Meier curve of overall survival. All cohorts and SCLC by CTFI.


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15.2
SAP version history v2.0
After the second version of the SAP was approved, a new protocol "substantial amendment No. 6" 
and “Non-Substantial Amendment No.2” were included; therefore the SAP has been updated to 
version 3 in accordance with the new version of the protocol as follows:

Study objectives. Assessment of antitumor activity by an Independent Review Committee (IRC) is 
included as a secondary objective in the small cell lung carcinoma (SCLC) cohort. 

Patient population. The maximum number of evaluable patients in this clinical trial is increased to 
350 mainly because of the elevated recruitment in the endometrial carcinoma cohort, which 
exceeded in 20 patients the planned number, together with the increase in the SCLC cohort to 100 
evaluable patients, and the re-opening of the metastatic breast carcinoma BRCA-positive cohort, 
which will recruit up to 25 patients. Consequently, clarification of the statistical analysis to be 
performed in case the number of evaluable patients included in any cohort of the study was higher 
than planned is incorporated. 

In order to have a deeper insight into the survival, the overall survival (OS), OS rate at 6 months 
and 12 months will be determined in each cohort.

Other not relevant minor comments/clarifications.
Detailed changes are presented in the next pages. Changes are highlighted in Italic bold and text 
removed has been crossed out.
Any changes in the automatic numbering of tables, sections and references in the SAP are not listed but 
will be implemented in the new version.
Section 1: Rationale
Original text:

PM01183 has shown antitumor activity in most of the tumor types selected in this clinical 
study. In the combination trial of PM01183 at 4.0 mg flat dose (FD) with 50 mg/m2 of 
doxorubicin every three weeks (q3wk) (PM1183-A-003-10), five of 12 evaluable patients with 
SCLC achieved partial response (42.0%), with a median time-to-progression (TTP) of 2.0 
months. In endometrial carcinoma, two of three patients treated with the combination 
PM01183 plus doxorubicin at the aforementioned dose and schedule had a complete response 
and a partial response, respectively. The third patient had disease stabilization longer than 4 
months. The median TTP was 10.1 months. Also with this combination, a patient with NET 
had a partial response with a TTP of 4.5 months. In a phase II clinical trial of PM01183 as 
single agent in MBC, two of 54 patients with germline BRCA 1/2 mutation had a complete 
response (3.7%) and 20 patients had partial response (37%). Twenty-three additional patients 
had disease stabilization (43%). One patient with H&N carcinoma treated with PM01183 as 
single agent at 2.6 mg/m2 q3wk achieved a disease stabilization of 4 months duration. Finally, 
one patient with a carcinoma of unknown primary site treated with PM01183 as single agent at 
7 mg FD q3wk had disease stabilization for 2.6 months.
Changes to:


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
PM01183 has shown antitumor activity in most of the tumor types selected in this clinical 
study. In the combination trial of PM01183 at 4.0 mg flat dose (FD) with 50 mg/m2 of 
doxorubicin every three weeks (q3wk) (PM1183-A-003-10), five of 12 evaluable patients with 
SCLC achieved partial response (42.0%), with a median time-to-progression (TTP) of 2.0 
months. In endometrial carcinoma, two of three patients treated with the combination 
PM01183 plus doxorubicin at the aforementioned dose and schedule had a complete response 
and a partial response, respectively. The third patient had disease stabilization longer than 4 
months. The median TTP was 10.1 months. Also with this combination, a patient with NET 
had a partial response with a TTP of 4.5 months. In a phase II clinical trial of PM01183 as 
single agent in MBC, one of 54 patients with germline BRCA 1/2 mutation had a complete 
response (2%) and 21 patients had partial response (39%). Twenty-three additional patients 
had disease stabilization (43%). One patient with H&N carcinoma treated with PM01183 as 
single agent at 2.6 mg/m2 q3wk achieved a disease stabilization of 4 months duration. Finally, 
one patient with a carcinoma of unknown primary site treated with PM01183 as single agent at 
7 mg FD q3wk had disease stabilization for 2.6 months.
Section 2.: Study Design
Original text:
If two confirmed responses are observed in the first 15 evaluable patients of each cohort, the 
recruitment of the corresponding cohort can be stopped. 
(….)
Finally,

A determined cohort can be early closed by the Sponsor in case of a low recruitment rate.
(….)
Patients will be evaluated at scheduled visits on three study periods: Pre-treatment, Treatment and 
Follow-up. This clinical trial will finish (clinical cut-off) when all evaluable patients have at least 12 
months of follow-up.
Changes to:
If two confirmed responses are observed in the first 15 evaluable patients of each cohort, the 
recruitment of the corresponding cohort can be stopped. 
Only in the SCLC cohort, an IRC will be performed on all images collected and will provide a 
radiographic response at each time point termed. These data and the clinical database 
information will be used to derive the independent review efficacy information following the 
RECIST v.1.1. Operational details for the IRC and the algorithm and its validation by an expert 
panel is described in detail in the IRC charter.


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(….)
Finally,

A determined cohort can be early closed by the Sponsor in case of a low recruitment rate.

Once the target of patients included in each cohort is reached, recruitment in this cohort 
will be kept “on hold” during the period of patients’ data analysis to assess their evaluability 
and the response rate. After this period, if the number of evaluable patients does not reach 
the planned target, recruitment will be re-opened and non-evaluable patients will be 
replaced. 
(….)
Patients will be evaluated at scheduled visits on three study periods: Pre-treatment, Treatment and 
Follow-up. This clinical trial will finish (clinical cut-off for each cohort except SCLC cohort) 
when all evaluable patients within each cohort have at least 12 months of follow-up from the first 
PM01183 infusion. Patients with SCLC will be followed-up until death.
Section 3.2: Secondary objectives
Original text:

To further characterize the antitumor activity of PM01183 in terms of duration of response 
(DR), clinical benefit [ORR or stable disease (SD) lasting over four months (SD ≥ 4 
months)], PFS, and one-year overall survival (1y-OS) in each cohort of advanced solid tumors 
[overall survival (OS) in the cohort of SCLC patients].
Changes to:

To further characterize the antitumor activity of PM01183 in terms of duration of response 
(DR), clinical benefit [ORR or stable disease (SD) lasting over four months (SD ≥ 4 months)], 
progression-free survival (PFS) by Investigator’s assessment (IA), and overall survival (OS) 
in each cohort of advanced solid tumors

To further investigate the antitumor activity of PM01183 in terms of ORR, DR, clinical 
benefit [ORR or SD ≥ 4 months] and PFS by an Independent Review Committee (IRC) in 
the cohort of SCLC patients.
Section 3.3: Endpoints
Original text:
Secondary Endpoints:
Efficacy:


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
Duration of Response (DR), defined as the time between the date when the response criteria 
(PR or CR, whichever one is first reached) are fulfilled to the first date when PD, recurrence or 
death is documented.

Clinical Benefit, defined as response or stable disease lasting over four months (SD ≥ 4 
months).

Progression-free Survival (PFS), defined as the period of time from the date of first infusion to 
the date of PD, death (of any cause), or last tumor evaluation. 

PFS4/PFS6, defined as the Kaplan-Meier estimates of the probability of being free from 
progression and death after the first infusion at these time points (4 and 6 months).

OS6/OS12, defined as the Kaplan-Meier estimates of the probability of being alive after the 
first infusion at these time points (6 and 12 months) (overall survival in the cohort of SCLC 
patients).
Changes to:
Secondary Endpoints:
Efficacy (all cohorts):

Duration of Response (DR) by IA, defined as the time between the date when the response 
criteria (PR or CR, whichever one is first reached) are fulfilled to the first date when disease 
progression (PD), recurrence or death is documented.

Clinical Benefit by IA, defined as ORR or SD lasting over four months (SD ≥ 4 months).

Progression-free Survival (PFS) by IA, defined as the period of time from the date of first 
infusion to the date of PD, death (of any cause), or last tumor evaluation. 

PFS4/PFS6 by IA, defined as the Kaplan-Meier estimates of the probability of being free from 
progression and death after the first infusion at these time points (4 and 6 months).

OS, defined as the period of time from the date of first infusion to the date of death or last 
contact in case of patients lost to follow-up or alive at the clinical cut-off stablished for the 
cohort.

OS6/OS12, defined as the Kaplan-Meier estimates of the probability of being alive after the first 
infusion at these time points (6 and 12 months).
Efficacy (only in the SCLC cohort): 

ORR, Clinical Benefit, DR, PFS and PFS4/PFS6 by IRC. The same definitions detailed for 
IA but following IRC evaluation will be used.
(…..)
Safety Profile:

Clinical examinations.

Clinical assessment of AEs and serious adverse events (SAEs).

Changes in laboratory parameters (hematological and biochemical, including liver function 
tests). 

Reasons for treatment discontinuations.


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
Reasons for dose reduction and treatment delays.
Section 4: Patients evaluability criteria
Original text:
(….)

“All Evaluable Patients” analysis set is defined as all eligible patients who have had at least 
one complete infusion of PM01183, and either have had at least one assessment (as per 
RECIST v1.1) or have been categorized as “treatment failures”. Patients who discontinue 
treatment due to any treatment-related toxicity before an appropriate tumor assessment has 
been performed or those who experience early death due to malignant disease will be defined 
as “treatment failures”. These patients will be included as non-evaluable for response in the 
analysis of objective response as per RECIST v1.1, although they will not be replaced as will 
be considered evaluable for efficacy.

“All Responding Patients” analysis set is defined as all evaluable patients who have had a 
confirmed CR or PR as overall best response according to the RECIST v1.1.
Changes to:
(…)

“All Evaluable Patients” analysis set is defined as all eligible patients, defined as patients 
accepted by the sponsor to take part in the trial, who have had at least one complete infusion 
of PM01183, and either have had at least one assessment (as per RECIST v1.1) or have been 
categorized as “treatment failures”. Patients who discontinue treatment due to any treatment-
related toxicity before an appropriate tumor assessment has been performed or those who 
experience early death due to malignant disease or those with treatment withdrawn due to 
clinical PD/symptomatic deterioration with no tumor assessments will be defined as 
“treatment failures”. These patients will be included as non-evaluable for response in the 
analysis of objective response as per RECIST v1.1, although they will not be replaced as will 
be considered evaluable for efficacy. For the IRC assessment in SCLC patients same 
definition will be followed but based on its assessment.

“All Responding Patients” analysis set is defined as all evaluable patients who have had a 
confirmed CR or PR as overall best response according to the RECIST v1.1. For the IRC 
assessment in SCLC patients same definition will be followed but based on its assessment.
Section 4.1 Included Population: 
Original text:
The “All Included Patients” dataset will be used for the descriptive analyses of disposition of patients 
and baseline characteristics.
Changes to:


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The “All Included Patients” dataset, defined as all patients accepted by the sponsor to take part in 
the trial, will be used for the descriptive analyses of disposition of patients and baseline 
characteristics in each cohort of advanced solid tumors.
Section 4.2 Efficacy Populations: 
Original text:
The “All Evaluable Patients” analysis set will be used for the primary endpoint analysis of ORR and 
for the secondary endpoints of DR, Clinical benefit (ORR or SD ≥ 4 months), PFS (including 
PFS4/PFS6 months), and OS6/OS12 months in each cohort of advanced solid tumors.
Changes to:
In all cohorts but SCLC, the “All Evaluable Patients” analysis set will be used for the primary 
endpoint analysis of ORR and for the secondary endpoints of DR, Clinical benefit (ORR or SD ≥ 4 
months), PFS (including PFS4/PFS6 months), and OS6/OS12 months in each cohort of advanced 
solid tumors. The “All Treated Patients” analysis set will also be used for the sensitivity analyses.
In SCLC cohort, the “All Treated Patients” analysis set will be used for the primary endpoint 
analysis of ORR and for the secondary endpoints of DR, Clinical benefit (ORR or SD ≥ 4 months), 
PFS (including PFS4/PFS6 months), and OS6/OS12 months in each cohort of advanced solid 
tumors. The “All Evaluable Patients” analysis set will also be used for the sensitivity analyses.
Section 4.3 Safety Population: 
Original text:
The safety analysis will be based on the “All Treated Patients” analysis set.
Changes to:
The safety analysis will be based on the “All Treated Patients” analysis set by cohort of tumor types 
and total population.
Section 5.1: Sample size
Original text:
(….)
The variance of the standardized test is based on the null hypothesis. The type I error (alpha) 
associated with this one-sided test is 0.025 and the type II error (beta) is 0.051 (normal approximation; 
~0.05 if exact binomial distribution); hence, statistical power is 95% (normal approximation; ~95% if 
exact binomial distribution). With these assumptions, if the number of patients who achieve a 
confirmed response is ≥ 23, then this would allow the rejection of the null hypothesis.
Changes to:
(…)


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The variance of the standardized test is based on the null hypothesis. The type I error (alpha) 
associated with this one-sided test is 0.025 and the type II error (beta) is 0.051 (normal approximation; 
~0.05 if exact binomial distribution); hence, statistical power is 95% (normal approximation; ~95% if 
exact binomial distribution). With these assumptions, if the number of patients who achieve a 
confirmed response is ≥ 23, then this would allow the rejection of the null hypothesis. The judgement 
of patient’s evaluability and replacement of non-evaluable patients were guided by the investigator 
assessment. 
Section 6.1 Planned Analyses and Definitions
Primary endpoint
Original text:
The primary study analysis except for SCLC cohort will be based on the ORR in the “All Evaluable 
Patients” population set. 
Overall response rate (ORR) is calculated as the number of patients who have had a confirmed CR or 
PR as overall best response according to the RECIST v1.1, divided by the number of patients in the 
“All Evaluable Patients” population set.
Changes to:
The primary study analysis except for SCLC cohort will be based on the ORR in the “All Evaluable 
Patients” population set. For SCLC cohort, the primary study analysis will be based on the ORR in 
the “All Treated Patients” population set.
Overall response rate (ORR) is calculated as the number of patients who have had a confirmed CR or 
PR as overall best response according to the RECIST v1.1, divided by the number of patients in the 
“All Evaluable Patients” (“All Treated Patients” in SCLC cohort) population set.
Secondary endpoints
Original text:
(…)
Duration of response (DR) is defined as the time from the first observation of response to the date of 
disease progression, recurrence or death. Other causes will be censored. Although the responses have 
to be confirmed according to RECIST v1.1, the first documentation (not the confirmation) will be 
taken into account to calculate DR. Patients who progress or die will be considered to have had an 
event, except if this event occurs after the start of subsequent antitumor therapy, in which case the 
patient will be censored at the time of last disease assessment prior to or on the first day of the first 
subsequent antitumor therapy.
Clinical benefit rate is calculated as the number of patients who have had a confirmed CR, PR, or SD 
≥ 4 months as overall best response according to the RECIST v1.1, divided by the number of patients 
in the “All Evaluable Patients” analysis set.
Progression-free survival (PFS) is defined as the time from the date of start of treatment to the date 
of documented progressive disease (PD) by RECIST v1.1 or death (regardless of the cause of death), 
whichever comes first. Patients who progress or die will be considered to have had an event of 
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the patient will be censored at the time of last disease assessment prior to or on the first day of the first 
subsequent antitumor therapy. If the patient is lost for the assessment of progression during the 
follow-up period, or has more than one missing follow-up between the date of last tumor assessment 
and the date of progression, death or further antitumor therapy, the PFS will be censored at the date of 
last valid disease assessment before the missing evaluations.
Overall survival (OS) is defined as the time from the date of start of treatment to the date of death or 
last contact. One year (1y-OS)/6 months overall survival is defined as the Kaplan-Meier estimate of 
the probability of patients being alive at 12/6 months after the date of start of treatment.
Changes to:
(…)
Duration of response (DR) is defined as the time from the first observation of response to the date of 
disease progression, recurrence or death. Other cases will be censored. Although the responses have to 
be confirmed according to RECIST v1.1, the first documentation (not the confirmation) will be taken 
into account to calculate DR. Patients who progress or die will be considered to have had an event, 
except if this event occurs after the start of subsequent antitumor therapy, in which case the patient 
will be censored at the time of last disease assessment prior to or on the first day of the first 
subsequent antitumor therapy.
Clinical benefit rate is calculated as the number of patients who have had a confirmed CR, PR, or SD 
≥ 4 months as overall best response according to the RECIST v1.1, divided by the number of patients 
in the “All Evaluable Patients” (“All Treated Patients” in SCLC cohort) analysis set.
Progression-free survival (PFS) is defined as the time from the date of start of treatment to the date 
of documented progressive disease (PD) by RECIST v1.1 or death (regardless of the cause of death), 
whichever comes first. Patients who progress or die will be considered to have had an event of 
progression, except if this event occurs after the start of subsequent antitumor therapy, in which case 
the patient will be censored at the time of last disease assessment prior to or on the first day of the first 
subsequent antitumor therapy. If the patient is lost for the assessment of progression during the 
follow-up period, or has more than one missing follow-up between the date of last tumor assessment 
and the date of progression, death or further antitumor therapy, the PFS/DR will be censored at the 
date of last valid disease assessment before the missing evaluations.
The date of response, the date of radiological progression, according to the investigator assessment 
and the independent assessment by IRC when applicable (i.e., SCLC cohort), the date of clinical 
PD and the date of death will be registered and documented, as appropriate.
(…)
Overall survival (OS) is defined as the time from the date of start of treatment to the date of death or 
last contact. One year (1y-OS)/6 months overall survival is defined as the Kaplan-Meier estimate of 
the probability of patients being alive at 12/6 months after the date of start of treatment.
A sensitivity analysis for all cohorts but SCLC will be performed for ORR, Clinical Benefit Rate, 
PFS and OS in the “All Treated Patients population”. For the SCLC cohort, the sensitivity analysis 
will be carried out the “All Evaluable Patients”.
Section 6.2: Efficacy Analysis Methods


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Original text:
Counts and percentages, with their corresponding exact 95% confidence intervals, will be calculated 
for the binomial endpoints (e.g., ORR, clinical benefit). 
Time-to-event variables (DR, PFS and OS) and their set time estimates (i.e., PFS 4/6 and OS 6/12) 
will be analyzed according to the Kaplan-Meier method. 
Waterfall plots will be used to describe the best variation of the sum of target lesions during treatment.
Changes to:
Counts and percentages, with their corresponding exact 95% confidence intervals, will be calculated 
for the binomial endpoints (e.g., ORR, clinical benefit). The confidence intervals based on the group 
sequential tests performed for each cohort will also be calculated.
Time-to-event variables (OS, PFS and DR) and their set time estimates (i.e., PFS 4/6 and OS 6/12) will 
be analyzed according to the Kaplan-Meier method.
In the SCLC cohort, the evaluation of the efficacy endpoints evaluated by IA and IRC will be shown 
and compared. The rate of concordance between both evaluation methods for best response, 
progression status and progression-free survival will be presented with 2-way frequency tables and 
measures of agreement.
Waterfall plots will be used to describe the best variation of the sum of target lesions during treatment.
The number of patients recruited in any cohort may differ from that pre-specified according to the 
sample size assumptions. Therefore, the main efficacy results will be calculated according to the 
planned cohort sample size and, if any cohort sample size differs at least 10% from the 
assumptions, a sensitivity analysis using all evaluable patients recruited (adjusting the 
corresponding boundaries to test the null hypothesis) will be performed.
The patient level response will be calculated by means of statistical programming. In the case of a 
Partial Response followed by a time point with a tumor size reduction lower than 30% compared to 
the baseline assessment but an increase in the size of the target lesions not qualifying for disease 
progression (e.g. increase of sum of target lesions compared with the nadir is lower than 20%) then 
the response will be considered maintained following RECIST advice( (“The definition of SD: a 
clarification” http://recist.eortc.org/recist-1-1-2/).
Example: Baseline evaluation: 38 mm, first evaluation: 26 mm (Tumor Size Reduction from 
baseline = 31.6% PR), second evaluation: 28 mm (Reduction from baseline = 26.3%, but increase 
from nadir = 7.7%).
The best overall response will be considered as confirmed PR.
Section 6.2.1: Primary Endpoint
Original text:
Exact binomial estimates with 95% confidence intervals (CIs) in each cohort will be calculated for the 
analysis of the main endpoint (ORR according to RECIST v1.1)
Changes to:


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Exact binomial estimates with 95% confidence intervals (CIs) in each cohort will be calculated for the 
analysis of the main endpoint (ORR according to RECIST v1.1by Investigator assessment)
Section 6.2.2: Secondary Endpoint
Original text:
Time-to-event endpoints (DR, PFS and OS) and their set time estimates (i.e. PFS4, PFS6 and OS 
6/12) will be analyzed according to the Kaplan-Meier method.
Changes to:
Exact binomial estimates with 95% confidence intervals (CIs) will be performed in the 
SCLC cohort for the analysis of the ORR according to RECIST v1.1 by IRC.
Time-to-event endpoints (DR, PFS and OS) and their set time estimates (i.e. PFS4, PFS6 and OS 
6/12) will be analyzed according to the Kaplan-Meier method.
Section 7: Statistical Methodology for Safety
Original text:
Patients will be evaluable for safety if they received any partial or complete infusion of PM01183.
Changes to:
Patients will be evaluable for safety if they received any partial or complete infusion of PM01183.
All AEs/laboratory visits reported as “End of treatment” visit will be mapped to the last cycle visit 
for each patient.
Section 7.1.1 changes to 7.1: Toxicity and Adverse Events
Original text:
(…)
The toxicity evaluation will be coded with the National Cancer Institute Common Terminology 
Criteria for Adverse Events (NCI-CTCAE) v4.
Summary of overall AEs will be done by System Organ Class (SOC) and Preferred Term (PT), by 
severity (worst toxicity grade), by relationship to the study drug and by AE outcome. Tables will be 
sorted by SOC/PT coded with MedRA.
(…)
Changes to:
(…)
The toxicity evaluation will be coded with the National Cancer Institute Common Terminology 
Criteria for Adverse Events (NCI-CTCAE) v4.
Treatment-emergent adverse events (TEAE) are defined as any adverse events aggravated in 
severity from baseline or having their onset between the first dose of the study drug  and 30 days 
after the last treatment dose, death or date of further therapy (whichever comes first). Adverse 


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Events Related to Study Drug or with Unknown relationship occurring more than 30 days after the 
last dose will also be taken into account as TEAEs. 
Summary of overall AEs will be done by System Organ Class (SOC) and Preferred Term (PT), by 
severity (worst toxicity grade), by relationship to the study drug and by AE outcome. Tables will be 
organized by category of events using SOC (i.e. alphabetical order) and PT in descending 
frequencies (i.e., from higher to lower).
(…)
Section 7.2 Clinical Laboratory Evaluation
Original text:
Overall cross tabulation will be presented for the worst grade during treatment versus the baseline 
toxicity grading of leukopenia, neutropenia, lymphopenia, thrombocytopenia and anemia.
If a grade 3/4 neutropenia or thrombocytopenia occurs during a cycle of treatment, the first day it 
reaches grade 3 or 4 (counting from the start of the cycle) and the duration of the abnormality (i.e., 
until recovery to grade ≤ 2) will be tabulated.
(…)
If a grade 3/4 AST or ALT increase occurs during a cycle of treatment, both the day it peaked 
(counting from the start of the cycle) and the duration of the abnormality (i.e., until recovery to grade 
≤ 2) will be tabulated.
Overall cross tabulation will be presented for the worst grade during treatment versus the baseline 
toxicity grading of biochemical abnormalities.
Changes to:
Overall cross tabulation will be presented for the worst grade during treatment versus the baseline 
severity grading of leukopenia, neutropenia, lymphopenia, thrombocytopenia and anemia.
If a grade ≥3 neutropenia or thrombocytopenia occurs during a cycle of treatment, the first day it 
reaches grade 3 or 4 (counting from the start of the cycle) and the duration of the abnormality (i.e., 
until recovery to grade ≤ 2) will be tabulated.
(…)
If a grade ≥3 AST or ALT increase occurs during a cycle of treatment, both the day it peaked 
(counting from the start of the cycle) and the duration of the abnormality (i.e., until recovery to grade 
≤ 2) will be tabulated.
Overall cross tabulation will be presented for the worst grade during treatment versus the baseline 
severity grading of biochemical abnormalities.
Section 8.9 Imputation of Incomplete Dates: 
Original text:


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The dates of certain historical or on-study clinical data are key components for statistical analysis. An 
incomplete date results from a missing day, month or year; in that case, the missing figure can be 
imputed, thus allowing the calculation of variables, such as duration and time of a specific event. 
However, when all dates (day, month and year) are missing, no imputation will be done.
Before Registration
If the day of a month is unknown, then the imputed day will be the 15th of the month; if the month is 
also unknown, then the imputed date will be the 1st of July. This assumption will only be valid if the 
imputed date occurs earlier than the first dose administration date; otherwise the imputed date will be 
the first day of the month of administration of the first dose (i.e. 01/ month of administration of the 
first dose/year).
(…)
After End of Treatment
To ensure the most conservative approach for the time-to-event variables (i.e., DR, PFS and OS), 
which can be affected by missing values, the following rules will be implemented: if the day of a date 
is unknown then the imputed day will be the 1st; if the month is also unknown, then the imputed date 
will be the 1st of July. This assumption will be valid if the imputed date occurs later than the last drug 
administration date; otherwise the imputed date will be the date of the last drug administration plus 
the predefined cycle length (i.e., 21 days if PM01183), except if the patient dies before, in which case 
the date of death minus 1 will be used.
Changes to:
The dates of certain historical or on-study clinical data are key components for statistical analysis. An 
incomplete date results from a missing day, month or year; in that case, the missing figure can be 
imputed, thus allowing the calculation of variables, such as duration and time of a specific event. 
However, when all dates (day, month and year) are missing, no imputation will be done unless 
otherwise specified. Whenever imputations are applicable, it will be clearly specified in 
the corresponding shell table, listing or figure in sections 10-16 of this SAP.
Before Registration
If the day of a month is unknown, then the imputed day will be the 1st. of the month; if the month is 
also unknown, then the imputed date will be the 1st of July. This assumption will only be valid if the 
imputed date occurs earlier than the first dose administration date; otherwise the imputed date will be 
the first day of the month of administration of the first dose (i.e. 01/ month of administration of the 
first dose/year).
Between treatment start and end of treatment
All date variables during treatment where information is needed and is not fully available, for example 
adverse events or concomitant medications, will be subject of imputation by means of SAS 
programming. If the day of a date is unknown then the imputed day will be 1, if the month and/or year 
is also unknown then the imputed date will 1/January (this assumption will be valid if the imputed 
date is later than the treatment start date; otherwise, the imputed date will be the treatment start date).
(…)
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To ensure the most conservative approach for the time-to-event variables (i.e., DR, PFS and OS), 
which can be affected by missing values, the following rules will be implemented: if the day of a date 
is unknown then the imputed day will be the 1st; if the month is also unknown, then the imputed date 
will be the 1st of July. This assumption will be valid if the imputed date occurs later than the last drug 
administration date; otherwise the imputed date will be the date of the last drug administration plus 
the predefined cycle length (i.e., 21 days if PM01183), except if the patient dies before, in which case 
the date of death minus 1 will be used. For OS, if a patient dies, the imputation event date should be 
the last date the patient is known to be alive plus one day.
Section 8.10: Decimal Places
Original text:
By default, all numeric results will be rounded to one decimal, except when variables are integers; in 
that case, they will be reported without decimals (for example, age in years, number of sites, etc.).
Changes to:
By default, all numeric results will be rounded to one decimal, except when variables are integers; in 
that case, they will be reported without decimals (for example, age in years, number of sites, etc.). 
Three decimal places will be used for Hazard Ratios or Odds Ratios. Four decimal places will be 
used for p-values.
Section 8.11: Subgroup Analyses
Original text:
Specific subgroup efficacy analysis will be done for all Evaluable patients with SCLC by CTFI (< 90 
days and ≥ 90 days).
No other specific subgroup analysis is being planned for the analysis.
Changes to:
Specific subgroup efficacy analyses will be done for patients with SCLC. These analyses will be 
performed by IA/IRC and in all evaluable/all treated patient populations. Pre-specified analyses are 
planned by CTFI (< 90 days and ≥ 90 days and/or Refractory (RR)[<30 days], Resistant (R) [>=30 
and <90 days], Sensitive (S)[>=90 and <180 days] and Very Sensitive (VS)[>=180 days]), excluding 
patients with CTFI<30 days and considering event to clinical progressions although they were not 
documented by radiological images. Any other exploratory analysis requested by physician at the 
analysis time will be clearly explained, specifying the selected patient population and following the 
same layout detailed for the other subgroup analyses.
If the number of patients recruited in any cohort differs at least 10% from the sample size 
assumptions, a sensitivity analysis for main efficacy endpoints using all evaluable patients will be 
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Pre-specified safety subgroup analyses are: by sex (male vs. female), by age (<65 years-old vs. ≥65 
years-old), by race (white vs. other), by number of prior lines (1 vs. >1 line), by BSA (<2 vs. ≥2) and 
by geographical area (USA vs. Europe vs. rest of the world). 
Section 8.15 Data Analysis Conventions
Original text:
All data analysis conventions, data calculations and grouping needed to perform the statistical analysis 
will be described in separate documents not included in this SAP. 
Changes to:
All data analysis conventions, data calculations and grouping needed to perform the statistical analysis 
not included in this SAP will be described in separate document. 
APPENDIX I
Original text:
Each table, listing and figure will have a comprehensive header identifying the tumor type (cohort) or 
the total population (if applicable).
…..
Changes to:
Each table, listing and figure will have a comprehensive header identifying the tumor type (cohort) or 
the total population (if applicable).
For this reason each SAP Table/Listing/Figure will have different granularity, i.e Table 11.1.1.1.x 
where “x” is a different sublevel of granularity. The following values apply:
Table/Listing/Figure granularity level
Contents
none
Totals all cohort
.b
BRCA 1/2-associated metastatic breast carcinoma
.i
Biliary tract carcinoma
.c
Carcinoma of unknown primary site
.e
Endometrial carcinoma
.w
Ewing’s family of tumors (EFTs)
.g
Germ cell tumor (GCTs)
.h
Head and neck carcinoma (H&N)
.n
Neuroendocrine tumors (NETs)
.s
Small cell lung cancer (SCLC)
.s1
Resistant*
.s2
Sensitive*
(*)For tables to be produced for resistant (.s1) and sensitive (.s2) populations, please see indications in the respective table or figure 
footnote.  


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Section 10.1: Patient Disposition.
Add new columns and tables:
Table 10.1.1 Number of patients included, treated and evaluable for the primary endpoint.
N
%
Included patients
Eligible patients*
Treated patients
Evaluable patients for efficacy
Evaluable patients for efficacy by IRC (SCLC cohort)**
(*) Patients who were considered eligible according to the registration screening form and were accepted to take part in the trial with 
the sponsor’s agreement in the screening reply form. (**) For sensitivity analysis.
Listing 10.2.2 Reasons for treatment discontinuation other than progressive disease and Listing 12.2.4 
Treatment discontinuation due to adverse events add one new column CTFI* and the footnote (*) 
Only for SCLC patients (RR, R, S, VS).
Table 10.1.5 Non-evaluable patients for efficacy analysis by IRC (SCLC cohort).
Patient id.
Reason
Section 10.2: Reasons for Treatment Discontinuation.
Table 10.2.1 Treatment discontinuation and Table 10.2.3 Reasons for treatment discontinuation by 
cycles received. Add new columns for the cutoff:
Table 10.2.1 Treatment discontinuation
Reason
N
%
Progressive disease
Treatment-related adverse event*
Non treatment-related adverse event*
Patient refusal to treatment*
Death**
Investigator’s decision*
Other* 
Ongoing at cutoff
Total
Note: Also for s1 and s2; (*) Specify (see Listing 10.2.2), (**) Cause of Death (See Table 12.3.2.1).
Listing 12.2.2 Reasons for treatment discontinuation other than progressive disease and Listing 12.2.4
Treatment discontinuation due to adverse events add one new column CTFI* and the footnote (*) 
Only for SCLC patients (RR, R, S, VS).
Table 10.2.3 Reasons for treatment discontinuation by cycles received.
Reason
Last cycle
1
2
…
Total


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Progressive disease
Treatment-related adverse event*
Non treatment-related adverse event*
Patient refusal to treatment*
Death**
Investigator’s decision*
Other*
Ongoing at cutoff
Total
(*) Specify (see Listing 10.2.2); (**) Cause of Death (See Table 12.3.2.1);
Table 10.2.5 Study discontinuation. Add the following footnote Note: Also for s1 and s2;
Section 11.1.1 Patients Characteristics at Baseline.
Original text:
Table 11.1.1.1 Baseline characteristics: Age at treatment registration.
N
Mean
Std. Deviation
Median
Min
Max
Age (years)
Table 11.1.1.2 Baseline characteristics: Age group.
Age
N
%
18-XX
X
XX.X
XX-YY
≥65
Total
Table 11.1.1.3 Baseline characteristics: Race.
N
%
American Indian or Alaskan Native
X
XX.X
Asian
Black or African American
Native Hawaiian or Other Pacific Islander
White
Other*
Total
(*) See Listing 11.1.1.4. 
Table 11.1.1.4 Other race, specify.
Patient id.
Specify
Changes to:
Table 11.1.1.1 Baseline characteristics: Age at treatment registration.
Age
N
%
18-XX
X
XX.X
XX-YY
≥65
Total
Mean, Std., Median, Range
Note: Also for s1 and s2.


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Table 11.1.1.2 Baseline characteristics: Gender.
N
%
Male
X
XX.X
Female
Total
Note: Also for s1 and s2.
Table 11.1.1.3 Baseline characteristics: Race.
N
%
American Indian or Alaskan Native
X
XX.X
Asian
Black or African American
Native Hawaiian or Other Pacific Islander
White
Other*
Total
Note: Also for s1 and s2; (*) See Listing 11.1.1.5. 
Table 11.1.1.4 Other race, specify.
Patient id.
CTFI*
Specify
(*) Only for SCLC.
Section 11.1.2 Disease at Diagnosis and Disease at Study Entry. 
Table 11.1.2.1 Time from first diagnosis to registration and Table 11.1.2.5 Time from advanced 
disease to registration are merged into one table. 
Tables 11.1.2.3 Stage at diagnosis, previous Table 11.2.2.7 changes to Table 11.1.2.6 Sites of disease 
and previous Table 11.1.2.10 changes to 11.1.2.9 Number of sites at baseline add the following 
footnote Note: Also for s1 and s2.
Previous Listing 11.1.2.8 changes to listing 11.1.2.7 Bone location add last column is removed.
Patient id.
Specify
Previous Table 11.2.2.6 changes to Table 11.2.2.5 Time from last progression before the study entry, 
add a new variable and footnote.
Table 11.1.2.1 Time from first diagnosis to registration and Time from advanced disease to 
registration.
N
Mean
Std.
Median
Min
Max
Time from diagnosis to registration (months)
Time from advanced disease (months)
Note: Also for s1 and s2.
Table 11.1.2.5 Time from last progression before study entry and TTP from last medical therapy.
N
Mean
Std.
Median
Min
Max
Time from last PD (weeks)
TTP to last medical therapy (months)
Note: Also for s1 and s2.


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A new table is included.
Table 11.1.2.10 Sum of target lesions at baseline.
N
%
>50 mm
X
XX.X
>100 mm
Bulky disease*
Note: Also for s1 and s2. (*) One lesion more than 50 mm.
Section 11.1.3 Disease at Diagnosis and Disease at Study Entry: Small Cell Lung Cancer 
(SCLC). New table and all tables add the following footnote Note: Also for s1 and s2. 
Table 11.1.3.2 History or current presence of CNS involvement.
*
N
%
Yes
X
XX.X
No
Total
Note: Also for s1 and s2.
Section 11.1.7 Disease at Diagnosis and Disease at Study Entry: Endometrial carcinoma.
Table 11.1.7.1 Endometrial carcinoma type (I/II is removed. This information will be available in data 
base listings.
Section 11.1.8 Disease at Diagnosis and Disease at Study Entry: BRCA 1/2-associated Metastatic 
Breast Carcinoma (MBC).
Original text:
Table 11.1.8.4 Hormonal status.
N
%
Triple negative
X
XX.X
ER and/or PR positive + HER2 negative
ER and/or PR positive + HER2 positive
ER and PR negative + HER2 positive
Total
Table 11.1.8.4 Hormonal status.
N
%
Triple negative
X
XX.X
ER and/or PR positive + HER2 negative
Hormone receptor positive*
Total
(*) ER and/or PR positive + HER2 positive and ER and PR negative + HER2 positive
Section 11.1.11 Disease at Diagnosis and Disease at Study Entry: Ewing's Family of Tumors 
(EFTs). Table 11.1.11.1 Anatomical subtype adds a new category.
Table 11.1.11.1 Anatomical subtype.
N
%
Osseous
X
XX.X
Extraosseous - Primitive neuroectodermal tumor


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Extraosseous - Askin tumor
*
Total
(*) Other, in case of none of the others CRF categories apply.
Section 11.1.13 Prior anticancer therapy. Some tables add new categories and add two new tables.
Table 11.1.13.1 Patients with prior surgery.
N
%
Yes
X
X.X
        Palliative
        Curative
No
Total
Previous Table 11.1.3.2 and 11.1.13.3 changes to Table 11.1.3.2 Patient with prior radiotherapy.
N
%
Yes
X
X.X
        Brachytherapy
        External (including IMRT)
        IMRT
No
Total
Table 11.1.13.4 Prior anticancer agents.
Antineoplastic and immunomodulating agents (ATC-class.)
N
%
Antineoplastic agents (L01)
X
XX.X
     Alkylating agents
           Nitrogen mustard analogues
           Alkyl sulphonates
Prior anticancer agents*
Hormones
Prior Immunotherapy
…
Biological agents     
…
….
(*) Therapies of interest for each tumor type e.g MBC, endometrial carcinoma, hormone, Biological agents etc…..
Table 11.1.13.5 PCI.
*
N
%
Yes
X
XX.X
No
Total
(*) Only for SCLC patients.  
  
Table 11.1.13.6 CTFI by subgroup.
*
N
%
Mean, Std., Median, 
Range**
CTFI< 90 days
X
XX.X
        RR
        R
CTFI≥ 90 days
        S
        VS


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Total
(*) Only for SCLC patients.
Table 11.1.13.7 Best response and TTP to last prior platinum.
*
N
%
CR
X
XX.X
PR
SD
PD
UK/NA
Total
TTP to last previous platinum Mean, Std., Median, Range
(*) Only for SCLC patients. Note: Also for s1 and s2;
Sections 11.1.14 Physical examination and Performance Status at Baseline, section 11.1.15 Vital 
Signs, Electrocardiogram, LVEF and other tests, section 11.1.16 Hematological Values at 
Baseline and section 11.1.17 Biochemical Values at Baseline.
Footnote is removed from the following tables: Table 11.1.14.1 Baseline physical examination, Table 
11.1.15.8 Baseline characteristics: pregnancy test and Table 11.1.15.9 Baseline characteristics: 
adequate contraception.
Table 11.1.14.2 Baseline physical examination: BSA, Weight and Height/Table 11.1.14.3 Baseline 
characteristics: ECOG Performance Status/table 11.1.16.1 Hematological abnormalities at 
baseline/Table 11.1.17.1 Biochemical abnormalities at baseline add the following footnote: Note: 
Also for s1 and s2.
Original text:
Table 11.1.16.2 Hematological values at baseline.
Parameter*
N
Mean
Std.
Median
Min
Max
Hemoglobin 
Platelets 
WBC
Neutrophils 
Lymphocytes
Monocytes 
(*) Parameter standard units in CRF.
Changes to:
Table 11.1.16.2 Hematological values at baseline.
Parameter*
N
Mean
Std.
Median
Min
Max
Hemoglobin (g/dl)
Platelets (x10*9/L)
WBC (x10*9/L)
Neutrophils (x10*9/L)
Lymphocytes (x10*9/L)
Monocytes (x10*9/L)
Section 11.1.15 Vital Signs, Electrocardiogram, LVEF and other tests


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Listing 11.1.1.15 Patients with abnormal electrocardiogram. 
Patient 
id.
Abnormality
Details*
Reason for 
clinically 
indicated 
repeat
PR interval 
(msec)
Heart rate 
(bpm)
QT interval 
(msec)
QRS 
complex 
(msec)
QTc 
Fridericia
QTc 
Bazett’s**
(*)For non-significant abnormalities, for further details see prior medical history or Signs and symptoms; (**) QTc (Bazett’s) = QT 
interval / √(60/Heart rate).
Section 11.1.18 Coagulation Values at Baseline
Original text:
Table 11.1.18.2 Coagulation values at baseline.
N
Mean
Std. deviation
Median
Min
Max
INR 
PT (sec)
PTT (sec)
Changes to:
Table 11.1.18.2 Coagulation values at baseline.
N
Mean
Std.
Median
Min
Max
INR 
PT (sec)
PT (ratio)
PTT (sec)
PTT (ratio)
Sections 11.1.19 Adverse Events at Baseline
Table 11.1.19.3 Adverse events at baseline adds the following footnote: Note: Also for s1 and s2. and 
Listing 11.1.19.4 Adverse events at baseline is removed.
Section 11.1.20 Concomitant Therapy and Procedures at Baseline
Table 11.2.20.1 Concomitant medication at baseline (ATC1/ATC2/ATC3/ATC4/PN). Add a new 
variable. And Table 11.1.20.3 Concomitant therapy is removed.
Section 11.3: Efficacy Analysis
Original text:
Efficacy analysis will be carried out on the “All Evaluable Patients” population and for all “Evaluable 
Patients” with SCLC by CTFI (< 90 days and ≥ 90 days).
Each table, listing and figure displayed in this section will have a comprehensive header identifying 
the tumor type (cohort), the total population (if applicable) or SCLC patients by CTFI.
Changes to:


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Efficacy analysis will be carried out on the “All Evaluable Patients” population. For SCLC patients 
in “All Treated Patients” and in “All Evaluable Patients” by IA/IRC and in all pre-specified 
analyses, by CTFI (< 90 days and ≥ 90 days and/or Refractory (RR)[<30 days], Resistant (R) [>=30 
and <90 days], Sensitive (S)[>=90 and <180 days] and Very Sensitive (VS)[>=180 days]), excluding 
patients with CTFI<30 days and considering event in the clinical progressions although they were 
not documented by radiological images.
Each table, listing and figure displayed in this section will have a comprehensive header identifying 
the tumor type (cohort), the total population (if applicable) or SCLC patients by CTFI or sensitivity 
analysis if recruitment in any cohort differs at least 10% from the assumptions. Any other 
exploratory analyses will be clearly specified by selected patient population and will be performed 
following the same table layout detailed below.
Section 11.3.1: Primary analysis. (Excluding SCLC cohort)
Add a new section by IRC,
Primary Analysis by IA:
Table 11.3.1.1 Response rate.
Response
N
%
Complete response (CR)
Partial response (PR)
Stable disease SD≥4 months
Stable disease SD<4 months
Progressive disease (PD)
Inevaluable for response*
(*) for example: early death, malignant disease; toxicity; tumor assessments not repeated/incomplete; other (specify).
Table 11.3.3.2 ORR.
Percentage
Lower 95% limit
Upper 95% limit
Response rate*
(*) Confirmed CR + PR. Binomial exact estimator and 95% CI.
Section 11.3.2 Secondary Analyses adds (excluding SCLC cohort). 
Original tables:
Table 11.3.2.1 Descriptive Duration of response (DR) by tumor type.
N
Mean
Std. deviation
Median
Min
Max
SCLC*
…..
Total
*Also by CTFI.
Table 11.3.2.2 Duration of response (DR).
DR
N
Events
Censored
Median DR
DR at 6 months


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DR at 12 months
Kaplan-Meier plot will also be shown (Figure 13.1.1). All cohorts and SCLC by CTFI.
Table 11.3.2.3 Clinical benefit rate.
Percentage
Lower 95% limit
Upper 95% limit
Clinical benefit rate*
(*) CR + PR + SD ≥ 4 months. Binomial exact estimator and 95% CI.
Table 11.3.2.4 Progression-free survival (PFS).
PFS
N
Events
Censored
Median PFS
PFS at 4 months
PFS at 6 months
Kaplan-Meier plot will also be shown (Figure 13.1.2). All cohorts and SCLC by CTFI.
Table 11.3.2.5 Overall survival (OS).
OS
N
Events
Censored
Median OS
OS at 6 months
OS at 12 months
Kaplan-Meier plot will also be shown (Figure 13.1.3). All cohorts and SCLC by CTFI.
Table 11.3.2.6 Characteristics of patients with clinical benefit*. 
Baseline characteristics
Study treatment characteristics
Cohort
Pat.
PS /
Age/Gender
Histology 
type / 
Histology 
grade
No. of 
prior 
regimens
Best 
response 
last 
therapy 
TTP last 
therapy 
Cycles 
received
Best 
response
PFS 
(mth)
OS 
(mth)
DR
(mth)
…
(*) CR + PR + SD SD ≥ 4 months.
Table 11.3.2.7 Median follow-up.
Follow-up*
Median
95% CI
PFS
OS
*Calculated using the Kaplan-Meier method reversing the censoring values. By descriptive methods also available under clinical 
request. 
Changes to:
Secondary Analyses by IA:
Table 11.3.2.1 Descriptive Duration of response (DR).
N
Mean
Std.Std.
Median
Min
Max


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Table 11.3.2.2 DR.
DR
N
Events
Censored
Median DR
DR at 4 months
DR at 6 months
DR at 12 months
Kaplan-Meier plot will also be shown (Figure 11.3.2.2).
Table 11.3.2.3 Clinical benefit rate and Disease control rate.
Percentage
Lower 95% limit
Upper 95% limit
Clinical benefit rate*
Disease control rate**
(*) CR + PR + SD ≥ 4 months. Binomial exact estimator and 95% CI.
(**) CR + PR + SD. Binomial exact estimator and 95% CI.
Table 11.3.2.4 PFS.
PFS
N
Events
Censored
Median PFS
PFS at 4 months
PFS at 6 months
Kaplan-Meier plot will also be shown (Figure 11.3.2.4).
Table 11.3.2.5 OS.
OS
N
Events
Censored
Median OS
OS at 6 months
OS at 12 months
Kaplan-Meier plot will also be shown (Figure 11.3.2.5).
Listing 11.3.2.6 Characteristics of patients with clinical benefit*. 
Baseline Characteristics**
Study treatment characteristics**
Patient id.
PS /
Age/Gender
Histology 
type / 
Histology 
grade
No. of prior 
regimens
Best 
response 
last 
therapy 
TTP last 
therapy 
Cycles 
received
Best 
response
PFS 
(mo)
OS 
(mo)
DR
(mo)
…
(*) CR + PR + SD ≥ 4 months.
(**) Any other clinically relevant variable will be added at the time of the analysis.
Table 11.3.2.7 Median follow-up.
Follow-up*
Median
95% CI/Range
PFS
OS
(*) Calculated using the Kaplan-Meier method reversing the censoring values and also by descriptive methods.


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New Section 11.3.3 SCLC cohort.
Primary Analysis (ORR):
Table 11.3.3.1 Response rate by IA (All treated patients).
Response
N
%
Complete response (CR)
Partial response (PR)
Stable disease SD≥4 months
Stable disease SD<4 months
Progressive disease (PD)
Inevaluable for response*
(*) for example: early death, malignant disease; toxicity; tumor assessments not repeated/incomplete; other (specify).
Table 11.3.3.2 ORR by IA (All treated patients).
Percentage
Lower 95% limit
Upper 95% limit
Response rate*
(*) Confirmed CR + PR. Binomial exact estimator and 95% CI.
Secondary and Supportive Analysis for ORR:
Table 11.3.3.3 Response rate by IA (All evaluable patients).
Response
N
%
Complete response (CR)
Partial response (PR)
Stable disease SD≥4 months
Stable disease SD<4 months
Progressive disease (PD)
Inevaluable for response*
(*) for example: early death, malignant disease; toxicity; tumor assessments not repeated/incomplete; other (specify).
Table 11.3.3.4 ORR by IA (All evaluable patients).
Percentage
Lower 95% limit
Upper 95% limit
Response rate*
(*) Confirmed CR + PR. Binomial exact estimator and 95% CI.
Table 11.3.3.5 Response rate by IRC (All treated patients).
Response
N
%
Complete response (CR)
Partial response (PR)
Stable disease SD≥4 months
Stable disease SD<4 months
Progressive disease (PD)
Inevaluable for response*
(*) for example: early death, malignant disease; toxicity; tumor assessments not repeated/incomplete; other (specify).
Table 11.3.3.6 ORR IRC (All treated patients).
Percentage
Lower 95% limit
Upper 95% limit
Response rate*
(*) Confirmed CR + PR. Binomial exact estimator and 95% CI.
Table 11.3.3.7 Response rate by IA and IRC (All treated patients).
Response
IA


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Complete 
response (CR)
Partial 
response 
(PR)
Stable 
disease 
SD≥4 
months
Stable 
disease 
SD<4 
months
Progressive 
disease (PD)
Inevaluable for 
response*
N
%
N
%
N
%
N
%
N
%
N
%
IRC
Complete 
response (CR)
Partial response 
(PR)
Stable disease 
SD≥4 months
Stable disease 
SD<4 months
Progressive 
disease (PD)
Inevaluable for 
response*
(*) for example: early death, malignant disease; toxicity; tumor assessments not repeated/incomplete; other (specify).
. For discrepancies see Listing 11.3.3.15. Percentage by columns.
Other Secondary Analyses:
Table 11.3.3.8 Descriptive* DR by IA and IRC.
N
Mean
Std.Std.
Median
Min
Max
IA
IRC
(*) Calculated with univariate procedures, not taking into account censoring, instead of Kaplan-Meier estimates.
Table 11.3.3.9 DR by IA and IRC.
IA
IRC
N
Events
Censored
Median DR
DR at 4 months
DR at 6 months 
DR at 12 months 
Kaplan-Meier plots will also be shown (Figure 11.3.3.9.1 DR by IA; Figure 11.3.3.9.2 DR by IRC and Figure 11.3.3.9.3 DR by IA 
and IRC)
Table 11.3.3.10 Clinical benefit rate and Disease control rate by IA and IRC (All treated patients).
Percentage
Lower 95% limit
Upper 95% limit
IA
Clinical benefit rate*
Disease control rate**
IRC
Clinical benefit rate*
Disease control rate**
(*) CR + PR + SD ≥ 4 months. Binomial exact estimator and 95% CI.
(**) CR + PR + SD. Binomial exact estimator and 95% CI.
Table 11.3.3.11 PFS by IA and IRC (All treated patients). 
IA
IRC
N
Events
Censored
Median PFS 


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PFS at 4 months 
PFS at 6 months 
Kaplan-Meier plot will also be shown. (Figure 11.3.3.11.1 PFS by IA (All treated patients), Figure 11.3.3.11.2 PFS by IRC (All 
treated patients) and Figure 11.3.3.11.3 PFS by IA and IRC (All treated patients))
Table 11.3.3.12 OS (All treated patients).
OS
N
Events
Censored
Median OS
OS at 6 months
OS at 12 months
Kaplan-Meier plot will also be shown (Figure 11.3.3.12).
Listing 11.3.3.13 Characteristics of patients with clinical benefit by CTFI by IA and IRC. (All 
treated patients). 
Baseline characteristics***
Study treatment characteristics***
Patient 
id.
CTFI**
PS /
Age/  
Gender
No. of 
prior 
regimens
Last prior 
therapy 
Best 
response/TTP 
last therapy 
Cycles 
received
Best response 
IA/IRC
PFS 
(mo)
IA/IRC
DR
(mo) 
IA/IRC
OS 
(mo)
…
(*) CR + PR + SD ≥ 4 months.
(**) RR, R, S, VS.
(***) Any other clinical relevant variable will be added at the analysis time.
Table 11.3.3.14 Median follow-up by IA and IRC. (All treated patients).
Follow-up*
Median
95% CI/Range
IA
PFS
OS
IRC
PFS
(*) Calculated using the Kaplan-Meier method reversing the censoring values and also by descriptive methods.
Listing 11.3.3.15 Concordance by IA and IRC. (All treated patients).
Patient id.
CTFI*
Study treatment characteristics by IA
Study treatment characteristics by IRC
Best response
PFS (mo)
DR (mo)
Best 
response
PFS (mo)
DR (mo)
(*) RR, R, S, VS.
Table 11.3.3.16 Progression type by IA and IRC. (All treated patients)
IA
IRC
N
%
N
%
Target lesion
Non-target lesion
New lesions 
                       CNS
                       CNS + Other
                       No CNS


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Death due to malignant disease
Other*
(*)Please specify;
Table 11.3.3.17 Censoring reason by IA and IRC. (All treated patients)
IA
IRC
N
%
N
%
Progression-free at last tumor assessment
   FU completed
   FU ongoing
Subsequent therapy before documented progression
Other*
(*)Please specify;
Subgroup Analysis by CTFI (< 90 days and ≥ 90 days/or Refractory (RR) [<30 days], Resistant (R) 
[>=30 and <90 days], Sensitive (S) [>=90 and <180 days] and Very Sensitive (VS)[>=180 days]):
Table 11.3.3.18 Response rate IA and IRC by CTFI (All treated patients).
Response
CTFI< 90 days
CTFI≥ 90 days
RR
R
Total
S
VS
Total
N
%
N
%
N
%
N
%
N
%
N
%
IA
Complete response (CR)
Partial response (PR)
Stable disease SD≥4 months
Stable disease SD<4 months
Progressive disease (PD)
Inevaluable for response*
IRC
Complete response (CR)
Partial response (PR)
Stable disease SD≥4 months
Stable disease SD<4 months
Progressive disease (PD)
Inevaluable for response*
(*) for example: early death, malignant disease; toxicity; tumor assessments not repeated/incomplete; other (specify).
Table 11.3.3.19 ORR IA and IRC by CTFI (All treated patients).
Response rate*
Percentage
Lower 95% limit
Upper 95% limit
IA
CTFI< 90 days
RR
R
Total
CTFI≥ 90 days
S
VS
Total
IRC
CTFI< 90 days
RR
R
Total
CTFI≥ 90 days
S
VS
Total
(*) Confirmed CR + PR. Binomial exact estimator and 95% CI. 
Table 11.3.3.20 Response rate IA and IRC by CTFI (All treated patients).
Response
IA


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Complete 
response (CR)
Partial 
response 
(PR)
Stable 
disease 
SD≥4 
months
Stable 
disease 
SD<4 
months
Progressive 
disease (PD)
Inevaluable for 
response*
N
%
N
%
N
%
N
%
N
%
N
%
CTFI< 90 days
IRC
Complete 
response (CR)
Partial response 
(PR)
Stable disease 
SD≥4 months
Stable disease 
SD<4 months
Progressive 
disease (PD)
Inevaluable*
CTFI≥ 90 days
IRC
Complete 
response (CR)
Partial response 
(PR)
Stable disease 
SD≥4 months
Stable disease 
SD<4 months
Progressive 
disease (PD)
Inevaluable for 
response*
(*) for example: early death, malignant disease; toxicity; tumor assessments not repeated/incomplete; other (specify).
For discrepancies see Listing 11.3.3.15; Percentage in columns
Table 11.3.3.21 Descriptive DR IA and IRC by CTFI.
N
Mean
Std.
Median
Min
Max
IA
CTFI< 90 days
RR
R
Total
CTFI≥ 90 days
S
VS
Total
IRC
CTFI< 90 days
RR
R
Total
CTFI≥ 90 days
S
VS
Total
Table 11.3.3.22 DR IA by CTFI.
CTFI< 90 days*
CTFI≥ 90 days*
RR**
R**
Total*
S**
VS**
Total*
N
Events
Censored
Median DR
DR at 4 months
DR at 6 months
DR at 12 months
(*/**) Kaplan-Meier plot will also be shown. (*) Table/Figure 11.3.3.22.1 with the following categories (CTFI< 90 days and CTFI≥ 


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90 days), (**) Table /Figure 11.3.3.22.2 with the following categories RR, R, S and VS.
Table 11.3.3.23 DR IRC by CTFI.
CTFI< 90 days*
CTFI≥ 90 days*
RR**
R**
Total*
S**
VS**
Total*
N
Events
Censored
Median DR
DR at 4 months
DR at 6 months
DR at 12 months
(*/**) Kaplan-Meier plot will also be shown. (*) Table/Figure 11.3.3.23.1 with the following categories (CTFI< 90 days and CTFI≥ 
90 days), (**) Table /Figure 11.3.3.23.2 with the following categories RR, R, S and VS.
Table 11.3.3.24 Clinical benefit rate and Disease control rate IA and IRC by CTFI (All treated 
patients).
Percentage
Lower 95% 
limit
Upper 95% 
limit
Clinical benefit rate*
IA
CTFI< 90 days
RR
R
Total
CTFI≥ 90 days
S
VS
Total
IRC
CTFI< 90 days
RR
R
Total
CTFI≥ 90 days
S
VS
Total
Disease control rate**
IA
CTFI< 90 days
RR
R
Total
CTFI≥ 90 days
S
VS
Total
IRC
CTFI< 90 days
RR
R
Total
CTFI≥ 90 days
S
VS
Total
(*) CR + PR + SD ≥ 4 months. Binomial exact estimator and 95% CI.
(**) CR + PR + SD. Binomial exact estimator and 95% CI.
Table 11.3.3.25 PFS IA by CTFI (All treated patients).
CTFI< 90 days*
CTFI≥ 90 days*
RR**
R**
Total*
S**
VS**
Total*
N
Events
Censored
Median PFS
PFS at 4 months
PFS at 6 months
(*/**) Kaplan-Meier plots will also be shown. (*)Table/Figure 11.3.3.25.1 with the following categories (CTFI< 90 days and CTFI≥ 
90 days), (**) Table/Figure 11.3.3.25.2 with the following categories RR, R, S and VS.


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Table 11.3.3.26 PFS IRC by CTFI (All treated patients).
CTFI< 90 days*
CTFI≥ 90 days*
RR**
R**
Total*
S**
VS**
Total*
N
Events
Censored
Median PFS
PFS at 4 months
PFS at 6 months
(*/**) Kaplan-Meier plots will also be shown. (*)Table/Figure 11.3.3.26.1 with the following categories (CTFI< 90 days and CTFI≥ 
90 days), (**) Table/Figure 11.3.3.26.2 with the following categories RR, R, S and VS.
Table 11.3.3.27 OS by CTFI (All treated patients).
CTFI< 90 days*
CTFI≥ 90 days*
R**
RR**
Total*
S**
VS**
Total*
N
Events
Censored
Median OS
OS at 6 months
OS at 12 months
(*/**) Kaplan-Meier plots will also be shown. (*)Table/Figure 11.3.3.27.1 with the following categories (CTFI< 90 days and CTFI≥ 
90 days), (**) Table/Figure 11.3.3.27.2 with the following categories RR, R, S and VS.
Subgroup Analysis excluding CTFI < 30 days:
Table 11.3.3.28 Response rate IA and IRC excluding CTFI<30 (All treated patients).
Response
N
%
IA
Complete response (CR)
Partial response (PR)
Stable disease SD≥4 months
Stable disease SD<4 months
Progressive disease (PD)
Inevaluable for response*
IRC
Complete response (CR)
Partial response (PR)
Stable disease SD≥4 months
Stable disease SD<4 months
Progressive disease (PD)
Inevaluable for response*
(*) for example: early death, malignant disease; toxicity; tumor assessments not repeated/incomplete; other (specify).
Table 11.3.3.29 ORR IA and IRC excluding CTFI<30 (All treated patients).
Response rate*
Percentage
Lower 95% limit
Upper 95% limit
IA
IRC
(*) Confirmed CR + PR. Binomial exact estimator and 95% CI.
Table 11.3.3.30 DR by IA and IRC excluding CTFI<30.
IA
IRC
N
Events
Censored
Median DR
DR at 4 months
DR at 6 months 
DR at 12 months 


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Kaplan-Meier plot will also be shown (Figure 11.3.3.30.1 DR by IA excluding CTFI<30 (All treated patients), Figure 11.3.3.30.2 DR 
by IRC excluding CTFI<30 (All treated patients) and 11.3.3.30.3 DR by IA and IRC excluding CTFI<30 (All treated patients))
Table 11.3.3.31 Clinical benefit rate and Disease Control Rate by IA and IRC excluding CTFI<30 
(All treated patients).
Percentage
Lower 95% limit
Upper 95% limit
IA
Clinical benefit rate*
Disease control rate**
IRC
Clinical benefit rate*
Disease control rate**
(*) CR + PR + SD ≥ 4 months. Binomial exact estimator and 95% CI.
(**) CR + PR + SD. Binomial exact estimator and 95% CI.
Table 11.3.3.32 PFS IA and IRC excluding CTFI<30 (All treated patients). 
IA
IRC
N
Events
Censored
Median PFS 
PFS at 4 months 
PFS at 6 months 
Kaplan-Meier plot will also be shown (Figure 11.3.3.32.1 PFS by IA excluding CTFI<30 (All treated patients), Figure 11.3.3.32.2 
PFS by IRC excluding CTFI<30 (All treated patients) and Figure 11.3.3.32.3 PFS by IA and IRC excluding CTFI<30 (All treated 
patients))
Table 11.3.3.33 OS excluding CTFI<30 (All treated patients).
OS
N
Events
Censored
Median OS
OS at 6 months
OS at 12 months
Kaplan-Meier plot will also be shown (Figure 11.3.3.33).
DR and PFS considering event in the clinical progressions:
Table 11.3.3.34 DR IA giving event in clinical PD (All treated patients).
DR
N
Events
Censored
Median DR
DR at 4 months
DR at 6 months
DR at 12 months
Kaplan-Meier plot will also be shown (Figure 11.3.3.34).
Table 11.3.3.35 PFS IA giving event in clinical PD (All treated patients).
PFS
N
Events
Censored
Median PFS
PFS at 4 months
PFS at 6 months
Kaplan-Meier plot will also be shown (Figure 11.3.3.35).


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12. Safety Analysis
Original text:
Safety analysis will be carried out on the “All Treated Patients” population.
Changes to:
Safety analysis will be carried out on the “All Treated Patients” population by cohort of tumor types 
and total population.
Section 12.1.1 Treatment Administration.
Table 12.1.1 Number of cycles administered and dose intensity adds the following footnote: Note: 
Also for s1 and s2.
Sections 12.1.2 Cycles Delays and 12.1.3 Dose Reductions: The following clarification has been 
added to both sections.
The first cycle will be excluded from all calculations.
Section 12.1.2 Cycle delays.
Listing 12.1.2.1 Delays and Listing 12.1.2.6 Cycle delays due to AEs add one new column CTFI* and 
the footnote (*) Only for SCLC patients (RR, R, S, VS).
Table 12.1.2.2 Number of patients and cycles with dosing delay, any relationship.
N
%
No. of patients treated
No. of patients susceptible of delay
No. of patients with any dose delay
No. of cycles administered
No. of cycles susceptible to be delayed
No. of cycles with dosing delay
No. of patients with 
No cycles delayed
1 cycle delayed 
2 cycles delayed
3 cycles delayed
Note: Also for s1 and s2;
Table 12.1.2.3 Number of patients and cycles with dosing delay, treatment related adds the following 
footnote: Note: Also for s1 and s2.
Table 12.1.2.4 Reasons for dosing delay according to the relationship is split into two by patients and 
cycles.


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Reasons for delays
N
%
No. of patients with any dose delay
Treatment-related
X
XX.X
Hematological
Non-hematological
Both
Non-treatment-related
No. of cycles with any dose delay
N
%
Treatment-related
X
XX.X
      Hematological
      Non-hematological
      Both
Non-treatment-related
Note: Also for s1 and s2;
Table 12.1.2.5 Length of dosing delay adds the following footnote: Note: Also for s1 and s2.
Section 12.1.3 Dose Reductions.
Listing 12.1.3.1 Dose Reductions and Listing 12.1.3.5 Dose reductions due to AEs add one new 
column CTFI* and the footnote (*) Only for SCLC patients (RR, R, S, VS).
Table 12.1.3.2 Number of patients and cycles with dose reduction, any relationship.
N
%
No. of patients treated
X
XX.X
No. of patients susceptible to have a dose reduction
No. of patients with any dose reduced
No. of patients with:
No PM01183 reduction
1 cycle with PM01183 dose reduced
2 cycles with PM01183 dose reduced
No. of cycles administered
No. of cycles susceptible to have any dose reduced
No. of cycles with PM01183 dose reduced 
Note: Also for s1 and s2;
Table 12.1.3.3 Number of patients and cycles with dose reduction, treatment related adds the 
following footnote: Note: Also for s1 and s2.
Table 12.1.3.4 Number of patients and cycles with dose reduction according to the relationship is split 
into two by patients and cycles.


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Reasons for reductions
N
%
No. patients with reductions
Treatment-related
X
XX.X
Hematological
Non-hematological
Both
Non-treatment-related
No. of cycles patients with reductions
N
%
Treatment-related
X
XX.X
      Hematological
      Non-hematological
      Both
Non-treatment-related
Note: Also for s1 and s2;
Section 12.2.1 Adverse Events changes to Treatment Emergent Adverse Events
Original text:
Adverse events will be described in this section; treatment-related events (stated as related to the study 
drug or of unknown relationship) will be tabulated. 
(…)
Changes to:
Treatment emergent adverse events will be described in this section; treatment-related events (stated 
as related to the study drug or of unknown relationship) will be tabulated. 
Section 12.2.2 Display of Adverse Events changes to 12.2.2 Treatment Emergent Adverse Events.
Original text:
Table 12.2.2.1 Summary of adverse events per patient
Category*
N
%
Patients with at least one AE regardless of relationship
Any treatment-related** AE
Any grade ≥3 AE
Any treatment-related grade ≥3 AE
Any SAE in DB
Any treatment-related SAE 
Any grade ≥3 SAE 
Any treatment-related grade ≥3 SAE 
AEs leading to death
Treatment-related AEs leading to death
AEs leading to dose delay
AEs leading to dose reduction
AEs leading to treatment discontinuation
Treatment-related AEs leading to treatment discontinuation
(…)
Table 12.2.2.2 Adverse events regardless of relationship. Worst grade by patient.
Table 12.2.2.3 Adverse events regardless of relationship. Worst grade by cycle.
Tables 12.2.2.2 to 12.2.2.5 will have the following pattern, but depending on the number and severity 


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of the adverse events observed, the NCI-CTCAE v4 grades may be grouped as 1-4 and 3/4 categories.
SOC
Preferred term
Grade 
1
…
Grade 
4
All*
N
%
…
N
%
N
%
Blood and lymphatic system 
disorders
Anemia NOS
...
…
Cardiac disorders
Arrhythmia NOS
…
(*)Any grade
Listing 12.2.2.7 Treatment-related grade 3/4 adverse events. Worst grade by cycle.
Listing 12.2.2.8 Grade 3/4 adverse events regardless of relationship. Worst grade per patient. 
Listing 12.2.2.9 Grade 3/4 adverse events regardless of relationship. Worst grade by cycle.
Listings 12.2.2.6 to 12.2.2.9 will have the following pattern:
(….)
Patient id.
Cycle*
SOC name
Preferred term
Grade
(*)NA in the patient summaries;
Changes to:
Table 12.2.2.1 Summary of Treatment emergent adverse events per patient.
Category**
N
%
Patients with at least one TEAE regardless of relationship
Any treatment-related** AE
Any grade ≥3 TEAE
Any treatment-related grade ≥3 AE
Any Treatment emergent SAE in DB
Any treatment-related SAE 
Any grade ≥3 Treatment emergent SAE 
Any treatment-related grade ≥3 SAE 
TEAEs leading to death
Treatment-related AE leading to death
TEAEs leading to dose delay***
TEAEs leading to dose reduction***
TEAEs leading to treatment discontinuation
Treatment-related AEs leading to treatment discontinuation
Note: Also for s1 and s2; (*) Percentage based on number of treated patients; (**) Treatment related adverse event is every event whose 
relationship is ‘Yes’ or ‘Unknown’. (***) TEAEs leading to dose delay and reduction according to the AE form, with no delay or 
reduction because the patient discontinues treatment and there is no additional cycle administered are not counted here.
Table 12.2.2.2 Treatment emergent adverse events regardless of relationship. Worst grade by patient.
Table 12.2.2.3 Treatment emergent adverse events regardless of relationship. Worst grade by cycle.
(…)
Tables 12.2.2.2 to 12.2.2.5 will have the following pattern, but depending on the number and severity 
of the adverse events observed, the NCI-CTCAE v4 grades may be grouped as ≥1 and ≥3 categories.


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SOC
Preferred term
Grade 
1
…
Grade 
4
Grade 
≥1
Grade 
≥3
N
%
…
N
%
N
%
N
%
Blood and lymphatic 
system disorders
Anemia NOS
...
…
Cardiac disorders
Arrhythmia NOS
Note: Tables 12.2.2.2 and 12.2.2.4 also for s1 and s2;
(….)
Listings 12.2.2.6 to 12.2.2.9 will have the following pattern:
Patient id.
CTFI**
Cycle*
SOC name
Preferred term
Grade
(*) NA in the per patient summaries;(**) CTFI only for SCLC patients (RR, R, S, VS)
Listing 12.2.2.7 Treatment-related grade ≥3 adverse events. Worst grade by cycle.
Listing 12.2.2.8 Grade ≥3 treatment emergent adverse events regardless of relationship. Worst grade 
per patient. 
Listing 12.2.2.9 Grade ≥3 treatment emergent adverse events regardless of relationship. Worst grade 
by cycle.
Section 12.3.1 Serious Adverse Events.
Original text:
Table 12.3.1.1 SAEs
Patient 
id.
Preferred  
term code
Adverse event 
reported 
(verbatim)
Status
Grade
Relationship
Onset date
Resolution
date
Action
Serious criteria
Changes to:
Table 12.3.1.1 SAEs
Patient 
id.
Preferred  
term code
Onset 
Cycle
Intended 
Dose of 
onset cycle
(mg/m2)
Adverse 
event 
reported 
(verbatim)
Status Grade Relationship
Onset date
Resolution
date
Action Serious criteria
Also the following tables are included:
Table 12.3.1.2 Treatment-related serious adverse events. Worst grade by patient.
Table 12.3.1.3 Treatment-related serious adverse events. Worst grade by cycle.
Table 12.3.1.4 Serious adverse events regardless of relationship. Worst grade by patient.
Table 12.3.1.5 Serious adverse events regardless of relationship. Worst grade by cycle.
Tables 12.3.1.2 to 12.3.1.5 will have the following pattern, but depending on the number and 


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severity of the adverse events observed, the NCI-CTCAE v4 grades may be grouped as ≥1 and ≥3 
categories.
SOC
Preferred term
Grade 
1
…
Grade 
4
All*
N
%
…
N
%
N
%
Blood and lymphatic system 
disorders
Anemia NOS
...
…
Cardiac disorders
Arrhythmia NOS
…
Note: Tables 12.312.2 and 12.3.1.4 also for s1 and s2;
Table 12.3.1.6 Treatment-related grade ≥3 serious adverse events. Worst grade per patient.
Table 12.3.1.7 Treatment-related grade ≥3 adverse events. Worst grade by cycle.
Table 12.3.1.8 Grade ≥3 adverse events regardless of relationship. Worst grade per patient.
Table 12.3.1.9 Grade ≥3 adverse events regardless of relationship. Worst grade by cycle.
Listings 12.3.1.6 to 12.3.1.9 will have the following pattern:
Patient id.
CTFI**
Cycle*
SOC name
Preferred term
Grade
(*)NA in the patient summaries ;(**) CTFI only for SCLC patients (RR, R, S, VS)
Section 12.3.2 Deaths
Original text:
Table 12.3.2.1 Cause of death.
Reason*
N
%
Malignant disease
Study drug-related AE
Non-study drug-related AE
Other 
Total
(*) Denominator=Number of patients who died.
Listing 12.3.2.2 Deaths.
Patient id.
Death 
date
Cause
No. of cycles 
administered
Last
infusion 
date
Time on 
treatment*
Time from
Last dose **
Comments
Autopsy
(*) Time on treatment: defined as date of last infusion plus 30 days, or date of death or subsequent therapy (whichever comes first) 
minus date of first infusion.  (**) Time from last dose defined as date of death minus date of last infusion. 
Listing 12.3.2.3 Adverse events with outcome death.
Patient id. 
Cycle
Preferred  term 
code
Adverse event 
reported 
(verbatim)
Grade
Relationship
Onset 
date 
Date of death
Action


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Changes to:
Table 12.3.2.1 Cause of death.
Reason*
N
%
Malignant disease
Study drug-related TEAE
Non-study drug-related TEAE
Other 
Total
Note: Also for s1 and s2; (*) Denominator=Number of patients who died.
Listing 12.3.2.2 Deaths.
Patient 
id.
CTFI***
Death 
date
Cause
No. of cycles 
administered
Last
infusion 
date
Time on 
treatment*
Time from
Last dose **
Comments
Autopsy
(*) Time on treatment: defined as date of last infusion plus 30 days, or date of death or subsequent therapy (whichever comes first) 
minus date of first infusion.  (**) Time from last dose defined as date of death minus date of last infusion. (***) Only for SCLC cohort 
(RR, R, S, VS).
Listing 12.3.2.3 Adverse events with outcome of death.
Patient id. 
Cycle
Preferred  term 
code
Adverse event 
reported 
(verbatim)
Grade
Relationship
Onset 
date 
Date of death
Action
Section 12.4.1 Hematological Abnormalities during Treatment and section 12.4.2 Biochemical 
Abnormalities during Treatment.
Tables 12.4.1.1 to 12.4.1.2 and Tables 12.4.2/3.1 to 12.4.2/3.2 will have the following pattern, but 
depending on the number and severity of the adverse events observed the NCI-CTCAE v4 grades may 
be grouped as ≥1 and ≥3 categories.
Grade 
1
…
Grade 
4*
Grade 
≥1
Grade 
≥3
N
%
…
N
%
N
%
N
%
….
….
Note: Tables 12.4.1/2.1 and 12.4.1/2.2 also for s1 and s2;
Section 12.5.2 LVEF, ECG and Other Related Tests
Original text:
Listing 12.5.2.1 LVEF evolution during the study.
LVEF(%)
Baseline*
Minimun* 
End of treatment*
Patient id.
Median (Range) Mean, Standard Deviation
(*) LVEF (%) value and method.


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Listing 12.5.2.2 Electrocardiogram results. Evolution during the study.
(*) Worst result of the cycle determinations.
Changes to:
Listing 12.5.2.1Patients with abnormal or clinical indicated LVEF during the study. 
Patient 
id.
Assessment 
date
Abnormality
Specify
Reason for 
clinically 
indicated repeat
Method
LVEF (%)
Institution 
normal range
Listing 12.5.2.2 Patients with abnormal or clinical indicated Electrocardiogram during the study.
Patient 
id.
Assessment 
date
Result
Specify
Reason 
for 
clinically 
indicated 
repeat
PR 
interval 
(msec)
Heart rate 
(bpm)
QT 
interval 
(msec)
QRS 
complex 
(msec)
QTc 
Fridericia
QTc*
(Bazett’s)
(*) QTc (Bazett’s) = QT interval / √(60/Heart rate).
Section 12.6 Concomitant Therapy / Procedures According to the ATC Classification. Add new tables 
and new variables in existing tables. New numbering of tables is needed
Table 12.6.1 Concomitant medication during treatment (ATC1, ATC2, ATC3 and ATC4 levels).
Table 12.6.3 Patients and cycles with any transfusions during treatment.
N
%
No. of patients with Platelet transfusions 
No. of cycles with Platelet transfusions
No. of patients with RBC
No. of cycles with RBC
No. of patients with GCSF
Section 12.4.4 Laboratory Values over Time.
Original text:
Tables 12.4.4.5 and 12.4.4.6 will have the following pattern:
All cycles
First cycle
N
%
N
%
Grade 3/4* onset day
Nadir (x109/L)
Duration of grade 3/4 decrease 
Day of recovery to grade 1/2 or baseline values**
(*) Grade 3 or 4; (**) grade 2 or less.
Tables 12.4.4.7 and 12.4.4.8 will have the following pattern:
All cycles
First cycle
N
%
N
%
Cycle/ECG result*
0
1
2
3
4
…
EOT
Patient id.
…


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Grade 3/4* onset day
Peak (x109/L)
Duration of grade 3/4 decrease
Day of recovery to grade 1/2 or baseline values**
(*) Grade 3 or 4; (**) grade 2 or less.
Changes to:
Tables 12.4.4.5 and 12.4.4.6 will have the following pattern:
All cycles
First cycle
N, mean, Std., median, 
Range
N, mean, Std., median, Range
Grade ≥3* onset day
Nadir (x109/L)
Duration of grade ≥3 (days)
Day of recovery to grade 1/2 or baseline values**
(*) Grade 3 or 4; (**) grade 2 or less.
Tables 12.4.4.7 and 12.4.4.8 will have the following pattern:
All cycles
First cycle
N, mean, Std., median, 
Range
N, mean, Std,. median, Range
Grade ≥3* onset day
Peak (x109/L)
Duration of grade ≥3 (days)
Day of recovery to grade 1/2 or baseline values**
(*) Grade 3 or 4; (**) grade 2 or less.
New Section 12.7 Subsequent therapy. This section contains some tables from previous section 12.6 
Concomitant Therapy / Procedures According to the ATC Classification. Tables 12.6.5 First 
Subsequent therapy and Table 12.6.6 First Subsequent therapy. Best Response (if available).
Original text:
Table 12.6.5 First Subsequent therapy.
N
%
Type
Medical therapy 
   …
Subsequent chemotherapy agents (ATC)
  …
   …
Table 12.6.6  First Subsequent therapy. Best response (if available).
Best response
First Subsequent therapy
CR
PR
SD
PD
NE
PM01183
CR
PR
SD
PD
NE
(*) If a low number of best responses to the subsequent therapy are available, a listing, instead of this table, will be 
provided. 
Changes to:


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Table 12.7.1 Any Subsequent medical therapy.
N
%
Type
  Medical therapy
  Radiotherapy
  Surgery
Number of subsequent medical therapies (Median and range)
0
1
2
…
Subsequent agents of medical therrapy (ATC)
  …
   …
Note: Also for s1 and s2;
Table 12.7.2 First Subsequent medical therapy.
N
%
Subsequent chemotherapy agents (ATC)
  …
   …
Note: Also for s1 and s2;
Table 12.7.3 First Subsequent medical therapy. Best response (if available).
Best response
First Subsequent therapy
CR
PR
SD
PD
NE
PM01183
CR
PR
SD
PD
NE
Note: Also for s1 and s2; (*) If a low number of best responses to the subsequent therapy are available, a listing, instead 
of this table, will be provided. In case of sufficient number of subsequent Immunotherapy, a separate table/listing will be 
performed for patients having immunotherapy as first subsequent therapy.
Table 12.7.4 First Subsequent medical therapy. PFS (if available).
PFS (months)
First Subsequent therapy
<1 month
[1-3) months
[3-6) months
[6-12) months
≥12 months
PM01183
<1 month
[1-3) months
[3-6) months
[6-12) months
≥12 months
Note: Also for s1 and s2;
Any other exploratory analyses will be performed at the analysis time if any relevant variable will 
be considered potentially relevant. Table’s layout will follow the same prior patterns.  
Any other exploratory analyses will be performed at the analysis time if any relevant variable will be 
considered potentially relevant. Table’s layout will follow the same prior patterns. 
New Section 12.8 Subgroup Analyses Related to Safety 


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Table 12.8.1 Worst grade ≥3by patient in special subgroups (Sex).
Table 12.8.2 Worst grade ≥3 by cycle in special subgroups (Sex).
Table 12.8.3 Worst grade ≥3 by patient in special subgroups (Age).
Table 12.8.4 Worst grade ≥3 by cycle in special subgroups (Age).
Table 12.8.5 Worst grade ≥3 by patient in special subgroups (Race).
Table 12.8.6 Worst grade ≥3 by cycle in special subgroups (Race).
Table 12.8.7 Worst grade ≥3 by patient in special subgroups (Number of prior lines).
Table 12.8.8 Worst grade ≥3 by cycle in special subgroups (Number of prior lines).
Table 12.8.9 Worst grade ≥3 by patient in special subgroups (BSA).
Table 12.8.10 Worst grade ≥3 by cycle in special subgroups (BSA).
Table 12.8.11 Worst grade ≥3 by patient in special subgroups (ECOG).
Table 12.8.12 Worst grade ≥3 by cycle in special subgroups (ECOG).
Table 12.8.13 Worst grade ≥3 by patient in special subgroups (Geographical area).
Table 12.8.14 Worst grade ≥3 by cycle in special subgroups (Geographical area).
Tables 12.8.1 to 12.8.12 will have the following pattern:
Laboratory abnormalities/ drug-
related AEs
Subgroup 1
Subgroup 2
….
No. of 
patients 
evaluated
Grade 
≥3
%
No. of 
patients 
evaluated
Grade 
≥3
%
No. of 
patients 
evaluated
Grade 
≥3
%
Thrombocytopenia
Neutropenia 
AP 
Bilirubin 
AST 
ALT 
CPK
Nausea
Vomiting


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Laboratory abnormalities/ drug-
related AEs
Subgroup 1
Subgroup 2
….
No. of 
patients 
evaluated
Grade 
≥3
%
No. of 
patients 
evaluated
Grade 
≥3
%
No. of 
patients 
evaluated
Grade 
≥3
%
Fatigue
Other*
(*)Any drug-related toxicity present in >=5% of patients in any group.
Section 13: Figures. This section has been updated according to the planned number of analysis 
described in section 11.3 Efficacy Analysis and due to the elevated number of figures displayed in this 
section the numbering of the figures is changed accordingly.
The following paragraph is added:
Figures displayed in this section will have a comprehensive header identifying the tumor type (cohort) 
or the total population (if applicable) and/or any other specific subgroups (e.g: CTFI categorized). 
See examples below, numbering will be updated accordingly.
Previous Figures from 13.1.4 Best RECIST Efficacy assessment in evaluable pts per tumor type to 
13.1.7 Barcharts of hematological/biochemical laboratory abnormalities per tumor type and 13.19 
Box-plots of change in LVEF/QTcF from baseline to lowest/highest value during study per tumor 
type/cycle are deleted.
Figure 13.1.2 Waterfall graph.
Waterfall for each tumor type will be also provided. Also SCLC by CTFI (RR, R, S VS).
Figure 13.1.2 Waterfall graph per tumor type by IRC (SCLC cohort)


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Waterfall for SCLC and by CTFI (RR, R, S, VS). 
NOTE: If the measurements of the first and the second radiologists are the same, the target lesions measurements of the first one 
will be selected. If the measurements of both radiologists are different and an adjudicator is involved, his/her endorsement will be 
selected. 
Figure 13.1.4 Best response, PFS and Reasons for discontinuation (SCLC cohort)
Also for s1 and s2. 


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Figure 13.1.5 Last previous TTP vs PFS PM01183 (SCLC cohort).
Note: For PM01183 responders and/or SD (if applicable)
Figures described in Section 11.3 Efficacy Analysis will have the following pattern depending on the 
number of groups represented.


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Section 14: DB Listings.
DB listings, ICH and BIMO listings are included in a new section renamed to Section 14. DB Listings, 
BIMO and ICH Listings.
All listings in this section add a mock table and include the name of variables to be listed.
CRF Listings.
Original text:
- Listing 14.1.1: Cover
- Listing 14.1.2: Study registration
- Listing 14.1.3: Demography
- Listing 14.1.4: Pregnancy test and adequate contraception
- Listing 14.1.5: Prior medical history
- Listing 14.1.6: Cancer history
- Listing 14.1.7: Prior surgery
- Listing 14.1.8: Prior radiotherapy
- Listing 14.1.9: Prior medical therapy
- Listing 14.1.10: Hematological laboratory values
- Listing 14.1.11: Biochemical laboratory values
- Listing 14.1.12: Coagulation laboratory values
- Listing 14.1.13: Physical examination
- Listing 14.1.14: Performance status
- Listing 14.1.15: Vital signs
- Listing 14.1.16: Electrocardiogram
- Listing 14.1.17: LVEF
- Listing 14.1.18: Prophylactic medication
- Listing 14.1.19: Drug administration
- Listing 14.1.20: Adverse events (including adverse events at baseline)
- Listing 14.1.21: Concomitant therapy/procedures
- Listing 14.1.22: Tumor assessment


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- Listing 14.1.23: Evaluation of response by cycle
- Listing 14.1.24: Best study overall response
- Listing 14.1.25: End of treatment
- Listing 14.1.26: Follow up
- Listing 14.1.27: Death report form
- Listing 14.1.28: Off study
Changes to:
Listing 14.1.1: Cover.
Patient id.
Informed Consent Date
Part of QT 
substudy?
QT informed
consent
date
Patient
QT inclusion
accepted
by Pharmamar?
PGN/PGx
consent
PGN/PGx
date
Listing 14.1.2: Study registration.
Patient id.
Patient inclusion accepted by Pharmamar?
Eligibility requirements?
Criterion identifier I/E
I/E details
Listing 14.1.3: Demography.
Patient id.
Age at inclusion
Gender
Race
Other Race, specify
Listing 14.1.4: Pregnancy test and adequate contraception.
Pregnancy test
Adequate contraception
Patient id.
Visit
Not
applicable?
Reason
Not 
done?
Sample 
date
Result
Reason 
for 
clinicall
y 
indicate
d repeat
Adequate 
contraception?
Specify
Listing 14.1.5: Prior medical history.
Patient id.
Event/Condition
System
Organ
Class
MedDRA
Preferred
Term
Onset date
End date
Ongoing?
Listing 14.1.6: Cancer history.
Current stage 
At diagnosis
Patient 
id.
Tumor 
type
….*
Date of 
advanced/metastasic 
disease
Date of 
last PD
Sites:Primary
tumor/local relapse
(Not for UPS)
Sites**
Diagnosis 
date
Stage
TNM
(*) For each tumor type CRF has specific categories. e.g: Endometrial patients; (Carcinoma type, Histology type, Other) 
(**)Tumor sites are nested for each patient obtained from Cancer History Form e.g: (Lung/Liver/LN:/Neck LN/Mediastinal LN); 
Listing 14.1.7: Prior surgery.
Patient id.
None?
Site and Procedures
Date
Intention


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Listing 14.1.8: Prior radiotherapy.
Patient id.
None?
Type
Intention
Site
Total dose
First dose
Last dose
Listing 14.1.9: Prior medical therapy.
Patient id.
None?
Regimen
Setting
Agent
Agent
Coded
Agent Class
Setting
Start Date
Stop Date
Best
Resp.
Prog. Date
Non PD
Listing 14.1.10: Hematological laboratory values.
Patient 
id.
Visit
Date
n
Clinically 
indicated 
repeat 
required?
Hemoglobin 
(g/dl)
Platelets 
(x10*9/L)
WBC 
(x10*9/L)
Neutrophils 
(x10*9/L)
Lymphocytes 
(x10*9/L)
Monocytes 
(x10*9/L)
Listing 14.1.11: Biochemical laboratory values.
Patient 
id.
Visit
Date
n
Clinically 
indicated 
repeat 
required?
Total Bilirubin 
(mg/dl)
Direct Bilirubin 
(mg/dl)
AST 
(IU/L)
ALT 
(IU/L)
AP 
(IU/L)
…..*
(*)GGT (IU/L), Glucose (mg/dL), Creatinine (mg/dl), CrCl (mL/min), NA (mmol/L), CL (mmol/L), K  (mmol/L), LDH (xULN), CPK 
(IU/L), Total Proteins (g/dl), Albumin (g/dl), CA (mg/dl), Mg (mg/dl), INR (ratio), PT (sec/ratio), PTT (sec/ratio), AFP (ng/m), hCG 
(IU/L)
A new listing is included:
Listing 14.1.12: Alpha Glycoprotein.
Patient id.
Visit
Date
n
Alpha-1-acid glycoprotein 
(MG/DL)
Comments 1
Comments 2
Listing 14.1.13: Coagulation laboratory values.
Patient id.
Visit
Date
n
Clinically indicated 
repeat required?
INR (ratio)
PT (sec)
PTT 
(sec)
Listing 14.1.14: Physical examination.
Patient id.
Visit
Not done
Date
Abnormalities
Weight
(Kg)
Height
(cm)
BSA
(m2)
Body System
Findings
Clinical Significance
Listing 14.1.15: Performance status.
Patient id.
Not Done 
Visit
ECOG
Listing 14.1.16: Vital signs.
Patient id.
Not done
Visit 
Date
Heart Rate
(BPM)
Systolic
(mmHG)
Diastolic
(mmHG)
Temperature 
(ºC)
Listing 14.1.17: Electrocardiogram.
Patient 
id.
Not 
done
Visit
ECG 
Date
Result
Abnormal, 
specify
PR
Interval(msec)
Heart 
rate 
QT
Interval(msec)
QRS
Interval(msec)
Corrected 
QT


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(bpm)
Fridericia
Listing 14.1.18: LVEF.
Patient id.
Not done
Visit
LVEF Date
Type
Value
Range
Result
Abnormal, specify
Reason for clinically indicated
Listing 14.1.19: Prophylactic medication.
Patient 
id.
Visit
Medication
Drug 
Type
...*
Route
Daily 
Dose
Units
Start 
date
End 
date
Time
Taken per 
protocol
Specify
(*) ATC1, ATC2, ATC3, ATC4.
Listing 14.1.20: Drug administration.
Reductions
Delays
Patient 
id.
Visit
Admin. 
date
Start 
time
End 
time
Intended  
dose
Total 
dose
Adm. 
Volume
Dose  
reduced?
Reason
Dose 
delayed?
Reason
Dose 
interrupted?
Listing 14.1.21: Adverse events (including adverse events at baseline).
Patient 
id.
Adverse 
Event 
Verbatim
NCI-
CTC 
Grade
SAE
Onset 
cycle
Onset 
date
Ongoing
End 
cyc.
End 
date
Ongoing/
Continuing
Relationship
Specify
Action
taken
Seriousness 
Criteria
Listing 14.1.22: Concomitant therapy/procedures.
Patient id.
Medication  
type
Medication
Reason
…*
Route/Dose(Units)/Time 
interval
Start 
date
End 
date
Indication
AE
Other
(*) ATC1, ATC4
Listing 14.1.23: Tumor assessment.
Target
Non target
New lesions
Patient
id.
…..*
Sum of
Diameters
Var.(%)
….*
Response
…*
Longest diameter
Non-measurable
(*) Visit, Not done, lesion, organ site, date, method. Sort by Visit and then by Start date,
Listing 14.1.24: Evaluation of response by cycle.
Patient id.
Visit
Not done?
Date
Response 
Target lesions
Response 
Non Target 
Lesions
New lesions?
Overall cycle response
Listing 14.1.25: Best study overall response by IA and IRC and End of treatment.
Patient id.
CTFI*
Best Response by 
IA**
Best Response by 
IRC*
End of treatment 
Reason
End of treatment, Specify
(*) Only for SCLC cohort. (**) Data obtained from radiological assessment of response in the CRF
Listing 14.1.26: Follow up.
Patient 
id.
Follow-
up date
Survival 
status
Previous 
PD 
or 
Therapy
TA 
Done
Reason
Type of 
therapy
Start 
date
End 
date
Treatment*
Best 
response**
Progression date**


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(*) Procedure for surgery, localization for radiotherapy or agent for medical therapy.
(**) Only for Medical therapy. Sort by FU date first and then by Start date.
Listing 14.1.27: Off study and Death report form.
Off study
Death report
Patient id.
Off study 
Reason
If other 
Specify
Off study date
Best response
Death 
Date
Cause
Specify
Autopsy?
Listing 14.1.28: Investigator comments and Investigator comments before end of study.
Patient id.
Page name
Instance
Variable
Comment
In the SCLC cohort and to fulfil the Office of Scientific Investigations (OSI) request that the items 
described in the draft Guidance for Industry Standardized Format for Electronic Submission of 
NDA and BLA Content for the Planning of Bioresearch Monitoring (BIMO) Inspections for CDER 
Submissions (February 2018) and the associated Bioresearch Monitoring Technical Conformance 
Guide Containing Technical Specifications will be provided following the recommended 
standardized formats.
https://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/FormsSubmissionRequireme
nts/UCM332466.pdf
https://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/FormsSubmissionRequireme
nts/UCM332468.pdf.
Table 15.1 Site Level Summary SCLC PM1183B00514
Site
Patients Screened
Patients Treated
Patients End of 
Treatment
Patients Off Study
Listings: 
Listing 15.2 Consented Subjects by Site.
Site
Patient id.
Informed
Consent date
Screening
failure?
Date of 
Screening 
failure
Met 
Eligibility
Criterion
Identifier
Details
Treated
Date of
First
treatment
Listing 15.3 Treatment Assignment by Site.
Site
Patient id.
DA Start date
First Intended dose
Listings 15.4 Discontinuations by Site.
Site
Patient id.
End of treatment Reason
End of treatment, Specify
Off study 
date
Off study 
Reason
If other 
Specify
Listings 15.5 Study Population by Site.
Site
Patient id.
Included population
Treated population
Reason
Evaluable population
Reason


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Listings 15.5 Inclusion and Exclusion Criteria by Site.
Site
Patient id.
Eligibility requirements?
Criterion identifier I/E
I/E details
Listings 15.6 Adverse Events by Site.
Site
Patient 
id.
Adverse 
Event 
Verbatim
NCI-
CTC 
Grade
SAE
Onset 
cycle
Onset 
date
End 
cyc.
End 
date
Relationship 
Specify
Action
taken
Seriousness 
Criteria
Listings 15.7 Protocol Deviations by Site.
Site
Patient id.
Deviation type
Deviation
Listings 15.8 Efficacy Endpoints by Site.
Site
Patient id.
Best 
response 
by IA
Best 
response 
by IRC
PFS by IA 
(months)
PFS by IRC 
(months)
DOR by IA 
(months)
DOR by IA 
(months)
OS
(months)
Death 
status
Listings 15.9 Concomitant Medications by Site.
Site
Patient 
id.
Medication  
type
Medication
Reason
…*
Route/Dose(Units)/Time 
interval
Start 
date
End 
date
Indication
(*) ATC1, ATC4
In accordance with ICH E-3 guidelines, the patient listings specified as Section 16.2 will be prepared 
by tumor type and for the total of patients.
Listing 16.2.1 Discontinued Patients.
Patient id.
Institution
Treated
Cycles 
received
First infusion 
date
Last infusion 
date
Reason for end of 
treatment
Comments
Listing 16.2.2 Protocol Deviations.
Patient id.
Type
Description
Listing 16.2.3 Patients Not Included in the Efficacy Analysis.
Patient id.
Non evaluable reason
Listing 16.2.4 Demographic Data.
Patient 
id.
Tumor 
type
Histology
type*
Stage*
Age/Years
ECOG
Weight 
(kg)
Height 
(cm)
BSA 
(m2)
Prior 
Radiotherapy
Prior agents for 
the
treatment
(*)At diagnosis.
Listing 16.2.5 Compliance and/or Drug Concentration Data.


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Patient id.
Drug
First 
Intended
dose
(mg/m2)
Cycles 
received
Start date 
(First 
cycle)
Start date 
(Last 
cycle)
Total dose 
(mg/m2)
Dose intensity 
per week 
(mg/m2/wk)
Relative 
Dose 
intensity  
(%)
Delays*
Reductions*
(*) Delays/reductions will be nested for each patient (cycle and reasons of delay/reduction). e.g: C1 hematological toxicity/C3 non 
drug related.
Listing 16.2.6 Individual Efficacy Response Data.
Patient id.
Best Response by 
IA
Best Response by 
IRC*
PFS by IA 
(months)
PFS by 
IRC* 
(months)
DOR by 
IA 
(months)
DOR by 
IRC* 
(months)
OS (months)
(*) Only for SCLC
Listing 16.2.7 Adverse Event Listing.
Patient id.
Literal
Preferred Term
Grade 
Coded 
Value
SAE
Onset date
Resolved 
date
Relationship
Action taken Serious criteria
Listing 16.2.8 Listing of Individual Laboratory Measurements by Patient.
Hemoglobin
(g/dL)
WBC
(10*9/L)
Neutrophils
(10*9/L)
Lymphocytes
(10*9/L)
…*
Patient id.
Cycle
Examination
date
Laboratory
Std.value
Std.value
Std.value
Std.value
Std.value
(*) Monocytes (x10*9/L), Direct Bilirubin (mg/dl),Total Bilirubin (mg/dl), AST IU/L),  ALT (IU/L)  AP (IU/L), GGT (IU/L), Glucose 
(mg/dL), Creatinine (mg/dl), CrCl (mL/min), NA (mmol/L), CL (mmol/L), K  (mmol/L), LDH (xULN), CPK (IU/L), Total Proteins 
(g/dl), Albumin (g/dl), CA (mg/dl), Mg (mg/dl), INR (ratio), PT (sec/ratio), PTT (sec/ratio), AFP (ng/m), hCG(IU/L).


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15.3
SAP version history v3.0
After the third version of the SAP was approved, in order to maintain the consistency in the SCLC 
cohort the “All Treated Patients” population set will be used for the descriptive analyses of baseline 
characteristics. The “All Included Patients” dataset will be used for the descriptive analyses of 
disposition of patients in each cohort of advanced solid tumors. In order to maintain the consistency in 
the presented cohorts all treated population will be used also for baseline characteristics in the other 
cohorts.

The “All treated patients” dataset will be used to describe baseline characteristics, and narratives 
will be used to describe patients who are included but not treated.

Other descriptive tables of interest for the SCLC cohort are included. 

Other not relevant minor comments/clarifications.
Detailed changes are presented in the next pages. Changes are highlighted in Italic bold and text 
removed has been crossed out.
Any changes in the automatic numbering of tables, sections and references in the SAP are not listed but 
will be implemented in the new version.
Section 4.1: Included population
Original text:
The “All Included Patients” dataset, defined as all patients accepted by the sponsor to take part in the 
trial, will be used for the descriptive analyses of disposition of patients and baseline characteristics in 
each cohort of advanced solid tumors.
Changes to:
The “All Included Patients” dataset, defined as all patients accepted by the sponsor to take part in the 
trial, will be used for the descriptive analyses of disposition of patients and baseline characteristics in 
each cohort of advanced solid tumors.
Section 10.1: Patient Disposition.
Adds ** and clarifies evaluable patients.
Table 10.1.1 Number of patients included, treated and evaluable for the primary endpoint.
N
%
Included patients
Eligible patients*
Treated patients
Evaluable patients for efficacy**
Evaluable patients for efficacy by IRC (SCLC cohort)***
(*) Patients who were considered eligible according to the registration screening form and were accepted to take part in the trial with the 
sponsor’s agreement in the screening reply form. (**) Includes patients treated with early death/or PD not documented by image 
(early PD). (***) For sensitivity analysis.


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Section 10.2 Reasons for Treatment Discontinuation.
Original text:
Each table, listing and figure displayed in this section will have a comprehensive header identifying 
the tumor type (cohort) or the total population (if applicable).
Changes to:
Section 10.2 Reasons for Treatment and Study Discontinuation.
Each table, listing and figure displayed in this section will have a comprehensive header identifying 
the tumor type (cohort) or the total population (if applicable). The reasons for treatment 
discontinuation will be calculated in the treated patient’s population. The rest of tables and listings 
in this section will be calculated in the included patient’s population.
Section 11.1: Demographic and Other Baseline Characteristics.
Original text:
Each table, listing and figure displayed in this section will have a comprehensive header identifying 
the tumor type (cohort) or the total population (if applicable).
Changes to:
Demographic and Other Baseline Characteristics will be carried out on the “All Treated Patients” 
population and narratives will be used to describe patients who are included but not treated.
Each table, listing and figure displayed in this section will have a comprehensive header identifying 
the tumor type (cohort) or the total population (if applicable).
Section 10.1.8: Disease at Diagnosis and Disease at Study Entry: BRCA 1/2-associated 
Metastatic Breast Carcinoma (MBC).
Original text:
Table 11.1.8.5 Receptor status. 
Positive
Negative
N
%
N
%
Estrogen receptor
X
XX.X
X
XX.X
Progesterone receptor
HER-2/neu receptor
Total


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Table 11.1.8.6 Hormonal status.
N
%
Triple negative
X
XX.X
ER and/or PR positive + HER2 negative
Hormone receptor positive*
Total
(*) ER and/or PR positive + HER2 positive and ER and PR negative + HER2 positive
Changes to:
Table 11.1.8.5 Receptor status. 
Positive
Negative
N
%
N
%
Estrogen receptor
X
XX.X
X
XX.X
Progesterone receptor
HER-2/neu receptor
Total
Table 11.1.8.6 Hormonal status.
N
%
ER and/or PR positive and HER2 negative
X
XX.X
ER and/or PR positive and HER2 positive
ER and/or PR negative and HER2 positive
Triple negative
Total
Note: Triple negative: HER2 negative ER negative and PR negative
Section 11.1.12: Prior History. Adds new tables of interest for SCLC cohort
Table 11.1.12.3 Smoker status.
*
N
%
Former/current
X
XX.X
Never                              
UK
Total
(*) Only for SCLC cohort and information obtained from CRF pages of Prior history.
Table 11.1.12.4 Paraneoplastic syndrome.
*
N
%
Yes 
X
XX.X
No                             
Total
(*) Only for SCLC cohort and information obtained from CRF pages AEs at baseline and/or Prior history. 
Section 11.1.17: Biochemical values at baseline. Add new tables of interest for SCLC cohort
Table 11.1.17.5 AAGP values at baseline.
N
Mean
Std.
Median
Min
Max
AAGP (xULN)  
Table 11.1.17.6 Abnormal LDH at baseline.
*
N
%


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Yes
X
XX.X
No                             
Total
(*) Only for SCLC cohort. Abnormal LDH: (>ULN) 
Section 11.3 Efficacy Analysis.
Original text:
Listing 11.3.3.13 Characteristics of patients with clinical benefit by CTFI by IA and IRC. (All treated
patients).
Baseline characteristics
Study treatment characteristics
Patient 
id.
CTFI**
PS /
Age/  
Gender
***
No. of 
prior 
regimens
Last prior 
therapy 
Best 
response/TTP 
last therapy 
Cycles 
received
Best response 
IA/IRC
PFS 
(mo)
IA/IRC
DR
(mo) 
IA/IRC
OS 
(mo)
…
(*) CR + PR + SD ≥ 4 months.
(**) RR, R, S, VS.
(***) Any other clinical relevant variable will be added at the analysis time.
Changes to:
Listing 11.3.3.13 Characteristics of patients with clinical benefit* by CTFI by IA and IRC. (All 
treated patients).
Baseline characteristics
Study treatment characteristics
Patient 
id.
CTFI**
PS /
Age/  
Gender
***
No. of 
prior 
regimens
Last prior 
therapy 
Best 
response/TTP 
last therapy 
Cycles 
received
Best response 
IA/IRC
PFS 
(mo)
IA/IRC
DR
(mo) 
IA/IRC
OS 
(mo)
…
(*) CR + PR + SD ≥ 4 months.
(**) RR, R, S, VS.
(***) Any other clinical relevant variable (including sites of disease, limited/extended disease, LDH [normal/abnormal] and alpha-
acid glycoprotein [xULN]) will be added at the analysis time.
Section 12.6 Concomitant Therapy / Procedures According to the ATC Classification. Add new 
variables in existing tables.
Original text:
Table 12.6.1 Concomitant medication during treatment (ATC1, ATC2, ATC3 and ATC4 levels).
Changes to:
Table 12.6.1 Concomitant medication during treatment (ATC1/ATC2/ATC3/ATC4/PN).
Section 12.8 Subgroup Analyses Related to Safety. Includes two new more listings and (*) specifies 
categorization.


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Original text:
Tables 12.8.1 to 12.8.12 will have the following pattern:
Laboratory abnormalities/ drug-
related AEs
Subgroup 1
Subgroup 2
….
No. of 
patients 
evaluated
Grade 
≥3
%
No. of 
patients 
evaluated
Grade 
≥3
%
No. of 
patients 
evaluated
Grade 
≥3
%
Thrombocytopenia
Neutropenia 
AP 
Bilirubin 
AST 
ALT 
CPK
Nausea
Vomiting
Fatigue
Other*
(*)Any drug-related toxicity present in >=5% of patients in any group.
Changes to:
Table 12.8.15 Worst grade ≥3 by patient in special subgroups (AAGP*).
Table 12.8.16 Worst grade ≥3 by cycle in special subgroups (AAGP*).
Tables 12.8.1 to 12.8.16 will have the following pattern:
Laboratory abnormalities/ drug-
related AEs
Subgroup 1
Subgroup 2
….
No. of 
patients/cycles
evaluated
Grade 
≥3
%
No. of 
patients/cycles
evaluated
Grade 
≥3
%
No. of 
patients/cycles
evaluated
Grade 
≥3
%
Thrombocytopenia
Neutropenia 
AP 
Bilirubin 
AST 
ALT 
CPK
Nausea
Vomiting
Fatigue


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Laboratory abnormalities/ drug-
related AEs
Subgroup 1
Subgroup 2
….
No. of 
patients/cycles
evaluated
Grade 
≥3
%
No. of 
patients/cycles
evaluated
Grade 
≥3
%
No. of 
patients/cycles
evaluated
Grade 
≥3
%
Other**
(*) Categories Age (<65 yrs vs >=65 yrs); Number of prior lines (1 line vs >=2 lines); BSA (=< 1.8 m2 vs. > 1.8 m2) Geographical 
area (Europe vs US.); Alpha-glycoprotein (ULN<= vs >ULN). (**)Any drug-related toxicity present in >=5% of patients in any 
group.
Section 13: Figures. Adds a new graph.
Figure13.1.6 Last previous Immunotherapy TTP vs PFS PM01183 (SCLC cohort).
Section 14 DB Listings, BIMO and ICH listing. 
Original text:
Listing 14.1.11 Biochemical laboratory values
Patient 
id.
Visit
Date
n
Clinically 
indicated 
repeat 
required?
Total Bilirubin 
(mg/dl)
Direct Bilirubin 
(mg/dl)
AST 
(IU/L)
ALT 
(IU/L)
AP 
(IU/L)
…..*
(*)GGT (IU/L), Glucose (mg/dL), Creatinine (mg/dl), CrCl (mL/min), NA (mmol/L), CL (mmol/L), K  (mmol/L), LDH (xULN), CPK 
(IU/L), Total Proteins (g/dl), Albumin (g/dl), CA (mg/dl), Mg (mg/dl), INR (ratio), PT (sec/ratio), PTT (sec/ratio), AFP (ng/m), hCG
(IU/L)
Changes to:
Listing 14.1.11 Biochemical laboratory values
Patient 
id.
Visit
Date
n
Clinically 
indicated 
repeat 
required?
Total Bilirubin 
(mg/dl)
Direct Bilirubin 
(mg/dl)
AST 
(IU/L)
ALT 
(IU/L)
AP 
(IU/L)
…..*


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(*)GGT (IU/L), Glucose (mg/dL), Creatinine (mg/dl), CrCl (mL/min), NA (mmol/L), CL (mmol/L), K  (mmol/L), LDH (xULN), CPK 
(IU/L), Total Proteins (g/dl), Albumin (g/dl), CA (mg/dl), Mg (mg/dl), INR (ratio), PT (sec/ratio), PTT (sec/ratio), AFP (ng/m), hCG
(IU/L)
Original text:
Listing 14 1.13 Coagulation laboratory values.
Patient id.
Visit
Date
n
Clinically indicated 
repeat required?
INR (ratio)
PT (sec)
PTT 
(sec)
Changes to:
Listing 14 1.13 Coagulation laboratory values.
Patient id.
Visit
Date
n
Clinically indicated 
repeat required?
INR (ratio)
PT (sec/ratio)
PTT 
(sec/ratio)
Original text:
Listing 16.2.4 Demographic Data.
Patient 
id.
Tumor 
type
Histology 
type*
Stage*
Age/Years
ECOG
Weight 
(kg)
Height 
(cm)
BSA 
(m2)
Prior 
Radiotherapy
Prior agents for 
the
treatment
(*)At diagnosis.
Changes to:
Listing 16.2.4 Demographic Data.
Patient 
id.
Tumor 
type
Histology 
type*
Stage*
Age/Gender
ECOG
Weight 
(kg)
Height 
(cm)
BSA 
(m2)
Prior 
Radiotherapy
Prior agents for 
the
treatment
(*)At diagnosis.


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15.4
SAP version history v4.0
After the fourth version of the SAP was approved, a new protocol "substantial amendment No. 7" was
included; therefore the SAP has been updated (highlighted in italic bold) in accordance with the new 
version (version 4) of the protocol as follows:

The duration of follow-up of patients in the SCLC cohort has been changed to at least 18 months 
from the first lurbinectedin infusion.

Other not relevant minor comments/clarifications/corrections.
Detailed changes are presented in the next pages. Changes are highlighted in Italic bold and text 
removed has been crossed out.
Any changes in the automatic numbering of tables, sections and references in the SAP are not listed but 
will be implemented in the new version.
Section 2 Study Design
Original text:
(….)
Patients will be evaluated at scheduled visits on three study periods: Pre-treatment, Treatment and 
Follow-up. This clinical trial will finish (clinical cut-off for each cohort except SCLC cohort) when all 
evaluable patients within each cohort have at least 12 months of follow-up from the first PM01183 
infusion. Patients with SCLC will be followed-up until death.
Changes to:
(….)
Patients will be evaluated at scheduled visits on three study periods: Pre-treatment, Treatment and 
Follow-up. This clinical trial will finish (clinical cut-off for each cohort except SCLC cohort) when all 
evaluable patients within each cohort have at least 12 months of follow-up from the first PM01183 
infusion. Patients with SCLC will be followed-up until death. for at least 18 months after the last 
patient enrolled received the first PM01183 infusion.
Section 8.9 Imputation of Incomplete dates
Original text:


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(….)
After End of Treatment
To ensure the most conservative approach for the time-to-event variables (i.e., DR, PFS and OS), 
which can be affected by missing values, the following rules will be implemented: if the day of a date 
is unknown then the imputed day will be the 1st; if the month is also unknown, then the imputed date 
will be the 1st of July. This assumption will be valid if the imputed date occurs later than the last drug 
administration date; otherwise the imputed date will be the date of the last drug administration plus 
the predefined cycle length (i.e., 21 days if PM01183), except if the patient dies before, in which case 
the date of death minus 1 will be used. For OS, if a patient dies the imputation event date should be 
the last date the patient is known to be alive plus one day.
Changes to:
(….)
After End of Treatment
To ensure the most conservative approach for the time-to-event variables (i.e., DR, PFS and OS), 
which can be affected by missing values, the following rules will be implemented: if the day of a date 
is unknown then the imputed day will be the 1st; if the month is also unknown, then the imputed date 
will be the 1st of July. This assumption will be valid if the imputed date occurs later than the last drug 
administration date; otherwise the imputed date will be the date of the last drug administration plus 
the predefined cycle length (i.e., 21 days if PM01183), except if the patient dies before, in which case 
the date of death minus 1 will be used. For OS, if a patient dies the imputation event date should be 
the last date the patient is known to be alive minus plus one day.
For the determination of treatment emergent AEs with incomplete dates that do not allow to know 
if they occurred during the treatment period, the following imputation rules will apply: 
-
If the start day, month and year are missing, the event will be considered treatment 
emergent.
-
If the start day and month are missing, no date imputation will be performed but the event 
will be considered TEAE, if the reported year is the same or occurs after the infusion year 
and also the reported year is the same or occurs before the EOT year.
-
If the start day is missing, no imputation date will be performed but the event will be
considered TEAE, if the reported month and year occur after the first infusion date
(month/year) and before the EOT date (month/year).
Section 8.11 Subgroup Analysis
Original text:


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Specific subgroup efficacy analyses will be done for patients with SCLC. These analyses will be 
performed by IA/IRC and in all evaluable/all treated patient populations, pre-specified analyses are by 
CTFI (< 90 days and ≥ 90 days and/or Refractory (RR) [<30 days], Resistant (R)[>=30 and <90 days], 
Sensitive (S) [>=90 and <180 days] and Very Sensitive (VS)[>=180 days]), excluding patients with 
CTFI<30 days and considering event to clinical progressions although they were not documented by 
radiological images. Any other exploratory analyses requested by the physician at the time of the 
analysis will be clearly explained, specifying the selected patient population and following the same 
layout detailed for the other subgroup analyses.
If the number of patients recruited in any cohort differs at least 10% from the sample size 
assumptions, a sensitivity analysis for main efficacy endpoints using all evaluable patients will be 
performed.
Changes to:
Specific subgroup efficacy analyses will be done for patients with SCLC. These analyses will be 
performed by IA/IRC and in all evaluable/all treated patient populations, pre-specified analyses are by 
CTFI defined as the time from the last dose of the last platinum containing therapy to the 
occurrence of progressive disease, (< 90 days and ≥ 90 days and/or Refractory (RR) [<30 days], 
Resistant (R)[>=30 and <90 days], Sensitive (S) [>=90 and <180 days] and Very Sensitive 
(VS)[>=180 days]), excluding patients with CTFI<30 days and considering event to clinical 
progressions although they were not documented by radiological images. Any other exploratory 
analyses requested by the physician at the time of the analysis will be clearly explained, specifying the 
selected patient population and following the same layout detailed for the other subgroup analyses.
If the number of patients recruited in any cohort differs at least 10% from the sample size 
assumptions, a sensitivity analysis for main efficacy endpoints using all evaluable patients will be 
performed.
Section 11 Efficacy Evaluation
In all survival tables and graphs PFS at 12 months and OS at 24 months will be also calculated.   
Table 11.3.3.7 add new information.
Table 11.3.3.7 Response rate and reliability by IA and IRC (All treated patients).
Response
IA
Complete 
response (CR)
Partial 
response (PR)
Stable 
disease 
SD≥4 
months
Stable 
disease 
SD<4 
months
Progressive 
disease (PD)
Inevaluable for 
response*
N
%
N
%
N
%
N
%
N
%
N
%
IRC
Complete 
response (CR)
Partial response 
(PR)
Stable disease 
SD≥4 months
Stable disease 


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SD<4 months
Progressive 
disease (PD)
Inevaluable for 
response
Test of Symmetry*
Statistic (S)
DF
Pr > S
Kappa statistics*
                                                               Value                                    ASE                                95% Confidence Limits
Simple kappa
Weighted kappa
Test of H0: Weighted Kappa = 0
ASE under H0
Z
One-sided Pr >  Z
Two-sided Pr > |Z|
(*) for example: early death, malignant disease; toxicity; tumor assessments not repeated/incomplete; other (specify).
For discrepancies see Listing 11.3.3.15. Percentage by columns. (**) Kappa Index for concordance of all response categories 
according to IA or IRC assessment.
New tables and graphs are included:
Survival in responders
Table 11.3.3.36 OS in responders by IA and by CTFI (All treated patients).
CTFI< 90 days*
CTFI≥ 90 days*
Total***
R**
RR**
Total*
S**
VS**
Total*
N
Events
Censored
Median OS
OS at 6 months
OS at 12 months
OS at 24 months
(*/**/***) Kaplan-Meier plots will also be shown. (*)Table/Figure 11.3.3.36.1 with the following categories (CTFI< 90 days and 
CTFI≥ 90 days), (**) Table/Figure 11.3.3.36.2 with the following categories RR, R, S and VS. (***) Table/Figure 11.3.3.36.3 for 
totals.
Table 11.3.3.37 OS in responders by IRC and by CTFI (All treated patients).
CTFI< 90 days*
CTFI≥ 90 days*
Total***
R**
RR**
Total*
S**
VS**
Total*
N
Events
Censored
Median OS
OS at 6 months
OS at 12 months
OS at 24 months
(*/**/***) Kaplan-Meier plots will also be shown. (*)Table/Figure 11.3.3.37.1 with the following categories (CTFI< 90 days and 
CTFI≥ 90 days), (**) Table/Figure 11.3.3.37.2 with the following categories RR, R, S and VS. (***) Table/Figure 11.3.3.37.3 for 
totals.


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…
Table 11.3.3.38 OS in responders by IA and IRC excluding CTFI<30 (All treated patients).
IA
IRC
N
Events
Censored
Median OS 
OS at 6 months
OS at 12 months
OS at 24 months
Kaplan-Meier plot will also be shown (Figure 11.3.3.38.1 OS in responders by IA excluding CTFI<30 (All treated patients), Figure 
11.3.3.38.2 OS in responders by IRC excluding CTFI<30 (All treated patients).
Section 12.3.1 Serious Adverse Events
Original text:
Tables 12.3.1.2 to 12.3.1.5 will have the following pattern, but depending on the number and severity 
of the adverse events observed, the NCI-CTCAE v4 grades may be grouped as ≥1 and ≥3 categories.
SOC
Preferred term
Grade 
1
…
Grade 
4
Grade 
≥1
Grade 
≥3
N
%
…
N
%
N
%
Blood and lymphatic 
system disorders
Anemia NOS
...
…
Cardiac disorders
Arrhythmia NOS
…
Note: Tables 12.3.2.2 and 12.2.3.4 also for s1 and s2;
Changes to:
SOC
Preferred term
Grade 
1
…
Grade 
4
Grade 
≥1
Grade 
≥3
N
%
…
N
%
N
%
N
%
Blood and lymphatic 
system disorders
Anemia NOS
...
…
Cardiac disorders
Arrhythmia NOS
…
Note: Tables 12.3.1.2 and 12.2.1.4 also for s1 and s2;
Section 12.4.4 Laboratory Values over Time
Original table:


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Tables 12.4.4.7 and 12.4.4.8 will have the following pattern:
All cycles
First cycle
N, Mean, Std., Median, 
Range
N, Mean, Std., Median, Range
Grade ≥3* onset day
Peak (x109/L)
Duration of grade ≥3 (days)
Day of recovery to grade 1/2 or baseline values**
(*) Grade 3 or 4; (**) grade 2 or less
Changes to:
Tables 12.4.4.7 and 12.4.4.8 will have the following pattern:
All cycles
First cycle
N, Mean, Std., Median, 
Range
N, Mean, Std., Median, Range
Grade ≥3* onset day
Peak (x109/L ULN)
Duration of grade ≥3 (days)
Day of recovery to grade 1/2 or baseline values**
(*) Grade 3 or 4; (**) grade 2 or less
Section 14 DB Listings, BIMO and ICH Listings 
Original table:
Listing 14.1.4 Pregnancy test and adequate contraception
Pregnancy test
Adequate contraception
Patient id.
Visit
Not
applicable?
Reason
Not 
done?
Sample 
date
Result
Reason 
for 
clinically 
indicated 
repeat
Adequate 
contraception?
Specify
Changes to:
Listing 14.1.4 Pregnancy test and adequate contraception
Pregnancy test
Adequate contraception
Patient id.
Visit
Not
applicable?
Reason
Not 
done?
Sample 
date
Result
Reason 
for 
clinically 
indicated 
repeat
Adequate 
contraception?
Specify
Original table:
Footnote from Listing 14.1.11 Biochemical laboratory values.


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(*)GGT (IU/L), Glucose (mg/dL), Creatinine (mg/dl), CrCl (mL/min), NA (mmol/L), CL (mmol/L), K  (mmol/L), LDH (xULN), CPK 
(IU/L), Total Proteins (g/dl), Albumin (g/dl), CA (mg/dl), Mg (mg/dl), AFP (ng/m), hCG (IU/L)
Changes to:
(*)GGT (IU/L), Glucose (mg/dL mmol/L), Creatinine (mg/dl), CrCl (mL/min), NA (mmol/L), CL (mmol/L), K  (mmol/L), LDH (xULN
IU/L), CPK (IU/L), Total Proteins (g/dl), Albumin (g/dl), CA (mg/dl mmol/L), Mg (mg/dl), AFP (ng/m), hCG (IU/L)
Original text:
In the SCLC cohort and to fulfil the Office of Scientific Investigations (OSI) request that the items 
described in the draft Guidance for Industry Standardized Format for Electronic Submission of NDA 
and BLA Content for the Planning of Bioresearch Monitoring (BIMO) Inspections for CDER 
Submissions (February 2018) and the associated Bioresearch Monitoring Technical Conformance 
Guide Containing Technical Specifications will be provided following the recommended standardized 
formats.
…
Table 15.1 Site Level Summary SCLC PM1183B00514
Site
Patients Screened
Patients Treated
Patients End of 
Treatment
Patients Off Study
Changes to:
In the SCLC cohort and To fulfil the Office of Scientific Investigations (OSI) request, that the items 
described in the draft Guidance for Industry Standardized Format for Electronic Submission of NDA 
and BLA Content for the Planning of Bioresearch Monitoring (BIMO) Inspections for CDER 
Submissions (February 2018) and the associated Bioresearch Monitoring Technical Conformance 
Guide Containing Technical Specifications will be provided following the recommended standardized 
formats.
…
Listing 15.1 Site Level Summary SCLC PM1183B00514.
Site
Patients Screened
Patients Treated
Patients End of 
Treatment
Patients Off Study
New BIMO listings are added:
Listings 15.11.1 Laboratory measurements by Site.
Site
Patient 
id.
Visit Date Laboratory Hemoglobin 
(g/dl)
Platelets 
(x10*9/L)
WBC 
(x10*9/L)
Neutrophils 
(x10*9/L)
Lymphocytes 
(x10*9/L)
Monocytes 
(x10*9/L)
…..*


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(*) Total Bilirubin, Direct Bilirubin in (mg/dl), AST, ALT, AP, GGT in (IU/L), Glucose (mmol/L), Creatinine (mg/dl), CrCl 
(mL/min), NA (mmol/L), CL (mmol/L), K (mmol/L), LDH (IU/L), CPK (IU/L), Total Proteins (g/dl), Albumin (g/dl), CA (mmol/L), 
Mg (mg/dl), INR (ratio), PT (sec/ratio), PTT (sec/ratio) AFP (ng/m), hCG (IU/L), AAGP (mg/dl).
Listings 15.11.2 Electrocardiogram by Site.
Site
Patient 
id.
Not 
Done Visit
Date
Results
Abnormal, 
Specify
PR 
interval 
(msec)
Heart rate 
(bpm)
QT Interval 
(msec)
QRS 
interval 
(msec)
Corrected 
QT 
Fridericia 
Listings 15.11.3 LVEF by Site.
Site
Patient 
id.
Not 
Done Visit
Date
Method
LVEF (%)
Range 
Lowe 
Limit
Abnormality
Specify
Reason for Clinically 
Indicated Repeat
Original table:
Footnote from Listing 16.2.8 Listing of Individual Laboratory Measurements by Patient.
(*) Monocytes (x10*9/L), Direct Bilirubin (mg/dl),Total Bilirubin (mg/dl), AST IU/L),  ALT (IU/L)  AP (IU/L), GGT (IU/L), Glucose 
(mg/dL), Creatinine (mg/dl), CrCl (mL/min), NA (mmol/L), CL (mmol/L), K  (mmol/L), LDH (xULN), CPK (IU/L), Total Proteins 
(g/dl), Albumin (g/dl), CA (mg/dl), Mg (mg/dl), INR (ratio), PT (sec/ratio), PTT (sec/ratio), AFP (ng/m), hCG(IU/L).
Changes to:
(*)Monocytes (x10*9/L), Direct Bilirubin (mg/dl),Total Bilirubin (mg/dl), AST IU/L),  ALT (IU/L)  AP (IU/L), GGT (IU/L), Glucose 
(mg/dL mmol/L), Creatinine (mg/dl), CrCl (mL/min), NA (mmol/L), CL (mmol/L), K  (mmol/L), LDH (xULN IU/L), CPK (IU/L), 
Total Proteins (g/dl), Albumin (g/dl), CA (mg/dl mmol/L), Mg (mg/dl), INR (ratio), PT (sec/ratio), PTT (sec/ratio), AFP (ng/m), hCG
(IU/L), AAGP (mg/dl).