Clinical trial NCT02566993
Conditions: Small-cell Lung Cancer
Sponsor: PharmaMar
Start date: 2016-08-30; Completion date: 2020-02-24
Enrollment: 613 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Phase III randomized clinical trial of lurbinectedin (PM01183)/doxorubicin (DOX) versus cyclophosphamide (CTX), doxorubicin (DOX) and vincristine (VCR) (CAV) or topotecan as treatment in patients with small-cell lung cancer (SCLC) who failed one prior platinum-containing line.

Detailed description:
Multicenter, open-label, randomized, controlled phase III clinical trial to evaluate and compare the activity and safety of an experimental arm consisting of PM01183/DOX combination followed by PM01183 alone, if applicable vs. best Investigator's choice between CAV or topotecan as a control arm, in SCLC patients who failed one prior platinum-containing line but no more than one prior chemotherapy-containing line.

Arms: arm 1: Lurbinectedin (PM01183) / Doxorubicin arm 2: CAV (Cyclophosphamide (CTX), Doxorubicin (DOX) and Vincristine (VCR)) arm 3: Topotecan
Interventions: intervention 1: Lurbinectedin (PM01183) intervention 2: Doxorubicin (DOX) intervention 3: Cyclophosphamide (CTX) intervention 4: Vincristine (VCR) intervention 5: Topotecan
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None intervention 4: None intervention 5: None

Protocol documents:
Prot_000.pdf: 
 
 
 
SPONSOR 
 
Pharma Mar, S.A. 
Avda de los Reyes, 1 
 
Polígono Industrial “La Mina” 
28770 Colmenar Viejo (Madrid), Spain 
Phone: + 34 918 466 000  
Fax:  
+ 34 918 466 003 
 
 
PharmaMar USA, Inc. 
230 Park Avenue, suite 1000 
New York, NY 10169 
USA 
Phone: +1 212 309 8737 
Fax: +1 646 435 5846 
 
 
 
 
CLINICAL TRIAL PROTOCOL 
 
 
Phase III Randomized Clinical Trial of Lurbinectedin (PM01183)/Doxorubicin 
(DOX) versus Cyclophosphamide (CTX), Doxorubicin (DOX) and Vincristine (VCR) 
(CAV) or Topotecan as Treatment in Patients with Small-Cell Lung Cancer (SCLC) 
Who Failed One Prior Platinum-containing Line (ATLANTIS Trial 
 
 
INVESTIGATIONAL MEDICINAL PRODUCTS: Lurbinectedin (Zepzelca®), and 
doxorubicin. 
Protocol No.: PM1183-C-003-14 
EudraCT No.: 2015-001641-89 
NCT Code: NCT02566993 
 
 
 
Protocol version 4.0: 3 May 2018 
 


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SPONSOR
Pharma Mar S.A.
Avda de los Reyes, 1
Polígono Industrial “La Mina” 
28770 Colmenar Viejo (Madrid) Spain
Phone: + 34 91 846 6000 
Fax:+ 34 91 846 6003
Pharma Mar USA, Inc.
205 East 42nd Street, suite 15003
New York, NY 10017, USA
Phone: + 1 646 880 4429
Fax : + 1 646 893 5856
CLINICAL TRIAL PROTOCOL
PM1183-C-003-14
Phase III Randomized Clinical Trial of Lurbinectedin (PM01183)/
Doxorubicin (DOX) versus Cyclophosphamide (CTX), Doxorubicin 
(DOX) and Vincristine (VCR) (CAV) or Topotecan as Treatment in 
Patients with Small-Cell Lung Cancer (SCLC) Who Failed One Prior 
Platinum-containing Line (ATLANTIS Trial)
INVESTIGATIONAL MEDICINAL PRODUCTS:
Lurbinectedin (PM01183), 
doxorubicin, cyclophosphamide, vincristine and topotecan.
Protocol Code: PM1183-C-003-14
EudraCT No: 2015-001641-89
Protocol version 4.0 including amendments #1 dated 18 March 2016, #2 dated 3
October 2016 and #3 dated 3 May 2018.
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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TABLE OF CONTENTS
STUDY CONTACTS .................................................................................................................................2
PRINCIPAL INVESTIGATORS..............................................................................................................3
SYNOPSIS ..................................................................................................................................................7
SCHEDULE OF ASSESSMENTS AND PROCEDURES....................................................................27
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS..........................................................30
1.
INTRODUCTION ...........................................................................................................................34
1.1
SMALL CELL LUNG CANCER ...................................................................................................34
1.2
INFORMATION ON THE STUDY DRUGS ....................................................................................37
1.2.1
Lurbinectedin (PM01183) ...................................................................................................37
1.2.1.1
Name and Chemical Information ............................................................................................... 37
1.2.1.2
Non-clinical Data ....................................................................................................................... 37
1.2.1.3
Clinical Data .............................................................................................................................. 40
1.2.2
Topotecan.............................................................................................................................48
1.2.3
CAV......................................................................................................................................48
1.3
STUDY RATIONALE...................................................................................................................50
1.3.1
Dose Rationale.....................................................................................................................50
2.
STUDY OBJECTIVES ...................................................................................................................51
2.1
PRIMARY ..................................................................................................................................51
2.2
SECONDARY..............................................................................................................................51
2.3
TERTIARY.................................................................................................................................51
3.
OVERALL STUDY DESIGN.........................................................................................................52
3.1
PRIMARY ENDPOINT ................................................................................................................55
3.2
SECONDARY ENDPOINTS..........................................................................................................55
3.3
TERTIARY ENDPOINTS .............................................................................................................56
4.
SELECTION OF PATIENTS.........................................................................................................56
4.1
INCLUSION CRITERIA...............................................................................................................56
4.2
EXCLUSION CRITERIA..............................................................................................................57
4.3
PATIENTS FOR THE PHARMACOGENETIC EVALUATIONS .......................................................58
5.
PLAN OF THE STUDY..................................................................................................................58
5.1
PLANNED TRIAL PERIODS (FOR THE WHOLE STUDY) ............................................................58
5.2
PLANNED TRIAL PERIODS (INDIVIDUALLY PER PATIENT)......................................................58
5.2.1
Discontinuations..................................................................................................................59
5.2.1.1
Treatment Discontinuation......................................................................................................... 59
5.2.1.2
Reasons for Treatment Discontinuation ..................................................................................... 59
5.2.1.3
Study Discontinuation................................................................................................................ 60
5.2.2
Protocol Deviations..............................................................................................................60
5.3
REPLACEMENT OF PATIENTS...................................................................................................61
5.4
PRE-TREATMENT ASSESSMENTS..............................................................................................61
5.5
PATIENT REGISTRATION..........................................................................................................62
5.6
PATIENT RANDOMIZATION......................................................................................................62
5.7
EVALUATIONS DURING TREATMENT.......................................................................................62
5.8
EVALUATIONS AT END OF TREATMENT ..................................................................................64
5.9
FOLLOW-UP AFTER END-OF-TREATMENT VISIT....................................................................65
6.
TREATMENT .................................................................................................................................66
6.1
DESCRIPTION OF TREATMENT.................................................................................................66
6.1.1
Drug Formulation and Supply............................................................................................66
6.1.1.1
Experimental Arm...................................................................................................................... 66
6.1.1.2
Control Arm ............................................................................................................................... 66
6.2
ADMINISTRATION OF STUDY MEDICATION.............................................................................66
6.2.1.1
Experimental Arm...................................................................................................................... 66


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6.2.1.2
Control Arm ............................................................................................................................... 67
6.3
STARTING DOSES AND SCHEDULE ...........................................................................................67
6.3.1.1
Experimental Arm...................................................................................................................... 67
6.3.1.2
Control Arm ............................................................................................................................... 68
6.4
PROPHYLACTIC MEDICATION .................................................................................................68
6.5
CRITERIA FOR TREATMENT CONTINUATION..........................................................................69
6.6
DOSE REDUCTION ....................................................................................................................70
6.7
CONCOMITANT MEDICATION..................................................................................................71
6.7.1
Allowed Medications/Therapies ..........................................................................................71
6.7.2
Prohibited Medications/Therapies ......................................................................................71
6.7.3
Drug-drug Interactions .......................................................................................................72
6.8
DRUG ACCOUNTABILITY..........................................................................................................73
6.9
TREATMENT COMPLIANCE......................................................................................................73
7.
STUDY EVALUATIONS ...............................................................................................................73
7.1
EFFICACY .................................................................................................................................73
7.2
SAFETY .....................................................................................................................................74
7.3
ADVERSE EVENTS DEFINITIONS ..............................................................................................75
7.3.1
Adverse Event (AE)..............................................................................................................75
7.3.2
Serious Adverse Event (SAE)..............................................................................................75
7.3.3
Death....................................................................................................................................75
7.3.4
Life-threatening Event.........................................................................................................76
7.3.5
Hospitalization or Prolongation of Hospitalization............................................................76
7.3.6
Unlisted/Unexpected Adverse Event ...................................................................................76
7.3.7
Adverse Reactions................................................................................................................76
7.3.8
Adverse Events Related to the Study Drug..........................................................................76
7.3.9
Expedited Reporting ............................................................................................................77
7.3.10
Assessment of Causal Relationship to the Study Drug ..................................................77
7.4
ADVERSE EVENTS REPORTING PROCEDURES.........................................................................77
7.4.1
Reporting Adverse Events....................................................................................................77
7.4.2
Reporting Serious Adverse Events ......................................................................................78
7.4.3
Reporting Pregnancy Cases Occurred within the Clinical Trial........................................78
7.5
ADVERSE EVENTS MONITORING .............................................................................................79
7.6
PATIENT-REPORTED OUTCOMES.............................................................................................79
7.7
PHARMACOKINETICS ...............................................................................................................79
7.7.1
Plasma Sampling .................................................................................................................79
7.7.2
Analytical Procedures..........................................................................................................80
7.7.3
Pharmacokinetic Parameters ..............................................................................................80
7.8
PHARMACOGENETIC EVALUATIONS........................................................................................80
8.
STATISTICAL METHODS...........................................................................................................81
8.1
SAMPLE SIZE ............................................................................................................................81
8.2
STATISTICAL ANALYSIS...........................................................................................................82
8.2.1
Efficacy Analyses.................................................................................................................82
8.2.2
Safety Analyses ....................................................................................................................82
8.2.3
Patient-reported Outcomes (PRO) Analyses.......................................................................83
8.2.4
Pharmacokinetic Analyses ..................................................................................................83
8.2.5
Pharmacokinetic/pharmacodynamic Correlation ..............................................................83
8.2.6
Pharmacogenetic Analyses..................................................................................................83
8.3
INTERIM SAFETY ANALYSIS.....................................................................................................83
9.
ADMINISTRATIVE SECTION ....................................................................................................84
9.1
ETHICS......................................................................................................................................84
9.2
MONITORING, AUDITING AND INSPECTING .............................................................................84
9.3
PATIENT INFORMED CONSENT ................................................................................................85
9.4
CONFIDENTIALITY/ PATIENTS IDENTIFICATION.....................................................................85
9.5
CASE REPORT FORMS..............................................................................................................85
9.6
INSURANCE ...............................................................................................................................86
9.7
RETENTION OF RECORDS.........................................................................................................86


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9.8
USE OF INFORMATION AND PUBLICATION ..............................................................................86
10.
REFERENCES............................................................................................................................87
11.
APPENDICES .............................................................................................................................92
APPENDIX 1: ECOG PERFORMANCE STATUS ASSESSMENT SCALE .......................................92
APPENDIX 2: CONTRACEPTION AND PREGNANCY TESTING...................................................93
APPENDIX 3: CALCULATION OF THE BODY SURFACE AREA. THE DUBOIS FORMULA....95
APPENDIX 4: LIST OF CYP1/CYP2/CYP3 INHIBITORS, INDUCERS AND SUBSTRATES.........96
APPENDIX 5: EVALUATION OF RESPONSE. THE RECIST. ..........................................................99
APPENDIX 6: LIST OF GENES TO BE INVESTIGATED IN THE PM01183 
PHARMACOGENETIC ANALYSIS....................................................................................................111
APPENDIX 7: DECLARATION OF HELSINKI.................................................................................112


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SYNOPSIS
TITLE
Phase III Randomized Clinical Trial of Lurbinectedin 
(PM01183)/Doxorubicin (DOX) versus Cyclophosphamide 
(CTX), Doxorubicin (DOX) and Vincristine (VCR) (CAV) 
or Topotecan as Treatment in Patients with Small-Cell 
Lung Cancer (SCLC) Who Failed One Prior Platinum-
containing Line (ATLANTIS Trial).
PROTOCOL CODE
PM1183-C-003-14
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 determine whether there is a difference in overall 
survival 
(OS) 
between 
lurbinectedin 
(PM01183)/doxorubicin (DOX) and a control arm 
consisting 
of 
best 
Investigator’s 
choice 
between 
cyclophosphamide 
(CTX), 
doxorubicin 
(DOX) 
and 
vincristine (VCR) (CAV) or topotecan, as treatment in 
SCLC patients after failure of one prior platinum-
containing line.
Secondary:

To analyze:
o
Difference in OS between PM01183/DOX and CAV, in 
patients with CAV as best Investigator’s choice.
o
OS/PFS in patients with and without baseline central 
nervous system (CNS) involvement. Subgroup analyses 
restricted to the sensitive and resistant populations (i.e., 
chemotherapy-free interval [CTFI] ≥90 days and CTFI 
<90 days) will also be performed.
o
Progression-free survival (PFS) by an Independent 
Review Committee (IRC).
o
Antitumor activity by IRC according to the Response 
Evaluation Criteria in Solid Tumors (RECIST) v.1.1.
o
Safety profile.
Tertiary:

To analyze:
o
Mid- and long-term survival (OS at 12, 18 and 24 
months, respectively).
o
Efficacy and safety profiles in the subgroups of the 
PM01183/DOX arm vs. CAV or topotecan.
o
PFS by Investigator’s Assessment (IA).
o
Antitumor activity by IA according to the RECIST 
v.1.1.
o
Patient-reported outcomes (PRO).


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o
Pharmacokinetics (PK) of the combination in patients 
treated in the experimental arm (PM01183/DOX).
o
PK/pharmacodynamic 
(PDy) 
correlations 
in 
the 
experimental arm, if any.
o
Pharmacogenetics of known polymorphisms in patients 
treated in the experimental arm.  
STUDY DESIGN
Multicenter, open-label, randomized, controlled phase III 
clinical trial to evaluate and compare the activity and safety of 
an 
experimental 
arm
consisting 
of 
PM01183/DOX 
combination followed by PM01183 alone, if applicable vs. best 
Investigator’s choice between CAV or topotecan as a control 
arm, in SCLC patients who failed one prior platinum-
containing line but no more than one prior chemotherapy-
containing line. 
Central randomization will be implemented; patients will be 
assigned to each arm at a 1:1 ratio. If the patient is randomized 
to the control arm, the assigned treatment will be based on the 
reported Investigator’s preference between CAV or topotecan. 
Stratification will be performed according to the CTFI after 
first line [≥180 days (very sensitive, VS) vs. 90-179 days 
(sensitive; S) vs. <90 days (resistant; R)], Eastern Cooperative 
Oncology Group performance status (ECOG PS) (0 vs. 1-2), 
baseline CNS involvement vs.
no involvement, prior 
immunotherapy against either programmed cell death protein-1 
(PD-1) or programmed death ligand-1 (PD-L1) (Yes vs. No)
and Investigator’s preference (best Investigator’s choice prior 
to randomization) between topotecan and CAV.
An Independent Review Committee (IRC), blinded to the 
treatment assigned to the patients, will determine the best 
patient response and assign the date of objective response or 
progression/censoring according to RECIST v.1.1. An 
Independent Data Monitoring Committee (IDMC) will oversee 
the conduct of the study. The IDMC should have access to 
unblinded efficacy and safety data throughout the trial to 
enable timely and informed judgments about risks and 
benefits.
The primary endpoint of the trial is the overall survival (OS). 
Secondary endpoints comprise difference in OS between 
PM01183/DOX and CAV, in patients with CAV as best 
Investigator’s choice; OS/PFS per RECIST v.1.1 in patients 
with and without baseline central nervous system (CNS) 
involvement; PFS per RECIST v.1.1 by an IRC; best antitumor 
response as per RECIST v.1.1 and duration of response (DR) 
(both assessed by IRC); and safety profile. Tertiary endpoints 
comprise mid- and long-term survival assessed by measuring 
OS at 12/18/24 months, PFS per RECIST v.1.1 by IA, best 
antitumor response as per RECIST v.1.1 and DR (both 
assessed by IA), PRO, subgroup analyses, PK, PK/PDy
correlations, and pharmacogenetics. 
In order to evaluate the overall safety in both arms, an interim 


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safety analysis is planned after the recruitment of 150 patients
(i.e., ~75 patients into each arm). Recruitment will not be put 
on hold while the interim safety analysis is being performed. 
Efficacy parameters will not be formally analyzed in this 
interim evaluation. Further safety and efficacy analyses could 
be performed upon request from the IDMC. 
If any formal interim OS/PFS analysis is performed, unblinded 
only to the IDMC, a type I error correction according to the 
Lan and DeMets error spending function that corresponds to 
the O'Brien-Fleming boundary will be used, calculated during 
the interim analyses to preserve an overall (one-sided) 0.005 
false positive error rate; if early termination does not occur, the 
alpha level of the final analysis will be chosen to preserve an 
overall (one-sided) 0.025 false positive error rate.
Crossover is not allowed.
STUDY POPULATION
Adult SCLC patients with ECOG PS 0-2 who have failed one 
prior platinum-containing line but no more than one 
chemotherapy-containing line (re-challenge is not allowed) 
without symptomatic or progressing CNS involvement at 
randomization.
STUDY POPULATION
Inclusion criteria
1) Voluntary written informed consent of the patient obtained 
before any study-specific procedure.
2) Adult patients aged ≥ 18 years. 
3) Histologically or cytologically confirmed diagnosis of 
limited or extensive stage SCLC which failed one prior 
platinum-containing regimen and with a chemotherapy-free 
interval (CTFI, time from the last dose of first-line 
chemotherapy to the occurrence of progressive disease) ≥ 
30 days. Small-cell carcinoma of unknown primary site 
with or without neuroendocrine features confirmed in 
histology test(s) performed on metastatic lesion(s) are 
eligible, if Ki-67/MIB-1 is expressed in >50% of tumor 
cells.
4) ECOG PS ≤ 2.
5) Adequate hematological, renal, metabolic and hepatic 
function in an assessment performed within 7 days (+ 3 day 
window) of randomization:
a) Hemoglobin ≥ 9.0 g/dl [patients may have received prior 
red blood cell (RBC) transfusion, if clinically indicated]; 
absolute neutrophil count (ANC) ≥ 2.0 x 109/l, and 
platelet count ≥ 100 x 109/l.
b) Alanine 
aminotransferase 
(ALT) 
and 
aspartate 
aminotransferase (AST) ≤ 3.0 x upper limit of normal 
(ULN).
c) Total bilirubin ≤ 1.5 x ULN or direct bilirubin ≤ ULN.
d) Albumin ≥ 3.0 g/dl.
e) Calculated creatinine clearance (CrCL) ≥ 30 ml/minute 


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(using Cockcroft and Gault’s formula).
f) Left 
ventricular 
ejection 
fraction 
(LVEF) 
by 
echocardiogram (ECHO) or multiple-gated acquisition 
(MUGA) scan within normal range (according to 
institutional standards).
g) Creatine phosphokinase (CPK) ≤ 2.5 x ULN (≤ 5.0 x 
ULN is acceptable if elevation is disease-related).
6) At least three weeks since last prior anticancer treatment 
and recovery to grade ≤ 1 from any adverse event (AE) 
related to previous anticancer treatment (excluding sensory 
neuropathy, anemia, asthenia and alopecia, all grade ≤ 2) 
according to the National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI-CTCAE, 
v.4).
7) Prior radiotherapy (RT): At least four weeks since 
completion of whole-brain RT (WBRT), at least two weeks 
since completion of prophylactic cranial irradiation (PCI), 
and to any other site not previously specified.  
8) Evidence of non-childbearing status for
women of 
childbearing potential (WOCBP). WOCBP must agree to 
use a highly effective contraceptive measure up to six 
weeks after treatment discontinuation. Valid methods to 
determine 
the 
childbearing 
potential, 
adequate 
contraception and requirements for WOCBP partners are 
described in APPENDIX 2. Fertile male patients with
WOCBP partners should use condoms during treatment and 
for four months following the last investigational medicinal 
product (IMP) dose.
Exclusion criteria
1) More than one prior chemotherapy-containing regimen 
(including patients re-challenged with same initial 
regimen). 
2) Patients who never received any platinum-containing 
regimen for SCLC treatment.
3) Prior 
treatment 
with 
PM01183, 
topotecan 
or 
anthracyclines.
4) Limited-stage patients who are candidates for local or 
regional therapy, including PCI, thoracic RT or both, must 
have been offered that option and completed treatment or 
refused it prior to randomization.
5) Impending need for palliative RT or surgery for 
pathological fractures and/or for medullary compression 
within four weeks prior to randomization.
6) Symptomatic, or steroid-requiring, or progressing CNS 
disease involvement during at least four weeks prior to 
randomization (asymptomatic, non-progressing patients 
taking steroids in the process of already being tapered 
within two weeks prior to randomization are allowed).
7) Concomitant diseases/conditions:


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a) History (within one year prior to randomization) or 
presence of unstable angina, myocardial infarction, 
congestive heart failure or clinically significant valvular 
heart disease.
b) Symptomatic 
or 
uncontrolled 
arrhythmia 
despite 
ongoing treatment.
c) Patients with any immunodeficiency, including those 
known to be or have been infected by human 
immunodeficiency virus (HIV).
d)
Ongoing, treatment-requiring, non-neoplastic chronic 
liver disease of any origin. For hepatitis B, this includes 
positive tests for both Hepatitis B surface antigen 
(HBsAg) and quantitative Hepatitis B polymerase chain 
reaction (PCR). For hepatitis C, this includes positive 
tests for both Hepatitis C antibody and quantitative 
Hepatitis C PCR.
e) Active infection or increased risk due to external 
drainages.
f) Intermittent or continuous oxygen requirement within 
two weeks prior to randomization. Patients with 
confirmed or suspected diagnosis of diffuse interstitial 
lung disease (ILD) or pulmonary fibrosis.
g) Patients with a second invasive malignancy treated with 
chemotherapy and/or RT. Patients with a previous 
malignancy that was completely resected with curative 
intention three or more years prior to randomization, and 
who has been continuously in remission since then will 
be permitted.
h) Limitation of the patient’s ability to comply with the 
treatment or to follow the protocol.
i) Documented or suspected invasive fungal infections 
requiring systemic treatment within 12 weeks of 
randomization.
8) Pregnant or breast feeding women. 
EXPECTED NUMBER 
OF PATIENTS
Approximately 600 patients with SCLC for whom one prior 
platinum-containing chemotherapy line failed will be stratified 
and randomized at a 1:1 ratio over 24
months (~25 
patients/month). 
In order to evaluate the overall safety in both arms, an interim 
safety analysis is planned after the recruitment of 150 patients
(i.e., ~75 patients into each arm). Recruitment will not be put 
on hold while the analysis is being performed. Further safety 
and efficacy analyses could be performed upon request from 
the IDMC.
REPLACEMENT OF
PATIENTS
No patients will be replaced. All efficacy analyses will be done 
on an intention-to-treat (ITT) basis.


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STUDY DRUGS 
FORMULATION
EXPERIMENTAL ARM:

PM01183: 
PM01183 drug product (DP) presented as a lyophilized 
powder for concentrate for solution for infusion in 4-mg 
vials 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 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 shown in Table 1.
Table 1. 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

Doxorubicin (DOX):
Commercially available presentations of vials containing 
DOX will be provided as appropriate.
CONTROL ARM:

Topotecan:
Commercially 
available 
i.v. 
presentations 
of 
vials 
containing topotecan will be provided as appropriate.

CAV:
o Cyclophosphamide (CTX): Commercially available 
presentations of vials containing CTX will be provided 
as appropriate.
o Doxorubicin 
(DOX):
Commercially 
available 
presentations of vials containing DOX will be provided 
as appropriate.
o Vincristine 
(VCR):
Commercially 
available 
presentations of vials containing VCR will be provided 
as appropriate.
ROUTE OF 
ADMINISTRATION
EXPERIMENTAL ARM:

Doxorubicin: i.v. through peripheral or central lines 
(according to local label), followed by

PM01183: i.v. infusion over one hour over a minimum of 
100 ml dilution on 5% glucose or 0.9% sodium chloride (at 


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a fixed rate) via a central line (or a minimum of 250 ml 
dilution if a peripheral line is used).
CONTROL ARM:

Topotecan: i.v. infusion daily through peripheral or central 
lines (according to local label), or

CAV:
CTX
i.v. through peripheral or central lines 
(according to local label),
DOX i.v. through peripheral or central lines (according to 
local label), and
VCR i.v. through peripheral or central lines (according to 
local label).
STARTING DOSES AND 
SCHEDULE
EXPERIMENTAL ARM:

DOX at 40.0 mg/m2 on Day 1, followed by,

PM01183 at 2.0 mg/m2 on Day 1 q3wk (three weeks ± 48 
hours = one treatment cycle). 
Note: in cycles with PK sampling, no more than ten 
minutes may pass between the end of DOX infusion and 
the start of PM01183 infusion. 
Up to a maximum of 10 cycles. Then, if applicable, DOX 
will be discontinued definitively and remaining patients 
will continue on maintenance until disease progression 
(PD), patient refusal or unacceptable toxicity despite 
applicable dose reductions, at:
o PM01183 at 3.2 mg/m2 on Day 1 q3wk. (if no more 
than one dose reduction applied while on combination 
therapy), or:
o PM01183 at 2.6 mg/m2 on Day 1 q3wk. (if more than 
one dose reduction applied while on combination 
therapy).
CONTROL ARM: 

Topotecan:
o Topotecan at 1.50 mg/m2 daily on Days 1-5 q3wk (three 
weeks ± 48 hours = one treatment cycle) for patients 
with calculated CrCL ≥ 60 ml/min.
o Topotecan at 1.25 mg/m2 daily on Days 1-5 q3wk (three 
weeks ± 48 hours = one treatment cycle) for patients 
with calculated CrCL between 40 and 59 ml/min.
o Topotecan at 0.75 mg/m2 daily on Days 1-5 q3wk (three 
weeks ± 48 hours = one treatment cycle) for patients 
with calculated CrCL between 30 and 39 ml/min.

CAV:
o
CTX at 1000 mg/m2 on Day 1, 
o
DOX at 45.0 mg/m2 on Day 1, and 
o
VCR at 2.0 mg total flat dose on Day 1 q3wk (three 
weeks ± 48 hours = one treatment cycle). 


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Up to a maximum of 10 cycles (Note: patients older than 
70 years should not receive a total cumulative DOX 
dose of more than 400 mg/m2). Then, if applicable, DOX 
will be discontinued definitively and the remaining patients 
will continue on maintenance until PD, patient refusal or 
unacceptable toxicity despite applicable dose reductions. 
Patients who are experiencing grade 2 neuropathy before 
receiving a new CAV cycle will not receive any further 
VCR infusions until neuropathy resolution to grade 1 is 
documented. Any recurrence of grade 2 neuropathy during 
treatment will result in a definitive discontinuation of VCR. 
Doses in both arms, experimental and control, will be capped 
at a body surface area (BSA) of 2.0 m2 for individuals 
exceeding this BSA value. Doses, except for VCR, will have to 
be recalculated for patients showing a ≥ 10% variation in total 
body weight from baseline or from last dose adjustment. 
PM01183 total doses in mg will be rounded to the first 
decimal, if necessary. DOX, CTX or topotecan total doses will 
be 
rounded, 
if 
applicable, 
according 
to 
institutional 
guidelines/standard practice.
PROPHYLACTIC 
MEDICATION
All patients, irrespectively of treatment arm will receive 
primary prophylaxis subcutaneously, with granulocyte colony-
stimulating factors (G-CSF). Type, dose, and scheme to be 
used may vary according to institutional/standard practices or
guidelines, if available. Nevertheless, a mandatory window of
at least 24 hours and up to 72 hours must be allowed from the 
last dose of study treatment, until G-CSF prophylaxis is 
started.
In addition, all patients will also receive standard antiemetic 
prophylaxis before each treatment infusion, as follows:

Intravenous corticosteroids (dexamethasone 8 mg, or 
equivalent, or at institutional antiemetic doses).

Intravenous serotonin (5-HT3) antagonists (ondansetron 8 
mg, or equivalent).
If necessary, in addition to the above, the duration of treatment 
with 5-HT3 antagonists and/or dexamethasone could be 
extended orally (if needed) (i.e. 4-8 mg/day for three 
consecutive days) and/or 10 mg of metoclopramide orally 
every eight hours could be added.
For the purpose of safety evaluations, an optimal prophylaxis 
is defined as all the aforementioned allowed medications at 
their respectively maximum dose.
Aprepitant or any other NK-1 antagonist or related Substance 
P-antagonists are forbidden in all patients allocated to the 
experimental arm.


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CRITERIA FOR 
TREATMENT 
CONTINUATION
In order to be re-treated, or to start treatment if first dosing was 
extended beyond the first 72 hours after randomization, 
patients will have to fulfill the criteria defined in Table 2.
Table 2. Criteria for treatment continuation.
Variable
Topotecan or CAV
(Day 1)
PM01183/DOX (Day 1),
or PM01183 alone (Day 1) 
whenever is applicable
ECOG PS
≤ 2
≤ 2
ANC
1.5 x 109/l
1.5 x 109/l
Platelets
100 x 109/l
100 x 109/l
Hemoglobin a
9.0 g/dl
9.0 g/dl
Total bilirubin
1.5 x ULN b, or
direct bilirubin 
ULN
1.5 x ULN, or
direct bilirubin ULN
Albumin
2.7 g/dl
2.7 g/dl
AST/ALT
3.0 x ULN
3.0 x ULN
CPK
-
Grade ≤ 1
(or ≤ 2 if disease-related 
grade ≤ 2 at baseline)  
Calculated CrCL 
(Cockcroft and 
Gault’s formula)
≥ 30 ml/min c
≥ 30 ml/min
LVEF *
* Patients assigned to 
CAV treatment: within
normal limits and not 
> 10% decrease (by 
MUGA) or > 20% 
decrease (by ECHO) from 
baseline before Cycle 3, 
Cycle 6 and Cycle 9, and 
if DOX cumulative dose 
≤ 405 mg/m2
Within normal limits and 
not > 10% decrease (by 
MUGA) or > 20% decrease 
(by ECHO) from baseline 
before Cycle 3, Cycle 6 and 
Cycle 9, and if DOX 
cumulative dose ≤ 360 
mg/m2
Other non-
hematological 
drug-related AEs 
(except increased 
AP, or grade 2 
alopecia, asthenia, 
and not optimally 
treated nausea 
and/or vomiting) d
Grade ≤ 1
Grade ≤ 1
a Patients may receive PRBC transfusion and/or EPO treatment if clinically indicated 
to increase/maintain adequate hemoglobin levels.
b Patients assigned to CAV with total bilirubin between 1.25-1.5 x ULN or direct 
bilirubin ≥ ULN will receive a maximum of 1.5 mg of VCR. 
c Patients with CrCL between 40 and 59 ml/min must be re-treated with 1.25 mg/m2 of 
i.v. topotecan daily, and patients with CrCL between 30 and 39 ml/min must receive 
no more than 0.75 mg/m2 of topotecan daily. 
d Any grade accepted for increased AP.
Those patients who experience grade ≥ 2 neuropathy while receiving CAV will stop 
VCR exclusively until resolution to at least grade 1 and, if applicable, will have their 
VCR dose reduced to 1.5 mg/cycle subsequently after resolution. If grade ≥ 2 
neuropathy re-occurs at any time, or if there is no resolution of the first episode to at 
least grade 1 after a minimum of four weeks of follow-up, VCR will be discontinued
definitively. 
AEs, adverse events; ALT, alanine aminotransferase; ANC, absolute neutrophil count; 
AP, alkaline phosphatase; AST, aspartate aminotransferase; CAV, CTX DOX and 
VCR; 
CPK, 
creatine 
phosphokinase; 
CrCL, 
creatinine 
clearance; 
CTX, 
cyclophosphamide; DOX, doxorubicin; ECHO, echocardiogram; ECOG PS, Eastern 
Cooperative Oncology Group performance status; EPO, erythropoietin; LVEF, left 
ventricular ejection fraction; MUGA, multiple-gated acquisition scan; PRBC, packed 
red blood cells; ULN, upper limit of normal; VCR, vincristine.


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If a patient does not meet the requirements for treatment 
continuation on Day 1 of any cycle after Cycle 1, re-
assessments will be performed periodically at intervals of at 
least 72 hours and treatment will be withheld until appropriate 
recovery, for a maximum of 22 days after the treatment due 
date. If there is no recovery after a 22-day delay, treatment 
must be discontinued and the EOT visit performed, except if 
objective clinical benefit is observed in tumor assessments, 
upon the Sponsor’s agreement, in which case up to 15 
additional days will be allowed to recover and meet the 
aforementioned requirements for treatment continuation.
DOSE REDUCTION
Patients who experience any grade ≥ 3 treatment-related non-
hematological toxicity (according to the NCI-CTCAE v.4) or 
febrile neutropenia or neutropenic infection or sepsis, and/or 
grade 4 thrombocytopenia or neutropenia, or treatment-related 
dose delays of more than five days, or frequent shorter dose 
delays (or skipped infusions if on topotecan) may only 
continue treatment, after appropriate dose reduction (see Table 
3).
Patients experiencing treatment-related non-optimally treated 
grade 3 nausea and/or vomiting, grade 3 fatigue/asthenia 
lasting < 3 days, grade 3 diarrhea lasting ≤ 2 days or not 
optimally treated, and/or non-clinically relevant isolated 
biochemical abnormalities (e.g. AP), may continue treatment at 
the same prior dose without dose reduction being applied, 
provided optimal concomitant treatment is given for the 
applicable toxicity.
Patients assigned to CAV treatment in the control arm with 
total bilirubin levels 1.25-1.5 x ULN or abnormally high direct 
bilirubin levels before the start of a new cycle will receive a 
maximum of 1.5 mg of VCR. Those patients assigned to CAV 
who experience grade ≥ 2 neuropathy will stop receiving VCR 
until resolution to at least grade 1. After resolution, treatment 
will be resumed at 1.5 mg of VCR; however, if there is re-
occurrence of grade ≥ 2 neuropathy after re-introduction of 
VCR, or if there is no resolution of the first episode to at least 
grade 1 after a minimum of four weeks of follow-up, VCR will 
be discontinued definitively.
Table 3. Levels of dose reduction in each treatment arm.
Dose 
reduction
Topotecan
daily dose
(q3wk) 
(mg/m2) 
CAV
(q3wk)§
DOX/
PM01183 
(q3wk) 
(mg/m2)
PM01183 
alone 
(q3wk)
(mg/m2)
1
(starting 
dose)
1.50a 1.25b 0.75c, d
CTX: 1000 mg/m2
DOX: 45 mg/m2
VCR: 2.0 mg FD
40 / 2.0
3.2
-1
1.25 1.00  NA
CTX: 750 mg/m2
DOX: 45 mg/m2
+/-VCR: 1.5 mg FD
30 / 2.0
2.6e
-2
1.00 0.75d
NA
CTX: 750 mg/m2
DOX: 35 mg/m2
+/-VCR: 1.5 mg FD
30 / 1.5
2.0


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All doses will be capped at a BSA of 2.0 m2.
PM01183 total doses in mg will be rounded to the first decimal, if necessary. DOX and 
topotecan total doses will be rounded, if applicable, according to institutional 
guidelines/standard practice.
§ Patients who continue maintenance treatment after DOX discontinuation beyond 
Cycle 10 will, under no circumstances, have their CTX dose reduced below 750 mg/m2
or their VCR dose reduced below 1.5 mg FD (although VCR could be discontinued, if 
needed).
a Starting dose for patients treated with topotecan with calculated CrCL ≥ 60  ml/min. 
b Starting dose for patients treated with topotecan with calculated CrCL of 40-59 
ml/min.
c Starting dose for patients treated with topotecan with calculated CrCL of 30-39 
ml/min. 
d No dose reduction below 0.75 mg/m2/day will be implemented under any 
circumstances.
e Starting dose for patients who had two prior dose reductions while on 
PM01183/DOX.
BSA, body surface area; CAV, CTX DOX and VCR; CrCL, creatinine clearance; 
CTX, cyclophosphamide; DOX, doxorubicin; FD, flat dose; mg, milligram; NA, not 
available; q3wk, every three weeks; VCR, vincristine.
Regardless of treatment arm, patients who experience any 
treatment-related 
grade 
4 
hypersensitivity 
and/or 
extravasations will permanently discontinue treatment.
Up to two dose reductions are allowed per patient, if needed, 
excluding those patients starting topotecan at 0.75 mg/m2 or 
those starting PM01183 alone at 2.6 mg/m2 after DOX 
discontinuation. Any patient who continues to experience 
treatment-related 
toxicity 
despite 
all 
applicable 
dose 
reductions, or who requires one after receiving topotecan at 
0.75 mg/m2, must stop treatment. Once the dose has been 
reduced for an individual patient, it will not be re-escalated 
under any circumstances. 
Note:
patients 
enrolled 
in 
the 
experimental 
arm 
(PM01183/DOX), or those assigned to CAV treatment in the 
control arm, who had one or no dose reductions while on the 
combination will discontinue DOX and remain on treatment 
from Cycle 11 onwards (or at any other time if DOX is 
discontinued earlier due to cardiac issues) with PM01183 alone 
at 3.2 mg/m2 and may undergo up to two additional dose 
reductions, whereas those who had two dose reductions while 
on the combination will discontinue DOX and remain on 
treatment from Cycle 11 onwards (or at any other time if DOX 
is discontinued earlier due to cardiac issues) with PM01183 
alone at 2.6 mg/m2 and may undergo one additional dose 
reduction. Patients assigned to CAV treatment in the control 
arm may continue treatment after DOX discontinuation on 
Cycle 11 with CTX +/- VCR, either at 1000 mg/m2/2.0 mg FD
or at 750 mg/m2/1.5 mg, respectively, as applicable. No 
individual dose reductions below CTX 750 mg/m2 or VCR 1.5 
mg FD are allowed. No single-agent PM01183 dose reduction 
below 
2.0 
mg/m2
will 
be 
implemented 
under 
any 
circumstances. 
Dose recalculations due to changes in BSA will not be 
considered dose reductions, as long as the targeted BSA dose 
remains unchanged.


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ALLOWED 
MEDICATIONS/
THERAPIES

Therapies for pre-existing and treatment-emergent medical 
conditions, 
including 
pain 
management 
and 
local 
management of mucositis/stomatitis.

Blood products and transfusions, as clinically indicated.

Bisphosphonates.

In case of nausea or vomiting, extended symptomatic 
treatment for emesis will be allowed.

Erythropoietin treatment according to the American 
Society of Clinical Oncology (ASCO) guidelines.

Low-molecular weight heparin (LMWH) and/or any other 
anticoagulants, as clinically indicated.

CNS irradiation if required, and/or limited field bone RT 
for pain control outside the thoracic wall.

Megestrol acetate for wasting syndrome.
PROHIBITED 
MEDICATIONS/
THERAPIES

Concomitant administration of any other antineoplastic 
therapy. 

Other investigational agents.

Immunosuppressive therapies other than corticosteroids for 
antiemetic prophylaxis or pain control, or low-dose 
replacement in patients requiring this approach. 

Aprepitant and other NK-1 antagonists (for patients 
allocated to the experimental arm).

Concomitant RT other than CNS irradiation, or limited-
field RT for pain control.
DRUG-DRUG 
INTERACTIONS
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 is possible.
A potentially significant interaction with aprepitant is 
suggested by available phase II data from ovarian cancer 
patients and phase I data from the PM1183-A-008-13 study. 
PM01183 clearance was reduced by 50%, approximately, in 
the presence of aprepitant. Although all patients eventually 
recovered, the use of aprepitant is currently forbidden in all 
phase II/III PM01183 studies.
A recent analysis of PK data from the PM1183-A-003-10 trial 
found that PM01183 exposure (area under the curve, AUC) 
reduced DOX clearance slightly (from 45 l/h to 35 l/h; a 20% 
reduction) and more markedly doxorubicinol clearance (from 
150 l/h to 75 l/h; a 50% reduction). A mechanistic explanation 
for this interaction is currently being studied. Taking into 
account these results, the DOX dose of 40.0 mg/m2 used in the 


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experimental arm in the present study is not expected to result 
in patient exposure to supratherapeutic levels of DOX or 
doxorubicinol.
EFFICACY 
EVALUATIONS
Antitumor activity will be assessed using the RECIST v.1.1 
and followed until PD by the appropriate method [computed 
tomography (CT) scan or magnetic resonance imaging (MRI)].
Irrespectively of treatment arm, radiological and clinical tumor 
assessment will be performed at baseline and every six weeks 
(± one week) after randomization until evidence of PD. 
A special effort will be made to continue follow-up and report 
tumor assessments in patients discontinuing the study 
treatment without progression by RECIST v.1.1.
Adequate CNS imaging (contrast enhanced-CT or MRI, if 
applicable) will be performed at baseline to document any 
disease involvement. In the event of CNS involvement being 
found, this assessment will be repeated while on treatment, 
regardless of treatment arm; otherwise, it will only be repeated 
if clinically indicated.
Irrespectively of treatment arm, patients with documented 
clinical benefit during treatment (either response or tumor 
shrinkage in target lesions and without clinical deterioration) 
may continue treatment while CNS irradiation is given, if 
appropriate.
After radiological PD is documented or a new systemic 
antitumor therapy is started, patients will be followed for 
survival every three months (± two weeks) during the first 18 
months after randomization, and then once every six months (± 
four weeks) until death or date of study termination, whichever 
occurs first. Once the whole recruitment is completed, the 
survival follow-up procedure will change: patients who 
discontinue treatment will be followed every three months 
according to a fixed calendar time (e.g., July, October, January, 
etc.) until death or study completion. For survival follow-up 
purposes, after radiological PD is documented or new therapy 
is started, a documented telephone call from the investigational 
sites will be adequate.
The date of clinical and/or radiological PD and the date of 
death will be registered and documented as appropriate.
Copies of CT scans, MRIs and any other documented means to 
evaluate tumor response or progression should be available for 
external radiological review by an IRC. The IRC will 
determine the patient’s best response and assign the date of 
objective response or progression/censoring according to the 
RECIST v.1.1.
In order to evaluate the overall safety in both arms, an interim
safety analysis is planned when 150 patients are recruited (i.e., 
~75 patients into each arm). Recruitment will not be put on 
hold while the interim safety analysis is being performed. 
Efficacy parameters will not be formally analyzed in this 


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interim evaluation. Further safety and efficacy analyses could 
be performed upon request from the IDMC.
If any formal interim OS/PFS analysis is performed, unblinded 
only to the IDMC, a type I error correction according to the 
Lan and DeMets error spending function that corresponds to 
the O'Brien-Fleming boundary will be used, calculated during 
the interim analyses to preserve an overall (one-sided) 0.005 
false positive error rate; if early termination does not occur, the 
alpha level of the final analysis will be chosen to preserve an 
overall (one-sided) 0.025 false positive error rate.
SAFETY 
EVALUATIONS
Patients will be evaluable for safety if they have received any 
partial or complete treatment infusion.
All AEs will be graded according to the NCI-CTCAE, v.4.
Treatment delays, dose omissions (if applicable), dose 
reductions, 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 after the last treatment infusion 
(end of treatment, EOT), or 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, whenever is 
possible.
Any patient having any treatment-related grade ≥ 3 AEs should 
have appropriate tests re-assessed at least every 72 hours until 
recovery to at least grade 2.
Safety evaluations will also be performed by the IDMC during 
the interim analysis, to be conducted when 150 patients are 
recruited (i.e., ~75 patients into each arm).
PATIENT-REPORTED 
OUTCOMES (PRO)
PRO will be assessed at baseline and every six weeks (± one 
week) from randomization until EOT, to determine if efficacy 
and side effects are accompanied by measurable changes in the 
quality of life of patients. The EORTC QLQ-C30 and EORTC 
QLQ-LC13 questionnaires will be used.
PHARMACOKINETIC 
EVALUATIONS
Blood samples (detailed in Table 4) will be collected from all 
patients enrolled exclusively in the experimental arm to 
analyze PM01183, DOX and its metabolite doxorubicinol. The 
samples will be obtained in two cycles: Cycle 1, and a second 
cycle between Cycles 2 and 4. The second cycle with PK 
sampling will be assigned once the patient has been 
randomized into the experimental arm. 


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Table 4. Samples for pharmacokinetic evaluations.
Sample 
No.
Time
Acceptable 
window times
Sampling time
For DOX
For PM01183
#1
0
1 to 5 min before 
treatment start
Predose
Preinfusion
#2
5 min
± 2 min
5 min after EOA
-
#3
1 h
± 4 min
-
5 min before EOI
#4
2 h
± 10 min
2 h after EOA
1 h after EOI
#5
96 h
± 24 h
96 h after EOA
95 h after EOI
DOX, doxorubicin; EOA, end of administration; EOI, end of infusion; h, 
hour; min, minute.
PHARMACOGENETIC 
EVALUATIONS
Pharmacogenetic sub-study:
To explore factors that may help to explain individual 
variability in main pharmacokinetic parameters, the presence 
or absence of germline mutations or polymorphisms will be 
analyzed in leukocyte DNA extracted from a blood sample 
obtained at any time during the study in the experimental arm. 
STUDY
ENDPOINTS
Primary endpoint: 

Overall survival (OS) will be calculated from the date of 
randomization to the date of death (death event) or last 
contact (in this case, survival will be censored on that 
date).
Secondary endpoints:

Difference in OS between PM01183/DOX and CAV, in 
patients with CAV as best Investigator’s choice.

Overall survival (OS)/progression-free survival (PFS) 
per RECIST v.1.1 in patients with and without baseline 
CNS involvement. Subgroup analyses restricted to the 
sensitive and resistant populations will also be performed.

Progression-free survival (PFS) by IRC is defined as the 
time from the date of randomization to the date of 
documented progression per RECIST v.1.1 or death 
(regardless of the cause of death). If the patient receives 
further antitumor therapy or is lost to follow-up before PD, 
PFS will be censored at the date of last tumor assessment 
before the date of subsequent antitumor therapy.

Best antitumor response by IRC will be the best 
response obtained in any evaluation according to RECIST 
v.1.1. 

Duration of response (DR) by IRC will be calculated 
from the date of first documentation of response per 
RECIST v.1.1 (complete or partial response, whichever 
comes first) to the date of documented PD or death. The 
censoring rules defined above for PFS will be used for DR. 

Treatment safety profile: AEs, serious adverse events 
(SAEs) and laboratory abnormalities will be coded by the 
Medical Dictionary for Regulatory Activities (MedDRA), 
graded according to the NCI-CTCAE v.4 and analyzed. 


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Dose reductions or delays required due to treatment-related 
AEs, and reasons for treatment discontinuations will also 
be assessed.
Tertiary endpoints:

Landmark analyses:
o Mid-
and long-term survival (OS at 12/18/24 
months) will be the Kaplan-Meier estimates of the 
probability of being alive at these time points.

Subgroup analyses: Subgroup analyses of efficacy and 
safety profiles in the PM01183/DOX arm vs. CAV based 
on Investigator’s preference will be performed to isolate 
the contribution of PM01183 in the PM01183/DOX 
combination arm. Patients for whom the preference of the 
Investigator prior to randomization is CAV will be 
analyzed to test the combination of PM01183/DOX vs.
CAV. Patients for whom the Investigator’s preference is 
topotecan will also be analyzed independently. 

Progression-free survival (PFS) per RECIST v.1.1 by 
IA.

Best antitumor response by IA. 

Duration of response (DR) by IA. 

Patient-reported outcomes (PRO): To measure the 
quality of life of patients, the EORTC QLQ-C30 and 
EORTC QLQ-LC13 questionnaires will be analyzed at 
baseline and every six weeks (± one week) until EOT. 

Plasma pharmacokinetics (PK) of PM01183 and DOX
will be evaluated using a sparse sampling scheme in 
patients treated in the experimental arm. Details will be 
given in a population PK analysis plan, and results will be 
presented in a separate report.

PK/PDy correlation: Population PK correlations of drug 
exposure with safety and efficacy will be explored in the 
experimental arm. Details will be given in specific 
population PK/PDy analysis plans, and results will be 
presented in separate reports.

Pharmacogenetics: This analysis will be performed in
patients treated in the experimental arm who specifically 
consent to participate in this sub-study. The presence or 
absence of known polymorphisms from a single sample 
collected at any time during the study will be assessed to 
explain the individual variability in the main PK 
parameters.
STATISTICAL 
METHODS
This phase III clinical trial is designed to determine whether 
there is a statistically significant difference in the OS between 
PM01183/DOX vs. CAV or topotecan as second-line treatment 
in SCLC patients after failure of one platinum-containing
chemotherapy line.
The primary study analysis (OS) will be performed by means 


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of the stratified log-rank test selecting the actual CNS and 
CTFI values of the stratification factors on the intention-to-
treat (ITT) population, defined as all randomized patients 
analyzed in the group where they were allocated.
Sample size calculation:
As mentioned above, this study is primarily designed to 
determine whether there is a statistically significant difference 
in the OS between patients treated with PM01183/DOX 
(experimental arm) and those treated with either CAV or
topotecan (control arm). 
The prospective assumptions are a one-sided 2.5% significance 
level with at least 90% power to detect a 25% decrease in the 
risk of death to be achieved with the experimental arm (hazard 
ratio, HR=0.75). OS with either CAV or topotecan is expected 
to be 7.5 months.
To obtain the required 508 events, approximately 600 patients 
with SCLC who failed
one
prior platinum-containing 
chemotherapy line will be stratified and randomized at a 1:1 
ratio. With the aforementioned prospective assumptions, 
recruitment is foreseen to be completed in 24 months, and a 
total study duration for final OS analysis of about three and a 
half years is planned.
The IDMC will oversee the conduct of the study. 
In order to evaluate the overall safety in both arms, an interim 
safety analysis is planned after the recruitment of 150 patients
(i.e., ~75 patients into each arm). Recruitment will not be put 
on hold while the interim safety analysis is being performed. 
Efficacy parameters will not be formally analyzed in this 
interim evaluation.
If formal interim analyses are conducted by the IDMC, a Lan 
and DeMets error spending function that corresponds to the 
O'Brien-Fleming boundary will be used, calculated during the 
interim analyses to preserve an overall (one-sided) 0.005 false 
positive error rate; if early termination does not occur, the 
alpha level of the final analysis will be chosen to preserve an 
overall (one-sided) 0.025 false positive error rate.
Randomization:
Central randomization will be implemented. Patients will be 
assigned to each group at a 1:1 ratio. If the patient is 
randomized to the control arm, the assigned treatment will be 
based on the reported Investigator’s preference between CAV 
or topotecan.  
Stratification:
Stratification will be performed according to the CTFI after 
first line [≥180 days (VS) vs. 90-179 days (S) vs. <90 days 
(R)], ECOG PS (0 vs. 1-2), baseline CNS involvement vs. no 
such involvement, and prior immunotherapy against either PD-
1 or PD-L1 (Yes vs. No) and Investigator’s preference (best 
Investigator’s choice prior to randomization) between 
topotecan and CAV.


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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: 
Time-to-event variables (OS, PFS and DR) and their set time 
estimates (e.g., OS 12/18/24) will be analyzed according to the 
Kaplan-Meier method. The stratified log-rank test (primary 
analysis) and the unstratified log-rank test on the ITT 
population will be used to compare the time-to-event variables.  
Cox regression will be used to calculate the risk reduction (OS, 
PFS and DR) and to evaluate the influence of the stratification 
variables and other potential prognostic factors on the time-to-
event efficacy endpoints. Continuous variables that would have 
been categorized as discrete variables will also be investigated 
in the continuum range, and if the adjustment is better, then the 
continuous
variable 
will 
be 
kept 
in 
the 
regression 
model.Counts and percentages, with their corresponding exact 
95% confidence intervals, will be calculated for the binomial 
endpoints (e.g., response rate). The Fisher’s exact test 
(univariate analyses) and logistic regressions will be used to 
compare the rates of the experimental arm and the control arm. 
Waterfall plots will be used to describe the best variation of the 
sum of target lesions during the treatment.
Safety analyses: 
AEs, 
SAEs, 
deaths, 
laboratory 
evaluations, 
dose 
delays/omissions/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. 
Exploratory Fisher’s exact tests will be performed to compare 
grade 4 or grade 3/4 between treatment arms.
Patients having any grade ≥3 laboratory abnormalities and/or 
treatment-related AEs must have the relevant tests re-assessed 
at least every 48-72 hours until recovery to at least grade 2 has 
been documented.
Patient-reported outcome (PRO) analyses:
PRO will be analyzed to determine if efficacy and side effects 
are accompanied by measurable changes. The analysis will be 
performed on summary scores of the EORTC QLQ-C30 and 
EORTC QLQ-LC13 questionnaires, as well as on subscales, 
and individual symptoms.
Pharmacokinetic (PK) analyses:
Pharmacokinetic data will be listed in the population PK report 
for all patients treated with PM01183 and DOX in the 


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experimental arm who had available concentrations of 
PM01183, DOX or doxorubicinol.  Patients will be excluded 
from the PK analysis if their data do not allow for accurate 
assessment of the PK (e.g., improper handling of PK samples; 
incomplete administration of the study agent; missing time or 
dosing information). All concentrations below the lowest 
quantifiable concentration or missing data will be labeled as 
such in the concentration data presentation. All patients and 
samples excluded from the analysis will be retained in the 
dataset, but they will be flagged out and the criteria for 
exclusion documented. 
Population PK analysis of plasma concentration-time data of 
PM01183, DOX and doxorubicinol will be performed using 
non-linear mixed-effects modeling. Data may be combined 
with additional trials to support a relevant structural model. 
Available patient characteristics (demographics, laboratory 
variables, genotypes, etc.) will be tested as potential covariates 
affecting PK parameters. Details will be given in a population 
PK analysis plan, and results will be presented in a separate 
report.
Pharmacokinetic/pharmacodynamic correlation:
Population PK data correlations of drug exposure with safety 
and efficacy parameters will be explored. Details will be given 
in specific population PK/PDy analysis plans, and results will 
be presented in separate reports.
Pharmacogenetic analyses:
The influence of genetic polymorphisms on main PK 
parameters will not be assessed or reported for individual 
clinical trials. Pharmacogenetic analysis will instead be 
performed using data aggregated from across the PM01183 
clinical development program and presented in a separate 
report.
DURATION OF STUDY 
PERIOD (per patient)
Patients will be evaluated at scheduled visits in three study 
periods:

Pre-treatment: from signature of ICF to first infusion of the 
study treatment.

Treatment: from first infusion of the study treatment to the 
end of treatment (EOT).

Follow-up: after EOT, patients will be followed every four 
weeks until resolution or stabilization of all toxicities, if any. 
Patients who discontinue treatment regardless of the reason 
but without documented disease progression at the time of 
discontinuation will be followed every six weeks (± one 
week) until disease progression or start of a new antitumor 
therapy, death or until the date of study termination (clinical 
cutoff), whichever occurs first. After disease progression is 
documented or a new antitumor therapy is started, patients 
will be followed every three months (± two weeks) during 
the first 18 months after randomization, and then once every 
six months (± four weeks) until death of any cause or date of 


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Protocol PM1183-C-003-14
study termination, whichever occurs first. Once the whole 
recruitment is completed, the survival follow-up procedure 
will change: patients who discontinue treatment will be 
followed every three months according to a fixed calendar 
time (e.g., July, October, January, etc.) until death or study 
completion.
Patients will be considered to be on-study from the signature of 
the ICF to the end of the follow-up period. Patients will be 
considered to be on-treatment for the duration of their 
treatment and until the day of EOT, immediately before the start 
of the follow-up period. This EOT is defined as 30 days after the 
day of the last study treatment infusion, unless the patient starts 
a new antitumor therapy or dies (whichever occurs first). An 
end-of-treatment visit (EOT visit) will be performed at 30 days 
(± 10 days) after the last study treatment administration, unless 
the patient starts any subsequent antitumor therapy, in which 
case the end-of-treatment visit should be performed immediately 
before the start of the new therapy, whenever possible.
Patients will receive the study treatment(s) while it is considered 
to be in their best interest. Specifically, individual treatment of a 
given patient will continue until:

Documented 
disease 
progression 
(unless 
exclusively 
asymptomatic CNS involvement, in an otherwise responding 
patient).

Unacceptable 
toxicity
after 
allowed/applicable 
dose 
reductions.

Intercurrent illness of sufficient magnitude to preclude safe 
continuation of the study.

Patient’s refusal and/or non-compliance with study 
requirements.

A major protocol deviation that may affect the risk/benefit 
ratio for the participating patient.
PLANNED TRIAL 
PERIODS (for the whole 
study)
The total duration of the study will be approximately 42 months. 
Planned start date (first patient on study): 2Q2016.
Planned enrollment period: approximately ~24 months.
Planned end-of-study date (clinical cutoff): approximately 18 
months after the last patient is randomized.


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SCHEDULE OF ASSESSMENTS AND PROCEDURES
Assessments and procedures
Screening
(days)
*
Treatment (q3wk)
End of 
treatment 
(EOT)
‡
Follow
-up
Cycle 1
Cycle 2**
Further cycles**
D1
D10
†
D1  D10
†
D1  
D10
†
Written informed consent
Before any 
study 
procedure
-
-
-
-
-
-
-
-
Demographic data
-14  to  0
-
-
-
-
-
-
-
-
Medical and cancer 
history/baseline conditions
-14  to  0
-
-
-
-
-
-
-
-
Assessment of signs and 
symptoms
-7  to  0
-
-
-
-
-
-
-
-
Treatment (1)
NA

-

-

-
NA
-
Complete physical 
examination, including 
weight, height and BSA (2)
-7  to  0
-
-

-

-

-
ECOG PS
-7  to  0
-
-

-

-

-
Vital signs (heart rate, blood 
pressure, temperature)
-7  to  0
-
-

-

-

-
Hematology (3)
-7  to  0
-

(3)

(3)

(3)

(3)
Always  if grade ≥ 3 
hematological 
abnormalities or a dose 
modification occurred 
in the preceding cycle, 
and before the first 
cycle after DOX 
discontinuation (C11)
in patients treated in 
the experimental arm, 
and in patients 
assigned to CAV in the 
control arm    
(3)
-
Biochemistry (3)
-7 to  0
-

(3)

(3)

(3)

(3)
Always if grade ≥ 3 
non-hematological 
abnormalities or a dose 
modification occurred 
in the preceding cycle
(3)
-
LVEF assessment (by 
MUGA or ECHO)
-14 to 0

Experimental arm: repeat before Cycles 3, 6, 9 and 11 
(first cycle after DOX discontinuation), and whenever 
clinically indicated due to suspicion of CHF 

Control arm (topotecan):
repeat whenever clinically 
indicated due to suspicion of CHF

Control arm (CAV):  repeat before Cycles 3, 6, 9 and 11 
(first cycle after DOX discontinuation), and whenever
clinically indicated due to suspicion of CHF
-
Pregnancy test (if 
applicable) (4)
-7  to  0
-
-

-

-

-
ECG (5) (+ cardiac 
assessment, if required)
-7  to  0

Experimental arm: repeat before Cycles 6 and 11 (first 
cycle after DOX discontinuation), and whenever clinically 
indicated 

Control arm
(topotecan):
repeat whenever clinically 
indicated

Control arm (CAV):  repeat before Cycles 6 and 11 (first 
cycle after DOX discontinuation), and whenever  clinically 
indicated 
-


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Assessments and procedures
Screening
(days)
*
Treatment (q3wk)
End of 
treatment 
(EOT)
‡
Follow
-up
Cycle 1
Cycle 2**
Further cycles**
D1
D10
†
D1  D10
†
D1  
D10
†
Pharmacokinetics 
(experimental arm only, in 
Cycle 1 and in another cycle 
randomly between Cycle 2 
and Cycle 4)
-

(6)
-

(6)
-

(6)
-
-
-
Pharmacogenetics 
(polymorphisms), only if 
specific written informed 
consent is given (7) 
One blood sample collected at any time during the study from patients 
treated in the experimental arm
-
Clinical and radiological 
tumor assessment (contrast 
enhanced helical CT-scan or 
MRI)
-14  to  0
Every 6 weeks (± one week)
(from randomization)
(8)
CNS radiological
assessment (contrast 
enhanced CT-scan or MRI)
-14 to 0
Repeat in the event of baseline CNS involvement, and also if 
clinically indicated
-
Patient-reported outcomes
questionnaires
-7 to 0
Every 6 weeks (± one week)
(from randomization) 
-
Survival information
NA
Throughout the ”on-treatment period”

Concomitant therapies
-7  to  0
Throughout the ”on-treatment period”
-
Adverse events
- §
Throughout the ”on-treatment period”
(9)
Regardless of the treatment administered, the same schedule of assessments will apply.  
Day 0 = day of randomization. Treatment (Day 1 of Cycle 1) must start within 72 hours after randomization. Otherwise, all 
applicable assessments outside accepted windows must be repeated and eligibility criteria must be reassessed. Concomitant 
medications or signs and symptoms with onset or any change occurring between Day 0 and Day 1 of Cycle 1 must also be reported
* During screening, an additional 3-day window will be allowed for assessment of signs and symptoms, complete physical 
examination, ECOG PS, vital signs, laboratory procedures, pregnancy tests, ECG, patient-reported outcomes and concomitant 
therapies; and a 14-day window for the assessment of demographic data, medical and cancer history, LVEF, radiological procedures 
and tumor assessments. Standard of care procedures prior to consent may be used for this study.
** Cycle 2 and further cycles will be administered every three weeks (± 48 hours) if the patient fulfills all re-treatment criteria.
† A ±3-day window will be allowed for Day 10 assessments, if applicable.
‡ At 30 ±10 days after the last treatment infusion, an EOT 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 treatment-related 
alteration.
§ Only information on SAEs that occur after signature of informed consent form is required. Grading should be as per NCI-CTCAE 
v. 4.
During treatment, a 3-day window will be allowed for clinical assessments (disease-related signs and symptoms, ECOG PS, 
vital signs, weight, BSA, etc.), laboratory procedures, and pregnancy tests; a 7-day window for ECG assessments, radiological 
procedures, tumor assessments and patient-reported outcomes; a 14-day window for LVEF assessments; and a 10-day 
window for the assessments at EOT. 
1.
Treatment will consist of the following:

In the experimental arm: DOX as an i.v. infusion + PM01183 as a 1-hour i.v. infusion, both on Day 1 q3wk. Upon reaching 
10 cycles of PM01183/DOX combination, non-progressing patients may continue treatment with PM01183 alone, at single-
agent doses, on Day 1 q3wk.

In the control arm: topotecan as an i.v. infusion daily on Days 1-5 q3wk, or CAV on Day 1 q3wk. Upon reaching 10 cycles 
of the CAV combination, non-progressing patients may continue treatment with CTX +/- VCR, as applicable, on Day 1 
q3wk.
2.
Height and BSA, calculated using the DuBois formula, need to be measured at baseline only; then, BSA must be recalculated 
whenever a ≥10% variation in total body weight from baseline or from last dose adjustment occurs, before treatment 
administration in subsequent cycles.
3.
Any patient having any grade ≥ 3 laboratory abnormalities and/or treatment-related AEs must have the relevant tests re-
assessed at least every 48-72 hours until recovery to at least grade 2 has been documented.
4.
Assessment of β-hCG only if the patient is a WOCBP. If abnormally elevated, an US should be performed in order to rule out a 
pregnancy. During the on-treatment period, testing should be repeated before every cycle (or, at least, monthly).
5.
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, with specialist assessment/judgment of further evaluation if appropriate.
6.
A total of five blood samples will be collected for pharmacokinetic analyses of PM01183, DOX and its metabolite 
doxorubicinol: four on Day 1 (before treatment start, 5 min after DOX administration, 5 min before the end of PM01183 
infusion, and 1 hour after the end of PM01183 infusion) and one on Day 5 (at 95 hours after the end of PM01183 infusion). 
7.
One blood sample will be collected at any time during the study from patients treated in the experimental arm.
8.
Patients who have withdrawn from the study without PD documentation should undergo tumor assessment every six weeks (± 


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Assessments and procedures
Screening
(days)
*
Treatment (q3wk)
End of 
treatment 
(EOT)
‡
Follow
-up
Cycle 1
Cycle 2**
Further cycles**
D1
D10
†
D1  D10
†
D1  
D10
†
one week) until PD, start of a new antitumor therapy,  death or date of study termination (clinical cutoff), whichever occurs first. 
After PD is documented or a new antitumor therapy is started, patients will be followed for survival every three months (± two 
weeks) during the first 18 months after randomization, and then once every six months (± four weeks) until death of any cause or 
date of study termination, whichever occurs first. Once the whole recruitment is completed, the survival follow-up procedure 
will change: patients who discontinue treatment will be followed every three months according to a fixed calendar time (e.g., 
July, October, January, etc.) until death or study completion.
9.
Patients who have withdrawn from the study with a drug-related AE should be followed every four weeks until recovery or 
stabilization. 
Hematology: Differential WBC counts, including absolute neutrophil and lymphocyte counts, platelet count and hemoglobin.
Biochemistry: Liver function test: ALT, AST, AP, total bilirubin (direct bilirubin if total is abnormally elevated); albumin, 
creatinine, CPK, glucose, calculated CrCL, serum electrolytes (Na+, K+, Ca++), LDH, and CRP (mandatory at baseline; then to be 
repeated only if clinically indicated). In addition, AAGP will be evaluated exclusively in patients enrolled into the experimental arm, 
at baseline and on Day 1 of cycles with PK sampling.
AAGP, alpha-1 acid glycoprotein; AE, adverse event; ALT, alanine aminotransferase; AP, alkaline phosphatase; AST, aspartate 
aminotransferase; BSA, body surface area; C, treatment cycle; CAV,  CTX DOX and VCR; CHF, congestive heart failure; CPK, 
creatine phosphokinase; CrCL, creatinine clearance; CRP, C-reactive protein; CT, computed tomography; CTX, cyclophosphamide; 
D, day; DOX, doxorubicin; ECG, electrocardiogram; ECOG, Eastern Cooperative Oncology Group Performance Status; EOT, end of 
treatment; hCG, human chorionic gonadotropin; i.v., intravenous; LDH, lactate dehydrogenase; MRI, magnetic resonance imaging;
NA, not applicable; NCI-CTCAE, National Cancer Institute Common Terminology Criteria for Adverse Events; PD, progressive 
disease; PS, performance status; q3wk, every three weeks; RECIST, Response Evaluation Criteria In Solid Tumors; SAE, serious 
adverse event; ULN, upper limit of normal; US, ultrasound; VCR, vincristine; WBC, white blood cells; WOCBP, woman of 
childbearing potential.


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
5-HT3
Serotonin
95% CI
95% Confidence Interval
ACE
Doxorubicin, Cyclophosphamide and Etoposide
AE(s)
Adverse Event(s)
ALT
Alanine Aminotransferase
ANC 
Absolute Neutrophil Count
AP
Alkaline Phosphatase
ASCO
American Society of Clinical Oncology
AST
Aspartate Aminotransferase
AUC
Area Under the Curve
AUCR
Area Under the Curve Ratio
β-hCGs
Beta Subunit of Human Chorionic Gonadotropins
BSA
Body Surface Area
BSC
Best Supportive Care
C
Treatment Cycle
CAV
Cyclophosphamide, Doxorubicin and Vincristine
CDDP
Cisplatin
CE
Carboplatin and Etoposide
CEV
Cyclophosphamide, Epirubicin and Vincristine
CHF
Congestive Heart Failure
CHOP
Cyclophosphamide, Doxorubicin, Vincristine and Prednisone
Cmax
Maximum Plasma Concentration
CI
Combination Index
CNS
Central Nervous System
COPD
Chronic Obstructive Pulmonary Disease
CPK
Creatine Phosphokinase
CR
Complete Response
CrCL
Creatinine Clearance
CRF
Case Report Form
CRP
C-reactive Protein
CT
Computed Tomography scan
CTFI
Chemotherapy-free Interval
CTX
Cyclophosphamide
d/D
Day(s)
DLT
Dose-limiting Toxicity
DNA
Deoxyribonucleic Acid


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DOX
Doxorubicin
DP
Drug Product
DR
Duration of Response
DSB
Double-strand Breaks
ECG
Electrocardiogram
ECHO
Echocardiogram
ECOG PS
Eastern Cooperative Oncology Group Performance Status
EOA
End of Administration
EOI
End of Infusion
EORTC
European Organization for Research and Treatment of Cancer
EOT
End of Treatment
EP
Etoposide and Cisplatin
EPO
Erythropoietin
ES
Extensive-stage disease
FD
Flat Dose
FDA
U.S. Food and Drug Administration
FiM
First-in-man (study)
FN
Febrile Neutropenia
FUP
Follow-up
GCIG 
Gynecologic Cancer Intergroup 
GCP
Good Clinical Practice
G-CSF
Granulocyte Colony-stimulating Factor
GMT
Greenwich Meridian Time
h
Hours
HBsAg
Hepatitis B Surface Antigen
hCG
Human Chorionic Gonadotropin
HIV
Human Immunodeficiency Virus
HR
Hazard Ratio; Homologous Recombination
IA
Investigator’s Assessment
IB
Investigator’s Brochure
IC50
Half Maximal Inhibitory Concentration 
ICF
Informed Consent Form
ICH
International Conference on Harmonization
ICL
Interstrand Crosslink
IDMC
Independent Data Monitoring Committee
IEC
Independent Ethics Committees
IG50
Concentration that Results in 50% of Cell Growth Inhibition
ILD
Interstitial Lung Disease
IMP
Investigational Medicinal Product


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INR
International Normalized Ratio
IP
Irinotecan and Cisplatin
IRB
Institutional Review Board
IRC
Independent Review Committee
IST
Investigator-sponsored Trial
ITT
Intention-to-treat
i.v.
Intravenous 
LC-MS/MS
Liquid Chromatography/Mass Spectrometry/Mass Spectrometry 
LDH
Lactate Dehydrogenase
LMWH
Low Molecular Weight Heparin
LS
Limited-stage disease
LVEF
Left Ventricular Ejection Fraction
MCD
Maximum Cumulative Dose
MedDRA
Medical Dictionary for Regulatory Activities
mg
Milligram
mo
Months
MRI
Magnetic Resonance Imaging
MTD
Maximum Tolerated Dose
MUGA
Multiple-gated Acquisition Scan
NA
Not Applicable; Not Available
NCI
National Cancer Institute
NCI-CTCAE
National Cancer Institute-Common Terminology Criteria for Adverse Events
NET
Neuroendocrine Tumor
NHL
Non-Hodgkin’s Lymphoma
NIHS
National Institute of Health Sciences
NR
Not Reported
NSCLC
Non-small Cell Lung Cancer
ORR
Overall Response Rate
OS
Overall Survival
PBPK
Physiologically-based Pharmacokinetic
PCI
Prophylactic Cranial Irradiation 
PCR
Polymerase Chain Reaction
PD
Progressive Disease
PD-1
Programmed Cell Death Protein-1
PD-L1
Programmed Death Ligand-1
PDy
Pharmacodynamic(s)
PFS
Progression-free Survival
PhV
Pharmacovigilance
PK
Pharmacokinetic(s)


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PR
Partial Response
PRBC
Packed Red Blood Cells
PRE TT
Pre-treatment
PRO
Patient-reported Outcomes
q3wk
Every Three Weeks
Qdx5x2
Two cycles of Five Daily Doses
Q7dx3
Three Consecutive Weekly Doses (D-0, 7, 14)
R
Resistant
RBC(s)
Red Blood Cell(s)
RD
Recommended Dose 
RECIST
Response Evaluation Criteria In Solid Tumors
RT
Radiotherapy
S
Sensitive
SAE(s)
Serious Adverse Event(s)
SCLC
Small Cell Lung Cancer
SD
Stable Disease
SIADH
Syndrome of Inappropriate Antidiuretic Hormone Secretion
STS
Soft Tissue Sarcoma
T/C
Treatment/Control
TCD
Total Cumulative Dose
TC-NER
Transcription-Coupled Nucleotide Excision Repair
TGD
Tumor Growth Delay
TOPO II
Topoisomerase II
TT
Treatment
TTP
Time to Progression
Uk
Unknown
ULN
Upper Limit of Normal
U.S.
United States of America
US
Ultrasound
VCR
Vincristine
VS
Very Sensitive
WBC
White Blood Cells
WBRT
Whole Brain Radiotherapy
wk
Week(s)
WMA
World Medical Association
WOCBP
Women Of Childbearing Potential


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1.
INTRODUCTION
1.1
SMALL CELL LUNG CANCER
Lung cancer is the most deadly cancer in Western countries, and despite recent 
advances in diagnosis, staging and evolving treatments, it remains the top-listed cause 
of cancer-related mortality [1]. In 2013, it caused approximately 160,000 deaths in the 
United States (U.S.) alone [2]. Small cell lung cancer (SCLC) constitutes approximately 
13% of all cases. SCLC is a unique disease that is distinct from non-small cell lung 
cancer (NSCLC), with histological features of neuroendocrine differentiation [3]. Its 
natural history of aggressive clinical behavior with early metastatic potential and wide 
dissemination at diagnosis carries the worst prognosis among all lung cancer subtypes. 
SCLC is intimately related to tobacco use; restrictive policies implemented during the 
last decades regarding tobacco consumption in the US had led to a sharp decline in 
incidence, from above 20% of lung cases in the 1970s [4]. 
Traditionally, the staging of SCLC separated those patients with limited-stage (LS) 
disease (with disease confined to thorax) from patients with extensive-stage (ES) 
disease (with disease showing involvement beyond the thorax). Approximately, 20% of 
all SCLC patients may present with central nervous system (CNS) metastases, and up to 
30% with bony and/or bone marrow involvement [5]. Therefore, the surgical 
management option is only restricted to diagnostic purposes or individual patients, not 
even those with limited-stage only because of potential occult metastases. 
SCLC typically shows high chemosensitivity, closer to what is commonly observed in 
non-Hodgkin lymphoma (NHL) patients, compared with
other solid tumors. 
Unfortunately, this chemosensitivity is also typically short-lasting, as eventually 
resistance emerges. These features led to multiple-agent combination chemotherapy 
being used upfront as a strategy to improve outcome. Since the late 1980s, platinum-
based chemotherapy remains the mainstay of therapy in both stages. Roth et al. [6]
compared EP [etoposide + cisplatin (CDDP)] to an anthracycline-containing regimen 
closely related to the cyclophosphamide (CTX), doxorubicin (DOX), vincristine (VCR) 
and prednisone (CHOP) combination used in aggressive lymphomas but without 
prednisone, CAV (CTX + DOX + VCR). No superiority was found in patients with ES
disease. However, in another trial [7] in patients with LS disease, EP showed a higher
median overall survival (OS) (14.5 vs. 9.7 months; p=0.0001) compared to CEV 
(epirubicin instead of DOX). In ES disease, the results did not reach statistical 
significance although a trend was noted (8.4 vs. 6.5 months; p=0.21). Investigators from 
the European Organization for Research and Treatment of Cancer (EORTC) [8] also 
compared EP to another DOX-containing regimen also used in lymphomas: the ACE 
(DOX, CTX and etoposide). Results regarding overall response rate (ORR) and 1-year 
survival rates were as follows: 77% vs. 72%, and 38% vs. 34%, respectively. However,
the significant higher proportion of grade 3/4 neutropenia and infections with ACE 
(90% vs. 73% and 57 vs. 29%; p=0.005) supported the choice of EP as a standard first-
line therapy. More recently, a metaanalysis of several first-line trials [9] showed 
equivalence between carboplatin and CDDP, when combined with etoposide; therefore, 
the EP and CP regimens might be interchangeable, and the different safety profile of 
each of these regimens can be adapted to a patient’s particular situation. In addition to 
chemotherapy, patients with LS disease may benefit from regional radiotherapy (RT) as 
well as those without CNS involvement at diagnosis benefit from prophylactic cranial 
irradiation (PCI) [10]. Stage at diagnosis remains an important prognostic factor 


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regarding likelihood of complete responses and OS [11]. Patients with LS have a 
median OS of approximately 16 months compared to only 7-8 months in patients with 
ES at diagnosis. 
Despite initial responses in up to 80% of patients, almost all patients will ultimately 
relapse/progress and die due to SCLC. Median- or long-term survivorship is extremely 
rare in this disease, with 5-year survival rates usually below 2-5% [12]. Investigational 
approaches, including alternating regimens without cross-resistance, maintenance 
therapy or chemotherapy intensification with colony-stimulating factor support did not 
show any improvement compared with standard EP or carboplatin and etoposide (CE)
treatment for 4-6 cycles initially, and have not been widely used in SCLC patients [13, 
14]. In Western countries, randomized trials aiming to improve results over EP (or CE) 
have repeatedly failed to show any improvement [15]. In Japan, however, results with 
irinotecan replacing the etoposide (i.e. IP vs. EP) showed an improved progression-free 
survival (PFS) and OS (6.9 vs.4.8 months; p=0.003 and 12.8 vs. 9.4 months; p=0.002, 
respectively) as well as a 2-year survival rate of 19.5% for IP compared to only 5.2% 
when given as first-line treatment [16]. Unfortunately, these results were not 
reproducible in two large US randomized studies in non-Japanese patients [17]. 
Patient outcome after failure of first-line treatment usually depends on chemotherapy-
free interval (CTFI) until progressive disease (PD) occurs. Exploratory small phase II 
studies showed that the ORR to subsequent therapies like paclitaxel, ifosfamide, 
gemcitabine [18], carboplatin or others is markedly dependent on this CTFI [19, 20]. 
Patients somewhat arbitrarily are usually categorized as resistant (R) if relapse occurs 
within less than 90 days from the last chemotherapy (usually also including refractory 
patients with a CTFI of 0 days), or as sensitive (S) if relapse occurs with a CTFI of 90 
days or more. Usually ORRs in the range of 0-5% are reported for R patients, while 
ORRs of 18-40% are commonly observed in S patients [21]. Of note, patients relapsing 
at six months or more after the end of the initial platinum-based treatment might 
especially benefit from re-challenging with the same treatment, with ORRs of as much 
as 65% being reported in some series/studies [22]. Hence, this is an option for this very 
selected population, although not universally accepted.
Available options after failure of first-line EP/CE in Western countries for both S and R 
patients are very limited. In fact, in Western countries regulatory approval is available 
only for topotecan, either as a standard intravenous (i.v.) formulation, or more recently 
for an oral formulation that has shown similar results in patients with decreased Eastern 
Cooperative Oncology Group performance status (ECOG PS) scores [23]. Standard 
topotecan was originally approved based on results from Von Pawel et al. [24] where 
211 patients were randomized and similar results compared to CAV were observed 
regarding antitumor activity (ORR: 24.3% vs. 18.3%, p=0.285; time-to-progression 
(TTP): 13.3 vs. 12.3 weeks, p=0.552; OS: 25.0 vs. 24.7 weeks, p=0.795) in a selected 
second-line patient population that excluded refractory patients and those progressing or 
relapsing within 60 days of initial therapy. In this study, topotecan was associated with 
significantly less grade 4 neutropenia and better patient symptom improvement, but 
with worst grade 4 thrombocytopenia and grade 3/4 anemia than CAV. It should be 
noted that, even though the study was not originally designed as a non-inferiority trial 
(to demonstrate that topotecan was not inferior to CAV in terms of response rate and 
duration), the lack of any statistically significant difference between topotecan and CAV 
for any of the major efficacy parameters evaluated as primary endpoints led to the initial 
regulatory approval of topotecan in the U.S. and most European countries. This study 
was published in 1999; unfortunately, since then no other treatments have shown any 


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improvement over topotecan or CAV in this setting despite some recent spectacular 
advances in the treatment of most other solid tumors. It seems that relapsed SCLC 
reflects the last frontier, representing a truly unmet medical need in which no significant 
improvement over a dismal median OS of around six months has been achieved for the 
last 30 years. Almost every single randomized trial done in this setting has failed. More 
recently [25], amrubicin, which has been approved in Japan as second-line treatment in 
SCLC, failed to improve results over standard topotecan in 637 patients randomized 2:1 
(median OS: 7.5 vs. 7.8 months, respectively; p=0.170). Nevertheless, it showed an 
improved ORR of 31.1% over 16.9% (p<0.001) and a marginal improvement in PFS of 
4.1 vs. 3.5 months, respectively (p<0.018). Active or rapidly progressing patients with 
CNS involvement, and very symptomatic patients with poor ECOG PS scores or 
especially frail with extensive bone involvement are usually excluded from clinical 
trials and are only offered best supportive care (BSC) or sometimes oral topotecan, 
because treatment-associated toxicity is not negligible in this situation and, as already 
mentioned, clinical benefit is often not a realistic goal. Comorbidities usually include 
those related to baseline conditions such as long exposure to tobacco [chronic 
obstructive pulmonary disease (COPD) and/or vascular disease], age, and some related 
to prior treatments such as prior mediastinal and/or extensive irradiation, cisplatin-
induced neuropathy or nephropathy. Finally, tumor-related paraneoplastic syndromes 
are very often associated with SCLC due to its neuroendocrine features, such as 
syndrome of inappropriate antidiuretic hormone secretion (SIADH), Cushing’s disease, 
malignant hypercalcemia, hyperviscosity syndrome related to polycythemia, Raynaud’s 
phenomena or thrombophlebitis, etc. These comorbidities sometimes conspire to make 
SCLC patients poor candidates for clinical trials.
Table 1. Efficacy results of selected salvage chemotherapy in relapsed SCLC patients.
Study (reference)
N
Treatment 
arms
ORR 
(%)
TTP
(mo)
OS 
(mo)
Von Pawel et al. 2014 [25]
637
Amrubicin (n=424)
31.1
4.1 
7.5
Topotecan (n=213)
16.9
3.5
7.8 
O’Brien et al. 2006 [23]
141
Topotecan (n=71)
7
3.8
6.0
BSC (n=70)
NR
NR
3.2
Joos et al. 2004 [26]
93
Paclitaxel
20
3.0
4.0
Ando et al. 2004 [27]
25
IP
80
3.6
7.9
Masters et al. 2003 [18]
42
Gemcitabine
12
NR
7.1
Von Pawel et al. 1999 [24]
211
Topotecan (n=104)
24.3
3.1 
5.8
CAV (n=107)
18.3
2.8
5.7
Lopez et al. 1985 [28]
30
EP
27
NR
3.7
BSC, best supportive care; CAV, CTX DOX and VCR; CTX, cyclophosphamide; DOX, doxorubicin; EP, etoposide 
and cisplatin; IP, irinotecan and cisplatin; mo, months; NR, not reported; ORR, overall response rate; OS, overall 
survival; TTP, time to progression; VCR, vincristine.
As shown in Table 1, most single agents and combinations tested in this setting have 
shown ORRs within the 20-30% range: Median TTP is typically around 3.5 months, 
which unfortunately leads to death occurring within one to three months after disease 
progression. Available therapies beyond second line are exploratory, and usually 
applicable only under exceptional circumstances, because most patients do not reach the 
option for additional treatment(s).


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1.2
INFORMATION ON THE STUDY DRUGS
1.2.1
Lurbinectedin (PM01183)
Please refer to the Investigator's Brochure (IB) for full information on PM01183.
1.2.1.1
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).
1.2.1.2
Non-clinical Data
PM01183 
contains 
a 
pentacyclic 
skeleton 
composed 
of 
two 
fused 
tetrahydroisoquinoline rings with an additional tetrahydro β-carboline moiety. The 
pentacyclic skeleton is mostly responsible for DNA minor groove recognition and 
binding. PM01183 reacts with the exocyclic amino group of guanines in the minor 
groove of DNA forming a covalent bond. PM01183 preferentially binds the following 
triplet of bases: AGC > CGG > TGG > AGG (the middle guanine being the site for 
covalent adducts formation) [29]. The resulting adduct is additionally stabilized through 
the establishment of van der Waals interactions and one or more hydrogen bonds with 
neighboring nucleotides in the opposite strand of the DNA double helix, thus creating 
the equivalent to a functional interstrand crosslink (ICL). The additional tetrahydro β-
carboline moiety protrudes from the DNA minor groove and could be interacting 
directly with specific factors involved in DNA repair and transcription pathways. 
PM01183 induces a rapid and massive degradation of transcribing RNA Pol II in 
several human tumor cell lines [30]. Lurbinectedin-mediated RNA Pol II degradation 
was abrogated in the presence of the transcriptional inhibitor DRB or the proteasome 


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inhibitor MG132, indicating that it is dependent on active transcription and the presence 
of functional proteasome machinery. In addition, the effect of lurbinectedin on RNA Pol 
II was dependent on the presence of a functional Transcription-Coupled Nucleotide 
Excision Repair (TC NER) repair system. These results suggest that RNA Pol II 
degradation mediated by lurbinectedin is dependent on transcription, proteasome and 
TC NER.
The resolution of functional ICLs is known to occur through the coordinated action of 
multiple DNA repair pathways, including homologous recombination (HR), a process 
that gives rise to double-strand breaks (DSBs). PM01183 treatment at nanomolar 
concentrations does indeed give rise to a high proportion of DSB-positive tumor cells 
with abundant γ-H2AX foci per cell [31]. Moreover, PM01183 induces a delayed 
progression of the S-phase and a G2/M arrest at both low and high nanomolar 
concentrations. Altogether these findings indicate that some of the PM01183-DNA 
adducts are eventually transformed into DSB inducing apoptosis. Of note, PM01183 is 
more active against HR-deficient cell lines [32]. 
On the other hand, PM01183 is able to interfere with the TC-NER machinery thereby 
attenuating the repair of specific NER substrates [33]. It is possible that the additional 
tetrahydro β-carboline moiety present in PM01183 interacts with TC-NER factors and 
could interfere with the repair mechanism. In fact, it was recently found that PM01183 
was less potent in NER deficient cells compared with NER-proficient cells indicating 
that this compound could be also targeting TC-NER-dependent DNA repair. Resistance 
to DNA alkylators and platinum regimens is often accompanied by increased NER 
activity indicating that these tumor cells could be particularly sensitive to PM01183.In 
this sense, PM01183 show unchanged or even enhanced activity towards two cisplatin 
resistant ovarian carcinoma cell lines and oxaliplatin-resistant colon carcinoma cell 
lines.
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 2), which were exposed to a range of 
PM01183 concentrations for 72 hours and then assayed for viability by a MTT short-
term assay [34].
Table 2. 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
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
IG50, concentration that results in 50% of cell growth inhibition.


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The antineoplastic in vivo activity of PM01183 was demonstrated in a panel of several 
different human-derived tumor types, i.e. breast, lung, bladder and ovarian (Table 3). 
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 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 xenografts [35].
Table 3. 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
D, day; Qdx5x2, two cycles of five daily doses; Q7dx3, three consecutive weekly doses (D-0, 7, 14); T/C, 
treatment/control.
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 [36-40]. 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) [41].
Combination of PM01183 and Doxorubicin
The in vivo antitumor activity of PM01183 administered alone and in combination with 
DOX was investigated in mice bearing A2780 xenografted tumors [42]. Treatments 
administered were: i) placebo; ii) PM01183 at four different dose levels, i.e. the 
maximum tolerated dose (MTD) (0.180 mg/kg), 0.75·MTD, 0.5·MTD and 0.25·MTD; 
iii) DOX at four different dose levels, MTD (8 mg/kg), 0.75·MTD, 0.5·MTD and 
0.25·MTD; and, iv) PM01183/DOX, administered with the combination at (1+1), 
(0.75+0.75), (0.50+0.50) and (0.25+0.25) of their respective MTDs. DOX was found to 
induce modest and dose-dependent antitumor activity in A2780-bearing animals; tumors 
were significantly (p<0.05) smaller with DOX than with placebo in all groups, except at 
the lowest dose level. The highest-dosed cohort also showed modest tumor growth 
delay (TGD), which was calculated as 90.0%. Single therapy of PM01183 in mice 
bearing A2780 xenografts also resulted in very modest though dose-dependent 
antitumor activity. Nevertheless, the combination of PM01183 and DOX showed a 
strong and dose-dependent antitumor activity: all groups of animals treated with the 
combination (except the lower) showed a highly significant (p < 0.01) reduction of 
tumor volume compared to placebo-treated animals. Of note, the group treated at 
(1+1)·MTD experienced a TGD of 184.0%. The antitumor effect induced by any 
treatment (single-agent or combination) was analyzed using the median-effect principle
[43]. The results suggested a synergistic combination index (CI), with values 1, in 
mice bearing ovarian (A2780) xenografted tumors.


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1.2.1.3
Clinical Data
The clinical development program of PM01183 was started in March 2009. Until 2016, 
this program comprises three single-agent phase I studies (two in solid tumors and one 
in acute adult leukemia/myelodysplastic syndrome patients); five combination phase Ib 
studies with gemcitabine, capecitabine, DOX, cisplatin, or paclitaxel with or without 
bevacizumab in patients with selected advanced solid tumors; five phase II studies (one 
as single agent or in combination with gemcitabine as second-line therapy in advanced 
NSCLC, and four as single agent in second-line pancreatic cancer, in BRCA-mutated or 
BRCA-unselected metastatic breast cancer, in platinum-resistant/refractory ovarian 
cancer, and in selected advanced solid tumors); one single-agent phase III study in 
platinum-resistant ovarian cancer trial; and two investigator-sponsored trials (ISTs) with 
PM01183 alone or in combination with DOX or gemcitabine in soft tissue sarcoma, and 
in combination with olaparib in advanced solid tumors. Until 15 January 2016, 932 
patients have been included in PM01183 clinical studies and 802 have been treated with 
PM01183-containing therapy: 440 in phase I trials, 267 in phase II trials, 63 in one 
phase III trial, and 32 in ISTs.
PM1183-A-001-08 Phase I Study
The first-in-man study (FiM) (PM1183-A-001-08) explored PM01183 administered as a 
1-hour i.v. infusion every three weeks (q3wk) in patients with solid tumors. The 
recommended dose (RD) was established at 4.0 mg/m2 q3wk or as an equivalent flat 
dose (FD) of 7.0 mg q3wk [44]. PM01183 clearance was not found to be related to body 
surface area (BSA) at the time, and thus the patients treated at the RD expansion cohort 
were treated with the FD. 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 required at the RD to prevent or ameliorate nausea and 
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 FiM study. 
Neutropenia was predictable and short-lasting, and rarely caused treatment delays. With 
the schedule used in the FiM study (Day 1, q3wk) nadir occurred during the second 
week (median was Day 13, range: Day 10-Day 15). One of 15 patients treated at the RD 
had grade 4 thrombocytopenia [the only dose-limiting toxicity (DLT) at the RD]; no 
grade 3 cases were reported. No cases of febrile neutropenia occurred in this phase I 
study. Evidence of antitumor activity was observed at the RD as a proof-of-concept, 
including one confirmed partial response (PR) according to the Response Evaluation 
Criteria In Solid Tumors (RECIST) in a pretreated pancreatic cancer patient.
Selected Single-agent Phase II Studies
PM01183 has in vitro and in vivo anticancer activity in several platinum-sensitive but 
also in resistant ovarian cancer-derived cell lines (IGROV-1, OVA9, A2780 and 
IGROV-1/CDDP, OVA9-RT, A2780/CDDP) and in mice-bearing tumor xenografts 
(both platinum-sensitive and resistant). Thus, a controlled, phase II exploratory clinical 
trial (PM1183-B-002-11) was conducted to evaluate the activity and safety of PM01183 
as a single agent in platinum-resistant/refractory advanced ovarian cancer. In the second 
stage of this study, 59 patients were stratified according to platinum resistance or 
refractoriness and randomized 1:1 to receive PM01183 at its single-agent RD of 7.0 mg 
FD q3wk or the control treatment, which was standard or weekly i.v. topotecan 
according to the Investigators’ preference. 


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The primary efficacy endpoint of the study was the overall response rate (ORR), defined 
as the percentage of patients with a response, CR or PR, according to the RECIST v.1.1 
or by Gynecologic Cancer Intergroup (GCIG) criteria (in patients with disease not 
measurable as per RECIST). Secondary endpoints included time-to-event variables 
(PFS and OS) and safety profile of PM01183. ORR was significantly better for 
PM01183: 23% vs. no responses in the topotecan arm. Ten of the 12 confirmed 
responses were obtained in patients with platinum-resistant disease (response rate=30% 
in this subpopulation). In addition, median PFS was significantly longer with PM01183 
(3.9 months) than with topotecan (2.0 months). The difference in median PFS between 
the two treatment arms was higher in patients with platinum-resistant disease: 5.0
months (95% CI, 2.7-6.9 months) in the PM01183 arm vs.1.7 months (95% CI, 1.3-3.2 
months) in the topotecan arm (HR: 0.34; log-rank test p=0.0018), thus confirming 
single-agent PM01183 activity in this specific subset of patients after platinum-
containing therapy failure/resistance.
Additionally, there are three ongoing phase II trials: one with PM01183 as single agent 
in metastatic breast cancer patients with known BRCA1-2 germline mutations; one 
designed to establish or confirm the proof of concept of single-agent PM01183 
anticancer activity in several difficult-to-treat tumors; and one randomized trial in 
NSCLC patients that is comparing docetaxel with PM01183 alone or in combination 
with gemcitabine as second-line therapy. One SCLC patient (regardless of treatment 
line) had been treated with single-agent PM01183 in these ongoing studies; this patient 
showed SD for less than four months and was still on treatment at cutoff (15 January 
2016). 
Pooled Phase II Safety Analysis
The dose and schedule initially evaluated in phase II studies with single-agent PM01183 
were those determined in the FiM study (PM1183-A-001-08), i.e. 7.0 mg FD (4.0 
mg/m2) as a 1-hour infusion q3wk. This was changed to a BSA-based dose and was 
reduced by 20% to 3.2 mg/m2 in order to limit severe myelosuppression, following the 
finding that occurrence of grade 3/4 neutropenia and thrombocytopenia could be related 
to BSA.
Available preliminary information on the adverse events (AEs) related to PM01183 and 
the laboratory abnormalities observed in phase II studies with single-agent PM01183 is 
shown below. This information is given separately for PM01183 administered at 7.0 mg 
FD and 3.2 mg/m2.
Adverse Events Related to PM01183 Given as a Flat Dose of 7.0 mg
The following tables show the AEs related to PM01183 given at 7.0 mg FD to 183 
patients in phase II studies PM1183-B-001-10, PM1183-B-002-10, PM1183-B-003-11 
and PM1183-B-004-13.


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Table 4. Adverse  events  related  (or   with  unknown relationship) to  single-agent  
PM01183 at 7.0 mg FD with   a   frequency   of   ≥   2%   from   ongoing    phase   II   
trials    (worst grade per patient).
AE SOC/MedDRA PT
NCI-CTCAE grade v 4.0
Total
(n=183)
1
2
3
4
n (%)
n (%)
n (%)
n (%)
n (%)
Blood and lymphatic system disorders
Febrile neutropenia
.
.
23 (12.6%)
9 (4.9%)
32 (17.5%)
Gastrointestinal disorders
Abdominal pain
13 (7.1%)
3 (1.6%)
1 (0.5%)
.
17 (9.3%)
Constipation
22 (12.0%)
10 (5.5%)
.
.
32 (17.5%)
Diarrhea
18 (9.8%)
10 (5.5%)
.
.
28 (15.3%)
Nausea
60 (32.8%)
43 (23.5%)
9 (4.9%)
.
112 (61.2%)
Stomatitis
9 (4.9%)
5 (2.7%)
.
.
14 (7.7%)
Vomiting
42 (23.0%)
27 (14.8%)
8 (4.4%)
.
77 (42.1%)
General disorders and administration site conditions
Edema peripheral
4 (2.2%)
1 (0.5%)
.
.
5 (2.7%)
Fatigue
40 (21.9%)
56 (30.6%)
30 (16.4%)
.
126 (68.9%)
Pyrexia
10 (5.5%)
1 (0.5%)
.
.
11 (6.0%)
Metabolism and nutrition disorders
Decreased appetite
18 (9.8%)
12 (6.6%)
3 (1.6%)
.
33 (18.0%)
Hypomagnesemia
5 (2.7%)
.
.
.
5 (2.7%)
Nervous system disorders
Dysgeusia
7 (3.8%)
.
.
.
7 (3.8%)
Headache
6 (3.3%)
1 (0.5%)
.
.
7 (3.8%)
Peripheral neuropathy
6 (3.3%)
3 (1.6%)
.
.
9 (4.9%)
Respiratory, thoracic and mediastinal disorders
Dyspnea
5 (2.7%)
1 (0.5%)
2 (1.1%)
.
8 (4.4%)
Skin and subcutaneous tissue disorders
Alopecia
7 (3.8%)
.
.
.
7 (3.8%)
Rash
3 (1.6%)
2 (1.1%)
.
.
5 (2.7%)
Vascular disorders
Phlebitis
2 (1.1%)
5 (2.7%)
.
.
7 (3.8%)
AE, adverse event; FD, flat dose; MedDRA, Medical Dictionary for Regulatory Activities; NCI-CTCAE, National Cancer 
Institute Common Terminology Criteria for Adverse Events; PT, preferred term; SOC, System Organ Class.
Table 5. Hematological and biochemical abnormalities with single-agent PM01183 at 
7.0 mg FD in phase II trials, regardless of relationship (worst grade per patient).
NCI-CTCAE grade v 4.0
Total
(n=183)
1
2
3
4
n (%)
n (%)
n (%)
n (%)
n (%)
Hematological abnormalities
Anemia
54 (29.5%)
79 (43.2%)
40 (21.9%)
.
173 (94.5%)
Leukopenia (n=182)
14 (7.7%)
37 (20.3%)
60 (33.0%)
48 (26.4%)
159 (87.4%)
Lymphopenia (n=182)
30 (16.5%)
65 (35.7%)
44 (24.2%)
22 (12.1%)
161 (88.5%)
Neutropenia 
4 (2.2%)
20 (10.9%)
39 (21.3%)
91 (49.7%)
154 (84.2%)
Thrombocytopenia
61 (33.3%)
22 (12.0%)
21 (11.5%)
32 (17.5%)
136 (74.3%)
Biochemical abnormalities
ALT increased 
76 (41.5%)
37 (20.2%)
37 (20.2%)
4 (2.2%)
154 (84.2%)
AP increased (n=180)
81 (45.0%)
23 (12.8%)
11 (6.1%)
.
115 (63.9%)
AST increased 
96 (52.5%)
18 (9.8%)
16 (8.7%)
2 (1.1%)
132 (72.1%)
Bilirubin increased
25 (13.7%)
6 (3.3%)
2 (1.1%)
3 (1.6%)
36 (19.7%)
CPK increased (n=176)
12 (6.8%)
2 (1.1%)
.
1 (0.6%)
15 (8.5%)
Creatinine increased
124 (67.8%)
20 (10.9%)
8 (4.4%)
1 (0.5%)
153 (83.6%)
ALT, alanine aminotransferase; AP, alkaline phosphatase; AST, aspartate aminotransferase; CPK, creatine phosphokinase; FD, 
flat dose; NCI-CTCAE, National Cancer Institute Common Terminology Criteria for Adverse Events.


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Table 6. All grade 3/4 adverse events related (or with unknown relationship) to single-
agent PM01183 at 7.0 mg FD in phase II trials (worst grade per patient).
AE SOC / MedDRA 
PT
Clinical trial and indication
Total
(n=183)
PM1183-B-
001-10
Pancreas
(n=44)
PM1183-B-
002-11
PRROC
(n=52)
PM1183-B-
003-11
MBC
(n=70)
PM1183-B-004-
13
NSCLC
(n=17)
NCI-CTCAE grade v 4.0
3
n (%)
4
n (%)
3
n (%)
4
n (%)
3
n (%)
4
n (%)
3
n (%)
4
n (%)
3
n (%)
4
n (%)
Blood and lymphatic system disorders
Febrile neutropenia
7
(15.9%)
2 
(4.5%)
9 
(17.3%)
2 
(3.8%)
7 
(10.0%)
3 
(4.3%)
.
2
(11.8%)
23
(12.6%)
9
(4.9%)
Gastrointestinal disorders
Abdominal pain
.
.
.
.
.
.
1 
(5.9%)
.
1 
(0.5%)
.
Gastrointestinal 
toxicity
.
.
1 
(1.9%)
.
.
.
.
.
1 
(0.5%)
.
Nausea
.
.
6 
(11.5%)
.
3 
(4.3%)
.
.
.
9 
(4.9%)
.
Vomiting
1 
(2.3%)
.
5 
(9.6%)
.
2 
(2.9%)
.
.
.
8 
(4.4%)
.
General disorders and administration site conditions 
Fatigue
3 
(6.8%)
.
18 
(34.6%)
.
7 
(10.0%)
.
2 
(11.8%)
.
30 
(16.4%)
.
Multi-organ failure
.
.
.
.
.
1 
(1.4%)
.
.
.
1 
(0.5%)
Pain
.
.
.
.
.
.
1 
(5.9%)
.
1 
(0.5%)
.
Hepatobiliary disorders
Hepatotoxicity
.
.
.
.
.
1 
(1.4%)
.
.
.
1 
(0.5%)
Infections and infestations
Fungal infection
.
.
.
.
.
.
.
1 
(5.9%)
.
1 
(0.5%)
Neutropenic sepsis
.
1 
(2.3%)
.
.
.
.
.
.
.
1 
(0.5%)
Pneumonia
1 
(2.3%)
.
.
.
.
.
.
.
1 
(0.5%)
.
Sepsis
.
2 
(4.5%)
.
.
.
.
.
.
.
2 
(1.1%)
Streptococcal 
infection
1 
(2.3%)
.
.
.
.
.
.
.
1 
(0.5%)
.
Toxic shock syndrome
.
.
.
.
.
.
.
1 
(5.9%)
.
1 
(0.5%)
Injury, poisoning and procedural complications
Medication error
.
.
.
.
1 
(1.4%)
.
.
.
1 
(0.5%)
.
Investigations
GGT increase
.
.
.
.
2 
(2.9%)
.
.
.
2 
(1.1%)
.
Urine output decrease
.
.
.
.
.
.
.
1 
(5.9%)
.
1 
(0.5%)
Metabolism and nutrition disorders
Acidosis
.
.
.
.
.
.
1 
(5.9%)
.
1 
(0.5%)
.
Decreased appetite
.
.
2 
(3.8%)
.
1 
(1.4%)
.
.
.
3 
(1.6%)
.
Dehydration
.
.
.
.
1 
(1.4%)
.
.
.
1 
(0.5%)
.
Failure to thrive
.
.
.
.
1 
(1.4%)
.
.
.
1 
(0.5%)
.
Hyperglycemia
.
.
.
.
1 
(1.4%)
.
.
.
1 
(0.5%)
.


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Protocol PM1183-C-003-14
AE SOC / MedDRA 
PT
Clinical trial and indication
Total
(n=183)
PM1183-B-
001-10
Pancreas
(n=44)
PM1183-B-
002-11
PRROC
(n=52)
PM1183-B-
003-11
MBC
(n=70)
PM1183-B-004-
13
NSCLC
(n=17)
NCI-CTCAE grade v 4.0
3
n (%)
4
n (%)
3
n (%)
4
n (%)
3
n (%)
4
n (%)
3
n (%)
4
n (%)
3
n (%)
4
n (%)
Hyperkalemia
1 
(2.3%)
.
.
.
.
.
1
(5.9%)
.
2 
(1.1%)
.
Hypoalbuminemia
.
.
.
.
.
.
1 
(5.9%)
.
1 
(0.5%)
.
Hypocalcemia
.
.
.
.
.
1 
(1.4%)
.
.
.
1 
(0.5%)
Hypokalemia
.
.
.
.
1 
(1.4%)
.
.
.
1 
(0.5%)
.
Hyponatremia
.
.
.
.
1 
(1.4%)
.
.
.
1 
(0.5%)
.
Musculoskeletal and connective tissue disorders
Rhabdomyolysis
.
.
1 
(1.9%)
.
.
.
.
.
1 
(0.5%)
.
Nervous system disorders
Depressed levels of 
consciousness
.
.
.
.
.
.
1 
(5.9%)
.
1 
(0.5%)
.
Renal and urinary disorders
Renal failure
1 
(2.3%)
.
.
.
.
.
1 
(5.9%)
.
2 
(1.1%)
.
Respiratory, thoracic and mediastinal disorders
Dyspnea
.
.
.
.
2 
(2.9%)
.
.
.
2 
(1.1%)
.
Hemoptysis
.
1 
(2.3%)
.
.
.
.
.
.
.
1 
(0.5%)
Hypoxia
.
.
.
.
.
.
1 
(5.9%)
.
1 
(0.5%)
.
Pleuritic pain
.
.
.
.
1 
(1.4%)
.
.
.
1 
(0.5%)
.
Pneumonitis
.
.
.
.
1 
(1.4%)
.
.
.
1 
(0.5%)
.
Respiratory failure
.
.
.
.
.
.
.
1 
(5.9%)
.
1 
(0.5%)
Vascular disorders
Hypertension
1 
(2.3%)
.
.
.
.
.
.
.
1 
(0.5%)
.
Hypotension
.
.
.
.
.
.
1 
(5.9%)
.
1 
(0.5%)
.
AE, adverse event; FD, flat dose; GGT, Gamma-glutamyltransferase; MedDRA, Medical Dictionary for Regulatory Activities; 
MBC. Metastatic breast cancer; NCI-CTCAE, National Cancer Institute Common Terminology Criteria for Adverse Events;
NSCLC, Non-small cell lung cancer; PRROC, platinum-resistant/refractory ovarian cancer; PT, preferred term; SOC, System
Organ Class.
In summary, myelosuppression is by far the most frequent toxicity observed at 7.0 mg 
FD in phase II trials with single-agent PM01183. Anemia was the hematological 
abnormality most frequently reported but was less likely to be severe: neutropenia and 
leukopenia had greater incidence in grade 3/4 events. Grade 3/4 neutropenia was 
characterized using Cycle 1 data from all PM01183-alone treated patients in ongoing 
phase II studies, to allow for uniform dose administration and no G-CSF prophylaxis 
that might alter results. The median duration of grade 3/4 neutropenia was 7 days 
(range: 2-14 days), with nadir occurring mostly by the end of the second week (median 
D15, range D4-D17). The time-course evolution of median neutrophils during Cycle 1 
for 183 patients (grade 4 in 69 of them) treated in phase II studies at 7.0 mg FD q3wk 


CL_0247 4.0
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Protocol PM1183-C-003-14
showed that most patients recovered to re-treatment criteria (grade 1) before the 
scheduled start of Cycle 2 (D22) (Figure 2). Overall, the incidence of grade 4 
neutropenia increased from 44.8% of patients in phase I studies to 49.7% in all phase II 
studies at 7.0 mg FD, yet the overall incidence of FN remained below the 20% threshold
(n=32, 17.5%) in phase II studies as a whole at cutoff (while in some specific settings, 
such as pancreatic cancer, ovarian cancer and BRCA+ breast cancer it is just above this 
threshold). Therefore, the use of primary G-CSF prophylaxis needs to be individualized 
carefully and cannot be recommended as a unique straightforward strategy at this point 
with PM01183 treatment alone.
Figure 2. Median neutrophil counts of patients in Cycle 1 treated with single-agent 
PM01183 at 7.0 mg FD in phase II trials (n=183).
FD, flat dose.
Grade 3/4 lymphopenia and thrombocytopenia also seem to have increased in frequency 
to approximately one third of patients treated at 7.0 mg FD, as compared to the highly 
selected phase I patient population.
Adverse Events Related to PM01183 Given as a BSA-based Dose of 3.2 mg/m2
All AEs related to PM01183 given at 3.2 mg/m2 to 29 patients in phase II studies 
PM1183-B-004-13 (n=3) and PM1183-B-005-14 (n=26) are shown in the following 
tables.
Table 7. Adverse  events  related  (or   with  unknown relationship) to  single-agent  
PM01183 at 3.2 mg/m2 with  a   frequency   of   ≥   2%   from   ongoing    phase   II   
trials (worst grade per patient).
AE SOC/MedDRA PT
NCI-CTCAE grade v 4.0
Total
(n=29)
1
2
3
4
n (%)
n (%)
n (%)
n (%)
n (%)
Blood and lymphatic system disorders
Febrile neutropenia
.
.
2 (6.9%)
.
2 (6.9%)
Gastrointestinal disorders
Abdominal pain upper
1 (3.4%)
.
.
.
1 (3.4%)
Constipation
2 (6.9%)
2 (6.9%)
.
.
4 (13.8%)
Glossitis
1 (3.4%)
.
.
.
1 (3.4%)
Nausea
2 (6.9%)
1 (3.4%)
.
.
3 (10.3%)
Vomiting
2 (6.9%)
1 (3.4%)
1 (3.4%)
.
4 (13.8%)
General disorders and administration site conditions
Fatigue
4 (13.8%)
6 (20.7%)
1 (3.4%)
.
11 (37.9%)
Metabolism and nutrition disorders
Decreased appetite
3 (10.3%)
.
.
.
3 (10.3%)
Dehydration
1 (3.4%)
.
.
.
1 (3.4%)
Grade 4
Grade 3
Grade 2
x 10^9/L
    0
    1
    2
    3
    4
    5
Cycle day
Baseline
[2-4]
[5-7]
[8-10]
[11-13]
[14-16]
[17-19]
[20-22]
PM11083


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Protocol PM1183-C-003-14
AE SOC/MedDRA PT
NCI-CTCAE grade v 4.0
Total
(n=29)
1
2
3
4
Electrolyte imbalance
.
.
.
1 (3.4%)
1 (3.4%)
Musculoskeletal and connective tissue disorders
Arthralgia
1 (3.4%)
.
.
.
1 (3.4%)
Musculoskeletal pain
1 (3.4%)
.
.
.
1 (3.4%)
Nervous system disorders
Cognitive disorder
1 (3.4%)
.
.
.
1 (3.4%)
Dysgeusia
1 (3.4%)
.
.
.
1 (3.4%)
Headache
1 (3.4%)
.
.
.
1 (3.4%)
Paresthesia
1 (3.4%)
.
.
.
1 (3.4%)
AE, adverse event; MedDRA, Medical Dictionary for Regulatory Activities; NCI-CTCAE, National Cancer Institute Common 
Terminology Criteria for Adverse Events; PT, preferred term; SOC, System Organ Class.
Table 8. Hematological and biochemical abnormalities with  single-agent  PM01183 at 
3.2 mg/m2 in phase II trials, regardless of relationship (worst grade per patient).
NCI-CTCAE grade v 4.0
Total
(n=24)
1
2
3
4
n (%)
n (%)
n (%)
n (%)
n (%)
Hematological abnormalities
Anemia
9 (37.5%)
8 (33.3%)
3 (12.5%)
.
20 (83.3%)
Leukopenia
7 (29.2%)
8 (33.3%)
2 (8.3%)
2 (8.3%)
19 (79.2%)
Lymphopenia (n=23)
4 (17.4%)
7 (30.4%)
4 (17.4%)
1 (4.3%)
16 (69.6%)
Neutropenia 
3 (12.5%)
3 (12.5%)
6 (25.0%)
2 (8.3%)
14 (58.3%)
Thrombocytopenia
9 (37.5%)
1 (4.2%)
.
.
10 (41.7%)
Biochemical abnormalities
ALT increase 
12 (50.0%)
3 (12.5%)
.
.
15 (62.5%)
AP increase
11 (45.8%)
2 (8.3%)
1 (4.2%)
.
14 (58.3%)
AST increase 
10 (41.7%)
1 (4.2%)
.
.
11 (45.8%)
Bilirubin increase
2 (8.3%)
1 (4.2%)
1 (4.2%)
.
4 (16.7%)
CPK increase
1 (4.2%)
.
.
.
1 (4.2%)
Creatinine increase
17 (70.8%)
3 (12.5%)
.
.
20 (83.3%)
Data not available for five patients treated in study PM1183-B-005-14.
ALT, alanine aminotransferase; AP, alkaline phosphatase; AST, aspartate aminotransferase; CPK, creatine 
phosphokinase; NCI-CTCAE, National Cancer Institute Common Terminology Criteria for Adverse Events.
Grade 3/4 hematological abnormalities found among patients treated with single-agent 
PM01183 at 3.2 mg/m2 comprised neutropenia (33.3% of patients), lymphopenia 
(20.8%) and leukopenia (16.7%). Severe anemia was found in 12.5% of patients but did 
not reach grade 4. Of note, no episodes of severe thrombocytopenia or grade 4 FN were 
reported. 
PM1183-A-003-10 Phase Ib Study (PM01183/Doxorubicin Combination)
The primary objective of this phase Ib study was to find a safe RD for further studies 
with this combination. Secondary objectives included assessing the safety, analyzing 
possible pharmacokinetic (PK) drug-drug interactions, and preliminarily assessing the 
antitumor activity of this combination in patients with several different solid tumors. 
Owing to patients with breast cancer or soft tissue sarcoma (STS) being eligible for 
inclusion, the chosen dose of DOX remained fixed at 50.0 mg/m2 q3wk, up to a 
maximum cumulative dose (MCD) of 450 mg/m2 throughout the study. After the MCD 
had been reached, patients continued treatment with PM01183 alone at its single-agent 
RD, for as long as treatment benefit was observed. The DOX dose was capped at 2.0 m2
of BSA. An amendment allowed the addition of a prospective cohort of patients with 
primary G-CSF prophylaxis during dose escalation, in order to explore the potential of 
this approach to reach a higher RD. 


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Primary G-CSF prophylaxis did not allow further dose escalation in this study. DLTs 
occurring at the MTD regardless of primary G-CSF prophylaxis were not exclusively 
related to neutropenia and also included non-hematological toxicities (grade 3 diarrhea) 
and grade 4 thrombocytopenia. Accordingly, primary G-CSF prophylaxis was not 
implemented during RD expansion. DLTs [febrile neutropenia (FN)] were initially
found in one of ten (10%) solid tumor patients without primary prophylaxis; as a result, 
PM01183 4.0 mg FD and DOX 50.0 mg/m2 was defined as the RD for this combination.
Objective antitumor activity was early noted during dose escalation in patients with 
most tumor types included. In particular, five responses were observed in 12 SCLC 
patients. Remarkably, all five responses occurred exclusively in seven evaluable 
patients treated after first-line chemotherapy failure (ORR: 71%; 95%CI: 29-96%); in 
contrast, no responses were observed among the five patients treated as third-line.
Two SCLC patients out of 15 evaluable patients at the RD cohort expansion had DLTs
in Cycle 1: FN (n=1) and grade 3 neutropenic infection (grade 3 lower respiratory tract 
infection) (n=1). Significant grade 3/4 myelosuppression occurred at all dose levels, and 
particularly at the RD, where grade 4 neutropenia/thrombocytopenia occurred in 
86%/19% of patients, respectively, and additionally 29% had FN and 10% had 
associated neutropenic infections within the expansion cohort of SCLC pts. Therefore 
the use of primary prophylaxis upfront seems justified in this specific population. Non-
hematological toxicities were mild and rarely reached grade 3/4. Nevertheless, the 
combination-associated myelosuppression raised the question of whether the RD 
defined in this cohort would be safe and tolerable in a less selected/restricted phase III 
population. In addition, the DOX dose used in SCLC patients is usually less than 50 
mg/m2 per cycle (either 45 mg/m2 with G-CSF support or 40 mg/m2 without it), as 
several tobacco-related comorbidities and prior mediastinal irradiation are highly 
prevalent in this context. As a result the phase Ib study was amended to reduce the DOX 
dose in the previous RD by 20% (i.e., to 40 mg/m2) to try to limit the potentially severe 
myelosuppression and explore the feasibility of this dose in less selected patients
(ECOG PS score=2 and without any age restriction). This amendment also adjusted the 
DOX dose to one that is more commonly used in these patients. The PM01183 dose was 
also adapted to a BSA-based dose of 2.0 mg/m2. The rationale for this change came 
from the results of a logistic regression analysis of pooled data from phase II clinical 
trials with single-agent PM01183 in several solid tumors, which suggested that patients 
with the lowest BSA values could have a greater possibility of developing grade 3/4 
thrombocytopenia
and/or neutropenia. Hence, the PM01183 4.0 mg FD was 
transformed to 2.0 mg/m2 q3wk, with the dose being capped at a BSA of 2.0 m2 to 
prevent patients from receiving more PM01183 than 4.0 mg FD q3wk, previously 
defined as the RD. Up to January 2016, a total of 45 SCLC patients were treated with 
PM01183 and DOX in this study. Response was observed in 20 of 40 SCLC patients 
treated as second-line therapy (ORR: 50%; 95%CI, 34-66%, with one CR and 19 PR). 
In addition, one of five SCLC patients treated as third-line therapy also responded. 
Patient accrual is currently ongoing.
Up to January 2016, in addition to patients treated in the DOX combination study, data 
are available from seven evaluable SCLC patients treated with the PM01183 and 
paclitaxel combination (in the third-line setting) in another phase Ib study (the PM1183-
A-007-13 trial). To that date, five of these seven patients had responded to treatment.


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1.2.2
Topotecan
Topotecan is a camptothecin analogue approved for treating relapsed ovarian 
carcinoma, SCLC, cervical cancer and some hematological malignancies.
Camptothecins, like other epipodophyllotoxins (etoposide, teniposide), exert their 
cytotoxic effect through covalent binding to the DNA-topoisomerase I complex, thus 
preventing the repair of single-strand DNA breaks.
Topotecan has a large distribution volume in humans; only 20-40% of plasma 
concentration is bound to albumin. Hence, extensive peripheral tissue binding is most 
likely responsible for this large steady-state distribution volume. Mild to moderate 
hepatic dysfunction seems not to alter topotecan PK [45], but patients with moderate to 
severe renal dysfunction (creatinine clearance < 40 ml/min) need to have a dose 
adjustment [46].
The most remarkable and dose-limiting toxicity of topotecan is myelosuppression, in 
particular grade 4 neutropenia, which occurs in more than half of the patients at the RD. 
Other toxicities are usually less severe and include diarrhea, nausea and vomiting, 
alopecia, rash, urticaria, fever, asthenia, weight loss, and hepatic enzymes elevation that 
in some cases is concomitant with hyperbilirubinemia.
The conventional dose and schedule of topotecan (standard regimen) is 1.5 mg/m2/daily 
times x 5 q3wk [47]. A weekly regimen (Days 1, 8 and 15 every four weeks) has also 
been used in order to minimize the hematological toxicity. Both regimens were 
prospectively compared in a randomized phase II study in patients with platinum-
resistant ovarian cancer [48]. Although the trial design had several limitations to draw 
conclusions regarding efficacy, both schedules reached similar OS rates. The weekly 
schedule showed a lower incidence of hematological toxicity, but objective responses 
were doubled (19% vs. 9%) and PFS values were better with the conventional schedule 
than with the weekly schedule. Therefore, it appears that the conventional schedule 
must be preferred as a standard of care. Moreover, the only regulatory approved 
regimen in SCLC patients is the standard as previously described or alternatively in 
patients with poorer ECOG PS the oral topotecan formulation was tested at 2.3 
mg/m2/daily times x 5 q3wk without G-CSF support was approved after showing 
improvement against BSC. Eckardt et al. published in 2007 similar results in 309 
sensitive relapsed patients with the oral regimen as compared to the i.v. standard, 
although this trial was not adequately powered to demonstrate non-inferiority trial and 
conclusions must be interpreted cautiously [49]. However, the conventional dose and 
schedule as originally approved in by the FDA in the mid 90’s is, since long, rarely used 
in the clinical daily practice outside clinical trials, due to the associated increased risk of 
infection, sepsis and myelosuppression. Alternatives are either dose reduction to 1.25 
mg/m2/daily times x 5, or even lower doses in less selected candidates or G-CSF 
primary prophylaxis upfront with or without prophylactic antibiotics in the more frail or 
risky patients. The lack of data available from adequate randomized prospective studies, 
to compare the efficacy or non-inferiority of initial lower doses of topotecan, makes this 
option inadequate in a pivotal study as a control arm. Therefore, in this study the use of 
primary prophylaxis with G-CSF will be universally implemented in all patients.
1.2.3
CAV
Developed in the 1970s, the CAV regimen consists of CTX, DOX and VCR. This 
multidrug combination was the chemotherapy backbone of the CHOP regimen (with 
prednisone added), used as a standard treatment to treat non-Hodgkin lymphomas 


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Protocol PM1183-C-003-14
(NHL). Before cisplatin availability, CAV was widely used to treat both SCLC and 
NSCLC. During the 1980s, CAV was gradually replaced by the EP regimen (in the first-
line setting) due to better results in some subsets (limited-stage disease), as well as a 
more manageable toxicity profile. As a result, CAV was relegated to the second-line 
setting, particularly in SCLC patients due to the lack of cross-resistance between EP and 
CAV [50].
Due to the rapidly evolving secondary resistance of the single agents observed in small 
uncontrolled clinical trials, and also to their limited efficacy, none of the drugs in the 
CAV combination were used to a significant extent as single agents in the clinical 
setting.  
CTX is an alkylant agent, a pro-drug that needs  hepatic activation  through microsomal 
oxidation (CYP3A4) to 4-hydroxy-CTX, which is then converted to aldophosphamide 
and finally to phosphoramide mustard and/or nornitrogen mustard [51]. Despite 99% 
bioavailability for the parent compound at doses below 300 mg, bioavailability becomes 
more variable at doses around 1000-2000 mg [52], hence its more frequent use as part 
of multidrug regimens in breast and ovarian cancer, STS, NHL, as well as in CAV 
regimens. 
DOX is the most commonly used anthracycline in solid tumors and lymphomas, 
together with the closely related epirubicin, which has an almost identical profile at 
equitoxic doses. Anthracyclines are associated with an increased risk of congestive heart 
failure (CHF), a risk that grows exponentially after reaching a maximal cumulative dose 
of 450 mg/m2 in a lifetime (900 mg/m2 for epirubicin). Anthracyclines are known to 
inhibit the DNA repair enzyme topoisomerase II (TOPO II), among other postulated 
actions. DOX is a well-known substrate for MDR1, gp170, and MRP1, the 
overexpression of which is the main primary or secondary resistance mechanism to 
anthracyclines [53]. 
Finally, VCR is a vinca alkaloid, which primarily inhibits tubulin polymerization, 
preventing cellular mitosis. Its contribution to the clinical activity of the CAV 
combination might well be anecdotal, as it has been difficult to assess directly. VCR is 
widely used in combinations like CHOP, or in multidrug series in rhabdomyosarcoma, 
and in pediatric multimodality treatment for Wilms’ tumor (mostly because of the high 
response rates observed in these patients). The dosing of vinca alkaloids should be 
carefully monitored and modified in patients with moderate to severe liver failure, 
usually according to bilirubin levels. Common toxicity includes constipation and 
cumulative (mostly sensory) neuropathy, which if undetected in time might become 
irreversible. 
In order to avoid drug extravasation while being infused, the administration of both 
DOX and VCR requires careful monitoring, as extensive local tissue damage may 
occur. Local heat may help inactivate VCR locally and contribute to limit the damage. 
MDR1 and MRP1, gp170 are both also involved in primary resistance to VCR. 
The conventional dose and schedule of CAV in SCLC is CTX 1000 mg/m2 followed by 
DOX 45.0 mg/m2 and VCR 2.0 mg total flat dose, all on Day 1 q3wk [24]. This regimen 
is associated with grade 3 or 4 neutropenia in approximately two-thirds of the exposed 
patients. Moreover, up to 25% of the neutropenic patients may experience fever or 
infection within 48 hours of developing grade 4 neutropenia and nearly 5% develop 
sepsis; therefore, and according to current available guidelines, it seems prudent to 
administer G-CSF primary prophylaxis to patients assigned to receive CAV treatment.


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Protocol PM1183-C-003-14
1.3
STUDY RATIONALE
Patients with relapsed SCLC have the worst prognosis among lung cancer patients, with 
usually a life expectancy of less than six months and few therapeutic options. New 
treatment options are eagerly needed, particularly agents with novel mechanisms of 
action and no cross-resistance with prior platinum-regimens.
No new treatment has been approved in Western countries over the last 15 years. In 
particular, almost none of the randomized clinical trials done over the last 30 years have 
shown a positive outcome improvement in this setting. 
PM01183 is a new chemical entity that induces double-strand DNA breaks through 
binding to the DNA minor groove. According to a COMPARE analysis, it does not 
have an overlapping mechanism of action with other 98 standard cytotoxic agents. 
Data from 40 second-line SCLC patients treated in the Phase Ib study with the 
PM01183 and DOX combination (PM1183-A-003-10) showed a confirmed and 
remarkably high activity consistent with the synergistic effects found in vitro/in vivo, 
which resulted in an ORR of 50%, including one CR. This activity is unprecedented, 
whereas historical data on an anthracycline-containing combination used in a similar 
setting show ORRs usually in the 20-30% range. Eleven of these patients were still 
ongoing treatment at the cutoff of January 2016; the median PFS observed was 3.6 
months (95%CI: 2.6-4.8 months). Analysis of updated data from 48 second-line SCLC 
patients treated in both cohorts with the PM01183 and DOX combination up to June 
2016 resulted in a median PFS of 4.1 months (95%CI: 2.6-5.3 months); this is higher 
than the median PFS of 3.5 months that is usually obtained with standard topotecan 
treatment. Overall, the aforementioned promising results warrant further study in a well-
designed, prospective, larger, randomized study to better define the role of this 
combination in the treatment of relapsed SCLC patients.
The analysis of updated data from the two cohorts of SCLC patients in study PM1183-
A-003-10 also found differences in the patients’ response to PM01183 and DOX 
depending on their CTFI after first-line therapy. When both cohorts were combined, 
patients with CTFI <30 days (n=11) had a median PFS of 1.3 months (95%CI: 1.2-3.4 
months), while those with CTFI ≥30 days (n=35) had a median PFS of 4.8 months 
(95%CI: 3.3-6.4 months). These findings suggested that SCLC patients with CTFI <30 
days responded significantly worse to the PM01183 and DOX combination compared to 
patients with CTFI ≥30 days. As a result, it was decided to exclude from this study all 
SCLC patients with CTFI <30 days after first-line therapy.
1.3.1
Dose Rationale
The dose of the PM01183 and DOX combination that will be evaluated in the 
Experimental Arm in the present study will be PM01183 2.0 mg/m2 and DOX 40.0 
mg/m2, both on Day 1 q3wk. This dose is based on the RD determined for this same 
schedule in trial PM1183-A-003-10 (i.e., PM01183 4.0 mg FD and DOX 50.0 mg/m2), 
with the PM01183 dose adapted to a BSA-based dose (4.0 mg FD = 2.0 mg/m2) and the 
DOX dose reduced by 20% to limit the incidence of myelosuppression. In addition, 
primary prophylaxis with subcutaneous G-CSF will be mandatory for all patients. 
Furthermore, a recent analysis of PK data from the PM1183-A-003-10 trial found that 
PM01183 reduced DOX clearance from 45 l/h to 35 l/h (a 20% reduction), and 
doxorubicinol clearance from 150 l/h to 75 l/h (a 50% reduction). Taking into account 
these results, the DOX dose of 40.0 mg/m2 used in the experimental arm in the present 


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study is not expected to result in patient exposure to toxic levels of DOX or 
doxorubicinol.
Patients enrolled in the Experimental Arm will receive up to a maximum of 10 cycles of 
the PM01183 and DOX combination. Then, DOX will be discontinued and patients will 
receive PM01183 at a dose of 3.2 mg/m2 on Day 1 q3wk. This dose is based on the RD 
determined for this schedule in trial PM1183-A-001-08 (i.e., 4.0 mg/m2 q3wk), reduced 
to 3.2 mg/m2 to limit severe myelosuppression.
The present study will also include a Control Arm where patients will receive either 
topotecan daily on Days 1-5 q3wk or a combination of CTX, DOX and VCR (CAV) on 
Day 1 q3wk. The doses chosen for these regimens are commonly used in the treatment 
of patients with solid tumors. Rationale for the Pharmacogenetic Sub-Study 
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 in the experimental arm.
2.
STUDY OBJECTIVES
2.1
PRIMARY
To determine whether there is a difference in overall survival (OS) between 
lurbinectedin (PM01183)/DOX and a control arm consisting of best Investigator’s 
choice between CTX, DOX and VCR (CAV) or topotecan, as treatment in SCLC 
patients after failure of one prior platinum-containing line.
2.2
SECONDARY
To analyze:
o
Difference in OS between PM01183/DOX and CAV, in patients with CAV as 
best Investigator’s choice.
o
OS/PFS in patients with and without baseline central nervous system (CNS) 
involvement. Subgroup analyses restricted to the sensitive and resistant
populations (i.e., chemotherapy-free interval [CTFI] ≥90 days and CTFI <90 
days) will also be performed.
o
Progression-free survival (PFS) by an Independent Review Committee (IRC).
o
Antitumor activity by IRC according to the RECIST v.1.1.
o
Safety profile.
2.3
TERTIARY
To analyze:
o
Mid- and long-term survival (OS at 12, 18 and 24 months, respectively).
o
Efficacy and safety profiles in the subgroups of the PM01183/DOX arm vs. 
CAV or topotecan.
o
PFS by Investigator’s Assessment (IA).
o
Antitumor activity by IA according to the RECIST v.1.1.


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o
Patient-reported outcomes (PRO).
o
Pharmacokinetics (PK) of the combination in patients treated in the 
experimental arm (PM01183/DOX).
o
PK/pharmacodynamic (PDy) correlations in the experimental arm, if any.
o
Pharmacogenetics of known polymorphisms in patients treated in the 
experimental arm.  
3.
OVERALL STUDY DESIGN
Multicenter, open-label, randomized, controlled phase III clinical trial to evaluate and 
compare the activity and safety of an experimental arm consisting of PM01183/DOX 
combination followed by PM01183 alone if applicable vs. best Investigator’s choice 
between CAV or topotecan as a control arm, in SCLC patients who failed one prior 
platinum-containing line but no more than one prior chemotherapy-containing line.
Central randomization will be implemented; patients will be assigned to each arm at a 
1:1 ratio. If the patient is randomized to the control arm, the assigned treatment will be 
based on the reported Investigator’s preference between CAV or topotecan. 
Stratification will be performed according to the chemotherapy-free interval (CTFI)
after first line [≥180 days (very sensitive, VS) vs. 90-179 days (sensitive; S) vs. <90 
days (resistant; R)], ECOG PS (0 vs. 1-2), baseline CNS involvement vs. no 
involvement, prior immunotherapy against either programmed cell death protein-1 (PD-
1) or programmed death ligand-1 (PD-L1) (Yes vs. No) and Investigator’s preference 
(best Investigator’s choice prior to randomization) between topotecan and CAV.
Up to 600 patients will be included in the trial.
An Independent Review Committee (IRC), blinded to the treatment assigned to the 
patients, will determine the best patient response and assign the date of objective 
response or 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.
An Independent Data Monitoring Committee (IDMC) will oversee the conduct of the 
study. The IDMC should have access to unblinded efficacy and safety data throughout 
the trial to enable timely and informed judgments about risks and benefits. Operational 
details for the IDMC will be detailed in the corresponding charter.
The primary endpoint of the trial is the overall survival (OS). Secondary endpoints 
comprise difference in OS between PM01183/DOX and CAV, in patients with CAV as 
best Investigator’s choice; OS/PFS per RECIST v.1.1 in patients with and without 
baseline central nervous system (CNS) involvement; PFS per RECIST v.1.1 by an IRC; 
best antitumor response as per RECIST v.1.1 and duration of response (DR) (both 
assessed by IRC); and safety profile. Tertiary endpoints comprise mid- and long-term 
survival assessed by measuring OS at 12/18/24 months, PFS per RECIST v.1.1 by IA, 
best antitumor response as per RECIST v.1.1 and DR (both assessed by IA), PRO, 
subgroup analyses, PK, PK/PDy correlations, and pharmacogenetics. 
In order to evaluate the overall safety in both arms, an interim safety analysis is planned 
after the recruitment of 150 patients (i.e., ~75 patients into each arm). Recruitment will 
not be put on hold while the interim safety analysis is being performed. Efficacy 
parameters will not be formally analyzed in this interim evaluation. Further safety and 
efficacy analyses could be performed upon request from the IDMC.


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If any formal interim OS/PFS analysis is performed, unblinded only to the IDMC, a 
type I error correction according to the Lan and DeMets error spending function that 
corresponds to the O'Brien-Fleming boundary will be used, calculated during the 
interim analyses to preserve an overall (one-sided) 0.005 false positive error rate; if 
early termination does not occur, the alpha level of the final analysis will be chosen to 
preserve an overall (one-sided) 0.025 false positive error rate.
Crossover is not allowed.
A summary of the study design is shown in Figure 3.
Patients assigned to the experimental arm (PM01183/DOX combination), as well as 
those assigned to the CAV regimen in the control arm, will continue treatment until 10 
cycles have been administered. After Cycle 10, non-progressing patients may continue 
PM01183 alone on Day 1 q3wk (experimental arm), or CTX +/- VCR (control arm), as 
applicable, until PD or unacceptable toxicity.


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Figure 3. Study design.
* Applicable assessments outside accepted windows must be repeated and treatment criteria must be fulfilled before 
treatment start.
** Recruitment will not be put on hold while the interim analysis is ongoing.
*** Assessment of LVEF and ECG must be conducted at the time of DOX discontinuation.
† See Table 13 in Section 6.6 for applicable starting doses and dose reduction scheme.
†† Patients will be followed every three months (± two weeks) during the first 18 months after randomization, and 
then once every six months (± four weeks) until death of any cause or date of study termination, whichever occurs 
first. Once the whole recruitment is completed, the survival follow-up procedure will change: patients who 
discontinue treatment will be followed every three months according to a fixed calendar time (e.g., July, October, 
January, etc.) until death or study completion.
††† Until 18 months after the last patient is randomized.
CAV, CTX
DOX and VCR; CNS, central nervous system; CTFI, chemotherapy-free interval; CTX, 
cyclophosphamide; D, day; DOX, doxorubicin; ECG, electrocardiogram; ECOG PS, Eastern Cooperative Oncology 
Group performance status; ICF, informed consent form; LVEF, left ventricular ejection fraction; OS, overall survival; 
PD, progressive disease; PD-1, programmed cell death protein-1; PD-L1, programmed death ligand-1; R, resistant; 
q3wk, every three weeks; S, sensitive; VCR, vincristine; VS, very sensitive; wk, week.


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Regardless of arm, patients will receive study treatment while it is considered to be in 
their best interest. Specifically, treatment will continue until disease progression (unless 
exclusively asymptomatic CNS involvement, in an otherwise responding patient), 
unacceptable toxicity after allowed/applicable dose reductions, intercurrent illness of 
sufficient magnitude to preclude safe continuation of the study, patient refusal, non-
compliance with the study requirements, or a major protocol deviation that may affect
the risk/benefit ratio for the participating patient.
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 omissions (if applicable), dose reductions, 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 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, whenever is 
possible.
Patients will be evaluated at scheduled visits during three predefined study periods: Pre-
treatment, Treatment and Follow-up (see Section 5.2). This clinical trial is expected to
finish (clinical cutoff) at approximately 18 months after the last patient is randomized.
3.1
PRIMARY ENDPOINT
Overall survival (OS) will be calculated from the date of randomization to the date 
of death (death event) or last contact (in this case, survival will be censored on that 
date).
3.2
SECONDARY ENDPOINTS
Difference in OS between PM01183/DOX and CAV, in patients with CAV as 
best Investigator’s choice.
Overall survival (OS)/progression-free survival (PFS) per RECIST v.1.1 in 
patients with and without baseline CNS involvement. Subgroup analyses 
restricted to the sensitive and resistant populations will also be performed.
Progression-free survival (PFS) by IRC is defined as the time from the date of 
randomization to the date of documented progression per RECIST v.1.1 or death 
(regardless of the cause of death). If the patient receives further antitumor therapy or 
is lost to follow-up before PD, PFS will be censored at the date of last tumor 
assessment before the date of subsequent antitumor therapy.
Best antitumor response by IRC will be the best response obtained in any 
evaluation according to RECIST v.1.1. 
Duration of response (DR) by IRC will be calculated from the date of first 
documentation of response per RECIST v.1.1 (complete or partial response, 
whichever comes first) to the date of documented PD or death. The censoring rules 
defined above for PFS will be used for DR. 
Treatment safety profile: AEs, serious adverse events (SAEs) and laboratory 
abnormalities will be coded by the Medical Dictionary for Regulatory Activities 
(MedDRA), graded according to the NCI-CTCAE v.4 and analyzed. Dose reductions 
or delays required due to treatment-related AEs, and reasons for treatment 
discontinuations will also be assessed.


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3.3
TERTIARY ENDPOINTS
Landmark analyses:
o Mid- and long-term survival (OS at 12/18/24 months) will be the Kaplan-
Meier estimates of the probability of being alive at these time points.
Subgroup analyses: Subgroup analyses of efficacy and safety profiles in the 
PM01183/DOX arm vs. CAV based on Investigator’s preference will be performed 
to isolate the contribution of PM01183 in the PM01183/DOX combination arm. 
Patients for whom the preference of the Investigator prior to randomization is CAV 
will be analyzed to test the combination of PM01183/DOX vs. CAV. Patients for 
whom the Investigator’s preference is topotecan will also be analyzed independently.
Progression-free survival (PFS) per RECIST v.1.1 by IA.
Best antitumor response by IA. 
Duration of response (DR) by IA. 
Patient-reported outcomes (PRO): To measure the quality of life of patients, the 
EORTC QLQ-C30 and EORTC QLQ-LC13 questionnaires will be analyzed at 
baseline and every six weeks (± one week) until EOT. 
Plasma pharmacokinetics (PK) of PM01183 and DOX will be evaluated using a 
sparse sampling scheme in patients treated in the experimental arm. Details will be 
given in a population PK analysis plan, and results will be presented in a separate 
report.
PK/Pharmacodynamic (PDy) correlation: Population PK correlations of drug 
exposure with safety and efficacy will be explored in the experimental arm. Details 
will be given in specific population PK/PDy analysis plans, and results will be 
presented in separate reports.
Pharmacogenetics: This analysis will be performed in patients treated in the 
experimental arm who specifically consent to participate in this sub-study. The 
presence or absence of known polymorphisms from a single sample collected at any 
time during the study will be assessed to explain the individual variability in the 
main PK parameters.
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) Voluntary written informed consent of the patient obtained before any study-specific 
procedure.
2) Adult patients aged ≥ 18 years. 
3) Histologically or cytologically confirmed diagnosis of limited or extensive stage 
SCLC which failed one prior platinum-containing regimen
and with a 
chemotherapy-free interval (CTFI, time from the last dose of first-line 
chemotherapy to the occurrence of progressive disease) ≥ 30 days. Small-cell 
carcinoma of unknown primary site with or without neuroendocrine features 
confirmed in histology test(s) performed on metastatic lesion(s) are eligible, if Ki-
67/MIB-1 is expressed in >50% of tumor cells.


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4) ECOG PS ≤ 2 (see APPENDIX 1).
5) Adequate hematological, renal, metabolic and hepatic function in an assessment 
performed within 7 days (+ 3 day window) of randomization:
a) Hemoglobin ≥ 9.0 g/dl [patients may have received prior red blood cell (RBC) 
transfusion, if clinically indicated]; absolute neutrophil count (ANC) ≥ 2.0 x 
109/l, and platelet count ≥ 100 x 109/l.
b) Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3.0 x 
upper limit of normal (ULN).
c) Total bilirubin ≤ 1.5 x ULN or direct bilirubin ≤ ULN.
d) Albumin ≥ 3.0 g/dl.
e) Calculated creatinine clearance (CrCL) ≥ 30 ml/minute (using Cockcroft and 
Gault’s formula).
f)
Left ventricular ejection fraction (LVEF) by echocardiogram (ECHO) or 
multiple-gated acquisition (MUGA) scan within normal range (according to 
institutional standards).
g) Creatine phosphokinase (CPK) ≤ 2.5 x ULN (≤ 5.0 x ULN is acceptable if 
elevation is disease-related).
6) At least three weeks since last prior anticancer treatment and recovery to grade ≤ 1 
from any AE related to previous anticancer treatment (excluding sensory 
neuropathy, anemia, asthenia and alopecia, all grade ≤ 2) according to the NCI-
CTCAE v.4.
7) Prior RT: At least four weeks since completion of whole-brain RT (WBRT), at least 
two weeks since completion of PCI, and to any other site not previously specified.  
8) Evidence of non-childbearing status for women of childbearing potential (WOCBP). 
WOCBP must agree to use a highly effective contraceptive measure up to six weeks 
after treatment discontinuation. Valid methods to determine the childbearing 
potential, adequate contraception and requirements for WOCBP partners are 
described in APPENDIX 2. Fertile male patients with WOCBP partners should use 
condoms during treatment and for four months following the last investigational 
medicinal product (IMP) dose.
4.2
EXCLUSION CRITERIA
1) More than one prior chemotherapy-containing regimen (including patients re-
challenged with same initial regimen).
2) Patients who never received any platinum-containing regimen for SCLC treatment.
3) Prior treatment with PM01183, topotecan or anthracyclines.
4) Limited-stage patients who are candidates for local or regional therapy, including 
PCI, thoracic RT or both, must have been offered that option and completed 
treatment or refused it prior to randomization.
5) Impending need for palliative RT or surgery for pathological fractures and/or for 
medullary compression within four weeks prior to randomization.
6) Symptomatic, or steroid-requiring, or progressing CNS disease involvement during 
at least four weeks prior to randomization (asymptomatic, non-progressing patients 
taking steroids in the process of already being tapered within two weeks prior to 
randomization are allowed).


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7) Concomitant diseases/conditions:
a) History (within one year prior to randomization) or presence of unstable angina, 
myocardial infarction, congestive heart failure or clinically significant valvular 
heart disease.
b) Symptomatic or uncontrolled arrhythmia despite ongoing treatment.
c) Patients with any immunodeficiency, including those known to be or have been 
infected by human immunodeficiency virus (HIV).
d) Ongoing, treatment-requiring, non-neoplastic chronic liver disease of any origin.
For hepatitis B, this includes positive tests for both Hepatitis B surface antigen 
(HBsAg) and quantitative Hepatitis B polymerase chain reaction (PCR). For 
hepatitis C, this includes positive tests for both Hepatitis C antibody and 
quantitative Hepatitis C PCR.
e) Active infection or increased risk due to external drainages.
f)
Intermittent or continuous oxygen requirement within two weeks prior to 
randomization. Patients with confirmed or suspected diagnosis of diffuse 
interstitial lung disease (ILD) or pulmonary fibrosis.
g) Patients with a second invasive malignancy treated with chemotherapy and/or 
RT. Patients with a previous malignancy that was completely resected with 
curative intention three or more years prior to randomization, and who has been 
continuously in remission since then will be permitted.
h) Limitation of the patient’s ability to comply with the treatment or to follow the 
protocol.
i)
Documented or suspected invasive fungal infections requiring systemic 
treatment within 12 weeks of randomization.
8) Pregnant or breast feeding women.
4.3
PATIENTS FOR THE PHARMACOGENETIC EVALUATIONS
Only patients who voluntarily sign the ICF for the pharmacogenetic sub-study will 
participate. Refusal to participate in the pharmacogenetic sub-study will not affect 
patient participation in the clinical study PM1183-C-003-14.
5.
PLAN OF THE STUDY
5.1
PLANNED TRIAL PERIODS (FOR THE WHOLE STUDY)
The total duration of the study will be approximately 42 months. 
Planned start date (first patient on study): second quarter 2016.
Planned enrollment period: approximately 24 months.
Planned end-of-study date (clinical cutoff): approximately 18 months after the last 
patient is randomized.
5.2
PLANNED TRIAL PERIODS (INDIVIDUALLY PER PATIENT)
Patients will be evaluated at scheduled visits during three study periods:

Pre-treatment: from signature of ICF to first infusion of the study treatment. 


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
Treatment: from first infusion of the study treatment to the end of treatment
(EOT) (see Section 5.2.1.1).

Follow-up: after EOT, patients will be followed every four weeks until resolution
or stabilization of all toxicities, if any. Patients who discontinue treatment 
regardless of the reason but without documented disease progression at the time of 
discontinuation will be followed every six weeks (± one week) until disease 
progression or start of a new antitumor therapy, death or until the date of study 
termination (clinical cutoff), whichever occurs first. After disease progression is 
documented or a new antitumor therapy is started, patients will be followed every 
three months (± two weeks) during the first 18 months after randomization, and 
then once every six months (± four weeks) until death of any cause or date of 
study termination, whichever occurs first. Once the whole recruitment is 
completed, the survival follow-up procedure will change: patients who 
discontinue treatment will be followed every three months according to a fixed 
calendar time (e.g., July, October, January, etc.) until death or study completion.
Patients will be considered to be on-study from the signature of the ICF to the end of 
the follow-up period. Patients will be considered to be on-treatment for the duration of 
their treatment and until the day of EOT, immediately before the start of the follow-up 
period. This EOT is defined as 30 days after the day of the last study treatment infusion, 
unless the patient starts a new antitumor therapy or dies (whichever occurs first). An 
end-of-treatment visit (EOT visit) will be performed at 30 days (± 10 days) after the last 
study treatment administration, unless the patient starts any subsequent antitumor 
therapy, in which case the end-of-treatment visit should be performed immediately 
before the start of the new therapy, whenever possible.
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 study treatment
infusion (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).
Should a patient decide to prematurely discontinue the study treatment (refuses 
treatment), all efforts will be made to complete and report the observations as 
thoroughly as possible. He/she should be asked if he/she can still be contacted for 
further information. The outcome of that discussion should be documented in the 
medical records.
5.2.1.2
Reasons for Treatment Discontinuation
Patients will receive the study treatment(s) while it is considered to be in their best 
interest. Specifically, individual treatment of a given patient will continue until:

Documented disease progression
(unless exclusively asymptomatic CNS 
involvement, in an otherwise responding patient).


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
Unacceptable toxicity (including treatment-related grade 4 hypersensitivity 
and/or extravasations,
and treatment-related toxicity occurring despite 
allowed/applicable dose reductions).

Treatment delay >22 days from the due date (except if objective clinical benefit 
is observed, with the Sponsor’s agreement).  

Intercurrent illness of sufficient magnitude to preclude safe continuation of the 
study.

Patient’s refusal and/or non-compliance with study requirements.

A major protocol deviation that may affect the risk/benefit ratio for the 
participating patient.

Any other reason that, in the Investigator’s judgment, precludes treatment 
continuation.
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 will 
remain on study until patient consent withdrawal, death, or the date of study termination 
(clinical cutoff) established by the Sponsor. The date and reason for study 
discontinuation will be clearly documented in the medical records of the patient. 
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 
related to obtaining the patients’ Informed Consent, data reporting, the responsibilities 
of the Investigator, etc.).
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 SAEs, 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 


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be notified, if applicable, to the pertinent IEC/IRB and to the Competent Authorities as 
established by local regulations.
5.3
REPLACEMENT OF PATIENTS
No patients will be replaced.
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 9.
Table 9. Screening period: pre-treatment assessments.
ASSESSMENT
TIME
1. Written 
informed consent
(general and 
pharmacogenetic 
sub-study)
Before any study procedures.
2. Medical and 
cancer history/ 
clinical 
examination
Demographic data.
Within 
14
days 
prior 
to 
randomization (Day 0).** 
Medical and cancer history/baseline condition:
o Primary diagnosis.
o Prior treatments (with best response and TTP, 
when available).
o Documented date of relapse.
Within 
14 
days 
prior 
to 
randomization (Day 0).*/**
Disease-related signs and symptoms.
Concomitant therapies.
Complete physical examination, including weight, 
height and calculation of BSA (see APPENDIX 3). 
Performance status (ECOG PS).
Vital signs: heart rate, blood pressure and body 
temperature.
Within 7 days prior to randomization 
(Day 0).*
Concomitant medications or signs 
and symptoms with onset or any 
change occurring between Day 0 and 
Day 1 of Cycle 1 must also be 
reported.
3. Laboratory tests
Hematology: differential WBC counts (including 
neutrophil and lymphocyte counts), platelet count 
and hemoglobin.
Biochemistry: Liver function test (ALT, AP, AST, 
total bilirubin), albumin, creatinine, CPK, glucose, 
calculated CrCL (as per Cockcroft and Gault’s 
formula), serum electrolytes (Na+, K+, Ca++), LDH, 
CRP and AAGP. 
Within 7 days prior to randomization 
(Day 0).*
AAGP will be evaluated exclusively 
in 
patients 
enrolled 
into 
the 
experimental 
arm, 
just 
before 
treatment start.
4. LVEF 
MUGA or ECHO.
Within 
14 
days 
prior 
to 
randomization (Day 0).**
5. Pregnancy test 
(if patient is a 
WOCBP)
Assessment of β-hCG (urine or serum).
If abnormally elevated, an US should be performed 
in order to rule out a pregnancy.
Within 7 days prior to randomization 
(Day 0), if applicable.*
6. 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, with 
specialist assessment/judgment of further evaluation 
if required.
Within 7 days prior to randomization 
(Day 0).*
7. Clinical and 
radiological tumor 
assessment
Contrast enhanced helical CT-scan or MRI.
Within 
14 
days 
prior 
to 
randomization (Day 0).**
8. CNS radiological 
assessment
Contrast enhanced CT-scan or MRI.
Within 
14 
days 
prior 
to 
randomization (Day 0).**
9. Patient-reported 
outcomes
EORTC 
QLQ-C30 
and 
EORTC 
QLQ-LC13 
questionnaires.
Within 7 days prior to randomization 
(Day 0).*


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ASSESSMENT
TIME
10. Adverse events
Only information on SAEs that occurred after 
signature of the informed consent form is required 
before treatment start. Grading should be as per the 
NCI-CTCAE v.4.
-
Regardless of the treatment administered, the same schedule of assessments will apply.  
* A +3-day window is allowed for assessment of signs and symptoms, complete physical examination (including 
weight, height and calculation of BSA), ECOG PS, vital signs, laboratory tests, pregnancy tests, ECG, and patient-
reported outcomes at screening.
** A +14-day window is allowed for medical and cancer history/baseline conditions, clinical and radiological tumor 
assessment (as per RECIST v.1.1), CNS radiological assessment, and LVEF assessment at screening.
AAGP, alpha-1 acid glycoprotein; 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; CrCL, creatinine clearance; CRP, C-reactive protein; CT, computed 
tomography; ECG, electrocardiogram; ECHO, echocardiogram; ECOG PS, Eastern Cooperative Oncology Group 
Performance Status; 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; RECIST, Response Evaluation Criteria In Solid Tumors, SAE, serious adverse event; 
TTP, time to progression; US, ultrasound; WBC, white blood cells; WOCBP, woman of childbearing potential.
5.5
PATIENT REGISTRATION
After the patient has signed the ICF, the patient will be registered into the trial and a 
patient number will be provided. This patient number should be used in all future 
documentation and correspondence referring to this patient.
5.6
PATIENT RANDOMIZATION
Central randomization will be implemented; patients will be assigned to each group at a 
1:1 ratio. If the patient is randomized to the control arm, the assigned treatment will be 
based on the reported Investigator’s preference between CAV or topotecan. 
Stratification will be performed according to the CTFI after first-line treatment [≥180 
days (VS) vs. 90-179 days (S) vs. <90 days (R)], ECOG PS (0 vs. 1-2), baseline CNS 
involvement vs. no involvement, prior immunotherapy against either PD-1 or PD-L1 
(Yes vs. No) and Investigator’s preference (best Investigator’s choice prior to 
randomization) between topotecan and CAV.
Day 0 is defined as the day of randomization. Treatment (Day 1 of Cycle 1) must start 
within 72 hours after randomization. Otherwise, all applicable assessments outside the 
accepted windows must be repeated and eligibility criteria must be reassessed if 
applicable.
5.7
EVALUATIONS DURING TREATMENT
The following assessments will be done while the patient is on treatment (Table 10).
Table 10. Evaluations during treatment.
ASSESSMENT
TIME
1. Clinical 
examination

Complete 
physical 
examination, 
including weight and calculation of 
BSA (see APPENDIX 3). 
Day 1 of Cycle 2 and subsequent cycles
(always prior to treatment infusion).*
BSA will be recalculated whenever a ≥10% 
variation in total body weight from baseline or 
from last dose adjustment occurs.
Performance status (ECOG PS).
Vital signs: heart rate, blood pressure 
and body temperature.
Day 1 of Cycle 2 and subsequent cycles
(always prior to treatment infusion).*
Concomitant therapies.
Throughout the “on treatment” period.**


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ASSESSMENT
TIME
2. Laboratory tests
Hematology: differential WBC counts 
(including neutrophil and lymphocyte 
counts), platelet count and hemoglobin.
Cycle 1: Day 10. *
Cycle 2: Day 1 and Day 10.*
Cycle 3 and beyond: Day 1 (always prior to 
treatment infusion). Always repeat on Day 10 
if grade ≥ 3 hematological abnormalities or a 
dose modification occurred in the preceding 
cycle, and before the first cycle after DOX 
discontinuation (Cycle 11) in patients treated 
in the experimental arm, and
in patients 
assigned to CAV in the control arm. *
Any patient presenting grade ≥ 3 treatment-
related AEs should have any relevant tests re-
assessed at least every 48-72 hours until 
recovery to at least grade 2.

Biochemistry:
Liver function test 
(ALT, AST, AP, total bilirubin), total 
proteins, 
albumin, 
creatinine, 
CPK, 
glucose, 
calculated 
CrCL 
(as 
per 
Cockcroft and Gault’s formula), serum 
electrolytes (Na+, K+, Ca++), LDH, CRP, 
and AAGP. 
Cycle 1: Day 10.* 
Cycle 2: Day 1 and Day 10.*
Cycle 3 and beyond: Day 1 of each cycle 
(always prior to treatment infusion). Always 
repeat on Day 10 if grade ≥ 3 non-
hematological 
abnormalities 
or 
a 
dose 
modification occurred in the preceding cycle.*
Any patient presenting grade ≥3 treatment-
related AEs should have any relevant tests re-
assessed at least every 48-72 hours until 
recovery to at least grade 2.
CRP will be evaluated only if clinically 
indicated.
AAGP will be evaluated
exclusively
in 
patients enrolled into the experimental arm on 
Day 1 of cycles with PK sampling (see Section 
7.7.1).
3. LVEF 
MUGA or ECHO.
Experimental arm: perform before Cycles 
3, 6, 9 and 11 (first cycle after DOX 
discontinuation), and whenever clinically 
indicated due to suspicion of CHF. *
Control arm (topotecan): perform whenever 
clinically indicated due to suspicion of 
CHF. *
Control arm (CAV): perform before Cycles 
3, 6, 9 and 11 (first cycle after DOX 
discontinuation), and whenever clinically 
indicated due to suspicion of CHF. *
4. Pregnancy test (if 
patient is a 
WOCBP) 
Assessment of β-hCG (urine or serum).
If abnormally elevated, an US should be 
performed in order to rule out a 
pregnancy.
Cycle 2 and further: Day +1 (always prior to 
treatment administration), or at least every 
month **
5. 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, with 
specialist assessment/judgment of further 
evaluation if appropriate.
Experimental arm: perform before Cycles 6 
and 
11 
(first 
cycle 
after 
DOX 
discontinuation), and whenever clinically 
indicated. *
Control arm (topotecan): perform whenever 
clinically indicated.*
Control arm (CAV): perform before Cycles 
6 
and 
11 
(first 
cycle 
after 
DOX 
discontinuation), and whenever clinically 
indicated. *
6. Pharmacokinetics 
(in the experimental 
arm only)
-
A total of five blood samples will be collected 
from patients treated in the experimental arm 
for PK analyses of PM01183, DOX and its 
metabolite doxorubicinol [four on Day 1 
(before treatment start, 5 min after DOX 


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ASSESSMENT
TIME
administration, 5 min before the end of 
PM01183 infusion, and 1 hour after the end of 
PM01183 infusion) and one on Day 5 (95 
hours after the end of PM01183 infusion)] in 
Cycle 1 and in another cycle (randomly 
between Cycle 2 and 4). The second cycle 
with blood sample collection for PK will be 
assigned once the patient is randomized into 
the experimental arm (see details in Section 
7.7.1).
7. Pharmacogenetics 
Only in those patients who give their 
written 
informed 
consent 
for 
the 
pharmacogenetic sub-study
One blood sample will be collected at any time 
during the study from patients treated in the 
experimental arm.
8. Clinical and 
radiological tumor 
assessment
Contrast enhanced helical CT-scan or 
MRI, as clinically relevant.
Every six weeks from randomization until 
evidence of PD.*
9. CNS radiological 
assessment
Contrast enhanced CT-scan or MRI.
Repeat in the event of baseline CNS 
involvement, and also if clinically indicated.
10. Patient-reported 
outcomes 
EORTC QLQ-C30 and EORTC QLQ-
LC13 questionnaires.
Every six weeks from  randomization.*
11. Survival 
information
-
Throughout the “on treatment” period.** 
12. Adverse events
As per NCI-CTCAE v.4.
Throughout the “on treatment” period.** 
Regardless of the treatment administered, the same schedule of assessments will apply.  
* A 3-day window will be allowed for clinical assessments (ECOG PS, vital signs, weight, BSA, etc.), and laboratory 
tests; a 7-day window for ECG assessments, radiological procedures, tumor assessments and patient-reported 
outcomes; a 14-day window for LVEF assessments; and a 10-day window for the assessments at EOT. 
** “On treatment period” = from first infusion of the study treatment (PM01183/DOX, CAV or topotecan) to EOT 
[30 days after the day of the last dose administration, 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 end of treatment].
AAGP, alpha-1 acid glycoprotein; AE, adverse event; ALT, alanine aminotransferase; AP, alkaline phosphatase; 
AST, aspartate aminotransferase; β-hCG, beta subunit of human chorionic gonadotropin; BSA, body surface area; 
CAV, CTX DOX and VCR; CHF, congestive heart failure; CNS, central nervous system; CPK, creatine 
phosphokinase; CrCL, creatinine clearance; CRP, C-reactive protein; CT, computed tomography; CTX, 
cyclophosphamide; DOX, doxorubicin; ECG, electrocardiogram; ECHO, echocardiogram; ECOG PS, Eastern 
Cooperative Oncology Group performance status; EOT, end of treatment; 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; PD, progressive disease; PK, 
pharmacokinetics; RECIST, Response Evaluation Criteria in Solid Tumors; VCR, vincristine; WBC, white blood 
cells; WOCBP, woman of childbearing potential.
5.8
EVALUATIONS AT END OF TREATMENT
The end-of-treatment visit will be scheduled at 30 days (± 10 days) after the last 
treatment infusion, unless the patient starts any 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 (including weight, if clinically relevant) and 
assessment of all ongoing AEs.

ECOG PS.

Vital signs.


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
Laboratory tests (hematology and biochemistry), if applicable and not previously 
done within the accepted window.

Pregnancy test (if patient is a WOCBP).

Clinical and radiological tumor assessment, if PD has not been documented 
previously or is the primary reason for treatment discontinuation (using contrast-
enhanced helical CT-scan or MRI as appropriate, according to the procedures 
done at baseline).

Patient-reported outcomes, if appropriate, not previously done, or if end of 
treatment occurred within the timing of the schedule (EORTC QLQ-C30 and 
EORTC QLQ-LC13 questionnaires).

Concomitant therapies.
All these evaluations will only have to be repeated for those parameters for which no 
measurement is available within ten days before the end-of-treatment visit, or for those 
parameters with values that were out of range in the last assessment (grade ≥2
according to NCI-CTCAE v.4) and considered as treatment-related whenever the 
medical condition of the patient may allow these evaluations.
Adverse events must be reported for 30 days after the last study treatment
administration. All 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 7.4.2).
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
Patients who have withdrawn from the study without progressive disease should 
undergo tumor assessment every six weeks (± one week) until PD, start of a new 
antitumor therapy,  death or date of study termination (clinical cutoff), whichever occurs 
first. After PD is documented or a new antitumor therapy is started, patients will be 
followed for survival every three months (± two weeks) during the first 18 months after 
randomization, and then once every six months (± four weeks) until death of any cause 
or date of study termination, whichever occurs first. Once the whole recruitment is 
completed, the survival follow-up procedure will change: patients who discontinue 
treatment will be followed every three months according to a fixed calendar time (e.g., 
July, October, January, etc.) until death or study completion.
The end-of-study date (clinical cutoff) is defined as 18 months after randomization of 
the last patient. The date and reason of the study discontinuation will be recorded on the 
patient’s CRF (see Section 5.2.1.1).
All AEs suspected to be related to the study treatment must be followed after the end of 
treatment every four weeks until recovery or stabilization.
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 a possibly treatment-related death, autopsy data should be provided when available.


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6.
TREATMENT
6.1
DESCRIPTION OF TREATMENT
6.1.1 Drug Formulation and Supply
6.1.1.1
Experimental Arm
Doxorubicin: 
Commercially available presentations of vials containing DOX will be provided as 
appropriate.
DOX will be prepared in accordance with the applicable Summary of Product 
Characteristics. Medication preparation records will be kept by the site.
PM01183:
PM01183 drug product (DP) presented as a lyophilized powder for concentrate for 
solution for infusion in 4-mg vials 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 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 by the site.
The full composition of the PM01183 4-mg vials and the reconstituted solution per 
ml is as shown in Table 11.
Table 11. 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
6.1.1.2
Control Arm
Topotecan: commercially available i.v. presentations of vials containing topotecan will 
be provided as appropriate.
CAV:  commercially available presentations of vials containing CTX, DOX and VCR 
will be provided as appropriate.
Topotecan or CAV (CTX, DOX and VCR) will be prepared in accordance with the 
applicable Summary of Product Characteristics. Medication preparation records will be 
kept by the site.
6.2
ADMINISTRATION OF STUDY MEDICATION
6.2.1.1
Experimental Arm
Doxorubicin: 
Intravenously through peripheral or central lines (according to local label),
followed by,


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PM01183:
Intravenous infusion over one hour over a minimum of 100 ml dilution on 5% 
glucose or 0.9% sodium chloride (at a fixed rate) via a central line (or a minimum 
of 250 ml dilution if a peripheral line is used).
Microscopically, 
dose-dependent 
diffuse 
edema 
associated 
with 
acute 
inflammatory reaction and necrosis were reported in the treatment sites of rabbits 
receiving PM01183 by paravenous administration at concentration relevant to 
current human use (0.003 and 0.03 mg/ml). Careful handling of PM01183 is 
advised. Short infusion times (one hour) make extravasation unlikely. 
Nevertheless, should extravasation occur, standard management is advised as soon 
as possible in order to limit tissue damage; no specific measures or antidotes are 
currently advised.
6.2.1.2
Control Arm
Topotecan:
Intravenously daily through peripheral or central lines (according to local label).
CAV:
CTX i.v. through peripheral or central lines (according to local label), 
DOX i.v. through peripheral or central lines (according to local label), and
VCR i.v. through peripheral or central lines (according to local label).
6.3
STARTING DOSES AND SCHEDULE
6.3.1.1
Experimental Arm
Doxorubicin at 40.0 mg/m2 on Day 1, followed by,
PM01183 at 2.0 mg/m2 on Day 1 q3wk (three weeks ± 48 hours = one treatment 
cycle). 
Note: in cycles with PK sampling, no more than ten minutes may pass between the 
end of DOX infusion and the start of PM01183 infusion.
Up to a maximum of 10 cycles. Then, if applicable, DOX will be discontinued
definitively and remaining patients will continue on maintenance until disease 
progression (PD), patient refusal or unacceptable toxicity despite applicable dose 
reductions, at:

PM01183 at 3.2 mg/m2 on Day 1 q3wk. (if no more than one dose reduction 
applied while on combination therapy), or:

PM01183 at 2.6 mg/m2 on Day 1 q3wk. (if more than one dose reduction 
applied while on combination therapy).
Doses will be capped at a BSA of 2.0 m2 for individuals exceeding this BSA value. 
Doses will have to be recalculated for patients showing a ≥ 10% variation in total body 
weight from baseline or from last dose adjustment. PM01183 total doses in mg will be 
rounded to the first decimal, if necessary. DOX doses will be rounded, if applicable, 
according to institutional guidelines/standard practice.


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6.3.1.2
Control Arm
Topotecan:

Topotecan at 1.50 mg/m2 daily on Days 1-5 q3wk (three weeks ± 48 hours = 
one treatment cycle) for patients with calculated CrCL ≥ 60 ml/min.

Topotecan at 1.25 mg/m2 daily on Days 1-5 q3wk (three weeks ± 48 hours = 
one treatment cycle) for patients with calculated CrCL between 40 and 59 
ml/min.

Topotecan at 0.75 mg/m2 daily on Days 1-5 q3wk (three weeks ± 48 hours = 
one treatment cycle) for patients with calculated CrCL between 30 and 39 
ml/min.
CAV:
CTX at 1000 mg/m2 on Day 1, 
DOX at 45.0 mg/m2 on Day 1, and 
VCR at 2.0 mg total flat dose on Day 1 q3wk (three weeks ± 48 hours = one 
treatment cycle). 
Up to a maximum of 10 cycles (Note: patients older than 70 years should not 
receive a total cumulative DOX dose of more than 400 mg/m2). Then, if 
applicable, DOX will be discontinued definitively and the remaining patients will 
continue on maintenance until PD, patient refusal or unacceptable toxicity despite 
applicable dose reductions. Patients who are experiencing grade 2 neuropathy 
before receiving a new CAV cycle will not receive any further VCR infusions 
until neuropathy resolution to grade 1 is documented. Any recurrence of grade 2 
neuropathy during treatment will result in a definitive discontinuation of VCR. 
All doses will be capped at a BSA of 2.0 m2 for individuals exceeding this BSA value. 
Doses, except for VCR, will have to be recalculated for patients showing a ≥ 10% 
variation in total body weight from baseline or from last dose adjustment. DOX, CTX or
topotecan doses will be rounded, if applicable, according to institutional 
guidelines/standard practice.
Skipped doses of topotecan will not be replaced.
6.4
PROPHYLACTIC MEDICATION
All patients, irrespectively of treatment arm will receive primary prophylaxis 
subcutaneously, with G-CSF. Type, dose, and scheme to be used may vary according to 
institutional/standard practices or guidelines, if available. Nevertheless, a mandatory
window of at least 24 hours and up to 72 hours must be allowed from the last dose of 
study treatment, until G-CSF prophylaxis is started.
In addition, all patients will also receive standard antiemetic prophylaxis before each 
treatment infusion, as follows:

Intravenous corticosteroids (dexamethasone 8 mg, or equivalent, or at institutional 
antiemetic doses).

Intravenous serotonin (5-HT3) antagonists (ondansetron 8 mg, or equivalent).
If necessary, in addition to the above, the duration of treatment with 5-HT3 antagonists 
and/or dexamethasone could be extended orally (if needed) (i.e. 4-8 mg/day for three 
consecutive days) and/or 10 mg of metoclopramide orally every eight hours could be 
added.


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For the purpose of safety evaluations, an optimal prophylaxis is defined as all the 
aforementioned allowed medications at their respectively maximum dose.
Aprepitant or any other NK-1 antagonist or related Substance P-antagonists are 
forbidden in all patients allocated to the experimental arm.
6.5
CRITERIA FOR TREATMENT CONTINUATION 
In order to be re-treated, or to start treatment if first dosing was extended beyond the 
first 72 hours after randomization, patients will have to fulfill all the re-treatment 
criteria defined in Table 12.
Table 12. Criteria for treatment continuation.
Variable
Topotecan or CAV
(Day 1)
PM01183/DOX (Day 1),
or PM01183 alone (Day 1) 
whenever is applicable
ECOG PS
≤ 2
≤ 2
ANC
1.5 x 109/l
1.5 x 109/l
Platelets
100 x 109/l
100 x 109/l
Hemoglobin a
9.0 g/dl
9.0 g/dl
Total bilirubin
1.5 x ULN b, or
direct bilirubin ULN
1.5 x ULN. or
direct bilirubin ULN
Albumin
2.7 g/dl
2.7 g/dl
AST/ALT
3.0 x ULN
3.0 x ULN
CPK
-
Grade ≤ 1
(or ≤ 2 if disease-related grade 
≤ 2 at baseline)  
Calculated CrCL (Cockcroft and 
Gault’s formula)
≥ 30 ml/min c
≥ 30 ml/min
LVEF *
* Patients assigned to CAV treatment: 
within normal limits and not > 10% 
decrease (by MUGA) or > 20% decrease 
(by ECHO) from baseline before Cycle 
3, Cycle 6 and Cycle 9, and if DOX 
cumulative dose ≤ 405 mg/m2
Within normal limits and not 
> 10% decrease (by MUGA) or 
> 20% decrease (by ECHO) 
from baseline before Cycle 3, 
Cycle 6 and Cycle 9, and if 
DOX cumulative dose ≤ 360 
mg/m2
Other non-hematological drug-
related AEs (except increased 
AP, or grade 2 alopecia, asthenia, 
and not optimally treated nausea 
and/or vomiting) d
Grade ≤ 1
Grade ≤ 1
a Patients may receive PRBC transfusion and/or EPO treatment if clinically indicated to increase/maintain 
adequate hemoglobin levels.
b Patients assigned to CAV with total bilirubin between 1.25-1.5 x ULN or direct bilirubin ≥ ULN will receive a 
maximum of 1.5 mg of VCR. 
c Patients with CrCL between 40 and 59 ml/min must be re-treated with 1.25 mg/m2 of i.v. topotecan daily, and 
patients with CrCL between 30 and 39 ml/min must receive no more than 0.75 mg/m2 of topotecan daily. 
d Any grade accepted for increased AP.
Those patients who experience grade ≥ 2 neuropathy while receiving CAV will stop VCR exclusively until 
resolution to at least grade 1 and, if applicable, will have their VCR dose reduced to 1.5 mg/cycle subsequently 
after resolution. If grade ≥ 2 neuropathy re-occurs at any time, or if there is no resolution of the first episode to at 
least grade 1 after a minimum of four weeks of follow-up, VCR will be discontinued definitively.
AEs, adverse events; ALT, alanine aminotransferase; ANC, absolute neutrophil count; AP, alkaline phosphatase; 
AST, aspartate aminotransferase; CAV, CTX DOX and VCR; CPK, creatine phosphokinase; CrCL, creatinine 
clearance; CTX, cyclophosphamide; DOX, doxorubicin; ECHO, echocardiogram; ECOG PS, Eastern Cooperative 
Oncology Group performance status; EPO, erythropoietin; LVEF, left ventricular ejection fraction; MUGA, 
multiple-gated acquisition scan; PRBC, packed red blood cells; ULN, upper limit of normal; VCR, vincristine.
If a patient does not meet the requirements for treatment continuation on Day 1 of any 
cycle after Cycle 1, re-assessments will be performed periodically at intervals of at least 
72 hours and treatment will be withheld until appropriate recovery, for a maximum of 
22 days after the treatment due date. If there is no recovery after a 22-day delay,


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treatment must be discontinued and the EOT visit performed, except if objective clinical 
benefit is observed in tumor assessments, upon the Sponsor’s agreement, in which case 
up to 15 additional days will be allowed to recover and meet the aforementioned 
requirements for treatment continuation
6.6
DOSE REDUCTION
Patients who experience any grade ≥ 3 treatment-related non-hematological toxicity 
(according to the NCI-CTCAE v.4) or febrile neutropenia or neutropenic infection or 
sepsis, and/or grade 4 thrombocytopenia or neutropenia, or treatment-related dose 
delays of more than five days, or frequent shorter dose delays (or skipped infusions if on 
topotecan) may only continue treatment, after appropriate dose reduction (see Table 13).
Patients experiencing treatment-related non-optimally treated grade 3 nausea and/or 
vomiting, grade 3 fatigue/asthenia lasting < 3 days, grade 3 diarrhea lasting ≤ 2 days or 
not optimally treated, and/or non-clinically relevant isolated biochemical abnormalities 
[e.g. alkaline phosphatase (AP)], may continue treatment at the same prior dose without 
any dose reduction being applied, provided optimal concomitant treatment is given for 
the applicable toxicity.
Patients assigned to CAV treatment in the control arm with total bilirubin levels 1.25-
1.5 x ULN or abnormally high direct bilirubin levels before the start of a new cycle will 
receive a maximum of 1.5 mg of VCR. Those patients assigned to CAV who experience 
grade ≥ 2 neuropathy will stop receiving VCR until resolution to at least grade 1. After 
resolution, treatment will be resumed at 1.5 mg of VCR; however, if there is re-
occurrence of grade ≥ 2 neuropathy after re-introduction of VCR, or if there is no 
resolution of the first episode to at least grade 1 after a minimum of four weeks of 
follow-up, VCR will be discontinued definitively.
Table 13. Levels of dose reduction in each treatment arm.
Dose 
reduction
Topotecan daily dose
(q3wk) 
(mg/m2) 
CAV
(q3wk)§
DOX/PM01183 
(q3wk) 
(mg/m2)
PM01183 alone 
(q3wk)
(mg/m2)
1
(starting 
dose)
1.50a
  1.25b
0.75c, d
CTX: 1000 mg/m2
DOX: 45 mg/m2
VCR: 2.0 mg FD
40 / 2.0
3.2
-1
1.25
1.00  
NA
CTX: 750 mg/m2
DOX: 45 mg/m2
+/- VCR: 1.5 mg FD
30 / 2.0
2.6e
-2
1.00
  0.75d
NA
CTX: 750 mg/m2
DOX: 35 mg/m2
+/- VCR: 1.5 mg FD
30 / 1.5
2.0
All doses will be capped at a BSA of 2.0 m2.
PM01183 total doses in mg will be rounded to the first decimal, if necessary. DOX and topotecan total doses will 
be rounded, if applicable, according to institutional guidelines/standard practice.
§ Patients who continue maintenance treatment after DOX discontinuation beyond Cycle 10 will, under no 
circumstances, have their Cy dose reduced below 750 mg/m2 or their VCR dose reduced below 1.5 mg FD 
(although VCR could be discontinued, if needed).
a Starting dose for patients treated with topotecan with calculated CrCL ≥ 60  ml/min. 
b Starting dose for patients treated with topotecan with calculated CrCL of 40-59 ml/min.
c Starting dose for patients treated with topotecan with calculated CrCL of 30-39 ml/min. 
d No dose reduction below 0.75 mg/m2/day will be implemented under any circumstances.
e Starting dose for patients who had two prior dose reductions while on PM01183/DOX.
BSA, body surface area; CAV, CTX DOX and VCR; CrCL, creatinine clearance; CTX, cyclophosphamide; 
DOX, doxorubicin; FD, flat dose; mg, milligram; NA, not available; q3wk, every three weeks; VCR, vincristine.


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Regardless of treatment arm, patients who experience any treatment-related grade 4 
hypersensitivity and/or extravasations will permanently discontinue treatment.
Up to two dose reductions are allowed per patient, if needed, excluding those patients 
starting topotecan at 0.75 mg/m2 or those starting PM01183 alone at 2.6 mg/m2 after 
DOX discontinuation. Any patient who continues to experience treatment-related 
toxicity despite all applicable dose reductions, or who requires one after receiving 
topotecan at 0.75 mg/m2, must stop treatment. Once the dose has been reduced for an 
individual patient, it will not be re-escalated under any circumstances. 
Note: patients enrolled in the experimental arm (PM01183/DOX), or those assigned to 
CAV treatment in the control arm, who had one or no dose reductions while on the 
combination will discontinue DOX and remain on treatment from Cycle 11 onwards (or 
at any other time if DOX is discontinued earlier due to cardiac issues) with PM01183 
alone at 3.2 mg/m2 and may undergo up to two additional dose reductions, whereas 
those who had two dose reductions while on the combination will discontinue DOX and 
remain on treatment from Cycle 11 onwards (or at any other time if DOX is withdrawn 
earlier due to cardiac issues) with PM01183 alone at 2.6 mg/m2 and may undergo one 
additional dose reduction. Patients assigned to CAV treatment in the control arm may 
continue treatment after DOX discontinuation on Cycle 11 with CTX +/- VCR, either at 
1000 mg/m2/2.0 mg FD or at 750 mg/m2/1.5 mg FD, respectively, as applicable. No 
individual dose reductions below CTX 750 mg/m2 or VCR 1.5 mg FD are allowed. No 
single-agent PM01183 dose reduction below 2.0 mg/m2 will be implemented under any 
circumstances. 
Dose recalculations due to changes in BSA will not be considered dose reductions, as 
long as the targeted BSA dose remains unchanged.
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 and local management of mucositis/stomatitis.
Blood products and transfusions, as clinically indicated.
Bisphosphonates.
In case of nausea or vomiting, extended symptomatic treatment for emesis will be 
allowed.
Erythropoietin treatment according to the American Society of Clinical Oncology 
(ASCO) guidelines.
Low-molecular weight heparin (LMWH) and/or any other anticoagulants, as 
clinically indicated.
CNS irradiation if required, and/or limited field bone RT for pain control outside 
the thoracic wall.
Megestrol acetate for wasting syndrome.
6.7.2
Prohibited Medications/Therapies
Concomitant administration of any other antineoplastic therapy. 
Other investigational agents.


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Immunosuppressive therapies other than corticosteroids for antiemetic prophylaxis 
or pain control, or low-dose replacement in patients requiring this approach. 
Aprepitant and other NK-1 antagonists (for patients allocated to the experimental 
arm).
Concomitant RT other than CNS irradiation, or limited-field RT for pain control.
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 have 
demonstrated that time dependent or irreversible inhibition for 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. 0.002 μM when expressed as 
unbound fraction; 1%).
According to the recommendations in the European Medicines Agency Guideline 
CPMP/EWP/560/95, the risk of inhibition in vivo was evaluated by comparing observed 
Ki values against unbound [I] (0.002 µM). If [I]/Ki ≥ 0.02, inhibition in vivo could not 
be excluded. The estimated [I]/Ki values were 0.011, 0.0016, 0.0003 and 0.0012 for 
CYP3A4m, CYP3A4t, CYP2B6 and CYP2C8, respectively. Therefore, an inhibitory 
effect of PM01183 on these CYPs can be ruled out.
The basic model proposed at the Food and Drug Administration (FDA) Guidance for 
Drug Interaction Studies (Draft February 2012) and the National Institute of Health 
Sciences (NIHS) Drug Interaction Guideline for Drug Development and Provision of 
Appropriate Information (Draft 2014) resulted in a R1 value of 2.15 for CYP3A4m, 
which suggests a potential inhibition for CYP3A4. However, when applying the 
mechanistic static model, the area under the curve ratio (AUCR) shows a value of 1.00
(Ah in the FDA Guidance or Ch in the NIHS Guideline was 0.99 and fm=0.4) and 
therefore the inhibitory effect of PM01183 on CYP3A4 can be discarded. 
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 4).
A potentially significant interaction with aprepitant is suggested by available phase II 
data from ovarian cancer patients and phase I data from the PM1183-A-008-13 study. 
PM01183 clearance was reduced by 50%, approximately, in the presence of aprepitant. 
Although all patients eventually recovered, the use of aprepitant is currently forbidden 
in all phase II/III PM01183 studies.
A recent analysis of PK data from the PM1183-A-003-10 trial found that PM01183 
exposure (area under the curve, AUC) reduced DOX clearance slightly (from 45 l/h to 
35 l/h; a 20% reduction) and more markedly doxorubicinol clearance (from 150 l/h to 
75 l/h; a 50% reduction). A mechanistic explanation for this interaction is currently 
being studied. Taking into account these results, the DOX dose of 40.0 mg/m2 used in 
the experimental arm in the present study is not expected to result in patient exposure to 
supratherapeutic levels of DOX or doxorubicinol.  


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6.8
DRUG ACCOUNTABILITY
Proper drug accountability will be done by the 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 aim of this clinical trial is to determine whether there is a statistically 
significant difference in the OS between PM01183/DOX and either CAV or topotecan 
as second-line treatment in SCLC patients after failure of one chemotherapy line.
Secondary endpoints of efficacy include difference in OS between PM01183/DOX and 
CAV, in patients with CAV as best Investigator’s choice; OS/PFS per RECIST v.1.1 in
patients with and without baseline central nervous system (CNS) involvement; PFS per 
RECIST v.1.1 by an IRC; and best antitumor response as per RECIST v.1.1 and 
duration of response (DR) (both assessed by IRC). Tertiary endpoints of efficacy 
comprise PFS per RECIST v.1.1 by IA, and best antitumor response as per RECIST 
v.1.1 and DR (both assessed by IA).
Antitumor activity will be assessed using the RECIST v. 1.1 (see APPENDIX 5) and 
followed until PD by the appropriate method [computed tomography (CT) scan or 
magnetic resonance imaging (MRI) of the pelvis, abdomen and chest].
Irrespectively of treatment arm, radiological and clinical tumor assessment will be 
performed at baseline and every six weeks (± one week) after randomization until 
evidence of PD.
A special effort will be made to continue follow-up and report tumor assessments in 
patients discontinuing the study treatment without progression by RECIST.
Adequate CNS imaging (contrast enhanced-CT or MRI, if applicable) will be performed 
at baseline to document any disease involvement. In the event of CNS involvement 
being found, this assessment will be repeated while on treatment, regardless of 
treatment arm; otherwise, it will only be repeated if clinically indicated.
Irrespectively of treatment arm, patients with documented clinical benefit during 
treatment (either response or tumor shrinkage in target lesions and without clinical 
deterioration) may continue treatment while CNS irradiation is given, if appropriate.
After radiological PD is documented or a new systemic antitumor therapy is started, 
patients will be followed for survival every three months (± two weeks) during the first 
18 months after randomization, and then once every six months (± four weeks) until 
death or date of study termination, whichever occurs first. Once the whole recruitment 


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is completed, the survival follow-up procedure will change: patients who discontinue 
treatment will be followed every three months according to a fixed calendar time (e.g.,
July, October, January, etc.) until death or study completion. For survival follow-up 
purposes, after radiological PD is documented or new therapy is started, a documented
telephone call from the investigational sites will be adequate.
The date of clinical and/or radiological PD and the date of death will be registered and 
documented as appropriate.
Copies of CT scans, MRIs and any other documented means to evaluate tumor response 
or progression should be available for external radiological review by an IRC. The IRC 
will determine the patient’s best response and assign the date of objective response or 
progression/censoring according to the RECIST v.1.1.
In order to evaluate the overall safety in both arms, an interim safety analysis is planned 
when 150 patients are recruited (i.e., ~75 patients into each arm). Recruitment will not 
be put on hold while the interim safety analysis is being performed. Efficacy parameters 
will not be formally analyzed in this interim evaluation. Further safety and efficacy 
analyses could be performed upon request from the IDMC.
If any formal interim OS/PFS analysis is performed, unblinded only to the IDMC, a 
type I error correction according to the Lan and DeMets error spending function that 
corresponds to the O'Brien-Fleming boundary will be used, calculated during the 
interim analyses to preserve an overall (one-sided) 0.005 false positive error rate; if 
early termination does not occur, the alpha level of the final analysis will be chosen to 
preserve an overall (one-sided) 0.025 false positive error rate.
7.2
SAFETY
Patients will be evaluable for safety if they have received any partial or complete 
treatment infusion. All AEs will be graded according to the NCI-CTCAE v.4. Treatment 
delays, dose omissions (if applicable), dose reductions, 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 after the last treatment infusion (end of treatment, EOT), or 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, whenever is possible.
Any patient having any treatment-related grade ≥ 3 AEs should have appropriate tests 
re-assessed at least every 48-72 hours until recovery to at least grade 2.
Hematological assessments must be repeated on Day 10 of Cycles 3 and following if 
grade ≥ 3 hematological abnormalities or a dose modification occurred in the preceding 
cycle, and in the first cycle of maintenance with PM01183 alone after DOX 
discontinuation.
Biochemical assessments must be repeated on Day 10 of Cycles 3 and following if 
grade ≥ 3 non-hematological abnormalities or a dose modification occurred in the 
preceding cycle.
Safety evaluations will also be performed by the IDMC during the interim analysis, to 
be conducted when 150 patients are recruited (i.e., ~75 patients into each arm).


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7.3
ADVERSE EVENTS DEFINITIONS
7.3.1
Adverse Event (AE)
An AE is any untoward medical occurrence in a patient or clinical investigation patient 
administered a pharmaceutical product which does not necessarily have a causal 
relationship with this treatment. 
An AE can therefore be any unfavorable and unintended sign, (e.g., an abnormal 
laboratory finding), or a disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product.
Illnesses with onset during the study or exacerbations of pre-existing illnesses, including
but not limited to clinically significant changes in physical examination findings and 
abnormal objective tests/procedures findings (e.g., X-ray, ECG) should be recorded. 
The criteria for determining whether an abnormal objective test finding should be 
reported as an AE are as follows:
The test result is associated with clinically significant symptoms, and/or
The test result leads to a change in the study dosing or discontinuation from the 
clinical trial, significant additional concomitant drug treatment or other therapy, 
and/or
The test result leads to any of the outcomes included in the definition of a SAE
(see definition below), and/or

The test result is considered to be clinically relevant by the Investigator.
“Disease progression” will not be reported as an AE, as this information will be used for 
efficacy assessment.
7.3.2
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,
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 medically significant
events; this criterion should be applied to AEs 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.
“Disease progression” as a term will not be reported as a SAE.
7.3.3
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.


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7.3.4
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 were more severe.
7.3.5
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 (see Section 7.4.2). 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 (i.e., laser eye surgery, arthroscopy, etc.).
7.3.6
Unlisted/Unexpected Adverse Event
An AE, the nature or severity of which is not consistent with the applicable reference 
safety information.
The Sponsor will use as the reference safety information for the evaluation of 
listedness/expectedness the IB for lurbinectedin (PM01183) and the SmPC for DOX, 
cyclophosphamide, vincristine and topotecan.
7.3.7
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.
7.3.8
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 7.3.10). 
The Investigator will assess the causal relationship of the IMP(s) to the SAE.


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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.
7.3.9
Expedited Reporting
The Sponsor is responsible for the appropriate expedited reporting according to the 
applicable legislation.
7.3.10 Assessment of Causal Relationship to the Study Drug
The Investigator must provide an assessment of the causal relationship of each SAE to 
the clinical trial IMP(s) 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 (i.e., the patient was not seen at his/her 
center) if none of the above can be used.
7.4
ADVERSE EVENTS REPORTING PROCEDURES
7.4.1
Reporting Adverse Events
The Sponsor will collect AEs until 30 days after administration of the last dose of study 
drug(s)/IMP(s) or until the start of a new antitumor therapy or until the date of death, 
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 medication errors and uses outside what is foreseen in the protocol, 
must be recorded in English using medical terminology in the source document and the 
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 
criteria for classification as a SAE requiring immediate notification to Pharma Mar S.A. 
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 
(e.g. biochemistry, hematology).
All episodes of febrile neutropenia must always be reported within 24 hours following 
the same procedure for reporting SAEs (see Section 7.4.2), including episodes that 
occurred in patients without seriousness criteria. For these cases, the seriousness 
criterion should be reported as a medically significant event.


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7.4.2
Reporting Serious Adverse Events
The Sponsor will collect SAEs from the time of signing of the 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 or until the date of death, 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) occurred after ICF signature regardless of relationship to 
the study drug(s)/IMP(s) must be reported immediately, and always within 24 hours to 
the Pharma Mar S.A. Pharmacovigilance Department, electronically by completing the 
applicable e-CRF section.
SAEs occurring during the screening phase (from ICF signature to randomization), 
SAEs that may occur off-study, or in case the electronic system fails or is not available,  
will be reported within 24 hours to the Pharmacovigilance Department using the paper 
SAE form by fax (+34 91 846 6004), e-mail (phv@pharmamar.com) or telephone (+34 
91 823 4617). 
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 alternative methods (not electronically), must be followed by 
a completed electronic SAE reporting on e-CRF from the investigational staff within 
one working day.
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.
7.4.3
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 and suspected pregnancy (including a positive pregnancy test 
regardless of age or disease state) of a patient occurring while on study drug, or within 
30 days after the administration of the last dose of the study drug(s)/IMP(s), are 
considered immediately reportable events. Beyond this timeframe, the investigator will 
report any pregnancy if there is any suspicion that the study drug(s)/IMP(s) might have 
an impact on the occurrence of the pregnancy.
The Investigator will report the following events immediately and always within 24 
hours from first knowledge:
Any occurrence of a pregnancy where any kind of exposure to the IMP(s) is 
suspected.
Possible exposure of a pregnant woman.
All reports of elevated/questionable or indeterminate beta human chorionic 
gonadotropins (β-hCGs).
Immediately after detecting a case of suspected pregnancy in a 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, suspected pregnancy, or positive pregnancy test must be reported to 
Pharma Mar S.A. Pharmacovigilance immediately using the Pregnancy Report form.


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The Investigator will follow the pregnancy until its outcome, and must notify Pharma 
Mar S.A. Pharmacovigilance 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  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 by facsimile within 24 hours of the 
Investigators’ knowledge of the event.
7.5
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 designed clinical research monitor in charge 
of the study, the consistency between the CRF/SAE data reported to the 
Pharmacovigilance Department and the patient's source data will be reviewed. When 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. 
SAEs will be continuously collected, assessed and reported throughout all the study as 
per the applicable legislation by the Pharma Mar S.A. Pharmacovigilance Department. 
Periodic safety reviews of SAE reports including events of special interest (e.g., 
neutropenia and thrombocytopenia) are to be conducted and documented by the 
Pharmacovigilance Department.
Non-serious AEs will be verified during monitoring visits by the clinical trial monitor, 
who will discuss them with the Investigators, if applicable. AEs will be assessed 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. Periodic safety review of safety data from the clinical database, i.e. AEs and 
laboratory data, will be performed along the study by the Pharma Mar S.A. 
Pharmacovigilance, Clinical Oncology and Data Management departments.
7.6
PATIENT-REPORTED OUTCOMES
To measure the quality of life of patients, the EORTC QLQ-C30 and EORTC QLQ-
LC13 questionnaires will be assessed every six weeks (± one week) until EOT.
7.7
PHARMACOKINETICS
7.7.1
Plasma Sampling
Blood samples (detailed in Table 14) will be collected from all patients enrolled 
exclusively in the experimental arm to analyze PM01183, DOX and its metabolite 
doxorubicinol. The samples will be obtained in two cycles: Cycle 1, and a second cycle 
between Cycles 2 and 4. The second cycle with PK sampling will be assigned once the 
patient has been randomized into the experimental arm.


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Table 14. Samples for pharmacokinetic evaluations.
Sample 
No.
Time
Acceptable 
window times
Sampling time 
For DOX
For PM01183
#1
0
1 to 5 min before 
treatment start
Predose
Preinfusion
#2
5 min
± 2 min
5 min after EOA
-
#3
1 h
± 4 min
-
5 min before EOI
#4
2 h
± 10 min
2 h after EOA
1 h after EOI
#5
96 h
± 24 h
96 h after EOA
95 h after EOI
DOX, doxorubicin; EOA, end of administration; EOI, end of infusion; h, hour; min, minute.
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. Use the PM01183 reference sampling times for samples 
#3 to #5 to manage any delays between DOX administration and PM01183 infusion.
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 five samples of about 9 ml each will be collected for the determination of 
plasma concentrations of PM01183 on Cycle 1 and in another cycle randomly between 
Cycle 2 and Cycle 4 (about 90 ml of whole blood) at the predefined times depicted in 
the above table. A Laboratory Manual will be provided with details on collection and 
storage of PK samples. Please read it carefully before PK sampling. In short, after 
collection, each sample will be centrifuged and the resulting plasma layer split into two
new tubes for the determination of PM01183 concentration, and of DOX and 
doxorubicinol concentrations. The plasma-containing tubes will be stored frozen until 
their shipment to the Central Laboratory for PK Samples (see details in the Study 
Contacts). All the material for PK procedures will be provided by the Sponsor(s). 
7.7.2
Analytical Procedures
Plasma samples will be analyzed to determine concentrations of PM01183, DOX and 
doxorubicinol using validated, specific, and sensitive liquid chromatography/mass 
spectrometry/mass spectrometry (LC-MS/MS) methods by or under the supervision of 
the Sponsor.
7.7.3
Pharmacokinetic Parameters
Pharmacokinetic analysis will be the responsibility of the Sponsor in accordance with 
the current Clinical Pharmacokinetics guidelines on population pharmacokinetic 
analyses [54, 55]. Clearance and volume of distribution will be the primary parameters 
of interest for the population PK analysis. Additional PK parameters will be calculated, 
if deemed appropriate.
7.8
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 will be 
analyzed in leukocyte DNA extracted from one blood sample obtained at any time 


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during the study in the experimental arm. A selection of genes involved in PM01183 
metabolism or transport will be investigated in order to identify genetic variants 
associated with PM01183 clearance (see APPENDIX 6 for details).
The collection and management of the polymorphisms samples for pharmacogenetics
are quite different than those for PK assessment (please, refer to the Laboratory Manual 
for details). The assessment of genetic polymorphisms is not affected by treatment. 
Therefore, the Sponsor may require the collection of additional polymorphisms samples 
for pharmacogenetics later on, if the first assessment has not been performed accurately. 
Only patients treated with PM01183 and DOX in the experimental arm who voluntarily 
sign the ICF for this pharmacogenetic sub-study will participate in the pharmacogenetic 
evaluation. Refusal to participate in this sub-study will not affect patient participation in
the clinical study PM1183-C-003-14. Patients with available PK and pharmacogenetic 
samples from this and other clinical trials with PM01183 will be included. Briefly, the 
pharmacogenetic analysis will investigate the impact of genetic variants in genes 
relevant for PM01183 disposition on unexplained between subjects variability in PK 
parameters obtained by the population PK model incorporating non genetic covariates 
using data aggregated from across the PM01183 clinical development program.
8.
STATISTICAL METHODS
This phase III clinical trial is designed to determine whether there is a statistically 
significant difference in the OS between PM01183/DOX vs. CAV or topotecan as 
second-line treatment in SCLC patients after failure of one platinum-containing
chemotherapy line.
The primary study analysis (OS) will be performed by means of the stratified log-rank 
test selecting the actual CNS and CTFI values of the stratification factors on the 
intention-to-treat (ITT) population, defined as all randomized patients analyzed in the 
group where they were allocated.
An IDMC will oversee the conduct of the study. 
8.1
SAMPLE SIZE
Patients will be randomized to receive DOX at 40 mg/m2 followed by PM01183 at 2.0
mg/m2 (experimental arm), and either CAV or topotecan (control arm).
The prospective assumptions are a one-sided 2.5% significance level with at least 90% 
power to detect a 25% decrease in the risk of death to be achieved with the 
experimental arm (HR=0.75). OS with either CAV or topotecan is expected to be 7.5
months [25].
To obtain the required 508 events, approximately 600 patients with SCLC who failed 
one prior platinum-containing chemotherapy line will be stratified and randomized at a 
1:1 ratio. With the aforementioned prospective assumptions, recruitment is foreseen to 
be completed in 24 months, and a total study duration for final OS analysis of about 
three and a half years is planned.
Stratification will be performed according to the CTFI after first line [≥180 days (VS)
vs. 90-179 days (S) vs. <90 days (R)], ECOG PS (0 vs. 1-2), baseline CNS 
involvement vs. no such involvement, prior immunotherapy against either PD-1 or PD-
L1 (Yes vs. No) and Investigator’s preference (best Investigator’s choice prior to 
randomization) between topotecan and CAV.


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In order to evaluate the overall safety in both arms, an interim safety analysis is 
planned after the recruitment of 150 patients (i.e., ~75 patients into each arm) (see 
Section 8.3). Recruitment will not be put on hold while the interim safety analysis is 
being performed.
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
Time-to-event variables (OS, PFS and DR) and their set time estimates (e.g., OS 
12/18/24) will be analyzed according to the Kaplan-Meier method. The stratified log-
rank test (primary analysis) and the unstratified log-rank test on the ITT population will 
be used to compare the time-to-event variables.
Cox regression will be used to calculate the risk reduction (OS, PFS and DR) and to 
evaluate the influence of the stratification variables and other potential prognostic 
factors on the time-to-event efficacy endpoints. Continuous variables that would have 
been categorized as discrete variables will also be investigated in the continuum range, 
and if the adjustment is better, then the continuous variable will be kept in the 
regression model.
Counts and percentages, with their corresponding exact 95% confidence intervals, will 
be calculated for the binomial endpoints (e.g., response rate). The Fisher’s exact test 
(univariate analyses) and logistic regressions will be used to compare the rates of the 
experimental arm and the control arm. 
Waterfall plots will be used to describe the best variation of the sum of target lesions 
during the treatment.
If the result of the primary endpoint analysis is statistically significant, the hierarchical 
step-up Hochberg procedure will be used to test the most relevant secondary efficacy 
endpoints (i.e., difference in OS in patients with CAV as best Investigator’s choice, and 
OS in the subgroup of patients without baseline CNS involvement) at the overall two-
sided significance level of 0.05.
8.2.2
Safety Analyses
AEs, SAEs, deaths, laboratory evaluations, dose delays/omissions/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. Exploratory Fisher’s exact tests will be performed to compare 
grade 4 or grade 3/4 between treatment arms. 
Patients having any grade ≥3 laboratory abnormalities and/or treatment-related AEs 
must have the relevant tests re-assessed at least every 48-72 hours until recovery to at 
least grade 2 has been documented.
The IDMC may request to review other preliminary safety/efficacy parameters, but no 
claim of superiority will be made.


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8.2.3
Patient-reported Outcomes (PRO) Analyses
PRO will be analyzed to determine if efficacy and side effects are accompanied by 
measurable changes. The analysis will be performed on summary scores of the EORTC 
QLQ-C30 and EORTC QLQ-LC13 questionnaires, as well as on subscales, and 
individual symptoms.
8.2.4
Pharmacokinetic Analyses
Pharmacokinetic data will be listed in the population PK report for all patients treated 
with PM01183 and DOX in the experimental arm who had available concentrations of 
PM01183, DOX or doxorubicinol.  Patients will be excluded from the PK analysis if 
their data do not allow for accurate assessment of the PK (e.g., improper handling of 
PK samples; incomplete administration of the study agent; missing time or dosing 
information). All concentrations below the lowest quantifiable concentration or 
missing data will be labeled as such in the concentration data presentation. All patients 
and samples excluded from the analysis will be retained in the dataset, but they will be 
flagged out and the criteria for exclusion documented. 
Population PK analysis of plasma concentration-time data of PM01183, DOX and 
doxorubicinol will be performed using non-linear mixed-effects modeling. Data may 
be combined with additional trials to support a relevant structural model. Available 
patient characteristics (demographics, laboratory variables, genotypes, etc.) will be 
tested as potential covariates affecting PK parameters. Details will be given in a 
population PK analysis plan, and results will be presented in a separate report.
8.2.5
Pharmacokinetic/pharmacodynamic Correlation
Population PK correlations of drug exposure with safety and efficacy will be explored. 
Details will be given in specific population PK/PDy analysis plans, and results will be 
presented in separate reports.
8.2.6
Pharmacogenetic Analyses 
The influence of genetic polymorphisms on main PK parameters will not be assessed 
or reported for individual clinical trials. Pharmacogenetic analysis will instead be 
performed using data aggregated from across the PM01183 clinical development 
program and presented in a separate report.
8.3
INTERIM SAFETY ANALYSIS
In order to evaluate the overall safety in both arms, an interim safety analysis is 
planned after the recruitment of 150 patients (i.e., ~75 patients into each arm). 
Recruitment will not be put on hold while the interim safety analysis is being 
performed. Efficacy parameters will not be formally analyzed in this interim 
evaluation. Further safety and efficacy analyses could be performed upon request from 
the IDMC.
As previously explained, if any formal interim OS/PFS analysis is performed, 
unblinded only to the IDMC, a type I error correction according to the Lan and 
DeMets error spending function that corresponds to the O'Brien-Fleming boundary 
will be used, calculated during the interim analyses to preserve an overall (one-sided) 
0.005 false positive error rate; if early termination does not occur, the alpha level of the 


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final analysis will be chosen to preserve an overall (one-sided) 0.025 false positive 
error rate.
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 7) 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 IEC/IRB approval/favorable 
opinion prior to initiation, according to pertinent regulations.
The decision of 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 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 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).
Participation in this trial implies acceptance of potential inspection by national or 
foreign Competent Authorities.


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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 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 the pharmacogenetic sub-study. The 
Investigator should allow the necessary time for the patient or his/her legally acceptable 
representative, when required, 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.
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.
Pharma Mar S.A. shall comply with the Directive 95/46/EEC of the European 
Parliament and of the Council 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.
9.5
CASE REPORT FORMS
Electronic 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 


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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, patient-reported outcomes, 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 databases, which comply with the 
Spanish Act implementing the Directive 95/46/EC of the European Parliament and of 
the Council of 24 October 1995 on the protection of individuals with regard to the 
processing of personal data. 
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 (R1) 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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Germano G, Frapolli R, Simone M, Tavecchio M, Erba E, Pesce S, Pasqualini F, 
Grosso F, Sanfilippo R, Casali PG, Gronchi A, Virdis E, Tarantino E, Pilotti S, Greco 
A, Nebuloni M, Galmarini CM, Tercero JC, Mantovani A, D'Incalci M, Allavena P. 
Antitumor and anti-inflammatory effects of trabectedin on human myxoid liposarcoma 
cells. Cancer research 2010;70(6):2235-44.
38.
Allavena P, Germano G, Belgiovine C, D'Incalci M, Mantovani A. Trabectedin: 
A drug from the sea that strikes tumor-associated macrophages. Oncoimmunology 
2013;2(6):e24614.
39.
D'Incalci M, Frapolli R, Germano G, Allavena P. New activities for the anti-
tumor agent trabectedin: taking two birds with one stone. Oncotarget 2013;4(4):496-7.
40.
Germano G, Frapolli R, Belgiovine C, Anselmo A, Pesce S, Liguori M, Erba E, 
Uboldi S, Zucchetti M, Pasqualini F, Nebuloni M, van Rooijen N, Mortarini R, 
Beltrame L, Marchini S, Fuso Nerini I, Sanfilippo R, Casali PG, Pilotti S, Galmarini 
CM, Anichini A, Mantovani A, D'Incalci M, Allavena P. Role of macrophage targeting 
in the antitumor activity of trabectedin. Cancer cell 2013;23(2):249-62.
41.
Romano M, Frapolli R, Zangarini M, Bello E, Porcu L, Galmarini CM, Garcia-
Fernandez LF, Cuevas C, Allavena P, Erba E, D'Incalci M. Comparison of in vitro and 
in vivo biological effects of trabectedin, lurbinectedin (PM01183) and Zalypsis(R) 
(PM00104). Int J Cancer 2013;133(9):2024-33.
42.
Guillen MJ. Antitumor activity of PM01183 in combination with doxorubicin in 
mice bearing human ovarian tumor (A2780) xenografts. Colmenar Viejo (Madrid), 
Spain: PharmaMar, S.A.U., 2010 PMAR10-NC033.
43.
Chou TC. Theoretical basis, experimental design, and computerized simulation 
of synergism and antagonism in drug combination studies. Pharmacol
Rev 
2006;58(3):621-81.
44.
Elez ME, Tabernero J, Geary D, Macarulla T, Kang SP, Kahatt C, Pita AS, 
Teruel CF, Siguero M, Cullell-Young M, Szyldergemajn S, Ratain MJ. First-in-human 
phase I study of Lurbinectedin (PM01183) in patients with advanced solid tumors. Clin 
Cancer Res 2014;20(8):2205-14.
45.
O'Reilly S, Rowinsky E, Slichenmyer W, Donehower RC, Forastiere A, Ettinger 
D, Chen TL, Sartorius S, Bowling K, Smith J, Brubaker A, Lubejko B, Ignacio V, 
Grochow LB. Phase I and pharmacologic studies of topotecan in patients with impaired 
hepatic function. J Natl Cancer Inst 1996;88(12):817-24.


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46.
O'Reilly S, Rowinsky EK, Slichenmyer W, Donehower RC, Forastiere AA, 
Ettinger DS, Chen TL, Sartorius S, Grochow LB. Phase I and pharmacologic study of 
topotecan in patients with impaired renal function. J Clin Oncol 1996;14(12):3062-73.
47.
Rowinsky EK, Grochow LB, Hendricks CB, Ettinger DS, Forastiere AA, 
Hurowitz LA, McGuire WP, Sartorius SE, Lubejko BG, Kaufmann SH, et al. Phase I 
and pharmacologic study of topotecan: a novel topoisomerase I inhibitor. J Clin Oncol 
1992;10(4):647-56.
48.
Sehouli J, Stengel D, Harter P, Kurzeder C, Belau A, Bogenrieder T, Markmann 
S, Mahner S, Mueller L, Lorenz R, Nugent A, Wilke J, Kuznik A, Doering G, Wischnik 
A, Sommer H, Meerpohl HG, Schroeder W, Lichtenegger W, Oskay-Oezcelik G. 
Topotecan Weekly Versus Conventional 5-Day Schedule in Patients With Platinum-
Resistant Ovarian Cancer: a randomized multicenter phase II trial of the North-Eastern 
German Society of Gynecological Oncology Ovarian Cancer Study Group. J Clin 
Oncol;29(2):242-8.
49.
Eckardt JR, von Pawel J, Pujol JL, Papai Z, Quoix E, Ardizzoni A, Poulin R, 
Preston AJ, Dane G, Ross G. Phase III study of oral compared with intravenous 
topotecan as second-line therapy in
small-cell lung cancer. J Clin Oncol 
2007;25(15):2086-92.
50.
Daniels JR, Chak LY, Sikic BI, Lockbaum P, Kohler M, Carter SK, Reynolds R, 
Bohnen R, Gandara D, Yu J. Chemotherapy of small-cell carcinoma of lung: a 
randomized comparison of alternating and sequential combination chemotherapy 
programs. J Clin Oncol 1984;2(11):1192-9.
51.
Colvin M, Brundrett RB, Kan MN, Jardine I, Fenselau C. Alkylating properties 
of phosphoramide mustard. Cancer Res 1976;36(3):1121-6.
52.
D'Incalci M, Bolis G, Facchinetti T, Mangioni C, Morasca L, Morazzoni P, 
Salmona M. Decreased half life of cyclophosphamide in patients under continual 
treatment. Eur J Cancer 1979;15(1):7-10.
53.
Marbeuf-Gueye C, Broxterman HJ, Dubru F, Priebe W, Garnier-Suillerot A. 
Kinetics of anthracycline efflux from multidrug resistance protein-expressing cancer 
cells compared with P-glycoprotein-expressing cancer cells. Mol Pharmacol 
1998;53(1):141-7.
54.
Schimmer AD, Hedley DW, Penn LZ, Minden MD. Receptor-
and 
mitochondrial-mediated apoptosis in acute leukemia: a translational view. Blood 
2001;98(13):3541-53.
55.
Faderl S, Thall PF, Kantarjian HM, Talpaz M, Harris D, Van Q, Beran M, 
Kornblau SM, Pierce S, Estrov Z. Caspase 2 and caspase 3 as predictors of complete 
remission and survival in adults with acute lymphoblastic leukemia. Clin Cancer Res 
1999;5(12):4041-7.


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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 17 March 2016). 
A woman is considered of childbearing potential (WOCBP) following menarche and 
until becoming post-menopausal unless permanently sterile. Permanent sterilization 
methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. A 
postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal 
range may be used to confirm a post-menopausal state in women not using hormonal 
contraception or hormonal replacement therapy. However, in the absence of 12 months 
of amenorrhea, a single FSH measurement is insufficient. Immediately after detecting a 
case of suspected pregnancy in a patient, the decision on her continued participation in 
the clinical trial will be jointly taken by the patient, the Investigator and the Sponsor, 
with the patient’s best interest in mind. A decision to continue the pregnancy will 
require immediate discontinuation any investigational medicinal product (IMP). 
A man is considered fertile after puberty unless permanently sterile by bilateral 
orchidectomy. Fertile male patients included in this study should refrain from fathering 
a child or donating sperm during the study and for four months following the last IMP 
dose. If they have WOCBP partners the male subject should use condom during 
treatment and for four months following the last IMP dose. 
Highly effective birth control methods are:
1. Combined (estrogen and progestogen containing) hormonal contraception 
associated with inhibition of ovulation 1:
a.
oral 
b. intravaginal 
c.
transdermal 
2. Progestogen-only hormonal contraception associated with inhibition of 
ovulation 1: 
a.
oral 
b. injectable
c.
implantable 2
3. Intrauterine device (IUD) 2
4. Intrauterine hormone-releasing system (IUS) 2
5. Bilateral tubal occlusion 2
6. Vasectomized partner 2,3
7. Sexual abstinence 4
8. A combination of male condom with either cap, diaphragm or sponge with 
spermicide (double barrier methods) are also considered acceptable, but not 
highly effective, birth control methods.
1 Hormonal contraception may be susceptible to interaction with the IMP, which may 
reduce the efficacy of the contraception method (see below).
2 Contraception methods that are considered to have low user dependency. 


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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: CALCULATION OF THE BODY SURFACE AREA. THE DUBOIS 
FORMULA
For calculating the patient’s body surface area (BSA):
BSA (m2) = 0.007184 x Height (cm)0.725 x Weight (kg)0.425
Reference:
DuBois D, DuBois E.F. A formula to estimate the approximate surface area if height and 
weight be known. Arch Intern Med 1916;17:863–71.


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APPENDIX 4: 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.
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.


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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/DrugInteractionsLabe
ling/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 5: 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): 228-247.2
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. Summary of major changes from RECIST 1.0 to RECIST 1.13.
Table 2. Time point response: patients with target (+/–non-target) disease.
Table 3. Time point response: patients with non-target disease only.
Table 4.  Best overall response when confirmation of complete response (CR) and 
partial response (PR) is  required.
                                                
2 A summary of major changes from RECIST 1.0 to RECIST 1.1 can be found at the beginning of this 
document (Table 1).
3This table is named Appendix I in the original RECIST 1.1 article.


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The main changes from RECIST 1.0 to RECIST 1.1 are shown in the following table.
Table 1. Summary of major changes from RECIST 1.0 to RECIST 1.1.
RECIST 1.0
RECIST 1.1
Rationale
Minimum size 
measurable 
lesions 
CT: 10 mm spiral 
20 mm non-spiral 
CT 10 mm; delete 
reference to 
spiral scan 
Most scans used have 5 mm or less 
slice thickness. Clearer to give 
instruction based on slice interval 
if it is greater than 5 mm 
Clinical: 20 mm 
Clinical: 10 mm 
(must be measurable 
with calipers) 
Caliper measurement will make 
this reliable 
Lymph node: not 
mentioned 
CT: 
≥ 15 mm short axis 
for target 
≥ 10–<15 mm for 
non-target 
< 10 mm is non-
pathological 
Since nodes are normal structure 
need to define pathological 
enlargement. Short axis is most 
sensitive 
Special 
considerations on 
lesion measurability 
–
Notes included on 
bone lesions, cystic 
lesions 
Clarify frequently asked questions 
Overall tumor 
burden 
10 lesions (5 per organ) 5 lesions (2 per 
organ) 
Data warehouse analysis shows no 
loss of information if lesion 
number reduced from 10 to 5. A 
maximum of 2 lesions per organ 
yields sufficient representation per 
disease site 
Response criteria 
target 
disease 
CR lymph node not 
mentioned 
CR lymph nodes 
must be <10 mm 
short axis 
In keeping with normal size of 
nodes 
PD 20% increase over 
smallest sum on 
study or new lesions 
PD 20% increase 
over smallest sum on 
study (including 
baseline if that is 
smallest) and 
at least 5 mm 
increase or new 
lesions 
Clarification that if baseline 
measurement is smaller than any 
on study measurement, it is 
reference against which PD is 
assessed 5 mm absolute increase to 
guard against over  calling PD 
when total sum is very small and 
20% increase is within 
measurement error 
Response criteria 
non-target 
disease 
‘Unequivocal 
progression’ 
considered as PD 
More detailed 
description of 
‘unequivocal 
progression’ to 
indicate that it should 
not normally trump 
target disease 
status. It must be 
representative of 
overall disease status 
change, not a single 
lesion increase 
Confusion with RECIST 1.0 where 
some were considering PD if 
‘increase’ in any non-target lesion, 
even when target disease is stable 
or responding 
New lesions 
–
New section on New 
lesions 
To provide guidance on when a 
lesion is considered new (and thus 
PD) 


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RECIST 1.0
RECIST 1.1
Rationale
Overall response 
Table integrated target 
and non-target 
lesions 
Two tables: one 
integrating target and 
non-target and the 
other of non-target 
only 
Special notes: 
How to assess and 
measure lymph nodes 
CR in face of residual 
tissue 
Discussion of 
‘equivocal’ 
progression 
To account for the fact that 
RECIST criteria are now being 
used in trials where PFS is the 
endpoint and not all patients have 
measurable (target) disease at 
baseline 
Frequently asked questions on 
these topics 
Confirmatory 
measure 
For CR and PR: criteria 
must be met again 4 
weeks after initial 
documentation 
Retain this 
requirement ONLY 
for non-randomized 
trials with  primary 
endpoint of response 
Data warehouse shows that 
response rates rise when 
confirmation is eliminated, but the 
only circumstance where this is 
important is in trials where there is 
no concurrent comparative control 
and where this measure is the 
primary endpoint 
Progression-free 
survival 
General comments only More specific 
comments on 
use of PFS (or 
proportion 
progression-free) as 
phase II endpoint 
Greater detail on PFS 
assessment in phase 
III trials 
Increasing use of PFS in phase III 
trials requires guidance on 
assessment of PD in patients with 
non-measurable disease 
Reporting of 
response 
results 
9 categories suggested 
for 
reporting phase II 
results 
Divided into phase II 
and phase III 
9 categories 
collapsed into 5 
In phase III, guidance 
given about reporting 
response 
Simplifies reporting and clarifies 
how to report phase II and III data 
consistently 
Response in phase 
III 
trials 
More relaxed 
guidelines 
possible if protocol 
specified 
This section removed 
and referenced in 
section 
above: no need to 
have different criteria 
for phase II and III 
Simplification of response 
assessment by reducing number of 
lesions and eliminating need for 
confirmation in randomized studies 
where response is not the primary 
endpoint makes separate ‘rules’ 
unnecessary 
Imaging appendix 
Appendix I 
Appendix II: updated 
with detailed 
guidance on use of 
MRI, PET/CT 
Other practical 
guidance included
Evolving use of newer modalities 
addressed. Enhanced guidance in 
response to frequent questions and 
from radiology review experience 
New appendices 
Appendix I: 
comparison of 
RECIST 1.0 and 1.1 
Appendix III: 
frequently asked 
questions


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RECIST 1.0
RECIST 1.1
Rationale
CR, complete response; CT, computed tomography; MRI, magnetic resonance imaging; RECIST, response 
evaluation criteria in solid tumors; PD, progressive disease; PET, positron emission tomography; PFS, progression-
free survival; PR, partial response.
1. MEASURABILITY OF TUMOR LESIONS AT BASELINE
1.1 Definitions
At baseline, tumor lesions/lymph nodes will be categorized as 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).
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 


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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.
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 


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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. 
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 


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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 x 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 
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.


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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 
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.


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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 
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 


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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. 
2.4.1 Time Point Response 
It is assumed that at each protocol speciﬁed time point, a response assessment occurs. 
Table 2 provides a summary of the overall response status calculation at each time point 
for patients who have measurable disease at baseline. 
Table 2. 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. 


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When patients have non-measurable (therefore non-target) disease only, Table 3 is to be 
used. 
Table 3. 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 
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 4. 


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Table 4.  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 6: LIST OF GENES TO BE INVESTIGATED IN THE PM01183 
PHARMACOGENETIC ANALYSIS
Table 1. List of genes.
Gene
group
Gene
subgroup
Gene symbol
(HGNC)
Gene name
Metabolism
Drug metabolizing 
enzymes (DMEs)
CYP3A4
Cytochrome P450 family 3 subfamily A member 4
CYP3A5
Cytochrome P450 family 3 subfamily A member 5
CYP3A7
Cytochrome P450 family 3 subfamily A member 7
CYP3A43
Cytochrome P450 family 3 subfamily A member 43
CYP2D6
Cytochrome P450 family 2 subfamily D member 6
DME electron 
donors
POR
Cytochrome P450 oxidoreductase
CYB5A
Cytochrome B5 type A
PGRMC1
Progesterone receptor membrane component 1
PGRMC2
Progesterone receptor membrane component 2
Regulators of DME 
expression*
Ligand-dependent nuclear receptors
NR1I2
Nuclear receptor subfamily 1 group I member 2
NR1I3
Nuclear receptor subfamily 1 group I member 3
VDR
Vitamin D (1,25- dihydroxyvitamin D3) receptor
NR1H4
Nuclear receptor subfamily 1 group H member 4
PPARA
Peroxisome proliferator activated receptor alpha
RARA
Retinoic acid receptor alpha
RXRA
Retinoid X receptor alpha
NR1H3
Nuclear receptor subfamily 1 group H member 3
NR1H2
Nuclear receptor subfamily 1 group H member 2
NR3C1
Nuclear receptor subfamily 3 group C member 1
ARNT
Aryl hydrocarbon receptor nuclear translocator
AHR
Aryl hydrocarbon receptor
NR5A2
Nuclear receptor subfamily 5 group A member 2
NR0B2
Nuclear receptor subfamily 0 group B member 2
Constitutive transcription factors
HNF4A
Hepatocyte nuclear factor 4 alpha
NR2F2
Nuclear receptor subfamily 2 group F member 2
CEBPB
CCAAT/enhancer binding protein beta
CEBPA
CCAAT/enhancer binding protein alpha
USF1
Upstream transcription factor 1
HNF1A
HNF1 homeobox A
FOXA3
Forkhead box A3
FOXA2
Forkhead box A2
PPARGC1A
PPARG coactivator 1 alpha
NCOA1
Nuclear receptor coactivator 1
Transcription factors signaling regulators
NFKB1
Nuclear factor kappa B subunit 1
NFKB2
Nuclear factor kappa B subunit 2
NFKBIA
NFKB inhibitor alpha
IL6R
Interleukin 6 receptor
IL6ST
Interleukin 6 signal transducer
Transport
Drug transporters
ABCB1
ATP binding cassette subfamily B member 1
Plasma binding 
proteins (PBP)
ALB
Albumin
ORM1
Orosomucoid 1
ORM2
Orosomucoid 2
* Also involved in the regulation of drug transporter and plasma binding protein genes expression.


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APPENDIX 7: 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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Protocol PM1183-C-003-14
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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Protocol PM1183-C-003-14
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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Protocol PM1183-C-003-14
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 


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

SAP_001.pdf: 
                                                          
 
                             
 
 
 
 
 
 
 
 
 
 
 
 
PM1183-C-003-14  
 
Phase III Randomized Clinical Trial of Lurbinectedin 
(PM01183)/Doxorubicin (DOX) versus Cyclophosphamide (CTX), 
Doxorubicin (DOX) and Vincristine (VCR) (CAV) or Topotecan as 
Treatment in Patients with Small-Cell Lung Cancer (SCLC) Who 
Failed One Prior Platinum-containing Line (ATLANTIS Trial) 
 
STATISTICAL ANALYSIS PLAN 
 
 
 
 
INVESTIGATIONAL MEDICINAL PRODUCTS: Lurbinectedin (Zepzelca®), and 
doxorubicin. 
Protocol No.: PM1183-C-003-14 
EudraCT No.: 2015-001641-89 
NCT Code: NCT02566993 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Version: v3.0  
Date: 04-SEP-2020    
 
-Confidential-  
 


                                                          
 
                             
TABLE OF CONTENTS  
 
 
1 
STUDY RATIONALE ............................................................................................. 6 
2 
OVERALL STUDY DESIGN.................................................................................. 6 
3 
PATIENTS EVALUABILITY CRITERIA ............................................................. 9 
3.1 
Intention-to-Treat (ITT) Population ................................................................... 9 
3.2 
Safety Population ............................................................................................... 9 
4 
OBJECTIVES AND ENDPOINTS .......................................................................... 9 
4.1 
Primary Objective .............................................................................................. 9 
4.2 
Secondary Objectives ........................................................................................ 9 
4.3 
Tertiary Objectives .......................................................................................... 10 
4.4 
Endpoints ......................................................................................................... 10 
5 
SAMPLE CONSIDERATIONS ............................................................................. 11 
5.1 
Randomization and Stratification .................................................................... 11 
5.2 
Sample Size ...................................................................................................... 12 
5.2.1 
Interim Safety Analysis ............................................................................ 12 
6 
STATISTICAL METHODOLOGY FOR EFFICACY .......................................... 12 
6.1 
Efficacy Definitions ......................................................................................... 12 
6.2 
Efficacy Analysis Methods .............................................................................. 14 
7 
STATISTICAL METHODOLOGY FOR SAFETY .............................................. 17 
7.1 
Toxicity and Adverse Events ........................................................................... 17 
7.2 
Clinical Laboratory Evaluation ........................................................................ 18 
7.3 
Physical Examination Findings ....................................................................... 18 
7.4 
Deaths and other Serious Adverse Events ....................................................... 18 
8 
OTHER ANALYSES ............................................................................................. 18 
8.1 
Baseline and Demographic Data ...................................................................... 18 
8.2 
Protocol Deviations .......................................................................................... 19 
8.3 
Treatment Administration ................................................................................ 19 
8.4 
Patient-reported Outcomes (PRO) ................................................................... 19 
8.5 
Subsequent Therapies ...................................................................................... 20 
8.6 
Imputation in Incomplete Dates ....................................................................... 20 
8.7 
Variable Unit Standardization ......................................................................... 20 
8.8 
Decimal Places, Missing Values and Allowed Assessment Windows ............ 21 
8.9 
Subgroup Analyses .......................................................................................... 21 
8.10 
Pharmacokinetic and Pharmacogenetic Analyses .................................... 21 
8.11 
Generalised Pairwise comparison assessment .......................................... 21 
9 
STATISTICAL SOFTWARE ................................................................................ 22 
10 Study Patients ......................................................................................................... 24 
10.1 
Patient Disposition .................................................................................... 24 
10.2 
Reasons for Treatment Discontinuation ................................................... 26 
10.3 
Protocol Deviations .................................................................................. 26 
11 Efficacy Evaluation ................................................................................................ 27 
11.1 
Demographic and other Baseline Characteristics ..................................... 27 
11.1.1 Patient Characteristics at Baseline ............................................................ 27 
11.1.2 Prior Anticancer Therapy ......................................................................... 33 
11.1.3 Prior Relevant Medical History ................................................................ 35 
11.1.4 Signs and Symptoms at Baseline .............................................................. 35 
11.1.5 Concomitant Medication at Baseline ........................................................ 36 
11.1.6 PRO scores at baseline ............................................................................. 36 


                                                          
 
                             
11.2 
Measurements of Treatment Compliance ................................................. 36 
11.3 
Efficacy Analysis ...................................................................................... 37 
12 Safety Analysis ....................................................................................................... 50 
12.1 
Extent of Exposure ................................................................................... 50 
12.1.1 Treatment Administration......................................................................... 50 
12.1.2 Cycle Delays ............................................................................................. 51 
12.1.3 Dose Reductions ....................................................................................... 53 
12.2 
Adverse Events (AEs) .............................................................................. 55 
12.2.1 Adverse Events ......................................................................................... 55 
12.2.2 Display of Adverse Events ....................................................................... 55 
12.2.3 Evolution of Signs and Symptoms during the Treatment ........................ 58 
12.2.4 Shift of AEs between combination and single agent administration ........ 59 
12.3 
Serious Adverse Events and Deaths. ........................................................ 59 
12.3.1 Serious Adverse Events ............................................................................ 59 
12.3.2 Deaths ....................................................................................................... 62 
12.4 
Clinical Laboratory Evaluation ................................................................ 62 
12.4.1 Hematological Abnormalities ................................................................... 62 
12.4.2 Biochemical Abnormalities ...................................................................... 64 
12.4.3 Other Metabolic Parameters ..................................................................... 65 
12.4.4 Laboratory Values over Time ................................................................... 66 
12.5 
Subgroup Analyses Related to Safety ...................................................... 71 
12.6 
Concomitant Medication during Treatment ............................................. 87 
12.7 
Subsequent Therapy ................................................................................. 87 
12.8 
PRO during Treatment ............................................................................. 88 
12.9 
Time to different deterioration in QoL assessments ................................. 91 
13 Clinical Database Listings ...................................................................................... 92 
14 ICH Listings ......................................................................................................... 100 
15 History of Changes ............................................................................................... 102 
15.1 
SAP amendment from v2.0 to v3.0 ........................................................ 102 
15.2 
SAP amendment from v1.0 to v2.0 ........................................................ 105 
 


                                                          
 
                             
ABBREVIATIONS AND GLOSSARY 
 
AE 
 
 Adverse Event 
ALT (SGPT)  Alanine Aminotransferase 
ANC  
 Absolute Neutrophil Count 
AP 
 
 Alkaline Phosphatase 
AST (SGOT)  Aspartate Aminotransferase 
ATC  
 Anatomical Therapeutic Chemical 
BMI 
 
 Body Mass Index 
BSA  
 Body Surface Area 
CAV  
 Cyclophosphamide, Doxorubicin and Vincristine 
CBR  
 Clinical Benefit Rate 
CHT  
 Chemotherapy 
CI 
 
 Confidence Interval 
CNS  
 Central Nervous System 
COPD  
 Chronic Obstructive Pulmonary Disease 
CPK  
 Creatine Phosphokinase 
CR 
 
 Complete Response 
CRF 
 
 Case Report Form 
CSF 
 
 Colony Stimulating Factor 
CT 
 
 Computed Tomography 
CTFI  
 Chemotherapy Free Interval 
CTX  
 Cyclophosphamide 
D 
 
 Day 
DCR  
 Disease Control Rate 
DF 
 
 Degrees of Freedom 
DNA  
 Deoxyribonucleic Acid 
DOX  
 Doxorubicin 
DR 
 
 Duration of Response 
ECG  
 Electrocardiogram 
eCRF  
 Electronic Case Report Form 
ECOG PS 
 Eastern Cooperative Oncology Group Performance Status 
EORTC 
 European Organization for Research and Treatment of Cancer 
EOT  
 End of Treatment 
EPO 
 
 Erythropoietin 
FU 
 
 Follow-up 
HR 
 
 Hazard Ratio 
IA 
 
 Investigator Assessment 
ICF 
 
 Informed Consent Form 
IDMC  
 Independent Data Monitoring Committee 
IRC 
 
 Independent Review Committee 
ITT 
 
 Intention-to-treat 
LDH  
 Lactate Dehydrogenase 
LR 
 
 Log Rank Test 
LVEF  
 Left Ventricular Ejection Fraction 
MedDRA 
 Medical Dictionary for Regulatory Activities 
mo 
 
 Months 
MRI 
 
 Magnetic Resonance Imaging 
NA 
 
 Not Available 


                                                          
 
                             
NCI-CTCAE National Cancer Institute Common Terminology Criteria for Adverse    
Events 
NE 
Not Evaluable 
NOS  
 Not Otherwise Specified 
ORR  
 Overall Response Rate 
OS 
 
 Overall Survival 
PCI 
 
 Prophylactic Cranial Irradiation 
PD 
 
 Progressive Disease 
PD-1  
 Programmed Cell Death Protein-1 
PD-L1  
 Programmed Death Ligand-1 
PDy 
 
 Pharmacodynamic(s) 
PFS 
 
 Progression Free Survival 
PK 
 
 Pharmacokinetic(s) 
PR 
 
 Partial Response 
PRO  
 Patient-Reported Outcomes 
PS 
 
 Performance Status 
PT 
 
 Preferred Term 
q3wk  
 Every Three Weeks 
QOL  
 Quality of Life 
R 
 
 Resistant 
RECIST 
 Response Evaluation Criteria In Solid Tumors 
S 
 
 Sensitive 
SAE 
 
 Serious Adverse Event 
SCLC  
 Small Cell Lung Cancer 
SD 
 
 Stable Disease 
SOC  
 System Organ Class 
STD 
 
 Standard Deviation 
TTF 
 
 Time to Treatment Failure 
UK 
 
 Unknown 
ULN  
 Upper Limit of Normal 
USA  
 United States of America 
VCR  
 Vincristine 
VS 
 
 Very Sensitive 
vs. 
 
 versus 
WBC  
 White Blood Cells 
WHO  
 World Health Organization 
wk 
 
 Week 


                                                          
 
                             
1 STUDY RATIONALE 
Patients with relapsed small cell lung cancer (SCLC) have the worst prognosis among 
lung cancer patients, with usually a life expectancy of less than six months and few 
therapeutic options. New treatment options are eagerly needed, particularly agents with 
novel mechanisms of action and no cross-resistance with prior platinum-regimens. 
No new treatment has been approved in Western countries over the last 15 years. In 
particular, almost none of the randomized clinical trials done over the last 30 years have 
shown a positive outcome improvement in this setting.  
PM01183 is a new chemical entity that induces double-strand deoxyribonucleic acid 
(DNA) breaks through binding to the DNA minor groove. According to a COMPARE 
analysis, it does not have an overlapping mechanism of action with other 98 standard 
cytotoxic agents.  
Data from the expanded cohort of second-line SCLC patients treated in an uncontrolled 
phase Ib study with the doxorubicin (DOX) combination showed a high activity in 
terms of objective responses and a relatively prolonged progression-free survival 
consistent with the synergistic effects found in vitro/in vivo. 
Therefore, a randomized trial has been proposed to compare the combination of 
lurbinectedin (PM01183) and doxorubicin vs. cyclophosphamide (CTX), DOX and 
vincristine (VCR) (CAV) or topotecan in the treatment of relapsed SCLC patients. 
A full rationale for the study may be found in the appropriate sections of the study 
Clinical Protocol. 
2 OVERALL STUDY DESIGN 
Multicenter, open-label, randomized, controlled phase III clinical trial to evaluate and 
compare the activity and safety of an experimental arm consisting of PM01183/DOX 
combination followed by PM01183 alone, if applicable vs. best Investigator’s choice 
between CAV or topotecan as a control arm, in SCLC patients with disease progression 
after one prior platinum-containing line but no more than one prior chemotherapy-
containing line. 
Central randomization will be implemented; patients will be assigned to each arm at a 
1:1 ratio. If the patient is randomized to the control arm (Arm B), the assigned treatment 
will be based on the reported Investigator’s preference between CAV or topotecan.  
A minimum recruitment of 165 patients (>45% of patients in the control arm) will be 
ensured in the anthracycline containing regimen, CAV, in order to have sufficient data 
to study the contribution of PM01183 to the PM01183/DOX combination compared to 
the CAV. 
Stratification will be performed according to the chemotherapy-free interval (CTFI) 
after first line [≥180 days (very sensitive, VS) vs. 90-179 days (sensitive; S) vs. <90 
days (resistant; R)], eastern cooperative oncology group performance status (ECOG PS) 
(0 vs. 1-2), baseline central nervous system (CNS) involvement vs. no involvement, 
prior immunotherapy against either programmed cell death protein-1 (PD-1) or 
programmed death ligand-1 (PD-L1) (Yes vs. No) and investigator’s preference for the 
control arm (Topotecan vs. CAV). 
Approximately 600 patients will be included in the trial. 
An Independent Review Committee (IRC), blinded to the treatment assigned to the 
patients, will determine the best patient response and assign the date of objective 
response or progression/censoring according to the Response Evaluation Criteria in 


                                                          
 
                             
Solid Tumors (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. 
An Independent Data Monitoring Committee (IDMC) will oversee the conduct of the 
study. Operational details for the IDMC will be detailed in the corresponding charter. 
The primary endpoint of the trial is the overall survival (OS). Secondary endpoints 
comprise difference in OS between PM01183/DOX and CAV, in patients with CAV as 
best Investigator’s choice; OS/progression free survival (PFS) per RECIST v.1.1 in 
patients with and without baseline central nervous system (CNS) involvement; PFS per 
RECIST v.1.1 by an IRC; best antitumor response as per RECIST v.1.1 and duration of 
response (DR) (both assessed by IRC); and safety profile. Tertiary endpoints comprise 
mid- and long-term survival assessed by measuring OS at 12/18/24 months, PFS per 
RECIST v.1.1 by investigator assessment (IA), best antitumor response as per RECIST 
v.1.1 and DR (both assessed by IA), patient reported outcomes (PRO), subgroup 
analyses, pharmacokinetics (PK), PK/pharmacodynamic (PDy) correlations, and 
pharmacogenetics.  
In order to check the overall safety in both arms, an interim safety analysis is planned 
after the recruitment of 150 patients (i.e., ~75 patients into each arm). Recruitment will 
not be put on hold while the interim safety analysis is being performed. Efficacy 
parameters will not be reviewed at this time, as follow-up will not have reached 
maturity at this point; therefore, no type I/II error corrections will be applied. Further 
safety and efficacy analyses could be performed upon request from the IDMC.  
There is no intention to claim superiority before the necessary number of events for the 
OS analysis has been reached. However, if formal interim analyses are requested by the 
IDMC, Lan and DeMets error spending function that corresponds to the O'Brien-
Fleming boundary will be used, calculated during the interim analyses to preserve an 
overall (one-sided) 0.005 false positive error rate; if early termination does not occur, 
the alpha level of the final analysis will be chosen to preserve an overall (one-sided) 
0.025 false positive error rate.   
Crossover is not allowed. 
Patients assigned to the experimental arm (PM01183/DOX combination), as well as 
those assigned to the CAV regimen in the control arm, will continue treatment until 10 
treatment cycles have been administered. After Cycle 10, non-progressing patients may 
continue PM01183 alone on Day 1 q3wk (experimental arm), or CTX +/- VCR (control 
arm), as applicable, until progressive disease (PD) or unacceptable toxicity. 
 
A summary of the study design is shown in the below figure. 


                                                          
 
                             
 
* Applicable assessments outside accepted windows must be repeated and treatment criteria must be fulfilled before 
treatment start. 
** Recruitment will not be put on hold while the interim analysis is ongoing. 
*** Assessment of LVEF and ECG must be conducted at the time of DOX withdrawal. 
† See Clinical Protocol for applicable starting doses and dose reduction scheme. 
†† Patients will be followed every three months (± two weeks) during the first 18 months after randomization, and 
then once every six months (± four weeks) until death of any cause or date of study termination, whichever occurs 
first. Once the whole recruitment is completed, the survival follow-up procedure will change: patients who 
discontinue treatment will be followed every three months according to a fixed calendar time (e.g., July, October, 
January, etc.) until death or study completion. 
††† Until 18 months after the last patient is randomized. 
CAV, CTX, DOX and VCR; CNS, central nervous system; CTFI, chemotherapy-free interval; CTX, 
cyclophosphamide; D, day; DOX, doxorubicin; ECG, electrocardiogram; ECOG PS, Eastern Cooperative Oncology 
Group performance status; ICF, informed consent form; LVEF, left ventricular ejection fraction; OS, overall survival; 
PD, progressive disease; PD-1, programmed cell death protein-1; PD-L1, programmed death ligand-1; R, resistant; 
q3wk, every three weeks; S, sensitive; VCR, vincristine; VS, very sensitive; wk, week. 
 
 
 


                                                          
 
                             
Regardless of arm, patients will receive study treatment while it is considered to be in 
their best interest. Specifically, treatment will continue until disease progression (unless 
exclusively asymptomatic CNS involvement, in an otherwise responding patient), 
unacceptable toxicity after allowed/applicable dose reductions, intercurrent illness of 
sufficient magnitude to preclude safe continuation of the study, patient refusal, non-
compliance with the study requirements, or a major protocol deviation that may affect 
the risk/benefit ratio for the participating patient. 
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 omissions (if applicable), dose reductions, 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 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, whenever is 
possible. 
Patients will be evaluated at scheduled visits during three predefined study periods: Pre-
treatment, Treatment and Follow-up. This clinical trial is expected to finish (clinical 
cutoff) at approximately 18 months after the last patient is randomized. 
3 PATIENTS EVALUABILITY CRITERIA 
Patients must fulfill all the inclusion/exclusion criteria to be eligible to participate in the 
study. Randomized patients will not be replaced. 
3.1 
 Intention-to-Treat (ITT) Population 
All patients randomized to either treatment arm independent of whether they received 
study drug or not, and analyzed in the group where they were allocated. 
3.2 
 Safety Population 
Safety population or “all treated patients” population will be defined as patients who 
have received at least part of one infusion of the investigational agents, and analyzed in 
the group where they were treated. 
4 OBJECTIVES AND ENDPOINTS 
4.1 
 Primary Objective 
 To determine whether there is a difference in overall survival (OS) between 
lurbinectedin (PM01183)/DOX and a control arm consisting of best Investigator’s 
choice between cyclophosphamide (CTX), doxorubicin (DOX) and vincristine 
(VCR) (CAV) or topotecan, as treatment in SCLC patients after failure of one prior 
platinum-containing line. 
4.2 
 Secondary Objectives 
 Difference in OS between PM01183/DOX and CAV, in patients with CAV as best 
Investigator’s choice. 
 OS/PFS in patients with and without baseline central nervous system (CNS) 
involvement. Subgroup analyses restricted to the sensitive and resistant populations 
(i.e., chemotherapy-free interval [CTFI] ≥90 days and CTFI <90 days) will also be 
performed.  


                                                          
 
                             
 Progression-free survival (PFS) by an Independent Review Committee (IRC). 
 Antitumor activity by IRC according to the Response Evaluation Criteria in Solid 
Tumors (RECIST) v.1.1. 
 Safety profile. 
4.3 
Tertiary Objectives 
 Mid- and long-term survival (OS at 12, 18 and 24 months, respectively). 
 Efficacy and safety profiles in the subgroups of the PM01183/DOX arm vs. CAV or 
topotecan. 
 PFS by Investigator’s Assessment (IA). 
 Antitumor activity by IA according to the RECIST v.1.1. 
 Patient-reported outcomes (PRO).  
 Pharmacokinetics (PK) of the combination in patients treated in the experimental 
arm (PM01183/DOX). 
 PK/pharmacodynamic (PDy) correlations in the experimental arm, if any. 
 Pharmacogenetics of known polymorphisms in patients treated in the experimental 
arm.   
4.4 
Endpoints 
Primary endpoint:  
 Overall survival (OS) will be calculated from the date of randomization to the date 
of death (death event) or last contact (in this case, survival will be censored on that 
date). 
Secondary endpoints: 
 Difference in OS between PM01183/DOX and CAV, in patients with CAV as 
best Investigator’s choice. 
 Overall survival (OS)/progression-free survival (PFS) per RECIST v.1.1 in 
patients with and without baseline CNS involvement. Subgroup analyses 
restricted to the sensitive and resistant populations will also be performed. 
 Progression-free survival (PFS) by IRC is defined as the time from the date of 
randomization to the date of documented progression per RECIST v.1.1 or death 
(regardless of the cause of death). If the patient receives further antitumor therapy or 
is lost to follow-up before PD, PFS will be censored at the date of last tumor 
assessment before the date of subsequent antitumor therapy. 
 Best antitumor response by IRC will be the best response obtained in any 
evaluation according to RECIST v.1.1. 
 Duration of response (DR) by IRC will be calculated from the date of first 
documentation of response per RECIST v.1.1 (complete or partial response, 
whichever comes first) to the date of documented PD or death. The censoring rules 
defined above for PFS will be used for DR. 
 Treatment safety profile: AEs, serious adverse events (SAEs) and laboratory 
abnormalities will be coded by the Medical Dictionary for Regulatory Activities 
(MedDRA), graded according to the NCI-CTCAE v.4 and analyzed. Dose 
reductions or delays required due to treatment-related AEs, and reasons for 
treatment discontinuations will also be assessed. 
 


                                                          
 
                             
Tertiary endpoints:  
 Landmark analyses: 
Mid- and long-term survival (OS at 12/18/24 months) will be the Kaplan-Meier 
estimates of the probability of being alive at these time points. 
 Subgroup analyses: Subgroup analyses of the PM01183/DOX arm vs. CAV  based 
on investigator’s preference will be performed to isolate the contribution of 
PM01183 in the PM01183/DOX combination arm. Patients for whom the preference 
of the investigator prior to randomization is CAV will be analyzed to test the 
combination of PM01183+DOX vs. CAV. Those for whom the investigator’s 
preference is topotecan will be also analyzed independently. Consequently, to avoid 
potential imbalance in the patient allocations, investigator’s preference for the 
control arm will be a stratification factor and the results will be shown between 
either option. 
 Progression-free survival (PFS) per RECIST v.1.1 by IA. 
 Best antitumor response by IA will be the best response obtained in any 
evaluation according to RECIST v.1.1.  
 Duration of response (DR) by IA will be calculated from the date of first 
documentation of response per RECIST v.1.1 (complete or partial response, 
whichever comes first) to the date of documented PD or death. The censoring rules 
defined above for PFS will be used for DR.  
 Patient-reported outcomes (PRO): To measure the quality of life of patients, the 
European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 
and EORTC QLQ-LC13 questionnaires will be analyzed at baseline and every six 
weeks (± one week) until EOT.  
 Plasma pharmacokinetics (PK) of PM01183 and DOX will be evaluated using a 
sparse sampling scheme in patients treated in the experimental arm. Details will be 
given in a population PK analysis plan, and results will be presented in a separate 
report. 
 PK/Pharmacodynamic (PDy) correlation: Population PK correlations of drug 
exposure with safety and efficacy will be explored in the experimental arm. Details 
will be given in specific population PK/PDy analysis plans, and results will be 
presented in separate reports. 
 Pharmacogenetics: This analysis will be performed in patients treated in the 
experimental arm who specifically consent to participate in this sub-study. The 
presence or absence of known polymorphisms from a single sample collected at any 
time during the study will be assessed to explain the individual variability in the 
main PK parameters. 
5 SAMPLE CONSIDERATIONS  
5.1 
 Randomization and Stratification 
Central dynamic randomization will be implemented; patients will be assigned to each 
group at a 1:1 ratio. If the patient is randomized to the control arm (Arm B), the 
assigned treatment will be based on the reported Investigator’s preference between 
CAV or topotecan.  
Stratification will be performed according to CTFI after first-line treatment [≥180 days 
(VS) vs. 90-179 days (S) vs. <90 days (R)], ECOG PS (0 vs. 1-2), baseline CNS 
involvement vs. no involvement, prior immunotherapy against either PD-1 or PD-L1 
(Yes vs. No) and investigator’s preference for the control arm (Topotecan vs. CAV). 


                                                          
 
                             
Day 0 is defined as the day of randomization. Treatment (Day 1 of Cycle 1) must start 
within 72 hours after randomization. Otherwise, all applicable assessments outside 
accepted windows must be repeated and eligibility criteria must be reassessed, if 
applicable. 
5.2 
 Sample Size 
This phase III clinical trial is designed to determine a statistically significant difference 
in the OS between PM01183/DOX vs. CAV or topotecan as second-line treatment in 
SCLC patients after failure of one platinum-containing chemotherapy (CHT) line. 
Patients will be randomized to receive DOX at 40 mg/m2 followed by PM01183 at 2.0 
mg/m2 (experimental arm), and either CAV or topotecan (control arm).  
The prospective assumptions are a 25% reduction in the relative risk of death (hazard 
ratio; HR=0.75) to be achieved with the experimental arm, at a one-sided 2.5% 
significance level with at least 90% power, following exponential distributions and 
fulfilling the proportional hazard assumption. Median OS with CAV or topotecan is 
expected to be around 7.5 months(1). It is forecasted that an observed HR of 
approximately 0.84 will have enough power to reject the null hypothesis. 
To obtain the required 508 events, approximately 600 patients with SCLC who failed 
one prior platinum-containing CHT line will be stratified and randomized at a 1:1 
ratio. With the aforementioned prospective assumptions, recruitment is foreseen to be 
completed in 24 months (~25 patients/month) and a total study duration of about three 
and a half years for the final OS analysis is planned. 
With the prospective assumptions above mentioned, about 265 OS events are expected 
in the control arm and 243 in the treatment arm.  
5.2.1  Interim Safety Analysis  
In order to evaluate the overall safety in both arms, an interim safety analysis is 
planned after the recruitment of 150 patients (i.e., ~75 patients into each arm). 
Recruitment will not be put on hold while the interim safety analysis is being 
performed. Efficacy parameters will not be reviewed at this time, as follow-up will not 
have reached maturity at this point; therefore, no type I/II error corrections will be 
applied. 
As previously explained, there is no intention to claim superiority before the necessary 
number of events for the OS analysis has been reached. However, if formal interim 
analyses are conducted by the IDMC, a Lan and DeMets error spending function that 
corresponds to the O'Brien-Fleming boundary will be used, calculated during the 
interim analyses to preserve an overall (one-sided) 0.005 false positive error rate; if 
early termination does not occur, the alpha level of the final analysis will be chosen to 
preserve an overall (one-sided) 0.025 false positive error rate.   
6 STATISTICAL METHODOLOGY FOR EFFICACY 
6.1 
 Efficacy Definitions 
Primary endpoint.  
Overall survival (OS) is defined as the time from the date of randomization to the date 
of death (death event) or last contact (in this case, survival will be censored on that 
date). Final OS analysis is planned 18 months after randomization of last patient 
(planned end of study date).  


                                                          
 
                             
After radiological PD is documented or a new antitumor therapy is started, patients will 
be followed for survival every three months (± two weeks) during the first 18 months 
after randomization, and then once every six months (± four weeks) until death of any 
cause or date of study termination, whichever occurs first. For survival follow-up (FU) 
purposes, after radiological PD is documented or new therapy is started, a documented 
telephone call from the investigational sites will be adequate. Once the whole 
recruitment is completed, the survival follow-up procedure will change and patients 
who discontinue treatment will be followed every three months according to a fixed 
calendar time (e.g., July, October, January, etc.) until death or study completion. 
 
Secondary/tertiary endpoints. 
Progression-free survival (PFS) by IRC is defined as the time from the date of 
randomization to the date of documented progression per RECIST v.1.1 or death 
(regardless of the cause of death). If the patient receives further antitumor therapy or is 
lost to follow-up before PD, PFS will be censored at the date of last tumor assessment 
before the date of subsequent antitumor therapy. 
Antitumor activity will be assessed using the RECIST v. 1.1 and followed until PD by 
the appropriate method [computed tomography (CT) scan or magnetic resonance 
imaging (MRI) of the pelvis, abdomen and chest]. 
Irrespectively of treatment arm, radiological and clinical tumor assessment will be 
performed symmetrically at baseline and every six weeks (± one week) after 
randomization until evidence of PD.  
Adequate CNS imaging (contrast enhanced-CT or MRI, if applicable) will be performed 
at baseline to document any disease involvement. This assessment will not be repeated 
routinely regardless of treatment arm, unless it is clinically indicated. 
Irrespectively of treatment arm, patients with documented clinical benefit during 
treatment (either response or tumor shrinkage in target lesions and without clinical 
deterioration) may continue treatment while CNS irradiation is given, if appropriate. 
Patients who have withdrawn from the treatment without PD documentation will 
continue with the tumor assessments every six weeks (± one week) until PD, start of a 
new antitumor therapy, death or date of study termination (clinical cut-off), whichever 
occurs first.  
The date of clinical and/or radiological PD and the date of death will be registered and 
documented as appropriate. 
Copies of CT scans, MRIs and any other documented means to evaluate tumor response 
or progression should be available for external radiological review by an IRC. The IRC 
will determine the patient’s best response and assign the date of objective response or 
progression/censoring according to the RECIST v.1.1. 
Crossover is not allowed. 
Progression-free survival (PFS) by IA will be calculated using the same methodology as 
explained above for IRC assessment but following Investigator assessments.  
Landmark analyses of OS at 12/18/24 months will be the Kaplan-Meier estimates of 
the probability of being alive at these time points. 
Difference in OS between PM01183/DOX and CAV, in patients with CAV as best 
Investigator’s choice will be measured using OS data derived for the primary endpoint 
calculation and selecting investigator’s preference ticked in the electronic case report 
form (eCRF). 


                                                          
 
                             
OS/PFS in patients with and without baseline CNS involvement will be measured using 
derived data and selecting the CNS involvement status reported in the eCRF. 
Afterwards, subgroup analyses of CNS involvement restricted to the sensitive and 
resistant populations will also be performed. 
Subgroup analyses of the PM01183/DOX arm vs. CAV or topotecan based on 
investigator’s preference. 
Best antitumor response by IRC/IA will be the best response obtained in any evaluation 
according to RECIST v.1.1.  
Duration of response (DR) will be calculated from the date of first documentation of 
response per RECIST v.1.1 (complete or partial response, whichever comes first) to the 
date of documented PD or death. The censoring rules defined above for PFS will be 
used for duration of response.  
Assessments must be done consistently in both treatment arms to ensure a symmetrical 
assessment of tumor response and progression. Every effort should be made to ensure 
that these assessments are done on the required date. Time to nth (i.e. 1, 2, 3…) disease 
assessment is defined as weeks between randomization and the recorded date of the nth 
assessment after randomization. 
 
Other supportive endpoints: 
 
Disease control rate (DCR) by IRC/IA, defined as percentage of patients with best 
response CR, PR or SD. 
 
Clinical benefit rate (CBR) by IRC/IA, defined as percentage of patients with best 
response CR, PR or SD ≥4 months. 
 
Time to treatment failure (TTF) by IA, defined as time from randomization to 
progression, EOT due to AE, EOT due to symptomatic deterioration or death will be 
calculated.  
 
Time to onset of first brain metastases by IA, defined as time from randomization to 
clinical diagnosis of brain mets will be calculated. 
 
6.2 
 Efficacy Analysis Methods 
Time-to-event variables (OS, PFS DR, TTF and time to onset of first brain metastases) 
and their set time estimates (e.g., OS 12/18/24) will be analyzed according to the 
Kaplan-Meier method.  
The stratified log-rank (LR) test, selecting CNS and CTFI values of the stratification 
factors, on the ITT population will be primarily used to compare the time-to-event 
variables. A sensitivity analysis will be performed using all randomization strata 
variables.  
Unstratified log-rank tests will also be calculated as supportive analyses.  
 
If the result of the primary endpoint analysis is statistically significant, the hierarchical 
step-up Hochberg procedure(2) will be used to test the most relevant secondary efficacy 
endpoints (i.e., difference in OS in patients with CAV as best Investigator’s choice, and 
OS in the subgroup of patients without baseline CNS involvement) at the overall two-


                                                          
 
                             
sided significance level of 0.05. The p-values for this procedure will be calculated using 
the corresponding unstratified log-rank test in each subgroup.  
 
The symmetry of tumor evaluations between treatment arms will be examined. The 
Wilcoxon test to compare time to disease assessments between treatment arms will be 
used to assess symmetry of evaluations. Moreover, Kaplan-Meier curves of the time 
from randomization and the first and second disease assessments will be plotted.  
Cox regression will be used to calculate the risk reduction (OS, PFS and DR) and to 
evaluate the influence of the stratification variables and other potential prognostic 
factors on the time-to-event efficacy endpoints.  
Mean Kaplan-Meier estimates will be used to compare areas under the curves for OS 
and PFS.  
Counts and percentages, with their corresponding exact 95% confidence intervals, will 
be calculated for the binomial endpoints (i.e., response rate). The Fisher’s exact test 
(univariate analyses) and logistic regressions (multivariate analyses) will be used to 
compare the response rates.  
Waterfall plots will be used to describe the best variation of the sum of target lesions 
diameters during the treatment. 
Multivariate models (main effects or including interaction terms, if appropriate) will 
include all stratification factors and/or prognostic factors/covariates widely reported and 
recognized by the scientific community: treatment (PM01183/DOX vs. control), CTFI 
after first-line treatment [as strata categories ≥180 days (VS) vs. 90-179 days (S) vs. <90 
days (R) or as usually reported ≥90 days vs. <90 days], ECOG PS (0 vs. 1-2 or coded as 
0 vs. 1 vs. 2), baseline CNS involvement (yes vs. no), prior immunotherapy against 
either PD-1 or PD-L1 (yes vs. no) [or independently by each group if enough 
representative cases, prior PD-1 (yes vs. no) and prior PD-L1 (yes vs. no) ], 
investigator’s preference for the control arm (Topotecan vs. CAV), geographical area 
(USA vs. Europe vs. rest of the world), sex (male vs. female), age, age at diagnosis, race 
(caucasian vs. other), smoking status (current vs. former vs. never), disease stage at 
study entry (limited vs. extensive), PD-L1 expression (if enough cases; <1% vs. ≥1% or 
<50% vs. ≥50%), prior lines (1 vs. >1 lines or coded as ordinal) , time from diagnosis to 
randomization, time elapsed from last dose of prior chemotherapy regimen to 
randomization, response to prior chemotherapy (yes vs. no), time to progression to prior 
chemotherapy, prior prophylactic cranial irradiation (PCI) (yes vs. no), prior 
consolidation with thoracic radiotherapy (yes vs. no), visceral metastases (yes vs. no), 
number of metastatic sites at baseline, body mass index (BMI), height, weight, body 
surface area (BSA), presence of any bulky (< 50 mm vs. ≥ 50 mm) lesion at baseline, 
measurable disease by RECIST v1.1 (yes vs. no), hypertension (yes vs. no), cardiac 
disease (yes vs. no) , diabetes (yes vs. no) , chronic obstructive pulmonary disease 
(COPD) (yes vs. no), secondary tumors (yes vs. no), steroids at baseline (yes vs. no), 
opioids at baseline (yes vs. no), paraneoplastic syndrome at baseline (yes vs. no),  
baseline lactate dehydrogenase (LDH) value (≤ upper limit of normal (ULN) vs. 
>ULN), hemoglobin value at baseline (g/dl), albumin value at baseline (g/dl), C-
reactive protein value at baseline (mg/dl), C-reactive protein/albumin baseline ratio and 
baseline global quality of life (QoL). In addition, continuous variables categorized as 
discrete variables will also be investigated in the continuum range and if they fit better 
then the continuous variable will be selected in the model. 
All variables with a good percentage of valid cases (approximately ≥ 90%) will be 
included in the multivariate analysis, although if any prognostic value lacks more than 


                                                          
 
                             
10% of values, sensitivity analyses considering multiple imputation methods will be 
performed. Within the multivariate stepwise Logistic/Cox regression analysis, the 
chosen significance level for entering an explanatory variable into the model will be 
0.05 (for all variables not in the model, the one with the smallest p-value will be entered 
if the p-value is less than or equal to the specified significance level). The significance 
level for removing an explanatory variable from the model will be 0.05 (for all variables 
in the model, the one with the largest p-value will be removed if the p-value exceeds the 
specified significance level). The parameter estimates, hazard ratios/odds ratios and p-
values of the variables retained in the model will be presented. 
Forest plots will be plotted for PFS and OS summarizing main results, stratification and 
factors/covariates used in multivariate analyses(3). Continuous variables not categorized 
by prior definition will be coded into two categories taking as reference the median 
value, below or equal the median value and above the median value. 
Median follow-up (FU) time for OS and PFS will be calculated in a descriptive way, 
taking  only  into account the censored values and using the Kaplan-Meier method for 
reversing the censoring values as described by Parmar(4). 
Concordance between IRC and IA PFS assessments will be evaluated by means of 
Kaplan-Meier curves. Forest plots for response will also be performed adapting them to 
show relevant information (e.g. percentages will be shown instead of medians).  
Sensitivity analyses for different PFS censoring will be performed. The following 
approaches will be calculated: 1) Date of progression based on scheduled time instead 
of recorded date (e.g. if progression occurs in the ninth week and assessment would 
have to be done in the sixth week then the expected date is used instead of the actual 
date); 2) First date of progression combining IRC and IA assessments (e.g. the lowest 
date between IRC and IA is used); 3) Date of progression moved to the prior tumor 
assessment date (e.g. if progression has not been documented in the second assessment 
and is documented in the third assessment then progression date is moved to the second 
assessment); 4) First date of progression or death not censoring data if further antitumor 
therapy is received before the documented progression.  
Proportional hazard assumption for OS and PFS will be checked by means of a Cox 
regression including treatment and its interaction with survival time(5). In case of strong 
rejection of proportionality, then restricted mean survival estimates will also 
be calculated in addition to HR(6,7).   
 


                                                          
 
                             
Main summary of efficacy analyses 
Order 
Endpoint 
Population 
Statistics 
Primary 
endpoint 
OS 
ITT population 
-Stratified log rank test 
(primary analysis) 
-Unstratified log rank test 
-Kaplan Meier estimates 
-Univariate Cox regression 
-Multivariate Cox regression 
Secondary 
endpoints 
PFS by IRC 
ITT population 
-Stratified log rank test 
-Unstratified log rank test 
-Kaplan Meier estimates 
-Univariate Cox regression 
-Multivariate Cox regression 
DOR by IRC 
ITT population: Responder 
patients 
-Kaplan Meier estimates 
Response rate by 
IRC 
ITT population 
-Fisher exact test 
-Logistic regression 
Subgroup 
analyses* 
ITT population (based on 
investigator’s preference) 
-Stratified log rank test 
-Unstratified log rank test 
-Kaplan Meier estimates 
-Univariate Cox regression 
-Multivariate Cox regression 
OS/PFS by no 
CNS involvement*  
ITT population (patients with 
no CNS) 
-Stratified log rank test 
-Unstratified log rank test 
-Kaplan Meier estimates 
-Univariate Cox regression 
-Multivariate Cox regression 
* If the result of the primary endpoint analysis is statistically significant, the Hochberg procedure will be 
used at the overall two-sided significance level of 0.05 to test  the difference between PM01183/DOX and 
CAV in OS in patients with CAV as best Investigator’s choice, and the difference in OS in the subgroup 
of patients without baseline CNS involvement. The unstratified log-rank tests will be used to calculate p-
values. IA, Investigator Assessment; IRC, Independent Review Committee; ITT, intention-to-treat; PFS, 
progression-free survival; OS, overall survival. 
7 STATISTICAL METHODOLOGY FOR SAFETY 
7.1 
 Toxicity and Adverse Events  
Patients will be evaluable for safety if they have received any partial or complete 
treatment infusion. All AEs will be graded according to the NCI-CTCAE v.4. Treatment 
delays, dose omissions (if applicable), dose reductions 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 after the last treatment infusion (end of treatment, EOT), or until the patient starts a 
new antitumor therapy or until the date of death, whichever occurs first. 
Any AEs will be coded using to the Medical Dictionary for Regulatory Activities 
(MedDRA). Any treatment-related AEs will be followed until recovery to at least grade 
1 or stabilization of symptoms, whenever is possible. 
Summary of overall AEs will be done by system organ class (SOC) and preferred term 
(PT), by severity (worst toxicity grade) and by relationship. Tables will be sorted by 
body system/preferred term. 
A frequency table will be made for the AEs leading to cycle delay, dose reduction, dose 
omissions (if applicable), or withdrawal of study medication. AEs leading to permanent 
treatment stop and AEs with outcome of death will also be presented by relationship to 
drug.  


                                                          
 
                             
Exploratory Fisher’s exact tests will be performed to compare the incidence of grade 4 
or grade 3/4 AEs between treatment arms. 
7.2 
 Clinical Laboratory Evaluation 
Laboratory results will be classified according to the NCI-CTCAE v.4. All laboratory 
visits reported as “End of treatment” visit will be mapped to the last cycle visit for each 
patient. 
The worst grade per patient will be tabulated during overall treatment and per cycle for 
hematology values [white blood cells (WBC), absolute neutrophil count (ANC), 
lymphocyte count, platelet count and hemoglobin] and for the following biochemistry 
tests: alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin, 
alkaline phosphatase (AP), creatine phosphokinase (CPK), creatinine, glucose, sodium, 
potassium and albumin. 
Exploratory Fisher’s exact tests will be performed to compare the incidence of grade 4 
or grade 3/4 laboratory evaluations between treatment arms. 
7.3 
 Physical Examination Findings 
Tables summarizing the performance status (PS), height, body weight and BSA 
(according to the Dubois and Dubois formula) at baseline will be prepared.  
In addition, changes in the ECOG PS and body weight of each patient during the 
treatment compared to baseline will be presented. 
7.4 
 Deaths and other Serious Adverse Events 
Deaths, and other serious adverse events (SAEs) will be tabulated following the same 
pattern than AEs. 
8 OTHER ANALYSES 
Non-continuous variables will be described in frequency tables using counts and 
percentages. Continuous variables will be described by median, mean, standard 
deviation (STD), minimum and maximum. 
8.1 
 Baseline and Demographic Data 
Baseline data such as demographics, cancer history, number of organs involved and 
sites of disease, prior therapy, laboratory values at baseline, prior relevant history, signs 
and symptoms, 
electrocardiogram, 
and concomitant medication [Anatomical 
Therapeutic Chemical – World Health Organization (ATC-WHO) coded] will be 
described following standard tables (detailed in Appendix I). 
CTFI is defined as the time from the last dose of the platinum drugs in the last platinum 
regimen to the occurrence of progressive disease. 
Prior immunotherapy to PD-1 or PD-L1 data will be collected from the screening page. 
For 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 value prior to or on the first day of treatment. 


                                                          
 
                             
8.2 
 Protocol Deviations 
Analysis of protocol deviations following ‘Protocol Deviation and Non-Compliance 
Management Plan’ will be done as described in Appendix I.  
8.3 
 Treatment Administration 
Total cumulative dose, time on treatment, dose intensity and relative dose intensity, 
administration delay, and dose reductions/omissions will be described following 
standard tables (detailed in Appendix I) and the reported cycle information on the case 
report form (CRF) pages will be used for the analyses.  
Time on treatment, expressed in weeks, is defined as last infusion date minus first 
infusion date plus 30 days, except if the patient dies or starts a new antitumor therapy 
within 30 days from the last infusion date, in which case the time on treatment will be 
the date of death or the date of the start of a new antitumor therapy minus the date of 
the first infusion. 
Total cumulative dose by drug, expressed in mg, is the sum of all the product doses 
from the first cycle until the last cycle, including the dose received in the last cycle. 
Intended dose intensity is the planned dose per cycle divided by the planned number of 
weeks by cycle (e.g. 2.0 mg/m2 for PM01183 when it is combined with DOX). 
Absolute dose intensity is the actual cumulative dose divided by the number of weeks 
of treatment. As a convention, for this calculation, the duration of the last cycle will be 
the predefined cycle length (e.g, 21 days).  Relative dose intensity (%) is the ratio of 
absolute dose intensity divided by the intended dose intensity. 
The items « Infusion delayed: yes/no» and « Dose reduced: yes/no» present on the 
treatment exposure CRF pages will be used to calculate delays and dose reductions, 
respectively. For cycles considered as delayed by the Investigator, the length of the 
delay will be calculated as: 
Duration of cycle delay:  Date of the current drug administration – Date of the previous 
drug administration – the predefined cycle length (i.e., 21 days).  
According to the protocol, non-progressing patients in the PM01183 + DOX may 
continue treatment with PM01183 alone on Day 1 q3wk after reaching 10 cycles of 
combination. Consequently, for PM01183 dose calculations two distinct summaries, if 
applicable, have to be performed. One when it is administered combined with DOX and 
another one when it is administered as single agent, once DOX has to be withdrawn. If 
necessary, same approach would be implemented in the control arm patients if DOX is 
withdrawn and the other intended doses are modified. 
8.4 
 Patient-reported Outcomes (PRO) 
To measure the quality of life of patients, EORTC QLQ-C30 and EORTC QLQ-LC13 
questionnaires will be analyzed every six weeks (± one week) from randomization until 
EOT. All visits reported as “End of treatment” visit will be mapped to the last cycle visit 
for each patient. 
PRO will be analyzed by means of longitudinal modelling, graphs and T-test 
comparisons to determine if efficacy and side effects are accompanied by measurable 
changes. The analysis will be performed on summary scores of EORTC QLQ-C30 and 
EORTC QLQ-LC13 questionnaires, as well as on subscales and individual symptoms. 


                                                          
 
                             
Scale scores were calculated by averaging items within scales and transforming average 
scores linearly. All of the scales range in score from 0 to 100. A high score for a 
functional scale represents a high/healthy level of functioning whereas a high score for a 
symptom scale or item represents a high level of symptomatology or problems. 
8.5 
 Subsequent Therapies 
A table summarizing the subsequent therapies received after treatment discontinuation 
will be shown and subgroup analyses will be implemented.  
8.6 
 Imputation in Incomplete Dates 
Dates of certain historical or current clinical activities are key component for statistical 
analysis. An incomplete date results from a missing day, month or year; in that case, the 
missing figure can be imputed allowing for the calculation of variables, such duration 
and time to certain event. However, when all of them, day, month and year, are missing 
no imputation will be done.  
Before randomization/treatment start date 
All variables needed to summarize for example prior information (e.g. first diagnosis 
date) where partial information is available 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 is also unknown then the imputed date will 1/July. This assumption will be 
valid if the imputed date is earlier than the randomization date; otherwise, the imputed 
date will be the first day of the month of the randomization date (i.e. 01/Randomization 
month date/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 earlier than the 
treatment start date; otherwise, the imputed date will be the treatment start date). 
After end of treatment 
A conservative approach for the variables collecting information after end of treatment 
where partial information is available (e.g., main time-to-event variables; PFS and OS) 
will be imputed by means of SAS programming. The following rules will be 
implemented: if the day of a date is unknown then the imputed day will be 1; if the 
month is also unknown, then the imputed date will be 1/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 last drug administration date plus 1 day.  
Once the OS follow-up assessments will be implemented following the calendar time if 
a patient deceased but his/her complete death date is missing then if month/year is 
known then death date will be imputed as 01/Month/Year, otherwise the death date will 
be imputed as last time to the patient was known to be alive plus 1 day. 
8.7 
 Variable Unit Standardization 
Variables reported with different units will be homogenized to standardized variables 
following the International System of Units (e.g. laboratory tests, biometrical 
assessments...) unless otherwise specified in the following sections. 


                                                          
 
                             
8.8 
 Decimal Places, Missing Values and Allowed Assessment Windows 
By default, all results will be rounded to one decimal place, except when variables are 
integer, which will be reported without decimals (e.g., age in years, number of sites, 
etc.). For representing p-values four decimals will be selected as default but they could 
be rounded to fewer decimals if necessary. Hazard ratios will be presented with three 
decimal places. 
Missing values will not be included in the calculation of outputs. Assessment windows 
as specified in the clinical protocol will be respected.  
8.9 
Subgroup Analyses 
Some preplanned efficacy analyses are the following: subgroup analyses based on 
comparison of PM01183/DOX with CAV or topotecan, subgroup analyses for 
stratification factors (mainly CNS and CTFI), subgroup analyses for patients with 
primary site different to lung, subgroup analyses if enough cases for baseline PD-L1 
expression (<1% vs. ≥1%) or PD-L1 expression (<50% vs. ≥50%), and the analysis of 
the subset of patients who received subsequent therapies. 
Special attention will be put in the subgroup analysis comparing treatment arms in the 
CTFI after first line subsets. Subsets will be defined as [≥90 days (sensitive) vs. <90 
days (resistant; R)] and adjusted p-values, one on patients with sensitive disease and one 
on patients with resistant disease, will be calculated by means of Bootstrap replication.  
Other subgroup analyses that are implemented a posteriori based on clinically findings 
will have an exploratory nature.  
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). 
8.10  Pharmacokinetic and Pharmacogenetic Analyses 
These analyses will be detailed and reported in separate documents. 
8.11 Generalised Pairwise comparison assessment 
A risk-benefit measure will be calculated using the generalised pairwise comparison(8). 
A favourable benefit outcome will be determined by differences in OS exceeding 2, 3 or 
4 months. An unfavourable risk outcome will be determined by the occurrence of any 
G3-4 adverse reaction or a clinically important adverse event:  
 
A clinically important adverse event will be defined as: 
 
- 
Any AE causing death or treatment discontinuation 
- 
Febrile neutropenia/neutropenic sepsis 
- 
Grade 4 neutropenia lasting > 3 days 
- 
Grade 4 thrombopenia or grade 3 thrombopenia concomitant with bleeding 
events. 
- 
Grade 4 AST/ALT or grade 3 lasting >14 days. 
- 
Treatment-related grade ≥ 2 ALT or AST increase concomitantly with ≥ 2 times  
 
 the  upper  limit  of  normal  (ULN)  total  bilirubin  increase  and  normal 
 
 alkaline phosphatase (AP).   
- 
Grade ≥ 3 creatine phosphokinase (CPK) increase. 
- 
Grade 3 fatigue lasting > 3 days.  


                                                          
 
                             
- 
Any other grade 3/4 non-hematological AE that is suspected to be related to 
study   drug(s), except nausea/vomiting (unless the patient is receiving an 
optimal anti-  emetic  regimen),  hypersensitivity  reactions,  extravasations  
and  non-clinically  relevant  isolated  biochemical   abnormalities [e.g.,  isolated  
increase  in  gamma-glutamyltransferase  (GGT)]. 
 
9 STATISTICAL SOFTWARE 
Medidata Rave® EDC will be used for data entry and clinical data management. 
Medidata Balance® will be used for dynamic randomization design and management. 
EAST® v.6.4 has been used to calculate sample size(9).  
SAS® v.9.4 or superior will be used for all statistical analysis outputs(10). 


                                                          
 
                             
REFERENCES 
 
1. von Pawel J, Jotte R, Spigel DR, O'Brien ME, Socinski MA, Mezger J, Steins 
M, Bosquee L, Bubis J, Nackaerts K, Trigo JM, Clingan P, Schutte W, Lorigan 
P, Reck M, Domine M, Shepherd FA, Li S, Renschler MF. Randomized phase 
III trial of amrubicin versus topotecan as second-line treatment for patients with 
small-cell lung cancer. J Clin Oncol 2014;32(35):4012-9. 
 
2. Multiple Endpoints in Clinical Trials Guidance for Industry, Draft (January 
2017) 
 
3. Qinghua (Kathy) Chen. Incorporating Graphics into Summary Report Tables 
using ODS and GTL. PharmaSUG2011 – Paper SP02. 
 
4. Parmar M. Machin D. Survival analysis. A practical approach. Wiley, 
Chichester, 1995. 
 
5. Introduction 
to 
SAS. 
 
UCLA: 
Statistical 
Consulting 
Group. 
from 
http://www.ats.ucla.edu/stat/sas/notes2/ 
(accessed 
November 
13, 
2013). 
http://www.ats.ucla.edu/stat/examples/asa/test_proportionality.htm(accessed 
November 13, 2013). 
 
6. Patrick Royston and Mahesh K. B. Parmar. The use of restricted mean survival 
time to estimate the treatment effect in randomized clinical trials when the 
proportional hazards assumption is in doubt. Statist. Med. 2011, 30 2409–2421. 
 
7. Klein et al. SAS and R Functions to Compute Pseudo-values for Censored Data 
Regression. Comput Methods Programs Biomed. 2008 March ; 89(3): 289–300. 
 
8.  Buyse M. Generalized pairwise comparisons for prioritized outcomes in the 
two-sample problem. Statist Med 29: 3245-57, 2010. 
 
9.  EAST manual. 
 
10. SAS OnlineDoc. 
 
 


                                                          
 
                             
APPENDIX I 
 
Applicable outputs will also be created at the time of the interim safety analysis. They 
will be specified as an appendix to the IDMC charter. 
10 Study Patients 
Study patient analysis will be carried out on the ITT population except for screening 
failures where no randomization is performed.  
10.1  Patient Disposition  
Main characteristics concerning inclusion in the study, end of treatment, withdrawal of 
the study and protocol deviations will be displayed in this section. 
Table 10.1.1 Disposition of screened patients 
Screening failure 
Total 
N 
% 
Yes 
 
 
No (Patient randomized) 
 
 
 
Listing 10.1.2 Screening failures 
Patient  
Inclusion/Exclusion criteria not met 
 
 
Table 10.1.3 Disposition of patients 
 
PM01183+DOX 
Control 
Total 
N 
% 
N 
% 
N 
% 
Randomized patients  
(ITT population) 
 
 
 
 
 
 
Treated patients 
(Safety population) 
 
 
 
 
 
 
 
Table 10.1.4 Disposition of patients in the control arm 
 
CAV 
Topotecan 
Total 
N 
% 
N 
% 
N 
% 
Randomized patients  
(ITT population) 
 
 
 
 
 
 
Treated patients 
(Safety population) 
 
 
 
 
 
 
 
 
Listing 10.1.5 Randomized patients who were not treated   
Treatment arm* 
Patient  
Reason 
 
 
 
*PM01183+DOX/Topotecan/CAV 


                                                          
 
                             
Table 10.1.6 Patients accrual by institution 
 
 
 
PM01183+DOX 
Control 
Total 
No. 
randomized 
Country 1 
Institution 1 
 
 
 
… 
 
 
 
Total 
 
 
 
… 
Institution 1 
 
 
 
… 
 
 
 
Total 
 
 
 
Total 
Institution 1 
 
 
 
… 
 
 
 
Total 
 
 
 
No.  
treated 
Country 1 
Institution 1 
 
 
 
… 
 
 
 
Total 
 
 
 
… 
Institution 1 
 
 
 
… 
 
 
 
Total 
 
 
 
Total 
Institution 1 
 
 
 
… 
 
 
 
Total 
 
 
 
Table 10.1.7 Study dates 
 
Date 
Date of first consent 
 
Date of first randomization 
 
Date of first dose of first patient 
 
Date of last consent 
 
Date of last randomization 
 
Date of first dose of last patient 
 
Date of last dose 
 
Last follow-up date 
 
 
Listing 10.1.8 Patients assigned to incorrect strata at the time of randomization   
Treatment arm* 
Patient  
Actual stratum  
(Screening form) 
Strata reported at randomization  
(Randomization form) 
 
 
 
 
*PM01183+DOX/Topotecan/CAV 
Table 10.1.9 Investigator’s preference for the control arm 
 
PM01183+DOX 
Topotecan 
CAV 
N 
% 
N 
% 
N 
% 
Topotecan 
 
 
 
 
 
 
CAV 
 
 
 
 
 
 
 


                                                          
 
                             
10.2 Reasons for Treatment Discontinuation 
 
Table 10.2.1 Treatment discontinuation 
Reason 
PM01183+DOX 
Control 
N 
% 
N 
% 
Progressive disease (PD) 
 
 
 
 
Patient refusal to treatment 
 
 
 
 
Death 
 
 
 
 
Investigator’s decision 
 
 
 
 
Study drug-related AE  
 
 
 
 
Non study drug-related AE  
 
 
 
 
Symptomatic deterioration 
 
 
 
 
Other 
 
 
 
 
Total* 
 
 
 
 
*Denominator is number of treated patients 
 
When reason for discontinuation is study drug-related AE or study drug-related death, 
identify patients and describe them in depth here. 
Listing 10.2.2 Reasons for treatment discontinuation other than progressive disease 
Treatment 
arm* 
Patient ID. 
Reason 
Last cycle 
Dose in the 
last cycle 
Date 
Specify (if 
applicable) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
*PM01183+DOX (Combination or PM01183 Alone)/Topotecan/CAV 
 
Listing 10.2.3 AEs with reported action taken equal to ‘treatment withdrawn’  
Treatment 
arm* 
Patient 
ID. 
Preferred  
term code 
Adverse 
event 
reported 
(verbatim) 
Grade  Relationship  SAE Onset 
date 
Resolved 
date 
Outcome 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
*PM01183+DOX (Combination or PM01183 Alone)/Topotecan/CAV 
 
Table 10.2.4 Reasons for off study 
Reason 
PM01183+DOX 
Control 
N 
% 
N 
% 
Study termination (clinical cut-off) 
 
 
 
 
Withdrawal of consent 
 
 
 
 
Death 
 
 
 
 
Lost to follow-up 
 
 
 
 
Other 
 
 
 
 
Total 
 
 
 
 
10.3  Protocol Deviations  
Classification will follow definitions made in Protocol Deviation and Non-Compliance 
Management Plan.  
Listing 10.3.1 Protocol deviations 
Treatment 
arm* 
Patient 
Classification 
Deviation Category 
Deviation 
 
 
 
 
 
*PM01183+DOX (Combination or PM01183 Alone)/Topotecan/CAV 
 


                                                          
 
                             
11 Efficacy Evaluation 
11.1  Demographic and other Baseline Characteristics 
Baseline/screening characteristics will be carried out on the ITT population.  
11.1.1  Patient Characteristics at Baseline 
Table 11.1.1.1 Baseline characteristics 
 
PM01183+DOX 
Control 
Total Topotecan  CAV 
N 
% 
N % 
N 
% 
N % 
Number of patients 
 
 
 
 
 
 
 
 
Sex 
Male 
Female 
 
 
 
 
 
 
 
 
Age (years)   
 
 
 
 
Median (range) 
Mean (std) 
Age  group 
18-49 
 
 
 
 
 
 
 
 
50-65 
 
 
 
 
 
 
≥65 
 
 
 
 
 
 
Childbearing potential?* 
Yes 
No 
 
 
 
 
 
 
 
 
Race 
American Indian or Alaska Native 
Asian 
Black or African American 
Native Hawaiian or Other Pacific Islander  
White 
 
 
 
 
 
 
 
 
Other (specify) 
 
 
 
 
 
 
Not applicable  
 
 
 
 
 
 
ECOG PS    
0 
1 
2 
… 
 
 
 
 
 
 
 
 
Smoking status 
Current 
Former  
Never  
 
 
 
 
 
 
 
 
Time from first diagnosis to randomization 
Median (range) 
Mean (std) 
 
 
 
 
Disease stage 
Limited 
Extensive 
 
 
 
 
 
 
 
 
Ki-67/MIB-1 expression (Small Cell non Lung patients) 
Median (range) 
Mean (std) 
 
 
 
 
 
 
 
 
Baseline CNS involvement 
Yes 
No 
 
 
 
 
 
 
 
 


                                                          
 
                             
 
PM01183+DOX 
Control 
Total Topotecan  CAV 
N 
% 
N % 
N 
% 
N % 
Disease involvement at baseline 
Bone 
Lung 
Lymph node 
Liver 
Brain 
… 
 
 
 
 
 
 
 
 
Visceral metastasis 
Yes 
No 
 
 
 
 
 
 
 
 
Number of sites involved** 
1 
2 
… 
Median (range) 
Mean (std) 
 
 
 
 
 
 
 
 
Measurable lesion/s at baseline 
Yes 
No 
 
 
 
 
 
 
 
 
Presence of any bulky (< 50 mm vs. ≥ 50 mm) lesion at 
baseline  
Yes 
No 
 
 
 
 
 
 
 
 
Paraneoplastic syndrome at baseline 
Yes 
  Cushing syndrome 
  SIADH 
  … 
No 
 
 
 
 
 
 
 
 
Physical examination by Body System examined 
Abnormalities found 
 Yes 
 No 
Clinically significant 
Not Clinically significant 
 
 
 
 
 
 
 
 
Weight (kg) 
Median (range) 
Mean (std) 
 
 
 
 
Height (cm) 
Median (range) 
Mean (std) 
 
 
 
 
Body surface area (m2) 
Median (range) 
Mean (std) 
 2 m2 
> 2 m2 
 
 
 
 


                                                          
 
                             
 
PM01183+DOX 
Control 
Total Topotecan  CAV 
N 
% 
N % 
N 
% 
N % 
BMI (kg/m2) 
Median (range) 
Mean (std) 
 
 
 
 
BMI categories 
 20 
20-25 
25-30 
 30 
 
 
 
 
 
 
 
 
LVEF   
Normal 
Significant abnormalities 
Non significant abnormalities 
 
 
 
 
 
 
 
 
ECG results   
PR interval (msec)  
Median (range) 
Mean (std) 
Heart Rate (bpm) 
Median (range) 
Mean (std) 
QT interval (raw) (msec) 
Median (range) 
Mean (std) 
QRS complex duration  (msec) 
Median (range) 
Mean (std) 
Fridericia corrected QT  
Median (range) 
Mean (std) 
 
 
 
 
LVEF results (MUGA) 
Median (range) 
Mean (std) 
LVEF results (ECHO) 
Median (range) 
Mean (std) 
 
 
 
 
Vital signs 
Heart rate (beats/minute) 
Median (range) 
Mean (std) 
Systolic blood pressure (mmHg) 
Median (range)  
Mean (std) 
Diastolic blood pressure (mmHg) 
Median (range) 
Mean (std) 
Temperature (ºC) 
Median (range) 
Mean (std) 
 
 
 
 
N(%) for categorical variables; Median (range)/Mean (std) for continuous variables 
*Denominator is number of female patients 
**Counted from Cancer History Form 
 
 
 
 
 
 


                                                          
 
                             
Table 11.1.1.2 Severity grade for hematological tests at baseline 
 
Total 
Grade  
0 
Grade  
1 
Grade  
2 
Grade  
3 
Grade  
4 
Grade     
1-4 
N 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
PM01183+DOX 
Leukopenia 
 
 
 
 
 
 
 
 
 
 
 
 
 
Anemia 
 
 
 
 
 
 
 
 
 
 
 
 
 
Thrombocytopenia 
 
 
 
 
 
 
 
 
 
 
 
 
 
Neutropenia 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lymphopenia 
 
 
 
 
 
 
 
 
 
 
 
 
 
Control 
Leukopenia 
 
 
 
 
 
 
 
 
 
 
 
 
 
Anemia 
 
 
 
 
 
 
 
 
 
 
 
 
 
Thrombocytopenia 
 
 
 
 
 
 
 
 
 
 
 
 
 
Neutropenia 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lymphopenia 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 11.1.1.3 Hematology values at baseline 
 
PM01183+DOX 
Control 
n 
Median (range) 
Mean (std) 
n 
Median (range) 
Mean (std) 
WBC 
 
 
Neutrophils 
 
 
Hemoglobin 
 
 
Platelets 
 
 
Lymphocytes 
 
 
Listing 11.1.1.4 Hematological tests not assessed at baseline 
Treatment arm* 
Patient ID. 
Lab. test 
 
… 
 
 
… 
 
*PM01183+DOX/Topotecan/CAV 
Listing 11.1.1.5 Hematological abnormalities grade≥1 at baseline 
Treatment arm* 
Patient ID. 
Test 
Grade 
 
… 
 
 
 
… 
 
 
*PM01183+DOX/Topotecan/CAV 
 


                                                          
 
                             
Table 11.1.1.6 Severity grade de for biochemical tests at baseline 
 
Total 
Grade  
0 
Grade  
1 
Grade  
2 
Grade  
3 
Grade  
4 
Grade     
1-4 
N 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
PM01183+DOX 
Creatinine increase 
 
 
 
 
 
 
 
 
 
 
 
 
 
CPK increase 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bilirubin increase 
 
 
 
 
 
 
 
 
 
 
 
 
 
AP increase 
 
 
 
 
 
 
 
 
 
 
 
 
 
AST increase 
 
 
 
 
 
 
 
 
 
 
 
 
 
ALT increase 
 
 
 
 
 
 
 
 
 
 
 
 
 
Control 
Creatinine increase 
 
 
 
 
 
 
 
 
 
 
 
 
 
CPK increase 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bilirubin increase 
 
 
 
 
 
 
 
 
 
 
 
 
 
AP increase 
 
 
 
 
 
 
 
 
 
 
 
 
 
AST increase 
 
 
 
 
 
 
 
 
 
 
 
 
 
ALT increase 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 11.1.1.7 Biochemistry values at baseline 
 
PM01183+DOX 
Control 
n 
Median (range) 
Mean (std) 
n 
Median (range) 
Mean (std) 
Creatinine 
 
 
Creatinine clearance 
 
 
CPK 
 
 
Total bilirubin 
 
 
AP 
 
 
AST 
 
 
ALT 
 
 
LDH 
  ≤ULN 
  >ULN 
 
 
Listing 11.1.1.8 Biochemical tests not assessed at baseline 
Treatment arm* 
Patient ID. 
Lab. test 
 
… 
 
 
… 
 
*PM01183+DOX/Topotecan/CAV 
Listing 11.1.1.9 Biochemical abnormalities grade≥1 at baseline 
Treatment arm* 
Patient ID. 
Test 
Grade 
 
… 
 
 
 
… 
 
 
*PM01183+DOX/Topotecan/CAV 
 


                                                          
 
                             
Table 11.1.1.10 Severity grade  for other metabolic tests at baseline 
 
Total 
Grade  
0 
Grade  
1 
Grade  
2 
Grade  
3 
Grade  
4 
Grade    
1-4 
N 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
PM01183+DOX 
Hyperglycemia 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hypernatremia 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hyperkalemia 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hypercalcemia 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hypoglycemia 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hyponatremia 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hypokalemia 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hypocalcemia 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hypoalbuminemia 
 
 
 
 
 
 
 
 
 
 
 
 
 
Control 
Hyperglycemia 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hypernatremia 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hyperkalemia 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hypercalcemia 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hypoglycemia 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hyponatremia 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hypokalemia 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hypocalcemia 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hypoalbuminemia 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 11.1.1.11 Other metabolic values at baseline 
 
PM01183+DOX 
Control 
 
n 
Median (range) 
Mean (std) 
n 
Median (range) 
Mean (std) 
Glucose 
 
 
Sodium 
 
 
Potassium 
 
 
Calcium 
 
 
Albumin 
 
 
CRP 
 
 
Listing 11.1.1.12 Metabolic tests not assessed at baseline 
Treatment arm* 
Patient ID. 
Lab. test 
 
… 
 
 
… 
 
*PM01183+DOX/Topotecan/CAV 
Listing 11.1.1.13 Other metabolic abnormalities grade≥1 at baseline 
Treatment arm* 
Patient ID. 
Test 
Grade 
 
… 
 
 
 
… 
 
 
*PM01183+DOX/Topotecan/CAV 
 


                                                          
 
                             
 
11.1.2  Prior Anticancer Therapy 
Table 11.1.2.1 Prior therapy 
 
PM01183+DOX 
Control 
Total 
Topotecan  
CAV 
N 
% 
N 
% 
N 
% 
N 
% 
Radiotherapy  
  Yes 
   No 
 
 
 
 
 
 
 
 
Prior prophylactic cranial irradiation (PCI) 
  Yes 
  No 
 
 
 
 
 
 
 
 
Prior surgery excluding diagnostic  
  Yes 
  No 
 
 
 
 
 
 
 
 
 
Table 11.1.2.2 Prior anticancer medical therapy 
 
PM01183+DOX 
Control 
Total 
Topotecan  
CAV 
N 
% 
N 
% 
N 
% 
N 
% 
Number of prior regimens  
   1 
   2 
   … 
  Median (range) 
  Mean (std) 
 
 
 
 
 
 
 
 
Type 
   Chemotherapy 
   Inmunotherapy  
   …  
Maintenance  
Yes 
No 
 
 
 
 
 
 
 
 
Number of prior chemotherapy lines  
   1 
   2 
   … 
  Median (range) 
  Mean (std) 
 
 
 
 
 
 
 
 
Number of prior chemotherapy agents 
   1 
   2 
   … 
  Median (range) 
  Mean (std) 
 
 
 
 
 
 
 
 
Prior agents of chemotherapy (ATC coded)* 
   Carboplatin 
   Cisplatin 
   Etoposide 
   … 
 
 
 
 
 
 
 
 
Prior inmunotherapies agents (ATC coded)* 
   Nivolumab 
   … 
 
 
 
 
 
 
 
 
 
 


                                                          
 
                             
 
PM01183+DOX 
Control 
Total 
Topotecan  
CAV 
N 
% 
N 
% 
N 
% 
N 
% 
Prior immunotherapy against either PD-1 
or PD-L1 
  Yes 
  No 
 
 
 
 
 
 
 
 
Prior immunotherapy against either PD-1 
or PD-L1 
  Yes (Both) 
  Yes (PD-1) 
  Yes (PD-L1) 
  No 
 
 
 
 
 
 
 
 
PD-L1 expression 
<1% 
1%-50% 
≥50% 
 
 
 
 
 
 
 
 
Prior investigational agents 
Others 
 
 
 
 
 
 
 
 
CTFI after first-line treatment (calculated 
from dates reported and as reported in 
screening form) 
  Median (range) 
  Mean (std) 
  ≥180 days (calculated) 
  90-179 days (calculated)   
  <90 days (calculated) 
  ≥180 days (screening form) 
  90-179 days (screening form)   
  <90 days (screening form) 
 
 
 
 
 
 
 
 
Time from last prior progression to 
randomization 
  Median (range) 
  Mean (std) 
 
 
 
 
 
 
TTP to prior chemotherapy* 
  Median (range) 
  Mean (std) 
 
 
 
 
 
 
Time from end date of last prior 
chemotherapy to randomization   
  Median (range) 
  Mean (std) 
 
 
 
 
 
 
Best response to last prior chemotherapy 
therapy 
   CR 
   PR 
   SD 
   PD 
   NE/UK/NA 
 
 
 
 
 
 
 
Best response to last prior immunotherapy 
against either PD-1 or PD-L1 
   CR 
   PR 
   SD 
   PD 
   NE/UK/NA 
 
 
 
 
 
 
 
* Sites have been instructed in the database completion guidelines to report one drug per record, but in the summary 
it may be requested to group some combinations, e.g. CAV  
**If total number of patients with maintenance is less than 15% then take out them from calculus, if percentage is 
higher then censored them at the initial time of the maintenance 


                                                          
 
                             
11.1.3 Prior Relevant Medical History 
A table with the description of the most relevant abnormalities found at baseline will be 
provided in this section. Special attention will be given to the most relevant 
comorbidities (see section 6.2).  
Table 11.1.3.1  Medical history  
SOC 
Preferred term 
PM01183+DOX 
Control 
Total 
Topotecan  
CAV 
N 
% 
N 
% 
N 
% 
N 
% 
Gastrointestinal disorders 
Constipation 
 
 
 
 
 
 
 
 
Diarrhoea NOS 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
… 
… 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
11.1.4 Signs and Symptoms at Baseline 
 
Signs and symptoms refer to any AE with onset date before the first treatment dose. 
 
Table 11.1.4.1 Patients with signs and symptoms at baseline 
 
PM01183+DOX 
Control 
Total 
Topotecan  
CAV 
N 
% 
N 
% 
N 
% 
N 
% 
No. of signs and symptoms per patient 
 
 
 
 
 
 
 
 
0 
1 
2 
 
 
 
 
 
 
 3 
 
 
 
 
 
 
Median (range) 
Mean (std) 
 
 
 
 
 
 
 
Table 11.1.4.2 Signs and symptoms at baseline (MedDRA coded) 
SOC 
Preferred term 
Total 
Grade  
1 
Grade  
2 
Grade  
3 
Grade  
4 
Grade     
1-4 
N 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
PM01183+DOX  
Gastrointestinal 
disorders 
Constipation 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
Control 
Gastrointestinal 
disorders 
Constipation 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
Listing 11.1.4.3 Signs and symptoms at baseline 
Treatment arm* 
Patient ID. 
Sign/symptom 
Grade 
Onset date 
 
  
  
 
  
  
*PM01183+DOX/Topotecan/CAV 
 


                                                          
 
                             
11.1.5 Concomitant Medication at Baseline 
Concomitant medication at baseline according to the ATC classification. 
Table 11.1.5.1 Concomitant medication at baseline (ATC1/ATC2/ATC4) 
 
PM01183+DOX 
Control 
Total 
Topotecan  
CAV 
N 
% 
N 
% 
N 
% 
N 
% 
Alimentary tract and 
 
 
 
 
 
 
 
 
  Antiacids 
 
 
 
 
 
 
    Magnesium compounds 
 
 
 
 
 
 
…. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood and blood forming 
 
 
 
 
 
 
  Antithrombotic agents 
 
 
 
 
 
 
     Vitamin K antagonists 
 
 
 
 
 
 
… 
 
 
 
 
 
 
… 
  … 
 
 
 
 
 
 
 
 
 
11.1.6  PRO scores at baseline 
Table 11.1.6.1 PRO scores at baseline 
Item 
PM01183+DOX 
Control 
Total 
Topotecan  
CAV 
N Median 
(range) 
Mean 
(std) 
N Median 
(range) 
Mean 
(std) 
N Median 
(range) 
Mean 
(std) 
N Median 
(range) 
Mean 
(std) 
EORTC QLQ-C30 
Item 1 
 
 
 
 
 
 
 
 
 
 
 
 
Item 2 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
Item 30 
 
 
 
 
 
 
 
 
 
 
 
 
EORTC QLQ-LC13 
Item 31 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
Item 43 
 
 
 
 
 
 
 
 
 
 
 
 
 
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 ITT population. 
Overall survival 
 
Table 11.3.1.1 OS (Stratified log rank test) 
Variable 
Stratification factors 
p-value* 
Treatment arm (main analysis) 
Actual values (CNS and CTFI) 
 
Treatment arm (sensitivity) 
Values reported for randomization 
(CNS and CTFI) 
 
Treatment arm (sensitivity) 
Actual values (all stratification 
factors) 
 
Treatment arm (sensitivity) 
Values reported for randomization 
(all stratification factors) 
 
*Stratified log rank test. 
 
Table 11.3.1.2 Median FU for OS 
 
Total (PM01183+DOX and Control) 
Follow-up (descriptive way) 
Median (range) 
 
Follow-up (reversing censor method) 
Median (95%CI) 
 
 
Table 11.3.1.3 OS  
  
PM01183+DOX 
Control 
Parameter 
p-value 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median OS  
(95% CI) 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
Mean OS 
 
 
 
- 
OS at 12 months  
(95% CI) 
 
 
Diff: 
 
OS at 18 months  
(95% CI) 
 
 
 
 
OS at 24 months  
(95% CI) 
 
 
Diff: 
 
Kaplan Meier plot (Figure 11.3.1.3) will be shown too. 
 
Table 11.3.1.4 Multivariate analysis of OS (Stratification factors and treatment arm only) 
Analysis of Maximum Likelihood Estimates 
Variable label 
Variable 
values 
DF 
Parameter 
estimate 
Standard 
error 
Chi-
square 
Pr > ChiSq 
Hazard 
ratio 
95% Hazard 
ratio 
confidence 
limits 
 
 
 
 
 
 
 
 
 
 
Table 11.3.1.5 Multivariate analysis of OS 
Analysis of Maximum Likelihood Estimates 
Variable label 
Variable 
values 
DF 
Parameter 
estimate 
Standard 
error 
Chi-
square 
Pr > ChiSq 
Hazard 
ratio 
95% Hazard 
ratio 
confidence 
limits 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(see list of covariates in section 6.2). 


                                                          
 
                             
Table 11.3.1.6 Proportional hazard assumption and restricted mean survival for OS 
Variable 
PM01183+DOX 
Control 
Interaction 
p-value 
 Restricted mean survival* 
 
 
 
*It will be calculated if proportional hazard assumption is not met. 
 
Forest plot (Figure 11.3.1.7) summarizing main results, stratification factors and 
covariates in terms of OS will be prepared. 
 
Overall survival (CAV comparison) 
 
Table 11.3.1.8 OS vs CAV (Stratified log rank test) 
Variable 
Stratification factors 
p-value* 
Treatment arm  
Actual values (CNS and CTFI) 
 
Treatment arm  
Values reported for randomization 
(CNS and CTFI) 
 
Treatment arm  
Actual values (all stratification 
factors) 
 
Treatment arm  
Values reported for randomization 
(all stratification factors) 
 
*Stratified log rank test. 
 
Table 11.3.1.9 OS vs CAV  
  
PM01183+DOX 
Control 
Parameter 
p-value 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median OS  
(95% CI) 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
Mean OS 
 
 
 
- 
OS at 12 months  
(95% CI) 
 
 
Diff: 
 
OS at 18 months  
(95% CI) 
 
 
 
 
OS at 24 months  
(95% CI) 
 
 
Diff: 
 
Kaplan Meier plot (Figure 11.3.1.9) will be shown too. 
 
Forest plot (Figure 11.3.1.10) summarizing main results, stratification factors and 
covariates in terms of OS will be prepared. 
 
Overall survival (non CNS comparison) 
 
Table 11.3.1.11 OS in non CNS (Stratified log rank test) 
Variable 
Stratification factors 
p-value* 
Treatment arm  
Actual values (CNS and CTFI) 
 
Treatment arm  
Values reported for randomization 
(CNS and CTFI) 
 
Treatment arm  
Actual values (all stratification 
factors) 
 
Treatment arm  
Values reported for randomization 
(all stratification factors) 
 
*Stratified log rank test. 
 


                                                          
 
                             
Table 11.3.1.12 OS in non CNS  
  
PM01183+DOX 
Control 
Parameter 
p-value 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median OS  
(95% CI) 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
Mean OS  
 
 
 
- 
OS at 12 months  
(95% CI) 
 
 
Diff: 
 
OS at 18 months  
(95% CI) 
 
 
 
 
OS at 24 months  
(95% CI) 
 
 
Diff: 
 
Kaplan Meier plot (Figure 11.3.1.12) will be shown too. 
 
Forest plot (Figure 11.3.1.13) summarizing main results, stratification factors and 
covariates in terms of OS will be prepared. 
 
Progression-free survival by IRC 
 
Table 11.3.1.14 PFS by IRC (primary analysis) 
Variable 
Stratification factors 
p-value* 
Treatment arm 
Actual values (CNS and CTFI) 
 
Treatment arm 
Values reported for randomization 
(CNS and CTFI) 
 
Treatment arm 
Actual values (all stratification 
factors) 
 
Treatment arm 
Values reported for randomization 
(all stratification factors) 
 
*Stratified log rank test. 
 
Table 11.3.1.15 Median FU for PFS by IRC 
 
Total (PM01183+DOX and Control) 
Follow-up (descriptive way) 
Median (range) 
 
Follow-up (reversing censor method) 
Median (95%CI) 
 
 
Table 11.3.1.16 PFS by IRC 
  
PM01183+DOX 
Control 
Parameter 
p-value 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median PFS  
(95% CI) 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
Mean PFS  
 
 
 
- 
PFS at 6 months  
(95% CI) 
 
 
Diff: 
 
PFS at 12 months  
(95% CI) 
 
 
Diff: 
 
Kaplan Meier plot (Figure 11.3.1.16) will be shown too. 
 


                                                          
 
                             
Table 11.3.1.17 Multivariate analysis of PFS by IRC (Stratification factors and treatment arm only) 
Analysis of maximum likelihood estimates 
Variable label 
Variable 
values 
DF 
Parameter 
estimate 
Standard 
error 
Chi-
square 
Pr > ChiSq 
Hazard 
ratio 
95% Hazard 
ratio 
confidence 
limits 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 11.3.1.18 Multivariate analysis of PFS by IRC 
Analysis of maximum likelihood estimates 
Variable label 
Variable 
values 
DF 
Parameter 
estimate 
Standard 
error 
Chi-
square 
Pr > ChiSq 
Hazard 
ratio 
95% Hazard 
ratio 
confidence 
limits 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(see list of covariates in section 6.2). 
 
Table 11.3.1.19 Proportional hazard assumption and restricted mean survival for PFS by IRC 
Variable 
PM01183+DOX 
Control 
Interaction 
p-value 
 Restricted mean survival* 
 
 
 
*It will be calculated if proportional hazard assumption is not met. 
 
Forest plot (Figure 11.3.1.20) summarizing main results, stratification factors and 
covariates in terms of PFS by IRC will be prepared. 
 
Progression-free survival by IA 
 
Table 11.3.1.21 PFS by IA (Stratified log rank test) 
Variable 
Stratification factors 
p-value* 
Treatment arm 
Actual values (CNS and CTFI) 
 
Treatment arm 
Values reported for randomization 
(CNS and CTFI) 
 
Treatment arm 
Actual values (all stratification 
factors) 
 
Treatment arm 
Values reported for randomization 
(all stratification factors) 
 
*Stratified log rank test. 
 
Table 11.3.1.22 Median FU for PFS by IA 
 
Total (PM01183+DOX and Control) 
Follow-up (descriptive way) 
Median (range) 
 
Follow-up (reversing censor method) 
Median (95%CI) 
 
 
 


                                                          
 
                             
Table 11.3.1.23 PFS by IA 
  
PM01183+DOX 
Control 
Parameter 
p-value 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median PFS  
(95% CI) 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
Mean PFS  
 
 
 
- 
PFS at 6 months  
(95% CI) 
 
 
Diff: 
 
PFS at 12 months  
(95% CI) 
 
 
Diff: 
 
Kaplan Meier plot (Figure 11.3.1.23) will be shown too. 
 
Table 11.3.1.24 Multivariate analysis of PFS by IA (Stratification factors and treatment arm only) 
Analysis of Maximum Likelihood Estimates 
Variable label 
Variable 
values 
DF 
Parameter 
estimate 
Standard 
error 
Chi-
square 
Pr > ChiSq 
Hazard 
ratio 
95% Hazard 
ratio 
confidence 
limits 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 11.3.1.25 Multivariate analysis of PFS by IA 
Analysis of Maximum Likelihood Estimates 
Variable label 
Variable 
values 
DF 
Parameter 
estimate 
Standard 
error 
Chi-
square 
Pr > ChiSq 
Hazard 
ratio 
95% Hazard 
ratio 
confidence 
limits 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(see list of covariates in section 6.2). 
 
Table 11.3.1.26 Proportional hazard assumption and restricted mean survival for PFS by IA 
Variable 
PM01183+DOX 
Control 
Interaction 
p-value 
 Restricted mean survival* 
 
 
 
*It will be calculated if proportional hazard assumption is not met. 
 
Forest plot (Figure 11.3.1.27) summarizing main results, stratification factors and 
covariates in terms of PFS by IA will be prepared 
 
Table 11.3.1.28 Time to disease assessments  
Disease assessment 
Treatment arm 
n 
Median (days) 
Wilcoxon p-value 
1 
PM01183+DOX 
 
 
 
  
Control 
 
 
2 
PM01183+DOX 
 
 
 
  
Control 
 
 
… 
PM01183+DOX 
 
 
 
  
Control 
 
 
-ITT population, Kaplan Meier plot (Figure 11.3.1.28) will be shown too. 
 


                                                          
 
                             
Concordance PFS IRC and PFS IA 
 
Table 11.3.1.29 Concordance PFS 
 
PM01183+DOX 
(IRC) 
PM01183+DOX 
(IA) 
Control  
(IRC) 
Control  
(IA) 
Parameter 
p-value 
N 
 
 
 
 
  
  
Events 
 
 
 
 
  
  
Censored 
 
 
 
 
  
  
Median PFS  
(95% CI) 
 
 
 
 
Log-Rank:  LR:  
PFS at 6 months  
(95% CI) 
 
 
 
 
 
 
PFS at 12 months  
(95% CI) 
 
 
 
 
 
 
Kaplan Meier plot (Figure 11.3.1.29) will be shown too. 
 
Sensitivity PFS analyses 
-Date of progression based on scheduled time instead of recorded date. 
 
Table 11.3.1.30 PFS based on scheduled time by IRC 
  
PM01183+DOX 
Control 
Parameter 
p-value 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median PFS  
(95% CI) 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
PFS at 6 months  
(95% CI) 
 
 
Diff: 
 
PFS at 12 months  
(95% CI) 
 
 
Diff: 
 
Kaplan Meier plot (Figure 11.3.1.30) will be shown too. 
 
Table 11.3.1.31 PFS based on scheduled time by IA 
  
PM01183+DOX 
Control 
Parameter 
p-value 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median PFS  
(95% CI) 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
PFS at 6 months  
(95% CI) 
 
 
Diff: 
 
PFS at 12 months  
(95% CI) 
 
 
Diff: 
 
Kaplan Meier plot (Figure 11.3.1.31) will be shown too. 
 


                                                          
 
                             
-First date of progression combining IRC and IA assessments. 
 
Table 11.3.1.32 PFS based on first date of progression 
  
PM01183+DOX 
Control 
Parameter 
p-value 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median PFS  
(95% CI) 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
PFS at 6 months  
(95% CI) 
 
 
Diff: 
 
PFS at 12 months  
(95% CI) 
 
 
Diff: 
 
Kaplan Meier plot (Figure 11.3.1.32) will be shown too. 
 
- Date of progression moved to the prior tumor assessment. 
 
Table 11.3.1.33 PFS moved to the prior tumor assessment by IRC 
  
PM01183+DOX 
Control 
Parameter 
p-value 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median PFS  
(95% CI) 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
PFS at 6 months  
(95% CI) 
 
 
Diff: 
 
PFS at 12 months  
(95% CI) 
 
 
Diff: 
 
Kaplan Meier plot (Figure 11.3.1.33) will be shown too. 
 
Table 11.3.1.34 PFS moved to the prior tumor assessment by IA 
  
PM01183+DOX 
Control 
Parameter 
p-value 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median PFS  
(95% CI) 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
PFS at 6 months  
(95% CI) 
 
 
Diff: 
 
PFS at 12 months  
(95% CI) 
 
 
Diff: 
 
Kaplan Meier plot (Figure 11.3.1.34) will be shown too. 
 
- First date of progression or death not censoring data if further antitumor therapy. 
 
Table 11.3.1.35 PFS not censoring if further antitumor by IRC 
  
PM01183+DOX 
Control 
Parameter 
p-value 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median PFS  
(95% CI) 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
PFS at 6 months  
(95% CI) 
 
 
Diff: 
 
PFS at 12 months  
(95% CI) 
 
 
Diff: 
 
Kaplan Meier plot (Figure 11.3.1.35) will be shown too. 


                                                          
 
                             
Table 11.3.1.36 PFS not censoring if further antitumor by IA 
  
PM01183+DOX 
Control 
Parameter 
p-value 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median PFS  
(95% CI) 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
PFS at 6 months  
(95% CI) 
 
 
Diff: 
 
PFS at 12 months  
(95% CI) 
 
 
Diff: 
 
Kaplan Meier plot (Figure 11.3.1.36) will be shown too. 
 
Objective response and duration of response by IRC 
 
Table 11.3.1.37 Response rate by IRC 
Response 
PM01183+DOX Control 
p-value 
N 
% 
N 
% 
CR 
 
 
 
 
 
PR 
 
 
 
 
 
SD 
 
 
 
 
 
PD 
 
 
 
 
 
Unknown* 
 
 
 
 
 
CR+PR; n (%) and binomial exact 95% confidence interval 
 
 
 
DCR; n (%) and binomial exact 95% confidence interval 
 
 
 
CBR; n (%) and binomial exact 95% confidence interval 
 
 
 
(*) Including NE, non-responders and insufficient data available. 
 
Table 11.3.1.38 Multivariate analysis of response rate by IRC (Stratification factors and treatment arm)  
Analysis of Maximum Likelihood Estimates 
Variable label Variable 
values 
DF 
Estimate 
Standard 
error 
Wald 
chi-
square 
Pr > ChiSq 
Odds 
ratio 
estimate 
95% Wald 
confidence 
limits 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 11.3.1.39 Multivariate analysis of response rate by IRC  
Analysis of Maximum Likelihood Estimates 
Variable label Variable 
values 
DF 
Estimate 
Standard 
error 
Wald 
chi-
square 
Pr > ChiSq 
Odds 
ratio 
estimate 
95% Wald 
confidence 
limits 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(See list of covariates in section 6.2). 
 
Forest plot (Figure 11.3.1.40) summarizing main results, stratification factors and 
covariates in terms of response by IRC will be prepared. 
A waterfall plot (Figure 11.3.1.41) describing the best variation of the sum of target 
lesions during the treatment will be prepared. 
 


                                                          
 
                             
Table 11.3.1.42 DR by IRC 
  
PM01183+DOX 
Control  
Parameter 
p-value 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median DR  
(95% CI) 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
 
Objective response and duration of response by IA 
 
Table 11.3.1.43 Response rate by IA 
Response 
PM01183+DOX Control 
p-value 
N 
% 
N 
% 
CR 
 
 
 
 
 
PR 
 
 
 
 
 
SD 
 
 
 
 
 
PD 
 
 
 
 
 
Unknown* 
 
 
 
 
 
CR+PR; n (%) and binomial exact 95% confidence interval 
 
 
 
DCR; n (%) and binomial exact 95% confidence interval 
 
 
 
CBR; n (%) and binomial exact 95% confidence interval 
 
 
 
(*) Including NE, non-responders and insufficient data available. 
 
Table 11.3.1.44 Multivariate analysis of response rate by IA (Stratification factors and treatment arm)  
Analysis of maximum likelihood estimates 
Variable label Variable 
values 
DF 
Estimate 
Standard 
error 
Wald 
chi-
square 
Pr > ChiSq 
Odds 
ratio 
estimate 
95% Wald 
confidence 
limits 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 11.3.1.45 Multivariate analysis of response rate by IA  
Analysis of maximum likelihood estimates 
Variable label Variable 
values 
DF 
Estimate 
Standard 
error 
Wald 
chi-
square 
Pr > ChiSq 
Odds 
ratio 
estimate 
95% Wald 
confidence 
limits 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(See list of covariates in section 6.2). 
 
A forest plot (Figure 11.3.1.46)  summarizing main results, stratification factors and 
covariates in terms of response by IA will be prepared. 
 
A waterfall plot (Figure 11.3.1.47) describing the best variation of the sum of target 
lesions during the treatment will be prepared. 
 
Table 11.3.1.48 DR by IA 
  
PM01183+DOX 
Control  
Parameter 
p-value 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median DR  
(95% CI) 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
 


                                                          
 
                             
Progression and censoring reasons by IRC/IA 
 
Table 11.3.1.49 Progression type by IRC/IA 
Reason 
IRC 
IA 
PM01183+DOX 
Control 
PM01183+DOX 
Control 
N 
% 
N 
% 
N 
% 
N 
% 
Target lesion 
 
 
 
 
 
 
 
 
Non-target lesion 
 
 
 
 
 
 
 
 
Death due to malignant disease 
 
 
 
 
 
 
 
 
Other* 
 
 
 
 
 
 
 
 
(*)Please specify. 
 
Table 11.3.1.50 Censoring reason by IRC/IA 
Reason 
IRC 
IA 
PM01183+DOX 
Control 
PM01183+DOX 
Control 
N 
% 
N 
% 
N 
% 
N 
% 
Free of progression last tumor 
assessment 
 
 
 
 
 
 
 
 
Subsequent therapy before 
documented progression 
 
 
 
 
 
 
 
 
Not treated 
 
 
 
 
 
 
 
 
Other* 
 
 
 
 
 
 
 
 
(*)Please specify. 
 
A sensitivity analysis by IA will be performed on patients who have CNS progression 
and continue on treatment excluding the CNS progression. These patients will be 
followed until the next progression or censoring in the last tumor assessment; if the 
patient is discontinued from treatment, he/she will be censored on that date. 
 
Table 11.3.1.51 Sensitivity PFS according to CNS progressions by IA 
  
PM01183+DOX 
Control 
Parameter 
p-value 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median PFS  
(95% CI) 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
PFS at 6 months  
(95% CI) 
 
 
Diff: 
 
PFS at 12 months  
(95% CI) 
 
 
Diff: 
 
Kaplan Meier plot (Figure 11.3.1.51) will be shown too. 
 
Time to treatment failure 
 
Table 11.3.1.52 Time to treatment failure by IA 
  
PM01183+DOX 
Control 
Parameter 
p-value 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median PFS  
(95% CI) 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
PFS at 6 months  
(95% CI) 
 
 
Diff: 
 
PFS at 12 months  
(95% CI) 
 
 
Diff: 
 
Kaplan Meier plot (Figure 11.3.1.52) will be shown too. 
 


                                                          
 
                             
Time to brain mets 
 
Table 11.3.1.53 Time to clinical diagnosis of brain mets by IA 
  
PM01183+DOX 
Control 
Parameter 
p-value 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median PFS  
(95% CI) 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
PFS at 6 months  
(95% CI) 
 
 
Diff: 
 
PFS at 12 months  
(95% CI) 
 
 
Diff: 
 
Kaplan Meier plot (Figure 11.3.1.53) will be shown too. 
 
Subgroup analyses 
Forest plots summarizing main results, stratification factors and covariates.  
 
Comparison between PM01183+DOX and CAV according to Investigator’s preference 
will be plotted.  
 
- Figure 11.3.1.54 PFS by IRC (PM01183 vs. CAV) 
- Figure 11.3.1.55 PFS by IA (PM01183 vs. CAV) 
- Figure 11.3.1.56 OS (PM01183 vs. CAV) 
- Figure 11.3.1.57 RR by IRC (PM01183 vs. CAV) 
- Figure 11.3.1.58 RR by IA (PM01183 vs. CAV)  
- Figure 11.3.1.59 DR by IRC (PM01183 vs. CAV) 
- Figure 11.3.1.60 DR by IA (PM01183 vs. CAV) 
 
Comparison between PM01183+DOX and Topotecan according to Investigator’s 
preference will be plotted.  
 
- Figure 11.3.1.61 PFS by IRC (PM01183 vs. Topotecan) 
- Figure 11.3.1.62 PFS by IA (PM01183 vs. Topotecan) 
- Figure 11.3.1.63 OS (PM01183 vs. Topotecan) 
- Figure 11.3.1.64 RR by IRC (PM01183 vs. Topotecan) 
- Figure 11.3.1.65 RR by IA (PM01183 vs. Topotecan)  
- Figure 11.3.1.66 DR by IRC (PM01183 vs. Topotecan) 
- Figure 11.3.1.67 DR by IA (PM01183 vs. Topotecan) 
 
Comparison in patients with no CNS involvement.  
 
- Figure 11.3.1.68 Patients with no CNS. PFS by IRC (PM01183 vs. Control) 
- Figure 11.3.1.69 Patients with no CNS. PFS by IA (PM01183 vs. Control) 
- Figure 11.3.1.70 Patients with no CNS. OS (PM01183 vs. Control) 
- Figure 11.3.1.71 Patients with no CNS. RR by IRC (PM01183 vs. Control) 
- Figure 11.3.1.72 Patients with no CNS. RR by IA (PM01183 vs. Control)  
- Figure 11.3.1.73 Patients with no CNS. DR by IRC (PM01183 vs. Control) 
- Figure 11.3.1.74 Patients with no CNS. DR by IA (PM01183 vs. Control) 
 
Comparison in patients with CNS involvement.  
 
- Figure 11.3.1.75 Patients with CNS. PFS by IRC (PM01183 vs. Control) 
- Figure 11.3.1.76 Patients with CNS. PFS by IA (PM01183 vs. Control) 
- Figure 11.3.1.77 Patients with CNS. OS (PM01183 vs. Control) 
- Figure 11.3.1.78 Patients with CNS. RR by IRC (PM01183 vs. Control) 
- Figure 11.3.1.79 Patients with CNS. RR by IA (PM01183 vs. Control)  


                                                          
 
                             
- Figure 11.3.1.80 Patients with CNS. DR by IRC (PM01183 vs. Control) 
- Figure 11.3.1.81 Patients with CNS. DR by IA (PM01183 vs. Control) 
 
Comparison in patients with no CNS involvement and CTFI≥90 days (sensitive).  
 
- Figure 11.3.1.82 Patients with no CNS in sensitive. PFS by IRC (PM01183 vs. Control) 
- Figure 11.3.1.83 Patients with no CNS in sensitive. PFS by IA (PM01183 vs. Control) 
- Figure 11.3.1.84 Patients with no CNS in sensitive. OS (PM01183 vs. Control) 
- Figure 11.3.1.85 Patients with no CNS in sensitive. RR by IRC (PM01183 vs. Control) 
- Figure 11.3.1.86 Patients with no CNS in sensitive. RR by IA (PM01183 vs. Control)  
- Figure 11.3.1.87 Patients with no CNS in sensitive. DR by IRC (PM01183 vs. Control) 
- Figure 11.3.1.88 Patients with no CNS in sensitive. DR by IA (PM01183 vs. Control) 
 
Comparison in patients with no CNS involvement and CTFI<90 days (resistant).  
 
- Figure 11.3.1.89 Patients with no CNS in resistant. PFS by IRC (PM01183 vs. Control) 
- Figure 11.3.1.90 Patients with no CNS in resistant. PFS by IA (PM01183 vs. Control) 
- Figure 11.3.1.91 Patients with no CNS in resistant. OS (PM01183 vs. Control) 
- Figure 11.3.1.92 Patients with no CNS in resistant. RR by IRC (PM01183 vs. Control) 
- Figure 11.3.1.93 Patients with no CNS in resistant. RR by IA (PM01183 vs. Control)  
- Figure 11.3.1.94 Patients with no CNS in resistant. DR by IRC (PM01183 vs. Control) 
- Figure 11.3.1.95 Patients with no CNS in resistant. DR by IA (PM01183 vs. Control) 
 
Comparison in patients with CTFI≥90 days (sensitive).  
 
- Figure 11.3.1.96 Patients with CTFI≥90 (sensitive). PFS by IRC (PM01183 vs. Control) 
- Figure 11.3.1.97 Patients with CTFI≥90 (sensitive). PFS by IA (PM01183 vs. Control) 
- Figure 11.3.1.98 Patients with CTFI≥90 (sensitive). OS (PM01183 vs. Control) 
- Figure 11.3.1.99 Patients with CTFI≥90 (sensitive). RR by IRC (PM01183 vs. Control) 
- Figure 11.3.1.100 Patients with CTFI≥90 (sensitive). RR by IA (PM01183 vs. Control)  
- Figure 11.3.1.101 Patients with CTFI≥90 (sensitive). DR by IRC (PM01183 vs. Control) 
- Figure 11.3.1.102 Patients with CTFI≥90 (sensitive). DR by IA (PM01183 vs. Control) 
 
Comparison in patients with CTFI<90 days (resistant).  
 
- Figure 11.3.1.103 Patients with CTFI<90 (resistant). PFS by IRC (PM01183 vs. Control) 
- Figure 11.3.1.104 Patients with CTFI<90 (resistant). PFS by IA (PM01183 vs. Control) 
- Figure 11.3.1.105 Patients with CTFI<90 (resistant). OS (PM01183 vs. Control) 
- Figure 11.3.1.106 Patients with CTFI<90 (resistant). RR by IRC (PM01183 vs. Control) 
- Figure 11.3.1.107 Patients with CTFI<90 (resistant). RR by IA (PM01183 vs. Control)  
- Figure 11.3.1.108 Patients with CTFI<90 (resistant). DR by IRC (PM01183 vs. Control) 
- Figure 11.3.1.109 Patients with CTFI<90 (resistant). DR by IA (PM01183 vs. Control) 
 
Patients with primary site different to lung will be plotted.  
 
- Figure 11.3.1.110 Primary site different to lung. PFS by IRC (PM01183+DOX vs. Control) 
- Figure 11.3.1.111 Primary site different to lung. PFS by IA (PM01183+DOX vs. Control) 
- Figure 11.3.1.112 Primary site different to lung. OS (PM01183+DOX vs. Control) 
- Figure 11.3.1.113 Primary site different to lung. RR by IRC (PM01183+DOX vs. Control) 
- Figure 11.3.1.114 Primary site different to lung. RR by IA (PM01183+DOX vs. Control)  
- Figure 11.3.1.115 Primary site different to lung. DR by IRC (PM01183+DOX vs. Control) 
- Figure 11.3.1.116 Primary site different to lung. DR by IA (PM01183+DOX vs. Control) 
 


                                                          
 
                             
For baseline PD-L1 expression (<1% vs. ≥1%). 
 
- Figure 11.3.1.117 Baseline PD-L1 expression. PFS by IRC (PM01183+DOX vs. Control) 
- Figure 11.3.1.118 Baseline PD-L1 expression. PFS by IA (PM01183+DOX vs. Control) 
- Figure 11.3.1.119 Baseline PD-L1 expression. OS (PM01183+DOX vs. Control) 
- Figure 11.3.1.120 Baseline PD-L1 expression. RR by IRC (PM01183+DOX vs. Control) 
- Figure 11.3.1.121 Baseline PD-L1 expression. RR by IA (PM01183+DOX vs. Control)  
- Figure 11.3.1.122 Baseline PD-L1 expression. DR by IRC (PM01183+DOX vs. Control) 
- Figure 11.3.1.123 Baseline PD-L1 expression. DR by IA (PM01183+DOX vs. Control) 
 
For baseline PD-L1 expression (<50% vs. ≥50%). 
 
- Figure 11.3.1.124 Baseline PD-L1 expression. PFS by IRC (PM01183+DOX vs. Control) 
- Figure 11.3.1.125 Baseline PD-L1 expression. PFS by IA (PM01183+DOX vs. Control) 
- Figure 11.3.1.126 Baseline PD-L1 expression. OS (PM01183+DOX vs. Control) 
- Figure 11.3.1.127 Baseline PD-L1 expression. RR by IRC (PM01183+DOX vs. Control) 
- Figure 11.3.1.128 Baseline PD-L1 expression. RR by IA (PM01183+DOX vs. Control)  
- Figure 11.3.1.129 Baseline PD-L1 expression. DR by IRC (PM01183+DOX vs. Control) 
- Figure 11.3.1.130 Baseline PD-L1 expression. DR by IA (PM01183+DOX vs. Control) 
 
Subsequent therapies. 
 
- Figure 11.3.1.131 Time to first subsequent therapy (PM01183+DOX vs. Control) 
- Figure 11.3.1.132 OS from first subsequent therapy (PM01183+DOX vs. Control) 
- Figure 11.3.1.133 OS censoring at first subsequent therapy (PM01183+DOX vs. Control) 
- Figure 11.3.1.134 OS in patients without subsequent therapy (PM01183+DOX vs. Control) 
- Figure 11.3.1.135 Time to first PD-1/PD-L1 subsequent therapy (PM01183+DOX vs. Control) 
- Figure 11.3.1.136 OS from first PD-1/PD-L1 therapy (PM01183+DOX vs. Control)  
 
In the Forest plots, continuous variables not categorized in the definition will be 
classified into two categories taking as reference the median value. The groups will be 
created as below or equal the median value, and above the median value. 
 
Subgroup analysis comparing PFS by IRC in the CTFI after first line subsets.  
 
Table 11.3.1.137 PFS by IRC according to prior CTFI 
Subset 
p-value* 
≥90 days (sensitive) 
 
<90 days (resistant; R) 
 
*Adjusted p-value by Bootstrap replication. 
 
Generalised Pairwise comparison 
 
Table 11.3.1.138 Generalised Pairwise comparison 
 
Arm A 
Arm B 
- 
p-value 
2 months OS and any G3-4 adverse reaction 
 
 
 
 
2 months OS and important AE 
 
 
 
 
3 months OS and any G3-4 adverse reaction 
 
 
 
 
3 months OS and important AE 
 
 
 
 
4 months OS and any G3-4 adverse reaction 
 
 
 
 
4 months OS and important AE 
 
 
 
 
 


                                                          
 
                             
Characteristics of responders  
 
A summary of the main characteristics of patients showing clinical benefit, defined as 
patients with response or PFS≥4 months by IRC/IA, will be shown. 
 
Listing 11.3.1.139 Characteristics of patients with clinical benefit  
Treatment 
arm* 
Patient 
ID. 
Age 
Strata 
Prior 
therapy** 
Cycles 
received 
RR 
by 
IRC/IA 
PFS 
by 
IRC/IA 
DR 
by 
IRC/IA 
OS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
*PM01183+DOX/Topotecan/CAV 
**Last prior therapy data; Setting, Best response and prior PFS. 
12 Safety Analysis 
Safety analysis will be carried out on the safety population.  
12.1  Extent of Exposure 
12.1.1  Treatment Administration 
Table 12.1.1.1  Number of cycles administered and time on treatment 
 
PM01183+DOX* 
Control 
Total Topotecan CAV 
No. of cycles administered per patient 
N 
% 
N % N 
% 
N % 
1 
 
 
 
 
 
 
 
 
2 
 
 
 
 
 
 
 
 
3 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
Median (range) / Mean (std) 
 
 
 
 
 
 
 Time on treatment (weeks) 
Median (range) / Mean (std) 
 
 
 
 
 
 
*Including when PM01183 is administered alone 
 
 
 
 
 
 
 
Table 12.1.1.2  Summary of dose received 
 
PM01183+DOX 
Control 
PM01183 
(combination) 
PM01183 
(alone) 
DOX Topotecan Cy DOX VCR 
Cumulative dose (mg/m²) 
 
 
 
 
 
 
 
Median (range) / Mean (std) 
Dose intensity (mg/m²/wk) 
 
 
 
 
 
 
 
Median (range) / Mean (std) 
Relative dose intensity (%)  
 
 
 
 
 
 
 
Median (range) / Mean (std) 
  


                                                          
 
                             
12.1.2 Cycle Delays  
12.1.2.1  Number of Patients and Cycles with Dosing Delay, any Relationship 
Table 12.1.2.1.1 Number of patients and cycles with dosing delay, any relationship 
 
PM01183+DOX 
Control 
Total 
Topotecan  
CAV 
N 
% 
N 
% 
N 
% 
N 
% 
No. of patients treated 
 
 
 
 
 
 
 
 
No. of patients susceptible to be delayed* 
 
 
 
 
 
 
 
 
No. of patients with any dose delay 
 
 
 
 
 
 
 
 
No. of patients with any drug related dose delay 
 
 
 
 
 
 
 
 
Hematological reason 
Non-hematological reason 
Both reasons 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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 
 
 
 
 
 
 
* Excluding patients who received only the first cycle.  
** All cycles excluding first cycle. 
*** Denominator= Number of cycles susceptible to be delayed.  
 
Table 12.1.2.1.2 Number of patients and cycles with dosing delay according to the relationship 
 
PM01183+DOX 
Control 
Total 
Topotecan  
CAV 
Rel** 
No 
Rel** 
No 
Rel** 
No 
Rel** 
No 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
No. of patients with  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
No cycles delayed 
 
 
 
 
1 cycle  
 
 
 
2 cycles 
 
 
 
 3 cycles 
 
 
 
No. of cycles with 
dosing delay* 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
* Denominator= Number of cycles susceptible to be delayed. 
**Related: Hematological reason, non-hematological reason or both. If the cause is related and not related the most 
conservative approach will be used (i.e. counted only once as related). 
 
Table 12.1.2.1.3 Duration of dosing delay 
Length of delay PM01183+DOX 
Control 
Total 
Topotecan  
CAV 
Rel* 
No 
All 
Rel* 
No 
All 
Rel* 
No 
All 
Rel* 
No 
All 
Median (range) 
Mean (std) 
 
 
 
 
 
 
 
 
 
 
 
 
 
N % N % N % N % N % N % N % N % N % N % N % N % 
<=7 days 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(7,14] days 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
>14 days 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 *Related: Hematological reason, non-hematological reason or both. If the cause is related and not related the most 
conservative approach will be used (i.e. counted only once as related). 


                                                          
 
                             
12.1.2.2  Number of Delays According to Cycle Number 
Table 12.1.2.2.1 Number and reasons of delays according to cycle number 
 
PM01183+DOX 
Control 
Total 
Topotecan  
CAV 
Cycle 
2 
Cycle 
nth 
All 
Cycle 
2 
Cycle 
nth 
All 
Cycle 
2 
Cycle 
nth 
All 
Cycle 
2 
Cycle 
nth 
All 
 
N % N % N % N % N % N % N % N % N % N % N % N % 
Number of 
delays 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Related* 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   Hema. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   Non hema. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  Both 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Non related* 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
* Denominator= Number of cycles susceptible to be delayed. 
 
The distribution of delays according to the cycle administered will be studied by means 
of counts and percentages. The reasons for cycle delay will be detailed, specifying how 
many were due to treatment and how many were not.  
 
Listing 12.1.2.2.2 Patients and cycles with dosing delays  
Treatment arm* 
Patient ID. 
Cycle 
Reason of 
delay 
Delay 
(days) 
 
 
 
 
 
 
 
 
 
 
*PM01183+DOX (Combination or PM01183 Alone)/Topotecan/CAV 
 
Listing 12.1.2.2.3 AEs associated with a cycle delay as action taken 
Treatment 
arm* 
Patient 
ID. 
Cycle Preferred  
term code 
Adverse 
event 
reported 
(verbatim) 
Grade Relationship  Onset 
date 
Resolved 
date 
Outcome 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
*PM01183+DOX (Combination or PM01183 Alone)/Topotecan/CAV 
 
 


                                                          
 
                             
12.1.3 Dose Reductions 
Table 12.1.3.1 Number of patients and cycles with dose reduction, any relationship 
 
PM01183+DOX 
Control 
Total 
Topotecan  
CAV 
N 
% 
N 
% 
N 
% 
N 
% 
No. of patients treated 
 
 
 
 
 
 
 
 
No. of patients susceptible to be dose reduced* 
 
 
 
 
 
 
 
 
No. of patients with dose reductions 
 
 
 
 
 
 
 
 
No. of patients with any drug related dose 
 
 
 
 
 
 
 
 
Hematological reason 
Non-hematological reason 
Both reasons 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
No. of cycles administered 
 
 
 
 
 
 
 
 
No. of cycles susceptible to be dose reduced** 
 
 
 
 
 
 
 
 
No. of cycles with dose reduction*** 
 
 
 
 
 
 
 
 
No. of patients with  
 
 
 
 
 
 
 
 
No reductions 
 
1 reduction  
 
2 reductions 
 
* Excluding patients who received only the first cycle.  
** All cycles excluding the first cycle.  
*** Denominator= Number of cycles susceptible to be reduced.  
 
Table 12.1.3.2 Number of patients and cycles with dose reduction according to relationship 
 
PM01183+DOX 
Control 
Total 
Topotecan  
CAV 
Rel** 
No 
Rel** 
No 
Rel** 
No 
Rel** 
No 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
No. of patients with  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
No reductions 
 
 
 
1 reduction 
 
 
 
2 reductions 
 
 
 
 3 reductions 
 
 
 
No. of cycles with 
dose reduction* 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
* Denominator= Number of cycles susceptible to be reduced. 
**Hematological reason, non-hematological reason or both. If the cause is related and not related the most 
conservative approach will be used (i.e. counted only once as related). 
 
Table 12.1.3.3 Number and reasons of reductions according to cycle number 
 
PM01183+DOX 
Control 
Total 
Topotecan  
CAV 
Cycle 
2 
Cycle 
nth 
All 
Cycle 
2 
Cycle 
nth 
All 
Cycle 
2 
Cycle 
nth 
All 
Cycle 
2 
Cycle 
nth 
All 
 
N % N % N % N % N % N % N % N % N % N % N % N % 
Number of 
reductions 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Related* 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   Hema. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   Non hema. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  Both 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Non related* 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 * Denominator= Number of cycles susceptible to be reduced. 


                                                          
 
                             
Listing  12.1.3.4 Dose reductions 
Treatment arm* 
Patient ID. 
Cycle 
Dose 
Reason 
 
 
 
 
 
 
 
 
 
 
*PM01183+DOX (Combination or PM01183 Alone)/Topotecan/CAV 
 
Listing 12.1.3.5 AEs associated with a dose reduction as action taken 
Treatment 
arm* 
Patient 
ID. 
Cycle Preferred  
term code 
Adverse 
event 
reported 
(verbatim) 
Grade Relationship Onset 
date 
Resolved 
date  
Serious 
Outcome 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
*PM01183+DOX (Combination or PM01183 Alone)/Topotecan/CAV 
 
 


                                                          
 
                             
12.2 Adverse Events (AEs) 
12.2.1  Adverse Events 
AE refers to any event with onset date after the first treatment dose. AEs will be 
described irrespective of their relationship to the drug and as drug-related events stated 
as Related to Study Drug or Unknown. Safety will be described according to the NCI-
CTCAE v.4. AEs consisting of laboratory abnormalities (e.g., neutropenia) may be 
under-reported as AEs. Since these events are better evaluated using objective 
laboratory results, laboratory abnormalities will be discussed in Section 12.4. 
The type of toxicity and worst grade or severity by cycle and by patient will be 
summarized according to System Organ Class (SOC) and Preferred Term (PT) as per 
the MedDRA dictionary. Subsequent grouping of similar or clinically related items 
might be appropriate at the time of the analysis. Tables will be organized by category of 
events using SOC and in descending frequencies (e.g. higher to lower). 
12.2.2  Display of Adverse Events 
Table 12.2.2.1 Summary of adverse events 
Category 
PM01183+DOX Control 
N (%) 
N (%) 
Number of patients with any AE 
 
 
Number of patients with any drug-related AE 
 
 
Number of patients with any grade 3/4 AE 
 
 
Number of patients with any grade 4 AE 
 
 
Number of patients with any grade 3/4 drug-related AE 
 
 
Number of patients with any grade 4 drug-related AE 
 
 
Number of patients with any SAE in clinical database 
 
 
Number of patients with any drug-related SAE in clinical database 
 
 
Number of patients with any grade 3/4 SAE in clinical database 
 
 
Number of patients with any grade 4 SAE in clinical database 
 
 
Number of patients with any grade 3/4 drug-related SAE in clinical database 
 
 
Number of patients with any grade 4 drug-related SAE in clinical database 
 
 
Number of patients with death associated with AEs 
 
 
Number of patients with death associated with drug-related AEs 
 
 
Number of patients with treatment discontinuations associated with AEs 
 
 
Number of patients with treatment discontinuations associated with drug-
related AEs 
 
 
Number of patients with delays associated with AEs 
 
 
Number of patients with delays associated with drug-related AEs 
 
 
Number of patients with reductions associated with AEs 
 
 
Number of patients with reductions associated with drug-related AEs 
 
 


                                                          
 
                                                
Table 12.2.2.2 Drug-related adverse events. Worst grade by patient 
Category/MedDRA Code 
Grade 
PM01183+DOX 
Control 
1 
2 
… 
G≥1 
G≥3 
1 
2 
… 
G≥1 
G≥3 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
Blood and lymphatic system disorders 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Anaemia NOS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cardiac disorders 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Arrhythmia NOS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
…  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
... 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 12.2.2.3 Drug-related adverse events. Worst grade by cycle 
Category/MedDRA Code 
Grade 
PM01183+DOX 
Control 
1 
2 
… 
G≥1 
G≥3 
1 
2 
… 
G≥1 
G≥3 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
Blood and lymphatic system disorders 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Anaemia NOS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cardiac disorders 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Arrhythmia NOS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
…  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
... 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


                                                          
 
                                                
 
Table 12.2.2.4 Adverse Events regardless of relationship. Worst grade by patient 
Category/MedDRA Code 
Grade 
PM01183+DOX 
Control 
1 
2 
… 
G≥1 
G≥3 
1 
2 
… 
G≥1 
G≥3 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
Blood and lymphatic system disorders 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Anaemia NOS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cardiac disorders 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Arrhythmia NOS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
…  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
... 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 12.2.2.5 Adverse Events regardless of relationship. Worst grade by cycle 
Category/MedDRA Code 
Grade 
PM01183+DOX 
Control 
1 
2 
… 
G≥1 
G≥3 
1 
2 
… 
G≥1 
G≥3 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
Blood and lymphatic system disorders 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Anaemia NOS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cardiac disorders 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Arrhythmia NOS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
…  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
... 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


                                                          
 
                                                
 
Listing 12.2.2.6 Drug-related grade 3/4 adverse events. Worst grade by cycle 
Treatment arm* 
Patient ID. 
Cycle 
SOC Name 
PTCode 
Grade 
 
 
 
 
 
 
 
 
 
 
 
 
*PM01183+DOX (Combination or PM01183 Alone)/Topotecan/CAV 
 
Listing 12.2.2.7 Grade 3/4 adverse events regardless of relationship. Worst grade by cycle 
Treatment arm* 
Patient ID. 
Cycle 
SOC Name 
PTCode 
Grade 
 
 
 
 
 
 
 
 
 
 
 
 
*PM01183+DOX (Combination or PM01183 Alone)/Topotecan/CAV 
 
12.2.3 Evolution of Signs and Symptoms during the Treatment 
Worst grade of signs and symptoms present at baseline in a percentage≥10% or grade ≥3 and their evolution during treatment will be 
shown regardless of relationship. 
 
 
Table 12.2.3.1 Shift of signs and symptoms during  treatment 
MedDRA PT 
Baseline grade 
Worst grade per patient during treatment  
Grade  
1 
Grade  
2 
Grade  
3 
Grade  
4 
N 
% 
N 
% 
N 
% 
N 
% 
PM01183+DOX 
Constipation 
1 
 
 
 
 
 
 
 
 
 
2 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
... 
1 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
Control 
Constipation 
1 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 


                                                          
 
                                                
12.2.4 Shift of AEs between combination and single agent administration 
In patients randomized to PM01183+Doxorubicin who will be treated with single agent PM01183 the worst grade of AEs related present in a 
percentage≥10% or with grade ≥3 and their evolution during single arm treatment will be shown. 
 
Table 12.2.4.1 Shift of AEs in PM01183 
MedDRA PT 
Worst grade per patient during 
combination treatment 
Worst grade per patient during single agent treatment  
Grade  
1 
Grade  
2 
Grade  
3 
Grade  
4 
N 
% 
N 
% 
N 
% 
N 
% 
PM01183+DOX 
Constipation 
1 
 
 
 
 
 
 
 
 
 
2 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
... 
1 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
12.3 Serious Adverse Events and Deaths.  
12.3.1  Serious Adverse Events 
Table 12.3.1.1 Drug-related serious adverse events. Worst grade by patient 
Category/MedDRA Code 
Grade 
PM01183+DOX 
Control 
1 
2 
… 
G≥1 
G≥3 
1 
2 
… 
G≥1 
G≥3 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
Blood and lymphatic system disorders 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Anaemia NOS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cardiac disorders 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Arrhythmia NOS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
…  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


                                                          
 
                                                
 
Table 12.3.1.2 Drug-related serious adverse events. Worst grade by cycle 
Category/MedDRA Code 
Grade 
PM01183+DOX 
Control 
1 
2 
… 
G≥1 
G≥3 
1 
2 
… 
G≥1 
G≥3 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
Blood and lymphatic system disorders 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Anaemia NOS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cardiac disorders 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
…  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
... 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 12.3.1.3 Serious adverse events regardless of relationship. Worst grade by patient 
Category/MedDRA Code 
Grade 
PM01183+DOX 
Control 
1 
2 
… 
G≥1 
G≥3 
1 
2 
… 
G≥1 
G≥3 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
Blood and lymphatic system disorders 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Anaemia NOS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cardiac disorders 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Arrhythmia NOS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
…  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
... 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
... 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


                                                          
 
                                                
 
Table 12.3.1.4 Serious adverse events regardless of relationship. Worst grade by cycle 
Category/MedDRA Code 
Grade 
PM01183+DOX 
Control 
1 
2 
… 
G≥1 
G≥3 
1 
2 
… 
G≥1 
G≥3 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
Blood and lymphatic system disorders 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Anaemia NOS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cardiac disorders 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Arrhythmia NOS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
…  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
... 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Listing 12.3.1.5 Drug-related grade 3/4 serious adverse events. Worst grade by cycle 
Treatment arm* 
Patient ID. 
Cycle 
SOC Name 
PTCode 
Grade 
 
 
 
 
 
 
 
 
 
 
 
 
*PM01183+DOX (Combination or PM01183 Alone)/Topotecan/CAV 
 
 
Listing 12.3.1.6 Grade 3/4 serious adverse events regardless of relationship. Worst grade by cycle 
Treatment arm* 
Patient ID. 
Cycle 
SOC Name 
PTCode 
Grade 
 
 
 
 
 
 
 
 
 
 
 
 
*PM01183+DOX (Combination or PM01183 Alone)/Topotecan/CAV 


                                                          
 
                             
12.3.2 Deaths 
Table 12.3.2.1 Cause of death 
Reason# 
PM01183+DOX 
Control 
Total 
Topotecan  
CAV 
N 
% 
N 
% 
N 
% 
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 
Treatment 
arm* 
Patient 
ID. 
Death 
date 
Cause Number of cycles 
administered 
Last 
infusion 
date 
Time on 
treatment** 
Time from 
Last dose*** 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
*PM01183+DOX (Combination or PM01183 Alone)/Topotecan/CAV 
**Time on treatment: defined as the date of the last infusion minus the first infusion date plus 30 days; or the date of 
death minus the first infusion date; or the date of start of new antitumor therapy minus the first infusion date 
(whichever comes first). 
***Time from the last dose: defined as the date of death minus the last infusion date.  
 
Listing 12.3.2.3 AEs reported as Fatal** 
Treatment 
arm* 
Patient 
ID.  
Cycle 
Preferred  
term code 
Adverse 
event 
reported 
(verbatim) 
Grade Relationship 
Onset 
date  Resolved date 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
*PM01183+DOX (Combination or PM01183 Alone)/Topotecan/CAV. **Outcome=death
12.4  Clinical Laboratory Evaluation 
12.4.1  Hematological Abnormalities 
Hematological toxicities classified according to NCI-CTCAE v.4 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 
 
Grade 
PM01183+DOX 
Control 
0 
1 
… 
G≥1 
G≥3 
0 
1 
… 
G≥1 
G≥3 
N % N % N % N % N % N % N % N % N % N % 
Leukopenia 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Anemia 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Thrombocytopenia 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Neutropenia 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lymphopenia 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


                                                          
 
                             
Listing 12.4.1.2 Hematological tests not assessed at any treatment visit by patient 
Treatment arm* 
Patient ID. 
Lab. test 
 
… 
 
 
… 
 
*PM01183+DOX/Topotecan/CAV 
 
Table 12.4.1.3 Hematological abnormalities, worst grade per cycle 
 
Grade 
PM01183+DOX 
Control 
0 
1 
… 
G≥1 
G≥3 
0 
1 
… 
G≥1 
G≥3 
N % N % N % N % N % N % N % N % N % N % 
Leukopenia 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Anemia 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Thrombocytopenia 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Neutropenia 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lymphopenia 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 12.4.1.4 Hematological abnormalities, worst grade per cycle by cycle 
 
Grade 
PM01183+DOX 
Control 
0 
1 
… 
G≥1 
G≥3 
0 
1 
… 
G≥1 
G≥3 
N % N % N % N % N % N % N % N % N % N % 
Cycle 1 
Leukopenia 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Anemia 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Thrombocytopenia 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Neutropenia 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lymphopenia 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cycle ... 
Listing 12.4.1.5 Hematological tests not assessed by patient and cycle 
Treatment arm* 
Patient ID. 
Cycle 
Lab. test 
 
… 
 
 
 
… 
 
 
*PM01183+DOX (Combination or PM01183 Alone)/Topotecan/CAV 
 
Listing 12.4.1.6 Grade 3/4 hematological abnormalities. Worst grade by cycle 
Treatment arm* 
Patient ID. 
Cycle 
Test 
Grade 
 
 
 
 
 
 
 
 
 
 
*PM01183+DOX (Combination or PM01183 Alone)/Topotecan/CAV 
 


                                                          
 
                             
12.4.2 Biochemical Abnormalities 
Table 12.4.2.1 Biochemical abnormalities, worst grade per patient 
 
Grade 
PM01183+DOX 
Control 
0 
1 
… 
G≥1 
G≥3 
0 
1 
… 
G≥1 
G≥3 
N % N % N % N % N % N % N % N % N % N % 
Creatinine increase 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CPK increase 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bilirubin increase 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AP increase 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AST increase 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ALT increase 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Listing 12.4.2.2 Biochemical tests not assessed at any treatment visit by patient 
Treatment arm* 
Patient ID. 
Lab. test 
 
… 
 
 
… 
 
*PM01183+DOX/Topotecan/CAV 
 
Table 12.4.2.3 Biochemical abnormalities, worst grade per cycle 
 
Grade 
PM01183+DOX 
Control 
0 
1 
… 
G≥1 
G≥3 
0 
1 
… 
G≥1 
G≥3 
N % N % N % N % N % N % N % N % N % N % 
Creatinine increase 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CPK increase 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bilirubin increase 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AP increase 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AST increase 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ALT increase 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 12.4.2.4 Biochemical abnormalities, worst grade per cycle by cycle 
 
Grade 
PM01183+DOX 
Control 
0 
1 
… 
G≥1 
G≥3 
0 
1 
… 
G≥1 
G≥3 
N % N % N % N % N % N % N % N % N % N % 
Cycle 1 
Creatinine increase 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CPK increase 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bilirubin increase 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AP increase 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AST increase 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ALT increase 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cycle ... 


                                                          
 
                             
 
Listing 12.4.2.5 Biochemical tests not assessed by patient and cycle 
Treatment arm* 
Patient ID. 
Cycle 
Lab. test 
 
… 
 
 
 
… 
 
 
*PM01183+DOX (Combination or PM01183 Alone)/Topotecan/CAV 
 
Listing 12.4.2.6 Grade 3/4 biochemical abnormalities. Worst grade by cycle 
Treatment arm* 
Patient ID. 
Cycle 
Test 
Grade 
 
 
 
 
 
 
 
 
 
 
*PM01183+DOX (Combination or PM01183 Alone)/Topotecan/CAV 
12.4.3  Other Metabolic Parameters 
Table 12.4.3.1 Metabolic abnormalities, worst grade per patient 
 
Grade 
PM01183+DOX 
Control 
0 
1 
… 
G≥1 
G≥3 
0 
1 
… 
G≥1 
G≥3 
N % N % N % N % N % N % N % N % N % N % 
Hyperglycemia 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hypernatremia 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hyperkalemia 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hypercalcemia 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hypoglycemia 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hyponatremia 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hypokalemia 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hypocalcemia 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hypoalbuminemia 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Listing 12.4.3.2 Metabolic tests not assessed at any treatment visit by patient 
Treatment arm* 
Patient ID. 
Lab. test 
 
… 
 
*PM01183+DOX/Topotecan/CAV 
 
Table 12.4.3.3 Metabolic abnormalities, worst grade per cycle 
 
Grade 
PM01183+DOX 
Control 
0 
1 
… 
G≥1 
G≥3 
0 
1 
… 
G≥1 
G≥3 
N % N % N % N % N % N % N % N % N % N % 
Hyperglycemia 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hypernatremia 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hyperkalemia 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hypercalcemia 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hypoglycemia 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hyponatremia 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hypokalemia 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hypocalcemia 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hypoalbuminemia 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


                                                          
 
                             
Table 12.4.3.4 Metabolic abnormalities, worst grade per cycle by cycle 
 
Grade 
PM01183+DOX 
Control 
0 
1 
… 
G≥1 
G≥3 
0 
1 
… 
G≥1 
G≥3 
N % N % N % N % N % N % N % N % N % N % 
Cycle 1 
Hyperglycemia 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hypernatremia 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hyperkalemia 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hypercalcemia 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hypoglycemia 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hyponatremia 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hypokalemia 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hypocalcemia 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hypoalbuminemia 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cycle ... 
Listing 12.4.3.5 Metabolic tests not assessed by patient and cycle 
Treatment arm* 
Patient ID. 
Cycle 
Lab. test 
 
… 
 
 
 
… 
 
 
*PM01183+DOX (Combination or PM01183 Alone)/Topotecan/CAV 
 
Listing 12.4.3.6 Grade 3/4 metabolic abnormalities. Worst grade by cycle 
Treatment arm* 
Patient ID. 
Cycle 
Test 
Grade 
 
 
 
 
 
 
 
 
 
 
*PM01183+DOX (Combination or PM01183 Alone)/Topotecan/CAV 
12.4.4  Laboratory Values over Time 
 
A summary of the laboratory values found in all patients will be shown.  
 
Laboratory abnormality categories will be defined as:  
-Hematological 
abnormalities, 
including 
leukopenia, 
neutropenia, 
anemia, 
thrombocytopenia and lymphopenia. 
-Biochemical abnormalities, including creatinine increase, CPK increase, total bilirubin 
increase, AP increase, AST increase and ALT increase. 
-Other metabolic abnormalities, including hyperglycemia, hypernatremia, hyperkalemia, 
hypercalcemia, 
hypoglycemia, 
hyponatremia, 
hypokalemia, 
hypocalcemia 
and 
hypoalbuminemia. 
 


                                                          
 
                             
Table 12.4.4.1 Summary of laboratory values 
Category 
PM01183+DOX 
Control 
N (%) 
N (%) 
Any abnormality (G1/4) in laboratory value (hema, bio or metabolic) 
 
 
Any abnormality (G3/4) in laboratory value (hema, bio or metabolic) 
 
 
Any abnormality (G4) in laboratory value (hema, bio or metabolic) 
 
 
Any abnormality (G1/4) in hematological value  
 
 
Any abnormality (G3/4) in hematological value 
 
 
Any abnormality (G4) in hematological value 
 
 
Any abnormality (G1/4) in biochemical value  
 
 
Any abnormality (G3/4) in biochemical value 
 
 
Any abnormality (G4) in biochemical value 
 
 
Any abnormality (G1/4) in other metabolic value  
 
 
Any abnormality (G3/4) in other metabolic value 
 
 
Any abnormality (G4) in other metabolic value 
 
 
 
The worst grade during treatment and in the first cycle compared to baseline will be 
shown for hematological and biochemical parameters. 
 
Table 12.4.4.2 Shift of hematological abnormalities, worst grade per patient vs. baseline 
 
Baseline grade* 
Worst grade per patient during treatment  
Grade  
0 
Grade  
1 
Grade  
… 
Grade  
4 
N 
% 
N 
% 
N 
% 
N 
% 
PM01183+DOX 
Leukopenia 
0 
 
 
 
 
 
 
 
 
 
1 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
Neutropenia 
0 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
…** 
0 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
Control 
Leukopenia 
0 
 
 
 
 
 
 
 
 
 
1 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
Neutropenia 
0 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
…** 
0 
 
 
 
 
 
 
 
 
*Defined as the last value recorded before or on the date of first infusion. 
** Anemia, thrombocytopenia and lymphopenia. 
 
Table 12.4.4.3 Shift of hematological abnormalities (PM01183), worst grade during combination vs. 
single agent 
 
Worst grade per 
patient during 
combination 
treatment 
Worst grade per patient during single agent treatment  
Grade  
0 
Grade  
1 
Grade  
… 
Grade  
4 
N 
% 
N 
% 
N 
% 
N 
% 
Leukopenia 
0 
 
 
 
 
 
 
 
 
 
1 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
Neutropenia 
0 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
…* 
0 
 
 
 
 
 
 
 
 
*Anemia, thrombocytopenia and lymphopenia. 


                                                          
 
                             
 
Table 12.4.4.4 Shift of biochemical abnormalities, worst grade per patient vs. baseline 
 
Baseline grade* 
Worst grade per patient during treatment  
Grade  
0 
Grade  
1 
Grade  
… 
Grade  
4 
N 
% 
N 
% 
N 
% 
N 
% 
PM01183+DOX 
ALT 
0 
 
 
 
 
 
 
 
 
 
1 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
AST 
0 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
…** 
0 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
Control 
ALT 
0 
 
 
 
 
 
 
 
 
 
1 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
AST 
0 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
…** 
0 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
*Defined as the last value recorded before or on the date of first infusion. 
** Total bilirubin, AP, CPK, creatinine, hyperglycemia, hypernatremia, hyperkalemia, hypoglycemia, hyponatremia, 
hypokalemia and hypoalbuminemia. 
 
Table 12.4.4.5 Shift of biochemical abnormalities (PM01183), worst grade during combination vs. single 
agent 
 
Worst grade per 
patient during 
combination 
treatment 
Worst grade per patient during single agent treatment  
Grade  
0 
Grade  
1 
Grade  
… 
Grade  
4 
N 
% 
N 
% 
N 
% 
N 
% 
ALT 
0 
 
 
 
 
 
 
 
 
 
1 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
AST 
0 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
…* 
0 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
* Total bilirubin, AP, CPK, creatinine, hyperglycemia, hypernatremia, hyperkalemia, hypoglycemia, hyponatremia, 
hypokalemia and hypoalbuminemia. 
 
Median intercycle figures showing PM01183+DOX and Control arms for laboratory 
values will be added.   
 
- Figure 12.4.4.6 Median nadir values for platelets 
- Figure 12.4.4.7 Median nadir values for neutrophils 
- Figure 12.4.4.8 Median peak values for AST  
- Figure 12.4.4.9 Median peak values for ALT  
 


                                                          
 
                             
Example intercycle graph 
 
 
 
Table 12.4.4.10 Fisher exact test. Worst grade <3 vs. grade ≥3 by patient 
 
PM01183+DOX 
Control 
p-
value 
Grade 
<3 
Grade  
≥3 
Grade 
<3 
Grade  
≥3 
Thrombocytopenia 
 
 
 
 
 
Neutropenia  
 
 
 
 
 
Febrile Neutropenia 
 
 
 
 
 
Neutropenic Sepsis 
 
 
 
 
 
Neutropenic Infection 
 
 
 
 
 
AP  
 
 
 
 
 
Bilirubin  
 
 
 
 
 
AST  
 
 
 
 
 
ALT  
 
 
 
 
 
CPK 
 
 
 
 
 
Nausea 
 
 
 
 
 
Vomiting 
 
 
 
 
 
Fatigue 
 
 
 
 
 
Other* 
 
 
 
 
 
*Any drug-related toxicity present in >=5% of patients in any group. 
 
 
 


                                                          
 
                             
Table 12.4.4.11 Fisher exact test. Worst grade <4 vs. grade ≥4 by patient 
 
PM01183+DOX 
Control 
p-
value 
Grade 
<4 
Grade  
≥4 
Grade 
<4 
Grade  
≥4 
Thrombocytopenia 
 
 
 
 
 
Neutropenia  
 
 
 
 
 
Febrile Neutropenia 
 
 
 
 
 
Neutropenic Sepsis 
 
 
 
 
 
Neutropenic Infection 
 
 
 
 
 
Other* 
 
 
 
 
 
*Any other clinical laboratory test or drug-related toxicity present in >=5% of patients in any group. 
 


                                                          
 
                             
12.5 Subgroup Analyses Related to Safety 
 
Information for laboratory abnormalities comes from hematology/biochemistry forms 
and not from the AE form. 
 
Table 12.5.1 Worst grade 3/4 by patient in special subgroups (Sex) 
Laboratory abnormalities/ drug-related AEs 
Male 
Female 
No. of 
patients 
 evaluated 
Grade  
3/4 
% 
No. of 
patients 
 evaluated 
Grade  
3/4 
% 
PM01183+DOX 
Thrombocytopenia 
 
 
 
 
 
 
Neutropenia  
 
 
 
 
 
 
AP  
 
 
 
 
 
 
Bilirubin  
 
 
 
 
 
 
AST  
 
 
 
 
 
 
ALT  
 
 
 
 
 
 
CPK 
 
 
 
 
 
 
Nausea 
 
 
 
 
 
 
Vomiting 
 
 
 
 
 
 
Fatigue 
 
 
 
 
 
 
Other* 
 
 
 
 
 
 
Control 
Thrombocytopenia 
 
 
 
 
 
 
Neutropenia  
 
 
 
 
 
 
AP  
 
 
 
 
 
 
Bilirubin  
 
 
 
 
 
 
AST  
 
 
 
 
 
 
ALT  
 
 
 
 
 
 
CPK 
 
 
 
 
 
 
Nausea 
 
 
 
 
 
 
Vomiting 
 
 
 
 
 
 
Fatigue 
 
 
 
 
 
 
Other* 
 
 
 
 
 
 
*Any drug-related toxicity present in >=5% of patients in any group. 
 


                                                          
 
                             
Table 12.5.2 Worst grade 3/4 by cycle in special subgroups (Sex) 
Laboratory abnormalities/ drug-related 
AEs 
Male 
Female 
No. of cycles 
evaluated 
Grade  
3/4 
% 
No. of cycles 
evaluated 
Grade 
3/4 
% 
PM01183+DOX 
Thrombocytopenia 
 
 
 
 
 
 
Neutropenia  
 
 
 
 
 
 
AP  
 
 
 
 
 
 
Bilirubin  
 
 
 
 
 
 
AST  
 
 
 
 
 
 
ALT  
 
 
 
 
 
 
CPK 
 
 
 
 
 
 
Nausea 
 
 
 
 
 
 
Vomiting 
 
 
 
 
 
 
Fatigue 
 
 
 
 
 
 
Other* 
 
 
 
 
 
 
Control 
Thrombocytopenia 
 
 
 
 
 
 
Neutropenia  
 
 
 
 
 
 
AP  
 
 
 
 
 
 
Bilirubin  
 
 
 
 
 
 
AST  
 
 
 
 
 
 
ALT  
 
 
 
 
 
 
CPK 
 
 
 
 
 
 
Nausea 
 
 
 
 
 
 
Vomiting 
 
 
 
 
 
 
Fatigue 
 
 
 
 
 
 
Other* 
 
 
 
 
 
 
*Any drug-related toxicity present in >=3% of cycles in any group. 


                                                          
 
                             
Table 12.5.3 Worst grade 3/4 by patient in special subgroups (Age) 
Laboratory abnormalities/ drug-related AEs 
≤65 years-old 
>65 years-old 
No. of 
patients 
 evaluated 
Grade  
3/4 
% 
No. of 
patients 
 evaluated 
Grade  
3/4 
% 
PM01183+DOX 
Thrombocytopenia 
 
 
 
 
 
 
Neutropenia  
 
 
 
 
 
 
AP  
 
 
 
 
 
 
Bilirubin  
 
 
 
 
 
 
AST  
 
 
 
 
 
 
ALT  
 
 
 
 
 
 
CPK 
 
 
 
 
 
 
Nausea 
 
 
 
 
 
 
Vomiting 
 
 
 
 
 
 
Fatigue 
 
 
 
 
 
 
Other* 
 
 
 
 
 
 
Control 
Thrombocytopenia 
 
 
 
 
 
 
Neutropenia  
 
 
 
 
 
 
AP  
 
 
 
 
 
 
Bilirubin  
 
 
 
 
 
 
AST  
 
 
 
 
 
 
ALT  
 
 
 
 
 
 
CPK 
 
 
 
 
 
 
Nausea 
 
 
 
 
 
 
Vomiting 
 
 
 
 
 
 
Fatigue 
 
 
 
 
 
 
Other* 
 
 
 
 
 
 
*Any drug-related toxicity present in >=5% of patients in any group. 
 


                                                          
 
                             
Table 12.5.4 Worst grade 3/4 by cycle in special subgroups (Age) 
Laboratory abnormalities/ drug-related 
AEs 
≤65 years-old 
>65 years-old 
No. of cycles 
evaluated 
Grade  
3/4 
% 
No. of cycles 
evaluated 
Grade 
3/4 
% 
PM01183+DOX 
Thrombocytopenia 
 
 
 
 
 
 
Neutropenia  
 
 
 
 
 
 
AP  
 
 
 
 
 
 
Bilirubin  
 
 
 
 
 
 
AST  
 
 
 
 
 
 
ALT  
 
 
 
 
 
 
CPK 
 
 
 
 
 
 
Nausea 
 
 
 
 
 
 
Vomiting 
 
 
 
 
 
 
Fatigue 
 
 
 
 
 
 
Other* 
 
 
 
 
 
 
Control 
Thrombocytopenia 
 
 
 
 
 
 
Neutropenia  
 
 
 
 
 
 
AP  
 
 
 
 
 
 
Bilirubin  
 
 
 
 
 
 
AST  
 
 
 
 
 
 
ALT  
 
 
 
 
 
 
CPK 
 
 
 
 
 
 
Nausea 
 
 
 
 
 
 
Vomiting 
 
 
 
 
 
 
Fatigue 
 
 
 
 
 
 
Other* 
 
 
 
 
 
 
*Any drug-related toxicity present in >=3% of cycles in any group. 
 
 


                                                          
 
                             
Table 12.5.5 Worst grade 3/4 by patient in special subgroups (Race) 
Laboratory abnormalities/ drug-related AEs 
White 
Other 
No. of 
patients 
 evaluated 
Grade  
3/4 
% 
No. of 
patients 
 evaluated 
Grade  
3/4 
% 
PM01183+DOX 
Thrombocytopenia 
 
 
 
 
 
 
Neutropenia  
 
 
 
 
 
 
AP  
 
 
 
 
 
 
Bilirubin  
 
 
 
 
 
 
AST  
 
 
 
 
 
 
ALT  
 
 
 
 
 
 
CPK 
 
 
 
 
 
 
Nausea 
 
 
 
 
 
 
Vomiting 
 
 
 
 
 
 
Fatigue 
 
 
 
 
 
 
Other* 
 
 
 
 
 
 
Control 
Thrombocytopenia 
 
 
 
 
 
 
Neutropenia  
 
 
 
 
 
 
AP  
 
 
 
 
 
 
Bilirubin  
 
 
 
 
 
 
AST  
 
 
 
 
 
 
ALT  
 
 
 
 
 
 
CPK 
 
 
 
 
 
 
Nausea 
 
 
 
 
 
 
Vomiting 
 
 
 
 
 
 
Fatigue 
 
 
 
 
 
 
Other* 
 
 
 
 
 
 
*Any drug-related toxicity present in >=5% of patients in any group. 
 


                                                          
 
                             
Table 12.5.6 Worst grade 3/4 by cycle in special subgroups (Race) 
Laboratory abnormalities/ drug-related 
AEs 
White 
Other 
No. of cycles 
evaluated 
Grade  
3/4 
% 
No. of cycles 
evaluated 
Grade 
3/4 
% 
PM01183+DOX 
Thrombocytopenia 
 
 
 
 
 
 
Neutropenia  
 
 
 
 
 
 
AP  
 
 
 
 
 
 
Bilirubin  
 
 
 
 
 
 
AST  
 
 
 
 
 
 
ALT  
 
 
 
 
 
 
CPK 
 
 
 
 
 
 
Nausea 
 
 
 
 
 
 
Vomiting 
 
 
 
 
 
 
Fatigue 
 
 
 
 
 
 
Other* 
 
 
 
 
 
 
Control 
Thrombocytopenia 
 
 
 
 
 
 
Neutropenia  
 
 
 
 
 
 
AP  
 
 
 
 
 
 
Bilirubin  
 
 
 
 
 
 
AST  
 
 
 
 
 
 
ALT  
 
 
 
 
 
 
CPK 
 
 
 
 
 
 
Nausea 
 
 
 
 
 
 
Vomiting 
 
 
 
 
 
 
Fatigue 
 
 
 
 
 
 
Other* 
 
 
 
 
 
 
*Any drug-related toxicity present in >=3% of cycles in any group. 
 


                                                          
 
                             
Table 12.5.7 Worst grade 3/4 by patient in special subgroups (Number of prior lines) 
Laboratory abnormalities/ drug-related 
AEs 
1 
>1 
No. of cycles 
evaluated 
Grade  
3/4 
% 
No. of cycles 
evaluated 
Grade 
3/4 
% 
PM01183+DOX 
Thrombocytopenia 
 
 
 
 
 
 
Neutropenia  
 
 
 
 
 
 
AP  
 
 
 
 
 
 
Bilirubin  
 
 
 
 
 
 
AST  
 
 
 
 
 
 
ALT  
 
 
 
 
 
 
CPK 
 
 
 
 
 
 
Nausea 
 
 
 
 
 
 
Vomiting 
 
 
 
 
 
 
Fatigue 
 
 
 
 
 
 
Other* 
 
 
 
 
 
 
Control 
Thrombocytopenia 
 
 
 
 
 
 
Neutropenia  
 
 
 
 
 
 
AP  
 
 
 
 
 
 
Bilirubin  
 
 
 
 
 
 
AST  
 
 
 
 
 
 
ALT  
 
 
 
 
 
 
CPK 
 
 
 
 
 
 
Nausea 
 
 
 
 
 
 
Vomiting 
 
 
 
 
 
 
Fatigue 
 
 
 
 
 
 
Other* 
 
 
 
 
 
 
*Any drug-related toxicity present in >=5% of patients in any group. 
 
 
 


                                                          
 
                             
Table 12.5.8 Worst grade 3/4 by cycle in special subgroups (Number of prior line) 
Laboratory abnormalities/ drug-related 
AEs 
1 
>1 
No. of cycles 
evaluated 
Grade  
3/4 
% 
No. of cycles 
evaluated 
Grade 
3/4 
% 
PM01183+DOX 
Thrombocytopenia 
 
 
 
 
 
 
Neutropenia  
 
 
 
 
 
 
AP  
 
 
 
 
 
 
Bilirubin  
 
 
 
 
 
 
AST  
 
 
 
 
 
 
ALT  
 
 
 
 
 
 
CPK 
 
 
 
 
 
 
Nausea 
 
 
 
 
 
 
Vomiting 
 
 
 
 
 
 
Fatigue 
 
 
 
 
 
 
Other* 
 
 
 
 
 
 
Control 
Thrombocytopenia 
 
 
 
 
 
 
Neutropenia  
 
 
 
 
 
 
AP  
 
 
 
 
 
 
Bilirubin  
 
 
 
 
 
 
AST  
 
 
 
 
 
 
ALT  
 
 
 
 
 
 
CPK 
 
 
 
 
 
 
Nausea 
 
 
 
 
 
 
Vomiting 
 
 
 
 
 
 
Fatigue 
 
 
 
 
 
 
Other* 
 
 
 
 
 
 
*Any drug-related toxicity present in >=3% of cycles in any group. 
 


                                                          
 
                             
Table 12.5.9 Worst grade 3/4 by patient in special subgroups (BSA) 
Laboratory abnormalities/ drug-related 
AEs 
<2 
≥2 
No. of cycles 
evaluated 
Grade  
3/4 
% 
No. of cycles 
evaluated 
Grade 
3/4 
% 
PM01183+DOX 
Thrombocytopenia 
 
 
 
 
 
 
Neutropenia  
 
 
 
 
 
 
AP  
 
 
 
 
 
 
Bilirubin  
 
 
 
 
 
 
AST  
 
 
 
 
 
 
ALT  
 
 
 
 
 
 
CPK 
 
 
 
 
 
 
Nausea 
 
 
 
 
 
 
Vomiting 
 
 
 
 
 
 
Fatigue 
 
 
 
 
 
 
Other* 
 
 
 
 
 
 
Control 
Thrombocytopenia 
 
 
 
 
 
 
Neutropenia  
 
 
 
 
 
 
AP  
 
 
 
 
 
 
Bilirubin  
 
 
 
 
 
 
AST  
 
 
 
 
 
 
ALT  
 
 
 
 
 
 
CPK 
 
 
 
 
 
 
Nausea 
 
 
 
 
 
 
Vomiting 
 
 
 
 
 
 
Fatigue 
 
 
 
 
 
 
Other* 
 
 
 
 
 
 
*Any drug-related toxicity present in >=5% of patients in any group. 
 
 
 


                                                          
 
                             
Table 12.5.10 Worst grade 3/4 by cycle in special subgroups (BSA) 
Laboratory abnormalities/ drug-related 
AEs 
<2 
≥2 
No. of cycles 
evaluated 
Grade  
3/4 
% 
No. of cycles 
evaluated 
Grade 
3/4 
% 
PM01183+DOX 
Thrombocytopenia 
 
 
 
 
 
 
Neutropenia  
 
 
 
 
 
 
AP  
 
 
 
 
 
 
Bilirubin  
 
 
 
 
 
 
AST  
 
 
 
 
 
 
ALT  
 
 
 
 
 
 
CPK 
 
 
 
 
 
 
Nausea 
 
 
 
 
 
 
Vomiting 
 
 
 
 
 
 
Fatigue 
 
 
 
 
 
 
Other* 
 
 
 
 
 
 
Control 
Thrombocytopenia 
 
 
 
 
 
 
Neutropenia  
 
 
 
 
 
 
AP  
 
 
 
 
 
 
Bilirubin  
 
 
 
 
 
 
AST  
 
 
 
 
 
 
ALT  
 
 
 
 
 
 
CPK 
 
 
 
 
 
 
Nausea 
 
 
 
 
 
 
Vomiting 
 
 
 
 
 
 
Fatigue 
 
 
 
 
 
 
Other* 
 
 
 
 
 
 
*Any drug-related toxicity present in >=3% of cycles in any group. 


                                                          
 
                             
  
Table 12.5.11 Worst grade 3/4 by patient in special subgroups (Geographical area) 
Laboratory abnormalities/ drug-
related AEs 
USA 
Europe 
Rest of the world 
No. of 
patients 
evaluated 
Grade  
3/4 
% 
No. of 
patients 
evaluated 
Grade  
3/4 
% 
No. of 
patients 
evaluated 
Grade  
3/4 
% 
PM01183+DOX 
Thrombocytopenia 
 
 
 
 
 
 
 
 
 
Neutropenia  
 
 
 
 
 
 
 
 
 
AP  
 
 
 
 
 
 
 
 
 
Bilirubin  
 
 
 
 
 
 
 
 
 
AST  
 
 
 
 
 
 
 
 
 
ALT  
 
 
 
 
 
 
 
 
 
CPK 
 
 
 
 
 
 
 
 
 
Nausea 
 
 
 
 
 
 
 
 
 
Vomiting 
 
 
 
 
 
 
 
 
 
Fatigue 
 
 
 
 
 
 
 
 
 
Other* 
 
 
 
 
 
 
 
 
 
Control 
Thrombocytopenia 
 
 
 
 
 
 
 
 
 
Neutropenia  
 
 
 
 
 
 
 
 
 
AP  
 
 
 
 
 
 
 
 
 
Bilirubin  
 
 
 
 
 
 
 
 
 
AST  
 
 
 
 
 
 
 
 
 
ALT  
 
 
 
 
 
 
 
 
 
CPK 
 
 
 
 
 
 
 
 
 
Nausea 
 
 
 
 
 
 
 
 
 
Vomiting 
 
 
 
 
 
 
 
 
 
Fatigue 
 
 
 
 
 
 
 
 
 
Other* 
 
 
 
 
 
 
 
 
 
*Any drug-related toxicity present in >=5% of patients in any group. 
 
 
 


                                                          
 
                             
Table 12.5.12 Worst grade 3/4 by cycle in special subgroups (Geographical area) 
Laboratory abnormalities/ drug-
related AEs 
USA 
Europe 
Rest of the world 
No. of 
patients 
evaluated 
Grade  
3/4 
% 
No. of 
patients 
evaluated 
Grade  
3/4 
% 
No. of 
patients 
evaluated 
Grade  
3/4 
% 
PM01183+DOX 
Thrombocytopenia 
 
 
 
 
 
 
 
 
 
Neutropenia  
 
 
 
 
 
 
 
 
 
AP  
 
 
 
 
 
 
 
 
 
Bilirubin  
 
 
 
 
 
 
 
 
 
AST  
 
 
 
 
 
 
 
 
 
ALT  
 
 
 
 
 
 
 
 
 
CPK 
 
 
 
 
 
 
 
 
 
Nausea 
 
 
 
 
 
 
 
 
 
Vomiting 
 
 
 
 
 
 
 
 
 
Fatigue 
 
 
 
 
 
 
 
 
 
Other* 
 
 
 
 
 
 
 
 
 
Control 
Thrombocytopenia 
 
 
 
 
 
 
 
 
 
Neutropenia  
 
 
 
 
 
 
 
 
 
AP  
 
 
 
 
 
 
 
 
 
Bilirubin  
 
 
 
 
 
 
 
 
 
AST  
 
 
 
 
 
 
 
 
 
ALT  
 
 
 
 
 
 
 
 
 
CPK 
 
 
 
 
 
 
 
 
 
Nausea 
 
 
 
 
 
 
 
 
 
Vomiting 
 
 
 
 
 
 
 
 
 
Fatigue 
 
 
 
 
 
 
 
 
 
Other* 
 
 
 
 
 
 
 
 
 
*Any drug-related toxicity present in >=3% of cycles in any group. 
 


                                                          
 
                             
Table 12.5.13 Worst grade by patient comparison vs. Topotecan 
Laboratory 
abnormalities/ drug-
related AEs 
Grade 
PM01183 
Topotecan 
0 
1 
… 
G≥1 
G≥3 
0 
1 
… 
G≥1 
G≥3 
N % N % N % N % N % N % N % N % N % N % 
Thrombocytopenia 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Neutropenia  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AP  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bilirubin  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AST  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ALT  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CPK 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Nausea 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vomiting 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fatigue 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Other* 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
*Any drug-related toxicity present in >=5% of patients in any group. 
 
 
Table 12.5.14 Worst grade by cycle comparison vs. Topotecan 
Laboratory 
abnormalities/ drug-
related AEs 
Grade 
PM01183 
Topotecan 
0 
1 
… 
G≥1 
G≥3 
0 
1 
… 
G≥1 
G≥3 
N % N % N % N % N % N % N % N % N % N % 
Thrombocytopenia 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Neutropenia  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AP  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bilirubin  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AST  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ALT  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CPK 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Nausea 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vomiting 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fatigue 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Other* 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
*Any drug-related toxicity present in >=5% of patients in any group. 


                                                          
 
                             
Table 12.5.15 Worst grade by patient comparison vs. CAV 
Laboratory 
abnormalities/ drug-
related AEs 
Grade 
PM01183 
CAV 
0 
1 
… 
G≥1 
G≥3 
0 
1 
… 
G≥1 
G≥3 
N % N % N % N % N % N % N % N % N % N % 
Thrombocytopenia 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Neutropenia  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AP  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bilirubin  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AST  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ALT  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CPK 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Nausea 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vomiting 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fatigue 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Other* 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
*Any drug-related toxicity present in >=5% of patients in any group. 
 
 
Table 12.5.16 Worst grade by cycle comparison vs. CAV 
Laboratory 
abnormalities/ drug-
related AEs 
Grade 
PM01183 
CAV 
0 
1 
… 
G≥1 
G≥3 
0 
1 
… 
G≥1 
G≥3 
N % N % N % N % N % N % N % N % N % N % 
Thrombocytopenia 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Neutropenia  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AP  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bilirubin  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AST  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ALT  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CPK 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Nausea 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vomiting 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fatigue 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Other* 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
*Any drug-related toxicity present in >=5% of patients in any group. 


                                                          
 
                             
LVEF and QT analyses will be performed comparing the PM01183+DOX arm vs. the 
Control arm, but an intrapatient comparison will also be conducted on patients who 
received combination and single-agent treatment in the PM01183+DOX arm.  
Table 12.5.17 LVEF decrease from baseline 
 
PM01183+DOX 
Control 
Total 
Topotecan  
CAV 
N 
% 
N 
% 
N 
% 
N 
% 
MUGA 
 
 
 
 
 
 
 
 
Absolute decrease ≥15% 
 
 
 
 
 
 
Absolute decrease ≥10%-15% 
 
 
 
 
 
 
Less than lower limit of normal 
and absolute 
 
 
 
 
 
 
ECHO 
 
 
 
 
 
 
Absolute decrease ≥15% 
 
 
 
 
 
 
Absolute decrease ≥10%-15% 
 
 
 
 
 
 
Less than lower limit of normal 
and absolute 
 
 
 
 
 
 
Figure 12.5.18 LVEF value during treatment 
 
Table 12.5.19 PM01183+DOX arm. LVEF decrease with combination or with single-agent treatment  
 
Combination 
PM01183 alone 
N 
% 
N 
% 
MUGA 
 
 
 
 
Absolute decrease ≥15% 
 
 
Absolute decrease ≥10%-15% 
 
 
Less than lower limit of normal and absolute 
decrease ≥5% 
 
 
ECHO 
 
 
Absolute decrease ≥15% 
 
 
Absolute decrease ≥10%-15% 
 
 
Less than lower limit of normal and absolute 
decrease ≥5% 
 
 


                                                          
 
                             
Table 12.5.20 QTcF worst value on treatment 
 
PM01183+DOX 
Control 
Total 
Topotecan  
CAV 
N 
% 
N 
% 
N 
% 
N 
% 
≥501ms 
 
 
 
 
 
 
 
 
≥481ms 
 
 
 
 
 
 
≥451ms 
 
 
 
 
 
 
Figure 12.5.21 QTcF value across treatment 
 
Table 12.5.22 PM01183+DOX arm. QTcF worst value with combination or single-agent treatment. 
 
Combination 
PM01183 alone 
N 
% 
N 
% 
≥501ms 
 
 
 
 
≥481ms 
 
 
≥451ms 
 
 
 
 


                                                          
 
                             
12.6 Concomitant Medication during Treatment  
Table 12.6.1 Concomitant medication during treatment (ATC1/ATC2/ATC4) 
Concomitant medication 
PM01183+DOX 
Control 
N 
% 
N 
% 
Alimentary tract and metabolism 
 
 
 
 
  Antiacids 
 
 
    Magnesium compounds 
 
 
…. 
 
 
 
 
 
 
 
 
 
 
Blood and blood forming organs 
 
 
  Antithrombotic agents 
 
 
     Vitamin K antagonists 
 
 
… 
 
 
Table 12.6.2 Transfusions or EPO 
 
PM01183+DOX 
Control 
Total 
Topotecan  
CAV 
N 
% 
N 
% 
N 
% 
N 
% 
Platelets transfusions 
 
 
 
 
 
 
 
 
RBC transfusions 
 
 
 
 
 
 
EPO 
 
 
 
 
 
 
Listing 12.6.3 Patients who have been treated with transfusions or EPO  
Treatment 
arm* 
Patient 
ID. 
Type 
Agent 
Route 
Dose 
Unit 
Start 
date 
Stop 
date 
Reason 
Indication 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
*PM01183+DOX (Combination or PM01183 Alone)/Topotecan/CAV 
12.7 Subsequent Therapy 
Table 12.7.1 Subsequent therapy 
 
PM01183+DOX 
Control 
Total 
Topotecan  
CAV 
N 
% 
N 
% 
N 
% 
N 
% 
Type 
 
 
 
 
 
 
 
 
  Chemotherapy 
 
 
 
 
 
 
  Surgery 
 
 
 
 
 
 
  Inmunotherapy 
 
 
 
 
 
 
  … 
 
 
 
 
 
 
Subsequent therapy agents* 
 
 
 
 
 
 
 
 
  Platinum 
 
 
 
 
 
 
  Taxanes 
 
 
 
 
 
 
  Nivolumab 
 
 
 
 
 
 
  Investigational agent 
 
 
 
 
 
 
   … 
 
 
 
 
 
 
* Sites have been instructed in the database completion guidelines to report one drug per record, but in the summary 
it may be requested to group some combinations, e.g. CAV 


                                                          
 
                             
12.8  PRO during Treatment  
Completion rate will be defined as the number of patients with answer to item X in the 
numerator and the number of available patients in each time moment as denominator.  
 
Missing data will not be taken into account in the analyses; anyway, if the quantity is 
considered relevant then supportive analyses will be performed applying a conservative 
approach of assuming missing data as failures.  
 
Table 12.8.1 Completion rate 
Item 
Cycle 
PM01183+DOX 
Control 
Missing 
(%) 
Completed 
(%) 
Missing 
(%) 
Completed 
(%) 
EORTC QLQ-C30 
 
 
 
 
Item 1 
Baseline  
 
 
 
 
 
Week 6 
 
 
 
 
 
… 
 
 
 
 
…. 
Baseline  
 
 
 
 
 
… 
 
 
 
 
Any item 
Baseline  
 
 
 
 
 
Week 6 
 
 
 
 
 
… 
 
 
 
 
EORTC QLQ-LC13 
 
 
 
 
Item 31 
Baseline  
 
 
 
 
 
Week 6 
 
 
 
 
 
… 
 
 
 
 
…. 
Baseline  
 
 
 
 
 
… 
 
 
 
 
Any item 
Baseline  
 
 
 
 
 
Week 6 
 
 
 
 
 
… 
 
 
 
 
EORTC QLQ-C30 and QLQ-LC13 
 
 
 
 
Any item 
Baseline  
 
 
 
 
 
… 
 
 
 
 
 
 Table 12.8.2 T-test change vs. baseline 
Item 
Cycle 
PM01183+DOX 
Control* 
p-value 
N 
Mean (std) 
N 
Mean (std) 
*Control refers to topotecan and/or CAV 
Item 1 
Week 6 
 
 
 
 
 
 
Week 12 
 
 
 
 
 
 
… 
 
 
 
 
 
…. 
Week 6 
 
 
 
 
 
 
Week 12 
 
 
 
 
 
 
… 
 
 
 
 
 
Item 43 
Week 6 
 
 
 
 
 
 
Week 12 
 
 
 
 
 
 
… 
 
 
 
 
 
*Control refers to topotecan 


                                                          
 
                             
Item 
Cycle 
PM01183+DOX 
Control* 
p-value 
N 
Mean (std) 
N 
Mean (std) 
Item 1 
Week 6 
 
 
 
 
 
 
Week 12 
 
 
 
 
 
 
… 
 
 
 
 
 
…. 
Week 6 
 
 
 
 
 
 
Week 12 
 
 
 
 
 
 
… 
 
 
 
 
 
Item 43 
Week 6 
 
 
 
 
 
 
Week 12 
 
 
 
 
 
 
… 
 
 
 
 
 
*Control refers to CAV 
Item 1 
Week 6 
 
 
 
 
 
 
Week 12 
 
 
 
 
 
 
… 
 
 
 
 
 
…. 
Week 6 
 
 
 
 
 
 
Week 12 
 
 
 
 
 
 
… 
 
 
 
 
 
Item 43 
Week 6 
 
 
 
 
 
 
Week 12 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
Table 12.8.3 Percentage of patients with an improvement ≥10% vs. baseline 
Item 
Cycle 
PM01183+DOX 
Control* 
p-value 
N 
% 
N 
% 
*Control refers to topotecan and/or CAV 
Item 1 
Week 6 
 
 
 
 
 
 
Week 12 
 
 
 
 
 
 
… 
 
 
 
 
 
…. 
Week 6 
 
 
 
 
 
 
Week 12 
 
 
 
 
 
 
… 
 
 
 
 
 
Item 43 
Week 6 
 
 
 
 
 
 
Week 12 
 
 
 
 
 
 
… 
 
 
 
 
 
*Control refers to topotecan 
Item 1 
Week 6 
 
 
 
 
 
 
Week 12 
 
 
 
 
 
 
… 
 
 
 
 
 
…. 
Week 6 
 
 
 
 
 
 
Week 12 
 
 
 
 
 
 
… 
 
 
 
 
 
Item 43 
Week 6 
 
 
 
 
 
 
Week 12 
 
 
 
 
 
 
… 
 
 
 
 
 


                                                          
 
                             
Item 
Cycle 
PM01183+DOX 
Control* 
p-value 
N 
% 
N 
% 
*Control refers to CAV 
Item 1 
Week 6 
 
 
 
 
 
 
Week 12 
 
 
 
 
 
 
… 
 
 
 
 
 
…. 
Week 6 
 
 
 
 
 
 
Week 12 
 
 
 
 
 
 
… 
 
 
 
 
 
Item 43 
Week 6 
 
 
 
 
 
 
Week 12 
 
 
 
 
 
 
… 
 
 
 
 
 
 
Longitudinal analyses will be performed assuming a mixed-effect model with treatment 
(Y), time effect (days after baseline), and a time-treatment interaction as covariates, 
using a covariance structure of autoregressive order 1. 
 
Table 12.8.4 Mixed effect model 
Item 
Estimated point change per day 
p-value 
Mean change during treatment 
*Control refers to topotecan and/or CAV 
Item 1 
 
 
 
…. 
 
 
 
Item 43 
 
 
 
*Control refers to topotecan 
Item 1 
 
 
 
…. 
 
 
 
Item 43 
 
 
 
*Control refers to CAV 
Item 1 
 
 
 
…. 
 
 
 
Item 43 
 
 
 
 
 


                                                          
 
                             
Figures 12.8.5-12.8.47 Means plot by each item 
 
 
12.9  Time to different deterioration in QoL assessments  
 
Time to deterioration to ≥10 points in the Global Health Status and the additional 
indirect QoL assessment of time to PS deterioration will be performed. Patients not 
reaching the event will be censored in the last available assessment. 
 
Table 12.9.1.1 Time to deterioration to ≥10 points in the Global Health Status 
  
PM01183+DOX 
Control 
Parameter 
p-value 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median time  
(95% CI) 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
Mean time  
 
 
 
- 
Kaplan Meier plot (Figure 12.9.1.1) will be shown too. 
 
Table 12.9.1.2 Time to PS deterioration 
  
PM01183+DOX 
Control 
Parameter 
p-value 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median time  
(95% CI) 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
Mean time  
 
 
 
- 
Kaplan Meier plot (Figure 12.9.1.2) will be shown too. PS deterioration is defined as PS>2 or increase in two levels 
from baseline value (e.g from 0 to 2). 
 


                                                          
 
                                                
APPENDIX II 
13 Clinical Database Listings 
 
Database listings including key variables showing all the recorded information following CRF’s Form name will be shown. 
 
-Listing 13.1.1: Subject 
Treatment arm 
Patient id. 
Country / Site 
Number 
Country 
Investigator First Name 
Investigator Last name 
Institution 
Address 
 
 
 
 
 
 
 
 
 
-Listing 13.1.2: Visit Date 
Treatment arm 
Patient id. 
Date of Visit 
 
 
 
 
-Listing 13.1.3: Screening 
Treatment 
arm 
Patient 
id. 
Protocol 
Version 
Informed 
consent 
date/ 
Planned 
date of 
treatment 
initiation 
SCLC 
confirmed 
diagnosis 
date 
Extensive 
stage 
disease 
ECOG 
PS/ 
CCL/ 
BSA 
Last 
dose of 
CT 
Date of 
CT PD 
/If Non-
PD, 
specify 
 
CTFI 
Additional 
treatment/ 
PD1 or PDL-
1 
 
CNS 
involvement 
Control arm 
preference 
Subject Met All 
Eligibility 
Requirements 
(If not, specify) 
Is patient 
a 
screening 
failure 
Screen 
Failure 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
-Listing 13.1.4: Randomization Details 
Treatment 
arm 
Patient 
id. 
Ready to 
randomization? 
Randomization 
ID 
Date and time of 
randomization 
Date of Patient randomization 
in the study 
Stratum 
name 
CTFI 
PS 
CNS 
PD-1 or 
PD-L1 
Actual treatment to 
be given 
Now 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
-Listing 13.1.5: Study Registration 
Treatment arm 
Patient id. 
Pharmacogenetics Substudy Registration 
PGt consent 
Date of PGt/PGx sample 
Date of blood sample 
 
 
 
 
 
 
 


                                                          
 
                                                
-Listing 13.1.6: Demographics 
Treatment arm 
Patient id. 
Date of birth 
Age 
(years) 
Gender 
Race 
(Other, specify) 
Is the patient of childbearing 
potential? 
(If No, reason/Other) 
Adequate 
contraception 
(If NA, specify) 
 
 
 
 
 
 
 
 
 
-Listing 13.1.7: Pregnancy Test 
Treatment arm 
Patient id. 
Visit 
Not done 
Which type of test was performed? 
Date of sample 
Result 
 
 
 
 
 
 
 
 
-Listing 13.1.8: Medical History 
Treatment arm 
Patient id. 
Medical History 
Description 
Verbatim 
Onset date 
Resolved date 
Ongoing? 
 
 
 
 
 
 
 
 
 
-Listing 13.1.9: Cancer History 
 
 
 
 
 
 
 
Brain metastases 
Smoking 
Treatment 
arm 
Patient 
id. 
Date of 
diagnosis 
Ki-67 
/MIB-1 
Expression 
PD-L1 
overexpression 
(If positive, 
please specify 
overexpression) 
Date of last 
progression 
before 
study entry 
Site (s) 
of 
current 
disease 
(If 
other, 
specify) 
Known  
Date of 
diagnosis  
Symptomatic 
Steroid  
within 
2 
weeks 
was 
Paraneoplastic 
syndrome 
(If Yes, 
specify 
which) 
Status 
Date 
started 
Ongoing 
(If no, 
date 
stopped) 
Pack 
years 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
-Listing 13.1.10: Prior Anticancer Therapy: Surgical Procedures 
Treatment arm 
Patient id. 
Prior surgery 
Procedures 
Date 
Surgery Result 
 
 
 
 
 
 
 
-Listing 13.1.11: Prior AntiCancer Therapy: RadioTherapy 
Treatment arm 
Patient id. 
Radiotherapy 
Site Anatomic 
Total Dose (Gy) 
First Dose 
Last Dose 
Indication 
 
 
 
 
 
 
 
 
 
-Listing 13.1.12: Prior AntiCancer Medical Therapy for Study Disease 
Treatment arm 
Patient id. 
Prior therapy 
Regimen number 
Type 
Agent 
Start date 
Stop date 
Best Response 
Progression Date 
Non PD 
 
 
 
 
 
 
 
 
 
 
 
 


                                                          
 
                                                
-Listing 13.1.13: Hematology 
Treatment arm 
Patient id. 
Visit 
Not done 
Date 
WBC 
Neutrophils 
Lymphocytes 
Platelets 
Hemoglobin 
 
 
 
 
 
 
 
 
 
 
 
-Listing 13.1.14: Biochemistry 
Treatment 
arm 
Patient 
id. 
Visit 
Not 
done 
Date 
ALT 
AST 
AP 
Total 
Bilirubin 
Direct 
Bilirubin 
Albumin 
Creatinine 
Creatinine 
Clearance 
CPK 
Glucose 
Na 
K 
 
Total 
Calcium 
CRP 
LDH 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
-Listing 13.1.15: Physical Examination 
Treatment arm 
Patient id. 
Visit 
Not done 
Date 
Abnormalities 
Body System 
Findings 
Weight 
Height 
BSA 
 
 
 
 
 
 
 
 
 
 
 
 
-Listing 13.1.16: Performance Status 
Treatment arm 
Patient id. 
Visit 
Not Done 
Date 
PS (ECOG) 
 
 
 
 
 
 
 
-Listing 13.1.17: Vital Signs 
Treatment arm 
Patient id. 
Visit 
Not done 
Date 
Heart rate 
BPS 
BPD 
Temperature 
 
 
 
 
 
 
 
 
 
 
-Listing 13.1.18: Electrocardiogram 
Treatment arm 
Patient id. 
Visit 
Not done 
Date 
Reason for clinically indicated 
Result 
Abnormal, specify 
PR 
Heart rate 
QT interval (raw) 
QRS complex duration 
QTcF 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
-Listing 13.1.19: Left Ventricular Ejection Fraction (LVEF) 
Treatment arm 
Patient id. 
Visit 
Not done 
Date 
Reason for clinically indicated 
Method 
LVEF (%) 
Lower limit of normality 
Result 
Abnormal, specify 
 
 
 
 
 
 
 
 
 
 
 
 
-Listing 13.1.20: Anti-emetic Prophylactic Medication (Per Protocol) 
Treatment arm 
Patient id. 
Visit 
Not Done 
Drug Type 
Specify 
Route 
Daily Dose 
Units 
Start date 
Stop date 
Taken per protocol 
Specify (not per protocol) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
-Listing 13.1.21: CSF Prophylactic Medication 
Treatment arm 
Patient id. 
Visit 
Not Done/Not Applicable 
Drug 
Route 
Daily Dose 
Units 
Start date 
Stop date 
 
 
 
 
 
 
 
 
 
 
 
 
 


                                                          
 
                                                
-Listing 13.1.22: PM01183 Administration 
Treatment 
arm 
Patient 
id. 
Visit 
Date 
 
Route 
Start 
time 
End 
time 
Intended 
dose  
Total 
intended 
dose 
Total 
dose 
Total 
volume 
given 
Reduction 
Reduction 
reason 
Delay 
Delay 
reason 
Interruption 
Interruption 
reason 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
-Listing 13.1.23: PM01183 Re-Administration 
Treatment arm 
Patient id. 
Visit 
Not done 
Date 
Route 
Start time 
End time 
Total dose 
Total volume given 
 
 
 
 
 
 
 
 
 
 
 
-Listing 13.1.24: Doxorubicin Administration 
Treatment 
arm 
Patient 
id. 
Visit 
Date 
 
Route 
Start 
time 
End 
time 
Intended 
dose  
Total 
intended 
dose 
Total 
dose 
Total 
volume 
given 
Reduction 
Reduction 
reason 
Delay 
Delay 
reason 
Interruption 
Interruption 
reason 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
-Listing 13.1.25: Doxorubicin Re-Administration 
Treatment arm 
Patient id. 
Visit 
Not done 
Date 
Route 
Start time 
End time 
Total dose 
Total volume given 
 
 
 
 
 
 
 
 
 
 
 
-Listing 13.1.26: Topotecan Administration 
Treatment 
arm 
Patient 
id. 
Visit 
Not 
Done 
Delay 
(reason) 
 
Day 
Date 
Route 
Start 
time 
End 
time 
Intended dose 
level 
Total intended 
dose 
Total 
dose 
Omission 
(reason) 
 
Reduction 
(reason) 
 
Interruption 
(reason) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
-Listing 13.1.27: Topotecan Re-Administration 
Treatment arm 
Patient id. 
Visit 
Day 
Not done 
Date 
Route 
Start time 
End time 
Total dose 
 
 
 
 
 
 
 
 
 
 
 
-Listing 13.1.28: Cyclophosphamide Administration 
Treatment 
arm 
Patient 
id. 
Visit 
Date 
 
Route 
Start 
time 
End 
time 
Intended 
dose  
Total 
intended 
dose 
Total 
dose 
Total 
volume 
given 
Reduction 
Reduction 
reason 
Delay 
Delay 
reason 
Interruption 
Interruption 
reason 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
-Listing 13.1.29: Cyclophosphamide Re-Administration 
Treatment arm 
Patient id. 
Visit 
Not done 
Date 
Route 
Start time 
End time 
Total dose 
Total volume given 
 
 
 
 
 
 
 
 
 
 
 


                                                          
 
                                                
-Listing 13.1.30: Vincristine Administration 
Treatment 
arm 
Patient 
id. 
Visit 
Date 
 
Route 
Start 
time 
End 
time 
Intended 
dose  
Total 
dose 
Total 
volume 
given 
Reduction 
Reduction 
reason 
Delay 
Delay 
reason 
Interruption 
Interruption 
reason 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
-Listing 13.1.31: Vincristine Re-Administration 
Treatment arm 
Patient id. 
Visit 
Not done 
Date 
Route 
Start time 
End time 
Total dose 
Total volume given 
 
 
 
 
 
 
 
 
 
 
 
-Listing 13.1.32: Adverse Events YN? 
Treatment arm 
Patient id. 
AEs 
 
 
 
 
-Listing 13.1.33: Adverse Events 
Treatment 
arm 
Patient 
id. 
Adverse 
Event 
Grade 
Start Date 
(Ongoing) 
End Date 
(Duration/ongoing) 
Relationship 
(PM1183/Topotecan/CAV/Specify) 
Action 
 
Serious Event (Death/Life 
Threat./Hospi./Disa./Conge./Other 
Impor./Infectious.) 
Outcome 
SAE 
associated 
to QC? 
Case 
ID 
Derived 
Subject 
number 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
-Listing 13.1.34: SAE Summary 
Treatment 
arm 
Patient 
id. 
Adverse 
Event 
Outcome 
Start 
Date 
Case 
ID 
Death 
Life 
Threat. 
Hospi. 
Admission 
Date 
Discharge 
Date 
Disa. 
Conge. 
Other 
Medi. 
Infec.  
Narrative 
Nulli. 
Related 
docs? 
Serious 
Event 
#Submi. 
to PHV 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
-Listing 13.1.35: SAE Attachments 
Treatment arm 
Patient id. 
Attachment 
 
 
 
 
-Listing 13.1.36: Concomitant Medication YN? 
Treatment arm 
Patient id. 
Concomitant medication? 
 
 
 
 
-Listing 13.1.37: Concomitant Medication 
Treatment 
arm 
Patient 
id. 
Type of 
Therapy 
Drug 
Name 
Route 
Dose 
Unit 
Frequency 
No. of 
doses 
No. of 
time 
units 
Time 
units 
Start 
Date 
End 
Date 
Ongoing 
Reason 
Indication 
AEs 
MH 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


                                                          
 
                                                
-Listing 13.1.38: Concomitant Procedures 
Treatment arm 
Patient id. 
None 
Procedure 
Indication 
Date of Procedure 
AE 
MH 
Result / Comments 
 
 
 
 
 
 
 
 
 
 
-Listing 13.1.39: Other Tests/Procedures 
Treatment arm 
Patient id. 
Not Done 
Test Name 
Test Date 
Result 
Unit 
 
 
 
 
 
 
 
 
-Listing 13.1.40: Target Lesions 
Treatment arm 
Patient id. 
Were Target Lesions 
assessed 
Target 
Lesions 
Lesion 
Number 
Organ 
Specify 
Lesion 
Description 
Date 
 
Method 
(specify) 
Longest diameter 
Sum of 
Diameters 
 
 
 
 
 
 
 
 
 
 
 
 
 
-Listing 13.1.41: Non Target Lesions 
Treatment arm 
Patient id. 
Were Non Target Lesions assessed. 
Non Target Lesions 
Organ 
Specify 
Lesion Description 
Date 
Method (specify) 
Response 
 
 
 
 
 
 
 
 
 
 
 
-Listing 13.1.42: New Lesions 
Treatment arm 
Patient id. 
New Lesions 
Organ 
Specify 
Lesion Description 
Date 
Method (specify) 
 
 
 
 
 
 
 
 
 
-Listing 13.1.43: Radiological Evaluation of Response 
Treatment arm 
Patient id. 
Evaluation (Not Done) 
Date 
Target lesions 
Non-Target lesions 
New lesion 
Not Done 
Overall cycle response 
 
 
 
 
 
 
 
 
 
 
-Listing 13.1.44: End of Treatment 
Treatment arm 
Patient id. 
Reason 
Specify (Investigator's decision) 
Specify (AE) 
Specify (Other) 
Symptomatic deterioration date 
Symptomatic deterioration, please specify 
 
 
 
 
 
 
 
 
 
-Listing 13.1.45: Follow Up 
Treatment arm 
Patient id. 
Date 
Survival 
Disease Status 
PD or any further therapy 
TA done 
TA not done 
Specify (not done) 
 
 
 
 
 
 
 
 
 
 
-Listing 13.1.46: Surgery Procedures for Study Disease (after End of Treatment) 
Treatment arm 
Patient id. 
Further surgery 
Procedure 
Date 
Surgery Result 
 
 
 
 
 
 
 
 
 


                                                          
 
                                                
-Listing 13.1.47: Radiotherapy (after End of Treatment) 
Treatment arm 
Patient id. 
Further radiotherapy 
Site  
Total 
dose 
(Gy) 
Start date 
End date 
Ongoing 
Indication 
 
 
 
 
 
 
 
 
 
 
-Listing 13.1.48: Medical Treatment (after End of Treatment) 
Treatment arm 
Patient id. 
Further therapy 
Agent 
Start date 
End date 
Ongoing 
Best response 
 
 
 
 
 
 
 
 
 
-Listing 13.1.49: Death Report Form 
Treatment arm 
Patient id. 
Date 
Cause 
Specify (Other) 
Autopsy 
Attachment 
 
 
 
 
 
 
 
 
-Listing 13.1.50: Off Study 
Treatment arm 
Patient id. 
Off Study 
Date 
Primary reason 
 
 
 
 
 
 
-Listing 13.1.51: Pharmacokinetics 
Treatment 
arm 
Patient 
id. 
PK 
Samples 
Sample 
No. 
Day 
Sampling 
time 
Acceptable 
window 
times 
Sampling 
time relative 
to the 
Doxorubicin 
infusion 
Sampling 
time 
relative to 
the 
PM01183 
infusion 
Not 
Done 
Date 
Actual 
time 
Derived 
DateTime 
Comments 
Cycle the next Pharmacokinetics is 
due at: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
-Listing 13.1.52: Polymorphisms 
Treatment arm 
Patient id. 
Cycle 
Date 
Time 
Derived date time 
Not Done  
Comments 
 
 
 
 
 
 
 
 
 
-Listing 13.1.53: Alpha-1 Acid Glycoprotein 
Treatment arm 
Patient id. 
AAGP sample taken? 
Date 
Comments 
 
 
 
 
 
 
-Listing 13.1.54: EORTC Quality of Life Questionnaire 
Treatment 
arm 
Patient 
id. 
Not 
Done 
Date 
Q1 to 
Q5 
Specify if not 
performed 
Q6 to 
Q28 
Specify if not 
performed 
Q29-
Q30 
Specify if not 
performed 
Q31-
Q41 
Q42 (if yes 
where) 
Q43 (If yes, how 
much did it help?) 
Specify if not 
performed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


                                                          
 
                                                
-Listing 13.1.55: Treatment Continuation 
Treatment arm 
Patient id. 
Add Next Cyle? 
 
 
 
 
-Listing 13.1.56: Investigator Comments 
Treatment arm 
Patient id. 
Visit 
Form 
Date 
Comment 
 
 
 
 
 
 
 
-Listing 13.1.57: Unscheduled 
Treatment arm 
Patient id. 
Visit 
LVEF 
ECG 
 
 
 
 
 
 
-Listing 13.1.58: IRC data 
Treatment arm 
Patient id. 
Visit 
Reviewer 
identification 
Target Response  
Non Target 
Response 
New Lesions 
Best response 
Progression 
Date 
First Response 
Date 
 
 
 
 
 
 
 
 
 
 


                                                          
 
                                                
APPENDIX III 
14 ICH Listings 
 
Following ICH E-3 guideline, patient listings specified as section 16.2 will be performed. 
 
- 16.2.1 Discontinued Patients 
Treatment 
arm 
Patient 
id. 
Country 
Institution 
Subject Met All 
Eligibility Requirements 
(If not, specify) 
Is patient a 
screening failure 
Screen 
Failure 
Date 
Randomization 
date 
Treated 
(Yes/No) 
Drug adm. Start 
date (First cycle) 
Cycles 
received 
End of 
Treatment 
(specify) 
Off 
Study 
(reason) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
- 16.2.2 Protocol Deviations 
Treatment arm 
Patient id. 
Severity 
Type 
Deviation 
 
 
 
 
 
 
- 16.2.3 Patients Not Included in the Efficacy Analysis 
Treatment arm 
Patient id. 
Reason 
 
 
 
 
- 16.2.4 Demographic Data 
Treatment 
arm 
Patient 
id. 
Investigator’s 
preference for 
the control 
arm 
Gender 
Age 
(years) 
Race 
(Other, 
specify) 
ECOG 
PS 
Smoking 
status 
Disease 
stage 
Ki-67/  
MIB-1 
expression 
Baseline 
CNS 
involvement 
Site (s) 
of current 
disease 
(If other, 
specify) 
BSA 
(m2) 
Prior Surgery/ 
Prior 
Radiotherapy 
CTFI 
(months) 
Prior 
PD-
1/ 
PD-
L1 
#Prior 
chemotherapy 
/Prior Agents 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
- 16.2.5 Compliance and/or Drug Concentration Data 
Treatment 
arm 
Patient 
id. 
Cycles 
received 
Cumulative 
dose (mg/m2) 
Dose intensity 
(mg/m2/wk) 
Relative dose 
intensity (%) 
Visit 
Treatment 
Date 
 
Intended 
dose level 
Reduction 
(reason) 
 
Delay 
(reason) 
 
Interruption 
(reason) 
 
Omission 
(reason) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


                                                          
 
                                                
- 16.2.6 Individual Efficacy Response Data 
Treatment 
arm 
Patient 
id. 
IRC 
IA 
OS (mo.) 
Event 
/Censored 
Overall 
response 
PFS 
(mo.) 
Event 
/Censored 
DR 
(mo.) 
Event /Censored 
reason 
Overall 
response 
CA125 
response 
PFS    
(mo.) 
Event /Censored 
DR 
(mo.) 
Event /Censored 
reason 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
- 16.2.7 Adverse Event Listing (each patient) 
Treatment 
arm 
Patient 
id. 
SOC 
PT 
Adverse 
Event 
Grade 
Start Date 
(Ongoing) 
End Date 
(Duration/ongoing) 
Relationship 
(PM1183/Topotecan/CAV/Specify) 
Action 
 
Serious Event (Death/Life 
Threat./Hospi./Disa./Conge./Other 
Impor./Infectious.) 
Outcome 
 
 
 
 
 
 
 
 
 
 
 
 
 
- 16.2.8 Listing of Individual Laboratory Measurements by Patient 
Treatment arm 
Patient id. 
Visit 
Date 
Test 
Standard Value 
Normal lab. range 
Grade 
 
 
 
 
 
 
 
 


                                                          
 
                             
15 History of Changes 
 
15.1 SAP amendment from v2.0 to v3.0 
 
Some issues/clarifications have appeared during programming tasks performed by an 
external contract research organization that have been added to the SAP v2.0 dated 
03/October/2018.  
 
A brief summary of these issues/clarifications is provided below. 
 
 Addition of summary for patients with disease control rate (CR+PR+SD) and 
clinical benefit rate (CR+PR+SD≥4 months).  
 Clarification of CTFI calculation and prior immunotherapy data source. 
 Clarification that two analyses are performed for Bootstrap replication 
 The prior and  subsequent therapies are recorded with one drug per row in 
accordance with database completion guidelines, but in the reporting it may be 
requested to group some combinations like CAV. 
 Correction of  typos in title section for figures 103 to 109 and category split for 
table 12.5.3-12.5.4 
Detailed changes are presented in the next pages. Changes are highlighted in Italic bold 
and text removed has been crossed out. 
 
6.1 
 Efficacy Definitions 
 
…. 
Other supportive endpoints: 
 
Disease control rate (DCR) by IRC/IA, defined as percentage of patients with best 
response CR, PR or SD. 
 
Clinical benefit rate (CBR) by IRC/IA, defined as percentage of patients with best 
response CR, PR or SD ≥4 months. 
 
Time to treatment failure (TTF) by IA, defined as time from randomization to 
progression, EOT due to AE, EOT due to symptomatic deterioration or death will be 
calculated.  
 
Time to onset of first brain metastases by IA, defined as time from randomization to 
clinical diagnosis of brain mets will be calculated. 
 
 
 
8.1 
 Baseline and Demographic Data 
Baseline data such as demographics, cancer history, number of organs involved and 
sites of disease, prior therapy, laboratory values at baseline, prior relevant history, signs 
and symptoms, 
electrocardiogram, 
and concomitant medication [Anatomical 


                                                          
 
                             
Therapeutic Chemical – World Health Organization (ATC-WHO) coded] will be 
described following standard tables (detailed in Appendix I). 
CTFI is defined as the time from the last dose of the platinum drugs in the last 
platinum regimen to the occurrence of progressive disease. 
Prior immunotherapy to PD-1 or PD-L1 data will be collected from the screening 
page. 
For 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 value prior to or on the first day of treatment. 
8.9 
Subgroup Analyses 
 
Some preplanned efficacy analyses are the following: subgroup analyses based on 
comparison of PM01183/DOX with CAV or topotecan, subgroup analyses for 
stratification factors (mainly CNS and CTFI), subgroup analyses for patients with 
primary site different to lung, subgroup analyses if enough cases for baseline PD-L1 
expression (<1% vs. ≥1%) or PD-L1 expression (<50% vs. ≥50%), and the analysis of 
the subset of patients who received subsequent therapies. 
Special attention will be put in the subgroup analysis comparing treatment arms in the 
CTFI after first line subsets. Subsets will be defined as [≥90 days (sensitive) vs. <90 
days (resistant; R)] and adjusted p-values, one on patients with sensitive disease and 
one on patients with resistant disease, will be calculated by means of Bootstrap 
replication.  
Other subgroup analyses that are implemented a posteriori based on clinically findings 
will have an exploratory nature.  
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). 
 
Table 11.1.2.2  Prior anticancer medical therapy 
 
PM01183+DOX 
Control 
Total 
Topotecan  
CAV 
N 
% 
N 
% 
N 
% 
N 
% 
… 
 
 
 
 
 
 
 
 
Prior agents of chemotherapy (ATC coded)* 
   Carboplatin 
   Cisplatin 
   Etoposide 
   … 
 
 
 
 
 
 
 
 
Prior inmunotherapies agents (ATC coded)* 
   Nivolumab 
   … 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
TTP to prior chemotherapy** 
  Median (range) 
  Mean (std) 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
* Sites have been instructed in the database completion guidelines to report one drug per record, but in the 
summary it may be requested to group some combinations, e.g. CAV  
**If total number of patients with maintenance is less than 15% then take out them from calculus, if percentage is 
higher then censored them at the initial time of the maintenance 
 


                                                          
 
                             
Table 11.3.1.37 Response rate by IRC 
Response 
PM01183+DOX Control 
p-value 
N 
% 
N 
% 
CR 
 
 
 
 
 
PR 
 
 
 
 
 
SD 
 
 
 
 
 
PD 
 
 
 
 
 
Unknown* 
 
 
 
 
 
CR+PR; n (%) and binomial exact 95% confidence interval 
 
 
 
DCR; n (%) and binomial exact 95% confidence interval 
 
 
 
CBR; n (%) and binomial exact 95% confidence interval 
 
 
 
Table 11.3.1.43 Response rate by IA 
Response 
PM01183+DOX Control 
p-value 
N 
% 
N 
% 
CR 
 
 
 
 
 
PR 
 
 
 
 
 
SD 
 
 
 
 
 
PD 
 
 
 
 
 
Unknown* 
 
 
 
 
 
CR+PR; n (%) and binomial exact 95% confidence interval 
 
 
 
DCR; n (%) and binomial exact 95% confidence interval 
 
 
 
CBR; n (%) and binomial exact 95% confidence interval 
 
 
 
 
Table 12.7.1 Subsequent therapy 
 
PM01183+DOX 
Control 
Total 
Topotecan  
CAV 
N 
% 
N 
% 
N 
% 
N 
% 
Type 
 
 
 
 
 
 
 
 
  Chemotherapy 
 
 
 
 
 
 
  Surgery 
 
 
 
 
 
 
  Inmunotherapy 
 
 
 
 
 
 
  … 
 
 
 
 
 
 
Subsequent therapy agents* 
 
 
 
 
 
 
 
 
  Platinum 
 
 
 
 
 
 
  Taxanes 
 
 
 
 
 
 
  Nivolumab 
 
 
 
 
 
 
  Investigational agent 
 
 
 
 
 
 
   … 
 
 
 
 
 
 
* Sites have been instructed in the database completion guidelines to report one drug per record, but in the 
summary it may be requested to group some combinations, e.g. CAV 
 
Comparison in patients with no CNS involvement and CTFI<90 days (resistant).  
 
- Figure 11.3.1.103 Patients with CTFI<90 (resistant). PFS by IRC (PM01183 vs. Control) 
- Figure 11.3.1.104 Patients with CTFI<90 (resistant). PFS by IA (PM01183 vs. Control) 
- Figure 11.3.1.105 Patients with CTFI<90 (resistant). OS (PM01183 vs. Control) 
- Figure 11.3.1.106 Patients with CTFI<90 (resistant). RR by IRC (PM01183 vs. Control) 
- Figure 11.3.1.107 Patients with CTFI<90 (resistant). RR by IA (PM01183 vs. Control)  
- Figure 11.3.1.108 Patients with CTFI<90 (resistant). DR by IRC (PM01183 vs. Control) 
- Figure 11.3.1.109 Patients with CTFI<90 (resistant). DR by IA (PM01183 vs. Control) 
 
 
 
 


                                                          
 
                             
Table 12.5.3 Worst grade 3/4 by patient in special subgroups (Age) 
Laboratory abnormalities/ drug-related AEs 
≤65 years-old 
>65 years-old 
No. of 
patients 
 evaluated 
Grade  
3/4 
% 
No. of 
patients 
 evaluated 
Grade  
3/4 
% 
 
Table 12.5.4 Worst grade 3/4 by cycle in special subgroups (Age) 
Laboratory abnormalities/ drug-related 
AEs 
≤65 years-old 
>65 years-old 
No. of cycles 
evaluated 
Grade  
3/4 
% 
No. of cycles 
evaluated 
Grade 
3/4 
% 
 
 
15.2 SAP amendment from v1.0 to v2.0 
 
Clarifications/modifications after the implementation of the 3rd substantial amendment 
to the protocol have been added to the SAP v1.0 dated on 03/October/2016. 
 
A brief summary is included below. 
 
 Primary endpoint change from PFS by IRC to OS and all the associated 
statistical updates (e.g. sample size, assumptions, analyses…).  
 Deletion of cap definition.  
 Clarification of the way the stratification factors should be handled in the 
analyses. A listing of patients assigned to the wrong strata at the time of 
randomization will also be included. 
 Inclusion of more detailed secondary endpoint analyses and the way multiplicity 
adjustment will be calculated.  
 If formal interim analyses are conducted, the procedure that alpha-spending will 
be corrected is explained.  
 Inclusion of time to treatment failure, time to brain metastasis and generalised 
pairwise comparison. 
 Modifications/clarifications of list of covariates, missing imputation and how 
EOT visit will be managed for laboratory/QoL analyses. 
 Inclusion of a new section of time to QoL deterioration. 
 Inclusion of shell listings for section 13 DB Listings and for section 14 ICH 
Listings. 
 Other not relevant minor comments/clarifications (not specified in the document 
to maintain the simplicity). 
 
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 (OVERALL STUDY DESIGN) 
Multicenter, open-label, randomized, controlled phase III clinical trial to evaluate and 
compare the activity and safety of an experimental arm consisting of PM01183/DOX 
combination followed by PM01183 alone, if applicable vs. best Investigator’s choice 
between CAV or topotecan as a control arm, in SCLC patients who failed with disease 
progression after one prior platinum-containing line but no more than one prior 
chemotherapy-containing line. 
Central randomization will be implemented; patients will be assigned to each arm at a 
1:1 ratio. If the patient is randomized to the control arm (Arm B), the assigned treatment 
will be based on the reported Investigator’s preference between CAV or topotecan. 
However, whenever the number of patients randomized to either CAV or topotecan 
reaches 55% of the total number of patients expected in the control arm, i.e., 165 
patients, then the assigned treatment will be restricted to the remaining option, i.e., that 
which has not reached 165 patients, until the end of accrual. 
A minimum recruitment of 165 patients (>45% of patients in the control arm) will be 
ensured in the anthracycline containing regimen, CAV, in order to have sufficient 
data to study the contribution of PM01183 to the PM01183/DOX combination 
compared to the CAV. 
… 
Up to Approximately 600 patients will be included in the trial. 
An Independent Review Committee (IRC), blinded to the treatment assigned to the 
patients, will determine the best patient response and assign the date of objective 
response or 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. 
… 
The primary endpoint of the trial is the progression free overall survival (PFS) per 
RECIST v.1.1 assessed by the IRC.OS). Secondary endpoints comprise overall survival 
(OS), mid- and long-term survival assessed by measuring OS at 12/18/24 months, PFS 
per RECIST v.1.1 by investigator assessment (IA),difference in OS between 
PM01183/DOX and CAV, in patients with CAV as best Investigator’s choice; OS/PFS 
per RECIST v.1.1 in patients with and without baseline central nervous system (CNS) 
involvement; PFS per RECIST v.1.1 by an IRC; best antitumor response as per 
RECIST v.1.1 and duration of response (DR) (both assessed by IRC); and IA), safety 
profile, patient reported outcomes (. Tertiary endpoints comprise mid- and long-term 
survival assessed by measuring OS at 12/18/24 months, PFS per RECIST v.1.1 by 
investigator assessment (IA), best antitumor response as per RECIST v.1.1 and DR 
(both assessed by IA), PRO),  subgroup analyses, PK, PK/PDy correlations, and 
pharmacogenetics. 
In order to check the overall safety in both arms, an interim safety analysis is planned 
after the recruitment of 150 patients (i.e., ~75 patients into each arm). Recruitment will 
not be put on hold while the interim safety analysis is being performed. Efficacy 
parameters will not be reviewed at this time, as follow-up will not have reached 
maturity at this point; therefore, no type I/II error corrections will be applied. Further 
safety and efficacy analyses could be performed upon request from the IDMC.  
There is no intention to claim superiority before the necessary number of events for the 
PFS OS analysis has been reached. However, if formal interim analyses are requested 
by the IDMC, the significance level will be determined by the observed number of 


                                                          
 
                             
events and will be controlled by the Lan and DeMets error spending function that 
corresponds to the O'Brien-Fleming boundaries boundary will be used, calculated 
during the interim analyses to preserve an overall (one-sided) 0.005 false positive 
error rate; if early termination does not occur, the alpha level of the final analysis 
will be chosen to preserve an overall (one-sided) 0.025 false positive error rate. 
… 
Figure is updated 
 
… 
§ Whenever the number of patients randomized to either CAV or topotecan reaches 
55% of the total number of patients expected in the control arm, i.e., 165 patients, then 
the assigned treatment will be restricted to the remaining option, i.e., that which has not 
reached 165 patients, until the end of accrual. 
… 


                                                          
 
                             
†† Patients will be followed every three months (± two weeks) during the first 18 months after randomization, and 
then once every six months (± four weeks) until death of any cause or date of study termination, whichever occurs 
first. Once the whole recruitment is completed, the survival follow-up procedure will change: patients who 
discontinue treatment will be followed every three months according to a fixed calendar time (e.g., July, October, 
January, etc.) until death or study completion. 
… 
 
Section 4 (OBJECTIVES AND ENDPOINTS) 
 
4.1 Primary Objective 
 To determine whether there is a difference in PFS by an Independent Review 
Committee (IRC overall survival (OS) between lurbinectedin (PM01183)/DOX and 
a control arm consisting of best Investigator’s choice between cyclophosphamide 
(CTX), doxorubicin (DOX) and vincristine (VCR) (CAV) or topotecan, as treatment 
in SCLC patients after failure of one prior platinum-containing line. 
4.2 Secondary Objectives 
 Difference in OS between PM01183/DOX and CAV, in patients with CAV as best 
Investigator’s choice. 
 OS/PFS in patients with and without baseline central nervous system (CNS) 
involvement. Subgroup analyses restricted to the sensitive and resistant 
populations (i.e., chemotherapy-free interval [CTFI] ≥90 days and CTFI <90 
days) will also be performed.  
 Progression-free overall survival (OSPFS) by an Independent Review Committee 
(IRC). 
 Antitumor activity by IRC according to the Response Evaluation Criteria in Solid 
Tumors (RECIST) v.1.1. 
 Safety profile. 
 
4.3 Tertiary Objectives 
… 
 Antitumor activity by IA according to the RECIST v.1.1. 
 Safety profile. 
… 
4.4 Endpoints 
 
Primary endpoint:  
 
Progression-free survival (PFS) by IRC is defined as the time from the date of 
randomization to the date of documented progression per RECIST v.1.1 or death 
(regardless of the cause of death). If the patient receives further antitumor therapy or is 
lost to follow-up before PD, PFS will be censored at the date of last tumor assessment 
before the date of subsequent antitumor therapy. 
 Overall survival (OS) will be calculated from the date of randomization to the date 
of death (death event) or last contact (in this case, survival will be censored on 
that date). 
 
Secondary endpoints:  
 Difference in OS between PM01183/DOX and CAV, in patients with CAV as best 
Investigator’s choice. 


                                                          
 
                             
 Overall survival (OS)/progression-free survival (PFS) per RECIST v.1.1 in 
patients with and without baseline CNS involvement. Subgroup analyses restricted 
to the sensitive and resistant populations will also be performed. 
 Progression-free survival (PFS) by IRC is defined as the time from the date of 
randomization to the date of documented progression per RECIST v.1.1 or death 
(regardless of the cause of death). If the patient receives further antitumor 
therapy or is lost to follow-up before PD, PFS will be censored at the date of last 
tumor assessment before the date of subsequent antitumor therapy. 
 Best antitumor response by IRC will be the best response obtained in any 
evaluation according to RECIST v.1.1. 
 Duration of response (DR) by IRC will be calculated from the date of first 
documentation of response per RECIST v.1.1 (complete or partial response, 
whichever comes first) to the date of documented PD or death. The censoring 
rules defined above for PFS will be used for DR. 
 Treatment safety profile: AEs, serious adverse events (SAEs) and laboratory 
abnormalities will be coded by the Medical Dictionary for Regulatory Activities 
(MedDRA), graded according to the NCI-CTCAE v.4 and analyzed. Dose 
reductions or delays required due to treatment-related AEs, and reasons for 
treatment discontinuations will also be assessed. 
Tertiary endpoints: 
… 
 Best antitumor response by IRC/IA will be the best response obtained in any 
evaluation according to RECIST v.1.1.  
 Duration of response (DR) by IRC/IA will be calculated from the date of first 
documentation of response per RECIST v.1.1 (complete or partial response, 
whichever comes first) to the date of documented PD or death. The censoring rules 
defined above for PFS will be used for DR.  
 Treatment safety profile: AEs, serious adverse events (SAEs) and laboratory 
abnormalities will be coded by the Medical Dictionary for Regulatory Activities 
(MedDRA), graded according to the NCI-CTCAE v.4 and analyzed. Dose 
reductions or delays required due to treatment-related AEs, and reasons for 
treatment discontinuations will also be assessed.  
 
Section 5.1 (Randomization and Stratification) 
Central dynamic randomization will be implemented; patients will be assigned to each 
group at a 1:1 ratio. If the patient is randomized to the control arm (Arm B), the 
assigned treatment will be based on the reported Investigator’s preference between 
CAV or topotecan. However, whenever the number of patients randomized to either 
CAV or topotecan reaches 55% of the total number of patients expected in the control 
arm, i.e., 165 patients, then the assigned treatment will be restricted to the remaining 
option, i.e., that which has not reached 165 patients, until the end of accrual.  
… 
Section 5.2 (Sample Size) 
This phase III clinical trial is designed to determine a statistically significant difference 
in the PFS by IRC OS between PM01183/DOX vs. CAV or topotecan as second-line 
treatment in SCLC patients after failure of one platinum-containing chemotherapy 
(CHT) line. 


                                                          
 
                             
Patients will be randomized to receive DOX at 40 mg/m2 followed by PM01183 at 2.0 
mg/m2 (experimental arm), and either CAV or topotecan (control arm).  
The prospective assumptions are a ~25% reduction in the relative risk of progression 
or death (hazard ratio; HR=0.75) to be achieved with the experimental arm, at a one-
sided 2.5% significance level with at least 90% power, following exponential 
distributions and fulfilling the proportional hazard assumption. Median PFSOS with 
CAV or topotecan is expected to be around 37.5 months(1). It is forecasted that an 
observed HR of approximately 0.84 will have enough power to reject the null 
hypothesis. 
To obtain the required 484508 events, approximately 600 patients with SCLC who 
failed one prior platinum-containing CHT line will be stratified and randomized at a 
1:1 ratio. With the aforementioned prospective assumptions, recruitment is foreseen to 
be completed in 1724 months (~3525 patients/month) , the required PFS events are 
expected to occur around three months after randomization of the last patient. 
Therefore the IDMC meeting after the IRC review to test PFS is expected to occur 
about six months after randomization of the last patient. For a final OS analysis and a 
total study duration of about three and a half years for the final OS analysis is 
planned. 
With the prospective assumptions above mentioned, about 253 PFS265 OS events are 
expected in the control arm and 231243 in the treatment arm.  
The IDMC will review the results and the IRC will determine the patient’s best 
response and assign the date of objective response or progression/censoring according 
to the RECIST v.1.1.Section 5.2.1 (Interim Safety Analysis) 
… 
As previously explained, there is no intention to claim superiority before the necessary 
number of events for the PFSOS analysis has been reached. However, if 
requestedformal interim analyses are conducted by the IDMC, the significance level 
will be determined by the observed number of events and will be controlled by thea 
Lan and DeMets error spending function that corresponds to the O'Brien-Fleming 
boundariesboundary will be used, calculated during the interim analyses to preserve 
an overall (one-sided) 0.005 false positive error rate; if early termination does not 
occur, the alpha level of the final analysis will be chosen to preserve an overall (one-
sided) 0.025 false positive error rate.   
 
15.1.1 OS Analysis 
OS has been selected as a secondary endpoint. A sample size of 600 patients is 
expected to have enough power to detect a clinically and statistically relevant 
treatment effect in OS. Assuming a median OS of ~7.5 months in the control arm (1) 
the Sponsor believes that the sample size would have enough power to test a HR~0.75.  
An interim OS analysis is planned for the time of the final PFS analysis. The 
significance level will be determined by the observed number of events and will be 
controlled by the Lan and DeMets error spending function that corresponds to the 
O'Brien-Fleming boundaries.  
The OS statistical analyses will be performed following the same approach as for PFS 
analyses. Consequently, the stratified log-rank test (primary analysis), the unstratified 
log-rank test and Cox regression on the ITT population will be calculated. 
The end of the study is set at 18 months after the randomization of the last patient; 
currently, and with the pre-established assumptions, ~500 events are expected to occur. 


                                                          
 
                             
 
Section 6.1 (Efficacy Definitions) 
Primary endpoint.  
Overall survival (OS) is defined as the time from the date of randomization to the date 
of death (death event) or last contact (in this case, survival will be censored on that 
date). Final OS analysis is planned 18 months after randomization of last patient 
(planned end of study date).  
After radiological PD is documented or a new antitumor therapy is started, patients 
will be followed for survival every three months (± two weeks) during the first 18 
months after randomization, and then once every six months (± four weeks) until 
death of any cause or date of study termination, whichever occurs first. For survival 
follow-up (FU) purposes, after radiological PD is documented or new therapy is 
started, a documented telephone call from the investigational sites will be adequate. 
Once the whole recruitment is completed, the survival follow-up procedure will 
change and patients who discontinue treatment will be followed every three months 
according to a fixed calendar time (e.g., July, October, January, etc.) until death or 
study completion. 
 
Secondary/tertiary endpoints. 
… 
After radiological PD is documented or a new antitumor therapy is started, patients will be 
followed for survival every three months (± two weeks) during the first 18 months after 
randomization, and then once every six months (± four weeks) until death of any cause or 
date of study termination, whichever occurs first. For survival follow-up (FU) purposes, 
after radiological PD is documented or new therapy is started, a documented telephone call 
from the investigational sites will be adequate. 
… 
Secondary endpoints. 
The hierarchical step-up Hochberg procedure will be used to test the secondary 
endpoints (i.e. OS and ORR) at the overall two-sided significance level of 0.05 in the 
event the primary endpoint is significant. 
Subgroup analyses of the PM01183/DOX arm vs. CAV or topotecan based on 
investigator’s preference. 
Overall survival (OS) is defined as the time from the date of randomization to the date 
of death (death event) or last contact (in this case, survival will be censored on that 
date). Counting out subsequent therapies impact, sample size is powered to detect OS 
differences in the 15-25% range. Final OS analysis is planned 18 months after 
randomization of last patient (planned end of study date). As previously mentioned, for 
interim OS analysis type I error will be controlled by the Lan and DeMets error 
spending function that corresponds to the O'Brien-Fleming boundaries. 
Landmark analyses of OS at 12/18/24 months will be the Kaplan-Meier estimates of 
the probability of being alive at these time points. 
… 
Landmark analyses of OS at 12/18/24 months will be the Kaplan-Meier estimates of 
the probability of being alive at these time points. 
Difference in OS between PM01183/DOX and CAV, in patients with CAV as best 
Investigator’s choice will be measured using OS data derived for the primary 
endpoint calculation and selecting investigator’s preference ticked in the eCRF. 


                                                          
 
                             
OS/PFS in patients with and without baseline CNS involvement will be measured 
using derived data and selecting the CNS involvement status reported in the eCRF. 
Afterwards, subgroup analyses of CNS involvement restricted to the sensitive and 
resistant populations will also be performed. 
Subgroup analyses of the PM01183/DOX arm vs. CAV or topotecan based on 
investigator’s preference. 
… 
Other supportive endpoints: 
 
Time to treatment failure (TTF) by IA, defined as time from randomization to 
progression, EOT due to AE, EOT due to symptomatic deterioration or death will be 
calculated.  
 
Time to onset of first brain metastases by IA, defined as time from randomization to 
clinical diagnosis of brain mets will be calculated. 
 
Section 6.2 (Efficacy Analysis Methods) 
Time-to-event variables (OS, PFS, OS DR, TTF and DRtime to onset of first brain 
metastases) and their set time estimates (e.g., OS 12/18/24) will be analyzed according 
to the Kaplan-Meier method.  
The stratified log-rank test, using all randomization strata variablesselecting CNS and 
CTFI values of the stratification factors, on the ITT population will be primarily used 
to compare the time-to-event variables. A sensitivity analysis will be performed using all 
randomization strata variables.  
Unstratified log-rank tests will also be calculated as supportive analyses.  
 
If the result of the primary endpoint analysis is statistically significant, the 
hierarchical step-up Hochberg procedure(2) will be used to test the most relevant 
secondary efficacy endpoints (i.e., difference in OS in patients with CAV as best 
Investigator’s choice, and OS in the subgroup of patients without baseline CNS 
involvement) at the overall two-sided significance level of 0.05. The p-values for this 
procedure will be calculated using the corresponding unstratified log-rank test in 
each subgroup.  
 
The symmetry of tumor evaluations between treatment arms will be examined. The 
Wilcoxon test to compare time to disease assessments between treatment arms will be 
used to assess symmetry of evaluations. Moreover, Kaplan-Meier curves of the time 
from randomization and the first and second disease assessments will be plotted.  
Cox regression will be used to calculate the risk reduction (OS, PFS, OS and DR) and to 
evaluate the influence of the stratification variables and other potential prognostic 
factors on the time-to-event efficacy endpoints.  
Mean Kaplan-Meier estimates will be used to compare areas under the curves for OS 
and PFS.  
Counts and percentages, with their corresponding exact 95% confidence intervals, will 
be calculated for the binomial endpoints (i.e., response rate). The Fisher’s exact test 
(univariate analyses) and logistic regressions (multivariate analyses) will be used to 
compare the response rates.  


                                                          
 
                             
Waterfall plots will be used to describe the best variation of the sum of target lesions 
diameters during the treatment. 
Multivariate models (main effects or including interaction terms, if appropriate) will 
include all stratification factors and/or prognostic factors/covariates widely reported and 
recognized by the scientific community: treatment (PM01183/DOX vs. control), CTFI 
after first-line treatment [as strata categories ≥180 days (VS) vs. 90-179 days (S) vs. <90 
days (R) or as usually reported ≥90 days vs. <90 days], ECOG PS (0 vs. 1-2 or coded as 
0 vs. 1 vs. 2), baseline CNS involvement (yes vs. no), prior immunotherapy against 
either PD-1 or PD-L1 (yes vs. no) [or independently by each group if enough 
representative cases, prior PD-1 (yes vs. no) and prior PD-L1 (yes vs. no) ], 
investigator’s preference for the control arm (Topotecan vs. CAV), geographical area 
(USA vs. Europe vs. rest of the world), sex (male vs. female), age, age at diagnosis, race 
(caucasian vs. other), smoking status (current vs. former vs. never), actual disease stage 
at study entry (limited vs. extensive), PD-L1 expression (if enough cases; <1% vs. ≥1% 
or <50% vs. ≥50%), prior lines (1 vs. >1 lines or coded as ordinal) , time from diagnosis 
to randomization, time elapsed from last dose of prior chemotherapy regimen to 
randomization, response to prior chemotherapy (yes vs. no), time to progression to prior 
chemotherapy, prior prophylactic cranial irradiation (PCI) (yes vs. no), prior 
consolidation with thoracic radiotherapy (yes vs. no), visceral metastases (yes vs. no), 
number of metastatic sites at baseline, body mass index (BMI), height, weight, body 
surface area (BSA), presence of any bulky (< 50 mm vs. ≥ 50 mm) lesion at baseline, 
measurable disease by RECIST v1.1 (yes vs. no), hypertension (yes vs. no), cardiac 
disease (yes vs. no) , diabetes (yes vs. no) , chronic obstructive pulmonary disease 
(COPD) (yes vs. no), secondary tumors (yes vs. no), steroids at baseline (yes vs. no), 
opioids at baseline (yes vs. no), paraneoplastic syndrome at baseline (yes vs. no),  
baseline lactate dehydrogenase (LDH) value (≤ upper limit of normal (ULN) vs. 
>ULN), hemoglobin value at baseline (g/dl), albumin value at baseline (g/dl), C-
reactive protein value at baseline (mg/dl), C-reactive protein/albumin baseline ratio 
and baseline global quality of life (QoL). In addition, continuous variables categorized 
as discrete variables will also be investigated in the continuum range and if the 
adjustment isthey fit better then the continualcontinuous variable will be selected in the 
model. 
All variables with a good percentage of valid cases (approximately ≥ 90%) will be 
included in the multivariate analysis, although if any prognostic value lacks more than 
10% of values, sensitivity analyses considering multiple imputation methods will be 
performed… 
… 
Median follow-up (FU) time for PFSOS and PFSOS will be calculated in a descriptive 
way, taking  only  into account the censored values and using the Kaplan-Meier method 
for reversing the censoring values as described by Parmar(4). 
… 
Sensitivity analyses for different PFS censoring will be performed. The following 
approaches will be calculated: 1) Date of progression based on scheduled time instead 
of recorded date (e.g. if progression occurs in the ninth week and assessment would 
have to be done in the sixth week then the expected date is used instead of the actual 
date); 2) First date of progression combining IRC and IA assessments (e.g. the lowest 
date between IRC and IA is used);and 3) Date of progression moved to the prior tumor 
assessment date (e.g. if progression has not been documented in the second assessment 
and is documented in the third assessment then progression date is moved to the second 
assessment); 4) First date of progression or death not censoring data if further 


                                                          
 
                             
antitumor therapy is received before the documented progression.  
Proportional hazard assumption for PFSOS and PFSOS will be checked by means of a 
Cox regression including treatment and its interaction with survival time(5). In case of 
strong rejection of proportionality, then restricted mean survival estimates will also 
be calculated in addition to HR(6,7).   
 
 
 
Main summary of efficacy analyses 
Order 
Endpoint 
Population 
Statistics 
Primary 
endpoint 
PFS by IRCOS 
ITT population 
-Stratified log rank test 
(primary analysis) 
-Unstratified log rank test 
-Kaplan Meier estimates 
-Univariate Cox regression 
-Multivariate Cox 
regression 
Secondary 
endpoints* 
OSPFS by IRC 
ITT population 
-Stratified log rank test 
-Unstratified log rank test 
-Kaplan Meier estimates 
-Univariate Cox regression 
-Multivariate Cox regression 
OS at 12/18/24 
months 
DOR by IRC 
ITT population: Responder 
patients 
-Kaplan Meier estimates 
Response rate by 
IRC 
ITT population 
-Fisher exact test 
-Logistic regression 
Subgroup 
analyses* 
ITT population (based on 
investigator’s preference) 
-Stratified log rank test 
-Unstratified log rank test 
-Kaplan Meier estimates 
-Univariate Cox regression 
-Multivariate Cox regression 
OS/PFS by no 
CNS involvement*  
ITT population (patients with 
no CNS) 
-Stratified log rank test 
-Unstratified log rank test 
-Kaplan Meier estimates 
-Univariate Cox regression 
-Multivariate Cox 
regression 
* TheIf the result of the primary endpoint analysis is statistically significant, the Hochberg procedure 
will be used at the overall two-sided significance level of 0.05 to test  the difference between 
PM01183/DOX and CAV in OS in patients with CAV as best Investigator’s choice, and the difference 
in OS in the subgroup of patients without baseline CNS involvement. The unstratified log-rank tests 
will be used to calculate p-values. IA, Investigator Assessment; IRC, Independent Review Committee; 
ITT, intention-to-treat; PFS, progression-free survival; OS, overall survival. 
 
Section 7.2 (Clinical Laboratory Evaluation) 
Laboratory results will be classified according to the NCI-CTCAE v.4. All laboratory 
visits reported as “End of treatment” visit will be mapped to the last cycle visit for 
each patient. 
… 
 
Section 8.4 (Patient-reported Outcomes (PRO)) 
To measure the quality of life of patients, EORTC QLQ-C30 and EORTC QLQ-LC13 
questionnaires will be analyzed every six weeks (± one week) from randomization until 


                                                          
 
                             
EOT. All visits reported as “End of treatment” visit will be mapped to the last cycle 
visit for each patient. 
 
Section 8.6 (Imputation in Incomplete Dates) 
… 
After end of treatment 
… 
Once the OS follow-up assessments will be implemented following the calendar time 
if a patient deceased but his/her complete death date is missing then if month/year is 
known then death date will be imputed as 01/Month/Year, otherwise the death date 
will be imputed as last time to the patient was known to be alive plus 1 day. 
 
Section 8.8 (Decimal Places, Missing Values and Allowed Assessment Windows) 
By default, all results will be rounded to one decimal place, except when variables are 
integer, which will be reported without decimals (e.g., age in years, number of sites, 
etc.). For representing p-values four decimals will be selected as default but they could 
be rounded to fewer decimals if necessary. Hazard ratios will be presented with three 
decimal places. 
… 
Section 8.9 (Subgroup Analyses) 
Some preplanned upfront efficacy analyses are the following: subgroup analyses based 
on comparison of PM01183/DOX with CAV or topotecan, subgroup analyses for 
stratification factors (mainly CNS and CTFI), subgroup analyses for patients with 
primary site different to lung, subgroup analyses if enough cases for baseline PD-L1 
expression (<1% vs. ≥1%) or PD-L1 expression (<50% vs. ≥50%), and the analysis of 
the subset of patients who received subsequent therapies. 
… 
Section 8.11 (Generalised Pairwise comparison assessment) 
 
8.11 Generalised Pairwise comparison assessment 
A risk-benefit measure will be calculated using the generalised pairwise 
comparison(8). A favourable benefit outcome will be determined by differences in OS 
exceeding 2, 3 or 4 months. An unfavourable risk outcome will be determined by the 
occurrence of any G3-4 adverse reaction or a clinically important adverse event:  
 
A clinically important adverse event will be defined as: 
 
- 
Any AE causing death or treatment discontinuation 
- 
Febrile neutropenia/neutropenic sepsis 
- 
Grade 4 neutropenia lasting > 3 days 
- 
Grade 4 thrombopenia or grade 3 thrombopeniaconcomitant with bleeding 
events. 
- 
Grade 4 AST/ALT or grade 3 lasting >14 days. 
- 
Treatment-related grade ≥ 2 ALT or AST increase concomitantly with ≥ 2 
times  
 
 the  upper  limit  of  normal  (ULN)  total  bilirubin  increase  and  normal 
 
 alkaline phosphatase (AP).   


                                                          
 
                             
- 
Grade ≥ 3 creatine phosphokinase (CPK) increase. 
- 
Grade 3 fatigue lasting > 3 days.  
- 
Any other grade 3/4 non-hematological AE that is suspected to be related to 
study   drug(s), except nausea/vomiting (unless the patient is receiving an 
optimal anti-  emetic  regimen),  hypersensitivity  reactions,  extravasations  
and  non-clinically  relevant  isolated  biochemical  
 abnormalities [e.g.,  
isolated  increase  in  gamma-glutamyltransferase  (GGT)]. 
 
Section 9 (STATISTICAL SOFTWARE) 
… 
EAST® v.6.34 has been used to calculate sample size(9).  
… 
 
Section REFERENCES 
 
… 
 
2 Multiple Endpoints in Clinical Trials Guidance for Industry, Draft (January 2017) 
 
… 
 
8 Buyse M. Generalized pairwise comparisons for prioritized outcomes in the two-
sample problem. Statist Med 29: 3245-57, 2010. 
 
… 
 
Section 10.1 (Patient Disposition) 
… 
Listing 10.1.8 Patients assigned to incorrect strata at the time of randomization   
Treatment arm* 
Patient  
Actual stratum  
(Screening form) 
Strata reported at randomization  
(Randomization form) 
 
 
 
 
*PM01183+DOX/Topotecan/CAV 
Table 10.1.9 Investigator’s preference for the control arm 
 
PM01183+DOX 
Topotecan 
CAV 
N 
% 
N 
% 
N 
% 
Topotecan 
 
 
 
 
 
 
CAV 
 
 
 
 
 
 
 
Section 11.1.1 (Patient Characteristics at Baseline) 
 
Table 11.1.1.1 Baseline characteristics 
Primary site 
SCLC 
Small-cell from extrapulmonary primary site  
 
 
 


                                                          
 
                             
Section 11.3 (Efficacy Analysis) 
 
Overall survival 
Table 11.3.1.1 OS (Stratified log rank test) 
Variable 
Stratification factors 
p-value* 
Treatment arm (main 
analysis) 
Actual values (CNS and CTFI) 
 
Treatment arm (sensitivity) 
Values reported for 
randomization (CNS and CTFI) 
 
Treatment arm (sensitivity) 
Actual values (all stratification 
factors) 
 
Treatment arm (sensitivity) 
Values reported for 
randomization (all stratification 
factors) 
 
*Stratified log rank test. 
… 
 
Table 11.3.1.3 OS  
  
PM01183+DOX 
Control 
Parameter 
p-value 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median OS  
(95% CI) 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
Mean OS 
 
 
 
- 
OS at 12 months  
(95% CI) 
 
 
Diff: 
 
OS at 18 months  
(95% CI) 
 
 
 
 
OS at 24 months  
(95% CI) 
 
 
Diff: 
 
Kaplan Meier plot (Figure 11.3.1.3) will be shown too. 
… 
 
Overall survival (CAV comparison) 
 
Table 11.3.1.8 OS vs CAV (Stratified log rank test) 
Variable 
Stratification factors 
p-value* 
Treatment arm  
Actual values (CNS and CTFI) 
 
Treatment arm  
Values reported for 
randomization (CNS and CTFI) 
 
Treatment arm  
Actual values (all stratification 
factors) 
 
Treatment arm  
Values reported for 
randomization (all stratification 
factors) 
 
*Stratified log rank test. 
 


                                                          
 
                             
Table 11.3.1.9 OS vs CAV  
  
PM01183+DOX 
Control 
Parameter 
p-value 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median OS  
(95% CI) 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
Mean OS 
 
 
 
- 
OS at 12 months  
(95% CI) 
 
 
Diff: 
 
OS at 18 months  
(95% CI) 
 
 
 
 
OS at 24 months  
(95% CI) 
 
 
Diff: 
 
Kaplan Meier plot (Figure 11.3.1.9) will be shown too. 
 
Forest plot (Figure 11.3.1.10) summarizing main results, stratification factors and 
covariates in terms of OS will be prepared. 
 
Overall survival (non CNS comparison) 
 
Table 11.3.1.11 OS in non CNS (Stratified log rank test) 
Variable 
Stratification factors 
p-value* 
Treatment arm  
Actual values (CNS and CTFI) 
 
Treatment arm  
Values reported for 
randomization (CNS and CTFI) 
 
Treatment arm  
Actual values (all stratification 
factors) 
 
Treatment arm  
Values reported for 
randomization (all stratification 
factors) 
 
*Stratified log rank test. 
 
Table 11.3.1.12 OS in non CNS  
  
PM01183+DOX 
Control 
Parameter 
p-value 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median OS  
(95% CI) 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
Mean OS  
 
 
 
- 
OS at 12 months  
(95% CI) 
 
 
Diff: 
 
OS at 18 months  
(95% CI) 
 
 
 
 
OS at 24 months  
(95% CI) 
 
 
Diff: 
 
Kaplan Meier plot (Figure 11.3.1.12) will be shown too. 
 
Forest plot (Figure 11.3.1.13) summarizing main results, stratification factors and 
covariates in terms of OS will be prepared. 
 


                                                          
 
                             
Progression-free survival by IRC 
 
Table 11.3.14 PFS by IRC (primary analysis) 
Variable 
Stratification factors 
p-value* 
Treatment arm 
Actual values (CNS and CTFI) 
 
Treatment arm 
Values reported for 
randomization (CNS and CTFI) 
 
Treatment arm 
Actual values (all stratification 
factors) 
 
Treatment arm 
Values reported for 
randomization (all stratification 
factors) 
 
*Stratified log rank test. 
 … 
 
Table 11.3.1.16 PFS by IRC 
  
PM01183+DOX 
Control 
Parameter 
p-value 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median PFS  
(95% CI) 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
Mean PFS  
 
 
 
- 
PFS at 6 months  
(95% CI) 
 
 
Diff: 
 
PFS at 12 months  
(95% CI) 
 
 
Diff: 
 
Kaplan Meier plot (Figure 11.3.1.16) will be shown too. 
 
… 
 
Progression-free survival by IA 
 
Table 11.3.1.21 PFS by IA (Stratified log rank test) 
Variable 
Stratification factors 
p-value* 
Treatment arm 
Actual values (CNS and CTFI) 
 
Treatment arm 
Values reported for 
randomization (CNS and CTFI) 
 
Treatment arm 
Actual values (all stratification 
factors) 
 
Treatment arm 
Values reported for 
randomization (all stratification 
factors) 
 
*Stratified log rank test. 
 
… 
 


                                                          
 
                             
Table 11.3.1.23 PFS by IA 
  
PM01183+DOX 
Control 
Parameter 
p-value 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median PFS  
(95% CI) 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
Mean PFS  
 
 
 
- 
PFS at 6 months  
(95% CI) 
 
 
Diff: 
 
PFS at 12 months  
(95% CI) 
 
 
Diff: 
 
Kaplan Meier plot (Figure 11.3.1.23) will be shown too. 
 
… 
 
- First date of progression or death not censoring data if further antitumor therapy. 
 
Table 11.3.1.35 PFS not censoring if further antitumor by IRC 
  
PM01183+DOX 
Control 
Parameter 
p-value 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median PFS  
(95% CI) 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
PFS at 6 months  
(95% CI) 
 
 
Diff: 
 
PFS at 12 months  
(95% CI) 
 
 
Diff: 
 
Kaplan Meier plot (Figure 11.3.1.35) will be shown too. 
 
Table 11.3.1.36 PFS not censoring if further antitumor by IA 
  
PM01183+DOX 
Control 
Parameter 
p-value 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median PFS  
(95% CI) 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
PFS at 6 months  
(95% CI) 
 
 
Diff: 
 
PFS at 12 months  
(95% CI) 
 
 
Diff: 
 
Kaplan Meier plot (Figure 11.3.1.36) will be shown too. 
 
… 
 


                                                          
 
                             
Time to treatment failure 
 
Table 11.3.1.52 Time to treatment failure by IA 
  
PM01183+DOX 
Control 
Parameter 
p-value 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median PFS  
(95% CI) 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
PFS at 6 months  
(95% CI) 
 
 
Diff: 
 
PFS at 12 months  
(95% CI) 
 
 
Diff: 
 
Kaplan Meier plot (Figure 11.3.1.52) will be shown too. 
 
Time to brain mets 
 
Table 11.3.1.53 Time to clinical diagnosis of brain mets by IA 
  
PM01183+DOX 
Control 
Parameter 
p-value 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median PFS  
(95% CI) 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
PFS at 6 months  
(95% CI) 
 
 
Diff: 
 
PFS at 12 months  
(95% CI) 
 
 
Diff: 
 
Kaplan Meier plot (Figure 11.3.1.53) will be shown too. 
… 
 
Comparison in patients with no CNS involvement.  
 
- Figure 11.3.1.68 Patients with no CNS. PFS by IRC (PM01183 vs. Control) 
- Figure 11.3.1.69 Patients with no CNS. PFS by IA (PM01183 vs. Control) 
- Figure 11.3.1.70 Patients with no CNS. OS (PM01183 vs. Control) 
- Figure 11.3.1.71 Patients with no CNS. RR by IRC (PM01183 vs. Control) 
- Figure 11.3.1.72 Patients with no CNS. RR by IA (PM01183 vs. Control)  
- Figure 11.3.1.73 Patients with no CNS. DR by IRC (PM01183 vs. Control) 
- Figure 11.3.1.74 Patients with no CNS. DR by IA (PM01183 vs. Control) 
 
Comparison in patients with CNS involvement.  
 
- Figure 11.3.1.75 Patients with CNS. PFS by IRC (PM01183 vs. Control) 
- Figure 11.3.1.76 Patients with CNS. PFS by IA (PM01183 vs. Control) 
- Figure 11.3.1.77 Patients with CNS. OS (PM01183 vs. Control) 
- Figure 11.3.1.78 Patients with CNS. RR by IRC (PM01183 vs. Control) 
- Figure 11.3.1.79 Patients with CNS. RR by IA (PM01183 vs. Control)  
- Figure 11.3.1.80 Patients with CNS. DR by IRC (PM01183 vs. Control) 
- Figure 11.3.1.81 Patients with CNS. DR by IA (PM01183 vs. Control) 
 
Comparison in patients with no CNS involvement and CTFI≥90 days (sensitive).  
 
- Figure 11.3.1.82 Patients with no CNS in sensitive. PFS by IRC (PM01183 vs. Control) 
- Figure 11.3.1.83 Patients with no CNS in sensitive. PFS by IA (PM01183 vs. Control) 
- Figure 11.3.1.84 Patients with no CNS in sensitive. OS (PM01183 vs. Control) 
- Figure 11.3.1.85 Patients with no CNS in sensitive. RR by IRC (PM01183 vs. Control) 
- Figure 11.3.1.86 Patients with no CNS in sensitive. RR by IA (PM01183 vs. Control)  
- Figure 11.3.1.87 Patients with no CNS in sensitive. DR by IRC (PM01183 vs. Control) 
- Figure 11.3.1.88 Patients with no CNS in sensitive. DR by IA (PM01183 vs. Control) 


                                                          
 
                             
 
Comparison in patients with no CNS involvement and CTFI<90 days (resistant).  
 
- Figure 11.3.1.89 Patients with no CNS in resistant. PFS by IRC (PM01183 vs. Control) 
- Figure 11.3.1.90 Patients with no CNS in resistant. PFS by IA (PM01183 vs. Control) 
- Figure 11.3.1.91 Patients with no CNS in resistant. OS (PM01183 vs. Control) 
- Figure 11.3.1.92 Patients with no CNS in resistant. RR by IRC (PM01183 vs. Control) 
- Figure 11.3.1.93 Patients with no CNS in resistant. RR by IA (PM01183 vs. Control)  
- Figure 11.3.1.94 Patients with no CNS in resistant. DR by IRC (PM01183 vs. Control) 
- Figure 11.3.1.95 Patients with no CNS in resistant. DR by IA (PM01183 vs. Control) 
 
Comparison in patients with CTFI≥90 days (sensitive).  
 
- Figure 11.3.1.96 Patients with CTFI≥90 (sensitive). PFS by IRC (PM01183 vs. Control) 
- Figure 11.3.1.97 Patients with CTFI≥90 (sensitive). PFS by IA (PM01183 vs. Control) 
- Figure 11.3.1.98 Patients with CTFI≥90 (sensitive). OS (PM01183 vs. Control) 
- Figure 11.3.1.99 Patients with CTFI≥90 (sensitive). RR by IRC (PM01183 vs. Control) 
- Figure 11.3.1.100 Patients with CTFI≥90 (sensitive). RR by IA (PM01183 vs. Control)  
- Figure 11.3.1.101 Patients with CTFI≥90 (sensitive). DR by IRC (PM01183 vs. Control) 
- Figure 11.3.1.102 Patients with CTFI≥90 (sensitive). DR by IA (PM01183 vs. Control) 
 
Comparison in patients with no CNS involvement and CTFI<90 days (resistant).  
 
- Figure 11.3.1.103 Patients with CTFI<90 (resistant). PFS by IRC (PM01183 vs. Control) 
- Figure 11.3.1.104 Patients with CTFI<90 (resistant). PFS by IA (PM01183 vs. Control) 
- Figure 11.3.1.105 Patients with CTFI<90 (resistant). OS (PM01183 vs. Control) 
- Figure 11.3.1.106 Patients with CTFI<90 (resistant). RR by IRC (PM01183 vs. Control) 
- Figure 11.3.1.107 Patients with CTFI<90 (resistant). RR by IA (PM01183 vs. Control)  
- Figure 11.3.1.108 Patients with CTFI<90 (resistant). DR by IRC (PM01183 vs. Control) 
- Figure 11.3.1.109 Patients with CTFI<90 (resistant). DR by IA (PM01183 vs. Control) 
 
… 
 
Generalised Pairwise comparison 
 
Table 11.3.1.138 Generalised Pairwise comparison 
 
Arm A 
Arm B 
- 
p-value 
2 months OS and any G3-4 adverse reaction 
 
 
 
 
2 months OS and important AE 
 
 
 
 
3 months OS and any G3-4 adverse reaction 
 
 
 
 
3 months OS and important AE 
 
 
 
 
4 months OS and any G3-4 adverse reaction 
 
 
 
 
4 months OS and important AE 
 
 
 
 
 
 
… 
 


                                                          
 
                             
12.9 Time to different deterioration in QoL assessments  
 
Time to deterioration to ≥10 points in the Global Health Status and the additional 
indirect QoL assessment of time to PS deterioration will be performed. Patients not 
reaching the event will be censored in the last available assessment. 
 
 
Table 12.9.1.1 Time to deterioration to ≥10 points in the Global Health Status 
  
PM01183+DOX 
Control 
Parameter 
p-value 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median time  
(95% CI) 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
Mean time  
 
 
 
- 
Kaplan Meier plot (Figure 12.9.1.1) will be shown too. 
 
Table 12.9.1.2 Time to PS deterioration 
  
PM01183+DOX 
Control 
Parameter 
p-value 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median time  
(95% CI) 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
Mean time  
 
 
 
- 
Kaplan Meier plot (Figure 12.9.1.2) will be shown too. PS deterioration is defined as PS>2 or increase in two 
levels from baseline value (e.g from 0 to 2). 
 
 
Adds to (13 DB Listings) 
Shell listings based on the unique forms for eCRF dated on 20APR2016 have been 
added to the main body of the SAP where they were not present previously. To avoid 
unnecessary multiplicity, they have not been repeated in this summary section. 
 
Adds to (14 ICH Listings) 
Shell listings have been added to the main body of the SAP where they were not present 
previously. To avoid unnecessary multiplicity, they have not been repeated in this 
summary section.