Clinical trial NCT02421588
Conditions: Ovarian Cancer
Sponsor: PharmaMar
Start date: 2015-05-01; Completion date: 2018-10-12
Enrollment: 442 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Multicenter, open-label, randomized, controlled phase III clinical trial to evaluate the activity and safety of PM01183 versus PLD or topotecan as control arm in patients with platinum-resistant ovarian cancer. PM01183 will be explored as single agent in the experimental arm (Arm A) versus PLD or topotecan in the control arm (Arm B).

Detailed description:

Arms: arm 1: lurbinectedin (PM01183) arm 2: pegylated liposomal doxorubicin

OR

topotecan
Interventions: intervention 1: Lurbinectedin (PM01183) intervention 2: Pegylated liposomal doxorubicin (PLD) intervention 3: Topotecan
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None

Protocol documents:
Prot_000.pdf: 
 
 
 
 
SPONSOR 
Pharma Mar S.A., Sociedad Unipersonal 
 
 Pharma Mar USA, Inc. 
Avda de los Reyes, 1  
 
 
 
 230 Park Avenue, suite 1000 
Polígono Industrial “La Mina” 
 
 
 New York, New York 10169, USA 
28770 Colmenar Viejo (Madrid) Spain 
 
Phone: + 1 212 309 8737 
Phone:+ 34 91 846 6000  
 
 
 
Fax : + 1 646 435 5846 
Fax:+ 34 91 846 6003 
 
 
 
CLINICAL TRIAL PROTOCOL 
 
 
 
Phase III Randomized Clinical Trial of Lurbinectedin (PM01183) 
versus Pegylated Liposomal Doxorubicin or Topotecan in Patients 
with Platinum-resistant Ovarian Cancer (CORAIL Trial) 
 
 
INVESTIGATIONAL MEDICINAL PRODUCTS: Lurbinectedin (PM01183), pegylated 
liposomal doxorubicin (PLD) and topotecan. 
Protocol Code: PM1183-C-004-14 
EudraCT No: 2014-005251-39 
Final Version 1.0 – 4 December 2014 
NCT Code: NCT02421588 


SPONSORS
Pharma Mar S.A., Sociedad Unipersonal
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.
230 Park Avenue, suite 1000
New York, New York 10169, USA
Phone: + 1 212 309 8737
Fax : + 1 646 435 5846
CLINICAL TRIAL PROTOCOL
PM1183-C-004-14
Phase III Randomized Clinical Trial of Lurbinectedin (PM01183) 
versus Pegylated Liposomal Doxorubicin or Topotecan in Patients 
with Platinum-resistant Ovarian Cancer (CORAIL Trial)
INVESTIGATIONAL MEDICINAL PRODUCTS:
Lurbinectedin (PM01183), 
pegylated liposomal doxorubicin (PLD) and topotecan.
Protocol Code: PM1183-C-004-14
EudraCT No: 2014-005251-39
Final Version 1.0 – 4 December 2014   
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.
CL_0220 1.0
Page 1 of 110
Protocol PM1183-C-004-14


PRINCIPAL INVESTIGATORS
A full list of Investigators will be available as a separate document. 
CL_0220 1.0
Page 4 of 110
Protocol PM1183-C-004-14


TABLE OF CONTENTS
STUDY CONTACTS .................................................................................................................................2
PRINCIPAL INVESTIGATORS..............................................................................................................4
SYNOPSIS ..................................................................................................................................................8
SCHEDULE OF ASSESSMENTS AND PROCEDURES....................................................................29
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS..........................................................31
1.
INTRODUCTION ...........................................................................................................................34
1.1
OVARIAN CANCER....................................................................................................................34
1.2
INFORMATION ON THE STUDY DRUGS ....................................................................................36
1.2.1
Lurbinectedin (PM01183) ...................................................................................................36
1.2.1.1
Name and Chemical Information ............................................................................................... 36
1.2.1.2
Non-clinical Data ....................................................................................................................... 36
1.2.1.3
Clinical Data .............................................................................................................................. 38
1.2.2
Pegylated Liposomal Doxorubicin ......................................................................................39
1.2.3
Topotecan.............................................................................................................................40
1.3
STUDY RATIONALE...................................................................................................................41
1.3.1
Preliminary Results of Study PM1183-B-002-11 ...............................................................42
1.4
RATIONALE FOR THE PM01183 DOSE.....................................................................................43
1.5
RATIONALE FOR THE INTERIM SAFETY ANALYSIS.................................................................45
1.6
RATIONALE FOR THE CONTROL ARM .....................................................................................45
1.7
RATIONALE FOR THE PHARMACOGENETIC SUB-STUDY.........................................................46
1.8
RATIONALE FOR THE PHARMACOGENOMICS SUB-STUDY......................................................46
2.
STUDY OBJECTIVES ...................................................................................................................47
2.1
PRIMARY ..................................................................................................................................47
2.2
SECONDARY..............................................................................................................................47
3.
OVERALL STUDY DESIGN.........................................................................................................47
3.1
PRIMARY ENDPOINT ................................................................................................................49
3.2
SECONDARY ENDPOINTS..........................................................................................................49
4.
SELECTION OF PATIENTS.........................................................................................................50
4.1
INCLUSION CRITERIA...............................................................................................................50
4.2
EXCLUSION CRITERIA..............................................................................................................51
4.3
PATIENTS FOR THE PHARMACOGENOMIC (PGX) AND PHARMACOGENETIC EVALUATIONS 52
5.
PLAN OF THE STUDY..................................................................................................................52
5.1
PLANNED TRIAL PERIODS (FOR THE WHOLE STUDY) ............................................................52
5.2
PLANNED TRIAL PERIODS (INDIVIDUALLY PER PATIENT)......................................................52
5.2.1
Discontinuations..................................................................................................................53
5.2.1.1
Treatment Discontinuation......................................................................................................... 53
5.2.1.2
Reasons for Treatment Discontinuation ..................................................................................... 54
5.2.1.3
Study Discontinuation................................................................................................................ 54
5.2.2
Protocol Deviations..............................................................................................................54
5.3
REPLACEMENT OF PATIENTS...................................................................................................55
5.4
PRE-TREATMENT ASSESSMENTS..............................................................................................55
5.5
PATIENT REGISTRATION..........................................................................................................56
5.6
PATIENT RANDOMIZATION......................................................................................................56
5.7
EVALUATIONS DURING TREATMENT.......................................................................................57
5.8
EVALUATIONS AT END OF TREATMENT ..................................................................................58
5.9
FOLLOW-UP AFTER END-OF-TREATMENT VISIT....................................................................59
6.
TREATMENT .................................................................................................................................59
6.1
DESCRIPTION OF TREATMENT.................................................................................................59
6.1.1
Drug Formulation and Supply............................................................................................59
6.1.1.1
Experimental Arm (PM01183): Arm A...................................................................................... 59
CL_0220 1.0
Page 5 of 110
Protocol PM1183-C-004-14


6.1.1.2
Control Arm (PLD and topotecan): Arm B................................................................................ 60
6.2
ADMINISTRATION OF STUDY MEDICATION.............................................................................60
6.2.1.1
Experimental Arm (PM01183): Arm A...................................................................................... 60
6.2.1.2
Control Arm (PLD and topotecan): Arm B................................................................................ 60
6.3
STARTING DOSES AND SCHEDULE ...........................................................................................60
6.3.1.1
Experimental Arm (PM01183): Arm A...................................................................................... 60
6.3.1.2
Control Arm (PLD and topotecan): Arm B................................................................................ 61
6.4
PROPHYLACTIC MEDICATION .................................................................................................61
6.5
CRITERIA FOR TREATMENT CONTINUATION..........................................................................61
6.6
DOSE REDUCTION ....................................................................................................................63
6.7
CONCOMITANT MEDICATION..................................................................................................65
6.7.1
Allowed Medications/Therapies ..........................................................................................65
6.7.2
Prohibited Medications/Therapies ......................................................................................66
6.7.3
Drug-drug Interactions .......................................................................................................66
6.8
DRUG ACCOUNTABILITY..........................................................................................................67
6.9
TREATMENT COMPLIANCE......................................................................................................67
7.
STUDY EVALUATIONS ...............................................................................................................67
7.1
EFFICACY .................................................................................................................................67
7.2
SAFETY .....................................................................................................................................68
7.3
ADVERSE EVENTS DEFINITIONS ..............................................................................................68
7.3.1
Adverse Event (AE)..............................................................................................................68
7.3.2
Serious Adverse Event (SAE)..............................................................................................69
7.3.3
Death....................................................................................................................................69
7.3.4
Life-threatening Event.........................................................................................................69
7.3.5
Hospitalization or Prolongation of Hospitalization............................................................69
7.3.6
Unlisted/Unexpected Adverse Event ...................................................................................70
7.3.7
Adverse Reactions................................................................................................................70
7.3.8
Adverse Events Related to the Study Drug..........................................................................70
7.3.9
Expedited Reporting ............................................................................................................70
7.3.10
Assessment of Causal Relationship to the Study Drug ..................................................70
7.4
ADVERSE EVENTS REPORTING PROCEDURES.........................................................................70
7.4.1
Reporting Adverse Events....................................................................................................70
7.4.2
Reporting Serious Adverse Events ......................................................................................71
7.4.3
Reporting Pregnancy Cases Occurred within the Clinical Trial........................................72
7.5
ADVERSE EVENTS MONITORING .............................................................................................72
7.6
PATIENT-REPORTED OUTCOMES.............................................................................................73
7.7
PHARMACOKINETICS ...............................................................................................................73
7.7.1
Blood Sampling....................................................................................................................73
7.7.2
Analytical Procedures..........................................................................................................74
7.7.3
Pharmacokinetic Parameters ..............................................................................................74
7.8
PHARMACOGENETIC EVALUATIONS........................................................................................74
7.9
PHARMACOGENOMIC (PGX) EVALUATIONS...........................................................................74
8.
STATISTICAL METHODS...........................................................................................................75
8.1
SAMPLE SIZE ............................................................................................................................75
8.2
STATISTICAL ANALYSIS...........................................................................................................76
8.2.1
Efficacy Analyses.................................................................................................................76
8.2.2
Safety Analyses ....................................................................................................................76
8.2.3
Patient-reported Outcomes (PRO) Analyses.......................................................................77
8.2.4
Pharmacokinetic Analyses ..................................................................................................77
8.2.5
Pharmacogenetic Analyses..................................................................................................77
8.2.6
Pharmacogenomic (PGx) Analyses.....................................................................................77
8.3
FUTILITY ANALYSIS.................................................................................................................78
8.4
INTERIM SAFETY ANALYSIS.....................................................................................................78
9.
ADMINISTRATIVE SECTION ....................................................................................................78
9.1
ETHICS......................................................................................................................................78
9.2
MONITORING, AUDITING AND INSPECTING .............................................................................79
9.3
PATIENT INFORMED CONSENT ................................................................................................79
CL_0220 1.0
Page 6 of 110
Protocol PM1183-C-004-14


9.4
CONFIDENTIALITY/ PATIENTS IDENTIFICATION.....................................................................80
9.5
CASE REPORT FORMS..............................................................................................................80
9.6
INSURANCE ...............................................................................................................................80
9.7
RETENTION OF RECORDS.........................................................................................................80
9.8
USE OF INFORMATION AND PUBLICATION ..............................................................................81
10.
REFERENCES............................................................................................................................82
11.
APPENDICES .............................................................................................................................88
APPENDIX 1: ECOG PERFORMANCE STATUS ASSESSMENT SCALE .......................................88
APPENDIX 2: EVALUATION OF RESPONSE. THE RECIST. ..........................................................89
APPENDIX 3: LIST OF CYP1/CYP2/CYP3 INHIBITORS, INDUCERS AND SUBSTRATES.......101
APPENDIX 4: DECLARATION OF HELSINKI.................................................................................104
CL_0220 1.0
Page 7 of 110
Protocol PM1183-C-004-14


SYNOPSIS
TITLE
Phase III Randomized Clinical Trial of Lurbinectedin 
(PM01183) versus
Pegylated Liposomal Doxorubicin or 
Topotecan in Patients with Platinum-resistant Ovarian Cancer 
(CORAIL Trial)
PROTOCOL CODE
PM1183-C-004-14
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 a difference in progression-free-survival 
(PFS) between lurbinectedin (PM01183) and pegylated 
liposomal doxorubicin (PLD) or topotecan in platinum-
resistant ovarian cancer patients
according to the 
Response Evaluation Criteria in Solid Tumors (RECIST) 
v.1.1.
Secondary:
To evaluate:
Overall survival (OS).

Antitumor activity.
Safety profile.
Patient-reported outcomes (PRO).
To characterize the plasma pharmacokinetics (PK) of 
PM01183 using a sparse sampling scheme in the 
PM01183 treatment arm (Arm A).
Subgroup analyses of the PM01183 arm versus PLD or 
topotecan.
To conduct an exploratory pharmacogenetic and 
pharmacogenomic (PGx) sub-study.
STUDY DESIGN
Multicenter, open-label, randomized, controlled phase III 
clinical trial to evaluate the activity and safety of PM01183 
versus PLD or topotecan as control arm in patients with 
platinum-resistant ovarian cancer.
PM01183 will be explored as single agent in the experimental 
arm (Arm A) versus PLD or topotecan in the control arm (Arm 
B).
Central randomization will be implemented in all patients that 
fulfill the inclusion criteria; patients will be assigned to each 
treatment arm at a 1:1 ratio. If the patient had not previously 
received PLD or topotecan, the assigned treatment in case the 
patient is randomized to the control arm (Arm B) will be based 
on the reported Investigator’s preference with regard to each 
one of these two drugs. However, if the number of patients 
randomized to either PLD or topotecan reaches 60% of the 
CL_0220 1.0
Page 8 of 110
Protocol PM1183-C-004-14


total number of patients expected in the control arm (i.e. 126 
patients), then the treatment of choice in the control arm will 
be restricted to the less frequent control drug until the end of 
accrual. Once the 60% is achieved for one of the two control 
agents, then the patient will not be eligible for this trial if this 
agent is the only possible option (e.g., the patient has been 
previously treated with topotecan, then PLD is the only 
possible option in case the patient is randomized to the Arm B
despite the fact that an accrual of 60% has been reached for 
PLD). Stratification will be performed according to Eastern 
Cooperative Oncology Group (ECOG) performance status (PS) 
(0 vs. ≥1), prior platinum-free interval (1-3 months vs. >3 
months), and prior chemotherapy (1-2 vs. 3 lines). 
Up to 420 patients will be included in the trial.
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.
An Independent Review Committee (IRC) will determine the 
best patient’s 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 interim safety analysis will be performed in the PM01183 
arm (Arm A) only when 40 patients are enrolled in this arm. 
Based on the results of this analysis, the IDMC may provide 
recommendations on the primary prophylactic use of colony-
stimulating factors (CSF) as part of the therapy in the 
experimental Arm A. The recruitment in both treatment arms 
will not be stopped during the conduct of the interim safety 
analysis. 
A futility analysis will be performed when 210 patients are 
recruited (i.e., ~105 patients enrolled in each arm). The 
recruitment will not be put on hold. The IDMC will review 
efficacy and safety data available at that time and, based on the 
observed results, might recommend stopping the trial; no claim 
for superiority in efficacy vs. the control arm is foreseen at that 
time.
Crossover after treatment discontinuation from control Arm B
to experimental Arm A is not allowed.
STUDY POPULATION
Patients with platinum-resistant [disease relapse or progression 
within one to six months after last platinum-containing 
chemotherapy; platinum-free interval (PFI=time between 
completion of the last platinum-containing regimen and the 
subsequent relapse or progression)] epithelial ovarian, 
fallopian tube or primary peritoneal cancer who have received 
no more than three prior systemic chemotherapy regimens. 
CL_0220 1.0
Page 9 of 110
Protocol PM1183-C-004-14


STUDY POPULATION
Inclusion criteria
1)
Voluntary written informed consent (IC) of the patient 
obtained before any study-specific procedure.
2)
Age 18 years.
3)
Histologically or cytologically confirmed diagnosis of 
unresectable epithelial ovarian, fallopian tube or primary 
peritoneal cancer. 
4)
Platinum-resistant disease (PFI: 1-6 months after last 
platinum-containing chemotherapy).
5)
Radiologically 
measurable 
and/or 
non-measurable 
progressive disease according to RECIST v 1.1.
6)
No more than three prior systemic chemotherapy regimens. 
Note: in case that a patient had started a new systemic 
chemotherapy without disease progression to the prior 
chemotherapy line (e.g., treatment discontinuations due to 
toxicity; neoadjuvant followed by adjuvant chemotherapy 
regimens), these two chemotherapy regimens will considered 
as one. 
7)
ECOG PS ≤2.
8)
Adequate hematological, renal, metabolic and hepatic 
function:
a)
Hemoglobin ≥ 9 g/dl [patients may have received prior 
red blood cell (RBC) transfusion]; 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)
Alkaline phosphatase (AP) < 5.0 x ULN.
d)
Total bilirubin ≤ ULN or direct bilirubin ≤ ULN if total 
bilirubin is > ULN.
e)
Albumin ≥ 3.0 g/dl.
f)
Calculated creatinine clearance (CrCL) ≥ 30 ml/min 
(using Cockcroft and Gault’s formula).
g)
Creatine phosphokinase (CPK) ≤ 2.5 x ULN.
9)
At least three weeks since last prior therapy, and grade ≤ 1 
from any adverse event (AE) derived from previous 
treatment (excluding grade ≤ 2 alopecia or peripheral 
neuropathy) according to the National Cancer Institute 
Common Terminology Criteria for Adverse Events (NCI-
CTCAE v. 4).
10) Women of childbearing potential must have pregnancy 
excluded by appropriate testing before study entry. A 
medically acceptable method of contraception must be 
maintained throughout the treatment period and for at least 
six months after treatment discontinuation.
CL_0220 1.0
Page 10 of 110
Protocol PM1183-C-004-14


Exclusion criteria
1)
Concomitant diseases/conditions:
a) History of cardiac disease: myocardial infarction or 
symptomatic/uncontrolled angina within the year prior 
to enrollment; or congestive heart failure defined as 
abnormal left ventricular ejection fraction (LVEF) <
50% assessed by multiple-gated acquisition
scan 
(MUGA) or equivalent by ultrasound (US); or 
symptomatic arrhythmia.
b) Patients with any immunodeficiency, including those 
known to be infected by human immunodeficiency virus 
(HIV).
c) Chronic active hepatitis or cirrhosis. For Hepatitis B, 
this includes positive tests for both Hepatitis B surface 
antigen 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.
d) Active uncontrolled infection.
e) Bowel obstruction.
f)
Requirement of permanent or frequent (i.e., once per 
week) external drainages within two weeks prior to 
randomization.
g) Limitation of the patient’s ability to comply with the 
treatment or to follow-up the protocol.
h) Any other major illness that, in the Investigator’s 
judgment, will substantially increase the risk associated 
with the patient’s participation in this study.
2)
Platinum-refractory or platinum-sensitive disease (PFI <1 or 
> 6 months).
3)
Prior treatment with PM01183, trabectedin, or with both 
PLD and topotecan.
Note: if 60% of recruitment is reached in one of the control 
treatment options (i.e., PLD or topotecan), patients could 
only be eligible if they did not previously receive the other 
control treatment option available (the Sponsor will inform 
the sites, if this occurs).
4)
Known brain metastases or leptomeningeal disease 
involvement.
5)
History of another neoplastic disease (except for curatively 
treated basal cell carcinoma, squamous cell carcinoma of 
the skin, or properly treated carcinoma in situ of the uterine 
cervix or breast) within three years prior to randomization.
6)
Pregnant or breast feeding women. 
CL_0220 1.0
Page 11 of 110
Protocol PM1183-C-004-14


INCLUSION CRITERIA 
FOR THE 
PHARMACOGENOMIC 
AND 
PHARMACOGENETIC 
SUB-STUDY
Only patients who voluntarily sign the informed consent (IC) 
for the PGx and pharmacogenetic sub-study will participate. 
Refusal to participate in the PGx and pharmacogenetic sub-
study will not affect patient participation in the clinical study 
PM1183-C-004-14.
EXPECTED NUMBER 
OF PATIENTS
Up to 420 patients will be randomized at a 1:1 ratio over 18 
months (~23 patients/month as mean estimate). 
A futility analysis is planned after the recruitment of 210 
patients. 
REPLACEMENT OF 
PATIENTS
Randomized patients will not be replaced. 
STUDY DRUGS 
FORMULATION
EXPERIMENTAL ARM (Arm A):

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 as 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
CONTROL ARM (Arm B):

PLD:
Commercially available intravenous (i.v.) presentations of 
vials containing PLD will be provided as appropriate.

Topotecan:
Commercially 
available 
i.v. 
presentations 
of 
vials 
containing topotecan will be provided as appropriate.
CL_0220 1.0
Page 12 of 110
Protocol PM1183-C-004-14


ROUTE OF 
ADMINISTRATION
EXPERIMENTAL ARM (Arm A):

PM01183:
Intravenously as a 1-hour infusion through peripheral or 
central lines.
A minimum total volume of 100 ml, diluted in 5% glucose 
or 0.9% sodium chloride, to be infused over about one hour, 
must be used for administration through a central venous 
catheter, or a minimum 250-ml dilution if a peripheral 
venous catheter is used.
CONTROL ARM (Arm B):

PLD:
Intravenously at an initial rate of 1 mg/min through 
peripheral or central lines. If no infusion reactions are 
observed, the rate of infusion can be increased to complete 
the administration of the drug over 1 hour.
Total PLD doses > 90 mg and 90 mg should be diluted in 
500 and 250 ml of 5% glucose solution for infusion, 
respectively.

Topotecan: 
Intravenously as a 30-min infusion through peripheral or 
central lines.
Topotecan will be diluted in a minimum of 50 ml of 0.9% 
sodium chloride or 5% glucose solution for infusion. 
STARTING DOSES AND 
SCHEDULE
EXPERIMENTAL ARM (Arm A):

PM01183 starting dose and schedule:
3.2 mg/m2 on Day 1 q3wk (three weeks = one treatment 
cycle)
Dose will be rounded to the first decimal.
CONTROL ARM (Arm B):

PLD starting dose and schedule:
50 mg/m2 on Day 1 q4wk (four weeks = one treatment 
cycle). 
Dose will be rounded to the first decimal.
Patients previously treated with PLD will be assigned to 
receive topotecan if they are randomized to the control arm.

Topotecan starting dose and schedule: 
1.50 mg/m2 daily on Days 1-5 q3wk (three weeks = one 
treatment cycle) for patients with calculated CrCL ≥ 60
ml/min.
1.25 mg/m2 daily on Days 1-5 q3wk for patients with 
calculated CrCL between 40 and 59 ml/min.
0.75 mg/m2 daily on Days 1-5 q3wk for patients with 
calculated CrCL between 30 and 39 ml/min.
Dose will be rounded to the first decimal.
CL_0220 1.0
Page 13 of 110
Protocol PM1183-C-004-14


Skipped doses of topotecan will not be replaced.
Patients previously treated with topotecan will be assigned 
to receive PLD if they are randomized to the control arm.
However, if the number of patients randomized to either 
PLD or topotecan reaches 60% of the total number of 
patients expected in the control arm (i.e. 126 patients), then 
the treatment of choice in the control arm will be restricted 
to the less frequent control drug until the end of accrual.
The dose for all three agents (PM01183, PLD or topotecan) 
will be capped at a body surface area (BSA) of 2.0 m2 in those 
patients who have a greater BSA. BSA will be calculated 
according to the standard nomogram used at each center.
PROPHYLACTIC 
MEDICATION
All patients will receive standard antiemetic prophylaxis before 
each treatment infusion, as follows:

Corticosteroids (dexamethasone i.v. at least 8 mg or 
equivalent, or at institutional standard antiemetic doses).

Serotonin (5-HT3) antagonists (ondansetron at least 8 mg 
i.v. or equivalent).
If necessary, in addition to the above, the duration of treatment 
with 5-HT3 antagonists and/or dexamethasone could be 
extended. Additional antiemetic agents can be administered as 
appropriate.
Aprepitant and equivalent agents (e.g., fosaprepitant) are 
forbidden in patients treated with PM01183.
For the purpose of safety evaluations, an optimal prophylaxis 
is defined as all the aforementioned allowed medications at 
their respectively maximum dose.
CRITERIA FOR 
TREATMENT 
CONTINUATION
Further treatment cycles (i.e., Cycle 2 or subsequent) will be 
administered every three weeks (PM01183 or topotecan) or 
every four weeks (PLD) (with a window of ± 48 hours in all of
them) if the patient fulfills all the re-treatment criteria defined 
in Table 2 (PM01183), Table 3 (PLD) or Table 4 (topotecan).
Table 2. Criteria for treatment continuation with PM01183 
(Arm A).
Variable 
Day 1
ECOG PS
≤ 2
ANC 
1.5 x 109/l
Platelets
100 x 109/l
Hemoglobin a
8 g/dl
Total bilirubin
1.5 x ULN or direct 
bilirubin ULN if total 
bilirubin > ULN
Albumin
2.7 g/dl
AST/ALT
3.0 x ULN
CPK
2.5 x ULN
Calculated CrCl 
(Cockcroft and Gault’s formula)
≥ 30 ml/min
CL_0220 1.0
Page 14 of 110
Protocol PM1183-C-004-14


Other non-hematological drug-related AEs 
(except isolated increased GGT and/or AP; grade 2 
alopecia, constipation, fatigue, neuropathy, and not 
optimally treated nausea)
Grade ≤ 1
a Patients may receive PRBC transfusion and/or EPO treatment if clinically indicated 
to increase/maintain adequate hemoglobin levels.
AEs, adverse events; ANC, absolute neutrophil count; AP, alkaline phosphatase; 
AST/ALT, aspartate aminotransferase/alanine aminotransferase; CPK, creatine 
phosphokinase; CrCL, creatinine clearance; ECOG PS, Eastern Cooperative Oncology 
Group performance status; EPO, erythropoietin; PRBC, packed red blood cells; ULN, 
upper limit of normal.
Table 3. Criteria for treatment continuation with PLD (Arm B).
Variable 
Day 1
ECOG PS
≤ 2
ANC 
1.5 x 109/l
Platelets
75 x 109/l
Hemoglobin a
8 g/dl
Total bilirubin
1.5 x ULN or direct 
bilirubin ULN if total 
bilirubin > ULN
Mucositis or hand-foot syndrome
Grade < 2
Calculated CrCl 
(Cockcroft and Gault’s formula)
≥ 30 ml/min
Other non-hematological drug-related AEs 
(except isolated increased GGT and/or AP; grade 2 
alopecia, constipation, fatigue, neuropathy, and not 
optimally treated nausea)
Grade ≤ 1
a Patients may receive PRBC transfusion and/or EPO treatment if clinically indicated 
to increase/maintain adequate hemoglobin levels.
AEs, adverse event(s); ANC, absolute neutrophil count; AP, alkaline phosphatase; 
CrCl, creatinine clearance; ECOG PS, Eastern Cooperative Oncology Group 
performance status; EPO, erythropoietin; GGT, gamma-glutamyltransferase; PPE, 
palmar-plantar erythrodysesthesia; PRBC, packed red blood cells; ULN, upper limit 
of normal.
Table 4. Criteria for treatment continuation with topotecan (Arm 
B).
Variable 
Day 1
ECOG PS
≤ 2
ANC 
1.5 x 109/l
Platelets
100 x 109/l
Hemoglobin a
8 g/dl
Total bilirubin
1.5 x ULN or direct 
bilirubin ULN if total 
bilirubin > ULN
AST/ALT
3.0 x ULN
Calculated CrCl 
(Cockcroft and Gault’s formula)
≥ 30 ml/min b
Other non-hematological drug-related AEs 
(except isolated increased GGT and/or AP, grade 2 
alopecia, constipation, fatigue, neuropathy, and not 
optimally treated nausea)
Grade ≤ 1
CL_0220 1.0
Page 15 of 110
Protocol PM1183-C-004-14


a Patients may receive PRBC transfusion and/or EPO treatment if clinically indicated 
to increase/maintain adequate hemoglobin levels.
b Patients with CrCL between 40 and 59 ml/min must be re-treated with no more than 
1.25 mg/m2 of topotecan daily, and patients with CrCL between 30 and 39 ml/min 
must receive no more than 0.75 mg/m2 of topotecan daily.
AEs, adverse events; ANC, absolute neutrophil count; AP, alkaline phosphatase; 
AST/ALT, aspartate aminotransferase/alanine aminotransferase; CPK, creatine 
phosphokinase; CrCL, creatinine clearance; ECOG PS, Eastern Cooperative Oncology 
Group performance status; EPO, erythropoietin; PRBC, packed red blood cells; ULN, 
upper limit of normal.
If a patient does not meet the requirements for treatment 
continuation on Day 1 of any cycle after Cycle 1, re-
assessments should be performed within one week, and 
treatment will be withheld until appropriate recovery, for a 
maximum of two weeks after the treatment due date. If there is 
no recovery after a 2-week delay, treatment must be 
discontinued, except if objective clinical benefit is adequately 
documented by the Investigator, and upon agreement with the 
Sponsor. Then, treatment may continue after appropriate dose 
reduction.
DOSE REDUCTION
Patients who experience any grade ≥ 3 treatment-related non-
hematological toxicity (according to the NCI-CTCAE v. 4) 
and/or grade 3 thrombocytopenia associated with bleeding or 
persistent at the time of re-treatment or grade 4, or frequent or 
prolonged treatment-related dose delays (> 1 week) (or skipped 
infusions if on topotecan) will continue treatment after 
appropriate dose reduction (see Table 5 for dose reduction in 
Arm A, PM01183; see Table 6 for dose reduction in Arm B, 
PLD or topotecan). 
Patients experiencing grade 4 neutropenia or any grade febrile 
neutropenia, or neutropenic infection during the preceding 
cycle or frequent treatment-related dose delays exclusively due 
to neutropenia may continue treatment without any dose 
reduction, but the patient must receive secondary prophylaxis 
with CSF starting at least 24 hours after the last infusion of the 
cycle. If despite appropriate CSF secondary prophylaxis, grade 
4 neutropenia or febrile neutropenia, neutropenic infection or 
the dose delay re-occurs, then dose reduction should be 
implemented.
Exceptions for dose reduction are: grade 3 nausea and/or 
vomiting not optimally prevented, grade 3 fatigue lasting 2 
days, grade 3 diarrhea lasting ≤ 1 day or not optimally treated, 
isolated grade 3 ALT or AST elevations not leading to dose 
delays and/or non-clinically relevant isolated biochemical 
abnormalities (e.g., GGT).
CL_0220 1.0
Page 16 of 110
Protocol PM1183-C-004-14


Table 5. Levels of dose reduction in Arm A (PM01183).
Arm A
PM01183 dose
(q3wk)
   (mg/m2) a
1 (starting dose)
3.2
-1
2.6
-2
2.0
a PM01183 dose will be capped at a body surface area (BSA) of 2.0 m2 in those 
patients who have a greater BSA.  
q3wk, every three weeks.
Table 6. Levels of dose reduction in Arm B (PLD or 
topotecan).
Arm B
PLD e
(q4wk)
(mg/m2)
Topotecan e
daily dose
(q3wk) 
(mg/m2) 
1 (starting dose)
50                     1.50 a
  1.25 b
0.75 c, d
-1
37.5
1.25
1.00
-
-2
  28 d
1.00
0.75 d
-
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 28 mg/m2 of PLD or 0.75 mg/m2/day of topotecan will be 
implemented under any circumstances.
e PLD and topotecan dose will be capped at a body surface area (BSA) of 2.0 m2 in 
those patients who have a greater BSA.  
CrCL, creatinine clearance; PLD, pegylated liposomal doxorubicin; q3wk, every three 
weeks; q4wk, every four weeks.
In case of grade ≥ 2 hand-foot syndrome (HFS) or stomatitis 
secondary to PLD treatment, the PLD treatment administration 
will be delayed until resolved to grade ≤1 or discontinued if 
not resolved within two weeks. In addition, subsequent doses 
will be reduced if the HFS or stomatitis is ≥ grade 3 (Table 7).
Table 7. PLD dose modification guidelines according to hand-
foot syndrome and stomatitis (Arm B).
Toxicity
grade
Hand-foot 
syndrome 
(HFS)
Stomatitis
Dose adjustment
1
Mild erythema, 
swelling, or 
desquamation 
not interfering 
with daily 
activities.
Painless 
ulcers, 
erythema, 
or mild 
soreness.
Re-treat 
unless 
patient 
has 
experienced previous grade 3 or 4 
HFS/mucositis. If so, delay up to two 
weeks and decrease dose one level. 
Return to original dose interval.
CL_0220 1.0
Page 17 of 110
Protocol PM1183-C-004-14


2
Erythema, 
desquamation, 
or swelling 
interfering with, 
but not 
precluding 
normal physical 
activities; small 
blisters or 
ulcerations less 
than 2 cm in 
diameter.
Painful 
erythema, 
edema, or 
ulcers, but 
can eat.
Delay dosing up to two weeks or until 
resolved to grade 0-1. If after two 
weeks there is no resolution, PLD 
should be discontinued. If resolved to 
grade 0-1 within two weeks, and there 
are no prior grade 3-4 HFS/mucositis, 
continue treatment at previous dose and 
return to original dose interval. If patient 
experienced previous grade 3-4 toxicity, 
continue treatment with one dose level 
reduction and return to original dose 
interval.
3
Blistering, 
ulceration, or 
swelling 
interfering with 
walking or 
normal daily 
activities; 
cannot wear 
regular clothing.
Painful 
erythema, 
edema, or 
ulcers, and 
cannot eat.
Delay dosing up to two weeks or until 
resolved to grade 0-1. Decrease dose 
one level and return to original dose 
interval. If after two weeks there is no 
resolution, PLD should be discontinued.
4
Diffuse or local 
process causing 
infectious 
complications, 
or a bed ridden 
state or 
hospitalization.
Requires 
parenteral 
or enteral 
support.
Delay dosing up to 2 weeks or until 
resolved to grade 0-1. Decrease dose 
one level and return to original interval. 
If after two weeks there is no resolution, 
PLD should be discontinued.
HFS, hand-foot syndrome; PLD, pegylated liposomal doxorubicin.
Patients treated with PLD who have LVEF decreased to < 45% 
or with a 20% decrease from the baseline value have to 
permanently discontinue PLD treatment. 
Control and experimental arms:
Patients who experience any treatment-related grade 3 or 4 
hypersensitivity and/or extravasations will permanently 
discontinue treatment irrespectively of arm allocation.
Up to two dose reductions are allowed per patient. Patients 
who continue to experience treatment-related toxicity and/or 
frequent dose delays after two dose reductions must be 
withdrawn from the study. Once the dose has been reduced for 
an individual patient, it will not be re-escalated under any 
circumstances irrespectively of arm allocation. 
ALLOWED 
MEDICATIONS/
THERAPIES

Therapies for pre-existing and treatment-emergent medical 
conditions, including pain management.

Blood products and transfusions, as clinically indicated.

Bisphosphonates.

In case of nausea or vomiting, extended symptomatic 
treatment for emesis will be allowed.

Colony-stimulating factors (CSFs) or erythropoietin 
treatment according to the American Society of Clinical 
Oncology (ASCO) guidelines.

Anticoagulants.
CL_0220 1.0
Page 18 of 110
Protocol PM1183-C-004-14


PROHIBITED 
MEDICATIONS/
THERAPIES

Concomitant administration of any antineoplastic therapy 
(other than those specifically allowed). 

Any radiotherapy other than limited field irradiation for 
cancer pain control exclusively. 

Immunosuppressive therapies other than corticosteroids for 
antiemetic prophylaxis and/or pain control. 

Aprepitant and equivalent agents (e.g., fosaprepitant) for 
patients allocated to the PM01183 arm (Arm A).

Primary CSF prophylaxis for patients allocated to the 
PM01183 arm (Arm A), unless recommended by the 
IDMC after the interim safety analysis.

Any other investigational agent/s. 
DRUG-DRUG 
INTERACTIONS
In vitro studies using human liver microsomes have shown that 
PM01183 has the potential to inhibit cytochrome CYP2B6, 
CYP2C8 and CYP3A4. Moreover, the Ki values compared 
with the achieved maximum plasma concentration (Cmax) 
values at relevant doses indicate that the likelihood of a 
clinically relevant inhibition of PM01183 is possible for 
CYP2B6 and CYP2C8 ([I]/Ki>0.1) and likely for CYP3A4 
([I]/Ki>1). Additional in vitro studies have demonstrated no 
time dependent inhibition or irreversible inhibition for 
cytochrome CYP3A4. The magnitude of the interaction is 
unknown at present. Therefore, caution should be exercised 
when PM01183 is administered concomitantly with CYP2B6, 
CYP2C8 and CYP3A4 substrates.
Additionally, in vitro studies with human microsomes have 
shown that CYP3A4 is the major CYP isoform involved in the 
metabolism of PM01183, followed by CYP2E1, CYP2D6 and 
CYP2C9. The estimated contribution of the other CYP 
isoenzymes to the PM01183 metabolism is considered to be 
negligible. Therefore, concomitant drugs which induce or 
inhibit any of these cytochromes, especially CYP3A4, should 
be carefully monitored or avoided, whenever is possible.
A potentially significant interaction with aprepitant is 
suggested by available phase II data from ovarian cancer 
patients. Four patients treated with aprepitant in Cycle 2 with 
available PK data had their PM01183 clearance reduced by 
50%, approximately, compared to their Cycle 1 exposure. 
Aprepitant use was forbidden in Cycle 1 in all patients. 
Clinically, some of these patients had unusually long-lasting 
neutropenia and/or severe thrombocytopenia during Cycle 2 as 
well. Although all patients eventually recovered, the use of 
aprepitant is currently forbidden in all phase II/III PM01183 
studies.
CL_0220 1.0
Page 19 of 110
Protocol PM1183-C-004-14


EFFICACY 
EVALUATIONS
Antitumor activity will be assessed using the RECIST v. 1.1 
and followed until disease progression (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 eight weeks from randomization until evidence of PD. 
Patients who finish treatment without radiological PD will 
continue with the tumor assessments every eight weeks (± two 
weeks) from randomization until PD, start of a new antitumor 
therapy, death or date of study termination (clinical cutoff), 
whichever occurs first.
After radiological PD is documented or a new antitumor 
therapy is started, patients will be followed for survival every 
three months (± two weeks) from the end-of-treatment visit 
until death or date of study termination, whichever occurs first. 
Once the whole recruitment is completed, the 3-month follow-
up for patients who discontinue treatment due to PD will be 
performed according to a calendar time. Follow-up for 
survival, after radiological PD is documented or new therapy is 
started, may be made by telephone calls to the investigational 
sites.
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 
RECIST v.1.1.
A futility analysis is planned when 210 patients are recruited. 
The IDMC will review the efficacy and safety data available at 
that time and, based on the observed results, might recommend 
stopping the trial; no claim for superiority in efficacy vs. the 
control arm is foreseen at that time.
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 reduction requirements and reason for 
treatment discontinuation will be monitored throughout the 
study.
The safety profile of patients will be monitored throughout the 
treatment and up to 30 days 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, whichever occurs 
first.
CL_0220 1.0
Page 20 of 110
Protocol PM1183-C-004-14


An interim safety analysis will be performed by the IDMC 
after the recruitment of the first 40 patients in the PM01183 
arm (Arm A) to assess if the addition of primary CSF 
prophylaxis might be necessary. Although febrile neutropenia 
did not occur in the first-in-human PM01183 single-agent 
study, according to pooled data available from all ongoing 
phase II studies at 7.0 mg flat dose (FD), it occurred in 
about 16% of patients. In this clinical trial, the expected 
percentage of febrile neutropenia is lower, as the PM01183 
dose will be administered based on BSA and with a dose (3.2 
mg/m2) below the RD found in the first-in-human PM01183 
trial (4.0 mg/m2 = 7.0 mg FD).
Furthermore, PM01183, PLD and topotecan dose will be 
capped at a BSA of 2.0 m2 in those patients who have a greater 
BSA. 
At the time of the interim safety analysis, recruitment in the 
control arm (Arm B, PLD and topotecan) is also expected to be 
40 patients.
Safety evaluations will be also performed by the IDMC during 
the futility analysis to be conducted in the two treatment arms 
once 210 patients are recruited (i.e., ~105 patients enrolled in 
each arm).
PATIENT-REPORTED 
OUTCOMES (PRO)
PRO will be assessed every eight weeks from randomization 
and while on treatment to determine if efficacy and side effects 
are accompanied by measurable changes in the quality of life 
of patients. EORTC QLQ-C30 and EORTC QLQ-OV28 
questionnaires will be used.
PHARMACOKINETIC 
EVALUATIONS
Sparse samples (detailed in Table 8) will be collected in all 
patients enrolled in the PM01183 arm (Arm A). The samples 
will be obtained in two cycles (in Cycle 1 and in a second 
cycle between Cycle 2 and 4). The selection of the 
second cycle with sample collection for the measurement of 
PM01183 will be assigned once the patient is randomized into 
Arm A.
Table 8. Blood samples for pharmacokinetic evaluations.
Sample 
No.
Sampling time
PK window
#1
Before PM01183 treatment start
1 to 5 min before 
treatment start
#2
5 min before PM01183 EOI
+/- 2 min
#3
1 hour after PM01183 EOI
+/- 10 min
#4
168 hours after PM01183 EOI
+/- 24 hours
EOI, end of infusion; PK, pharmacokinetics.
CL_0220 1.0
Page 21 of 110
Protocol PM1183-C-004-14


PHARMACOGENETIC 
EVALUATIONS
To explore factors that may help to explain individual 
variability in main pharmacokinetic (PK) parameters, the 
presence or absence of germline mutations or polymorphisms 
will be analyzed in leukocyte DNA extracted from a blood 
sample obtained before treatment start in the PM01183 arm
(Arm A). 
PHARMACOGENOMIC 
EVALUATIONS
The analysis of potential predictive factors to PM01183 
treatment will be analyzed on prior available paraffin-
embedded tumor tissue samples from consenting patients. 
Samples from Arm B will be also analyzed and used as 
controls in order to differentiate between the prognostic or 
predictive value of any obtained finding. The potential 
predictive factors will include genes involved in DNA repair 
mechanisms (such as nucleotide excision repair, homologous 
recombination repair or mismatch repair) and other factors 
related to the mechanism of action of PM01183 or to the 
pathogenesis of the disease, and their expression will be 
analyzed at the mRNA or protein level by quantitative 
polymerase chain reaction (PCR) and immunohistochemistry, 
respectively; their polymorphisms and mutations might be also 
analyzed, if relevant.
STUDY 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 treatment. 
SECONDARY ENDPOINTS:

Progression-free survival (PFS) per RECIST v.1.1 by 
Investigator’s Assessment (IA).

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).

Landmark analyses:
o PFS at 6 and 12 months by IRC/IA will be the Kaplan-
Meier estimates of the probability of being free from 
progression (per RECIST v.1.1) and death at these time 
points. 
o OS at 12 and 24 months will be the Kaplan-Meier 
estimates of the probability of being alive at these time 
points.

Best antitumor response by IRC/IA will be the best 
response obtained in any evaluation according to RECIST 
v.1.1. Irrespectively of treatment arm, radiological and clinical 
tumor assessment will be performed symmetrically at baseline 
CL_0220 1.0
Page 22 of 110
Protocol PM1183-C-004-14


and every eight weeks from randomization until evidence of 
PD. Patients who finish treatment without radiological PD will 
continue with the tumor assessments every eight weeks (± two 
weeks) from randomization until PD, start of a new antitumor 
therapy, death or date of study termination (clinical cutoff), 
whichever occurs first.

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 duration of response.

Best response according to tumor marker evaluation (CA-
125) will be the best response obtained according to 
Gynecologic Cancer Intergroup (GCIG) criteria. Irrespectively 
of treatment arm, tumor marker assessment will be performed 
symmetrically at baseline and every eight weeks from 
randomization until evidence of PD. 

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 be also 
assessed.

Patient-reported outcomes (PRO): To measure the quality 
of life of patients, EORTC QLQ-C30 and EORTC QLQ-
OV28 questionnaires will be analyzed every eight weeks in all 
three treatment arms.

Plasma
pharmacokinetics (PK) of PM01183
will be 
evaluated using a sparse sampling scheme in the PM01183 
treatment arm (Arm A). Details will be given in a population 
PK analysis plan and the results of the population PK analysis 
will be presented in a separate report.

Subgroup analyses: Subgroup analyses of the PM01183 arm 
versus PLD or topotecan will be performed. Details of these 
analyses will be provided in the Statistical Analysis Plan.

Pharmacogenetics: This analysis will be performed in those 
patients who signed the IC for the PGx sub-study. The 
presence or absence of known polymorphisms from a single 
sample collected just before the PM01183 treatment start will 
be assessed to explain the individual variability in the main 
PK parameters.

Pharmacogenomics:
This exploratory analysis will be 
performed in those patients treated in any arm who signed the 
IC for the PGx sub-study. Samples from Arm B will be used 
as controls in order to differentiate between the prognostic or 
predictive value of any obtained finding. mRNA or protein 
expression levels of factors involved in DNA repair 
mechanisms, or related to the mechanism of action of 
PM01183 or to the pathogenesis of the disease, will be 
CL_0220 1.0
Page 23 of 110
Protocol PM1183-C-004-14


evaluated from prior available tumor tissue samples obtained 
at diagnosis or relapse. Their mutational status might be also 
analyzed. Their correlation with the clinical response and 
outcome after treatment will be assessed.
STATISTICAL 
METHODS
This phase III clinical trial is designed to determine a 
statistically significant difference in PFS by IRC between 
PM01183 and a control arm with PLD or topotecan in ovarian 
cancer patients with platinum-resistant disease.
The primary study endpoint (PFS by IRC) will be calculated by 
means of the stratified log-rank test 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. 
Sample size calculation:
Patients will be randomized to receive PM01183 given as 3.2
mg/m2 (experimental Arm A) or either topotecan or PLD 
(control arm, Arm B).
The prospective assumptions are a 30% reduction in the relative 
risk of progression or death [hazard ratio (HR)=0.70) to be 
achieved with the experimental arm (PM01183), at a one-sided 
2.5% significance level with at least 90% power, following 
exponential distributions and fulfilling the proportional hazard 
assumption. Median PFS with control arm is expected to be 
around 3.5 months. It is forecasted that an observed HR of 
approximately 0.8 will have enough power to reject the null 
hypothesis. 
Approximately 420 patients with platinum-resistant ovarian 
cancer will be necessary to stratify and randomize at a 1:1 ratio
over 18 months (~23 patients/month). 
The IDMC will review the results of the analyses. The IRC will
determine the patient’s best response and assign the date of 
objective response or progression/censoring according to 
RECIST v.1.1.
A futility analysis with no claim for efficacy when 210 patients 
are recruited (i.e., ~105 patients enrolled in each arm) and the 
final analysis to reject the null hypothesis (HR=1) are planned; 
the significance level will be determined by the actual observed 
number of events, and to maintain scientific integrity spending 
function will be defined by O’Brien-Fleming boundaries. 
Following the prospective assumptions, the futility analysis will 
occur before one year after start of recruitment. At this moment, 
with the available information collected after balancing efficacy 
and safety, the IDMC might recommend stopping the trial.
Randomization:
Central randomization will be implemented in all patients that 
fulfill the inclusion criteria. Randomization of patients should 
occur as close in time as possible to the administration of the 
first dose of study drug. Patients will be assigned to each 
treatment arm at a 1:1 ratio. 
CL_0220 1.0
Page 24 of 110
Protocol PM1183-C-004-14


If the patient had not previously received PLD or topotecan, the 
assigned treatment in case the patient is randomized to the 
control arm (Arm B) will be based on the reported Investigator’s 
preference with regard to each one of these two drugs. However, 
if the number of patients randomized to either PLD or topotecan 
reaches 60% of the total number of patients expected in the 
control arm (i.e. 126 patients), then the treatment of choice in 
the control arm will be restricted to the less frequent control 
drug until the end of accrual.
Stratification:
Stratification will be performed according to ECOG PS (0 vs. 
≥1), prior PFI (1-3 months vs.
>3 months) and prior 
chemotherapy (1-2 vs. 3 lines).
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 (PFS, OS and DR) and their set time 
estimates (i.e., PFS 6/12 and OS 12/24) will be analyzed 
according to the Kaplan-Meier method. The stratified log-rank 
test on the ITT population will be primarily used to compare the 
time-to-event variables. 
Unstratified log-rank tests will be also calculated as supportive 
analyses. 
The symmetry of tumor evaluations between the 
different arms will be examined.  Sensitivity analyses for 
different PFS censoring (e.g. date of progression based on 
scheduled time instead of registered date) will be performed, 
these analyses will be detailed in the SAP.
Cox regression will be used to calculate the risk reduction (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. 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 
continual variable will be chosen.
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 will be used to compare the 
response rates of the experimental arm (PM01183) and the 
control arm (PLD and topotecan). 
Waterfall plots will be used to describe the best variation of the 
sum of target lesions during the treatment.
CL_0220 1.0
Page 25 of 110
Protocol PM1183-C-004-14


Safety analyses: 
AEs, 
SAEs, 
deaths, 
laboratory 
evaluations, 
dose 
delays/skipped/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.
An interim safety analysis, performed when 40 patients are 
enrolled in the PM01183 arm (Arm A), will test if the addition 
of primary CSF prophylaxis might be necessary. With the 
information available at that time, a Bayesian test assuming 
non-informative prior distribution will be done to assess the null 
hypothesis of febrile neutropenia 20% versus the alternative 
hypothesis of febrile neutropenia >20%. If the probability 
associated with the alternative hypothesis is higher than 50% 
(e.g., 8 cases out of 40 patients), the addition of primary CSF 
prophylaxis would be considered necessary. 
At the time of the interim safety analysis, recruitment in the 
control arm (Arm B, PLD and topotecan) is also expected to be 
40 patients.
The IDMC may request to review other preliminary 
safety/efficacy parameters, but no claim of superiority will be 
done; therefore, no type I/II error corrections will be applied.
A safety evaluation will also be performed by the IDMC as part 
of the futility analysis, when a total of 210 patients are included.
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 EORTC QLQ-C30 and 
EORTC QLQ-OV28 questionnaires, as well as on subscales, 
and individual symptoms.
Pharmacokinetic analyses:
Sparse PK data will be listed in the population PK-report for all 
patients with available concentrations in the PM01183 treatment 
arm (Arm A). 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 will be performed using non-linear mixed-effects 
modeling. Data may be combined with those of a selection of 
phase I or II studies 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 
CL_0220 1.0
Page 26 of 110
Protocol PM1183-C-004-14


PK analysis plan and the results of the population PK analysis 
will be presented in a separate report.
Pharmacogenetic analyses:
The influence of known polymorphisms on main PK parameters 
will be assessed by Student’s test or Mann-Whitney’s U test as 
appropriate.
Pharmacogenomic analyses: 
Analysis of RNA/protein expression, polymorphisms and 
mutations will be performed blind and with clinical data 
compiled only after all analyses are completed. A Fisher´s exact 
test/logistic regression for categorical variables and log rank 
test/Cox regression for time to event variables will be used to 
test whether a specific profile is associated with clinical 
outcome. The prognostic value of markers will be explored for 
objective response, PFS and OS. In each case, if applicable, a 
multivariate model will be developed by stepwise selection. All 
tests of statistical significance will be two-sided, and 
significance will be set at 0.05.
DURATION OF STUDY 
PERIOD (per patient)
Patients will be evaluated at scheduled visits during three study 
periods:

Pre-treatment: from signature of IC to the first infusion of 
the study treatment.

Treatment: from the first infusion of the study treatment to 
the end of treatment (EOT).

Follow-up: after EOT, patients will be followed every four 
weeks until resolution or stabilization of all toxicities, if any. 
Patients who finish treatment without radiological disease 
progression will be followed every eight weeks (± two 
weeks) from randomization until disease progression or start 
of a new antitumor therapy, death or until the date of study 
termination (clinical cutoff), whichever occurs first. After 
radiological disease progression is documented or a new 
antitumor therapy is started, patients will be followed at 
least every three months (± two weeks) until death or date of 
study termination, whichever occurs first. Once the whole 
recruitment is completed, the 3-month follow-up for patients 
who discontinue treatment due to disease progression will 
be performed according to a calendar time.
Patients will be considered to be on-study from the signature of 
the informed consent form (ICF) until death or study 
termination. Patients will be considered to be on-treatment
from Day 1 of Cycle 1 until the day of EOT. 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 within 30 days (± 7 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.
CL_0220 1.0
Page 27 of 110
Protocol PM1183-C-004-14


Patients will receive the study treatment(s) while it is considered 
to be in their best interest. Specifically, treatment will continue 
until:

Disease progression.

Unacceptable toxicity.

Intercurrent illness of sufficient magnitude to preclude safe 
continuation of the study.

Investigator’s decision.

Patient refusal.

Non-compliance with the study requirements.

A major protocol deviation that may affect the risk/benefit 
ratio for the participating patient.

Requirement of > two dose reductions. 
PLANNED TRIAL 
PERIODS (for the whole
study)
The total duration of the study will be approximately 42 months, 
including approximately a 18-month enrolment period. 
Planned start date (first patient on study): approximately first
quarter 2015.
Planned enrolment period: approximately 18 months.
Planned end-of-study date (clinical cutoff): 24 months after 
randomization of the last patient.
CL_0220 1.0
Page 28 of 110
Protocol PM1183-C-004-14


SCHEDULE OF ASSESSMENTS AND PROCEDURES
Assessments and 
procedures
Screening*
(days before first 
drug infusion)
Treatment
End of 
treatment 
(EOT)
‡
Follow-up
Cycle
1
Cycle 
2**
Further 
cycles**
D1
D8
D1
D8
D1
D8
Written informed consents 
(general and for 
pharmacogenetic and PGx 
sub-study)
Before any study 
procedure
-
-
-
-
-
-
-
-
Demographic data
-28  to  0
-
-
-
-
-
-
-
-
Medical and cancer 
history/baseline conditions
-14  to  0
(+1 week)
-
-
-
-
-
-
-
-
Assessment of disease-
related signs and symptoms
-14  to  0
(+1 day)
-
-
-
-
-
-
-
-
Complete physical 
examination, including 
weight, height and 
calculation of BSA (1)
-14  to  0          
(+1 day)
-
-

-

-
-
-
ECOG PS
-7  to  0
(+1 day)
-
-

-

-

-
Vital signs (heart rate, 
blood pressure, 
temperature)
-7  to  0
(+1 day)
-
-

-

-
-
-
Laboratory tests (2)
-7  to  0
(+3 days)
-




-

-
Pregnancy test (if 
applicable) (3)
-7  to  0
(+3 days)
Repeat if applicable
-
ECG (4)
-7  to  0
(+3 days)
Repeat if clinically indicated
-
LVEF by ECHO or MUGA
-14  to  0
(+2 weeks)
Repeat if clinically indicated
In patients treated with PLD (Arm B), to be repeated 
every four cycles (or more frequently, if clinically 
indicated). After exceeding a cumulative 
anthracycline dose of 450 mg/m2, LVEF will be 
assessed before each PLD infusion 
-
Pharmacokinetics 
(PM01183 treatment arm 
only, in Cycle 1 and in a 
second cycle between Cycle 
2 and Cycle 4)
-

(5)

(5)

(6)

(6)
    
(6)

(6)
-
-
Pharmacogenetics 
(polymorphisms), in Cycle 1 
only if written informed 
consent given  
-

(7)
-
-
-
-
-
-
-
Pharmacogenomics (PGX), 
if written informed consent 
given  
Available stored 
paraffin-embedded 
tumor tissue 
samples
-
-
Radiological tumor 
assessment (contrast 
enhanced helical CT-scan or 
MRI, as clinically relevant) 
-14  to  0
(+2 weeks)
Every eight weeks from randomization until 
evidence of PD
(8)
Tumor marker evaluation 
(CA-125)
-7  to  0
(+3 days)
Every eight weeks from randomization until 
evidence of PD (9)
(9,10)
Patient-reported outcomes
(EORTC QLQ-C30 and 
EORTC QLQ-OV28 
questionnaires)
-7 to 0
(+1 day)
Every eight weeks from 
randomization

-
CL_0220 1.0
Page 29 of 110
Protocol PM1183-C-004-14


Assessments and 
procedures
Screening*
(days before first 
drug infusion)
Treatment
End of 
treatment 
(EOT)
‡
Follow-up
Cycle
1
Cycle 
2**
Further 
cycles**
D1
D8
D1
D8
D1
D8
Concomitant therapies
-14  to  0
Throughout the ”on-treatment period”***
-
Adverse events
- §
Throughout the ”on-treatment period”***
(11)
Regardless of the treatment administered, the same schedule of assessments will apply. 
* Screening procedures will have to be repeated in case that the first infusion of the study treatment is given out of the established 
windows. Note: Randomization of patients should occur as close in time as possible to the administration of the first dose of 
study drug.
**Further treatment cycles will be administered every three weeks (± 48 hours) for PM01183 (Arm A) and topotecan (Arm B), or 
every four weeks (± 48 hours) for PLD (Arm B) if the patient fulfills all re-treatment criteria.
***“On treatment period” = from first infusion of the study treatment (PM01183, PLD 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].
‡ At 30 ±7 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 whenever the medical condition of the patient may allow these evaluations.
§ Only information on SAEs that occur after signature of informed consent form is required. Grading should be as per NCI-CTCAE 
v. 4.
Time windows for Cycle 2 and further: a 3-day window will be allowed for laboratory tests and ECG, a 1-week window for 
tumor assessments as per RECIST v.1.1, tumor marker evaluation and patient-reported outcomes, a 1-day window for 
clinical assessments (ECOG PS, vital signs, weight, BSA, etc.), a 7-day window for the assessments at EOT, and a 2-week 
window for the follow-up period. 
1.
Height to be measured at baseline only.
2.
Any patient presenting grade 4 treatment-related AEs should have any relevant tests re-assessed at least within 72 hours 
until recovery to at least grade 3.
3.
Beta subunit-human chorionic gonadotropin (ß-hCG) (urine or serum).
4.
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
5.
A total of four blood samples (before PM01183 treatment start, 5 min before the end of PM01183 infusion, and 1 hour and 168 
hours after the end of PM01183 infusion) will be collected for pharmacokinetic PM01183 analyses in Cycle 1 in patients treated 
in Arm A.
6.
A total of four blood samples (before PM01183 treatment start, 5 min before the end of PM01183 infusion, and 1 hour and 168 
hours after the end of PM01183 infusion) will be collected in a second cycle (between Cycle 2 and 4) in patients treated in Arm 
A. The second cycle with blood sample collection for PK will be assigned once the patient is randomized into the PM01183 
arm.
7.
One blood sample will be collected before treatment start in patients treated in Arm A (if informed written consent given) for 
the pharmacogenetic sub-study.
8.
Patients who finish treatment without radiological PD will continue with the tumor assessments every eight weeks (± two 
weeks) from randomization until PD, start of a new antitumor therapy, death or date of study termination (clinical cutoff), 
whichever occurs first. After radiological PD is documented or a new antitumor therapy is started, patients will be followed for 
survival at least every three months (± two weeks) from the end-of-treatment visit until death or date of study termination, 
whichever occurs first. Once the whole recruitment is completed, the 3-month follow-up for patients who discontinue treatment 
due to PD will be performed according to a calendar time.
9.
To be repeated only if baseline levels were higher than normal.
10. To be measured every eight weeks (at the same time than radiological tumor assessments) in case of discontinuation without 
disease progression or until start of a new antitumor therapy, death or date of study termination (clinical cutoff), whichever 
occurs first.
11. Patients withdrawn from the study with a drug-related AE should be followed every four weeks until recovery to at least grade 
1 or stabilization. 
Laboratory tests include:
Hematology: Differential WBC counts, including neutrophil, lymphocyte and monocyte counts, platelet count and hemoglobin.
Biochemistry: Liver function test (ALT, AST, AP, GGT, total bilirubin; direct bilirubin only if total bilirubin is abnormally 
high); total proteins, albumin, creatinine, CPK, glucose, calculated CrCL (as per Cockcroft and Gault’s formula), and serum 
electrolytes (Na+, K+, Cl-).
AE, adverse event; ALT, alanine aminotransferase; AP, alkaline phosphatase; AST, aspartate aminotransferase; BSA, body surface 
area; CPK, creatine phosphokinase; CrCL, creatinine clearance; CT, computed tomography; ECG, electrocardiogram; ECHO, 
echocardiogram; ECOG, Eastern Cooperative Oncology Group Performance Status; EOT, end of treatment; GGT, gamma-glutamyl 
transferase; hCG, human chorionic gonadotropin; 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; PLD, pegylated liposomal doxorubicin; PS, performance status; RECIST, Response Evaluation 
Criteria In Solid Tumors; SAE, serious adverse event; ULN, upper limit of normal; WBC, white blood cells.
CL_0220 1.0
Page 30 of 110
Protocol PM1183-C-004-14


LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
5-HT3
Serotonin
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
β-hCGs
Beta Subunit of Human Chorionic Gonadotropins
BSA
Body Surface Area
Cmax
Maximum Plasma Concentration
CI
Confidence Interval
CPK
Creatine Phosphokinase
CR
Complete Response
CrCL
Creatinine Clearance
CRF
Case Report Form
CSF
Colony-stimulating Factors
CT
Computed Tomography
d/D
Day(s)
DNA
Deoxyribonucleic Acid
DP
Drug Product
DR
Duration of Response
DSB
Double-strand Breaks
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
EORTC
European Organization for Research and Treatment of Cancer
EOI
End of Infusion
EOT
End of Treatment
EPO
Erythropoietin
FD
Flat Dose
FIGO
International Federation of Gynecology and Obstetrics
FiM
First-in-human (study)
FUP
Follow-up
GCIG 
Gynecologic Cancer Intergroup 
Gem
Gemcitabine
GCP
Good Clinical Practice
GGT
Gamma Glutamyltransferase
CL_0220 1.0
Page 31 of 110
Protocol PM1183-C-004-14


GMT
Greenwich Meridian Time
hCG
Human Chorionic Gonadotropin
HFS
Hand-foot Syndrome
HNPCC
Hereditary Non-polyposis Colorectal Cancer 
HIV
Human Immunodeficiency Virus
HR
Hazard Ratio/Homologous Recombination
IA
Investigator’s Assessment
IB
Investigator’s Brochure
IC
Informed Consent
IC50
Half Maximal Inhibitory Concentration 
ICF
Informed Consent Form
ICH
International Conference on Harmonization
IDMC
Independent Data Monitoring Committee
IEC
Independent Ethics Committees
IG50
Concentration that Results in 50% of Cell Growth Inhibition
IMP
Investigational Medicinal Product
IRB
Institutional Review Board
IRC
Independent Review Committee
ITT
Intention-to-treat
IUD
Intrauterine Device
i.v.
Intravenous 
LC-MS/MS
Liquid Chromatography/Mass Spectrometry/Mass Spectrometry 
LVEF
Left Ventricular Ejection Fraction
MedDRA
Medical Dictionary for Regulatory Activities
mg
Milligram
mo
Months
MRI
Magnetic Resonance Imaging
MUGA
Multiple-gated Acquisition Scan
NA
Not Available
NCI
National Cancer Institute
NCI-CTCAE
National Cancer Institute-Common Terminology Criteria for Adverse Events
NER
Nucleotide Excision Repair
NSCLC
Non-small Cell Lung Cancer
ORR
Overall Response Rate
OS
Overall Survival
PCR
Polymerase Chain Reaction
PD
Progressive Disease
PFI
Platinum-free Interval
PFS
Progression-free Survival
CL_0220 1.0
Page 32 of 110
Protocol PM1183-C-004-14


PGx
Pharmacogenomics
PhV
Pharmacovigilance
PK
Pharmacokinetic
PLD
Pegylated Liposomal Doxorubicin
PPE
Palmar-plantar Erythrodysesthesia
PR
Partial Response
PRBC
Packed Red Blood Cells
PRE TT
Pre-treatment
PRO
Patient-reported Outcomes
PS
Performance Status
q3wk
Every Three Weeks
q4wk
Every Four Weeks
Qdx5x2
Two cycles of Five Daily Doses
Q7dx3
Three Consecutive Weekly Doses (D-0, 7, 14)
RBC(s)
Red Blood Cell(s)
RD
Recommended Dose 
RNA
Ribonucleic Acid
RECIST
Response Evaluation Criteria In Solid Tumors
SAE(s)
Serious Adverse Event(s)
SCLC
Small Cell Lung Cancer
SD
Stable Disease
TT
Treatment
TTP
Time to Progression
ULN
Upper Limit of Normal
US
Ultrasound
USA
United States of America
WBC
White Blood Cells
wk/wks
Week/weeks
WMA
World Medical Association
CL_0220 1.0
Page 33 of 110
Protocol PM1183-C-004-14


1.
INTRODUCTION
1.1
OVARIAN CANCER
Epithelial ovarian carcinoma is one of the most common gynecological malignancies 
and has the highest rate of cancer-related mortality among gynecological cancers in 
developed countries. It is the seventh most frequent cause of cancer death in women 
worldwide [1] and the fifth in the USA [2]. Half of the cases occur in women over 65 
years. 
Most ovarian cancers are sporadic; hereditary syndromes account for 10-15% of cases. 
Approximately 90% of hereditary ovarian cancer cases are associated with mutations in 
BRCA1 (chromosome 17) and BRCA2 (chromosome 13). Women with mutations in 
BRCA1 have a 40-50% chance of developing ovarian cancer and those with BRCA2 
mutations have a 15-25% risk [3-5]. Hereditary non-polyposis colorectal cancer 
(HNPCC, Lynch II syndrome) carries an ovarian cancer risk of 12% [6]. Hereditary 
syndromes have to be distinguished from familiar syndromes. Women who have a 
single family member with epithelial ovarian cancer have a 4-5% risk, and those with 
two affected relatives have a 7% risk of developing ovarian cancer [7].
Due to the absence of specific clinical symptoms and the lack of standard screening 
tests for early diagnosis, nearly 75% of the patients have advanced stage at diagnosis. 
The International Federation of Gynecology and Obstetrics (FIGO) classification is the 
most extended staging system used. Survival rates at 5 years do correlate with the FIGO 
stage at diagnosis: 5-year survival exceeds 90% in early stages (IA, IB), but decreases to 
40% and 20% in advanced stages (III and IV, respectively) [8]. 
Maximal 
surgical 
cytoreduction, 
followed 
by 
platinum-based 
combination 
chemotherapy are the standard of care for patients with advanced ovarian cancer. 
Combinations of platinum salts (carboplatin or cisplatin) with paclitaxel are highly 
active and induce objective response in 75% of patients, including nearly 40% of 
clinical complete responses [9, 10]. Complete response (CR) rate is higher in patients 
with early FIGO stage at diagnosis and in those with optimal debulking surgery. 
Platinum/paclitaxel combinations have also shown a significant improvement in 
progression-free survival (PFS) (18 vs. 13 months) and overall survival (OS) (38 vs. 24 
months) 
compared 
to 
platinum 
combinations 
with 
older 
alkylant 
agents 
(cyclophosphamide), and therefore have become the standard frontline chemotherapy 
for advanced disease. 
Despite this highly effective treatment, three quarters of the patients relapse and die due 
to progressive disease. The goal of treatment of relapsed ovarian cancer is palliative, as 
there is no realistic chance of curing patients whose disease has relapsed. On this basis, 
quality of life, prolongation of survival and control of cancer related symptoms are the 
primary goals of treatment of recurrent disease [11].
Given its therapeutic and prognostic relevance [12, 13], recurrent ovarian cancer is 
usually classified according to the length of platinum-free interval (PFI), defined as the 
time between completion of the last platinum-containing regimen and the subsequent 
relapse or progression. Ovarian cancer with a PFI longer than six months (i.e., the time 
between completion of the last platinum-containing chemotherapy and the date of 
relapse is longer than 6 months), is classified as platinum-sensitive. Patients with 
platinum-sensitive ovarian cancer have high likelihood of responding to a subsequent 
platinum-based chemotherapy and generally respond to non-platinum-based therapies as 
well. They have an overall better survival prognosis. Several therapeutic options are 
CL_0220 1.0
Page 34 of 110
Protocol PM1183-C-004-14


available for platinum-sensitive disease, including platinum combinations with 
paclitaxel, gemcitabine or pegylated liposomal doxorubicin (PLD) [14-16], and non-
platinum agents either alone or in combination (e.g., trabectedin plus PLD) [17-23].
In contrast, patients with platinum-resistant disease (PFI: 1-6 months) and those 
progressing or failing to achieve a response to a platinum-containing combination 
(platinum-refractory; PFI < 1 month) are less likely to respond to any subsequent 
therapy and have the worst prognosis in survival expectancy. Therapeutic options for 
these patients are very limited, and response rates rarely exceed 15%. Combination 
chemotherapy has not proven superior to monotherapy and it is usually more toxic.  
The preferred chemotherapy for patients with platinum-resistant ovarian cancer is a 
single non-platinum agent. None of the approved chemotherapy agents (topotecan, PLD 
or paclitaxel) has been proved superior in OS in platinum-resistant ovarian cancer 
patients. Indeed, to date no approval of any available chemotherapies was granted on 
the basis of results in this specific disease setting; rather, results available for the 
relapsed ovarian cancer population in general were extrapolated. Response rates with 
single agents in platinum resistant disease are usually within the 10-15% range; PFS 
ranges 3 to 4 months, and OS is usually below one year with some exceptions (Table 1). 
Combination of chemotherapy with bevacizumab has not shown a statistically 
significant OS advantage over chemotherapy alone.
Table 1. Efficacy results of non-platinum chemotherapy in clinical trials conducted in 
platinum-resistant/platinum-refractory ovarian cancer patients.
Study (reference)
No of 
patients
* 
Treatment arms (n)
Refractory 
(%)
ORR 
(%)
PFS 
(mo)
OS 
(mo)
Ten Bokkel Huinink et al.
(1997) [24]
119
Topotecan (60)
57
13.3
NA
NA
Paclitaxel (59)
56
6.7
NA
NA
Gordon et al. (2001) [25]
254
Topotecan (124)
NA
6.5
3.4
10.3
PLD (130)
NA
12.3
2.3
8.9
Gore et al. (2001) [26]
152
Oral topotecan (77)
52
8.0
NA
NA
i.v. topotecan (75)
52
8.0
NA
NA
Mutch et al. (2007) [27]
195
Gemcitabine (99)
NA
6.1
3.6 
Gem/PLD 
12.7
PLD (96)
NA
8.3
3.1
PLD/Gem 
13.5 
Vergote et al. (2009) [28]
461
Canfosfamide  (231)
41
4.3
2.3
8.5
PLD (130)
15
10.9
4.3
14.2 
Topotecan (87)
10.8
Vergote et al. (2010) [29]
125
Canfosfamide plus PLD (65)
20
12.3
5.6
11.8 
PLD  (62)
13
8.3
3.7
7.8 
Sehouli et al. (2011) [30]
194
Topotecan standard (97)
NA
19.0
4.4
9.3
Topotecan weekly (97)
NA
9.0
3.0
9.6
Colombo et al. (2012)
[31]
829
Patupilone (412)
20.1
15.5
3.7
13.2
PLD (419)
18.8
7.9
3.7
12.7
Pujade-Lauraine et al.
2012 [32]
Witteveen et al. 2013 [33]
(AURELIA trial)
361
Chemotherapy ** (182)
Not 
allowed
12.6
3.4
13.3
Chemotherapy** plus
bevacizumab (179)
30.9
6.7
16.6
*Including both platinum-resistant and platinum-refractory ovarian cancer.  
**Chemotherapy=topotecan (daily or weekly), weekly paclitaxel or PLD.
Gem, gemcitabine; mo, months; NA, data not available; ORR, overall response rate; OS, overall survival; PFS, 
progression-free survival; PLD, pegylated liposomal doxorubicin.
CL_0220 1.0
Page 35 of 110
Protocol PM1183-C-004-14


The treatment of patients with platinum-resistant ovarian cancer is usually chosen based 
on the individual safety profile, since all these agents show very similar and limited 
efficacy, and the therapy aim is mainly to delay disease progression and palliate 
symptoms. These patients are usually candidates for clinical trials testing new treatment 
options.
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 is a new synthetic tetrahydroisoquinoline alkaloid which binds the 
deoxyribonucleic acid (DNA) minor groove, causing spatial distortion of DNA and 
protein complexes and leading to the formation of DNA double-strand breaks (DSBs), 
thus inducing apoptosis and delaying progression through the cell cycle S/G2 phase. 
PM01183 has a negative COMPARE analysis when compared against other 98 standard 
anticancer agents in the standard National Cancer Institute (NCI) panel of 36 cell lines. 
Thus, its mechanism of action is likely to differ significantly from all the other drugs. It 
only showed a positive correlation (S-rank > 0.8) with trabectedin [34]. 
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 
CL_0220 1.0
Page 36 of 110
Protocol PM1183-C-004-14


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 [35].
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
Colon
LoVo
2.0·10-9
HCT 116
6.5·10-8
HT-29
2.4·10-9
Lung
A-549
1.3·10-9
NCI-H460
1.6·10-9
NCI-H23
5.4·10-10
Ovarian
A2780
1.6·10-9
IGROV-1
9.8·10-9
Pancreas
MiaPaca-2
1.1·10-9
PANC-1
2.9·10-9
IG50, concentration that results in 50% of cell growth inhibition.
The antineoplastic in vivo activity of PM01183 was demonstrated in a panel of several 
different human-derived tumor types, i.e., breast, colon, lung, ovarian and prostate 
(Table 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 intravenous (i.v.) injection. 
PM01183 demonstrated statistically significant antitumor activity (p<0.05) against 
breast, lung and ovarian xenografts at different time points during the experiment, but 
had a more moderate antitumor profile against bladder, pancreas and prostate [36].
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
Pancreas
Capan-1
Q7dx3
0.18 (0.54)
61
D-61
Prostate
PC-3
Q7dx3
0.18 (0.54)
65
D-27
D, day; Qdx5x2, two cycles of five daily doses; Q7dx3, three consecutive weekly doses (D-0, 7, 14); T/C, 
treatment/control.
Toxicology studies in rats and dogs showed that the main target organs were the bone 
marrow and the liver. The effect of a single bolus injection of PM01183 on 
cardiovascular parameters [arterial blood pressure, heart rate and lead II 
electrocardiogram (ECG)] was evaluated in dogs for six hours [37]. This study showed 
no effects on heart, blood pressure, lead II ECG variables (PR, QT, QTcF and QTcV 
intervals, and QRS duration), ECG gross morphology or rhythm in dogs treated with 
PM01183 at doses up to 0.01 mg/kg (0.2 mg/m2). Additionally, two different studies
CL_0220 1.0
Page 37 of 110
Protocol PM1183-C-004-14


found no electrophysiological alterations in the heart rate and ECGs of dogs following 
single or repeated PM01183 administration at doses up to 0.05 mg/kg (1 mg/m2) [38, 
39].
The antineoplastic in vitro activity of PM01183 was also evaluated in combination with 
other antineoplastic agents in solid and non-solid tumor cell lines [40, 41]. In solid 
tumor models, two combinations were strongly synergistic: PM01183 combined with 
topotecan (colon HT29, pancreas PANC-1 and glioblastoma U87MG cell lines) and 
PM01183 combined with erlotinib (lung A-549, gastric HGC-27 and prostate PC-3 cell 
lines). Some other standard agents, including platinum agents like oxaliplatin and 
cisplatin, showed synergistic activity in combination with PM01183 in different cell 
lines.
Part of the in vivo antitumor activity of lurbinectedin (PM01183) could be related to 
host-mediated effects that occur in vivo but not in vitro. Recent studies have highlighted 
the ability of trabectedin to modify the tumor microenvironment; particularly the drug 
seems to induce a decrease in the tumor-associated macrophages with significant down-
regulation of cytokines, chemokines and angiogenic factors [42-46]. 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) [47].
1.2.1.3
Clinical Data
Based on the positive preclinical results described above, the clinical development 
program of PM01183 was started in March 2009. Currently, this program comprises 
three phase I single-agent studies (two in solid tumors and one in acute adult leukemia 
patients), five phase Ib combination studies with gemcitabine, capecitabine, 
doxorubicin, cisplatin, or paclitaxel with or without bevacizumab, in patients with 
selected advanced solid tumors, and four phase II studies: one trial as single agent or in 
combination with gemcitabine as second-line therapy in advanced non-small cell lung 
cancer (NSCLC), and three studies as single agent in second-line pancreatic cancer, in 
BRCA-mutated or in BRCA-unselected metastatic breast cancer patients and in 
platinum-resistant/refractory ovarian cancer. As of 15 January 2014, 366 patients (331 
with solid tumors and 35 with advanced acute leukemia) had been treated with 
PM01183 in clinical trials within the clinical development program of this compound: 
198 patients in phase I trials (35 with advanced acute leukemia) and 168 patients in 
phase II trials. 
The two phase I trials which were exploring single-agent PM01183 schedules in solid 
tumor patients finished recruitment and a recommended dose (RD) was selected for 
further study in phase II trials. The first-in-human 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 RD was established at 4.0 mg/m2/q3wk [48]; since 
PM01183 clearance was found to be unrelated to body surface area (BSA), all patients 
in the RD expansion cohort were treated at an equivalent flat dose (FD) of 7.0 mg q3wk. 
In this and subsequent studies, the median terminal plasma half-life was around 60 
hours, though inter-individual variability was high. No evidence of drug accumulation 
was found. Non-hematological toxicity was generally mild and reversible. Standard 
antiemetic prophylaxis was used at the RD to control grade 2 nausea and/or vomiting. 
Hematological toxicity, particularly grade 4 non-febrile neutropenia, was the most 
relevant toxicity and occurred in 40% of patients at the RD in the single-agent phase I 
studies. Neutropenia was generally predictable and short-lasting, and rarely caused 
treatment delays. In the FiM study (Day 1, q3wk) nadir usually occurred during the 
CL_0220 1.0
Page 38 of 110
Protocol PM1183-C-004-14


second week. One of 15 patients treated at the RD had a dose-limiting toxicity (grade 4 
thrombocytopenia). No cases of febrile neutropenia occurred in this study, although 
patient selection might have played a role. 
To explore the feasibility of an alternative schedule (Day 1 and 8, q3wk), a second 
phase I trial (PM1183-A-005-11) was started in advanced non-colorectal cancer patients
following a prospective FD escalation. The RD was 5 mg FD on Day 1 and 8 q3wk; 
myelosuppression limited further dose escalation (around 40% of patients developed 
grade 4 neutropenia). Severe neutropenia was reversible in all cases, but two patients at 
the RD had grade 4 neutropenia lasting for more than one week. No unexpected 
toxicities were found. The safety profile of this schedule seems similar to that of the 
Day 1 q3wk trial, although neutropenia appeared more prolonged and may require 
additional dose adjustment. 
Based on the results from single-agent phase I clinical trials, the Day 1 q3wk schedule 
has a good compliance and is more convenient. Therefore, the Day 1 q3wk schedule 
was selected for further clinical trials.
Antitumor activity has been observed with PM01183 either as single agent or in 
combination with other cytotoxics. Objective responses have been observed in patients 
with the following solid tumors (other than platinum-resistant ovarian cancer): 
pancreatic cancer, breast cancer, NSCLC, small cell lung cancer (SCLC), and other
tumor types (neuroendocrine tumors, endometrial adenocarcinomas, bladder cancer, and 
soft tissue sarcoma). Results of the phase II trial in patients with platinum 
refractory/resistant ovarian cancer are summarized in the study rationale (Section 1.3.1).
1.2.2
Pegylated Liposomal Doxorubicin
Pegylated liposomal doxorubicin (PLD) is the anthracycline anticancer agent 
doxorubicin encapsulated within pegylated liposomes. This formulation has specific 
pharmacokinetic (PK) properties, including a smaller distribution volume, a higher area 
under the curve (AUC) value, a slower clearance and a longer elimination half-life [49]. 
Moreover, as much as 90-95% of circulating doxorubicin in the plasma of treated 
patients is encapsulated within liposomes, which significantly attenuates doxorubicin 
plasma peak concentration and likely reduces its associated toxicity (particularly 
nausea, vomiting and cardiotoxicity) compared to the standard doxorubicin formulation 
[50]. For this same reason, other toxicities than are rather unusual with the standard 
formulation are more frequent with PLD and sometimes even dose-limiting although 
usually not life-threatening, such as mucositis and palmar-plantar erythrodysesthesia 
(PPE).
Mechanistically, the antitumor activity of PLD is essentially the same as that of standard 
doxorubicin. It acts mainly by inhibiting topoisomerase II through covalent binding, and 
secondarily by the generation of free radicals that may damage the DNA and 
ribonucleic acid (RNA) and interfere with vital detoxifying intracellular processes. 
However, some studies have shown that liposome encapsulation favors higher 
intratumoral levels of doxorubicin than in healthy surrounding tissue due to the leaking 
properties of tumor microvessels.
PLD is currently approved in Western countries, alone or in combination, for treating 
several cancer types, including ovarian cancer, breast cancer, Kaposi’s sarcoma and 
multiple myeloma.
When used alone, starting PLD doses of 50 mg/m2 every 4 weeks (q4wk) have been 
widely used, although a dose reduction of approximately 20% is sometimes required 
CL_0220 1.0
Page 39 of 110
Protocol PM1183-C-004-14


according to individual tolerance. Besides the mucositis and PPE, other common 
toxicities associated with PLD are alopecia (which is reversible after treatment 
discontinuation), flushing, headache, dyspnea, hypotension and mild myelosuppression.
PLD activity was identified in early phase II studies in relapsed ovarian cancer. This led 
to the design of a phase III study by Gordon et al. [25] where the efficacy of PLD was 
compared to that of standard topotecan in recurrent ovarian cancer. In this trial, no 
clinical or statistically significant difference was found between PLD and topotecan in a 
pre-planned subgroup analysis of platinum-refractory or resistant patients with respect 
to response rate (6.5% vs. 12.3%), time to tumor progression (9.1 weeks vs. 13.6 
weeks), and OS (36 weeks vs. 41 weeks), respectively [25].
PLD has been subsequently compared to gemcitabine in a phase II trial in patients with 
platinum-resistant ovarian cancer. There were no statistical differences between the two 
arms for median OS (13.5 vs 12.7 months) or PFS (3.1 months versus 3.6 months) [27].
More recently, PLD has been used as the comparator arm in other phase III trials testing 
new single-agent chemotherapeutics, such as canfosfamide and patupilone in women 
with recurrent ovarian cancer [28, 29, 31].
1.2.3
Topotecan
Topotecan is a camptothecin analogue approved for treating relapsed ovarian 
carcinoma, lung cancer, 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 pharmacokinetics [51], but patients 
with moderate to severe renal dysfunction (creatinine clearance < 40 ml/min) need to 
have a dose adjustment [52].
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, fatigue, 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 [53]. 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 [54]. 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.
Topotecan activity in recurrent ovarian cancer was compared to paclitaxel in a 
randomized phase III study in paclitaxel and topotecan-naïve pretreated patients [24]. 
Response rates, PFS and OS data slightly favored the topotecan arm, but the differences 
CL_0220 1.0
Page 40 of 110
Protocol PM1183-C-004-14


were not statistically significant except for time to progression. These results were 
further supported in a phase II study in patients who had failed a prior 
paclitaxel/platinum containing regimen, with a consistent 12.4% response rate in 
platinum-resistant patients [55]. Patient selection remains critical to try to minimize the 
impact of topotecan-associated toxicity in these patients. As mentioned in the above, 
section, topotecan was also compared to PLD in a randomized trial of 474 patients with 
recurrent ovarian cancer (combined platinum-resistant and platinum-sensitive disease)
[25]. There was no clinical or statistical difference between PLD and topotecan in the 
platinum-refractory or resistant subpopulation in objective response, time to tumor 
progression and OS.
1.3
STUDY RATIONALE
Patients with platinum-resistant ovarian cancer have poor prognosis among relapsed 
ovarian cancer. New treatment options are needed, particularly agents with novel 
mechanisms of action.
PM01183 is a new chemical entity that induces double-strand DNA breaks through 
binding to the DNA minor groove. As per COMPARE analysis, it does not have an 
overlapping mechanism of action with other 98 standard cytotoxic agents. 
PM01183 has in vitro and in vivo anticancer activity in several platinum sensitive and 
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). 
On the basis of preclinical results, a controlled, phase II exploratory clinical trial to 
evaluate the activity and safety of PM01183 as a single agent in platinum-
resistant/refractory advanced ovarian cancer was conducted (PM1183-B-002-11) [56, 
57].
The study consisted of two stages:
In the first stage, 18 patients were to receive PM01183 as a 7.0 mg FD 1-hour i.v. 
infusion q3wk. If the minimum threshold of antitumor activity was met (at least two 
confirmed tumor responses), then:
In the second stage, 60 patients were to be stratified according to platinum-
resistance or refractoriness and randomized 1:1 to receive PM01183 at the same 
dose and schedule as in the first stage or to the control arm. The control arm 
initially consisted of standard PLD q4wk for patients not previously treated with 
PLD, or standard i.v. topotecan daily times five q3wk for patients previously treated 
with PLD or with any contraindication to receive PLD. However, due to the 
worldwide shortage of PLD, the protocol was amended replacing the PLD treatment
option with a weekly topotecan schedule. Therefore, the control arm consisted of 
i.v. topotecan on Days 1-5 q3wk (standard regimen) or on Days 1, 8 and 15 q4wk 
(weekly regimen), according to the Investigators’ preference. During the second 
stage, crossover from control arm to the experimental arm was allowed in patients 
with disease progression. If ≥8 patients of the total of 48 evaluable PM01183 
patients achieved the primary endpoint, PM01183 was to be considered for further 
clinical development in this setting.
The primary efficacy endpoint of the study was the ORR, defined as the percentage of 
patients with a response, CR or partial response (PR), according to the Response 
Evaluation Criteria in Solid Tumors (RECIST) v. 1.1 or by Gynecologic Cancer 
CL_0220 1.0
Page 41 of 110
Protocol PM1183-C-004-14


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.
1.3.1
Preliminary Results of Study PM1183-B-002-11 
A total of 81 patients were recruited; all of them were evaluable for analysis at cutoff 
(May 2014). In the first stage, six of 22 patients treated with PM01183 responded to 
treatment; therefore, the trial proceeded to the second stage.
In the second stage, 59 patients were included: 30 were treated with PM01183 and 29 
with topotecan (eight with standard treatment and 21 with weekly treatment). 
In the total population, 49 patients (61%) had platinum-resistant disease: 33 (65%) were 
treated with PM01183 and 16 (55%) with topotecan. 
Preliminary efficacy results are summarized in Table 4. 
Table 4. Preliminary efficacy data of study PM1183-B-002-11 (May 2014).
PM01183
(n=52)
Topotecan (n=29)
p-value
Best response, overall  (RECIST/GCIG)
Confirmed (RECIST/GCIG), n (%)  
(95% CI)
11 (9/2*) (21%)
(11-35%)
0 (0%)
(0-12%)
0.006
CR
1 (2%)
0 (0%)
PR 
10 (19%)
0 (0%)
SD
26 (50%)
15 (52%)
PD
14 (27%)
14 (48%)
Treatment failure
1 (2%)
0 (0%)
Confirmed+unconfirmed (RECIST/GCIG), n (%)
15 (12/3) (29%)
0 (0%)
Response according to platinum status
Platinum-resistant (PM01183 n=33/Topotecan
n=16)
10 (30%) 
(95% CI: 16-49)
-
Platinum-refractory (PM01183 n=18/Topotecan 
n=13)
1 (5%) 
(95% CI: 0-26)
-
Duration of confirmed responses (months)
4.6 
(95% CI: 2.5-5.9)
-
Disease control rate (%)
71
52
Progression-free survival (median and 95% CI) 
(months)
3.5 
(95% CI, 2.5-5.0)
2.0 
(95% CI, 1.4-2.8)
HR=0.48;
log-rank 
p=0.005
Overall survival (median and 95% CI) 
(months)
11.1 
(95% CI, 9.5-21.8)
7.3 
(95% CI, 3.3-14.9)
HR=0.52; 
log-rank 
p=0.016
*Nine responses according to RECIST and two responses according to GCIG criteria.
CI, confidence interval; CR, complete response; GCIG, Gynecologic Cancer Intergroup; HR, hazard ratio; PD, 
disease progression; PR, partial response; RECIST, Response Evaluation Criteria in Solid Tumors (v.1.1); SD, stable 
disease.
ORR was significantly better for PM01183: 21% vs. no responses in the topotecan arm. 
Ten of the 11 confirmed responses were obtained in patients with platinum-resistant 
disease (response rate=30% in this subpopulation). 
In all patients, median PFS was significantly longer with PM01183 (3.5 months) than 
that of 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 topotecan 
CL_0220 1.0
Page 42 of 110
Protocol PM1183-C-004-14


arm (HR: 0.34; log-rank test p=0.002). Median PFS was 5.7 months in this 
subpopulation in the PM01183 arm for the second stage. At the time of the analysis of 
the OS data, 32% of cases were censored. Data showed a median OS of 11.1 months in 
PM01183 arm vs. 7.3 months in topotecan arm. In the subset of patients with platinum-
resistant disease, median OS was 13.5 months in PM01183 treated patients vs. 8.3 
months in the control arm (HR: 0.44; log-rank test p=0.023). The median OS in the 
PM01183 platinum-resistant population during the second stage had not been reached 
yet.
Preliminary safety results showed that most frequent grade 3/4 adverse events were 
fatigue (36.5% of patients), nausea (15.4%) and febrile neutropenia (21.2%) in 
PM01183-treated patients, and febrile neutropenia (10.3%) in topotecan-treated 
patients. 
The most frequent grade 3/4 laboratory abnormality irrespective of their relationship 
with the study treatment was neutropenia in both PM01183-treated patients (84.6%) and 
topotecan-treated patients (41.4%) 
In summary, the primary endpoint of this phase II study was met. PM01183 showed 
statistically significant superiority in ORR/PFS/OS over topotecan in platinum-
resistant/refractory ovarian cancer and, particularly, in the platinum-resistant 
population. Therefore, further studies with PM01183 in platinum-resistant ovarian 
cancer are warranted.
1.4
RATIONALE FOR THE PM01183 DOSE 
The recommended dose (RD) originally found in the first-in-human trial was 4.0 mg/m2
administered i.v. (1-hour infusion) on day 1 q3wk. Since no relationship was observed 
between BSA and PM01183 clearance, a 7.0 mg FD q3wk was implemented in the 
expansion cohort of this phase I trial and finally adopted as RD for phase II trials [48]. 
To date, grade 3/4 neutropenia and thrombocytopenia have been reported in 71% and 
27%, respectively, of treated patients in all single-agent phase II trials at this flat dose; 
in addition, febrile neutropenia has been reported in 16% of these patients. A recent 
pooled data logistic regression analysis suggested that grade 3/4 neutropenia and 
thrombocytopenia could be related to BSA. Other parameters evaluated during the 
logistic regression (e.g. fatigue, vomiting, nausea or ALT level) have shown a similar 
trend (i.e. increased probability of severe events with low BSA values), but relationship 
was not as strong. Owing to these findings, and being conservative, a BSA-based dosing 
strategy will be used in the present phase III study to limit severe toxicity.
Furthermore, in order to improve tolerability, a PM01183 dose level 20% lower than the 
original RD of 4.0 mg/m2 will be implemented in the current phase III clinical trial.
Hence, the PM01183 dose level will be 3.2 mg/m2.
A retrospective analysis of patients treated with PM01183 as flat dose in phase II trials 
showed that, when the PM01183 dose was transformed according to the patients’ BSA 
value, grade 4 neutropenia was found in 9% of patients receiving a dose ≤ 3.2 mg/m2 at 
any time during the treatment period (i.e. taking into account dose reductions) (n=23) 
vs. 47% of those receiving a dose > 3.2 mg/m2 (n=172). Febrile neutropenia was 
observed in 4% of patients treated at ≤ 3.2 mg/m2 vs. 16% of those treated at > 3.2 
mg/m2. Furthermore, no grade 4 thrombocytopenia or PM01183-related grade 3 nausea 
or vomiting was observed at or below the starting dose for this phase III trial.
CL_0220 1.0
Page 43 of 110
Protocol PM1183-C-004-14


In th
stabi
a BS
Simu
PM0
in a s
with 
95% 
dose
centr
PFS, p
Usin
platin
the P
henc
   
he PM1183
ilizations we
A-based PM
ulations we
01183 expos
solid red lin
PM01183 
CI limits). 
s and time
ral trend of 
Figure 2. P
plat
progression-fr
ng the same
num-resista
PM1183-B-0
e, efficacy w
3-B-002-11 
ere observe
M01183 dos
ere perform
sure, change
ne the PFS o
in the PM1
The gray l
s reported 
the simulati
Progression-
inum-resist
ree survival.
e PKPD mo
ant disease a
002-11 trial
was not affe
phase II 
ed in platinu
se close to 3
med using 
es in tumor 
observed in
1183-B-002
ines are the
in the trial
ions. 
-free surviv
ant ovarian 
odel for effi
at the dose l
l. The PFS 
fected.
trial, objec
um-resistan
3.2 mg/m2 o
a PKPD 
size and CA
n platinum-r
2-11 trial (s
e PFS simul
l, and the c
val in real an
cancer in th
icacy, 300 t
level of 3.2
curves in th
ctive respon
t ovarian ca
or even low
model tha
A-125 level
resistant ova
lash red lin
lated for 30
central soli
nd simulate
he PM1183
trials were 
2 mg/m2 and
he simulatio
nses and p
ancer patien
er. 
at linked P
ls, and PFS
arian cancer
nes are the u
00 replicated
d black lin
d data for p
-B-002-11 
simulated f
d using the 
ons were sim
prolonged t
nts who rec
PM01183 d
. Figure 2 s
r patients tr
upper and l
d trials usin
ne represent
patients with
trial.
for patients
schedule us
milar (Figu
tumor 
ceived 
doses, 
shows 
reated 
lower 
ng the 
ts the 
h 
s with 
sed in 
ure 3);
CL_0220 1.0
Page 44 of 110
Protocol PM1183-C-004-14


plati
PFS, p
A fut
enrol
migh
that t
1.5
Data
an in
plann
analy
stimu
Altho
study
FD, i
febri
(with
in the
1.6
PLD
trial, 
cance
confi
statis
resist
Figure 3. P
inum-resista
progression-fr
tility analys
lled in each
ht be issued
time.
RATIONAL
a from the p
ncidence of
ned when 4
ysis will be 
ulating facto
ough febrile
y, according
it occurred 
le neutrope
h a capped d
e first-in-hu
RATIONAL
 and topote
 are widely
er whose di
firmatory ph
stically sign
tant subpop
Progression-
ant ovarian 
ree survival.
sis will be p
h arm). Base
d; no claim 
LE FOR THE
phase II stud
f febrile ne
40 patients
done to eva
ors (CSFs) 
e neutropen
g to pooled
in about 16
enia is lowe
dose at a BS
uman PM01
LE FOR THE
ecan, the tw
y accepted s
isease has p
hase III tria
nificant dif
pulation in
-free surviv
cancer in th
performed w
ed on the ob
for superio
E INTERIM S
dy in ovaria
eutropenia s
s are enroll
aluate the re
in this arm.
nia did not o
d data avail
% of patien
er, as the PM
SA of 2.0 m
1183 trial (4
E CONTROL
wo agents inc
standard trea
progressed o
al comparin
fference be
n ORR, TT
val in real an
he PM1183
mg/m2.
when 210 pa
bserved resu
ority in effic
SAFETY AN
an cancer po
slightly ove
led in the P
equirement 
 
occur in the
able from a
nts. In this c
M01183 do
m2) and at a 
4.0 mg/m2 =
L ARM
cluded in th
atment opti
or relapsed
ng topotecan
tween both
TP and OS
nd simulate
-B-002-11 t
atients are r
ults, a recom
cacy vs. the
NALYSIS
opulation (P
er 20%. An
PM01183 a
of primary 
e first-in-hu
all ongoing
clinical trial
se will be a
dose (3.2 m
= 7.0 mg FD
he control a
ions for its u
after platin
n versus PL
h drugs in 
S [25]. Fu
d data for p
trial at the d
recruited (i.
mmendation
e control ar
PM1183-B-
n interim sa
arm (Arm 
prophylact
uman PM01
 phase II st
, the expect
administere
mg/m2) belo
D).
arm of this p
use in patie
num-based c
LD did not
the platinu
urthermore, 
patients with
dose level o
e., ~105 pa
n to stop the
rm is forese
-002-11) sh
afety analy
A); this in
ic use of co
183 single-
tudies at 7.
ted percenta
d based on 
ow the RD f
phase III cl
ents with ov
chemotherap
t find clinic
um-refracto
no statist
h 
of 3.2 
atients
e trial 
een at 
howed 
ysis is 
nterim 
olony-
-agent 
0 mg 
age of 
BSA
found 
inical 
varian 
py. A 
cal or 
ry or 
ically 
CL_0220 1.0
Page 45 of 110
Protocol PM1183-C-004-14


significant difference in OS has been observed between PLD and topotecan in a phase 
III trial where canfosfamide was explored versus a control arm using PLD or topotecan
[28].
1.7
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 before PM01183 treatment.
1.8
RATIONALE FOR THE PHARMACOGENOMICS SUB-STUDY 
The antitumor activity of PM01183 is associated with the following cell events, as 
described in Leal et al. [58]: 
PM01183 binds to the minor groove of DNA. This binding occurs in preferred GC-
rich trinucleotide sequences, preferably AGC. The binding of PM01183 to the DNA 
produces a stabilization of the DNA duplex. This could account for the need of the 
same DNA repair machinery that usually deals with inter-strand cross-links and 
involves proteins from both homologous recombination (HR) and nucleotide 
excision repair (NER) machineries.
PM01183 induces DNA double-strand breaks (DSBs). In fact, treatment of cells with 
the drug induces the formation of foci of -H2AX, which is indicative of the 
formation of DSBs. In addition, treatment of cells with PM01183 leads to cell cycle 
delay in the S phase, activation of the DNA damage checkpoint, and cell death by 
apoptosis. 
PM01183 interferes with DNA repair. Experimental data reveal that the NER system 
is essential to overcome PM01183-induced DNA damage. When the pattern of 
sensitivity to PM01183 was analyzed in a collection of 5000 haploid deletion 
mutants of the yeast Saccharomyces cerevisiae, Rad13(orthologue of human XPG) 
haploid deletion mutants were found to be more resistant to PM01183 than wild-type 
cells, therefore indicating the dependence of the cytotoxic effect of this compound to 
a functional NER system. XPG is a member of the NER system.
Objective of the Pharmacogenomic Sub-study
The experimental data indicate that PM01183 binds to DNA and interferes with NER 
pathway, inducing DSBs and cell death by apoptosis. Thus, it seems of interest to 
conduct studies correlating the tumor/patient and genes/proteins determinant in the 
efficiency/deficiency of the DNA repair pathways and the outcome of patients 
exposed to PM01183. The ultimate goal is the characterization of such patients who 
shall be prone to respond or show resistance to PM01183, in order to implement a
customized therapy in the future.
Initially, the mRNA and/or protein expression levels of genes involved in DNA 
repair mechanisms (such as nucleotide excision repair, homologous recombination 
repair or mismatch repair) and other factors related to the mechanism of action of 
lurbinectedin or to the pathogenesis of the disease will be determined in paraffin-
embedded tumor tissue blocks from consenting patients. Their polymorphisms and 
mutations might be also analyzed, if relevant.
CL_0220 1.0
Page 46 of 110
Protocol PM1183-C-004-14


2.
STUDY OBJECTIVES
2.1
PRIMARY
To determine a difference in progression-free survival (PFS) between 
lurbinectedin (PM01183) and PLD or topotecan in platinum-resistant ovarian 
cancer patients according to RECIST v.1.1.
2.2
SECONDARY
To evaluate:
Overall survival (OS).
Antitumor activity.
Safety profile.
Patient-reported outcomes (PRO).
To characterize the plasma pharmacokinetics (PK) of PM01183 using a sparse 
sampling scheme in the PM01183 treatment arm (Arm A).
Subgroup analyses of the PM01183 arm versus PLD or topotecan.
To conduct an exploratory pharmacogenetic and pharmacogenomic (PGx) sub-
study.
3.
OVERALL STUDY DESIGN
Multicenter, open-label, randomized, controlled phase III clinical trial to evaluate the 
activity and safety of PM01183 versus PLD or topotecan as control arm in patients with 
platinum-resistant ovarian cancer.
A single-agent PM01183 dose will be explored in the experimental arm (Arm A) versus
PLD or topotecan in the control arm (Arm B).
Central randomization will be implemented in all patients that fulfill the inclusion 
criteria; patients will be assigned to each treatment arm at a 1:1 ratio. If the patient had 
not previously received PLD or topotecan, the assigned treatment in case that the patient 
is randomized to the control arm (Arm B) will be based on the reported Investigator’s 
preference with regard to each one of these two drugs. However, if the number of 
patients randomized to either PLD or topotecan reaches 60% of the total number of 
patients expected in the control arm (i.e. 126 patients), then the treatment of choice in 
the control arm will be restricted to the less frequent control drug until the end of 
accrual. Once the 60% is achieved for one of the two control agents, then the patient 
will not be eligible for this trial if this agent is the only possible option (e.g., the patient 
has been previously treated with topotecan, then PLD is the only possible option in case 
the patient is randomized to the Arm B despite the fact that an accrual of 60% has been 
reached for PLD). Stratification will be performed according to Eastern Cooperative 
Oncology Group (ECOG) performance status (PS) (0 vs. ≥1), prior platinum-free 
interval (1-3 months vs. >3 months), and prior chemotherapy (1-2 vs. 3 lines). 
Up to 420 patients will be included in the trial.
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.
An Independent Review Committee (IRC) will determine the best patient’s response 
and assign the date of objective response or progression/censoring according to RECIST 
CL_0220 1.0
Page 47 of 110
Protocol PM1183-C-004-14


v.1.1
pane
An in
40 pa
provi
thera
stopp
A fu
will n
time 
claim
Cros
Arm 
A sum
1. Operation
l is describe
nterim safe
atients are e
ide recomm
apy in the e
ped during t
utility analy
not be put o
and, based
m for efficac
sover after 
A is not all
mmary of th
nal details f
ed in detail 
ty analysis 
enrolled in t
mendations 
xperimenta
the conduct
sis will be 
on hold. Th
d on the ob
cy in compa
treatment d
lowed.
he study de
for the IRC 
in the IRC 
will be per
this arm. Ba
on the pri
al Arm A. T
t of the inter
performed 
e IDMC wi
bserved resu
arison with 
discontinua
esign is show
Figur
and the alg
charter.
rformed in t
ased on the 
imary prop
The recruitm
rim safety a
when 210 p
ill review ef
ults, might 
the control 
ation from t
wn in Figure
re 4. Study d
gorithm and
the PM0118
results of th
phylactic us
ment in both
analysis. 
patients are
fficacy and 
recommend
arm will be
the control 
e 4.
design.
d its validat
83 arm only
his analysis
se of CSFs
h treatment 
e recruited. 
safety data
d stopping 
e made at th
Arm B to t
tion by an e
y (Arm A) 
s, the IDMC
s as part o
arms will n
The recruit
a available a
the trial, b
his analysis.
the experim
expert 
when 
C may 
of the 
not be 
tment 
at that 
but no 
mental 
CL_0220 1.0
Page 48 of 110
Protocol PM1183-C-004-14


Patients will receive the study treatment while it is considered to be in their best interest. 
Specifically, treatment will continue until disease progression, unacceptable toxicity, 
intercurrent illness of sufficient magnitude to preclude safe continuation of the study, 
Investigator’s decision, patient refusal, non-compliance with the study requirements, a 
major protocol deviation that may affect the risk/benefit ratio for the participating 
patient, or requirement of > two dose reductions.
All adverse events (AEs) will be graded according to the National Cancer Institute 
Common Terminology Criteria for Adverse Events (NCI-CTCAE) v.4. Treatment 
delays, dose reduction requirements and reason for treatment discontinuation will be 
monitored throughout the study. The safety profile of patients will be monitored 
throughout the treatment and up to 30 days 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, whichever occurs first.
Patients will be evaluated at scheduled visits on three study periods: Pre-treatment, 
Treatment and Follow-up (see Section 5.2). This clinical trial will finish (clinical cutoff) 
when all required OS events have occurred according to statistical assumptions.
3.1
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 treatment. 
3.2
SECONDARY ENDPOINTS
Progression-free survival (PFS) per RECIST v.1.1 by Investigator’s Assessment 
(IA).
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).
Landmark analyses:
o PFS at 6 and 12 months by IRC/IA will be the Kaplan-Meier estimates of the 
probability of being free from progression (per RECIST v.1.1) and death at 
these time points. 
o OS at 12 and 24 months will be the Kaplan-Meier estimates of the probability 
of being alive at these time points.
Best antitumor response by IRC/IA will be the best response obtained in any 
evaluation according to RECIST v.1.1. Irrespectively of treatment arm, radiological 
and clinical tumor assessment will be performed symmetrically at baseline and every 
eight weeks from randomization until evidence of PD. Patients who finish treatment 
without radiological PD will continue with the tumor assessments every eight weeks
(± two weeks) from randomization until PD, start of a new antitumor therapy, death 
or date of study termination (clinical cutoff), whichever occurs first.
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, 
CL_0220 1.0
Page 49 of 110
Protocol PM1183-C-004-14


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. 
Best response according to tumor marker evaluation (CA-125) will be the best 
response obtained according to GCIG criteria. Irrespectively of treatment arm, tumor 
marker assessment will be performed symmetrically at baseline and every eight 
weeks from randomization until evidence of PD. 
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 be also assessed.
Patient-reported outcomes (PRO): To measure the quality of life of patients, 
EORTC QLQ-C30 and EORTC QLQ-OV28 questionnaires will be analyzed every 
eight weeks in all three treatment arms.
Plasma pharmacokinetics (PK) of PM01183 will be evaluated using a sparse 
sampling scheme in the PM01183 treatment arm (Arm A). Details will be given in a 
population PK analysis plan and the results of the population PK analysis will be 
presented in a separate report.
Subgroup analyses: Subgroup analyses of the PM01183 arm versus PLD or 
topotecan will be performed. Details of these analyses will be provided in the 
Statistical Analysis Plan.
Pharmacogenetics: This analysis will be performed in those patients who signed the 
IC for the PGx sub-study. The presence or absence of known polymorphisms from a 
single sample collected just before the PM01183 treatment start will be assessed to 
explain the individual variability in the main PK parameters.
Pharmacogenomics: This exploratory analysis will be performed in those patients 
treated in any arm who signed the IC for the PGx sub-study. Samples from Arm B 
will be used as controls in order to differentiate between the prognostic or predictive 
value of any obtained finding. mRNA or protein expression levels of factors involved 
in DNA repair mechanisms, or related to the mechanism of action of PM01183 or to 
the pathogenesis of the disease, will be evaluated from prior available tumor tissue 
samples obtained at diagnosis or relapse. Their mutational status might be also 
analyzed. Their correlation with the clinical response and outcome after treatment 
will be assessed.
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 (IC) of the patient obtained before any study-
specific procedure.
2) Age 18 years.
3) Histologically or cytologically confirmed diagnosis of unresectable epithelial 
ovarian, fallopian tube or primary peritoneal cancer 
CL_0220 1.0
Page 50 of 110
Protocol PM1183-C-004-14


4) Platinum-resistant disease (PFI: 1-6
months after last platinum-containing 
chemotherapy).
5) Radiologically measurable and/or non-measurable progressive disease according to 
RECIST v 1.1.
6) No more than three prior systemic chemotherapy regimens. Note: in case that a 
patient had started a new systemic chemotherapy without disease progression to the 
prior chemotherapy line (e.g., treatment discontinuations due to toxicity; 
neoadjuvant 
followed 
by 
adjuvant 
chemotherapy 
regimens), 
these 
two 
chemotherapy regimens will considered as one. 
7) ECOG PS ≤ 2 (see APPENDIX 1).
8) Adequate hematological, renal, metabolic and hepatic function:
a) Hemoglobin ≥ 9 g/dl [patients may have received prior red blood cell (RBC) 
transfusion]; 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) Alkaline phosphatase (AP) < 5.0 x ULN.
d) Total bilirubin ≤ ULN or direct bilirubin ≤ ULN if total bilirubin is > ULN.
e) Albumin ≥ 3.0 g/dl.
f)
Calculated creatinine clearance (CrCL) ≥ 30 ml/min (using Cockcroft and 
Gault’s formula).
g) Creatine phosphokinase (CPK) ≤ 2.5 x ULN.
9) At least three weeks since last prior therapy, and grade ≤ 1 from any AE derived 
from previous treatment (excluding grade ≤ 2 alopecia or peripheral neuropathy) 
according to the NCI-CTCAE v. 4.
10) Women of childbearing potential must have pregnancy excluded by appropriate 
testing before study entry. A medically acceptable method of contraception* must 
be maintained throughout the treatment period and for at least six months after 
treatment discontinuation.
* Acceptable methods of contraception include intrauterine device (IUD), complete 
abstinence (non-periodic), oral contraceptive, subdermal implant, or double barrier.
4.2
EXCLUSION CRITERIA
1) Concomitant diseases/conditions:
a) History of cardiac disease: myocardial infarction or symptomatic/uncontrolled 
angina within the year prior to enrollment; or congestive heart failure defined as 
abnormal left ventricular ejection fraction (LVEF) < 50% assessed by multiple-
gated acquisition scan (MUGA) or equivalent by ultrasound (US); or 
symptomatic arrhythmia.
b) Patients with any immunodeficiency, including those known to be infected by 
human immunodeficiency virus (HIV).
c) Chronic active hepatitis or cirrhosis. For Hepatitis B, this includes positive tests 
for both Hepatitis B surface antigen 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.
CL_0220 1.0
Page 51 of 110
Protocol PM1183-C-004-14


d) Active uncontrolled infection.
e) Bowel obstruction.
f)
Requirement of permanent or frequent (i.e., once per week) external drainages 
within two weeks prior to randomization.
g) Limitation of the patient’s ability to comply with the treatment or to follow-up 
the protocol.
h) Any other major illness that, in the Investigator’s judgment, will substantially 
increase the risk associated with the patient’s participation in this study.
2) Platinum-refractory or platinum-sensitive disease (PFI <1 or >6 months).
3) Prior treatment with PM01183, trabectedin, or with both PLD and topotecan.
4) Known brain metastases or leptomeningeal disease involvement.
5) History of another neoplastic disease (except for curatively treated basal cell 
carcinoma, squamous cell carcinoma of the skin, or properly treated carcinoma in 
situ of the uterine cervix or breast) within three years prior to randomization.
6) Pregnant or breast feeding women.
4.3
PATIENTS FOR THE PHARMACOGENOMIC (PGX)
AND PHARMACOGENETIC 
EVALUATIONS
Only patients who voluntarily sign the IC for the PGx and pharmacogenetic sub-study 
will participate. Refusal to participate in the PGx and pharmacogenetic sub-study will 
not affect patient participation in the clinical study PM1183-C-004-14.
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, including 
approximately a 18-month enrolment period. 
Planned start date (first patient on study): approximately first quarter 2015.
Planned enrolment period: approximately 18 months.
Planned end-of-study date (clinical cutoff): 24 months after randomization of the last 
patient.
5.2
PLANNED TRIAL PERIODS (INDIVIDUALLY PER PATIENT)
Patients will be evaluated at scheduled visits during three study periods:

Pre-treatment: from signature of IC to the first infusion of the study treatment. 

Treatment: from the first infusion of the study treatment to the end of treatment
(EOT) (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 finish treatment without 
radiological disease progression will be followed every eight weeks from 
randomization until disease progression or start of a new antitumor therapy, death 
or until the date of study termination (clinical cutoff), whichever occurs first. 
After radiological disease progression is documented or a new antitumor therapy 
is started, patients will be followed at least every three months (± two weeks) until 
death or date of study termination, whichever occurs first. Once the whole 
CL_0220 1.0
Page 52 of 110
Protocol PM1183-C-004-14


Patie
form
treat
after 
a new
(EOT
admi
the e
thera
FU
5.2.1
5.2
Treat
treatm
conv
last d
thera
new 
The 
Case
Shou
treatm
thoro
infor
recor
recruitment
treatment d
time.
ents will be 
m (ICF) unt
tment from
the day of 
w antitumo
T visit) will
inistration, u
end-of-treatm
apy.
UP, follow-up
1
Disconti
.1.1
Treat
tment disco
ment (PM
vention, the 
dose of the
apy or death
therapy or t
primary rea
e Report For
uld a patie
ment), all 
oughly as p
rmation. Th
rds.
t is comple
due to disea
 considered
til death or
m Day 1 of C
the last stu
or therapy 
l be perform
unless the p
ment visit s
p; ICF, inform
inuations
tment Disco
ontinuation 
01183, PL
date of end
e study trea
h, whicheve
the date of d
ason for any
rm (CRF).
ent decide 
efforts wi
possible. Sh
he outcome
eted, the 3-
ase progres
d to be on-s
r study term
Cycle 1 unti
udy treatmen
or dies (wh
med within 
patient starts
should be p
Figure
med consent fo
ontinuation
occurs whe
LD or top
d of treatmen
atment (trea
er occurs fir
death will b
y treatment
to prematu
ll be mad
he should b
e of that di
-month foll
ssion will b
study from 
mination. P
il the day of
nt infusion 
hichever oc
30 days (±
s any subse
performed im
e 5. Study p
orm; PRE TT,
n
en an enrol
potecan) re
nt is define
atment disco
rst, in which
be considere
t discontinu
turely disco
e to comp
be asked if 
iscussion sh
low-up for 
be performe
the signatu
Patients wil
f EOT. This
(see Figure
ccurs first).
± 7 days) af
equent antitu
mmediately
periods.
 pre-treatmen
led patient 
egardless o
d as 30 day
ontinuation
h case the d
ed the date o
uation will b
ontinue the
plete and r
she can st
hould be d
patients w
ed according
ure of the in
ll be consid
s EOT is de
e 5), unless 
. An end-o
fter the last
umor therap
y before the 
nt; TT, treatme
ceases to r
of the circ
ys after the d
n), start of a
date of admi
of EOT.
be recorded
e study tre
report the 
till be conta
documented
who discont
g to a calen
nformed co
dered to be
efined as 30
the patient 
of-treatment
t study treat
py, in which
start of the
ent; wks, week
receive the 
cumstances
day of the d
a new antit
inistration o
d on the pat
eatment (re
observation
acted for fu
d in the me
tinue 
ndar 
onsent
e on-
0 days 
starts 
t visit 
tment 
h case 
e new 
ks.
study 
. By 
day of 
tumor 
of this 
ient’s 
efuses 
ns as 
urther 
edical 
CL_0220 1.0
Page 53 of 110
Protocol PM1183-C-004-14


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, treatment will continue until:

Disease progression.

Unacceptable toxicity.

Intercurrent illness of sufficient magnitude to preclude safe continuation of the 
study.

Investigator’s decision.

Patient refusal.

Non-compliance with study requirements.

A major protocol deviation that may affect the risk/benefit ratio for the 
participating patient.

Requirement of > two dose reductions.
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). 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 
CL_0220 1.0
Page 54 of 110
Protocol PM1183-C-004-14


documented, and those considered particularly relevant (i.e., those related to ethical 
issues, to fulfillment of GCP guidelines and with an effect on the risk/benefit ratio) will 
be notified, if applicable, to the pertinent IEC/IRB and to the Competent Authorities as 
established by local regulations.
5.3
REPLACEMENT OF PATIENTS
Randomized patients will not 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 5.
Table 5. Screening period: pre-treatment assessments.
ASSESSMENT
TIME
1. Written 
informed consent
(general and 
pharmacogenetic 
and PGx sub-
study)
Before any study procedures.
2. Medical and 
cancer history/ 
clinical 
examination
Demographic data.
Within 28 days prior to first infusion.
Medical and cancer history/baseline condition:
o Primary diagnosis.
o Prior treatments (with best response and TTP, 
when available).
o Documented date of relapse.
Disease-related signs and symptoms.
Complete physical examination, including weight, 
height and calculation of BSA. 
Concomitant therapies.
Within 14 days prior to first 
infusion.*/**
Performance status (ECOG PS).
Vital signs: heart rate, blood pressure and body 
temperature.
Within 7 days prior to first infusion.*
3. Laboratory tests
Hematology: differential WBC counts (including 
neutrophil,
lymphocyte
and monocyte
counts), 
platelet count and hemoglobin.
Biochemistry: Liver function test (ALT, AST, AP, 
GGT, total bilirubin; direct bilirubin only if total 
bilirubin is abnormally high); total proteins, albumin, 
creatinine, CPK, glucose, calculated CrCL (as per 
Cockcroft
and 
Gault’s 
formula), 
and 
serum 
electrolytes (Na+, K+, Cl-). 
Within 
7 
days 
prior 
to 
first 
infusion.***
4. Pregnancy test 
(if women of 
childbearing 
potential)
Assessment of β-hCG (urine or serum).
Within 7 days prior to first infusion, 
if applicable.***
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.
Within 
7 
days 
prior 
to 
first 
infusion.***
6. LVEF 
ECHO or MUGA.
Within 14 days prior to first 
infusion.****
7. PGx 
Available stored paraffin-embedded tumor tissue 
samples; only in those patients that give their written 
informed consent for the PGx sub-study.
-
CL_0220 1.0
Page 55 of 110
Protocol PM1183-C-004-14


ASSESSMENT
TIME
8. Radiological 
tumor assessment
Contrast enhanced helical CT-scan or MRI, as 
clinically relevant.
Within 14 days prior to first 
infusion.****
9. Tumor marker 
evaluation
CA-125.
Within 
7 
days 
prior 
to 
first 
infusion.***
10. Patient-
reported outcomes
EORTC 
QLQ-C30 
and 
EORTC 
QLQ-OV28 
questionnaires.
Within 7 days prior to first infusion.*
11. Adverse events
Only information on SAEs that occurred after 
signature of the informed consent is required before 
treatment start. Grading should be as per the NCI-
CTCAE v.4.
-
Regardless of the treatment administered, the same schedule of assessments will apply.  
*A 1-day window is allowed for assessment of disease-related signs and symptoms, complete physical examination, 
ECOG PS, vital signs, and patient-reported outcomes at screening.
**A +1-week window is allowed for medical and cancer history/baseline conditions at screening. 
***A +3-day window is allowed for laboratory tests, CA-125 assessment, pregnancy tests and ECG at screening.
****A +2-week window is allowed for LVEF and tumor assessments as per RECIST v.1.1.
ALT, alanine aminotransferase; AP, alkaline phosphatase; AST, aspartate aminotransferase; β-hCG, beta subunit of 
human chorionic gonadotropin; BSA, body surface area; CPK, creatine phosphokinase; CrCL, creatinine clearance; 
CT, computed tomography; ECG, electrocardiogram; ECHO, echocardiography; ECOG, Eastern Cooperative 
Oncology Group; EORTC, European Organization for Research and Treatment of Cancer; GGT, gamma 
glutamyltransferase; LVEF, left ventricular ejection fraction; MRI, magnetic resonance imaging; MUGA, multiple-
gated acquisition scan; NCI-CTCAE, National Cancer Institute Common Terminology Criteria for Adverse Events; 
PGx, pharmacogenomics; PS, performance status; RECIST, Response Evaluation Criteria In Solid Tumors, SAE, 
serious adverse event; TTP, time to progression; WBC, white blood cells.
Screening procedures will have to be repeated in case that the first infusion of the study 
treatment is given out of the established windows.  
5.5
PATIENT REGISTRATION
After the patient has signed the ICF, 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 in all patients that fulfill the inclusion 
criteria. Randomization of patients should occur as close in time as possible to the 
administration of the first dose of study drug. Patients will be assigned to each treatment 
arm at a 1:1 ratio. If the patient had not previously received PLD or topotecan, the 
assigned treatment in case that the patient is randomized to the control arm (Arm B) will 
be based on the reported Investigator’s preference with regard to each one of these two 
drugs. However, if the number of patients randomized to either PLD or topotecan 
reaches 60% of the total number of patients expected in the control arm (i.e. 126 
patients), then the treatment of choice in the control arm will be restricted to the less 
frequent control drug until the end of accrual. Stratification will be performed according 
to ECOG PS (0 vs. ≥1), prior PFI (1-3 months vs. >3 months) and prior chemotherapy 
(1-2 vs. 3 lines). 
CL_0220 1.0
Page 56 of 110
Protocol PM1183-C-004-14


5.7
EVALUATIONS DURING TREATMENT
The following assessments will be done while the patient is on treatment (Table 6).
Table 6. Evaluations during treatment.
ASSESSMENT
TIME
1. Clinical 
examination
Complete physical examination, including 
weight and calculation of BSA. 
Cycle 2 and beyond: Day 1 of each cycle 
(always prior to treatment infusion).*
Performance status (ECOG PS).
Vital signs: heart rate, blood pressure and 
body temperature.
Day 1 of each cycle (always prior to 
treatment infusion).*
Concomitant therapies.
Throughout the “on treatment” period.**
2. Laboratory tests

Hematology:
differential WBC counts 
(including 
neutrophil,
lymphocyte
and 
monocyte
counts), 
platelet 
count 
and 
hemoglobin.
Biochemistry: Liver function test (ALT, 
AST, AP, GGT, total bilirubin; direct bilirubin 
only if total bilirubin is abnormally high); total 
proteins, albumin, creatinine, CPK, glucose, 
calculated CrCL (as per Cockcroft and Gault’s 
formula), and serum electrolytes (Na+, K+, Cl-). 
Cycle 1: Day 8.*
Cycle 2: Day 1 (always prior to treatment 
infusion) and Day 8.*
Cycle 3 and beyond: Day 1 of each cycle 
(always prior to treatment infusion). *
Any patient presenting grade 4 treatment-
related AEs should have any relevant tests 
re-assessed at least within 72 hours until 
recovery to at least grade 3.
3. Pregnancy test (if 
women of 
childbearing 
potential) 
Assessment of β-hCG (urine or serum).
Repeat if applicable.
4. ECG
Cardiac rhythm will be identified in ECG 
intervals of at least 30 seconds of duration, PR 
interval, QT interval (raw), heart rate and QRS 
complex.
Repeat if clinically indicated. 
5. LVEF 
ECHO or MUGA.
Repeat if clinically indicated.
In patients treated with PLD (Arm B), to 
be repeated every four cycles (or more 
frequently, if clinically indicated). After 
exceeding a cumulative anthracycline 
dose of 450 mg/m2, LVEF will be 
assessed before each PLD infusion.
6. Pharmacokinetics 
(in the PM01183 
treatment arm only)
-
A total of eight blood samples (before 
PM01183 treatment start, 5 min before 
the end of PM01183 infusion, and 1 hour 
and 168 hours after the end of PM01183 
infusion) 
will 
be 
collected 
for 
pharmacokinetic PM01183 analyses in 
Cycle 1 (four samples) and in a second 
cycle (between Cycle 2 and 4; four 
samples) in patients treated in Arm A. 
The second cycle with blood sample 
collection for PK will be assigned once 
the patient is randomized into Arm A (see 
details in Section 7.7.1).
7. Pharmacogenetics 
Only in those patients that give their written 
informed consent for the pharmacogenetic sub-
study
One blood sample will be collected 
before treatment start in patients treated 
in 
Arm 
A 
along 
with 
the 
first 
pharmacokinetic sample of Cycle 1 for 
the pharmacogenetic sub-study.
8. Radiological 
tumor assessment
Contrast enhanced helical CT-scan or MRI, as 
clinically relevant.
Every eight weeks from randomization 
until evidence of PD.*
CL_0220 1.0
Page 57 of 110
Protocol PM1183-C-004-14


ASSESSMENT
TIME
9. Tumor marker 
evaluation 
CA-125.
Every eight weeks from randomization 
until evidence of PD, but only if baseline 
levels were higher than normal.*
10. Patient-reported 
outcomes 
EORTC QLQ-C30 and EORTC QLQ-OV28 
questionnaires.
Every eight weeks from  randomization.*
11. 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 laboratory tests and ECG, a 1-week window for tumor assessments as per 
RECIST v.1.1, tumor marker evaluation and patient-reported outcomes, and a 1-day window for clinical assessments 
(ECOG PS, vital signs, weight, BSA, etc.). 
** “On treatment period” = from first infusion of the study treatment (PM01183, PLD 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].
AE, adverse event; ALT, alanine aminotransferase; AP, alkaline phosphatase; AST, aspartate aminotransferase; β-
hCG, beta subunit of human chorionic gonadotropin; BSA, body surface area; CPK, creatine phosphokinase; CrCL, 
creatinine clearance; CT, computed tomography; ECG, electrocardiogram; ECHO, echocardiography; ECOG, 
Eastern Cooperative Oncology Group; EOT, end of treatment; EORTC, European Organization for Research and 
Treatment of Cancer; GGT, gamma glutamyltransferase; 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; PLD, pegylated liposomal doxorubicin; PS, performance status; RECIST, 
Response Evaluation Criteria in Solid Tumors,  WBC, white blood cells.
5.8
EVALUATIONS AT END OF TREATMENT
The end-of-treatment visit will be scheduled within 30 days (± 7 days) after the last 
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:

ECOG PS.

Concomitant therapies.

Laboratory tests (hematology and biochemistry).

Pregnancy test (if applicable).

ECG (if clinically indicated).

LVEF by ECHO or MUGA (if clinically indicated).

Radiological tumor assessment (only in those patients who discontinue treatment 
without radiological PD when the end-of-treatment visit coincides with the 
planned every-eight-weeks evaluation schedule).

Tumor marker (CA-125) evaluation, if baseline levels were higher than normal.

Patient-reported outcomes (EORTC QLQ-C30 and
EORTC QLQ-OV28 
questionnaires).

Adverse events. 
All these evaluations will only have to be repeated for those parameters for which no 
measurement is available within 10 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.
CL_0220 1.0
Page 58 of 110
Protocol PM1183-C-004-14


Adverse events must be reported for 30 days after the last study treatment
administration. All serious adverse events (SAEs) occurring within 30 days of the last 
study treatment administration or until the start of a new antitumor therapy, whichever 
occurs first, will be reported. Beyond this period of time, only those suspected to be 
treatment-related SAEs will be reported (Section 7.4.2).
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 finish treatment without radiological disease progression will be followed 
every eight weeks (± two weeks) from randomization until disease progression or start 
of a new antitumor therapy, death or until the date of study termination (clinical cutoff), 
whichever occurs first. Radiological tumor assessments and a tumor marker (CA-125) 
evaluation (if baseline levels were higher than normal) will be conducted during each of 
these follow-up visits. After radiological disease progression is documented or a new 
antitumor therapy is started, patients will be followed at least every three months (± two 
weeks) until death or date of study termination, whichever occurs first. Once the whole 
recruitment is completed, the 3-month follow-up for patients who discontinue treatment 
due to disease progression will be performed according to a calendar time. In this 
survival follow-up, for the purpose of collecting information, a documented telephone 
call would be acceptable. 
The end-of-study date (clinical cutoff) is defined as 24 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 until the event or its sequelae resolve or stabilize at a level acceptable to the
Investigator.
Additional parameters and/or increased frequency of observations should be performed 
at the Investigator’s discretion and according to the nature of the observed AEs. In case 
of death, autopsy data should be provided when available.
6.
TREATMENT
6.1
DESCRIPTION OF TREATMENT
6.1.1 Drug Formulation and Supply
6.1.1.1
Experimental Arm (PM01183): Arm A
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.
CL_0220 1.0
Page 59 of 110
Protocol PM1183-C-004-14


The full composition of the PM01183 4-mg vials and the reconstituted solution per ml 
is as shown in Table 7.
Table 7. 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 (PLD and topotecan): Arm B
PLD:
Commercially available i.v. presentations of vials containing PLD will be provided 
as appropriate.
Topotecan:
Commercially available i.v. presentations of vials containing topotecan will be 
provided as appropriate.
PLD and topotecan 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 (PM01183): Arm A
Intravenously as a 1-hour infusion through peripheral or central lines.
A minimum total volume of 100 ml, diluted in 5% glucose or 0.9% sodium chloride, to 
be infused over about one hour, must be used for administration through a central 
venous catheter, or a minimum 250-ml dilution if a peripheral venous catheter is used.
6.2.1.2
Control Arm (PLD and topotecan): Arm B

PLD:
Intravenously at an initial rate of 1 mg/min through peripheral or central lines. If no 
infusion reactions are observed, the rate of infusion can be increased to complete 
the administration of the drug over 1 hour.
Total PLD doses > 90 mg and 90 mg should be diluted in 500 and 250 ml of 5% 
glucose solution for infusion, respectively.
Topotecan: 
Intravenously as a 30-min infusion through peripheral or central lines.
Topotecan will be diluted in a minimum of 50 ml of 0.9% sodium chloride or 5% 
glucose solution for infusion.
6.3
STARTING DOSES AND SCHEDULE
6.3.1.1
Experimental Arm (PM01183): Arm A
3.2 mg/m2 on Day 1 q3wk (three weeks = one treatment cycle)
Dose will be rounded to the first decimal.
CL_0220 1.0
Page 60 of 110
Protocol PM1183-C-004-14


6.3.1.2
Control Arm (PLD and topotecan): Arm B
PLD starting dose and schedule:
50 mg/m2 on Day 1 q4wk (four weeks = one treatment cycle). 
Dose will be rounded to the first decimal.
Patients previously treated with PLD will be assigned to receive topotecan if they 
are randomized to the control arm.
Topotecan starting dose and schedule: 
1.50 mg/m2 daily on Days 1-5 q3wk (three weeks = one treatment cycle) for 
patients with calculated CrCL ≥ 60 ml/min.
1.25 mg/m2 daily on Days 1-5 q3wk for patients with calculated CrCL between 
40 and 59 ml/min.
0.75 mg/m2 daily on Days 1-5 q3wk for patients with calculated CrCL between 
30 and 39 ml/min.
Dose will be rounded to the first decimal.
Skipped doses of topotecan will not be replaced.
Patients previously treated with topotecan will be assigned to receive PLD if they are 
randomized to the control arm.
However, if the number of patients randomized to either PLD or topotecan reaches 60% 
of the total number of patients expected in the control arm (i.e. 126 patients), then the 
treatment of choice in the control arm will be restricted to the less frequent control drug 
until the end of accrual (see Section 5.6).
The dose for all three agents (PM01183, PLD or topotecan) will be capped at a body 
surface area (BSA) of 2.0 m2 in those patients who have a greater BSA. BSA will be 
calculated according to the standard nomogram used at each center.
6.4
PROPHYLACTIC MEDICATION
All patients will receive standard antiemetic prophylaxis before each treatment infusion, 
as follows:

Corticosteroids (dexamethasone i.v. at least 8 mg or equivalent, or at institutional 
standard antiemetic doses).

Serotonin (5-HT3) antagonists (ondansetron at least 8 mg i.v. or equivalent).
If necessary, in addition to the above, the duration of treatment with 5-HT3 antagonists 
and/or dexamethasone could be extended. Additional antiemetic agents can be 
administered as appropriate.
Aprepitant and equivalent agents (e.g., fosaprepitant) are forbidden in patients treated 
with PM01183.
For the purpose of safety evaluations, an optimal prophylaxis is defined as all the 
aforementioned allowed medications at their respectively maximum dose.
6.5
CRITERIA FOR TREATMENT CONTINUATION 
Further treatment cycles (i.e., Cycle 2 or subsequent) will be administered every three 
weeks (PM01183 or topotecan) or every four weeks (PLD) (with a window of ± 48 
CL_0220 1.0
Page 61 of 110
Protocol PM1183-C-004-14


hours in all three treatment arms) if the patient fulfills all the re-treatment criteria 
defined in Table 8 (PM01183), Table 9 (PLD) or Table 10 (topotecan).
Table 8. Criteria for treatment continuation with PM01183 (Arm A).
Variable 
Day 1
ECOG PS
≤ 2
ANC 
1.5 x 109/l
Platelets
100 x 109/l
Hemoglobin a
8 g/dl
Total bilirubin
1.5 x ULN or direct bilirubin ULN
if total bilirubin > ULN
Albumin
2.7 g/dl
AST/ALT
3.0 x ULN
CPK
2.5 x ULN
Calculated CrCl 
(Cockcroft and Gault’s formula)
≥ 30 ml/min
Other non-hematological drug-related AEs 
(except isolated increased GGT and/or AP; grade 2 
alopecia, constipation, fatigue, neuropathy, and not 
optimally treated nausea)
Grade ≤ 1
a Patients may receive PRBC transfusion and/or EPO treatment if clinically indicated to increase/maintain 
adequate hemoglobin levels.
AEs, adverse events; ANC, absolute neutrophil count; AP, alkaline phosphatase; AST/ALT, aspartate 
aminotransferase/alanine aminotransferase; CPK, creatine phosphokinase; CrCL, creatinine clearance; 
ECOG PS, Eastern Cooperative Oncology Group performance status; EPO, erythropoietin; PRBC, packed 
red blood cells; ULN, upper limit of normal.
Table 9. Criteria for treatment continuation with PLD (Arm B).
Variable 
Day 1
ECOG PS
≤ 2
ANC 
1.5 x 109/l
Platelets
75 x 109/l
Hemoglobina
8 g/dl
Total bilirubin
1.5 x ULN or direct bilirubin ULN
if total bilirubin > ULN
Mucositis or hand-foot syndrome
Grade < 2
Calculated CrCl 
(Cockcroft and Gault’s formula)
≥ 30 ml/min
Other non-hematological drug-related AEs 
(except isolated increased GGT and/or AP; grade 2 
alopecia, constipation, fatigue, neuropathy, and not 
optimally treated nausea)
Grade ≤ 1
CL_0220 1.0
Page 62 of 110
Protocol PM1183-C-004-14


Variable 
Day 1
a Patients may receive PRBC transfusion and/or EPO treatment if clinically indicated to increase/maintain 
adequate hemoglobin levels.
AEs, adverse event(s); ANC, absolute neutrophil count; AP, alkaline phosphatase; CrCl, creatinine 
clearance; ECOG PS, Eastern Cooperative Oncology Group performance status; EPO, erythropoietin; 
GGT, gamma-glutamyltransferase; PPE, palmar-plantar erythrodysesthesia; PRBC, packed red blood 
cells; ULN, upper limit of normal.
Table 10. Criteria for treatment continuation with topotecan (Arm B).
Variable 
Day 1
ECOG PS
≤ 2
ANC 
1.5 x 109/l
Platelets
100 x 109/l
Hemoglobin a
8 g/dl
Total bilirubin
1.5 x ULN or direct 
bilirubin ULN if total 
bilirubin > ULN
AST/ALT
3.0 x ULN
Calculated CrCl 
(Cockcroft and Gault’s formula)
≥ 30 ml/min b
Other non-hematological drug-related AEs 
(except isolated increased GGT and/or AP, grade 2 alopecia, 
constipation, fatigue, neuropathy, and not optimally treated 
nausea)
Grade ≤ 1
a Patients may receive PRBC transfusion and/or EPO treatment if clinically indicated to increase/maintain 
adequate hemoglobin levels.
b Patients with CrCL between 40 and 59 ml/min must be re-treated with no more than 1.25 mg/m2 of 
topotecan daily, and patients with CrCL between 30 and 39 ml/min must receive no more than 0.75 
mg/m2 of topotecan daily.
AEs, adverse events; ANC, absolute neutrophil count; AP, alkaline phosphatase; AST/ALT, aspartate 
aminotransferase/alanine aminotransferase; CPK, creatine phosphokinase; CrCL, creatinine clearance; 
ECOG PS, Eastern Cooperative Oncology Group performance status; EPO, erythropoietin; PRBC, 
packed red blood cells; ULN, upper limit of normal.
If a patient does not meet the requirements for treatment continuation on Day 1 of any 
cycle after Cycle 1, re-assessments should be performed within one week, and treatment 
will be withheld until appropriate recovery, for a maximum of two weeks after the 
treatment due date. If there is no recovery after a 2-week delay, treatment must be 
discontinued, except if objective clinical benefit is adequately documented by the 
Investigator, and upon agreement with the Sponsor. Then, treatment may continue after 
appropriate dose reduction.
6.6
DOSE REDUCTION
Patients who experience any grade ≥ 3 treatment-related non-hematological toxicity 
(according to the NCI-CTCAE v. 4) and/or grade 3 thrombocytopenia associated with 
bleeding or persistent at the time of re-treatment or grade 4, or frequent or prolonged 
treatment-related dose delays (> 1 week) (or skipped infusions if on topotecan) will 
continue treatment after appropriate dose reduction (see Table 11 for dose reduction in 
Arm A, PM01183; see Table 12 for dose reduction in Arm B, PLD or topotecan). 
CL_0220 1.0
Page 63 of 110
Protocol PM1183-C-004-14


Patients experiencing grade 4 neutropenia or any grade febrile neutropenia, or 
neutropenic infection during the preceding cycle or frequent treatment-related dose 
delays exclusively due to neutropenia may continue treatment without any dose 
reduction, but the patient must receive secondary prophylaxis with CSF starting at least 
24 hours after the last infusion of the cycle. If despite appropriate CSF secondary 
prophylaxis, grade 4 neutropenia or febrile neutropenia, neutropenic infection or the 
dose delay re-occurs, then dose reduction should be implemented.
Exceptions for dose reduction are: grade 3 nausea and/or vomiting not optimally 
prevented, grade 3 fatigue lasting 2 days, grade 3 diarrhea lasting ≤ 1 day or not 
optimally treated, isolated grade 3 ALT or AST elevations not leading to dose delays 
and/or non-clinically relevant isolated biochemical abnormalities (e.g., GGT).
Table 11. Levels of dose reduction in Arm A (PM01183).
Arm A
PM01183 dose
(q3wk)
   (mg/m2) a
1 (starting dose)
3.2
-1
2.6
-2
2.0
a PM01183 dose will be capped at a body surface area (BSA) of 2.0 m2 in those patients who have a 
greater BSA.
q3wk, every three weeks.  
Table 12. Levels of dose reduction in Arm B (PLD or topotecan).
Arm B
PLD e
(q4wk)
(mg/m2)
Topotecan e
daily dose
(q3wk) 
(mg/m2) 
1 (starting dose)
50
  1.50 a
  1.25 b
0.75 c, d
-1
37.5
1.25
1.00
-
-2
  28 d
1.00
0.75 d
-
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 28 mg/m2 of PLD or 0.75 mg/m2/day of topotecan will be implemented under 
any circumstances.
e PLD and topotecan dose will be capped at a body surface area (BSA) of 2.0 m2 in those patients who 
have a greater BSA.
CrCL, creatinine clearance; PLD, pegylated liposomal doxorubicin; q3wk, every three weeks; q4wk, 
every four weeks.
In case of grade ≥ 2 hand-foot syndrome (HFS) or stomatitis secondary to PLD 
treatment, the PLD treatment administration will be delayed until resolved to grade ≤1 
or discontinued if not resolved within two weeks. In addition, subsequent doses will be 
reduced if the HFS or stomatitis is ≥ grade 3 (Table 13).
CL_0220 1.0
Page 64 of 110
Protocol PM1183-C-004-14


Table 13. PLD dose modification guidelines according to hand-foot syndrome and 
stomatitis (Arm B).
Toxicity 
grade
Hand-foot syndrome 
(HFS)
Stomatitis
Dose adjustment
1
Mild erythema, 
swelling, or 
desquamation not 
interfering with daily 
activities.
Painless ulcers, 
erythema, or mild 
soreness.
Re-treat 
unless 
patient 
has 
experienced 
previous grade 3 or 4 HFS/mucositis. If so, 
delay up to two weeks and decrease dose one 
level. Return to original dose interval.
2
Erythema, 
desquamation, or 
swelling interfering 
with, but not precluding 
normal physical 
activities; small blisters 
or ulcerations less than 
2 cm in diameter.
Painful erythema, 
edema, or ulcers, 
but can eat.
Delay dosing up to two weeks or until resolved 
to grade 0-1. If after two weeks there is no 
resolution, PLD should be discontinued. If 
resolved to grade 0-1 within two weeks, and there 
are no prior grade 3-4 HFS/mucositis, continue 
treatment at previous dose and return to original 
dose interval. If patient experienced previous 
grade 3-4 toxicity, continue treatment with one 
dose level reduction and return to original dose 
interval.
3
Blistering, ulceration, 
or swelling interfering 
with walking or normal 
daily activities; cannot 
wear regular clothing.
Painful erythema, 
edema, or ulcers, 
and cannot eat.
Delay dosing up to two weeks or until resolved 
to grade 0-1. Decrease dose one level and return 
to original dose interval. If after two weeks there 
is no resolution, PLD should be discontinued.
4
Diffuse or local process 
causing infectious 
complications, or a bed 
ridden state or 
hospitalization.
Requires 
parenteral or 
enteral support.
Delay dosing up to 2 weeks or until resolved to 
grade 0-1. Decrease dose one level and return to 
original dose interval. If after two weeks there is 
no resolution, PLD should be discontinued.
HFS, hand-foot syndrome; PLD, pegylated liposomal doxorubicin.
Patients treated with PLD who have LVEF decreased to < 45% or with a 20% decrease 
from the baseline value have to permanently discontinue PLD treatment. 
Control and experimental arms:
Patients who experience any treatment-related grade 3 or 4 hypersensitivity and/or 
extravasations will permanently discontinue irrespectively of arm allocation.
Up to two dose reductions are allowed per patient. Patients who continue to experience 
treatment-related toxicity and/or frequent dose delays after two dose reductions must be 
withdrawn from the study. Once the dose has been reduced for an individual patient, it 
will not be re-escalated under any circumstances irrespectively of arm allocation. 
6.7
CONCOMITANT MEDICATION
All treatments received by the patient during the “on-treatment” period of the trial must 
be documented in the CRF.
6.7.1
Allowed Medications/Therapies
Therapies for pre-existing and treatment-emergent medical conditions, including pain 
management.
Blood products and transfusions, as clinically indicated.
Bisphosphonates.
CL_0220 1.0
Page 65 of 110
Protocol PM1183-C-004-14


In case of nausea or vomiting, extended symptomatic treatment for emesis will be 
allowed.
CSFs or erythropoietin treatment according to the American Society of Clinical 
Oncology (ASCO) guidelines.
Anticoagulants.
6.7.2
Prohibited Medications/Therapies
Concomitant administration of any antineoplastic therapy (other than those 
specifically allowed). 
Any radiotherapy other than limited field irradiation for cancer pain control 
exclusively. 
Immunosuppressive therapies other than corticosteroids for antiemetic prophylaxis 
and/or pain control. 
Aprepitant and equivalent agents (e.g., fosaprepitant) for patients allocated to the 
PM01183 arm (Arm A).
Primary CSF prophylaxis for patients allocated to the PM01183 arm (Arm A), unless 
recommended by the IDMC after the interim safety analysis.
Any other investigational agent/s.
6.7.3
Drug-drug Interactions
In vitro studies using human liver microsomes have shown that PM01183 has the 
potential to inhibit cytochrome CYP2B6, CYP2C8 and CYP3A4. Moreover, the Ki 
values compared with the achieved maximum plasma concentration (Cmax) values at 
relevant doses indicate that the likelihood of a clinically relevant inhibition of PM01183 
is possible for CYP2B6 and CYP2C8 ([I]/Ki>0.1) and likely for CYP3A4 ([I]/Ki>1). 
Additional in vitro studies have demonstrated no time dependent inhibition or 
irreversible inhibition for cytochrome  CYP3A4. The magnitude of the interaction is 
unknown at present. Therefore, caution should be exercised when PM01183 is 
administered concomitantly with CYP2B6, CYP2C8 and CYP3A4 substrates.
Additionally, in vitro studies with human microsomes have shown that CYP3A4 is the 
major CYP isoform involved in the metabolism of PM01183, followed by CYP2E1, 
CYP2D6 and CYP2C9. The estimated contribution of the other CYP isoenzymes to the 
PM01183 metabolism is considered to be negligible. Therefore, concomitant drugs 
which induce or inhibit any of these cytochromes, especially CYP3A4, should be 
carefully monitored or avoided, whenever is possible (see APPENDIX 3).
A potentially significant interaction with aprepitant is suggested by available phase II 
data from ovarian cancer patients. Aprepitant use was forbidden in Cycle 1 in all 
patients. Four patients treated with aprepitant in Cycle 2 with available PK data had 
their PM01183 clearance reduced by 50%, approximately, compared to their Cycle 1 
exposure. Clinically, some of these patients had unusually long-lasting neutropenia 
and/or severe thrombocytopenia during Cycle 2. Although all patients eventually 
recovered, the use of aprepitant is currently forbidden in the PM01183 treatment arms 
from all phase II/III PM01183 studies.
CL_0220 1.0
Page 66 of 110
Protocol PM1183-C-004-14


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 a difference in PFS between 
PM01183 and PLD or topotecan in platinum-resistant ovarian cancer patients.
Secondary endpoints of efficacy include antitumor activity according to RECIST v.1.1.
Antitumor activity will be assessed using the RECIST v. 1.1 (see APPENDIX 2) and 
followed until disease progression (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 eight weeks from randomization until 
evidence of PD. Patients who finish treatment without radiological PD will continue 
with the tumor assessments every eight weeks (± two weeks) from randomization until 
PD, start of a new antitumor therapy, death or date of study termination (clinical cutoff), 
whichever occurs first.
After radiological PD is documented or a new antitumor therapy is started, patients will 
be followed for survival at least every three months (± two weeks) from the end-of-
treatment visit until death or date of study termination, whichever occurs first. Once the 
whole recruitment is completed, the 3-month follow-up for patients who discontinue 
treatment due to PD will be performed according to a calendar time. Follow-up for 
survival, after radiological PD is documented or new therapy is started, may be made by 
telephone calls to the investigational sites.
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 RECIST v.1.1.
A futility analysis is planned when 210 patients are recruited (~105 patients enrolled in 
each arm). The IDMC will review the efficacy and safety data available at that time and, 
based on the observed results, might recommend stopping the trial; no claim for 
superiority in efficacy vs. the control arm is foreseen at that time.
CL_0220 1.0
Page 67 of 110
Protocol PM1183-C-004-14


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 reduction requirements and reason for treatment discontinuation will be 
monitored throughout the study.
The safety profile of patients will be monitored throughout the treatment and up to 30 
days 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, whichever occurs first.
An interim safety analysis will be performed by the IDMC after the recruitment of the 
first 40 patients in the PM01183 arm (Arm A) to assess if the addition of primary CSF 
prophylaxis might be necessary. Although febrile neutropenia did not occur in the first-
in-human PM01183 single-agent study, based on pooled data available from all ongoing 
phase II studies at 7.0 mg FD, it occurred in about 16% of patients. In this clinical trial, 
the expected percentage of febrile neutropenia is lower, as the PM01183 dose will be 
administered based on BSA and at a dose (3.2 mg/m2) below the RD found in the first-
in-human PM01183 trial (4.0 mg/m2 = 7.0 mg FD).
Furthermore, PM01183, PLD and topotecan dose will be capped at a BSA of 2.0 m2 in 
those patients who have a greater BSA. 
At the time of the interim safety analysis, recruitment in the control arm (Arm B, PLD 
and topotecan) is also expected to be 40 patients.
Safety evaluations will be also performed by the IDMC during the futility analysis to be 
conducted in all treatment arms once 210 patients are recruited.
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.
CL_0220 1.0
Page 68 of 110
Protocol PM1183-C-004-14


“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.
Grade 5 should be used for events which lead immediately (within 24 hours) and 
directly to death, and grade 4 should be used with outcome death for events which lead 
to death after a longer time period, and that may also be linked to additional morbidities.
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 
CL_0220 1.0
Page 69 of 110
Protocol PM1183-C-004-14


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 Reference Safety 
Information for PLD 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.
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 
CL_0220 1.0
Page 70 of 110
Protocol PM1183-C-004-14


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.
7.4.2
Reporting Serious Adverse Events
The Sponsor will collect SAEs from the time of signing of the informed consent form 
(ICF) until 30 days after administration of the last dose of study drug(s)/IMP(s) or until 
the start of a new antitumor therapy 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 patient registration regardless of relationship 
to the study drug(s)/IMP(s) must be reported immediately, and always within 24 hours 
to the Pharma Mar S.A. Pharmacovigilance Department, electronically by completing 
the applicable 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 4556). 
Out of office hours [Greenwich Meridian Time (GMT)], assistance on SAE reporting 
can be obtained by calling the Pharmacovigilance Department at +34 91 823 4742. 
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.
CL_0220 1.0
Page 71 of 110
Protocol PM1183-C-004-14


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.
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 
CL_0220 1.0
Page 72 of 110
Protocol PM1183-C-004-14


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, EORTC QLQ-C30 and EORTC QLQ-OV28 
questionnaires will be analyzed every eight weeks from randomization and while on 
treatment.
7.7
PHARMACOKINETICS
7.7.1
Blood Sampling
Sparse samples (detailed in Table 14) will be collected in all patients enrolled in the 
PM01183 arm (Arm A). The samples will be obtained in two cycles (in Cycle 1 and in a 
second cycle between Cycle 2 and 4). The selection of the second cycle with sample 
collection for the measurement of PM01183 will be assigned once the patient is 
randomized into Arm A.
Table 14. Blood samples for pharmacokinetic evaluations.
Sample No.
Sampling time
PK window
#1
Before PM01183 treatment start
1 to 5 min before treatment start
#2
5 min before PM01183 EOI
+/- 2 min
#3
1 hour after PM01183 EOI
+/- 10 min
#4
168 hours after PM01183 EOI
+/- 24 hours
EOI, end of infusion; PK, pharmacokinetics.
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
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 eight samples of about 4 ml each will be collected for the determination of 
plasma concentrations of PM01183 on Cycle 1 and in a second cycle between Cycle 2 
CL_0220 1.0
Page 73 of 110
Protocol PM1183-C-004-14


and 4 (about 32 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 transferred into a new tube for 
the determination of PM01183 concentration. 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 using a 
validated, specific, and sensitive liquid chromatography/mass spectrometry/mass 
spectrometry (LC-MS/MS) method by or under the supervision of the Sponsor.
7.7.3
Pharmacokinetic Parameters
Pharmacokinetic analysis will be the responsibility of the Sponsor in accordance with 
the current Clinical Pharmacokinetics guidelines on population pharmacokinetic 
analyses [59, 60]. 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 that may 
be involved in the metabolism and/or transport of PM01183 will be analyzed in 
leukocyte DNA extracted from one blood sample (10 ml) obtained before PM01183 
treatment in Cycle 1 in patients treated with PM01183 (Arm A). The collection and 
management of the polymorphisms samples are quite different than those for PK 
assessment (please, refer to the Laboratory Manual for details). The assessment of 
polymorphisms is not affected by treatment. Therefore, the Sponsor may require the 
collection of additional polymorphisms samples later on, if the first assessment has not 
been performed accurately. Only patients who voluntarily sign the IC 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-004-14.
7.9
PHARMACOGENOMIC (PGX) EVALUATIONS
Provision of samples for PGx analyses will be optional and performed upon patient 
consent by signing the PGx IC. For those patients who consent to participate in the PGx 
study, available tumor tissue blocks obtained at diagnosis of the disease will be 
collected during his/her participation in the associated clinical trial. Samples from Arm 
B will be used as controls in order to differentiate between the prognostic or predictive 
value of any obtained finding.
The following analyses will be done in paraffin-embedded tumor tissue from consenting 
patients: 
CL_0220 1.0
Page 74 of 110
Protocol PM1183-C-004-14



Quantitation of mRNA expression of selected genes involved in DNA repair 
mechanisms and/or related to the mechanism of action of PM01183 or to the 
pathogenesis of the disease by real-time qRT-PCR.

Quantitation of protein expression of selected genes involved in DNA repair 
mechanisms and/or related to the mechanism of action of PM01183 or to the 
pathogenesis of the disease by IHC in tumor tissue microarrays constructed.

Analysis of polymorphisms and mutations of the above mentioned selected 
genes will be analyzed, if relevant, by qRT-PCR and/or DNA sequencing.
Expression levels of the different markers will be correlated with the patient’s clinical 
outcome.
8.
STATISTICAL METHODS
This phase III clinical trial is designed to determine a statistically significant difference 
in PFS by IRC between PM01183 and a control arm with PLD or topotecan in ovarian 
cancer patients with platinum-resistant disease.
The primary study endpoint (PFS by IRC) will be calculated by means of the stratified 
log-rank test 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 PM01183 given as 3.2 mg/m2 (experimental 
arm, Arm A), or either topotecan or PLD (control arm, Arm B).
The prospective assumptions are a 30% reduction in the relative risk of progression or 
death (HR=0.7) to be achieved with the experimental arm (PM01183), at a one-sided 
2.5% significance level with at least 90% power, following exponential distributions 
and fulfilling the proportional hazard assumption. Median PFS with control arm is 
expected to be around 3.5 months. It is forecasted that an observed HR of 
approximately 0.8 will have enough power to reject the null hypothesis.
Approximately 420 patients with platinum resistant ovarian cancer will be necessary to 
stratify and randomize at a 1:1 ratio over 18 months (~23 patients/month). The 
required 332 PFS events are expected to occur around six months after randomization 
of the last patient. Therefore, the IDMC meeting after the IRC review to test PFS is 
expected to occur about one year after randomization of the last patient.
The IDMC will review the results of the analyses. The IRC will determine the patient’s 
best response and assign the date of objective response or progression/censoring 
according to RECIST v.1.1.
A futility analysis with no claim for efficacy when 210 patients are recruited and the 
final analysis to reject the null hypothesis (HR=1) are planned; the significance level 
will be determined by the actual observed number of events, and to maintain scientific 
integrity spending function will be defined by O’Brien-Fleming boundaries. Following 
the prospective assumptions, the futility analysis will occur before one year after start 
of recruitment. At this moment, with the available information collected after 
balancing efficacy and safety, the IDMC might recommend stopping the trial. 
CL_0220 1.0
Page 75 of 110
Protocol PM1183-C-004-14


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 (PFS, OS and DR) and their set time estimates (i.e., PFS 6/12 
and OS 12/24) will be analyzed according to the Kaplan-Meier method. The stratified 
log-rank test on the ITT population will be primarily used to compare the time-to-event 
variables.
Unstratified log-rank tests will also be calculated as supportive analyses. The symmetry 
of tumor evaluations between the different arms will be examined.  Sensitivity analyses 
for different PFS censoring (e.g. date of progression based on scheduled time instead of 
registered date) will be performed, these analyses will be detailed in the SAP.
Cox regression will be used to calculate the risk reduction (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. 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 continual variable will be chosen.
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 will be used to compare the response rates 
of the experimental arm (PM01183) and the control arm (PLD and topotecan). 
Waterfall plots will be used to describe the best variation of the sum of target lesions 
during the treatment.
8.2.2
Safety Analyses
AEs, SAEs, deaths, laboratory evaluations, dose delays/skipped/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. 
An interim safety analysis, performed when 40 patients are enrolled in the PM01183
arm (Arm A), will test if the addition of primary CSF prophylaxis might be necessary. 
With the information available at that time, a Bayesian test assuming non-informative 
prior distribution will be done to assess the null hypothesis of febrile neutropenia 20% 
versus the alternative hypothesis of febrile neutropenia >20%. If the probability 
associated with the alternative hypothesis is higher than 50% (e.g., 8 cases out of 40 
patients), the addition of primary CSF prophylaxis would be considered necessary.  
At the time of the interim safety analysis, recruitment in the control arm (Arm B, PLD 
and topotecan) is also expected to be 40 patients.
CL_0220 1.0
Page 76 of 110
Protocol PM1183-C-004-14


The IDMC may request to review other preliminary safety/efficacy parameters, but no 
claim of superiority will be done; therefore, no type I/II error corrections will be 
applied.
A safety evaluation will also be performed by the IDMC as part of the futility analysis, 
when a total of 210 patients are included.
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 EORTC 
QLQ-C30 and EORTC QLQ-OV28 questionnaires, as well as on subscales, and 
individual symptoms.
8.2.4
Pharmacokinetic Analyses
Sparse PK data will be listed in the population PK-report for all patients with available 
concentrations in the PM01183 treatment arm (Arm A). 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 will be 
performed using non-linear mixed-effects modeling. Data may be combined with those 
of a selection of phase I or II studies 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 the results of the population PK analysis will be 
presented in a separate report.
8.2.5
Pharmacogenetic Analyses 
The influence of known polymorphisms on main PK parameters will be assessed by 
Student’s test or Mann-Whitney’s U test as appropriate.
8.2.6
Pharmacogenomic (PGx) Analyses 
Analysis of RNA/protein expression, polymorphisms and mutations will be performed 
blind and with clinical data compiled only after all analyses are completed. A Fisher´s 
exact test/logistic regression for categorical variables and log rank test/Cox regression 
for time to event variables will be used to test whether a specific profile is associated 
with clinical outcome. The prognostic value of markers will be explored for objective 
response, PFS and OS. In each case, if applicable, a multivariate model will be 
developed by stepwise selection. All tests of statistical significance will be two-sided, 
and significance will be set at 0.05.
CL_0220 1.0
Page 77 of 110
Protocol PM1183-C-004-14


8.3
FUTILITY ANALYSIS
A futility analysis will be performed when 210 patients are recruited (i.e., ~105 patients
enrolled in each arm). The recruitment will not be put on hold. The IDMC will review 
efficacy and safety data available at that time and, based on the observed results, might 
recommend stopping the trial.
Following the prospective assumptions, this futility analysis will occur before one year 
after start of recruitment. The significance level will be determined by the actual 
observed number of events, and type II error will be controlled by O’Brien-Fleming 
boundaries.
8.4
INTERIM SAFETY ANALYSIS
An interim safety analysis, performed when 40 patients are enrolled in the PM01183 
arm (Arm A), will test if the addition of primary CSF prophylaxis might be necessary. 
With the information available at that time, a Bayesian test assuming non-informative 
prior distribution will be done to assess the null hypothesis of febrile neutropenia ≤ 20% 
versus the alternative hypothesis of febrile neutropenia >20%. If the probability 
associated with the alternative hypothesis is higher than 50% (e.g., 8 cases out of 40 
patients), the addition of primary CSF prophylaxis would be considered necessary.  
At the time of the interim safety analysis, recruitment in the control arm (Arm B, PLD 
and topotecan) is also expected to be 40 patients.
The IDMC may request to review other preliminary safety/efficacy parameters, but no 
claim of superiority will be done; therefore, no type I/II error corrections will be 
applied.
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 4) 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.
CL_0220 1.0
Page 78 of 110
Protocol PM1183-C-004-14


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 (R1) 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 (R1) 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 (R1) Guideline for GCP, Section 1.6).
Participation in this trial implies acceptance of potential inspection by national or 
foreign Competent Authorities.
9.3
PATIENT INFORMED CONSENT
The rights, safety and well-being of the trial patients are the most important 
considerations and should prevail over interests of science and society.
The ICFs will include all elements required by ICH, GCP and applicable regulatory 
requirements.
Prior to inclusion into the trial, the Investigator or a person designated by the 
Investigator, must provide the patient with one copy of the Informed Consent Forms
(ICFs). This copy must provide written full information about the clinical trial, in a 
language that is non-technical and easily understood, as well as on the sub-study (PGx 
and pharmacogenetic). The Investigator should allow the necessary time for the patient 
or his/her legally acceptable representative to inquire about the details of the clinical 
trial; then, the ICFs must be freely signed and personally dated by the patient and by the 
person who conducted the Informed Consent discussion before the beginning of the 
study. The patient should receive a copy of the signed ICFs and any other written 
information provided to study patients prior to participation in the trial.
During a patient's participation in the trial, any updates to the consent forms and any 
updates to the written information will be provided to him/her.
If there is a need to obtain new consent from the patients, the Investigator or a person 
designated by the Investigator should inform the patients of any new information 
relevant to the patients’ willingness to continue participation in the study, before 
obtaining the written consent.
CL_0220 1.0
Page 79 of 110
Protocol PM1183-C-004-14


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 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 
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. 
CL_0220 1.0
Page 80 of 110
Protocol PM1183-C-004-14


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.
CL_0220 1.0
Page 81 of 110
Protocol PM1183-C-004-14


10. REFERENCES
1.
Nagourney RA, Link JS, Blitzer JB, Forsthoff C, Evans SS. Gemcitabine plus 
cisplatin repeating doublet therapy in previously treated, relapsed breast cancer patients. 
J Clin Oncol 2000;18(11):2245-9.
2.
Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin 
2013;63(1):11-30.
3.
Risch HA, McLaughlin JR, Cole DE, Rosen B, Bradley L, Kwan E, Jack E, 
Vesprini DJ, Kuperstein G, Abrahamson JL, Fan I, Wong B, Narod SA. Prevalence and 
penetrance of germline BRCA1 and BRCA2 mutations in a population series of 649 
women with ovarian cancer. American journal of human genetics 2001;68(3):700-10.
4.
Ford D, Easton DF, Bishop DT, Narod SA, Goldgar DE. Risks of cancer in 
BRCA1-mutation 
carriers. 
Breast 
Cancer 
Linkage 
Consortium. 
Lancet 
1994;343(8899):692-5.
5.
Finch A, Beiner M, Lubinski J, Lynch HT, Moller P, Rosen B, Murphy J, 
Ghadirian P, Friedman E, Foulkes WD, Kim-Sing C, Wagner T, Tung N, Couch F, 
Stoppa-Lyonnet D, Ainsworth P, Daly M, Pasini B, Gershoni-Baruch R, Eng C, 
Olopade OI, McLennan J, Karlan B, Weitzel J, Sun P, Narod SA. Salpingo-
oophorectomy and the risk of ovarian, fallopian tube, and peritoneal cancers in women 
with a BRCA1 or BRCA2 Mutation. JAMA : the journal of the American Medical 
Association 2006;296(2):185-92.
6.
Aarnio M, Mecklin JP, Aaltonen LA, Nystrom-Lahti M, Jarvinen HJ. Life-time 
risk of different cancers in hereditary non-polyposis colorectal cancer (HNPCC) 
syndrome. International journal of cancer Journal international du cancer 
1995;64(6):430-3.
7.
Daly M, Obrams GI. Epidemiology and risk assessment for ovarian cancer. 
Seminars in oncology 1998;25(3):255-64.
8.
Heintz AP, Odicino F, Maisonneuve P, Quinn MA, Benedet JL, Creasman WT, 
Ngan HY, Pecorelli S, Beller U. Carcinoma of the ovary. FIGO 26th Annual Report on 
the Results of Treatment in Gynecological Cancer. Int J Gynaecol Obstet 2006;95 Suppl 
1:S161-92.
9.
Neijt JP, Engelholm SA, Tuxen MK, Sorensen PG, Hansen M, Sessa C, de 
Swart CA, Hirsch FR, Lund B, van Houwelingen HC. Exploratory phase III study of 
paclitaxel and cisplatin versus paclitaxel and carboplatin in advanced ovarian cancer. J 
Clin Oncol 2000;18(17):3084-92.
10.
McGuire WP, Hoskins WJ, Brady MF, Kucera PR, Partridge EE, Look KY, 
Clarke-Pearson DL, Davidson M. Cyclophosphamide and cisplatin compared with 
paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer. N Engl J 
Med 1996;334(1):1-6.
11.
Martin LP, Schilder RJ. Management of recurrent ovarian carcinoma: current 
status and future directions. Seminars in oncology 2009;36(2):112-25.
CL_0220 1.0
Page 82 of 110
Protocol PM1183-C-004-14


12.
Markman M, Rothman R, Hakes T, Reichman B, Hoskins W, Rubin S, Jones W, 
Almadrones L, Lewis JL, Jr. Second-line platinum therapy in patients with ovarian 
cancer previously treated with cisplatin. J Clin Oncol 1991;9(3):389-93.
13.
Gore ME, Fryatt I, Wiltshaw E, Dawson T. Treatment of relapsed carcinoma of 
the ovary with cisplatin or carboplatin following initial treatment with these compounds. 
Gynecol Oncol 1990;36(2):207-11.
14.
Parmar MK, Ledermann JA, Colombo N, du Bois A, Delaloye JF, Kristensen 
GB, Wheeler S, Swart AM, Qian W, Torri V, Floriani I, Jayson G, Lamont A, Trope C. 
Paclitaxel plus platinum-based chemotherapy versus conventional platinum-based 
chemotherapy in women with relapsed ovarian cancer: the ICON4/AGO-OVAR-2.2 
trial. Lancet 2003;361(9375):2099-106.
15.
Pfisterer J, Plante M, Vergote I, du Bois A, Hirte H, Lacave AJ, Wagner U, 
Stahle A, Stuart G, Kimmig R, Olbricht S, Le T, Emerich J, Kuhn W, Bentley J, 
Jackisch C, Luck HJ, Rochon J, Zimmermann AH, Eisenhauer E. Gemcitabine plus 
carboplatin compared with carboplatin in patients with platinum-sensitive recurrent 
ovarian cancer: an intergroup trial of the AGO-OVAR, the NCIC CTG, and the EORTC 
GCG. J Clin Oncol 2006;24(29):4699-707.
16.
Pujade-Lauraine E, Wagner U, Aavall-Lundqvist E, Gebski V, Heywood M, 
Vasey PA, Volgger B, Vergote I, Pignata S, Ferrero A, Sehouli J, Lortholary A, 
Kristensen G, Jackisch C, Joly F, Brown C, Le Fur N, du Bois A. Pegylated liposomal 
Doxorubicin and Carboplatin compared with Paclitaxel and Carboplatin for patients 
with platinum-sensitive ovarian cancer in late relapse. J Clin Oncol 2010;28(20):3323-9.
17.
Monk BJ, Herzog TJ, Kaye SB, Krasner CN, Vermorken JB, Muggia FM, 
Pujade-Lauraine E, Lisyanskaya AS, Makhson AN, Rolski J, Gorbounova VA, Ghatage 
P, Bidzinski M, Shen K, Ngan HY, Vergote IB, Nam JH, Park YC, Lebedinsky CA, 
Poveda AM. Trabectedin plus pegylated liposomal Doxorubicin in recurrent ovarian 
cancer. J Clin Oncol 2010;28(19):3107-14.
18.
Hoskins P, Eisenhauer E, Beare S, Roy M, Drouin P, Stuart G, Bryson P, 
Grimshaw R, Capstick V, Zee B. Randomized phase II study of two schedules of 
topotecan in previously treated patients with ovarian cancer: a National Cancer Institute 
of Canada Clinical Trials Group study. J Clin Oncol 1998;16(6):2233-7.
19.
Rose PG, Blessing JA, Mayer AR, Homesley HD. Prolonged oral etoposide as 
second-line therapy for platinum-resistant and platinum-sensitive ovarian carcinoma: a 
Gynecologic Oncology Group study. J Clin Oncol 1998;16(2):405-10.
20.
Bajetta E, Di Leo A, Biganzoli L, Mariani L, Cappuzzo F, Di Bartolomeo M, 
Zilembo N, Artale S, Magnani E, Celio L, Buzzoni R, Carnaghi C. Phase II study of 
vinorelbine in patients with pretreated advanced ovarian cancer: activity in platinum-
resistant disease. J Clin Oncol 1996;14(9):2546-51.
21.
Muggia FM, Hainsworth JD, Jeffers S, Miller P, Groshen S, Tan M, Roman L, 
Uziely B, Muderspach L, Garcia A, Burnett A, Greco FA, Morrow CP, Paradiso LJ, 
Liang LJ. Phase II study of liposomal doxorubicin in refractory ovarian cancer: 
antitumor activity and toxicity modification by liposomal encapsulation. J Clin Oncol 
1997;15(3):987-93.
CL_0220 1.0
Page 83 of 110
Protocol PM1183-C-004-14


22.
Lund B, Hansen OP, Theilade K, Hansen M, Neijt JP. Phase II study of 
gemcitabine (2',2'-difluorodeoxycytidine) in previously treated ovarian cancer patients. 
J Natl Cancer Inst 1994;86(20):1530-3.
23.
Fennelly D, Aghajanian C, Shapiro F, O'Flaherty C, McKenzie M, O'Connor C, 
Tong W, Norton L, Spriggs D. Phase I and pharmacologic study of paclitaxel 
administered weekly in patients with relapsed ovarian cancer. J Clin Oncol 
1997;15(1):187-92.
24.
ten Bokkel Huinink W, Gore M, Carmichael J, Gordon A, Malfetano J, Hudson 
I, Broom C, Scarabelli C, Davidson N, Spanczynski M, Bolis G, Malmstrom H, 
Coleman R, Fields SC, Heron JF. Topotecan versus paclitaxel for the treatment of 
recurrent epithelial ovarian cancer. J Clin Oncol 1997;15(6):2183-93.
25.
Gordon AN, Fleagle JT, Guthrie D, Parkin DE, Gore ME, Lacave AJ. Recurrent 
epithelial ovarian carcinoma: a randomized phase III study of pegylated liposomal 
doxorubicin versus topotecan. J Clin Oncol 2001;19(14):3312-22.
26.
Gore M, Oza A, Rustin G, Malfetano J, Calvert H, Clarke-Pearson D, 
Carmichael J, Ross G, Beckman RA, Fields SZ. A randomised trial of oral versus 
intravenous topotecan in patients with relapsed epithelial ovarian cancer. Eur J Cancer 
2002;38(1):57-63.
27.
Mutch DG, Orlando M, Goss T, Teneriello MG, Gordon AN, McMeekin SD, 
Wang Y, Scribner DR, Jr., Marciniack M, Naumann RW, Secord AA. Randomized 
phase III trial of gemcitabine compared with pegylated liposomal doxorubicin in 
patients with platinum-resistant ovarian cancer. Journal of clinical oncology : official 
journal of the American Society of Clinical Oncology 2007;25(19):2811-8.
28.
Vergote I, Finkler N, del Campo J, Lohr A, Hunter J, Matei D, Kavanagh J, 
Vermorken JB, Meng L, Jones M, Brown G, Kaye S. Phase III randomised study of 
canfosfamide (Telcyta, TLK286) versus pegylated liposomal doxorubicin or topotecan 
as third-line therapy in patients with platinum-refractory or -resistant ovarian cancer. 
Eur J Cancer 2009;45(13):2324-32.
29.
Vergote I, Finkler NJ, Hall JB, Melnyk O, Edwards RP, Jones M, Keck JG, 
Meng L, Brown GL, Rankin EM, Burke JJ, Boccia RV, Runowicz CD, Rose PG. 
Randomized phase III study of canfosfamide in combination with pegylated liposomal 
doxorubicin compared with pegylated liposomal doxorubicin alone in platinum-resistant
ovarian cancer. Int J Gynecol Cancer 2010;20(5):772-80.
30.
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. Journal of 
clinical oncology : official journal of the American Society of Clinical Oncology 
2011;29(2):242-8.
31.
Colombo N, Kutarska E, Dimopoulos M, Bae DS, Rzepka-Gorska I, Bidzinski 
M, Scambia G, Engelholm SA, Joly F, Weber D, El-Hashimy M, Li J, Souami F, Wing 
P, Engelholm S, Bamias A, Schwartz P. Randomized, open-label, phase III study 
comparing patupilone (EPO906) with pegylated liposomal doxorubicin in platinum-
CL_0220 1.0
Page 84 of 110
Protocol PM1183-C-004-14


refractory or -resistant patients with recurrent epithelial ovarian, primary fallopian tube, 
or primary peritoneal cancer. Journal of clinical oncology : official journal of the 
American Society of Clinical Oncology 2012;30(31):3841-7.
32.
Pujade-Lauraine E, Hilpert F, Weber B, Reuss A, Poveda A, Kristensen G, 
Sorio R, Vergote IB, Witteveen P, Bamias A, Pereira D, Wimberger P, Oaknin A, Mirza 
MR, Follana P, Bollag DT, Ray-Coquard I, AURELIA Investigators. AURELIA: A 
randomized phase III trial evaluating bevacizumab (BEV) plus chemotherapy (CT) for 
platinum (PT)-resistant recurrent ovarian cancer (OC). J Clin Oncol 30 2012;suppl; 
abstr LBA5002.
33.
Witteveen P, Lortholary A, Fehm T, et al. Final overall survival results from 
Aurelia, an open-label randomized phase III trial of chemotherapy with or without 
bevacizumab for platinum-resistant recurrent ovarian cancer. . ESMO Congress 2013 
Presidential session II: best and late breaking abstracts 2013:Abstract #5.
34.
Kelter G. Final Report. In vitro evaluation of 14 novel marine compounds for 
anti-cancer activity in 36 human tumor cell lines in a monolayer assay. Oncotest 
protocol No. P62A. 14 December 2005. Report No.
35.
Moneo V. Colmenar Viejo (Madrid), Spain: PharmaMar S.A.U., 2008 
BCCP08001.
36.
Elices M. Comparison of the antitumor profiles of sacidin analogs PM00104 and
PM01183. PUSA-SR012. . Cambridge, MA, U.S.A.: PharmaMar USA, Inc., 2004.
37.
Sutton A. Cardiovascular effects of PM01183 in conscious, telemetered Beagle 
dogs. 2008. ZNA14886.005. Edinburgh, UK: Aptuit Ltd., 2008 ZNA14886.005.
38.
Salerno D. Single Dose Intravenous Toxicity Study of PM01183 in Dogs (with a 
14 Day Treatment-Free Period). Rome, Italy: Research Toxicology Centre S.p.A., 2008 
RTC 64720.
39.
Salerno D. Multiple-Cycle Toxicity Study Following 4 Cycles of Administration 
by Intravenous Route to Dogs (with a 3 Week Treatment-Free Period). Rome, Italy: 
Research Toxicology Centre S.p.A., 2008 RTC 73520.
40.
Santamaría G, Moneo V, García Fernández LF. Study nº PMAR10-CB004. 
PharmaMar, SAU, Spain 2010.
41.
Santamaría G, Moneo V, García Fernández LF, Galmarini CM. Study nº 
PMAR10-CB026. PharmaMar, SAU, Spain 2010.
42.
Allavena P, Signorelli M, Chieppa M, Erba E, Bianchi G, Marchesi F, Olimpio 
CO, Bonardi C, Garbi A, Lissoni A, de Braud F, Jimeno J, D'Incalci M. Anti-
inflammatory properties of the novel antitumor agent yondelis (trabectedin): inhibition 
of 
macrophage 
differentiation 
and 
cytokine 
production. 
Cancer 
research 
2005;65(7):2964-71.
43.
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.
CL_0220 1.0
Page 85 of 110
Protocol PM1183-C-004-14


44.
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.
45.
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.
46.
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.
47.
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). International journal of cancer Journal international du cancer 
2013;133(9):2024-33.
48.
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.
49.
Harrington KJ, Gooden CSR, Mohammedtaghi S, al. e. Biodistribution and 
pharmacokinetics of IN-111 labeled Stealth liposomes in patients with solid tumors. 
Proc Am Soc Clin Oncol 1996;15:477 (Abstr #1511).
50.
Gordon AN, Granai CO, Rose PG, Hainsworth J, Lopez A, Weissman C, 
Rosales R, Sharpington T. Phase II study of liposomal doxorubicin in platinum- and 
paclitaxel-refractory epithelial ovarian cancer. J Clin Oncol 2000;18(17):3093-100.
51.
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.
52.
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.
53.
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.
54.
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.
CL_0220 1.0
Page 86 of 110
Protocol PM1183-C-004-14


55.
Bookman MA, Malmstrom H, Bolis G, Gordon A, Lissoni A, Krebs JB, Fields 
SZ. Topotecan for the treatment of advanced epithelial ovarian cancer: an open-label 
phase II study in patients treated after prior chemotherapy that contained cisplatin or 
carboplatin and paclitaxel. J Clin Oncol 1998;16(10):3345-52.
56.
Poveda A, Berton-Rigaud D, Ray-Coquard I, Alexandre J, Provansal M, 
Fernandez C, Guerra EM, Casado A, Gonzalez Martin A, Del Campo JM. 
Lurbinectedin (PM01183) activity in platinum-resistant/refractory ovarian cancer 
patients: Updated results of an ongoing two stage phase II study. Eur J Cancer 
2013;49(Suppl 2):732 (abstract No.3065).
57.
Poveda A, Berton-Rigaud D, Ray-Coquard IL, Alexandre J, Provansal M, Soto 
A, Kahatt CM, Szyldergemajn SA, Nieto A, Fernandez C, Guerra-Alia E, Casado A, 
Gonzalez-Martin A, Del Campo JM. Lurbinectedin (PM01183), an active compound in 
platinum-resistant/refractory ovarian cancer (PRROC) patients: Results of a two-stage, 
controlled phase II study. Journal of clinical oncology : official journal of the American 
Society of Clinical Oncology 2014;32  (5s):(suppl; abstr 5505).
58.
Leal JF, Martinez-Diez M, Garcia-Hernandez V, Moneo V, Domingo A, 
Bueren-Calabuig JA, Negri A, Gago F, Guillen-Navarro MJ, Aviles P, Cuevas C, 
Garcia-Fernandez LF, Galmarini CM. PM01183, a new DNA minor groove covalent 
binder with potent in vitro and in vivo anti-tumour activity. Br J Pharmacol 
2010;161(5):1099-110.
59.
On reporting the results of population pharmacokinetic analyses. Committee for 
Medicinal Products for Human Use (CHMP);CHMP/EWP/185990/06,London, 21 June 
2007.
60.
Guidance for Industry Population Pharmacokinetics. US Department of Health 
and Human Services, Food and Drug Administration, Center for Drug Evaluation and 
Research (CDER), Center for Biologics Evaluation and Research (CBER);February 
1999, CP1.
CL_0220 1.0
Page 87 of 110
Protocol PM1183-C-004-14


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. 
CL_0220 1.0
Page 88 of 110
Protocol PM1183-C-004-14


APPENDIX 2: 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.
CL_0220 1.0
Page 89 of 110
Protocol PM1183-C-004-14


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) 
CL_0220 1.0
Page 90 of 110
Protocol PM1183-C-004-14


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
CL_0220 1.0
Page 91 of 110
Protocol PM1183-C-004-14


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 
CL_0220 1.0
Page 92 of 110
Protocol PM1183-C-004-14


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 
CL_0220 1.0
Page 93 of 110
Protocol PM1183-C-004-14


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 
CL_0220 1.0
Page 94 of 110
Protocol PM1183-C-004-14


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.
CL_0220 1.0
Page 95 of 110
Protocol PM1183-C-004-14


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.
CL_0220 1.0
Page 96 of 110
Protocol PM1183-C-004-14


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 
CL_0220 1.0
Page 97 of 110
Protocol PM1183-C-004-14


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. 
CL_0220 1.0
Page 98 of 110
Protocol PM1183-C-004-14


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. 
CL_0220 1.0
Page 99 of 110
Protocol PM1183-C-004-14


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. 
CL_0220 1.0
Page 100 of 110
Protocol PM1183-C-004-14


APPENDIX 3: LIST OF CYP1/CYP2/CYP3 INHIBITORS, INDUCERS AND 
SUBSTRATES
Table 1. Classification of In Vivo Inhibitors of CYP Enzymes (1)
CYP 
enzymes
Strong Inhibitors (2)  
≥ 5-fold increase in 
AUC
or > 80% decrease in CL
Moderate inhibitors (3)  
≥ 2 but < 5-fold increase in 
AUC or 50-80% decrease in CL
Weak inhibitors (4)  
≥ 1.25 but < 2-fold increase in 
AUC or 20-50% decrease in CL
CYP1A2
Ciprofloxacin, enoxacin,
fluvoxamine
Methoxsalen, mexiletine,
oral contraceptives, 
phenylpropanolamine,
thiabendazole, zileuton
Acyclovir, allopurinol, caffeine, 
cimetidine,
Daidzein, (5), disulfiram, Echinacea, 
(5) famotidine, norfloxacin, 
propafenone, propranolol, 
terbinafine, ticlopidine, verapamil
CYP2B6
Clopidogrel, ticlopidine
prasugrel
CYP2C8
Gemfibrozil(6)
Fluvoxamine, ketoconazole, 
trimethoprim
CYP2C9
Amiodarone, fluconazole,
miconazole, oxandrolone
Capecitabine, cotrimoxazole,
etravirine, fluvastatin, fluvoxamine, 
metronidazole, sulfinpyrazone, 
tigecycline,
voriconazole, zafirlukast
CYP2C19
Fluconazole, (7)
Fluvoxamine, (8)
ticlopidine (9)
Esomeprazole, fluoxetine, 
moclobemide,
omeprazole, voriconazole
Allicin (garlic derivative), 
armodafinil, carbamazepine,
cimetidine,
etravirine,
human growth hormone (rhGH),
felbamate,
ketoconazole,
oral contraceptives (10)
CYP3A
Boceprevir,
clarithromycin, 
conivaptan,
grapefruit juice, (11) 
indinavir, itraconazole, 
ketoconazole,
lopinavir/ritonavir,
mibefradil, (12)
nefazodone, nelfinavir,
posaconazole, ritonavir,
saquinavir,
telaprevir,
telithromycin,
voriconazole
Amprenavir, aprepitant,
atazanavir, ciprofloxacin,
darunavir/ritonavir, diltiazem, 
erythromycin, fluconazole, 
fosamprenavir, grapefruit juice, 
(11)
imatinib, verapamil
Alprazolam, amiodarone, 
amlodipine, atorvastatin, 
bicalutamide, cilostazol, cimetidine,
cyclosporine, fluoxetine, 
fluvoxamine, ginkgo, (5) goldenseal, 
(5)
isoniazid, nilotinib,
oral contraceptives, ranitidine, 
ranolazine,
tipranavir/ritonavir, zileuton
CYP2D6
Bupropion, fluoxetine,
paroxetine, quinidine
Cinacalcet, duloxetine,
terbinafine
Amiodarone, celecoxib,
cimetidine, desvenlafaxine, 
diltiazem, diphenhydramine, 
Echinacea, (5) escitalopram, 
febuxostat, gefitinib,
hydralazine, hydroxychloroquine,
imatinib, methadone,
oral contraceptives, propafenone, 
ranitidine,
ritonavir, sertraline,
telithromycin, verapamil
1.
Please note the following: This is not an exhaustive list. For an updated list, see the following link: 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/uc
m080499.htm.
2.
A strong inhibitor for a specific CYP is defined as an inhibitor that increases the AUC of a substrate for that 
CYP by equal or more than 5-fold.
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.
CL_0220 1.0
Page 101 of 110
Protocol PM1183-C-004-14


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)
CL_0220 1.0
Page 102 of 110
Protocol PM1183-C-004-14


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.
CL_0220 1.0
Page 103 of 110
Protocol PM1183-C-004-14


APPENDIX 4: 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.
CL_0220 1.0
Page 104 of 110
Protocol PM1183-C-004-14


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.
CL_0220 1.0
Page 105 of 110
Protocol PM1183-C-004-14


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.
CL_0220 1.0
Page 106 of 110
Protocol PM1183-C-004-14


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 
CL_0220 1.0
Page 107 of 110
Protocol PM1183-C-004-14


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 
CL_0220 1.0
Page 108 of 110
Protocol PM1183-C-004-14


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 
CL_0220 1.0
Page 109 of 110
Protocol PM1183-C-004-14


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.
CL_0220 1.0
Page 110 of 110
Protocol PM1183-C-004-14

SAP_001.pdf: 
                                                          
 
                            
 
 
 
 
 
 
 
 
 
 
PM1183-C-004-14 (NCT02421588)  
 
Phase III Randomized Clinical Trial of Lurbinectedin (PM01183) 
versus Pegylated Liposomal Doxorubicin or Topotecan in Patients with 
Platinum-resistant Ovarian Cancer (CORAIL Trial) 
 
STATISTICAL ANALYSIS PLAN 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Version: v2.0 
Date: 30-AUG-2017    
 
 
 
-Confidential-  
 


                                                          
 
                            
TABLE OF CONTENTS  
 
 
1 
STUDY RATIONALE ............................................................................................. 6 
2 
OVERALL STUDY DESIGN.................................................................................. 6 
3 
PATIENTS EVALUABILITY CRITERIA ............................................................. 8 
3.1 
Intention-to-Treat (ITT) Population ................................................................... 8 
3.2 
Safety Population ............................................................................................... 8 
4 
OBJECTIVES AND ENDPOINTS .......................................................................... 8 
4.1 
Primary Objective .............................................................................................. 8 
4.2 
Secondary Objectives ........................................................................................ 8 
4.3 
Endpoints ........................................................................................................... 9 
5 
SAMPLE CONSIDERATIONS ............................................................................. 10 
5.1 
Randomization and Stratification .................................................................... 10 
5.2 
Sample Size ...................................................................................................... 10 
5.2.1 
Futility Analysis ....................................................................................... 11 
5.2.2 
Interim Safety Analysis ............................................................................ 11 
6 
STATISTICAL METHODOLOGY FOR EFFICACY .......................................... 11 
6.1 
Efficacy Definitions ......................................................................................... 11 
6.2 
Efficacy Analysis Methods .............................................................................. 13 
7 
STATISTICAL METHODOLOGY FOR SAFETY .............................................. 15 
7.1 
Toxicity and Adverse Events ........................................................................... 15 
7.2 
Clinical Laboratory Evaluation ........................................................................ 15 
7.3 
Physical Examination Findings ....................................................................... 15 
7.4 
Deaths and other Serious Adverse Events ....................................................... 16 
8 
OTHER ANALYSES ............................................................................................. 16 
8.1 
Baseline and Demographic Data ...................................................................... 16 
8.2 
Protocol Deviations .......................................................................................... 16 
8.3 
Treatment Administration ................................................................................ 16 
8.4 
Patient-reported Outcomes (PRO) ................................................................... 17 
8.5 
Subsequent Therapies ...................................................................................... 17 
8.6 
Imputation in Incomplete Dates ....................................................................... 17 
8.7 
Variable Unit Standardization ......................................................................... 18 
8.8 
Decimal Places, Missing Values and Allowed Assessment Windows ............ 18 
8.9 
Subgroup Analyses .......................................................................................... 18 
8.10 
Pharmacokinetic, Pharmacogenetic and Pharmacogenomic Analyses..... 18 
9 
STATISTICAL SOFTWARE ................................................................................ 18 
10 Study Patients ......................................................................................................... 20 
10.1 
Patient Disposition .................................................................................... 20 
10.2 
Reasons for Treatment Discontinuation ................................................... 22 
10.3 
Protocol Deviations .................................................................................. 22 
11 Efficacy Evaluation ................................................................................................ 23 
11.1 
Demographic and other Baseline Characteristics ..................................... 23 
11.1.1 Patient Characteristics at Baseline ............................................................ 23 
11.1.2 Prior Anticancer Therapy ......................................................................... 29 
11.1.3 Prior Relevant Medical History ................................................................ 31 
11.1.4 Signs and Symptoms at Baseline .............................................................. 31 
11.1.5 Concomitant Medication at Baseline ........................................................ 32 
11.1.6 PRO Analyses ........................................................................................... 32 
11.2 
Measurements of Treatment Compliance ................................................. 32 


                                                          
 
                            
11.3 
Efficacy Analysis ...................................................................................... 32 
12 Safety Analysis ....................................................................................................... 42 
12.1 
Extent of Exposure ................................................................................... 42 
12.1.1 Treatment Administration......................................................................... 42 
12.1.2 Cycle Delays ............................................................................................. 42 
12.1.3 Dose Reductions ....................................................................................... 45 
12.2 
Adverse Events (AEs) .............................................................................. 47 
12.2.1 Adverse Events ......................................................................................... 47 
12.2.2 Display of Adverse Events ....................................................................... 47 
12.2.3 Evolution of Signs and Symptoms during the Treatment ........................ 51 
12.3 
Serious Adverse Events and Deaths. ........................................................ 52 
12.3.1 Serious Adverse Events ............................................................................ 52 
12.3.2 Interim Bayesian Safety Analysis............................................................. 55 
12.3.3 Deaths ....................................................................................................... 55 
12.4 
Clinical Laboratory Evaluation ................................................................ 56 
12.4.1 Hematological Abnormalities ................................................................... 56 
12.4.2 Biochemical Abnormalities ...................................................................... 57 
12.4.3 Other Metabolic Parameters ..................................................................... 59 
12.4.4 Laboratory Values over Time ................................................................... 60 
12.5 
Subgroup Analyses Related to Safety ...................................................... 65 
12.6 
Concomitant Medication during Treatment ............................................. 75 
12.7 
Subsequent Therapy ................................................................................. 76 
12.8 
PRO at treatment ...................................................................................... 76 
13 DB Listings ............................................................................................................. 80 
14 ICH Listings ........................................................................................................... 87 
15 History of Changes ................................................................................................. 89 
 


                                                          
 
                            
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 
CI 
 
 Confidence Interval 
CPK  
 Creatine Phosphokinase 
CR 
 
 Complete Response 
CRF 
 
 Case Report Form 
CT 
 
 Computed Tomography 
DF 
 
 Degrees of Freedom 
DNA  
 Deoxyribonucleic Acid 
DR 
 
 Duration of Response 
ECG  
 Electrocardiogram 
ECOG  
 Eastern Cooperative Oncology Group 
EORTC 
 European Organization for Research and Treatment of Cancer 
EOT  
 End of Treatment 
EPO 
 
 Erythropoietin 
FU 
 
 Follow-up 
CSF 
 
 Colony Stimulating Factor 
HR 
 
 Hazard Ratio 
IA 
 
 Investigator Assessment 
IC 
 
 Informed Consent 
IDMC  
 Independent Data Monitoring Committee 
IORT  
 Intraoperative Radiation Therapy 
IRC 
 
 Independent Review Committee 
ITT 
 
 Intention-to-treat 
LR 
 
 Log Rank Test 
MedDRA 
 Medical Dictionary for Regulatory Activities 
mo 
 
 Months 
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 
PARPi  
 Poly(ADP-ribose) Polymerase Inhibitors 
PD 
 
 Progressive Disease 
PLD 
 
 Pegylated Liposomal Doxorubicin 
PFS 
 
 Progression Free Survival 
PR 
 
 Partial Response 
PRO  
 Patient-Reported Outcomes 
PS 
 
 Performance Status 
PT 
 
 Preferred Term 


                                                          
 
                            
RECIST 
 Response Evaluation Criteria In Solid Tumors 
SAE 
 
 Serious Adverse Event 
SD 
 
 Stable Disease 
SOC  
 System Organ Class 
STD 
 
 Standard Deviation 
UK 
 
 Unknown 
USA  
 United States of America 
vs. 
 
 versus 
WBC  
 White Blood Cells 
WHO  
 World Health Organization 


                                                          
 
                            
1 STUDY RATIONALE 
Patients with relapsed platinum-resistant ovarian cancer have poor prognosis. New 
treatment options are needed to treat these patients, particularly agents with novel 
mechanisms of action. 
PM01183 is a new chemical entity that induces double-strand DNA breaks through 
binding to the DNA minor groove. PM01183 has in vitro and in vivo anticancer activity 
in several platinum sensitive and resistant ovarian cancer-derived cell lines. 
On the basis of preclinical results, a controlled, phase II exploratory clinical trial 
including a randomized stage was conducted to evaluate the activity and safety of 
PM01183 as a single agent in platinum-resistant/refractory advanced ovarian 
cancer (PM1183-B-002-11). The primary endpoint of the study was the overall response 
rate (ORR). The global endpoint was met, and the results of the randomized second 
stage of the study showed PM01183 more active than topotecan in this indication. 
Therefore, a randomized trial has been proposed to compare lurbinectedin (PM01183) 
vs. pegylated liposomal doxorubicin (PLD) or topotecan in advanced ovarian cancer 
patients with platinum-resistant disease. 
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 the 
activity and safety of PM01183 vs. PLD or topotecan as control arm in patients with 
platinum-resistant ovarian cancer. 
A single-agent PM01183 dose will be explored in the experimental arm (Arm A) vs. 
PLD or topotecan in the control arm (Arm B). 
Central randomization will be implemented in all patients who fulfill the inclusion 
criteria; patients will be assigned to each treatment arm at a 1:1 ratio. If the patient had 
not previously received PLD or topotecan, the assigned treatment in case the patient is 
randomized to the control arm (Arm B) will be based on the reported Investigator’s 
preference with regard to each of these two drugs. However, if the number of patients 
randomized to either PLD or topotecan reaches 60% of the total number of patients 
expected in the control arm (i.e., 126 patients), then the treatment of choice in the 
control arm will be restricted to the less frequent control drug until the end of accrual. 
Once the 60% is achieved for one of the two control agents, the patient will not be 
eligible for this trial if this agent is the only possible option (e.g., if the patient has 
been previously treated with topotecan, then PLD is the only possible option if the 
patient is randomized to Arm B and the patient will not be eligible if an accrual of 60% 
has been reached for PLD). Stratification will be performed according to Eastern 
Cooperative Oncology Group (ECOG) performance status (PS) (0 vs. ≥1), prior 
platinum-free interval (1-3 months vs. >3 months) (Platinum Free Interval = PFI: time 
elapsed between completion of the last platinum-containing regimen and the 
subsequent relapse or progression) and prior chemotherapy (1-2 vs. 3 lines).  
Up to 420 patients with platinum resistant ovarian cancer (disease relapse or 
progression within one to six months after last platinum-containing chemotherapy) will 
be included in the trial. 
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. 


                                                          
 
                            
An Independent Review Committee (IRC) will determine the best patient’s response 
and assign the date of objective response or progression/censoring according to 
Response Evaluation Criteria In Solid Tumors (RECIST) v.1.1. Operational details for 
the IRC, the algorithm and its validation by an expert panel is described in detail in the 
IRC charter. 
An interim safety analysis will be performed in the PM01183 arm only (Arm A) when 
40 patients are enrolled in this arm. Based on the results of this analysis, the IDMC may 
provide recommendations on the primary prophylactic use of colony stimulating factors 
(CSFs) as part of the therapy in the experimental Arm A. The recruitment in both 
treatment arms will not be stopped during the conduct of the interim safety analysis.  
A futility analysis will be performed when 210 patients are recruited. The recruitment 
will not be put on hold. The IDMC will review efficacy and safety data available at 
that time and, based on the observed results, might recommend stopping the trial; no 
claim for efficacy in comparison with the control arm will be made at this analysis.  
Crossover after treatment discontinuation from the control Arm B to the experimental 
Arm A is not allowed. 
A summary of the study design is shown in the below figure. 
 


                                                          
 
                            
Patients will receive the study treatment while it is considered to be in their best 
interest. Specifically, treatment will continue until disease progression, unacceptable 
toxicity, intercurrent illness of sufficient magnitude to preclude safe continuation of the 
study, Investigator’s decision, patient refusal, non-compliance with the study 
requirements, a major protocol deviation that may affect the risk/benefit ratio for the 
participating  patient, or requirement of > two dose reductions. 
All adverse events (AEs) will be graded according to the National Cancer Institute 
Common Terminology Criteria for Adverse Events (NCI-CTCAE) v.4. Treatment 
delays, dose reduction requirements and reason for treatment discontinuation will be 
monitored throughout the study. The safety profile of patients will be monitored 
throughout the treatment and up to 30 days 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, whichever occurs first. 
Patients will be evaluated at scheduled visits on three study periods: Pre-treatment, 
Treatment and Follow-up. This clinical trial will finish (clinical cutoff) 24 months after 
randomization of the last patient. 
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 a difference in progression-free survival (PFS) between lurbinectedin 
(PM01183) and PLD or topotecan in platinum-resistant ovarian cancer patients 
according to RECIST v.1.1. 
4.2 
 Secondary Objectives 
To evaluate: 
 Overall survival (OS).  
 Antitumor activity.  
 Safety profile. 
 Patient-reported outcomes (PRO). 
  To characterize the plasma pharmacokinetics (PK) of PM01183 using a sparse 
sampling scheme in the PM01183 treatment arm (Arm A). 
  Subgroup analyses of the PM01183 arm vs. PLD or topotecan. 


                                                          
 
                            
 To conduct an exploratory pharmacogenetic and pharmacogenomic (PGx) sub-
study.  
 
4.3 
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 treatment.  
Secondary endpoints:  
 Progression-free survival (PFS) per RECIST v.1.1 by Investigator’s 
Assessment (IA). 
 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). 
 Landmark analyses: 
o 
PFS at 6 and 12 months by IRC/IA will be the Kaplan-Meier estimates of 
the probability of being free from progression (per RECIST v.1.1) and death 
at these time points. 
o 
OS at 12 and 24 months will be the Kaplan-Meier estimates of the 
probability of being alive at these time points. 
  Best antitumor response by IRC/IA will be the best response obtained in any 
evaluation according to the RECIST v.1.1. before progressive disease. Irrespectively 
of treatment arm, radiological and clinical tumor assessment will be performed 
symmetrically at baseline and every eight weeks from randomization until evidence 
of PD. Patients who finish treatment without PD will continue with the tumor 
assessments every eight weeks (± two weeks) from randomization until PD, start of 
a new antitumor therapy, death or date of study termination (clinical cut-off), 
whichever occurs first. 
 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 duration of response.  
 Best response according to tumor marker evaluation (CA-125) will be the best 
response obtained according to GCIG criteria. Irrespectively of treatment arm, 
tumor marker assessment will be performed symmetrically at baseline and every 
eight weeks from randomization until evidence of PD.  
 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 be also assessed. 
  Patient-reported outcomes (PRO): To measure the quality of life of patients, 
EORTC QLQ-C30 and EORTC QLQ-OV28 questionnaires will be completed by 
the patients every eight weeks in all three treatment arms. 


                                                          
 
                            
 Plasma pharmacokinetics (PK) of PM01183 will be evaluated using a sparse 
sampling scheme in the PM01183 treatment arm (Arm A). Details will be given in a 
population PK analysis plan and the results of the population PK analysis will be 
presented in a separate report. 
  Subgroup analyses: Subgroup analyses of the PM01183 arm vs. PLD or topotecan 
outcomes will be performed.  
 Pharmacogenetics: This analysis will be performed in those patients who signed 
the IC for the PGx sub-study. The presence or absence of known polymorphisms 
from a single sample collected just before the PM01183 treatment start will be 
assessed to explain the individual variability in the main PK parameters. 
 Pharmacogenomics: This exploratory analysis will be performed in those patients 
treated in any arm who signed the IC for the PGx sub-study. Samples from Arm B 
will be used as controls in order to differentiate between the prognostic or predictive 
value of any obtained finding. mRNA or protein expression levels of factors 
involved in DNA repair mechanisms, or related to the mechanism of action of 
PM01183 or to the pathogenesis of the disease, will be evaluated from prior 
available tumor tissue samples obtained at diagnosis or relapse. Their mutational 
status might also be analyzed. Their correlation with the clinical response and 
outcome after treatment will be assessed. 
5 SAMPLE CONSIDERATIONS  
5.1 
 Randomization and Stratification 
Central randomization will be implemented in all patients who fulfill the eligibility 
criteria. Randomization of patients should occur as close in time as possible to the 
administration of the first dose of study drug. Patients will be assigned to each treatment 
arm (Arm A or Arm B) at a 1:1 ratio. If the patient had not previously received PLD or 
topotecan, the assigned treatment in case that the patient is randomized to the control 
arm (Arm B) will be based on the reported Investigator’s preference with regard to each 
one of these two drugs. However, if the number of patients randomized to either PLD or 
topotecan reaches the 60% of the total number of patients expected in the control arm 
(i.e., 126 patients), then the treatment of choice in the control arm will be restricted to 
the less frequent control drug until the end of accrual. Stratification will be performed 
according to ECOG PS (0 vs. ≥1), prior platinum-free interval [PFI] (1-3 months vs. >3 
months) and prior chemotherapy (1-2 vs. 3 lines).  
5.2 
 Sample Size 
This phase III clinical trial is designed to determine a statistically significant difference 
in PFS by IRC between PM01183 and a control arm with PLD or topotecan in ovarian 
cancer patients with platinum-resistant disease. 
Patients will be randomized to receive PM01183 given as 3.2 mg/m2 (Arm A) or either 
topotecan or PLD (Arm B).  
The prospective assumptions are a 30% reduction in the relative risk of progression or 
death (HR=0.7) to be achieved with the experimental arm (PM01183), at a one-sided 
2.5% significance level with at least 90% power, following exponential distributions 
and fulfilling the proportional hazard assumption. Median PFS with control arm is 
expected to be around 3.5 months. It is forecasted that an observed HR of 
approximately 0.8 will have enough power to reject the null hypothesis (HR=1). 


                                                          
 
                            
Approximately 420 patients with platinum resistant ovarian cancer will be necessary to 
stratify and randomize at a 1:1 ratio over 18 months (~23 patients/month). The 
required 332 PFS events are expected to occur around six months after randomization 
of the last patient. Therefore, the IDMC meeting after the IRC review to test PFS is 
expected to occur about one year after randomization of the last patient. 
With the prospective assumptions above mentioned, about 175 PFS events are 
expected in the control arm and 157 in the PM01183 treatment arm.  
The IDMC will review the results of the analyses. 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. 
5.2.1  Futility Analysis 
A futility analysis will be performed when 210 patients are recruited (i.e., ~105 
patients enrolled in each arm). The recruitment will not be put on hold.  
In the futility analysis, the sponsor will make no claim of efficacy, consequently this 
futility analysis and the final analysis to reject the null hypothesis (HR=1) are planned; 
the significance level will be determined by the actual number of observed events by 
IR. To maintain scientific integrity, type II error will be controlled by a spending 
function defined by O’Brien-Fleming boundaries. Following the prospective 
assumptions, the interim analysis will occur at less than one year after start of 
recruitment. At this moment, with the available information collected after balancing 
efficacy and safety, the IDMC might recommend stopping the trial.  
The IDMC may request to review other preliminary safety/efficacy parameters, but no 
claim of superiority will be done; therefore, no type I/II error corrections will be 
applied. 
5.2.2 Interim Safety Analysis 
An interim safety analysis, performed when 40 patients are enrolled in Arm A, will test 
if the addition of primary CSF prophylaxis might be necessary in this arm. With the 
information available at that time, a Bayesian test assuming non-informative prior 
distribution will be done to assess the null hypothesis of febrile neutropenia ≤ 20% vs. 
the alternative hypothesis of febrile neutropenia >20%. If the probability associated 
with the alternative hypothesis is higher than 50% (e.g., 8 cases out of 40 patients), the 
addition of primary CSF prophylaxis will be considered necessary.  
At the time of the interim safety analysis, recruitment in Arm B (PLD or topotecan) is 
also expected to be approximately 40 patients. 
The IDMC may request to review other preliminary safety/efficacy parameters, but no 
claim of superiority will be done; therefore, no type I/II error corrections will be 
applied. 
6 STATISTICAL METHODOLOGY FOR EFFICACY 
6.1 
 Efficacy Definitions 
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 treatment. 
Irrespectively of treatment arm, radiological and clinical tumor assessment will be 
performed symmetrically at baseline and every eight weeks from randomization until 
evidence of PD is found. Patients who finish treatment without radiological PD will 
continue with the tumor assessments every eight weeks (± two weeks) from 
randomization until PD, start of a new antitumor therapy, death or date of study 
termination (clinical cut-off), whichever occurs first. 
After radiological PD is documented or a new antitumor therapy is started, patients will 
be followed for survival at least every three months (± two weeks) from the end-of-
treatment visit until death or date of study termination, whichever occurs first. Once the 
whole recruitment is completed, the 3-month follow-up for patients who discontinue 
treatment due to PD will be performed according to calendar time. Follow-up for 
survival, after radiological PD is documented or new therapy is started, may be made by 
telephone calls to the investigational sites. 
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 RECIST v.1.1. 
Crossover after treatment discontinuation from Arm B to Arm A is not allowed. 
Secondary endpoints. 
Progression-free survival (PFS) by IA will be calculated using the same methodology as 
explained above for IRC assessment but following investigator assessments.  
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). If applicable and more than one OS analysis is performed type I error will be 
controlled by spending function defined by O’Brien-Fleming boundaries. Counting out 
subsequent therapies impact, sample size is powered to detect OS differences in the 20-
30% range.  Final OS analysis is planned 24 months after randomization of last patient 
(planned end of study date).  
Landmark analyses of PFS at 6/12 months by IRC/IA and OS at 12/24 months will be 
the Kaplan-Meier estimates of the probability of being free from progression and/or 
alive at these time points. 
Best antitumor response by IRC/IA will be the best response obtained in any evaluation 
according to RECIST v.1.1.  
Radiological antitumor activity will be assessed using the RECIST v. 1.1 on a set of 
measurable lesions identified at baseline as target lesions, and/or non-measurable 
lesions (if any) identified at baseline as non-target lesions and followed until disease 
progression (PD) by the appropriate method [computed tomography (CT) scan or 
magnetic resonance imaging (MRI)]. 
Duration of response (DR) will be calculated from the date of first documentation of 
response (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 
radiology assessment after randomization. 
Best response according to tumor marker evaluation (CA-125) will be the best response 
obtained according to GCIG criteria(1). Irrespectively of treatment arm, tumor marker 
assessment will be performed symmetrically at baseline and every eight weeks from 
randomization until evidence of PD.  
6.2 
 Efficacy Analysis Methods 
Time-to-event variables (PFS, OS and DR) and their set time estimates (i.e., PFS 6/12 
and OS 12/24) will be analyzed according to the Kaplan-Meier method.  
The stratified log-rank test, using actual values for all randomization strata variables, on 
the ITT population will be primarily used to compare the time-to-event variables. If the 
actual value is not a pre-defined category the value will be added to the most similar 
category (e.g., patients with more than three prior chemotherapy lines will be included 
in the 3-lines category).  
Unstratified log-rank tests will also be calculated as supportive analyses.  
The symmetry of tumor evaluations between the different arms will be examined. 
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 first and second disease assessment will be plotted. If 
necessary, internal symmetry between the two different treatments in the control arm 
will be checked following the same approach.  
Cox regression will be used to calculate the risk reduction (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.  
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 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 vs. control), ECOG PS (0 
vs. ≥1 or coded as 0 vs. 1 vs. 2)  prior platinum-free interval (1-3 months vs. >3 months 
or used as continuous variable), prior chemotherapy (1-2 vs. 3 lines or coded as 1 vs. 2 
vs. 3) , geographical area (USA vs. Europe vs. rest of the world), investigator’s 
preference for the control arm (Topotecan vs. PLD), age, age at diagnosis, race 
(caucasian vs. other), histology type (serous/papillary vs. other), histology grade 
(poorly/undifferentiated vs. other), primary tumor site (ovarian vs. other), FIGO stage at 
diagnosis (metastatic/locally advanced [stage III] vs. other), FIGO stage at study entry 
(metastatic vs.  locally advanced [stage III]/other), BRCA status (mutated vs. other), 
clinical/radiological signs of intestinal subocclusion at entry (yes vs. no), site of current 
disease: lung/liver (yes vs. no), liver metastases (yes vs. no), number of prior metastatic 
sites (≤2 vs. >2), body mass index (BMI), height, weight, body surface area (BSA), time 
from diagnosis to first infusion, prior cytoreduction (optimal vs. suboptimal vs. no 
surgery), prior radiotherapy (yes vs. no), platinum resistance (primary vs. secondary), 
clinically evidence of ascites at baseline (yes vs. no), time elapsed from last dose of last 
prior platinum-containing regimen to randomization, prior antiangiogenic treatment 


                                                          
 
                            
with bevacizumab (yes vs. no), prior PARPi (yes vs. no),  presence of any bulky (< 50 
mm vs. ≥ 50 mm) lesion at baseline, measurable disease (yes vs. no), sum of all target 
lesion diameters, baseline CA-125, albumin value at baseline, PFS prior line, response 
to last platinum therapy (yes vs. no) and baseline global QoL. In addition, continuous 
variables categorized as discrete variables will also be investigated in the continuum 
range and if the adjustment is 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. 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 for PFS and OS summarizing main results, stratification and 
factors/covariates used in multivariate analyses will be plotted(2).  
Median follow-up (FU) time for PFS and OS will be calculated in the descriptive way, 
only taking into account the censored values and using the Kaplan-Meier method for 
reversing the censoring values as described by Parmar(3). 
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 eleventh week and assessment would 
have to be done in the eighth 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).  
Proportional hazard assumption for PFS and OS will be checked by means of a Cox 
regression including treatment and its interaction with survival time(4). In case of strong 
rejection of proportionality, then restricted mean survival estimates will also 
be calculated in addition to HR(5,6).   
 
Main summary of efficacy analyses 
Endpoint 
Population 
Statistics 
PFS by IRC  
(primary endpoint) 
ITT population 
-Stratified log rank test 
OS  
ITT population 
-Stratified log rank test  
-Unstratified log rank test 
-Kaplan Meier estimates 
-Univariate Cox regression 
-Multivariate Cox regression 
PFS by IRC/IA 
ITT population 
-Stratified log rank test (IA)  
-Unstratified log rank test 
-Kaplan Meier estimates 
-Univariate Cox regression 
-Multivariate Cox regression 


                                                          
 
                            
Endpoint 
Population 
Statistics 
Response rate by 
IRC/IA 
ITT population 
-Fisher exact test 
-Logistic regression 
Duration of response 
by IRC/IA 
ITT population 
 (in patients achieving a response) 
-Unstratified log rank test 
-Kaplan Meier estimates 
ITT: Intention-to-treat; IRC: Independent Review Committee; IA: Investigator Assessment; 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 reduction requirements and reason for treatment discontinuation will be 
monitored throughout the study. 
The safety profile of patients will be monitored throughout the treatment and up to 30 
days 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). Treatment-related AEs will be followed, whenever possible, until recovery 
to at least grade 1 or stabilization of symptoms, whenever possible. 
Summary of overall AEs will be done by body system and preferred term, 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, 
skipped dose (topotecan only), 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.  
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 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) for all randomized patients. 
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 for tabulation and 
analysis. However all the baseline assessments will be listed (see section 13). 
8.2 
 Protocol Deviations 
Analysis of protocol deviations following the ‘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.  
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. 
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. 
Intended dose intensity is the planned dose per cycle divided by the planned number of 
weeks by cycle. 
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 (i.e., 21 days or 28 days in case of PLD).  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 drug 


                                                          
 
                            
administration CRF page 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 if PM01183/topotecan 
or 28 days if PLD).  
8.4 
 Patient-reported Outcomes (PRO) 
To measure the quality of life of patients, EORTC QLQ-C30 and EORTC QLQ-OV28 
questionnaires will be analyzed every eight weeks from randomization and while on 
treatment. 
PRO will be analyzed by means of longitudinal modelling 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-
OV28 questionnaires, as well as on subscales and individual symptoms. 
8.5 
 Subsequent Therapies 
A table summarizing the subsequent therapies received after discontinuation will be 
shown. Special attention will be focused on patients receiving any platinum compound 
as first subsequent treatment, and analyses to test between treatment arms if potential 
platinum-free interval prolongation is associated with survival.  
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 
 
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 randomization month 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. 
 
If the date of subsequent therapy is incomplete (day or month is missing) and the patient 
had documented disease progression, the date of subsequent therapy will be imputed to 
the end of the month when the progression occurred. If the subsequent therapy is given 
before progression to the study treatment, the rules specified above will apply. 
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.  
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 
Subgroup analyses implemented a posteriori based on clinically findings will have an 
exploratory nature.  
Some exceptions are the upfront preplanned exploratory analyses, such as efficacy 
subgroup analyses based on comparison of PM01183 with PLD or topotecan, subgroup 
analyses for stratification factors, and the analysis of the subset of patients who received 
a platinum compound as first subsequent treatment.  
Pre-specified safety subgroup analyses are: by age (<65 years-old vs. ≥65 years-old), by 
race (white vs. other), by number of prior chemotherapy lines (1-2 vs. 3 lines) and by 
geographical area (USA vs. Europe vs. rest of the world). 
8.10  Pharmacokinetic, Pharmacogenetic and Pharmacogenomic Analyses 
These analyses will be detailed and reported in separate documents. 
9 STATISTICAL SOFTWARE 
Medidata Rave® EDC will be used for data entry and clinical data management. 
Medidata Balance® will be used for randomization design and management. 
EAST® v.6.3 has been used to calculate sample size(7).  
SAS® version 9.2 or superior will be used for all statistical analyses(8). 


                                                          
 
                            
REFERENCES 
 
1. Rustin GJ, Vergote I, Eisenhauer E, Pujade-Lauraine E, Quinn M et al. 
Definitions for response and progression in ovarian cancer clinical trials 
incorporating RECIST 1.1 and CA 125 agreed by the Gynecological Cancer 
Intergroup (GCIG). Int J Gynecol Cancer 2011 Feb;21(2):419-23. 
 
2. Qinghua (Kathy) Chen. Incorporating Graphics into Summary Report Tables 
using ODS and GTL. PharmaSUG2011 – Paper SP02. 
 
3. Parmar M. Machin D. Survival analysis. A practical approach. Wiley, 
Chichester, 1995. 
 
4. 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). 
 
5. 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. 
 
6. 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. 
 
7. EAST manual. 
 
8. SAS OnlineDoc. 
  
 


                                                          
 
                            
APPENDIX I 
 
Applicable outputs will also be created at the time of interim analyses. 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 
Control 
Total 
N 
% 
N 
% 
N 
% 
Randomized patients  
(ITT population) 
 
 
 
 
 
 
Treated patients 
(Safety population) 
 
 
 
 
 
 
Table 10.1.4 Disposition of patients in the control arm 
 
Topotecan 
PLD 
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/PLD/Topotecan 


                                                          
 
                            
Table 10.1.6 Patients accrual by institution 
 
 
 
PM01183 
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/PLD/Topotecan 
Table 10.1.9 Investigator’s preference for the control arm 
 
PM01183 
Topotecan 
PLD 
N 
% 
N 
% 
N 
% 
Topotecan 
 
 
 
 
 
 
PLD 
 
 
 
 
 
 
 


                                                          
 
                            
10.2 Reasons for Treatment Discontinuation 
 
Table 10.2.1 Treatment discontinuation 
Reason 
PM01183 
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 
 
 
 
 
 
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 
Date 
Specify (if 
applicable) 
 
 
 
 
 
 
 
 
 
 
 
 
*PM01183/PLD/Topotecan 
 
Listing 10.2.3 AEs with reported ‘treatment withdrawn’  
Treatment 
arm* 
Patient 
id. 
Preferred  
term code
Adverse 
event 
reported 
(verbatim)
Grade Relationship SAE Onset 
date 
Resolved 
date 
Outcome
 
 
 
 
 
 
*PM01183/PLD/Topotecan 
 
Table 10.2.4 Reasons for off study 
Reason 
PM01183 
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 the definitions of the Protocol Deviation and Non-Compliance 
Management Plan.  
Listing 10.3.1 Protocol deviations 
Treatment 
arm* 
Patient 
Classification 
Deviation Category 
Deviation 
 
 
 
 
 
*PM01183/PLD/Topotecan 
 


                                                          
 
                            
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
Control 
Total
PLD Topotecan
N 
% 
N % N %
N 
% 
Number of patients 
 
 
 
 
 
 
 
 
Age   
 
 
 
 
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 
… 
 
 
 
 
 
 
 
 
Time from first diagnosis to randomization 
Median (range) 
Mean (std) 
 
 
 
 
Primary site 
Ovarian 
Fallopian 
Peritoneal 
 
 
 
 
 
 
 
 
Histology type 
Serous/Papillary 
Endometrioid 
Clear cell 
Mucinous 
Other (specify) 
 
 
 
 
 
 
 
 
Histology grade 
Well differentiated 
Moderately differentiated 
Poorly differentiated 
Undifferentiated 
UK 
 
 
 
 
 
 
 
 


                                                          
 
                            
 
PM01183
Control 
Total
PLD Topotecan
N 
% 
N % N %
N 
% 
FIGO stage at diagnosis 
I 
IA 
IB 
… 
 
 
 
 
 
 
 
 
FIGO stage at study entry 
I 
IA 
IB 
… 
 
 
 
 
 
 
 
 
BRCA status 
UK 
BRCA1 
BRCA2 
Not mutated 
 
 
 
 
 
 
 
 
Clinical/radiological signs of Intestinal subocclusion
Yes 
No 
 
 
 
 
 
 
 
 
Clinical evidence of ascites at baseline 
Yes 
No 
 
 
 
 
 
 
 
 
Sites of current disease 
Peritoneal 
Lymph node 
… 
 
 
 
 
 
 
 
 
Number of sites involved 
1 
2 
… 
Median (range) 
Mean (std) 
 
 
 
 
 
 
 
 
Physical examination by Body System examined 
Abnormalities found 
 Yes 
 No 
Clinically significant 
Not Clinically significant 
 
 
 
 
 
 
 
 
Weight 
Median (range) 
Mean (std) 
 
 
 
 
Height 
Median (range) 
Mean (std) 
 
 
 
 
Body surface area 
Median (range) 
Mean (std) 
 
 
 
 


                                                          
 
                            
 
PM01183
Control 
Total
PLD Topotecan
N 
% 
N % N %
N 
% 
BMI 
Median (range) 
Mean (std) 
 
 
 
 
BMI categories 
≤ 20 
20-25 
25-30 
> 30 
 
 
 
 
 
 
 
 
ECG   
Normal 
Significant abnormalities 
Non significant abnormalities 
 
 
 
 
 
 
 
 
LVEF   
Normal 
Significant abnormalities 
Non significant abnormalities 
 
 
 
 
 
 
 
 
ECG results   
PR interval  
Median (range) 
Mean (std) 
Heart Rate  
Median (range) 
Mean (std) 
QT interval (raw)  
Median (range) 
Mean (std) 
QRS complex duration  
Median (range) 
Mean (std) 
Fridericia corrected QT  
Median (range) 
Mean (std) 
 
 
 
 
LVEF results 
Median (range) 
Mean (std) 
 
 
 
 
Vital signs 
Heart rate  
Median (range) 
Mean (std) 
Systolic blood pressure  
Median (range)  
Mean (std) 
Diastolic blood pressure 
Median (range) 
Mean (std) 
Temperature  
Median (range) 
Mean (std) 
 
 
 
 
N(%) for categorical variables; Median (range)/Mean (std) for continuous variables 
 
 
 
 
 


                                                          
 
                            
Table 11.1.1.2 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 
Leukopenia 
 
 
 
 
 
 
 
 
 
 
 
 
 
Anemia 
 
 
 
 
 
 
 
 
 
 
 
 
 
Thrombocytopenia 
 
 
 
 
 
 
 
 
 
 
 
 
 
Neutropenia 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lymphopenia 
 
 
 
 
 
 
 
 
 
 
 
 
 
Control 
Leukopenia 
 
 
 
 
 
 
 
 
 
 
 
 
 
Anemia 
 
 
 
 
 
 
 
 
 
 
 
 
 
Thrombocytopenia 
 
 
 
 
 
 
 
 
 
 
 
 
 
Neutropenia 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lymphopenia 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 11.1.1.3 Hematology values at baseline 
PM01183 
Control 
n 
Median (range) 
Mean (std) 
n 
Median (range) 
Mean (std) 
WBC 
 
 
Neutrophils 
 
 
Hemoglobin 
 
 
Platelets 
 
 
Lymphocytes 
 
 
Monocytes 
 
 
Listing 11.1.1.4 Hematological tests not assessed at baseline 
Treatment arm 
Patient id. 
Lab. test 
 
… 
 
 
… 
 
Listing 11.1.1.5 Hematological abnormalities grade≥1 at baseline 
Treatment arm 
Patient id. 
Test 
Grade 
 
… 
 
 
 
… 
 
 
 


                                                          
 
                            
Table 11.1.1.6 Grade 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 
Creatinine increase 
 
 
 
 
 
 
 
 
 
 
 
 
 
CPK increase 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bilirubin increase 
 
 
 
 
 
 
 
 
 
 
 
 
 
AP increase 
 
 
 
 
 
 
 
 
 
 
 
 
 
GGT increase 
 
 
 
 
 
 
 
 
 
 
 
 
 
AST increase 
 
 
 
 
 
 
 
 
 
 
 
 
 
ALT increase 
 
 
 
 
 
 
 
 
 
 
 
 
 
Control 
Creatinine increase 
 
 
 
 
 
 
 
 
 
 
 
 
 
CPK increase 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bilirubin increase 
 
 
 
 
 
 
 
 
 
 
 
 
 
AP increase 
 
 
 
 
 
 
 
 
 
 
 
 
 
GGT increase 
 
 
 
 
 
 
 
 
 
 
 
 
 
AST increase 
 
 
 
 
 
 
 
 
 
 
 
 
 
ALT increase 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 11.1.1.7 Biochemistry values at baseline 
PM01183 
Control 
n 
Median (range) 
Mean (std) 
n 
Median (range) 
Mean (std) 
Creatinine 
 
 
Creatinine clearance 
 
 
CPK 
 
 
Total bilirubin 
 
 
AP 
 
 
GGT 
 
 
AST 
 
 
ALT 
 
 
Listing 11.1.1.8 Biochemical tests not assessed at baseline 
Treatment arm 
Patient id. 
Lab. test 
 
… 
 
 
… 
 
Listing 11.1.1.9 Biochemical abnormalities grade≥1 at baseline 
Treatment arm 
Patient id. 
Test 
Grade 
 
… 
 
 
 
… 
 
 
 


                                                          
 
                            
Table 11.1.1.10 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 
Hyperglycemia 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hypernatremia 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hyperkalemia 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hypoglycemia 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hyponatremia 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hypokalemia 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hypoalbuminemia 
 
 
 
 
 
 
 
 
 
 
 
 
 
Control 
Hyperglycemia 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hypernatremia 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hyperkalemia 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hypoglycemia 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hyponatremia 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hypokalemia 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hypoalbuminemia 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 11.1.1.11 Other metabolic values at baseline 
PM01183 
Control 
n 
Median (range) 
Mean (std) 
n 
Median (range) 
Mean (std) 
Glucose 
 
 
Sodium 
 
 
Potassium 
 
 
Albumin 
 
 
Listing 11.1.1.12 Metabolic tests not assessed at baseline 
Treatment arm 
Patient id. 
Lab. test 
 
… 
 
 
… 
 
 
Listing 11.1.1.13 Other metabolic abnormalities grade≥1 at baseline 
Treatment arm 
Patient id. 
Test 
Grade 
 
… 
 
 
 
… 
 
 
 


                                                          
 
                            
 
11.1.2  Prior Anticancer Therapy 
Table 11.1.2.1 Prior therapy 
PM01183 
Control 
Total 
PLD 
Topotecan 
N 
% 
N 
% 
N 
% 
N 
% 
Radiotherapy (Y/N) 
 
 
 
 
 
 
 
 
 Type 
   External 
   Brachytherapy 
   IORT 
 Intention 
   Curative 
   Palliative 
 
 
 
 
 
 
Cytoredutive surgery (Y/N) 
Primary cytoreduction (Y/N) 
-Optimal 
-Suboptimal 
      Interval cytoreduction (Y/N)  
-Optimal 
-Suboptimal 
      Secondary cytoreduction (Y/N)  
-Optimal 
            -Suboptimal 
 
 
 
 
 
 
 
 
Other surgical procedures (Y/N) 
Intention 
   -Diagnostic/exploratory 
   -Radical 
   -Palliative 
 
 
 
 
 
 
 
 
 


                                                          
 
                            
Table 11.1.2.2 Prior anticancer medical therapy 
 
PM01183 
Control 
Total 
PLD 
Topotecan 
N 
% 
N
%
N
%
N 
% 
Number of prior regimens  
   1 
   2 
   … 
  Median (range) 
  Mean (std) 
 
 
 
 
 
 
 
 
Setting 
   Adjuvant 
   Neoadjuvant 
   Advanced/Metastatic 
 
 
 
 
 
 
 
 
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 
   … 
 
 
 
 
 
 
 
 
Prior biological agents (ATC coded) 
   Bevacizumab 
   … 
 
 
 
 
 
 
 
 
Prior investigational agents 
Prior hormonal agents 
Others
 
 
 
 
 
 
 
 
Platinum-free Interval (calculated from dates reported 
and as reported in screening form) 
  Median (range) 
  Mean (std) 
  1-3 months (calculated) 
  >3 months (calculated)   
 1-3 months (screening form) 
  >3 months (screening form) 
 
 
 
 
 
 
 
 
Time from prior last progression to randomization 
  Median (range) 
  Mean (std) 
 
 
 
 
 
 
 
 
PFS to last prior therapy 
  Median (range) 
  Mean (std) 
 
 
 
 
 
 
 
 
Best response to last prior therapy 
   CR 
   PR 
   SD 
   PD 
   NE/UK/NA 
 
 
 
 
 
 
 
 
 


                                                          
 
                            
11.1.3  Prior Relevant Medical History 
A table with the description of the more relevant abnormalities found at baseline will be 
provided in this section. 
Table 11.1.3.1  Medical history  
SOC 
Preferred term 
PM01183 
Control 
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 
Control 
Total 
PLD 
Topotecan 
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  
Gastrointestinal 
disorders 
Constipation 
 
 
 
 
 
 
 
 
 
 
 
Diarrhoea 
NOS 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
Control 
Gastrointestinal 
disorders 
Constipation 
 
 
 
 
 
 
 
 
 
 
 
Diarrhoea 
NOS 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
Listing 11.1.4.3 Signs and symptoms at baseline 
Treatment arm*
Patient id. 
Sign/symptom 
Grade 
Onset date 
 
 
 
 
*PM01183/PLD/Topotecan 


                                                          
 
                            
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) 
Concomitant medication at baseline 
PM01183 
Control 
N 
% 
N 
% 
Alimentary tract and metabolism 
 
 
 
 
  Antiacids 
 
 
    Magnesium compounds 
 
 
…. 
 
 
 
 
 
 
 
 
 
 
Blood and blood forming organs 
 
 
  Antithrombotic agents 
 
 
     Vitamin K antagonists 
 
 
… 
 
 
 
11.1.6  PRO Analyses 
Table 11.1.6.1 PRO scores at baseline 
Item 
PM01183 
Control 
Total 
PLD 
Topotecan 
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-OV28 
Item 31 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
Item 58 
 
 
 
 
 
 
 
 
 
 
 
 
 
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. 
Table 11.3.1.1 PFS by IRC (primary analysis) 
Variable 
Stratification factors 
p-value* 
Treatment arm (main analysis) 
Actual values 
 
Treatment arm (sensitivity) 
Values reported for randomization 
 
*Stratified log rank test. 
 
 


                                                          
 
                            
 
Progression-free survival by IRC 
 
Table 11.3.1.2 Median FU for PFS by IRC 
 
Total (PM01183 and Control) 
Follow-up (descriptive way) 
Median (range) 
 
Follow-up (reverse censoring method) 
Median (95%CI) 
 
 
Table 11.3.1.3 PFS by IRC 
  
PM01183 
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 11.3.1.3) will be shown too. 
 
Table 11.3.1.4 Multivariate analysis of PFS by IRC (Stratification factors and treatment arm) 
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 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 11.3.1.6 Proportional hazard assumption and restricted mean survival for PFS by IRC 
Variable 
PM01183 
Control 
Interaction 
p-value 
 Restricted mean survival*
 
 
 
*It will be calculated if proportional hazard assumption is not met. 
 
A forest plot (Figure 11.3.1.7) summarizing main results, stratification factors and 
covariates in terms of PFS by IRC will be plotted. 
 


                                                          
 
                            
Progression-free survival by IA 
 
Table 11.3.1.8 PFS by IA (Stratified log rank test) 
Variable 
Stratification factors 
p-value* 
Treatment arm (main analysis) 
Actual values 
 
Treatment arm (sensitivity) 
Values reported for randomization 
 
*Stratified log rank test. 
 
Table 11.3.1.9 Median FU for PFS by IA 
 
Total (PM01183 and Control) 
Follow-up (descriptive way) 
Median (range) 
 
Follow-up (reverse censoring method) 
Median (95%CI) 
 
 
 
Table 11.3.1.10 PFS by IA 
  
PM01183 
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 11.3.1.10) will be shown too. 
 
Table 11.3.1.11 Multivariate analysis of PFS by IA (Stratification factors and treatment arm) 
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 11.3.1.12 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 11.3.1.13 Proportional hazard assumption and restricted mean survival for PFS by IA 
Variable 
PM01183 
Control 
Interaction 
p-value 
 Restricted mean survival*
 
 
 
*It will be calculated if proportional hazard assumption is not met. 
 
A forest plot (Figure 11.3.1.14) summarizing main results, stratification factors and 
covariates in terms of PFS by IA will be plotted. 


                                                          
 
                            
 
Table 11.3.1.15 Time to disease assessments  
Disease assessment 
Treatment arm 
n 
Median (days) 
Wilcoxon p-value 
1 
PM01183 
 
 
 
  
Control 
 
 
2 
PM01183 
 
 
 
  
Control 
 
 
… 
PM01183 
 
 
 
  
Control 
 
 
-ITT population, Kaplan Meier plot (Figure 11.3.1.15) will be shown too. 
 
Concordance PFS IRC and PFS IA 
 
Table 11.3.1.16 Concordance PFS 
 
PM01183 
(IRC) 
PM01183 
(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 11.3.1.16) will be shown too. 
 
Sensitivity PFS analyses 
-Date of progression based on scheduled time instead of recorded date. 
 
Table 11.3.1.17 PFS based on scheduled time by IRC 
  
PM01183 
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 11.3.1.17) will be shown too. 
 
Table 11.3.1.18 PFS based on scheduled time by IA 
  
PM01183 
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 11.3.1.18) will be shown too. 
 
 


                                                          
 
                            
-First date of progression combining IRC and IA assessments 
 
Table 11.3.1.19 PFS based on first date of progression 
  
PM01183 
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 11.3.1.19) will be shown too. 
 
- Date of progression moved to the prior tumor assessment. 
 
Table 11.3.1.20 PFS moved to the prior tumor assessment by IRC 
  
PM01183 
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 11.3.1.20) will be shown too. 
 
Table 11.3.1.21 PFS moved to the prior tumor assessment by IA 
  
PM01183 
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 11.3.1.21) will be shown too. 
 
Overall survival 
 
Table 11.3.1.22 OS (Stratified log rank test) 
Variable 
Stratification factors 
p-value* 
Treatment arm (main analysis) 
Actual values 
 
Treatment arm (sensitivity) 
Values reported for randomization 
 
*Stratified log rank test. 
 
Table 11.3.1.23 Median FU for OS 
 
Total (PM01183 and Control) 
Follow-up (descriptive way) 
Median (range) 
 
Follow-up (reverse censoring method) 
Median (95%CI) 
 
 
 


                                                          
 
                            
 
Table 11.3.1.24 OS  
  
PM01183 
Control 
Parameter 
p-value 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median OS  
(95% CI) 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
OS at 12 months  
(95% CI) 
 
 
Diff: 
 
OS at 24 months  
(95% CI) 
 
 
Diff: 
 
Kaplan Meier plot (Figure 11.3.1.24) will be shown too. 
 
Table 11.3.1.25 Multivariate analysis of OS (Stratification factors and treatment arm) 
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 11.3.1.26 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 11.3.1.27 Proportional hazard assumption and restricted mean survival for OS 
Variable 
PM01183 
Control 
Interaction 
p-value 
 Restricted mean survival*
 
 
 
*It will be calculated if proportional hazard assumption is not met. 
 
A forest plot (Figure 11.3.1.28)  summarizing main results, stratification factors and 
covariates in terms of OS will be plotted. 
 
Objective response and duration of response by IRC 
 
Table 11.3.1.29 Response rate by IRC 
Response 
PM01183 
Control 
p-value 
N 
% 
N 
% 
CR 
 
 
 
 
 
PR 
 
 
 
 
 
SD 
 
 
 
 
 
PD 
 
 
 
 
 
Unknown*
 
 
 
 
 
CR+PR; n (%) and binomial exact 95% confidence interval 
 
 
 
(*) Including NE, non-responders and insufficient data available. 


                                                          
 
                            
 
Table 11.3.1.30 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 11.3.1.31 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). 
 
A forest plot (Figure 11.3.1.32) summarizing main results, stratification factors and 
covariates in terms of response by IRC will be plotted.  
 
A waterfall plot (Figure 11.3.1.33) describing the best variation of the sum of target 
lesions during the treatment will be plotted. 
 
Table 11.3.1.34 DR by IRC 
  
PM01183 
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 11.3.1.35 Response rate by IA 
Response 
PM01183 
Control 
p-value 
N 
% 
N 
% 
CR 
 
 
 
 
 
PR 
 
 
 
 
 
SD 
 
 
 
 
 
PD 
 
 
 
 
 
Unknown*
 
 
 
 
 
CR+PR; n (%) and binomial exact 95% confidence interval 
 
 
 
(*) Including NE, non-responders and insufficient data available. 
 
 
Table 11.3.1.36 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 11.3.1.37 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 11.3.1.38)  summarizing main results, stratification factors and 
covariates in terms of response by IA will be plotted. 
 
A waterfall plot (Figure 11.3.1.39) describing the best variation of the sum of target 
lesions during the treatment will be plotted. 
 
Table 11.3.1.40 DR by IA 
  
PM01183 
Control  
Parameter 
p-value 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median DR  
(95% CI) 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
 
CA-125 Objective response 
 
Table 11.3.1.41 CA-125 response rate 
Response 
PM01183 
Control 
p-value 
N 
% 
N 
% 
CR 
 
 
 
 
 
PR 
 
 
 
 
 
SD 
 
 
 
 
 
PD 
 
 
 
 
 
Unknown*
 
 
 
 
 
CR+PR; n (%) and binomial exact 95% confidence interval 
 
 
 
(*) Including NE, non-responders and insufficient data available. 
 
 
Table 11.3.1.42 CA-125 response rate (excluding UK category) 
Response 
PM01183 
Control 
p-value 
N 
% 
N 
% 
CR 
 
 
 
 
 
PR 
 
 
 
 
 
SD 
 
 
 
 
 
PD 
 
 
 
 
 
CR+PR; n (%) and binomial exact 95% confidence interval 
 
 
 
 
 


                                                          
 
                            
Progression and censoring reasons by IRC/IA 
 
Table 11.3.1.43 Progression type by IRC/IA 
Reason 
IRC 
IA 
PM01183 
Control 
PM01183 
Control 
N 
% 
N 
% 
N 
% 
N 
% 
Target lesion 
 
 
 
 
 
 
 
 
Non-target lesion 
 
 
 
 
 
 
 
 
Death due to malignant disease 
 
 
 
 
 
 
 
 
Other* 
 
 
 
 
 
 
 
 
(*)Please specify. 
 
Table 11.3.1.44 Censoring reason by IRC/IA 
Reason 
IRC 
IA 
PM01183 
Control 
PM01183 
Control 
N 
% 
N 
% 
N 
% 
N 
% 
Free of progression last tumor 
assessment 
 
 
 
 
 
 
 
 
Subsequent therapy before documented 
progression 
 
 
 
 
 
 
 
 
Not treated 
 
 
 
 
 
 
 
 
Other* 
 
 
 
 
 
 
 
 
(*)Please specify. 
 
Subgroup analyses 
 
Forest plots summarizing main results, stratification factors and covariates for the 
comparison between PM01183 and PLD will be plotted.  
 
- Figure 11.3.1.45 PFS by IRC (PM01183 vs PLD) 
- Figure 11.3.1.46 PFS by IA (PM01183 vs PLD) 
- Figure 11.3.1.47 OS (PM01183 vs PLD) 
- Figure 11.3.1.48 RR by IRC (PM01183 vs PLD) 
- Figure 11.3.1.49 RR by IA (PM01183 vs PLD) 
- Figure 11.3.1.50 DR by IRC (PM01183 vs PLD) 
- Figure 11.3.1.51 DR by IA (PM01183 vs PLD) 
- Figure 11.3.1.52 CA125 by IRC (PM01183 vs PLD) 
 
Forest plots summarizing main results, stratification factors and covariates for the 
comparison between PM01183 and Topotecan will be plotted.  
 
- Figure 11.3.1.53 PFS by IRC (PM01183 vs Topotecan) 
- Figure 11.3.1.54 PFS by IA (PM01183 vs Topotecan) 
- Figure 11.3.1.55 OS (PM01183 vs Topotecan) 
- Figure 11.3.1.56 RR by IRC (PM01183 vs Topotecan) 
- Figure 11.3.1.57 RR by IA (PM01183 vs Topotecan)  
- Figure 11.3.1.58 DR by IRC (PM01183 vs Topotecan) 
- Figure 11.3.1.59 DR by IA (PM01183 vs Topotecan) 
- Figure 11.3.1.60 CA125 by IRC (PM01183 vs Topotecan) 
 
Forest plots summarizing main results, stratification factors and covariates for the 
comparison between PM01183 and Control arm selecting patients who received as first 
subsequent therapy a platinum line will be plotted.  
 
- Figure 11.3.1.61 PFS by IRC (PM01183 vs Control) 
- Figure 11.3.1.62 PFS by IA (PM01183 vs Control) 
- Figure 11.3.1.63 OS (PM01183 vs Control) 


                                                          
 
                            
- Figure 11.3.1.64 RR by IRC (PM01183 vs Control) 
- Figure 11.3.1.65 RR by IA (PM01183 vs Control)  
- Figure 11.3.1.66 DR by IRC (PM01183 vs Control) 
- Figure 11.3.1.67 DR by IA (PM01183 vs Control) 
- Figure 11.3.1.68 CA125 by IRC (PM01183 vs Control) 
 
In the forest plots continuous variables not categorized in the definition will be coded 
into two categories taking as reference the median value, below or equal the median 
value and above the median value. 
 
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 11.3.1.69 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/PLD/Topotecan 
**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 dose intensity 
 
PM01183 
PLD 
Topotecan 
No. of cycles administered per patient 
N 
% 
N
% 
N 
% 
1 
 
 
 
 
 
 
2 
 
 
 
 
 
 
3 
 
 
 
 
 
 
… 
 
 
 
 
 
 
Median (range) / Mean (std) 
 
 
 
 Time on treatment (weeks) 
Median (range) / Mean (std) 
 
 
 
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 
Control 
Total 
PLD 
Topotecan 
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 reason 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
No. of cycles administered 
 
 
 
 
 
 
 
 
No. of cycles susceptible to be delayed** 
 
 
 
 
 
 
 
 
No. of cycles with dosing delay*** 
 
 
 
 
 
 
 
 
No. of patients with  
 
 
 
 
 
 
 
 
No cycle 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 
Control 
Total 
PLD 
Topotecan 
Rel** 
No 
Rel** 
No 
Rel** 
No 
Rel** 
No 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
No. of patients with  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
No 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 
Control 
Total 
PLD 
Topotecan 
Rel* 
No 
Total 
Rel* 
No 
Total 
Rel* 
No 
Total 
Rel* 
No 
Total 
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 
Control 
Total 
PLD 
Topotecan 
Cycle 2 
Cycle nth 
Total 
Cycle 2 
Cycle nth 
Total 
Cycle 2 
Cycle nth 
Total 
Cycle 2 
Cycle nth 
Total 
 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
Number of delays 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Treatment-related* 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   Hematological 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   Non-hematological 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  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) 
 
 
 
 
 
 
 
 
 
 
 
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 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 


                                                          
 
                                                
 
12.1.3 Dose Reductions 
 
Table 12.1.3.1 Number of patients and cycles with dose reduction, any relationship 
 
PM01183 
Control 
Total 
PLD 
Topotecan 
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 reduction 
 
 
 
 
 
 
 
 
Hematological reason 
Non-hematological reason 
Both reason 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
No. of cycles administered 
 
 
 
 
 
 
 
 
No. of cycles susceptible to be dose reduced** 
 
 
 
 
 
 
 
 
No. of cycles with dose reduction*** 
 
 
 
 
 
 
 
 
No. of patients with  
 
 
 
 
 
 
 
 
No reduction 
 
 
 
 
 
 
1 reduction  
 
 
 
 
 
 
2 reductions 
 
 
 
 
 
 
≥ 3 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 
Control 
Total 
PLD 
Topotecan 
Rel** 
No 
Rel** 
No 
Rel** 
No 
Rel** 
No 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
No. of patients with  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
No reduction 
 
 
 
 
 
 
 
 
 
 
 
 
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 
Control 
Total 
PLD 
Topotecan 
Cycle 2 
Cycle nth 
Total 
Cycle 2 
Cycle nth 
Total 
Cycle 2 
Cycle nth 
Total 
Cycle 2 
Cycle nth 
Total 
 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
Number of reductions 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Treatment-related* 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   Hematological 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   Non-hematological 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  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 
 
 
 
 
 
 
 
 
 
 


                                                          
 
                                                
 
Listing 12.1.3.5AEs 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 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
12.2 Adverse Events (AEs) 
12.2.1  Adverse Events 
Treatment emergent 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 v4. 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 
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 DB 
 
 
Number of patients with any drug-related SAE in DB 
 
 


                                                          
 
                                                
Category 
PM01183 
Control 
N (%) 
N (%) 
Number of patients with any grade 3/4 SAE in DB 
 
 
Number of patients with any grade 4 SAE in DB 
 
 
Number of patients with any grade 3/4 drug-related SAE in DB 
 
 
Number of patients with any grade 4 drug-related SAE in DB 
 
 
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 
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 
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 
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 
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, PLD or Topotecan 
 
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, PLD or Topotecan 


                                                          
 
                                                
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 
Constipation 
1 
 
 
 
 
 
 
 
 
 
2 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
... 
1 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
Control 
Constipation 
1 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
Diarrhea 
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 
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 
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 
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 
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, PLD or Topotecan 
 
 
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, PLD or Topotecan 


                                                          
 
                            
12.3.2 Interim Bayesian Safety Analysis 
For PM01183 a bayesian test assuming non-informative prior distribution will be done 
to assess the null hypothesis of febrile neutropenia < 20% versus the alternative 
hypothesis of febrile neutropenia ≥20%. If the probability associated with the alternative 
hypothesis is higher than 50%, at the interim analysis with the first 40 patients treated in 
arm A, the addition of primary CSF prophylaxis will be considered necessary.  
 
Table 12.3.2.1 Bayesian test 
 
Probability of being under null 
hypothesis 
Probability of being under alternative hypothesis
Observed 
Proportion 
 
 
 
12.3.3 Deaths 
 
Table 12.3.3.1 Cause of death 
Reason# 
PM01183 
Control 
Total 
PLD 
Topotecan 
N 
% 
N 
% 
N 
% 
N 
% 
Malignant disease 
 
 
 
 
 
 
 
 
Study drug-related AE  
 
 
 
 
 
 
 
 
Non study drug-related AE 
 
 
 
 
 
 
 
 
Other  
 
 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 (#) Denominator=Number of patients who died 
 
Listing 12.3.3.2 Deaths 
Treatment 
arm* 
Patient 
id. 
Death 
date 
Cause Number of cycles 
administered 
Last 
infusion 
date 
Time on 
treatment** 
Time from 
Last dose*** 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
*PM01183, PLD or Topotecan 
**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 12.3.3.3 AEs reported as Fatal 
Treatment 
arm* 
Patient 
id.  
Cycle
Preferred  
term code 
Adverse 
event 
reported 
(verbatim) 
Grade
Relationship 
Onset 
date  Resolved date
 
 
 
 
 
 
 
 
 
*PM01183, PLD or Topotecan 


                                                          
 
                            
12.4  Clinical Laboratory Evaluation 
12.4.1  Hematological Abnormalities 
Hematological toxicities classified according to NCI-CTCAE v4 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 
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, PLD or Topotecan 
 
Table 12.4.1.3 Hematological abnormalities, worst grade per cycle 
 
Grade 
PM01183 
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 
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, PLD or Topotecan 
 
Listing 12.4.1.6 Grade 3/4 hematological abnormalities. Worst grade by cycle 
Treatment arm*
Patient id. 
Cycle 
Test 
Grade 
 
 
 
 
 
 
 
 
 
 
*PM01183, PLD or Topotecan 
12.4.2  Biochemical Abnormalities 
 
Table 12.4.2.1 Biochemical abnormalities, worst grade per patient 
 
Grade 
PM01183 
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 
GGT 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, PLD or Topotecan 
 
Table 12.4.2.3 Biochemical abnormalities, worst grade per cycle 
 
Grade 
PM01183 
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 
GGT increase 
AST increase 
ALT increase 
 
Table 12.4.2.4 Biochemical abnormalities, worst grade per cycle by cycle 
 
Grade 
PM01183 
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 
GGT 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, PLD or Topotecan 
 
Listing 12.4.2.6 Grade 3/4 biochemical abnormalities. Worst grade by cycle 
Treatment arm* 
Patient id. 
Cycle 
Test 
Grade 
 
 
 
 
 
 
 
 
 
 
*PM01183, PLD or Topotecan 
 


                                                          
 
                            
12.4.3  Other Metabolic Parameters 
 
Table 12.4.3.1 Metabolic abnormalities, worst grade per patient 
 
Grade 
PM01183 
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 
Hypoglycemia 
Hyponatremia 
Hypokalemia 
Hypoalbuminemia 
Listing 12.4.3.2 Metabolic tests not assessed at any treatment visit by patient 
Treatment arm*
Patient id. 
Lab. test 
 
… 
 
*PM01183, PLD or Topotecan 
 
 
Table 12.4.3.3 Metabolic abnormalities, worst grade per cycle 
 
Grade 
PM01183 
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 
Hypoglycemia 
Hyponatremia 
Hypokalemia 
Hypoalbuminemia 
 


                                                          
 
                            
Table 12.4.3.4 Metabolic abnormalities, worst grade per cycle by cycle 
 
Grade 
PM01183 
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 
Hypoglycemia 
Hyponatremia 
Hypokalemia 
Hypoalbuminemia 
Cycle ... 
Listing 12.4.3.5 Metabolic tests not assessed by patient and cycle 
Treatment arm*
Patient id. 
Cycle 
Lab. test 
 
… 
 
 
 
… 
 
 
*PM01183, PLD or Topotecan 
 
Listing 12.4.3.6 Grade 3/4 metabolic abnormalities. Worst grade by cycle 
Treatment arm*
Patient id. 
Cycle 
Test 
Grade 
 
 
 
 
 
 
 
 
 
 
*PM01183, PLD or Topotecan 
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, GGT increase, AST increase and ALT increase. 
-Other metabolic abnormalities, including hyperglycemia, hypernatremia, hyperkalemia, 
hypoglycemia, hyponatremia, hypokalemia and hypoalbuminemia. 
 
Table 12.4.4.1 Summary of laboratory values 
Category 
PM01183 
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 
 
 


                                                          
 
                            
Category 
PM01183 
Control 
N (%) 
N (%) 
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 
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, worst grade during first cycle vs. baseline 
 
Baseline grade* 
Worst grade per patient during first cycle  
Grade  
0 
Grade  
1 
Grade  
… 
Grade  
4 
N 
% 
N 
% 
N 
% 
N 
% 
PM01183 
Leukopenia 
0 
 
 
 
 
 
 
 
 
 
1 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
Neutropenia 
0 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
…** 
0 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
Control 
Leukopenia 
0 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
Neutropenia 
0 
 
 
 
 
 
 
 
 
…** 
0 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
*Defined as the last value recorded before or on the date of first infusion. 
** Anemia, thrombocytopenia and lymphopenia. 


                                                          
 
                            
Table 12.4.4.4 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 
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, GGT, CPK, creatinine, hyperglycemia, hypernatremia, hyperkalemia, hypoglycemia, 
hyponatremia, hypokalemia and hypoalbuminemia. 
 
 
Table 12.4.4.5 Shift of biochemical abnormalities, worst grade during first cycle vs. baseline 
 
Baseline grade* 
Worst grade per patient during first cycle  
Grade  
0 
Grade  
1 
Grade  
… 
Grade  
4 
N 
% 
N 
% 
N 
% 
N 
% 
PM01183 
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, GGT, CPK, creatinine, hyperglycemia, hypernatremia, hyperkalemia, hypoglycemia, 
hyponatremia, hypokalemia and hypoalbuminemia. 
 


                                                          
 
                            
 
Median intercycle figures showing PM01183 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 
Control 
p-
value
Grade 
<3 
Grade 
≥3 
Grade 
<3 
Grade 
≥3 
Thrombocytopenia 
 
 
 
 
 
Neutropenia  
ALKP  
Bilirubin  
SGOT-AST  
SGPT-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 
Control 
p-
value
Grade 
<4 
Grade 
≥4 
Grade 
<4 
Grade 
≥4 
Thrombocytopenia 
 
 
 
 
 
Neutropenia  
ALKP  
Bilirubin  
SGOT-AST  
SGPT-ALT  
CPK 
Nausea 
Vomiting 
Fatigue 
Other* 
*Any 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 AE form. 
 
Table 12.5.1 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 
Thrombocytopenia 
 
 
 
 
 
 
Neutropenia  
ALKP  
Bilirubin  
SGOT-AST  
SGPT-ALT  
CPK 
Nausea 
Vomiting 
Fatigue 
Other* 
Control 
Thrombocytopenia 
Neutropenia  
ALKP  
Bilirubin  
SGOT-AST  
SGPT-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 (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 
Thrombocytopenia 
 
 
 
 
 
 
Neutropenia  
ALKP  
Bilirubin  
SGOT-AST  
SGPT-ALT  
CPK 
Nausea 
Vomiting 
Fatigue 
Other* 
Control 
Thrombocytopenia 
Neutropenia  
ALKP  
Bilirubin  
SGOT-AST  
SGPT-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 (Race) 
Laboratory abnormalities/ drug-related AEs 
White 
Other 
No. of 
patients 
 evaluated 
Grade 
3/4 
%
No. of 
patients 
 evaluated 
Grade 
3/4 
%
PM01183 
Thrombocytopenia 
 
 
 
 
 
 
Neutropenia  
ALKP  
Bilirubin  
SGOT-AST  
SGPT-ALT  
CPK 
Nausea 
Vomiting 
Fatigue 
Other* 
Control 
Thrombocytopenia 
Neutropenia  
ALKP  
Bilirubin  
SGOT-AST  
SGPT-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 (Race) 
Laboratory abnormalities/ drug-related 
AEs 
White 
Other 
No. of cycles 
evaluated 
Grade 
3/4 
%
No. of cycles 
evaluated 
Grade
3/4 
%
PM01183 
Thrombocytopenia 
 
 
 
 
 
 
Neutropenia  
ALKP  
Bilirubin  
SGOT-AST  
SGPT-ALT  
CPK 
Nausea 
Vomiting 
Fatigue 
Other* 
Control 
Thrombocytopenia 
Neutropenia  
ALKP  
Bilirubin  
SGOT-AST  
SGPT-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 (Number of prior chemotherapy lines) 
Laboratory abnormalities/ drug-related 
AEs 
1-2 
3 
No. of cycles 
evaluated 
Grade 
3/4 
%
No. of cycles 
evaluated 
Grade
3/4 
%
PM01183 
Thrombocytopenia 
 
 
 
 
 
 
Neutropenia  
ALKP  
Bilirubin  
SGOT-AST  
SGPT-ALT  
CPK 
Nausea 
Vomiting 
Fatigue 
Other* 
Control 
Thrombocytopenia 
Neutropenia  
ALKP  
Bilirubin  
SGOT-AST  
SGPT-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 (Number of prior chemotherapy lines) 
Laboratory abnormalities/ drug-related 
AEs 
1-2 
3 
No. of cycles 
evaluated 
Grade 
3/4 
%
No. of cycles 
evaluated 
Grade
3/4 
%
PM01183 
Thrombocytopenia 
 
 
 
 
 
 
Neutropenia  
ALKP  
Bilirubin  
SGOT-AST  
SGPT-ALT  
CPK 
Nausea 
Vomiting 
Fatigue 
Other* 
Control 
Thrombocytopenia 
Neutropenia  
ALKP  
Bilirubin  
SGOT-AST  
SGPT-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 (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 
Thrombocytopenia 
 
 
 
 
 
 
 
 
 
Neutropenia  
ALKP  
Bilirubin  
SGOT-AST  
SGPT-ALT  
CPK 
Nausea 
Vomiting 
Fatigue 
Other* 
Control 
Thrombocytopenia 
Neutropenia  
ALKP  
Bilirubin  
SGOT-AST  
SGPT-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 (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 
Thrombocytopenia 
 
 
 
 
 
 
 
 
 
Neutropenia  
ALKP  
Bilirubin  
SGOT-AST  
SGPT-ALT  
CPK 
Nausea 
Vomiting 
Fatigue 
Other* 
Control 
Thrombocytopenia 
Neutropenia  
ALKP  
Bilirubin  
SGOT-AST  
SGPT-ALT  
CPK 
Nausea 
Vomiting 
Fatigue 
Other* 
*Any drug-related toxicity present in >=3% of cycles in any group. 


                                                          
 
                            
Table 12.5.9 Worst grade by patient comparison vs. PLD 
Laboratory 
abnormalities/ drug-
related AEs 
Grade 
PM01183 
PLD 
0 
1 
… 
G≥1 
G≥3 
0 
1 
… 
G≥1 
G≥3 
N % N % N % N % N % N % N % N % N % N %
Thrombocytopenia 
Neutropenia  
ALKP  
Bilirubin  
SGOT-AST  
SGPT-ALT  
CPK 
Nausea 
Vomiting 
Fatigue 
Other* 
*Any drug-related toxicity present in >=5% of patients in any group. 
 
 
Table 12.5.10 Worst grade by cycle comparison vs. PLD 
Laboratory 
abnormalities/ drug-
related AEs 
Grade 
PM01183 
PLD 
0 
1 
… 
G≥1 
G≥3 
0 
1 
… 
G≥1 
G≥3 
N % N % N % N % N % N % N % N % N % N %
Thrombocytopenia 
Neutropenia  
ALKP  
Bilirubin  
SGOT-AST  
SGPT-ALT  
CPK 
Nausea 
Vomiting 
Fatigue 
Other* 
*Any drug-related toxicity present in >=5% of patients in any group. 


                                                          
 
                            
Table 12.5.11 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  
ALKP  
Bilirubin  
SGOT-AST  
SGPT-ALT  
CPK 
Nausea 
Vomiting 
Fatigue 
Other* 
*Any drug-related toxicity present in >=5% of patients in any group. 
 
 
Table 12.5.12 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  
ALKP  
Bilirubin  
SGOT-AST  
SGPT-ALT  
CPK 
Nausea 
Vomiting 
Fatigue 
Other* 
*Any drug-related toxicity present in >=5% of patients in any group. 


                                                          
 
                            
 
12.6  Concomitant Medication during Treatment  
Table 12.6.1 Concomitant medication during treatment (ATC1/ATC2/ATC4) 
Concomitant medication 
PM01183 
Control 
N 
% 
N 
% 
Alimentary tract and metabolism 
 
 
 
 
  Antiacids 
 
 
    Magnesium compounds 
 
 
…. 
 
 
 
 
 
 
 
 
 
 
Blood and blood forming organs 
 
 
  Antithrombotic agents 
 
 
     Vitamin K antagonists 
 
 
… 
 
 
 
Table 12.6.2 CSF, transfusions or EPO 
 
PM01183 
Control 
Total 
PLD 
Topotecan 
N 
% 
N 
% 
N 
% 
N 
% 
CSF 
 
 
 
 
 
 
 
 
  CSF (prophylactic) 
 
 
 
 
 
 
  CSF (therapeutic) 
 
 
 
 
 
 
Platelets transfusions 
 
 
 
 
 
 
RBC transfusions 
 
 
 
 
 
 
EPO 
 
 
 
 
 
 
 
Listing 12.6.3 Patients who have been treated with CSF, transfusions or EPO  
Treatment 
arm* 
Patient 
id. 
Type 
Agent 
Route 
Dose 
Unit 
Start 
date 
Stop 
date 
Reason 
Indication 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
*PM01183, PLD or Topotecan 
 
Table 12.6.4  Neutropenia by CSF, worst grade in the first cycle 
 
Grade 
CSF=YES 
CSF=NO 
0 
1 
… 
G≥1 
G≥3 
0 
1 
… 
G≥1 
G≥3 
N % N % N % N % N % N % N % N % N % N %
PM01183
PLD
Topotecan
 


                                                          
 
                            
12.7 Subsequent Therapy 
Table 12.7.1 Subsequent therapy 
 
  PM01183 
Control 
Total 
PLD 
Topotecan 
N 
% 
N 
% 
N 
% 
N 
% 
Type 
 
 
 
 
 
 
 
 
  Chemotherapy 
 
 
 
 
 
 
  Surgery 
 
 
 
 
 
 
   … 
 
 
 
 
 
 
Subsequent chemotherapy 
 
 
 
 
 
 
 
 
  Platinum 
 
 
 
 
 
 
  Taxanes 
 
 
 
 
 
 
   … 
 
 
 
 
 
 
12.8 PRO at treatment   
Completion rate is defined as the number of patients with answer to item X in the 
numerator and the number of patients on treatment in each time point 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 
Control 
Missing 
(%) 
Completed 
(%) 
Missing 
(%) 
Completed 
(%) 
EORTC QLQ-C30 
 
 
 
 
Item 1 
Baseline  
 
 
 
 
 
Week 6 
 
 
 
 
 
… 
 
 
 
 
…. 
Baseline  
 
 
 
 
 
… 
 
 
 
 
Any item 
Baseline  
 
 
 
 
 
Week 6 
 
 
 
 
 
… 
 
 
 
 
EORTC QLQ-OV28 
 
 
 
 
Item 31 
Baseline  
 
 
 
 
 
Week 6 
 
 
 
 
 
… 
 
 
 
 
…. 
Baseline  
 
 
 
 
 
… 
 
 
 
 
Any item 
Baseline  
 
 
 
 
 
Week 6 
 
 
 
 
 
… 
 
 
 
 
EORTC QLQ-C30 and QLQ-OV28 
 
 
 
 
Any item 
Baseline  
 
 
 
 
 
… 
 
 
 
 
 


                                                          
 
                            
 Table 12.8.2 T-test change vs. baseline 
Item 
Cycle 
PM01183 
Control* 
p-value 
N 
Mean (std) 
N 
Mean (std) 
*Control refers to PLD and/or topotecan 
Item 1 
Week 6 
 
 
 
 
 
 
Week 12 
 
 
 
 
 
 
… 
 
 
 
 
 
…. 
Week 6 
 
 
 
 
 
 
Week 12 
 
 
 
 
 
 
… 
 
 
 
 
 
Item 58 
Week 6 
 
 
 
 
 
 
Week 12 
 
 
 
 
 
 
… 
 
 
 
 
 
*Control refers to PLD  
Item 1 
Week 6 
 
 
 
 
 
 
Week 12 
 
 
 
 
 
 
… 
 
 
 
 
 
…. 
Week 6 
 
 
 
 
 
 
Week 12 
 
 
 
 
 
 
… 
 
 
 
 
 
Item 58 
Week 6 
 
 
 
 
 
 
Week 12 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
*Control refers to topotecan 
Item 1 
Week 6 
 
 
 
 
 
 
Week 12 
 
 
 
 
 
 
… 
 
 
 
 
 
…. 
Week 6 
 
 
 
 
 
 
Week 12 
 
 
 
 
 
 
… 
 
 
 
 
 
Item 58 
Week 6 
 
 
 
 
 
 
Week 12 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 12.8.3 Percentage of patients with an improvement ≥10% vs. baseline 
Item 
Cycle 
PM01183 
Control* 
p-value 
N 
% 
N 
% 
*Control refers to PLD and/or topotecan 
Item 1 
Week 6 
 
 
 
 
 
 
Week 12 
 
 
 
 
 
 
… 
 
 
 
 
 
…. 
Week 6 
 
 
 
 
 
 
Week 12 
 
 
 
 
 
 
… 
 
 
 
 
 


                                                          
 
                            
Item 
Cycle 
PM01183 
Control* 
p-value 
N 
% 
N 
% 
Item 58 
Week 6 
 
 
 
 
 
 
Week 12 
 
 
 
 
 
 
… 
 
 
 
 
 
*Control refers to PLD 
Item 1 
Week 6 
 
 
 
 
 
 
Week 12 
 
 
 
 
 
 
… 
 
 
 
 
 
…. 
Week 6 
 
 
 
 
 
 
Week 12 
 
 
 
 
 
 
… 
 
 
 
 
 
Item 58 
Week 6 
 
 
 
 
 
 
Week 12 
 
 
 
 
 
 
… 
 
 
 
 
 
*Control refers to topotecan 
Item 1 
Week 6 
 
 
 
 
 
 
Week 12 
 
 
 
 
 
 
… 
 
 
 
 
 
…. 
Week 6 
 
 
 
 
 
 
Week 12 
 
 
 
 
 
 
… 
 
 
 
 
 
Item 58 
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 PLD and/or topotecan 
Item 1 
 
 
 
…. 
 
 
 
Item 58 
 
 
 
*Control refers to PLD 
Item 1 
 
 
 
…. 
 
 
 
Item 58 
 
 
 
*Control refers to topotecan 
Item 1 
 
 
 
…. 
 
 
 
Item 58 
 
 
 
 


                                                          
 
                            
Figures 12.8.5-12.8.62 Means plot by each item 
 
  
 


                                                          
 
                                                
APPENDIX II 
13 DB 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 
Date 
of 
birth 
Informed 
consent 
date 
Planned 
date of 
treatment 
initiation 
Histology 
PFI 
PS 
#Regimens 
Prior agents 
(Preference) 
RECIST 
(Measurable) 
ANC 
(10^9/L) 
BSA 
 
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 
PFI 
PS 
Prior 
chemotherapy 
Actual 
treatment to 
be given 
Now 
 
 
 
 
 
 
 
 
 
 
 
 
 
-Listing 13.1.5: Study Registration 
Treatment arm 
Patient id. 
Informed consent date 
PGt/PGx consent 
Date of PGt/PGx sample 
Date of blood 
sample 
Adequate contraception 
(If NA, specify) 
 
 
 
 
 
 
 
 
 
 
 


                                                          
 
                                                
-Listing 13.1.6: Demographics 
Treatment arm 
Patient id. 
Date of birth 
Age 
(years) 
Is the patient of childbearing potential? 
Race 
(Other, specify) 
Estimated DOB 
 
 
 
 
 
 
 
 
-Listing 13.1.7: Pregnancy Test 
Treatment arm 
Patient id. 
Visit 
Not done 
Which type of test was performed? 
Date of sample 
Reason for clinically 
indicated repeat 
 
Result 
 
 
 
 
 
 
 
 
 
-Listing 13.1.8: Medical History 
Treatment arm 
Patient id. 
Medical history 
Description 
Verbatim 
Onset date 
Resolved date 
Ongoing? 
 
 
 
 
 
 
 
 
MedDRA codes will be also added. 
 
-Listing 13.1.9: Cancer History 
Treatment 
arm 
Patient 
id. 
Date of 
diagnosis 
Primary site 
Histology type 
ovarian 
Histology 
grade 
FIGO stage at 
diagnosis 
FIGO 
stage at 
study 
entry 
BRCA 
Status 
Radiological and/or 
clinical signs of 
intestinal 
subocclusion? 
Clinically 
evident ascites 
Date of last 
progression 
Site (s) 
of 
current 
disease 
(If other, 
specify) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
-Listing 13.1.10: Prior Anticancer Therapy: Cytoreductive surgeries 
Treatment arm 
Patient id. 
None 
Procedure 
Specify 
Date 
Optimal/Suboptimal 
 
 
 
 
 
 
 
 
-Listing 13.1.11: Prior AntiCancer Therapy: Other Surgical Procedures 
Treatment arm 
Patient id. 
Prior surgery 
Procedures 
Date 
Intention 
 
 
 
 
 
 
 
-Listing 13.1.12: Prior AntiCancer Therapy: RadioTherapy 
Treatment arm 
Patient id. 
Radiotherapy 
Type 
Intention 
Site anatomic 
Total dose 
(Gy) 
First dose 
Last dose 
 
 
 
 
 
 
 
 
 
 
 
 


                                                          
 
                                                
-Listing 13.1.13: Prior AntiCancer Medical Therapy for Study Disease 
Treatment arm 
Patient id. 
Prior 
therapy 
Regimen 
Type 
Agent 
Route 
Setting 
Start 
date 
Stop 
date 
Best 
response 
Progression 
date 
Non 
PD 
Prior 
anthracycline 
containing 
regimen? 
If Yes, provide 
total 
doxorubicin 
cumulative dose 
(mg/m2) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ATC codes will be also added. 
 
-Listing 13.1.14: Hematology 
Treatment arm 
Patient id. 
Visit 
Not done 
Date 
WBC 
Neutrophils 
Lymphocytes 
Monocytes 
Platelets 
Hemoglobin 
Clinically indicated repeat 
 
 
 
 
 
 
 
 
 
 
 
 
 
-Listing 13.1.15: Biochemistry 
Treatment 
arm 
Patient 
id. 
Visit 
Not 
done 
Date 
ALT 
AST 
AP 
GGT 
Total 
Bilirubin 
Direct 
Bilirubin 
Total 
Proteins 
Albumin 
Creatinine 
Creatinine 
Clearance 
CPK 
Glucose 
Na 
K 
 
Cl 
Clinically 
indicated 
repeat 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
-Listing 13.1.16: Physical Examination 
Treatment arm 
Patient id. 
Visit 
Not done 
Date 
Abnormalities 
Body system 
Findings 
Clinical significance 
Weight 
Height 
BSA 
 
 
 
 
 
 
 
 
 
 
 
 
 
-Listing 13.1.17: Performance Status 
Treatment arm 
Patient id. 
Visit 
Not done 
Date 
PS (ECOG) 
 
 
 
 
 
 
 
-Listing 13.1.18: Vital Signs 
Treatment arm 
Patient id. 
Visit 
Not done 
Date 
Heart rate 
BPS 
BPD 
Temperature 
 
 
 
 
 
 
 
 
 
 
-Listing 13.1.19: 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 13.1.20: Left Ventricular Ejection Fraction (LVEF) 
Treatment arm 
Patient id. 
Visit 
Not done 
Date 
Reason for clinically indicated 
Method 
LVEF (%) 
Range (%) 
Result 
Abnormal, specify 
LVEF (derived) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


                                                          
 
                                                
-Listing 13.1.21: 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) 
 
 
 
 
 
 
 
 
 
 
 
 
 
ATC codes will be also added. 
 
-Listing 13.1.22: CSF Prophylactic Medication 
Treatment arm 
Patient id. 
Visit 
Not Done/Not Applicable 
Drug 
Route 
Daily dose 
Units 
Start date 
Stop date 
 
 
 
 
 
 
 
 
 
 
ATC codes will be also added. 
 
-Listing 13.1.23: PM01183 Administration 
Treatment 
arm 
Patient 
id. 
Visit 
Date 
 
Route 
Start 
time 
End 
time 
Intended 
dose 
level 
Total 
intended 
dose 
Total 
dose 
Total 
volume 
given 
Reduction 
Reduction 
reason 
Delay 
Delay 
reason 
Interruption 
Interruption 
reason 
Date 
end 
time 
derived 
Cycle 
Number 
of doses 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
-Listing 13.1.24: PM01183 Re-Administration 
Treatment arm 
Patient id. 
Visit 
Not done 
Date 
Route 
Start time 
End time 
Total dose 
Total volume given 
 
 
 
 
 
 
 
 
 
 
 
-Listing 13.1.25: 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) 
 
No. of 
doses 
Cycle 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
-Listing 13.1.26: Topotecan Re-Administration 
Treatment arm 
Patient id. 
Visit 
Day 
Not done 
Date 
Route 
Start time 
End time 
Total dose 
 
 
 
 
 
 
 
 
 
 
 
-Listing 13.1.27: PLD Administration 
Treatment 
arm 
Patient 
id. 
Visit 
Date 
Route 
Start 
time 
End 
time 
Intended dose 
level 
Total intended 
dose 
Total 
dose 
Total volume 
given 
Reduction 
(reason) 
Delay 
(reason) 
Interruption 
(reason) 
Cycle 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
-Listing 13.1.28: PLD Re-Administration 
Treatment arm 
Patient id. 
Visit 
Not done 
Date 
Route 
Start time 
End time 
Total dose 
Total volume given 
 
 
 
 
 
 
 
 
 
 
 


                                                          
 
                                                
-Listing 13.1.29: Adverse Events YN? 
Treatment arm 
Patient id. 
AEs 
 
 
 
 
-Listing 13.1.30: Adverse Events 
Treatment 
arm 
Patient 
id. 
Adverse 
event 
Grade 
Start date 
(Ongoing) 
End date 
(Duration/ongoing) 
Relationship 
(PM1183/Topotecan/PLD/Specify) 
Action 
 
Serious Event (Death/Life 
Threat./Hospi./Disa./Conge./Other 
Impor./Infectious.) 
Outcome 
SAE 
associated 
to QC? 
Case 
ID 
Derived 
subject 
number 
 
 
 
 
 
 
 
 
 
 
 
 
 
MedDRA codes will be also added. 
 
-Listing 13.1.31: 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 13.1.32: SAE Attachments 
Treatment arm 
Patient id. 
Attachment 
 
 
 
 
-Listing 13.1.33: Concomitant Medication YN? 
Treatment arm 
Patient id. 
Concomitant medication? 
 
 
 
 
-Listing 13.1.34: 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 
Other, 
specify 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ATC codes will be also added. 
 
-Listing 13.1.35: Concomitant Procedures 
Treatment arm 
Patient id. 
Not Done 
Procedure 
Indication 
Date of Procedure 
AE 
MH 
Result / Comments 
 
 
 
 
 
 
 
 
 
MedDRA codes will be also added. 
 
-Listing 13.1.36: Other tests/procedures 
Treatment arm 
Patient id. 
Not done 
Test name 
Test date 
Test result 
Test unit 
 
 
 
 
 
 
 
MedDRA codes will be also added. 


                                                          
 
                                                
 
-Listing 13.1.37: 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 13.1.38: Non Target Lesions 
Treatment arm 
Patient id. 
Were non target lesions assessed. 
Non target lesions 
Organ 
Specify 
Lesion description 
Date 
Method (specify) 
Response 
 
 
 
 
 
 
 
 
 
 
 
-Listing 13.1.39: New Lesions 
Treatment arm 
Patient id. 
New lesions 
Organ 
Specify 
Lesion description 
Date 
Method (specify) 
 
 
 
 
 
 
 
 
 
-Listing 13.1.40: 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 13.1.41: Tumor Markers 
Treatment arm 
Patient id. 
Not done 
Date 
CA125 
Clinically indicated repeat 
Age (Hidden) 
 
 
 
 
 
 
 
 
-Listing 13.1.42: End of Treatment 
Treatment arm 
Patient id. 
Reason 
Specify (Investigator's decision) 
Specify (AE) 
Specify (Other) 
Symptomatic deterioration date 
Symptomatic deterioration, please specify 
 
 
 
 
 
 
 
 
 
-Listing 13.1.43: Follow Up 
Treatment arm 
Patient id. 
Date 
Survival 
Disease status 
PD or any further therapy 
TA done 
TA not done 
Specify (not done) 
 
 
 
 
 
 
 
 
 
 
-Listing 13.1.44: Surgery procedures for Study Disease (after End of Treatment) 
Treatment arm 
Patient id. 
Further surgery 
Procedure 
Date 
Surgery Result 
 
 
 
 
 
 
 
-Listing 13.1.45: Radiotherapy/Brachytherapy (after End of Treatment) 
Treatment arm 
Patient id. 
Further radiotherapy 
Site 
Start date 
End date 
Ongoing 
Total dose (Gy) 
 
 
 
 
 
 
 
 
 
 


                                                          
 
                                                
-Listing 13.1.46: Medical Treatment (after End of Treatment) 
Treatment arm 
Patient id. 
Further therapy 
Agent 
Route 
Start date 
End date 
Ongoing 
Best response 
 
 
 
 
 
 
 
 
 
ATC codes will be also added. 
 
-Listing 13.1.47: Death Report Form 
Treatment arm 
Patient id. 
Date 
Cause 
Specify (Other) 
Autopsy 
Attachment 
 
 
 
 
 
 
 
 
-Listing 13.1.48: Off Study 
Treatment arm 
Patient id. 
Off study 
Date 
Primary reason 
 
 
 
 
 
 
-Listing 13.1.49: Pharmacokinetics 
Treatment arm 
Patient id. 
PK samples 
Sample No. 
Day 
Sampling time 
Not done 
Date 
Actual time 
Derived DateTime 
Comments 
Cycle the next Pharmacokinetics is due at: 
 
 
 
 
 
 
 
 
 
 
 
 
 
-Listing 13.1.50: 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-
Q54 
Specify if not 
performed 
Q55-
Q56 
Specify if not 
performed 
Q57-
Q58 
Specify if not 
performed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
-Listing 13.1.51: Treatment Continuation 
Treatment arm 
Patient id. 
Add next cycle? 
 
 
 
 
-Listing 13.1.52: Investigator Comments 
Treatment arm 
Patient id. 
Visit 
Form 
Date 
Comment 
 
 
 
 
 
 
 
-Listing 13.1.53: Unscheduled 
Treatment arm 
Patient id. 
Visit 
Pregnancy test 
LVEF 
ECG 
 
 
 
 
 
 


                                                          
 
                                                
APPENDIX III 
14 ICH Listings 
 
Following ICH E-3 guidelines, patient listings will be prepared as specified for section 16.2. 
 
- 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. 
Age 
(years) 
Race 
(Other, 
specify) 
ECOG 
PS 
Histology 
type 
ovarian 
FIGO 
stage 
at 
study 
entry 
Radiological 
and/or clinical 
signs of intestinal 
subocclusion? 
Clinically 
evident 
ascites 
BRCA 
Status 
Site (s) of 
current 
disease (If 
other, 
specify) 
BSA 
(m2) 
Prior 
surgery 
Prior 
radiotherapy 
PFI 
(months) 
#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/PLD/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 
 
Clarifications/modifications, highlighted in italic bold, have been added to the SAP v1.0 
dated on 30/April/2015. 
 
• Company Logo has been updated 
• 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 be also included. 
• Modifications/clarifications of list of covariates. 
• Clarification in the incomplete dates imputation rules. 
• Inclusion of neutropenia summary in the first cycle in patients with or without 
GCSF. 
• 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). 
 
Original (Cover) 
 
 
 
Changes to (Cover) 
 
 
 
Original Text (Section 6.2 Efficacy Analysis Methods): 
The stratified log-rank test, using all randomization strata variables, on the ITT 
population will be primarily used to compare the time-to-event variables.  
 
Changes to (Section 6.2 Efficacy Analysis Methods): 
The stratified log-rank test, using actual values for all randomization strata variables, 
on the ITT population will be primarily used to compare the time-to-event variables. If 


                                                          
 
                            
the actual value is not a pre-defined category the value will be added to the most 
similar category (e.g. patients with more than three prior chemotherapy lines will be 
included in the 3-lines category). 
 
Original Text (Section 6.2 Efficacy Analysis Methods): 
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 vs. control), ECOG PS (0 
vs. ≥1 or coded as 0 vs. 1 vs. 2)  prior platinum-free interval (1-3 months vs. >3 months 
or used as continuous variable), prior chemotherapy (1-2 vs. 3 lines or coded as 1 vs. 2 
vs. 3) , geographical area (USA vs. Europe vs. rest of the world), age, age at diagnosis, 
race (caucasian vs. other), histology type (serous/papillary vs. other), histology grade 
(poorly/undifferentiated vs. other), primary tumor site (ovarian vs. other), FIGO stage at 
diagnosis (metastatic/locally advanced [stage III] vs. other), FIGO stage at study entry 
(metastatic vs.  locally advanced [stage III]/other), BRCA status (mutated vs. other), 
clinical/radiological signs of intestinal subocclusion at entry (yes vs. no), site of current 
disease: lung/liver (yes vs. no), liver metastases (yes vs. no), number of prior metastatic 
sites (1 vs. >1), body mass index (BMI), height, weight, body surface area (BSA), time 
from diagnosis to first infusion, prior radical surgery (yes [primary vs. interval vs. 
secondary cytoreduction] vs. no), prior radiotherapy (yes vs. no), platinum resistance 
(primary vs. secondary), clinically evidence of ascites at baseline (yes vs. no), time 
elapsed from last dose of last prior platinum-containing regimen to randomization, prior 
antiangiogenic agents (yes vs. no),  presence of any bulky (< 50 mm vs. ≥ 50 mm) 
lesion at baseline, measurable (yes vs. no), sum of all target lesion diameters, baseline 
CA-125, PFS prior line and baseline global QoL. In addition, continuous variables 
categorized as discrete variables will also be investigated in the continuum range and if 
the adjustment is better then the continual variable will be selected in the model. 
 
Changes to (Section 6.2 Efficacy Analysis Methods): 
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 vs. control), ECOG PS (0 
vs. ≥1 or coded as 0 vs. 1 vs. 2)  prior platinum-free interval (1-3 months vs. >3 months 
or used as continuous variable), prior chemotherapy (1-2 vs. 3 lines or coded as 1 vs. 2 
vs. 3) , geographical area (USA vs. Europe vs. rest of the world), investigator’s 
preference for the control arm (Topotecan vs. PLD), age, age at diagnosis, race 
(caucasian vs. other), histology type (serous/papillary vs. other), histology grade 
(poorly/undifferentiated vs. other), primary tumor site (ovarian vs. other), FIGO stage at 
diagnosis (metastatic/locally advanced [stage III] vs. other), FIGO stage at study entry 
(metastatic vs.  locally advanced [stage III]/other), BRCA status (mutated vs. other), 
clinical/radiological signs of intestinal subocclusion at entry (yes vs. no), site of current 
disease: lung/liver (yes vs. no), liver metastases (yes vs. no), number of prior metastatic 
sites (≤2 vs. >2), body mass index (BMI), height, weight, body surface area (BSA), time 
from diagnosis to first infusion, prior radical surgery (yes [primary vs. interval vs. 
secondary cytoreduction] vs. no), prior cytoreduction (optimal vs. suboptimal vs. no 
surgery), prior radiotherapy (yes vs. no), platinum resistance (primary vs. secondary), 
clinically evidence of ascites at baseline (yes vs. no), time elapsed from last dose of last 
prior platinum-containing regimen to randomization, prior antiangiogenic treatment 
with bevacizumab agents (yes vs. no), prior PARPi (yes vs. no),   presence of any bulky 
(< 50 mm vs. ≥ 50 mm) lesion at baseline, measurable disease (yes vs. no), sum of all 


                                                          
 
                            
target lesion diameters, baseline CA-125, albumin value at baseline, PFS prior line, 
response to last platinum therapy (yes vs. no) and baseline global QoL. In addition, 
continuous variables categorized as discrete variables will also be investigated in the 
continuum range and if the adjustment is better then the continuous variable will be 
selected in the model. 
 
Original Text (Section 8.6 Imputation in Incomplete Dates): 
Dates of certain historical or current clinical activities...  
Before randomization 
 
All variables needed to summarize... 
 
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. 
 
Changes to (Section 8.6 Imputation in Incomplete Dates): 
Dates of certain historical or current clinical activities...  
Before randomization 
 
All variables needed to summarize... 
 
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. 
 
If the date of subsequent therapy is incomplete (day or month is missing) and the 


                                                          
 
                            
patient had documented disease progression, the date of subsequent therapy will be 
imputed to the end of the month when the progression occurred. If the subsequent 
therapy is given before progression to the study treatment, the rules specified above 
will apply. 
 
Table/listing added (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/PLD/Topotecan 
Table 10.1.9 Investigator’s preference for the control arm 
 
PM01183 
Topotecan 
PLD 
N 
% 
N 
% 
N 
% 
Topotecan 
 
 
 
 
 
 
PLD 
 
 
 
 
 
 
 
Original Text (Section 11.3 Efficacy Analysis): 
 
Table 11.3.1.1 PFS by IRC (primary analysis) 
Variable 
p-value* 
Treatment arm 
 
*Stratified log rank test. 
 
Changes to (Section 11.3 Efficacy Analysis): 
 
Table 11.3.1.1 PFS by IRC (primary analysis) 
Variable 
Stratification factors 
p-value* 
Treatment arm (main analysis) 
Actual values 
 
Treatment arm (sensitivity) 
Values reported for randomization 
 
*Stratified log rank test. 
 
Original Text (Section 11.3 Efficacy Analysis): 
 
Table 11.3.1.8 PFS by IA (Stratified log rank test) 
Variable 
p-value* 
Treatment arm 
 
*Stratified log rank test. 
 
Changes to (Section 11.3 Efficacy Analysis): 
 
Table 11.3.1.8 PFS by IA (Stratified log rank test) 
Variable 
Stratification factors 
p-value* 
Treatment arm (main analysis) 
Actual values 
 
Treatment arm (sensitivity) 
Values reported for randomization 
 
*Stratified log rank test. 
 
Original Text (Section 11.3 Efficacy Analysis): 
 
Table 11.3.1.22 OS (Stratified log rank test) 
Variable 
p-value* 
Treatment arm 
 
*Stratified log rank test. 
 


                                                          
 
                            
Changes to (Section 11.3 Efficacy Analysis): 
 
Table 11.3.1.22 OS (Stratified log rank test) 
Variable 
Stratification factors 
p-value* 
Treatment arm (main analysis) 
Actual values 
 
Treatment arm (sensitivity) 
Values reported for randomization 
 
*Stratified log rank test. 
Adds to (12.6 Concomitant Medication during Treatment) 
 
Table 12.6.4 Neutropenia by CSF, worst grade in the first cycle 
 
Grade 
CSF=YES 
CSF=NO 
0 
1 
… 
G≥1 
G≥3 
0 
1 
… 
G≥1 
G≥3 
N % N % N % N % N % N % N % N % N % N %
PM01183
PLD
Topotecan
 
Adds to (13 DB Listings) 
Shell listings based on the unique forms for eCRF dated on 13MAY2015 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.