Phase III Randomized Clinical Trial of Lurbinectedin (PM01183) Versus Pegylated Liposomal Doxorubicin or Topotecan in Patients With Platinum-resistant Ovarian Cancer (CORAIL Trial)
Phase: PHASE3
Conditions: Ovarian Cancer
Sponsor: PharmaMar

 
 
 
 
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.
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PRINCIPAL INVESTIGATORS
A full list of Investigators will be available as a separate document. 
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TABLE OF CONTENTS
STUDY CONTACTS .................................................................................................................................2
PRINCIPAL INVESTIGATORS..............................................................................................................4
SYNOPSIS ..................................................................................................................................................8
SCHEDULE OF ASSESSMENTS AND PROCEDURES....................................................................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
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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
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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
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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 
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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. 
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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.
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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. 
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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.
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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.
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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
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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
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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).
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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.
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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.
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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.
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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.
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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.
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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 
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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 
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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. 
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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.
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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 
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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.
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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.
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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

-
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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.
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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
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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
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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
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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 
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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.
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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 
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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
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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 
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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 
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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 
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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 
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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 
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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.
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ically 
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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.
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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 
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v.1.1
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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, 
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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 
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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.
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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 
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Patie
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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 
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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.
-
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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). 
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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.*
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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.
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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.
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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.
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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 
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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
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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). 
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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).
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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.
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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.
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6.8
DRUG ACCOUNTABILITY
Proper drug accountability will be done by the appropriate trained study personnel. 
Each study site will keep records to allow a comparison of quantities of drug received 
and used at each site for monitoring purposes. The Investigator at each study site will be 
the person ultimately responsible for drug accountability at the site.   
All unused drug supplied by the Sponsor will be properly destroyed at the study site. 
Documentation of this procedure must be provided to the clinical trial monitor. If the 
Sponsor agrees, unused drug supplies may be returned to the drug repository.
6.9
TREATMENT COMPLIANCE
The Investigator is ultimately responsible for supervising compliance with the 
instructions described in this study protocol.
7.
STUDY EVALUATIONS
7.1
EFFICACY
The primary aim of this clinical trial is to determine 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.
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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.
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“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 
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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 
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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.
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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 
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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 
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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: 
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
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. 
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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.
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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.
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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.
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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.
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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. 
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9.8
USE OF INFORMATION AND PUBLICATION
Before the investigators of this study submit a paper or abstract for publication or 
otherwise publicly disclose information concerning the study drug or products, Pharma 
Mar S.A. must be provided with at least 60 days to revise and approve the proposed 
publication or disclosure to ensure that confidential and proprietary data are protected.
If Pharma Mar S.A. determines that patentable patient matter is disclosed in the 
proposed publication or disclosure, the publication or disclosure will be withheld for a 
period of time considered convenient. If the study is part of a multicenter study, the first 
publication of the study shall be made in conjunction with the presentation of a joint, 
multicenter publication of the study results with the investigators and the institutions 
from all appropriate sites that are contributing data, analysis and comments. However, if 
such a multicenter publication is not submitted within 12 months after conclusion, 
abandonment or termination of the study at all sites, the present study may be published 
individually in accordance with the procedure established above.
The order of the coauthors will reflect the relative contribution of each one to study 
development and analysis. In general, the first author will be the investigator who 
recruits the highest number of patients with information finally available for data 
analysis. Relevant Pharma Mar S.A. personnel who have fully participated in the study 
must be considered for co-authorship of the publication.
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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.
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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.
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11. APPENDICES
APPENDIX 1: ECOG PERFORMANCE STATUS ASSESSMENT SCALE
Grade
ECOG PS*
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light house work, office work
2
Ambulatory and capable of all self-care but unable to carry out any work 
activities. Up and about more than 50% of waking hours
3
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours
4
Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair
5
Dead
*As published in Am. J. Clin. Oncol 5:649-655, 1982: Oken, M.M., Creech, R.H., Tormey, D.C., Horton, 
J., Davis, T.E., McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern 
Cooperative Oncology Group. 
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APPENDIX 2: EVALUATION OF RESPONSE. THE RECIST.
This document summarizes the main information contained in RECIST version 1.1. 
Further details can be found in the original article: Eisenhauer EA, Therasse P, 
Bogaerts J, et al.: New response evaluation criteria in solid tumours: revised RECIST 
guideline (version 1.1). Eur J Cancer 2009; 45(2): 228-247.2
LIST OF ABBREVIATIONS
CR
Complete Response
CRF
Case Report Form
CT
Computed Tomography
FDG-PET
Fluorodeoxyglucose-Positron Emission Tomography
MRI
Magnetic Resonance Imaging
NE
Not Evaluable
PD
Progressive Disease
PET
Positron Emission Tomography
PFS
Progression-free Survival
PR
Partial Response
PSA
Prostate-specific Antigen
RECIST
Response Evaluation Criteria in Solid Tumors
SD
Stable Disease
TTP
Time to Progression
LIST OF TABLES
Table 1. Summary of major changes from RECIST 1.0 to RECIST 1.13.
Table 2. Time point response: patients with target (+/–non-target) disease.
Table 3. Time point response: patients with non-target disease only.
Table 4.  Best overall response when confirmation of complete response (CR) and 
partial response (PR) is  required.
                                                
2 A summary of major changes from RECIST 1.0 to RECIST 1.1 can be found at the beginning of this 
document (Table 1).
3This table is named Appendix I in the original RECIST 1.1 article.
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The main changes from RECIST 1.0 to RECIST 1.1 are shown in the following table.
Table 1. Summary of major changes from RECIST 1.0 to RECIST 1.1.
RECIST 1.0
RECIST 1.1
Rationale
Minimum size 
measurable 
lesions 
CT: 10 mm spiral 
20 mm non-spiral 
CT 10 mm; delete 
reference to 
spiral scan 
Most scans used have 5 mm or less 
slice thickness. Clearer to give 
instruction based on slice interval 
if it is greater than 5 mm 
Clinical: 20 mm 
Clinical: 10 mm 
(must be measurable 
with calipers) 
Caliper measurement will make 
this reliable 
Lymph node: not 
mentioned 
CT: 
≥ 15 mm short axis 
for target 
≥ 10–<15 mm for 
non-target 
< 10 mm is non-
pathological 
Since nodes are normal structure 
need to define pathological 
enlargement. Short axis is most 
sensitive 
Special 
considerations on 
lesion measurability 
–
Notes included on 
bone lesions, cystic 
lesions 
Clarify frequently asked questions 
Overall tumor 
burden 
10 lesions (5 per organ) 5 lesions (2 per 
organ) 
Data warehouse analysis shows no 
loss of information if lesion 
number reduced from 10 to 5. A 
maximum of 2 lesions per organ 
yields sufficient representation per 
disease site 
Response criteria 
target 
disease 
CR lymph node not 
mentioned 
CR lymph nodes 
must be <10 mm 
short axis 
In keeping with normal size of 
nodes 
PD 20% increase over 
smallest sum on 
study or new lesions 
PD 20% increase 
over smallest sum on 
study (including 
baseline if that is 
smallest) and 
at least 5 mm 
increase or new 
lesions 
Clarification that if baseline 
measurement is smaller than any 
on study measurement, it is 
reference against which PD is 
assessed 5 mm absolute increase to 
guard against over  calling PD 
when total sum is very small and 
20% increase is within 
measurement error 
Response criteria 
non-target 
disease 
‘Unequivocal 
progression’ 
considered as PD 
More detailed 
description of 
‘unequivocal 
progression’ to 
indicate that it should 
not normally trump 
target disease 
status. It must be 
representative of 
overall disease status 
change, not a single 
lesion increase 
Confusion with RECIST 1.0 where 
some were considering PD if 
‘increase’ in any non-target lesion, 
even when target disease is stable 
or responding 
New lesions 
–
New section on New 
lesions 
To provide guidance on when a 
lesion is considered new (and thus 
PD) 
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RECIST 1.0
RECIST 1.1
Rationale
Overall response 
Table integrated target 
and non-target 
lesions 
Two tables: one 
integrating target and 
non-target and the 
other of non-target 
only 
Special notes: 
How to assess and 
measure lymph nodes 
CR in face of residual 
tissue 
Discussion of 
‘equivocal’ 
progression 
To account for the fact that 
RECIST criteria are now being 
used in trials where PFS is the 
endpoint and not all patients have 
measurable (target) disease at 
baseline 
Frequently asked questions on 
these topics 
Confirmatory 
measure 
For CR and PR: criteria 
must be met again 4 
weeks after initial 
documentation 
Retain this 
requirement ONLY 
for non-randomized 
trials with  primary 
endpoint of response 
Data warehouse shows that 
response rates rise when 
confirmation is eliminated, but the 
only circumstance where this is 
important is in trials where there is 
no concurrent comparative control 
and where this measure is the 
primary endpoint 
Progression-free 
survival 
General comments only More specific 
comments on 
use of PFS (or 
proportion 
progression-free) as 
phase II endpoint 
Greater detail on PFS 
assessment in phase 
III trials 
Increasing use of PFS in phase III 
trials requires guidance on 
assessment of PD in patients with 
non-measurable disease 
Reporting of 
response 
results 
9 categories suggested 
for 
reporting phase II 
results 
Divided into phase II 
and phase III 
9 categories 
collapsed into 5 
In phase III, guidance 
given about reporting 
response 
Simplifies reporting and clarifies 
how to report phase II and III data 
consistently 
Response in phase 
III 
trials 
More relaxed 
guidelines 
possible if protocol 
specified 
This section removed 
and referenced in 
section 
above: no need to 
have different criteria 
for phase II and III 
Simplification of response 
assessment by reducing number of 
lesions and eliminating need for 
confirmation in randomized studies 
where response is not the primary 
endpoint makes separate ‘rules’ 
unnecessary 
Imaging appendix 
Appendix I 
Appendix II: updated 
with detailed 
guidance on use of 
MRI, PET/CT 
Other practical 
guidance included
Evolving use of newer modalities 
addressed. Enhanced guidance in 
response to frequent questions and 
from radiology review experience 
New appendices 
Appendix I: 
comparison of 
RECIST 1.0 and 1.1 
Appendix III: 
frequently asked 
questions
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RECIST 1.0
RECIST 1.1
Rationale
CR, complete response; CT, computed tomography; MRI, magnetic resonance imaging; RECIST, response 
evaluation criteria in solid tumors; PD, progressive disease; PET, positron emission tomography; PFS, progression-
free survival; PR, partial response.
1. MEASURABILITY OF TUMOR LESIONS AT BASELINE
1.1 Definitions
At baseline, tumor lesions/lymph nodes will be categorized as measurable or non-
measurable as follows:
1.1.1 Measurable
Tumor Lesions:
Must be accurately measured in at least one dimension (longest diameter in the plane of 
measurement is to be recorded) with a minimum size of: 

10 mm by computed tomography (CT) scan (irrespective of scanner type) 
and magnetic resonance imaging (MRI) (no less than double the slice 
thickness and a minimum of 10 mm).

10 mm caliper measurement by clinical exam (when superficial). 

20 mm by chest X-ray (if clearly defined and surrounded by aerated lung).
Malignant Lymph Nodes:
To be considered pathologically enlarged and measurable, a lymph node must be ≥ 15 
mm in short axis when assessed by CT scan (CT scan slice thickness recommended to 
be no greater than 5 mm). At baseline and in follow-up, only the short axis will be 
measured and followed (see Schwartz et al. Eur J Cancer. 2009; 45(2):261-267). See 
also notes below on ‘Baseline documentation of target and non-target lesions’ for 
information on lymph node measurement. 
1.1.2 Non-measurable
All other lesions, including small lesions (longest diameter < 10 mm or pathological 
lymph nodes with ≥ 10 to < 15 mm short axis) as well as lesions considered truly non-
measurable. Lesions considered truly non-measurable include: leptomeningeal disease, 
ascites, pleural or pericardial effusion, inflammatory breast disease, lymphangitic 
involvement of skin or lung, and abdominal masses/abdominal organomegaly identified 
by physical exam that is not measurable by reproducible imaging techniques. 
1.1.3 Special Considerations Regarding Lesion Measurability
Bone lesions, cystic lesions, and lesions previously treated with local therapy require 
particular comment:
Bone Lesions:

Bone scan, positron emission tomography (PET) scan or plain films are not 
considered adequate imaging techniques to measure bone lesions. However, 
these techniques can be used to confirm the presence or disappearance of bone 
lesions. 

Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, that can be evaluated by cross sectional imaging techniques such as 
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CT or MRI can be considered as measurable lesions if the soft tissue component
meets the definition of measurability described above.

Blastic bone lesions are non-measurable.
Cystic Lesions:

Lesions that meet the criteria for radiographically defined simple cysts should 
not be considered as malignant lesions (neither measurable nor non-measurable) 
since they are, by definition, simple cysts.

‘Cystic lesions’ thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the definition of measurability described above. 
However, if non-cystic lesions are present in the same patient, these are 
preferred for selection as target lesions.
Lesions with Prior Local Treatment:

Tumor lesions situated in a previously irradiated area, or in an area subjected to 
other loco-regional therapy, are usually not considered measurable unless there 
has been demonstrated progression in the lesion. Study protocols should detail 
the conditions under which such lesions would be considered measurable.
1.2. Specifications by Methods of Measurement
1.2.1 Measurement of Lesions
All measurements should be recorded in metric notation, using calipers if clinically 
assessed. All baseline evaluations should be performed as close as possible to the 
treatment start and never more than four weeks before the beginning of the treatment.
1.2.2 Method of Assessment
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. Imaging based 
evaluation should always be done rather than clinical examination unless the lesion(s) 
being followed cannot be imaged but are assessable by clinical exam.
Clinical Lesions: 
Clinical lesions will only be considered measurable when they are superficial and ≥ 10 
mm diameter as assessed using calipers (e.g., skin nodules). For the case of skin lesions, 
documentation by color photography including a ruler to estimate the size of the lesion 
is suggested. As noted above, when lesions can be evaluated by both clinical exam and 
imaging, imaging evaluation should be undertaken since it is more objective and may 
also be reviewed at the end of the study.
Chest X-Ray: 
Chest CT is preferred over chest X-ray, particularly when progression is an important 
endpoint, since CT is more sensitive than X-ray, particularly in identifying new lesions. 
However, lesions on chest X-ray may be considered measurable if they are clearly 
defined and surrounded by aerated lung. See original article, Appendix II, for more 
details.
Computed Tomography (CT), Magnetic Resonance Imaging (MRI):
CT is the best currently available and reproducible method to measure lesions selected 
for response assessment. This guideline has defined measurability of lesions on CT scan 
based on the assumption that CT slice thickness is 5 mm or less. As is described in 
original article (Appendix II), when CT scans have slice thickness greater than 5 mm, 
the minimum size for a measurable lesion should be twice the slice thickness. MRI is 
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also acceptable in certain situations (e.g., for body scans). More details concerning the 
use of both CT and MRI for assessment of objective tumor response evaluation are 
provided in the original article, Appendix II.
Ultrasound:
Ultrasound is not useful in assessment of lesion size and should not be used as a method 
of measurement. Ultrasound examinations cannot be reproduced in their entirety for 
independent review at a later date and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken from one 
assessment to the next (described in greater detail in the original article, Appendix II). If 
new lesions are identified by ultrasound in the course of the study, confirmation by CT 
or MRI is advised. If there is concern about radiation exposure at CT, MRI may be used 
instead of CT in selected instances.
Endoscopy, Laparoscopy: 
The use of these techniques for objective tumor evaluation is not advised. However, 
they can be useful to confirm complete pathological response when biopsies are 
obtained or to determine relapse in trials where recurrence following complete response 
or surgical resection is an endpoint.
2. TUMOR RESPONSE EVALUATION
2.1 Assessment of Overall Tumor Burden and Measurable Disease
To assess objective response or future progression, it is necessary to estimate the overall 
tumor burden at baseline and use this as a comparator for subsequent measurements. 
Only patients with measurable disease at baseline should be included in protocols where 
objective tumor response is the primary endpoint. Measurable disease is defined by the 
presence of at least one measurable lesion (as detailed above in Section 1. Measurability 
of tumor at baseline). In studies where the primary endpoint is tumor progression (either 
time to progression or proportion with progression at a fixed date), the protocol must 
specify if entry is restricted to those with measurable disease or whether patients having 
non-measurable disease only are also eligible.
2.2 Baseline Documentation of “Target” and “Non-target” Lesions
When more than one measurable lesion is present at baseline, all lesions up to a 
maximum of ﬁve lesions total (and a maximum of two lesions per organ) representative 
of all involved organs should be identiﬁed as target lesions and will be recorded and 
measured at baseline (this means in instances where patients have only one or two organ 
sites involved that a maximum of two and four lesions will be recorded, respectively). 
For evidence to support the selection of only ﬁve target lesions, see analyses on a large 
prospective database in the article by Bogaerts et al. Eur J Cancer 2009;45:248–260. 
Target lesions should be selected on the basis of their size (lesions with the longest 
diameter), be representative of all involved organs, but in addition should be those that 
lend themselves to reproducible repeated measurements. It may be the case that, on 
occasion, the largest lesion does not lend itself to reproducible measurement, in which 
circumstance the next largest lesion which can be measured reproducibly should be 
selected. To illustrate this point see the example in the original article, Figure 3 of 
Appendix II. 
Lymph nodes merit special mention since they are normal anatomical structures which 
may be visible by imaging even if not involved by tumor. As noted in the previous 
section, pathological nodes which are defined as measurable and may be identified as 
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target lesions must meet the criterion of a short axis of ≥ 15 mm by CT scan. Only the 
short axis of these nodes will contribute to the baseline sum. The short axis of the node 
is the diameter normally used by radiologists to judge if a node is involved by solid 
tumor. Nodal size is normally reported as two dimensions in the plane in which the 
image is obtained (for CT scan this is almost always the axial plane; for MRI the plane 
of acquisition may be axial, sagittal or coronal). The smaller of these measures is the 
short axis. For example, an abdominal node which is reported as being 20 mm x 30 mm 
has a short axis of 20 mm and qualifies as a malignant, measurable node. In this 
example, 20 mm should be recorded as the node measurement (see also the example in 
the original article, Figure 4 of Appendix II). All other pathological nodes (those with 
short axis ≥ 10 mm but < 15 mm) should be considered non-target lesions. Nodes that 
have a short axis < 10 mm are considered non-pathological and should not be recorded 
or followed. 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for 
all target lesions will be calculated and reported as the baseline sum diameters. If lymph 
nodes are to be included in the sum, then as noted above, only the short axis is added 
into the sum. The baseline sum diameters will be used as reference to further 
characterize any objective tumor regression in the measurable dimension of the disease.
All other lesions (or sites of disease) including pathological lymph nodes should be 
identified as non-target lesions and should also be recorded at baseline. Measurements 
are not required and these lesions should be followed as ‘present’, ‘absent’, or in rare 
cases ‘unequivocal progression’ (more details to follow). In addition, it is possible to 
record multiple non-target lesions involving the same organ as a single item on the case 
record form (e.g., ‘multiple enlarged pelvic lymph nodes’ or ‘multiple liver 
metastases’).
2.3 Response Criteria
This section provides the definitions of the criteria used to determine objective tumor 
response for target lesions.
2.3.1 Evaluation of Target Lesions
Complete Response (CR):
Disappearance of all target lesions. Any pathological 
lymph nodes   (whether target or non-target) must have 
reduction in short axis to < 10 mm.
Partial Response (PR):
At least a 30% decrease in the sum of diameters of target 
lesions, taking as reference the baseline sum diameters.
Progressive Disease (PD):
At least a 20% increase in the sum of diameters of target 
lesions, taking as reference the smallest sum on study 
(this includes the baseline sum if that is the smallest on 
study). In addition to the relative increase of 20%, the 
sum must also demonstrate an absolute increase of at least 
5 mm. (Note: the appearance of one or more new lesions 
is also considered progression). 
Stable Disease (SD):
Neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD taking as reference 
the smallest sum diameters while on study.
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2.3.2 Special Notes on the Assessment of Target Lesions
Lymph Nodes:
Lymph nodes identified as target lesions should always have the actual short axis 
measurement recorded (measured in the same anatomical plane as the baseline 
examination), even if the nodes regress to below 10 mm on study. This means that when 
lymph nodes are included as target lesions, the ‘sum’ of lesions may not be zero even if 
complete response criteria are met, since a normal lymph node is defined as having a 
short axis of < 10 mm. Case report forms (CRFs) or other data collection methods may 
therefore be designed to have target nodal lesions recorded in a separate section where, 
in order to qualify for CR, each node must achieve a short axis < 10 mm. For PR, SD 
and PD, the actual short axis measurement of the nodes is to be included in the sum of 
target lesions.
Target Lesions that Become ‘Too Small to Measure’:
While on study, all lesions (nodal and non-nodal) recorded at baseline should have their 
actual measurements recorded at each subsequent evaluation, even when very small 
(e.g., 2 mm). However, sometimes lesions or lymph nodes which are recorded as target 
lesions at baseline become so faint on CT scan that the radiologist may not feel 
comfortable assigning an exact measure and may report them as being ‘too small to 
measure’. When this occurs it is important that a value be recorded on the CRF. If it is 
the opinion of the radiologist that the lesion has likely disappeared, the measurement 
should be recorded as 0 mm. If the lesion is believed to be present and is faintly seen 
but too small to measure, a default value of 5 mm should be assigned (Note: It is less 
likely that this rule will be used for lymph nodes since they usually have a definable size 
when normal and are frequently surrounded by fat such as in the retroperitoneum; 
however, if a lymph node is believed to be present and is faintly seen but too small to 
measure, a default value of 5 mm should be assigned in this circumstance as well). This 
default value is derived from the 5 mm CT slice thickness (but should not be changed 
with varying CT slice thickness). The measurement of these lesions is potentially non-
reproducible, therefore providing this default value will prevent false responses or 
progressions based upon measurement error. To reiterate, however, if the radiologist is 
able to provide an actual measure, that should be recorded, even if it is below 5 mm.
Lesions that Split or Coalesce on Treatment:
As noted in the original article, Appendix II, when non-nodal lesions ‘fragment’, the 
longest diameters of the fragmented portions should be added together to calculate the 
target lesion sum. Similarly, as lesions coalesce, a plane between them may be 
maintained that would aid in obtaining maximal diameter measurements of each 
individual lesion. If the lesions have truly coalesced such that they are no longer 
separable, the vector of the longest diameter in this instance should be the maximal 
longest diameter for the ‘coalesced lesion’.
2.3.3 Evaluation of Non-target Lesions
This section provides the definitions of the criteria used to determine the tumor response 
for the group of non-target lesions. While some non-target lesions may actually be 
measurable, they need not be measured and instead should be assessed only 
qualitatively at the time points specified in the protocol.
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Complete Response (CR):
Disappearance of all non-target lesions and normalization 
of tumor marker level. All lymph nodes must be non-
pathological in size (< 10 mm short axis).
Non-CR/Non-PD:
Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal 
limits. 
Progressive Disease (PD):
Unequivocal progression (see comments below) of 
existing non-target lesions (Note: the appearance of one or 
more new lesions is also considered progression).
2.3.4 Special Notes on Assessment of Progression of Non-target Disease
The concept of progression of non-target disease requires additional explanation as 
follows:
When the Patient Also Has Measurable Disease:
In this setting, to achieve ‘unequivocal progression’ on the basis of the non-target 
disease, there must be an overall level of substantial worsening in non-target disease 
such that, even in presence of SD or PR in target disease, the overall tumor burden has 
increased sufficiently to merit discontinuation of therapy (see examples in the original 
article, Appendix II and further details below). A modest ‘increase’ in the size of one or 
more non-target lesions is usually not sufficient to quality for unequivocal progression 
status. The designation of overall progression solely on the basis of change in non-target 
disease in the face of SD or PR of target disease will therefore be extremely rare.
When the Patient Has only Non-measurable Disease:
This circumstance arises in some phase III trials when it is not a criterion of study entry 
to have measurable disease. The same general concepts apply here as noted above, 
however, in this instance there is no measurable disease assessment to factor into the 
interpretation of an increase in non-measurable disease burden. Because worsening in 
non-target disease cannot be easily quantified (by definition: if all lesions are truly non-
measurable) a useful test that can be applied when assessing patients for unequivocal 
progression is to consider if the increase in overall disease burden based on the change 
in non-measurable disease is comparable in magnitude to the increase that would be 
required to declare PD for measurable disease: i.e., an increase in tumor burden 
representing an additional 73% increase in ‘volume’ (which is equivalent to a 20% 
increase diameter in a measurable lesion). Examples include an increase in a pleural 
effusion from ‘trace’ to ‘large’, an increase in lymphangitic disease from localized to 
widespread, or may be described in protocols as ‘sufficient to require a change in 
therapy’. Some illustrative examples are shown in the original article, Figures 5 and 6 of 
Appendix II. If ‘unequivocal progression’ is seen, the patient should be considered to 
have had overall PD at that point. While it would be ideal to have objective criteria to 
apply to non-measurable disease, the very nature of that disease makes it impossible to 
do so, therefore the increase must be substantial.
2.3.5 New Lesions
The appearance of new malignant lesions denotes disease progression; therefore, some 
comments on detection of new lesions are important. There are no speciﬁc criteria for 
the identiﬁcation of new radiographic lesions; however, the ﬁnding of a new lesion 
should be unequivocal: i.e., not attributable to differences in scanning technique, change 
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in imaging modality or ﬁndings thought to represent something other than tumor (for 
example, some ‘new’ bone lesions may be simply healing or ﬂare of pre-existing 
lesions). This is particularly important when the patient’s baseline lesions show PR or 
CR. For example, necrosis of a liver lesion may be reported on a CT scan report as a 
‘new’ cystic lesion, which it is not. 
A lesion identiﬁed on a follow-up study in an anatomical location that was not scanned 
at baseline is considered a new lesion and will indicate disease progression. An example 
of this is the patient who has visceral disease at baseline and while on study has a CT or 
MRI brain ordered which reveals metastases. The patient’s brain metastases are 
considered to be evidence of PD even if he/she did not have brain imaging at baseline. 
If a new lesion is equivocal, for example because of its small size, continued therapy 
and follow-up evaluation will clarify if it represents truly new disease. If repeat scans 
conﬁrm there is deﬁnitely a new lesion, then progression should be declared using the 
date of the initial scan. 
2.4 Evaluation of Best Overall Response
The best overall response is the best response recorded from the start of the study 
treatment until the end of treatment taking into account any requirement for 
conﬁrmation. On occasion a response may not be documented until after the end of 
therapy so protocols should be clear if post-treatment assessments are to be considered 
in determination of best overall response. Protocols must specify how any new therapy 
introduced before progression will affect best response designation. The patient’s best 
overall response assignment will depend on the ﬁndings of both target and non-target 
disease and will also take into consideration the appearance of new lesions. 
Furthermore, depending on the nature of the study and the protocol requirements, it may 
also 
require 
conﬁrmatory 
measurement 
(see 
Section 
2.6. 
Confirmatory 
Measurement/Duration of Response). Speciﬁcally, in non-randomized trials where 
response is the primary endpoint, conﬁrmation of PR or CR is needed to deem either 
one the ‘best overall response’. This is described further below. 
2.4.1 Time Point Response 
It is assumed that at each protocol speciﬁed time point, a response assessment occurs. 
Table 2 provides a summary of the overall response status calculation at each time point 
for patients who have measurable disease at baseline. 
Table 2. Time point response: patients with target (+/–non-target) disease.
Target lesions
Non-target lesions
New
lesions
Overall
response
CR
CR
No
CR
CR
Non-CR/non-PD
No
PR
CR
Not evaluated
No
PR
PR
Non-PD or not all evaluated
No
PR
SD
Non-PD or not all evaluated
No
SD
Not all evaluated
Non- PD
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
CR, complete response; NE, inevaluable; PD, progressive disease; PR, partial response; SD, stable disease. 
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When patients have non-measurable (therefore non-target) disease only, Table 3 is to be 
used. 
Table 3. Time point response: patients with non-target disease only.
Non-target lesions
New lesions
Overall response
CR
No
CR
Non-CR/non-PD
No
Non-CR/non-PDa
Not all evaluated
No
NE
Unequivocal PD
Yes or No
PD
Any
Yes
PD
CR, complete response, NE, inevaluable; PD, progressive disease. 
a ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is increasingly used as endpoint 
for assessment of efficacy in some trials; so, to assign this category when no lesions can be measured is not advised.
2.4.2 Missing Assessments and Inevaluable Designation
When no imaging/measurement is done at all at a particular time point, the patient is not 
evaluable (NE) at that time point. If only a subset of lesion measurements are made at 
an assessment, usually the case is also considered NE at that time point, unless a 
convincing argument can be made that the contribution of the individual missing 
lesion(s) would not change the assigned time point response. This would be most likely 
to happen in the case of PD. For example, if a patient had a baseline sum of 50 mm with 
three measured lesions and at follow-up only two lesions were assessed, but those gave 
a sum of 80 mm, the patient will have achieved PD status, regardless of the contribution 
of the missing lesion.
2.4.3 Best Overall Response: All Time Points 
The best overall response is determined once all the data for the patient is known.
Best Response Determination in Trials Where Conﬁrmation of Complete or Partial 
Response IS NOT Required: 
Best response in these trials is deﬁned as the best response across all time points (for 
example, a patient who has SD at ﬁrst assessment, PR at second assessment, and PD on 
last assessment has a best overall response of PR). When SD is believed to be best 
response, it must also meet the protocol speciﬁed minimum time from baseline. If the 
minimum time is not met when SD is otherwise the best time point response, the 
patient’s best response depends on the subsequent assessments. For example, a patient 
who has SD at ﬁrst assessment, PD at second and does not meet minimum duration for 
SD, will have a best response of PD. The same patient lost to follow-up after the ﬁrst 
SD assessment would be considered inevaluable. 
Best Response Determination in Trials Where Conﬁrmation of Complete or Partial 
Response IS Required: 
Complete or partial responses may be claimed only if the criteria for each are met at a 
subsequent time point as speciﬁed in the protocol (generally four weeks later). In this 
circumstance, the best overall response can be interpreted as in Table 4. 
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Table 4.  Best overall response when confirmation of complete response (CR) and partial 
response (PR) is  required.
Overall response.
First time point
Overall response.
Subsequent time point
BEST overall response
CR
CR
CR
CR
PR
SD, PD or PRa
CR
SD
SD provided minimum criteria for SD duration met, 
otherwise, PD
CR
PD
SD provided minimum criteria for SD duration met, 
otherwise, PD
CR
NE
SD provided minimum criteria for SD duration met, 
otherwise NE
PR
CR
PR
PR
PR
PR
PR
SD
SD
PR
PD
SD provided minimum criteria for SD duration met, 
otherwise, PD
PR
NE
SD provided minimum criteria for SD duration met, 
otherwise NE
NE
NE
NE
CR, complete response; NE, inevaluable; PD, progressive disease; PR, partial response; SD, stable disease. 
a If a CR is truly met at first time point, then any disease seen at a subsequent time point, even disease meeting PR 
criteria relative to baseline, makes the disease PD at that point (since disease must have reappeared after CR). Best 
response would depend on whether minimum duration for SD was met. However, sometimes ‘CR’ may be claimed 
when subsequent scans suggest small lesions were likely still present and in fact the patient had PR, not CR at the 
first time point. Under these circumstances, the original CR should be changed to PR and the best response is PR. 
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APPENDIX 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.
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4.
A weak inhibitor for a specific CYP is defined as an inhibitor that increases the AUC of a sensitive substrate for 
that CYP by less than 2-fold but equal to or more than 5-fold.
5.
Herbal product.
6.
Gemfibrozil also inhibits OATP1B1.
7.
Fluconazole is listed as a strong CYP2C19 inhibitor based on the AUC ratio of omeprazole, which is also 
metabolized by CYP3A; fluconazole is a moderate CYP3A inhibitor.
8.
Fluvoxamine strongly inhibits CYP1A2 and CYP2C19, but also inhibits CYP2C8/2C9 and CYP3A;
9.
Ticlopidine strongly inhibits CYP2C19, but also inhibits CYP3A, CYP2B6, and CYP1A2.
10. Effect seems to be due to CYP2C19 inhibition by ethinyl estradiol.
11. The effect of grapefruit juice varies widely among brands and is concentration-, dose-, and preparation-
dependent. Studies have shown that it can be classified as a “strong CYP3A inhibitor” when a certain 
preparation was used (e.g., high dose, double strength) or as a “moderate CYP3A inhibitor” when another 
preparation was used (e.g., low dose, single strength).
12. Withdrawn from the United States market because of safety reasons.
Table 2. Classification of In Vivo Inducers of CYP Enzymes (1)
CYP
enzymes
Strong Inducers
≥ 80% decrease in AUC
Moderate Inducers
50-80% decrease in AUC
Weak Inducers
20-50% decrease in AUC
CYP1A2
Montelukast, phenytoin, 
smokers versus non-smokers (2)
Moricizine, omeprazole, 
phenobarbital,
CYP2B6
Efavirenz, rifampin
Nevirapine
CYP2C8
Rifampin
CYP2C9
Carbamazepine,
rifampin
Aprepitant, bosentan, 
phenobarbital, St. John’s wort 
(3,4)
CYP2C19
Rifampin
Artemisinin
CYP3A
Avasimibe, (5) 
carbamazepine, phenytoin, 
rifampin, St. John’s wort 
(3)
Bosentan, efavirenz, etravirine, 
modafinil, nafcillin
Amprenavir, aprepitant, 
armodafinil, echinacea,(4)
pioglitazone, prednisone, 
rufinamide
CYP2D6
None known
None known
None known
1.
Please note the following: This is not an exhaustive list. For an updated list, see the following link: 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabelin
g/ucm080499.htm.
2.
For a drug that is a substrate of CYP1A2, the evaluation of the effect of induction of CYP1A2 can be 
carried out by comparative PK studies in smokers vs. non-smokers.
3.
The effect of St. John’s wort varies widely and is preparation-dependent.
4.
Herbal product.
5.
Not a marketed drug.
Table 3. Examples (1) of Sensitive In Vivo CYP Substrates and CYP Substrates with 
Narrow Therapeutic Range
CYP
enzymes
Sensitive substrates (2)
Substrates with
narrow therapeutic range (3)
CYP1A2
Alosetron, caffeine,
duloxetine, melatonin, ramelteon,
tacrine, tizanidine
Theophylline, tizanidine
CYP2B6 (4)
Bupropion, efavirenz
CYP2C8
Repaglinide (5)
Paclitaxel
CYP2C9
Celecoxib
Warfarin, phenytoin
CYP2C19
Lansoprazole, omeprazole, S-mephenytoin
S-mephenytoin
CYP3A (6)
Alfentanil, aprepitant, budesonide, buspirone, conivaptan, 
darifenacin, darunavir, dasatinib, dronedarone, eletriptan, 
eplerenone, everolimus, felodipine, indinavir, fluticasone, 
lopinavir, lovastatin, lurasidone, maraviroc, midazolam, 
nisoldipine, quetiapine, saquinavir, sildenafil, simvastatin, 
sirolimus, tolvaptan, tipranavir, triazolam, vardenafil
Alfentanil, astemizole, (7) 
cisapride, (7) cyclosporine, 
dihydroergotamine, ergotamine, 
fentanyl, pimozide, quinidine, 
sirolimus, tacrolimus,
terfenadine (7)
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CYP
enzymes
Sensitive substrates (2)
Substrates with
narrow therapeutic range (3)
CYP2D6
Atomoxetine, desipramine,
dextromethorphan, metoprolol,
nebivolol, perphenazine, tolterodine,
venlafaxine
Thioridazine
1.
Note that this is not an exhaustive list.
For an updated list, see the following link: 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabe
ling/ucm080499.htm.
2.
Sensitive CYP substrates refers to drugs whose plasma AUC values have been shown to increase 5-fold 
or higher when co-administered with a known CYP inhibitor.
3.
CYP substrates with narrow therapeutic range refers to drugs whose exposure-response relationship 
indicates that small increases in their exposure levels by the concomitant use of CYP inhibitors may lead 
to serious safety concerns (e.g., Torsades de Pointes).
4.
The AUC of these substrates were not increased by 5-fold or more with a CYP2B6 inhibitor, but they 
represent the most sensitive substrates studied with available inhibitors evaluated to date.
5.
Repaglinide is also a substrate for OATP1B1, and it is only suitable as a CYP2C8 substrate if the 
inhibition of OATP1B1 by the investigational drug has been ruled out.
6.
Because a number of CYP3A substrates (e.g., darunavir, maraviroc) are also substrates of P-gp, the 
observed increase in exposure could be due to inhibition of both CYP3A and P-gp.
7.
Withdrawn from the United States market because of safety reasons.
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APPENDIX 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.
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6.
The primary purpose of medical research involving human subjects is to 
understand the causes, development and effects of diseases and improve 
preventive, diagnostic and therapeutic interventions (methods, procedures and 
treatments). Even the best proven interventions must be evaluated continually 
through research for their safety, effectiveness, efficiency, accessibility and 
quality.
7.
Medical research is subject to ethical standards that promote and ensure respect 
for all human subjects and protect their health and rights.
8.
While the primary purpose of medical research is to generate new knowledge, 
this goal can never take precedence over the rights and interests of individual 
research subjects.
9.
It is the duty of physicians who are involved in medical research to protect the 
life, health, dignity, integrity, right to self-determination, privacy, and 
confidentiality of personal information of research subjects. The responsibility 
for the protection of research subjects must always rest with the physician or 
other health care professionals and never with the research subjects, even though 
they have given consent.
10.
Physicians must consider the ethical, legal and regulatory norms and standards 
for research involving human subjects in their own countries as well as 
applicable international norms and standards. No national or international 
ethical, legal or regulatory requirement should reduce or eliminate any of the 
protections for research subjects set forth in this Declaration.
11.
Medical research should be conducted in a manner that minimises possible harm 
to the environment.
12.
Medical research involving human subjects must be conducted only by 
individuals with the appropriate ethics and scientific education, training and 
qualifications. Research on patients or healthy volunteers requires the 
supervision of a competent and appropriately qualified physician or other health 
care professional.
13.
Groups that are underrepresented in medical research should be provided 
appropriate access to participation in research.
14.
Physicians who combine medical research with medical care should involve 
their patients in research only to the extent that this is justified by its potential 
preventive, diagnostic or therapeutic value and if the physician has good reason 
to believe that participation in the research study will not adversely affect the 
health of the patients who serve as research subjects.
15.
Appropriate compensation and treatment for subjects who are harmed as a result 
of participating in research must be ensured.
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Risks, Burdens and Benefits
16.
In medical practice and in medical research, most interventions involve risks and 
burdens.
Medical research involving human subjects may only be conducted if the 
importance of the objective outweighs the risks and burdens to the research 
subjects.
17.
All medical research involving human subjects must be preceded by careful 
assessment of predictable risks and burdens to the individuals and groups 
involved in the research in comparison with foreseeable benefits to them and to 
other individuals or groups affected by the condition under investigation.
Measures to minimise the risks must be implemented. The risks must be 
continuously monitored, assessed and documented by the researcher.
18.
Physicians may not be involved in a research study involving human subjects 
unless they are confident that the risks have been adequately assessed and can be 
satisfactorily managed.
When the risks are found to outweigh the potential benefits or when there is 
conclusive proof of definitive outcomes, physicians must assess whether to 
continue, modify or immediately stop the study.
Vulnerable Groups and Individuals
19.
Some groups and individuals are particularly vulnerable and may have an 
increased likelihood of being wronged or of incurring additional harm.
All vulnerable groups and individuals should receive specifically considered
protection.
20.
Medical research with a vulnerable group is only justified if the research is 
responsive to the health needs or priorities of this group and the research cannot 
be carried out in a non-vulnerable group. In addition, this group should stand to
benefit from the knowledge, practices or interventions that result from the 
research.
Scientific Requirements and Research Protocols
21.
Medical research involving human subjects must conform to generally accepted 
scientific principles, be based on a thorough knowledge of the scientific 
literature, other relevant sources of information, and adequate laboratory and, as 
appropriate, animal experimentation. The welfare of animals used for research 
must be respected.
22.
The design and performance of each research study involving human subjects 
must be clearly described and justified in a research protocol.
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The protocol should contain a statement of the ethical considerations involved 
and should indicate how the principles in this Declaration have been addressed. 
The protocol should include information regarding funding, sponsors, 
institutional affiliations, potential conflicts of interest, incentives for subjects and 
information regarding provisions for treating and/or compensating subjects who 
are harmed as a consequence of participation in the research study.
In clinical trials, the protocol must also describe appropriate arrangements for 
post-trial provisions.
Research Ethics Committees
23.
The research protocol must be submitted for consideration, comment, guidance
and approval to the concerned research ethics committee before the study 
begins. This committee must be transparent in its functioning, must be 
independent of the researcher, the sponsor and any other undue influence and 
must be duly qualified. It must take into consideration the laws and regulations 
of the country or countries in which the research is to be performed as well as 
applicable international norms and standards but these must not be allowed to 
reduce or eliminate any of the protections for research subjects set forth in this 
Declaration.
The committee must have the right to monitor ongoing studies. The researcher 
must provide monitoring information to the committee, especially information 
about any serious adverse events. No amendment to the protocol may be made 
without consideration and approval by the committee. After the end of the study, 
the researchers must submit a final report to the committee containing a 
summary of the study’s findings and conclusions.
Privacy and Confidentiality
24.
Every precaution must be taken to protect the privacy of research subjects and 
the confidentiality of their personal information.
Informed Consent
25.
Participation by individuals capable of giving informed consent as subjects in 
medical research must be voluntary. Although it may be appropriate to consult 
family members or community leaders, no individual capable of giving informed 
consent may be enrolled in a research study unless he or she freely agrees.
26.
In medical research involving human subjects capable of giving informed 
consent, each potential subject must be adequately informed of the aims, 
methods, sources of funding, any possible conflicts of interest, institutional 
affiliations of the researcher, the anticipated benefits and potential risks of the 
study and the discomfort it may entail, post-study provisions and any other 
relevant aspects of the study. The potential subject must be informed of the right 
to refuse to participate in the study or to withdraw consent to participate at any 
time without reprisal. Special attention should be given to the specific 
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information needs of individual potential subjects as well as to the methods used 
to deliver the information.
After ensuring that the potential subject has understood the information, the 
physician or another appropriately qualified individual must then seek the 
potential subject’s freely-given informed consent, preferably in writing. If the 
consent cannot be expressed in writing, the non-written consent must be 
formally documented and witnessed.
  
All medical research subjects should be given the option of being informed 
about the general outcome and results of the study.
27.
When seeking informed consent for participation in a research study the 
physician must be particularly cautious if the potential subject is in a dependent 
relationship with the physician or may consent under duress. In such situations 
the informed consent must be sought by an appropriately qualified individual 
who is completely independent of this relationship.
28.
For a potential research subject who is incapable of giving informed consent, the 
physician must seek informed consent from the legally authorised representative. 
These individuals must not be included in a research study that has no likelihood 
of benefit for them unless it is intended to promote the health of the group 
represented by the potential subject, the research cannot instead be performed 
with persons capable of providing informed consent, and the research entails 
only minimal risk and minimal burden.
29.
When a potential research subject who is deemed incapable of giving informed 
consent is able to give assent to decisions about participation in research, the 
physician must seek that assent in addition to the consent of the legally 
authorised representative. The potential subject’s dissent should be respected.
30.
Research involving subjects who are physically or mentally incapable of giving 
consent, for example, unconscious patients, may be done only if the physical or 
mental condition that prevents giving informed consent is a necessary 
characteristic of the research group. In such circumstances the physician must 
seek informed consent from the legally authorised representative. If no such 
representative is available and if the research cannot be delayed, the study may
proceed without informed consent provided that the specific reasons for 
involving subjects with a condition that renders them unable to give informed 
consent have been stated in the research protocol and the study has been 
approved by a research ethics committee. Consent to remain in the research must 
be obtained as soon as possible from the subject or a legally authorised 
representative.
31.
The physician must fully inform the patient which aspects of their care are 
related to the research. The refusal of a patient to participate in a study or the 
patient’s decision to withdraw from the study must never adversely affect the 
patient-physician relationship.
32.
For medical research using identifiable human material or data, such as research 
on material or data contained in biobanks or similar repositories, physicians 
must seek informed consent for its collection, storage and/or reuse. There may 
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be exceptional situations where consent would be impossible or impracticable to 
obtain for such research. In such situations the research may be done only after 
consideration and approval of a research ethics committee.
Use of Placebo
33.
The benefits, risks, burdens and effectiveness of a new intervention must be 
tested against those of the best proven intervention(s), except in the following 
circumstances:
Where no proven intervention exists, the use of placebo, or no intervention, is 
acceptable; or
Where for compelling and scientifically sound methodological reasons the use of 
any intervention less effective than the best proven one, the use of placebo, or no 
intervention is necessary to determine the efficacy or safety of an intervention
and the patients who receive any intervention less effective than the best proven 
one, placebo, or no intervention will not be subject to additional risks of serious 
or irreversible harm as a result of not receiving the best proven intervention.
Extreme care must be taken to avoid abuse of this option.
Post-Trial Provisions
34.
In advance of a clinical trial, sponsors, researchers and host country 
governments should make provisions for post-trial access for all participants 
who still need an intervention identified as beneficial in the trial. This 
information must also be disclosed to participants during the informed consent 
process.
Research Registration and Publication and Dissemination of Results
35.
Every research study involving human subjects must be registered in a publicly 
accessible database before recruitment of the first subject.
36.
Researchers, authors, sponsors, editors and publishers all have ethical 
obligations with regard to the publication and dissemination of the results of 
research. Researchers have a duty to make publicly available the results of their 
research on human subjects and are accountable for the completeness and 
accuracy of their reports. All parties should adhere to accepted guidelines for 
ethical reporting. Negative and inconclusive as well as positive results must be 
published or otherwise made publicly available. Sources of funding, institutional 
affiliations and conflicts of interest must be declared in the publication. Reports 
of research not in accordance with the principles of this Declaration should not 
be accepted for publication.
Unproven Interventions in Clinical Practice
37.
In the treatment of an individual patient, where proven interventions do not exist 
or other known interventions have been ineffective, the physician, after seeking 
expert advice, with informed consent from the patient or a legally authorised 
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representative, may use an unproven intervention if in the physician's judgement 
it offers hope of saving life, re-establishing health or alleviating suffering. This 
intervention should subsequently be made the object of research, designed to 
evaluate its safety and efficacy. In all cases, new information must be recorded 
and, where appropriate, made publicly available.
Disclaimer: ©2013 World Medical Association, Inc. All Rights Reserved. All intellectual property rights 
in the Declaration of Helsinki are vested in the World Medical Association. Previous permissions granted 
to publish or reproduce otherwise WMA policy don’t apply to this version of the Declaration of Helsinki 
until January 1st, 2014. For further questions, please contact the WMA secretariat at 
secretariat@wma.net.
CL_0220 1.0
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Protocol PM1183-C-004-14