Clinical trial NCT01525589
Conditions: Breast Cancer
Keywords: Breast cancer PM01183 lurbinectedin Pharma Mar
Sponsor: PharmaMar
Start date: 2012-06-13; Completion date: 2018-10-01
Enrollment: 111 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
A Clinical Trial of PM01183 in Metastatic Breast Cancer to assess the antitumor activity of PM01183 ,to evaluate whether the presence of a known germline mutation in BRCA 1/2 predicts response to PM01183 in Metastatic Breast Cancer (MBC) patients, to evaluate the safety profile of this PM01183 to analyze the pharmacokinetics (PK) and PK/PD (pharmacokinetic/pharmacodynamic) correlations and to evaluate the pharmacogenomic (PGx) expression profile in tumor samples.

Detailed description:
A Multicenter Phase II Clinical Trial of PM01183 in BRCA 1/2-Associated or Unselected Metastatic Breast Cancer to assess the antitumor activity of PM01183 in terms of overall response rate (ORR), duration of response (DR),clinical benefit \[ORR or stable disease lasting over three months (SD \> 3 months)\], progression free survival (PFS), and one-year overall survival (1y-OS) and to evaluate whether the presence of a known germline mutation in BRCA 1/2 predicts response to PM01183 in MBC patients, to explore the activity of PM01183 in specific breast cancer subpopulations according to hormonal receptor status, HER-2 overexpression, number and/or type of prior therapies, or according to other available histological/molecular classifications, to evaluate the safety profile of this PM01183 administration schedule \[Day 1 every three weeks (q3wk)\] in this patient population, to analyze the pharmacokinetics (PK) of PM01183 in this patient population, to explore PK/PD (pharmacokinetic/ pharmacodynamic) correlations, if applicable and to evaluate the pharmacogenomic (PGx) expression profile of selected putative markers potentially predictive of response to PM01183, in tissues from tumor samples.

Arms: arm 1: None
Interventions: intervention 1: PM01183
Intervention descriptions: intervention 1: PM01183 drug product (DP) is presented as a lyophilized powder for concentrate for solution for infusion with two strengths: 1 mg/vial and 4 mg/vial

Protocol documents:
Prot_000.pdf: 
 
 
 
SPONSOR 
 
Pharma Mar, S.A. 
Avda de los Reyes, 1 
 
Polígono Industrial “La Mina” 
28770 Colmenar Viejo (Madrid), Spain 
Phone: + 34 918 466 000  
Fax:  
+ 34 918 466 003 
 
 
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 
 
 
 
A Multicenter Phase II Clinical Trial of PM01183 in BRCA 1/2-Associated or 
Unselected Metastatic Breast Cancer 
 
 
INVESTIGATIONAL MEDICINAL PRODUCT: PM01183 
Protocol No.: PM1183-B-003-11 
EudraCT No.: 2011-006108-11 
NCT Code: 01525589 
 
 
 
Protocol version 4.0 (including amendments #1 dated 3 December 2013, #2 dated 28 
October 2014, and #3 dated 8 March 2016) 
 


 
SPONSORS
Pharma Mar, S.A.
Avda. de los Reyes, 1
Polígono Industrial “La Mina”
28770 Colmenar Viejo (Madrid), Spain
Phone: + 34 91 846 6000
Fax :
+ 34 91 846 6003
Pharma Mar USA, Inc.
230 Park Avenue, suite 1000
New York, NY 10169, USA
Phone: +1 212 309 8737
Fax:
+1 646 435 5846
CLINICAL TRIAL PROTOCOL
PM1183-B-003-11
A Multicenter Phase II Clinical Trial of PM01183 in BRCA 1/2-Associated or 
Unselected Metastatic Breast Cancer
INVESTIGATIONAL MEDICINAL PRODUCT:
PM01183
Protocol Code:
PM1183-B-003-11
EudraCT No:
2011-006108-11
Protocol version 4.0 (including amendments #1 dated 3 December 2013, #2 
dated 28 October 2014, and #3 dated 8 March 2016)
This study will be conducted in compliance with the protocol, Good Clinical Practice (GCP)
and the applicable regulatory requirements.
Confidentiality statement
The information and data included in this protocol contain trade secrets and privileged or 
confidential information which is the property of the Sponsors. No person is authorized to 
make it public without written permission of the Sponsors. These restrictions on disclosure 
will apply equally to all future information supplied to you which is indicated as privileged 
or confidential. This material may be disclosed to and used by your staff and associates as it 
may be necessary to conduct the clinical study.


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


TABLE OF CONTENTS
STUDY CONTACTS ................................................................................................................................ 2
PRINCIPAL INVESTIGATORS............................................................................................................. 4
TABLE OF CONTENTS.......................................................................................................................... 5
SYNOPSIS ................................................................................................................................................. 7
SCHEDULE OF ASSESSMENTS AND PROCEDURES................................................................... 21
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS......................................................... 23
1.
INTRODUCTION ...................................................................................................................27
1.1.
Breast Cancer.................................................................................................................27
1.2.
Information On Study Drugs ..........................................................................................28
1.2.1.
PM01183................................................................................................................................. 28
1.2.1.1.
Non-clinical Data.......................................................................................................... 29
1.2.1.1.1.
Antineoplastic Activity In Vitro ............................................................................... 29
1.2.1.1.2.
Antineoplastic Activity In Vivo................................................................................ 29
1.2.1.2.
PM01183 Clinical Data................................................................................................. 30
1.3.
Study Rationale...............................................................................................................31
2.
OVERALL STUDY DESIGN..................................................................................................32
3.
STUDY OBJECTIVES............................................................................................................33
3.1.
Primary...........................................................................................................................33
3.2.
Secondary .......................................................................................................................33
4.
SELECTION OF PATIENTS ..................................................................................................33
4.1.
Inclusion Criteria ...........................................................................................................33
4.2.
Exclusion Criteria...........................................................................................................34
5.
TREATMENT .........................................................................................................................35
5.1.
Study Medications...........................................................................................................35
5.1.1.
Study Drug Formulation and Supply....................................................................................... 35
5.2.
Administration of Study Medications..............................................................................36
5.2.1.
Route of administration, starting dose, and schedule............................................................... 36
5.2.2.
Criteria for Treatment Continuation ........................................................................................ 36
5.2.3.
Dose Reduction ....................................................................................................................... 37
5.2.4.
Dose Escalation....................................................................................................................... 38
5.3.
Concomitant Medication ................................................................................................38
5.3.1.
Prophylactic Medications ........................................................................................................ 38
5.3.2.
Allowed Medications/Therapies.............................................................................................. 38
5.3.3.
Prohibited Medications/Therapies........................................................................................... 39
5.3.4.
Drug-drug Interactions ............................................................................................................ 39
5.3.5.
Protein Binding........................................................................................................................ 39
5.3.6.
Urinary Excretion.................................................................................................................... 40
5.4.
Drug Accountability .......................................................................................................40
5.5.
Treatment Compliance ...................................................................................................40
6.
PLAN OF THE STUDY...........................................................................................................40
6.1.
Duration of Study (Whole Population)...........................................................................40
6.2.
Duration of Study (Per Patient)......................................................................................40
6.2.1.
End of Treatment and Off-study.............................................................................................. 41
6.2.1.1.
End of Treatment .......................................................................................................... 41
6.2.1.2.
Reasons for End of Treatment....................................................................................... 41
6.2.1.3.
Off-study....................................................................................................................... 41
6.2.2.
Protocol Deviations ................................................................................................................. 42
6.3.
Screening Evaluations....................................................................................................42
6.4.
Patient Registration........................................................................................................44
6.5.
Patient Randomization ...................................................................................................44
6.6.
Evaluations During Treatment .......................................................................................44
6.7.
Evaluations at End of Treatment ....................................................................................46
6.8.
Follow-up after End-of-treatment Visit ..........................................................................47
6.9.
Study Completion (As a Whole - Clinical Cut-off)..........................................................47
6.10.
Replacement of Patients .................................................................................................47
7.
STUDY EVALUATIONS .......................................................................................................48


7.1.
Efficacy...........................................................................................................................48
7.2.
Safety ..............................................................................................................................48
8.
STATISTICAL METHODS ....................................................................................................49
8.1.
Endpoints........................................................................................................................49
8.1.1.
Primary Endpoint .................................................................................................................... 49
8.1.2.
Secondary Endpoints............................................................................................................... 49
8.2.
Sample Size.....................................................................................................................49
8.2.1.
Randomization......................................................................................................................... 50
8.3.
Statistical Analysis..........................................................................................................50
8.3.1.
Efficacy Analyses.................................................................................................................... 50
8.3.2.
Safety Analyses....................................................................................................................... 51
8.3.3.
Safety Stopping Rule............................................................................................................... 51
9.
PHARMACOKINETICS.........................................................................................................51
9.1.
Evaluation Of Pharmacokinetics....................................................................................52
9.2.
Pharmacokinetic Statistical Methods .............................................................................53
10.
PHARMACOGENOMIC SUBSTUDY...................................................................................53
11.
ADVERSE EVENTS ...............................................................................................................54
11.1.
Definitions ......................................................................................................................54
11.1.1.
Adverse Event (AE) ................................................................................................................ 54
11.1.2.
Serious Adverse Event (SAE) ................................................................................................. 54
11.1.2.1.
Death............................................................................................................................. 55
11.1.2.2.
Life-threatening Event .................................................................................................. 55
11.1.2.3.
Hospitalization or Prolongation of Hospitalization....................................................... 55
11.1.3.
Unlisted/Unexpected Adverse Event....................................................................................... 55
11.1.4.
Adverse Events Related to Study Drugs.................................................................................. 55
11.1.5.
Expedited Reporting................................................................................................................ 56
11.1.6.
Assessment of Causal Relationship to the Study Drug............................................................ 56
11.2.
Procedures......................................................................................................................56
11.2.1.
Reporting Adverse Events....................................................................................................... 56
11.2.2.
Reporting Serious Adverse Events .......................................................................................... 57
11.2.3.
Reporting Pregnancy Cases Occurred within the Clinical Trial .............................................. 57
11.3.
Adverse Events Monitoring.............................................................................................58
12.
ADMINISTRATIVE SECTION..............................................................................................59
12.1.
Ethics..............................................................................................................................59
12.2.
Monitoring, Auditing and Inspecting..............................................................................59
12.3.
Patient Informed Consent Form.....................................................................................60
12.4.
Confidentiality / Identification of Patients......................................................................60
12.5.
Case Report Forms.........................................................................................................61
12.6.
Insurance........................................................................................................................61
12.7.
Retention of Records.......................................................................................................61
12.8.
Use of Information and Publications..............................................................................61
13.
REFERENCES.........................................................................................................................63
APPENDICES ......................................................................................................................................... 65
APPENDIX 1. ECOG PERFORMANCE STATUS ASSESSMENT SCALE ................................... 65
APPENDIX 2. EVALUATION OF RESPONSE. THE RECIST........................................................ 66
APPENDIX 3. NATIONAL COMPREHENSIVE CANCER NETWORK (NCCN) CRITERIA 
FOR CONSIDERATION OF BRCA1/2 GENETIC TESTING.......................................................... 76
APPENDIX 4. LIST OF CYP1/CYP2/CYP3 INHIBITORS, INDUCERS AND SUBSTRATES.... 77
APPENDIX 5. DECLARATION OF HELSINKI ................................................................................ 80


SYNOPSIS
TITLE
A Multicenter Phase II Clinical Trial of PM01183 in BRCA 
1/2-Associated or Unselected Metastatic Breast Cancer
PROTOCOL CODE
PM1183-B-003-11
INVESTIGATORS / 
TRIAL LOCATION
A full list of investigators will be available as a separate 
document.
STUDY OBJECTIVES 
Primary:

To assess the antitumor activity of PM01183 in terms of 
overall response rate (ORR), according to RECIST 
v1.1, in each cohort of metastatic breast cancer (MBC) 
patients.
Secondary:

To further characterize the antitumor activity of 
PM01183 in terms of duration of response (DR),
clinical benefit [ORR or stable disease lasting over 
three months (SD > 3 months)], progression free 
survival (PFS), and one-year overall survival (1y-OS).

To evaluate whether the presence of a known germline 
mutation in BRCA 1/2 predicts response to PM01183 in 
MBC patients.

To explore the activity of PM01183 in specific breast 
cancer subpopulations according to hormonal receptor 
status, HER-2 overexpression, number and/or type of 
prior therapies, or according to
other available 
histological/molecular classifications/parameters.

To evaluate the safety profile of this PM01183 
administration schedule [Day 1 every three weeks 
(q3wk)] in this patient population.

To analyze the pharmacokinetics (PK) of PM01183 in 
this patient population.

To 
explore 
PK/PD 
(pharmacokinetic/
pharmacodynamic) correlations, if applicable.

To evaluate the pharmacogenomic (PGx) expression 
profile of selected putative markers potentially 
predictive of response to PM01183, in tissues from 
tumor samples.
STUDY DESIGN
This is a multicenter, open-label, exploratory, phase II clinical 
trial evaluating the efficacy and safety of PM01183 
administration to patients with previously treated MBC.
Two cohorts of patients with advanced breast cancer will be 
prospectively evaluated in the trial according to germline 
BRCA1/2 status (mutated [cohort A] vs. unselected [cohort 
B]). A third cohort (A1) will include advanced breast cancer 


patients with deleterious BRCA1/2 mutation who received 
prior treatment with poly (ADP-ribose) polymerase (PARP) 
inhibitors:

Cohort A (BRCA+ cohort): At least 53 evaluable patients 
with known deleterious BRCA1/2 mutation status at study 
entry. 

Cohort A1 (BRCA+/PARPi cohort): 20 evaluable patients 
with known deleterious BRCA1/2 mutation status and 
prior treatment with PARP inhibitors (PARPi). 

Cohort B (unselected cohort): At least 64 evaluable 
patients without known deleterious BRCA1/2 mutation 
status at study entry, i.e., either:
o
Patients known to have no deleterious BRCA1/2 
mutations (BRCA−), or
o
Patients whose BRCA 1/2 mutation status is 
unknown
(BRCA-UK). 
BRCA1/2 
germline 
mutation status will be assessed in all patients in 
this subgroup responding to PM01183 treatment.
An interim analysis based on the primary endpoint (ORR) is 
planned after 20 and 30 evaluable patients have been treated 
in cohorts A and B, respectively. No interim analysis is 
planned for cohort A1. If less than four out of 20 patients in 
Cohort A, or less than three out of 30 patients in Cohort B 
achieve an objective confirmed response (as per RECIST 
v1.1), recruitment to that cohort will be terminated. 
Otherwise, recruitment will continue until at least 53 and 64 
evaluable patients are included in cohort A and cohort B, 
respectively. Sample size and cohort design will be re-
evaluated at this point in order to estimate the 95% 
confidence interval (CI)
with the desired precision. 
Recruitment to either cohort (e.g., Cohort B) might be halted 
while interim analysis is being performed, if appropriate.
PATIENT ELIGIBILITY
Inclusion criteria
All patients
1. Women ≥ 18 and ≤ 75 years of age. 
2. Voluntary signed informed consent form (ICF), obtained 
before any specific study procedure. 
3. Histologically proven diagnosis of metastatic breast 
carcinoma. 
4.
No more than three prior chemotherapy-containing
regimens for MBC.
5. Patients with known HER-2 overexpressing tumors must 
have failed at least one prior trastuzumab-containing 
regimen for metastatic disease.
6. Measurable disease as defined by RECIST v1.1.
7. Eastern 
Cooperative 
Oncology 
Group 
(ECOG) 
performance status (PS) 0 or 1.
8. Adequate major organ function:


a. Hemoglobin ≥ 9 g/dl, prior red blood cell (RBC) 
transfusions are allowed
if clinically indicated; 
absolute neutrophil count (ANC) ≥ 1.5 x 109/l; and 
platelet count ≥ 100 x 109/l.
b. Alanine aminotransferase (ALT), and aspartate 
aminotransferase (AST) 3.0 x upper limit of normal 
(ULN).
c. Total bilirubin 1.5 x ULN or direct bilirubin 
ULN.
d. Albumin ≥ 3 g/dl.
e. Serum creatinine ≤ 1.5 x ULN.
f. Creatine phosphokinase (CPK) ≤ 2.5 x ULN.
9. Washout periods prior to Day 1 of Cycle 1: 
a. At least three weeks since the last chemotherapy (six 
weeks if therapy contained nitrosureas or systemic 
mitomycin C).
b. At least four weeks since the last monoclonal 
antibody (MAb) containing therapy or radiotherapy 
(RT) > 30 Gy.
c. At least one week since the last hormonal therapy.
d. At 
least 
two 
weeks 
since 
the 
last 
biological/investigational therapy (excluding MAbs) 
or palliative RT (≤ 10 fractions or ≤ 30 Gy total 
dose).
10. Grade ≤ 1 toxicity due to any previous cancer therapy 
according to the National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI-CTCAE, 
v4). Grade ≤ 2 is allowed in case of alopecia, skin toxicity, 
asthenia and/or peripheral sensory neuropathy.
11. Patients of child-bearing potential must agree to use a 
medically approved contraception method until at least six 
weeks after the last study drug administration.
Patients in Cohorts A and A1
12. Known deleterious germline mutation of BRCA1/2.
Patients in Cohort A1
13. Prior treatment with PARP inhibitors.
Exclusion criteria
All patients
1.
Prior treatment with PM01183 or trabectedin.
2.
Prior RT in more than 35% of the bone marrow.
3.
Prior or concurrent malignant disease unless in complete 
remission for more than five years. Exceptions are 
contralateral
ductal 
or 
lobular
breast 
carcinoma, 
adequately treated in situ carcinoma of the cervix, basal or 
squamous skin cell carcinoma, in situ melanoma, and in 
situ transitional bladder cell carcinoma, which are allowed 
to enter the study.
4.
Histology other than ductal or lobular carcinoma of the 


breast.
5.
Symptomatic, steroid requiring or progressive central 
nervous system (CNS) involvement. In case of known 
brain metastasis, clinical stability and lack of radiological
progression of lesions should be demonstrated for at least 
the immediate six weeks before study entry.
6.
Exclusively bone-limited disease.
7.
Relevant diseases
or clinical situations which may 
increase patient’s risk:
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 or treatment-requiring arrhythmia.
b.
Grade ≥ 3 dyspnea or daily intermittent oxygen 
requirement
c.
Active uncontrolled infection.
d.
Unhealed wound or presence of any external drainage.
e.
Chronically active hepatitis B virus (HBV) or hepatitis 
C virus (HCV).
f.
Immunocompromised patients, including those known 
to be infected by human immunodeficiency virus 
(HIV).
g.
Known 
myopathy 
or 
persistent 
CPK 
elevations 
> 
2.5 
x 
ULN 
in 
two 
different 
determinations performed one week apart.
8.
Pregnant or breastfeeding women.
9.
Impending need for RT (uncontrolled painful bone 
metastasis and/or risk of spinal cord compression).
10. Limitation of the patient’s ability to comply with the 
treatment or to follow-up the protocol.
Patients in Cohort B
11. Known deleterious germline mutation of BRCA1/2.
No. of patients
About 110 evaluable patients are expected to be finally 
included in the three cohorts: Cohort A (BRCA+), Cohort 
A1 (BRCA+/PARPi), and Cohort B (unselected).
No. of sites
This is a multicenter study. A full list of investigators will 
be available as a separate document.


STUDY DRUG
Formulation
PM01183 drug product (DP) is presented as a lyophilized 
powder for concentrate for solution for infusion with two 
strengths, 1 mg and 4 mg vials, which will be supplied by the 
Sponsors for the purposes of this study.
Before use, the 1-mg vial and 4-mg vial should be 
reconstituted with 2 ml and 8 ml of water for injection, 
respectively, to give a solution containing 0.5 mg/ml 
PM01183. For administration to patients as an i.v. infusion, 
reconstituted vials should be diluted either 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 1-mg and 4-mg vials 
and the reconstituted solution per ml is as follows: 
Component
PM01183
1 mg
PM01183
4 mg
Concentration per 
vial after 
reconstitution
PM01183
1.00 mg
4.00 mg
0.50 mg/ml
Sucrose
200.00 mg
800.00 mg
100.00 mg/ml
Lactic acid
5.52 mg
22.08 mg
2.76 mg/ml
Sodium hydroxide
1.28 mg
5.12 mg
0.64 mg/ml
Route of administration,
starting dose, and schedule
Patients included under protocol versions 1.0 and 2.0 will 
receive PM01183 intravenously (i.v.) as a one-hour infusion 
on Day 1 q3wk at a starting dose of 7.0 mg (FD) (three 
weeks = one treatment cycle).
Patients included from protocol version 3.0 onward (after 
implementation of amendment no. 2) will receive PM01183 
i.v. as a one-hour infusion on Day 1 q3wk at a starting dose 
of 3.5 mg/m2 (three weeks = one treatment cycle). Dose will 
be capped at BSA of 2.0 m2 (i.e., dose will not exceed 7 mg).
BSA will be calculated according to standard practice at each 
center.
PM01183 will be administered over a minimum total volume 
of 100 ml of solution for infusion (either on 5% glucose or 
0.9% sodium chloride) through a central catheter or over a 
minimum total volume of 250 ml if through a peripheral line, 
always over one hour at a fixed infusion rate.
Antiemetic prophylactic 
medication
Patients must
receive standard antiemetic prophylactic 
medication at least 30 minutes before the administration of 
PM01183, as follows:
Corticosteroids (dexamethasone i.v. or equivalent at 
institutional standard antiemetic doses)
Serotonin (5-HT3) antagonists (ondansetron 8 mg i.v. 
or equivalent)
If necessary and in addition to the above, any of the 
following could apply:
Administration of 10 mg of metoclopramide (or 
equivalent) every eight hours
Extended treatment with 5-HT3 antagonists and/or 


dexamethasone 
Aprepitant and directly related agents (e.g., fosaprepitant) are 
forbidden.
An optimal antiemetic prophylaxis is defined, for the 
purpose of safety evaluations, as any of the aforementioned 
medications at their respectively maximum dosages.
Treatment continuation 
criteria
If a patient does not meet the requirements for re-treatment on 
Day 1 of any following cycle, regardless of the reason, re-
assessments will be performed every 48-72 hours. Treatment 
will be then withheld, up to a maximum of three weeks 
beyond its due date, until appropriate recovery. 
Patients not meeting re-treatment criteria after a maximum 
three-week delay must be withdrawn from the trial, except in 
case of objective clinical benefit (upon Sponsors’ agreement). 
For any delay lasting more than one week due to treatment-
related toxicity (unless exclusively due to neutropenia), a dose 
reduction must be implemented upon recovery following the 
rules explained in the next section. Conversely, if the delay 
was exclusively due to neutropenia related to PM01183, 
treatment may continue without dose reduction but with
appropriate secondary prophylaxis with granulocyte colony-
stimulating factor (G-CSF).
Variable 
Re-treatment
Day 1 
ECOG-PS
≤ 2
Hemoglobin*
8.0 g/dl
ANC
1.5 x 109/l
Platelets
75 x 109/l
AST/ALT
3.0 x ULN
Total bilirubin or 
direct bilirubin
1.5 x ULN or
x ULN 
Albumin
2.7 g/dl
Serum creatinine
≤2.0 x ULN
CPK
Grade ≤ 1
Other non-hematological drug-related AEs 
(except isolated increased GGT and/or
AP¥, grade 3 asthenia lasting < 1 week, 
non-optimally treated nausea and/or 
vomiting) 
Grade ≤ 2
* Patients may receive packed red blood cells (PRBC) transfusion and/or 
erythropoietin (EPO) treatment, if clinically indicated, to increase/maintain 
adequate hemoglobin levels.
¥ Any grade accepted for non-drug-related increase of GGT and/or AP.
AE, adverse event; ANC, absolute neutrophil count; AP, alkaline phosphatase; 
AST/ALT, aspartate aminotransferase/alanine aminotransferase; CPK, creatinine 
phosphokinase; ECOG, Eastern Cooperative Oncology Group; GGT, gamma-
glutamyltransferase; PS, performance status; ULN, upper limit of normal.


Dose reduction criteria
Study treatment may continue with an appropriate dose 
reduction (see table below) if patient’s benefit is perceived by 
the Investigator (upon Sponsors’ agreement), even after the
patient experienced any of the following:

Grade ≥ 3 treatment-related non-hematological toxicity. 
Exceptions are: grade ≥ 3 nausea and/or vomiting not 
optimally treated, grade 3 asthenia lasting < 1 week, grade 
3 diarrhea lasting ≤ 2 days or not optimally treated, grade 
3-4 hypersensitivity and/or extravasation reactions, grade 
3 transient ALT/AST elevations which are rapidly 
reversible and not leading to subsequent delays, and/or not 
clinically relevant biochemical abnormalities [i.e., in 
gamma-glutamyltransferase (GGT), lactate dehydrogenase 
(LDH) and/or alkaline phosphatase (AP) levels], none of 
which require dose reduction to be implemented.

Grade 4 thrombocytopenia or grade 3 thrombocytopenia 
concomitantly with grade ≥3 bleeding.

Frequent or prolonged (>1 week) dose delays due to 
treatment-related toxicity.
Patients experiencing grade 4 neutropenia or febrile 
neutropenia during the preceding cycle, or treatment delays 
exclusively due to neutropenia that lasted > 1 week, may 
continue treatment without any dose reduction but must 
receive secondary prophylaxis with G-CSF instead. The G-
CSF 
secondary 
prophylaxis 
will 
be 
administrated 
subcutaneously at 300 μg/day for five consecutive days 
starting on Day +3 of the corresponding cycle. If despite 
appropriate G-CSF prophylaxis, grade 4 neutropenia or febrile 
neutropenia re-occurs, then dose reduction should be 
implemented.
The guidelines for dose reduction are shown in the table 
below:
Dose 
reduction
level*
PM01183 dose (mg, FD)
Patients included under 
protocol versions 1.0, 2.0
PM01183 dose (mg/m2)
Patients included from
protocol version 3.0
onward**
  1
7.0
3.5
−1
6.0
2.6
−2
5.0
2.0
* Except for grade ≥ 3 nausea and/or vomiting not optimally treated, grade 3 
asthenia lasting < 1 week, grade 3 diarrhea lasting ≤ 2 days or not optimally 
treated, grade 3-4 hypersensitivity and/or extravasation reactions, grade 3 
transient ALT/AST elevations which are rapidly reversible and not leading to 
subsequent delays, and/or not clinically relevant biochemical abnormalities (i.e., 
in GGT, LDH and/or AP levels), none of which require dose reduction to be 
implemented. 
**Dose will be capped at BSA of 2.0 m2 (starting dose will not exceed 7 mg).
BSA will be calculated according to standard practice at each center.
ALT/AST, aspartate aminotransferase/alanine aminotransferase; AP, alkaline 
phosphatase; FD, flat dose GGT, gamma-glutamyltransferase; LDH, lactate 
dehydrogenase.
Up to two dose reductions are allowed per patient. 
Once the dose has been reduced for an individual patient, it 
will not be re-escalated under any circumstances.


Allowed 
medication/therapy 
Therapies for pre-existing and treatment-emergent 
medical conditions, including pain management.
Blood products and transfusions, as clinically indicated.
Bisphosphonates.
In case of nausea or vomiting, secondary prophylaxis 
and/or symptomatic treatment for emesis according to 
American Society of Clinical Oncology (ASCO) 
guidelines.
Erythropoietin (EPO) according to ASCO guidelines.
Granulocyte colony-stimulating factor (G-CSF) for the 
treatment of grade 4 neutropenia, any grade febrile 
neutropenia or neutropenic infection. After Cycle 1, 
secondary prophylaxis is allowed if applicable.
Anticoagulation therapy for the treatment or secondary 
prophylaxis of deep vein thrombosis. 
Luteinizing 
hormone-releasing 
hormone 
(LHRH) 
agonists, in women of reproductive age.
Prohibited 
medication/therapy
Concomitant administration of any other antineoplastic 
therapy,
except therapy with LHRH agonist if 
applicable.
Any other investigational agents.
Immunosuppressive 
therapies 
other 
than 
corticosteroids. 
Primary G-CSF prophylaxis or treatment of non-febrile 
grade ≤ 3 neutropenia with G-CSF (unless previously 
agreed case-by-case between the Investigator and the 
Sponsor).
Aprepitant, 
fosaprepitant,
and 
directly 
related 
compounds.
Radiotherapy (RT), except for limited-field
bone 
radiation for pain control purposes.
PM01183 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.
EFFICACY 
EVALUATIONS
The primary objective of the study is to assess the antitumor 
activity of PM01183 as the overall response rate (ORR), 
defined as the percentage of evaluable patients with a 
response, either complete (CR) or partial (PR).
Overall response rate (ORR) will be assessed using RECIST 
v1.1, on a set of measurable lesions identified at baseline as 
target lesions, and non-target lesions (if any) identified at 
baseline as non-target lesions and followed until PD by an 
appropriate method [helical computerized tomography (CT) 
scan, magnetic resonance imaging (MRI) and/or clinical 
assessment]. 
Radiological and/or clinical (whenever appropriate) tumor 
assessment will be performed at baseline and every six 
weeks (two cycles) until Cycle 6 or evidence of PD. After 
Cycle 6, tumor assessment will be performed every nine 
weeks (three cycles) until evidence of PD. If an objective 
response is observed, according to RECIST v1.1, it must be 
confirmed by the same method at least four weeks after the 
date of the first documentation of response.
The date of response, the date of clinical or radiological PD, 
and the date of death will be registered and documented as 
appropriate.
A copy of the imaging tests conducted on the patients during 
this clinical trial may be requested by the Sponsor for 
evaluation. In addition, an independent radiological review 
committee may be set up, upon Sponsors’ request, to review 
tumor assessment performed for all responding patients 
(partial or complete response) after study completion.
Patients will be categorized as “treatment failure” if: 

Discontinue treatment due to any treatment-related 
toxicity before an appropriate tumor assessment has 
been performed, or

Withdraw PM01183 after more than two weeks on 
treatment without any formal evaluation.
These data will be included as non-evaluable (NE) in the 


analysis of objective response as per RECIST v1.1, although 
these patients will not need to be replaced as they will be 
considered evaluable for efficacy. 
BRCA1/2 germline 
mutation analysis
In patients included in Cohort B who respond to PM01183 
treatment and whose BRCA 1/2 mutation status is unknown at 
study entry, an analysis will be performed in order to confirm 
or exclude deleterious germline BRCA 1/2 mutation. To this 
end, a blood sample will be collected at the time of response.
SAFETY EVALUATIONS
Patients will be evaluable for safety if they received at least 
one partial or complete infusion of PM01183.
All adverse events (AEs) will be graded according to NCI-
CTCAE v4.
The safety profile of patients will be monitored throughout 
treatment and up to 30 days after the last PM01183 infusion 
(EOT) or until the date of death, whichever occurs first.
Treatment delays, dose reduction requirements, G-CSF and/or 
transfusions 
requirements, 
and 
reasons 
for 
treatment 
discontinuation will be monitored throughout the study.
Any treatment-related AEs will be followed until recovery to 
grade ≤ 1 or stabilization of symptoms, whenever possible.
PHARMACOKINETICS
PK parameters of plasma PM01183 will be evaluated 
immediately before and during the first two cycles with a 
limited sampling schedule of ten samples in at least 30 treated 
patients in cohorts A or B. The sampling schedule during each 
cycle will be as shown below. 
Sample
Time
# 1
Before infusion
# 2
5 min before the end of the infusion (EOI)
# 3
15 minutes after EOI
# 4
1 hour after EOI
# 5
2 hours after EOI
# 6
4 hours after EOI
# 7*
5 hours and 30 min after EOI
# 8**
24 hours after EOI
# 9***
72 hours after EOI
# 10****
168 hours after EOI
*
There is a 30-minute window (before and after the stated point) 
in the sampling time.
**
There is a two-hour window (before and after the stated point) 
in the sampling time.
***
There is a two-hour window before the stated point, or until 24 
hours after the stated point in the sampling time (this sample must be 
collected within Day 4 or 5).
**** Preferred time; if weekends or other reasons make the 
sampling on time difficult, it may be obtained with a 24-hour 
window before or after the stated time. In any case, the sampling 
time should differ by at least 24 hours from the prior sample.
EOI, End of Infusion; h, hour(s); min, minutes.


PK parameters will be calculated using non-compartmental 
analysis (NCA) and population methods, after pooling data 
from this study with data obtained from other PM01183 
clinical studies.
PHARMACOGENOMIC 
(PGx) SUBSTUDY
Objective
The main objective of the PGx study (optional for cohorts A 
and B, required for cohort A1) is the identification of 
potential biomarkers of sensitivity or resistance to PM01183 
and whose expression might be predictive of the clinical 
outcome after treatment with PM01183.
Requirements

PM01183-treated patients with prior paraffin-embedded 
tumor samples, if available.

For cohorts A and B, patients who voluntarily sign the 
ICF for the PGx study will participate (refusal will not 
affect patient participation in the clinical study PM1183-
B-003-11).

For cohort A1, availability of a baseline (taken at any 
time between the end of last antitumor therapy and 
before first study drug infusion) tumor biopsy is also 
required. For those patients whose disease is not 
amenable to tumor biopsy, approval by the Sponsors
must be requested prior to inclusion.
Pharmacogenomic evaluations
Potential biomarkers of PM01183 activity will be analyzed 
on paraffin-embedded tumor samples obtained at baseline. 
Additionally, if archived tumor samples are available from 
the primary tumor and/or from metastases, analyses will be 
performed in both. Samples will be labeled according to its 
origin: diagnosis (primary tumor or metastasis) or baseline 
sample.
The expression levels and subcellular localization of selected 
molecules involved in different DNA repair mechanisms, 
such as nucleotide excision repair (e.g., XPG), homologous 
recombination repair (e.g., RAD51), among others, will be 
analyzed. Specifically, mRNA and protein from tumor 
samples 
will 
be 
subjected 
to 
quantitative 
reverse 
transcription polymerase chain reaction (qRT-PCR) and 
immunohistochemistry (IHC) in tissue microarrays (TMA), 
and immunofluorescence in whole tumor sections. The 
polymorphisms and mutational status of genes involved in 
DNA repair mechanisms or related to the mechanism of 
action of PM01183 or to the disease might also be analyzed, 
if relevant.


STATISTICAL 
METHODS
Primary Endpoint
Overall response rate (ORR), according to RECIST v1.1.
Secondary Endpoints
Duration of response (DR).
Clinical benefit, defined as the percentage of patients with 
ORR or SD > 3 months, according to RECIST v1.1.
Progression-free survival (PFS).
Overall survival rate at one year (1y-OS).
Treatment safety: AEs, serious AEs (SAEs) and laboratory 
abnormalities will be graded according to the NCI-
CTCAE (v4).
PK analysis and PK/PD correlation, if applicable.
PGx expression profile, in tissues from tumor samples.
Sample Size Considerations
The primary endpoint for this phase II study is to evaluate 
ORR.

Cohort A (BRCA+):
At least 53 evaluable patients will be recruited to test the 
null hypothesis that ORR is 20% or less (p 0.20) vs. the 
alternative hypothesis that 40% or more patients have 
objective response (p ≥ 0.4). With these assumptions, if 
the number of evaluable patients with objective response 
is ≥ 17, then this would allow the rejection of the null 
hypothesis.

Cohort A1 (BRCA+/PARPi):
At least 20 evaluable patients will be recruited for an 
exploratory analysis: if the number of patients responding 
is ≥4 (20%), the lower limit of the exact binomial 95% 
confidence interval will be higher than 5% and lack of 
activity in this subpopulation will be ruled out.

Cohort B (unselected):
At least 64 evaluable patients will be recruited to test the 
null hypothesis that ORR is 10% or less (p 0.10) vs. the 
alternative hypothesis that 25% or more patients have 
objective response (p ≥ 0.25). With these assumptions, if 
the number of evaluable patients with objective response 
is ≥ 12, then this would allow the rejection of the null 
hypothesis.
The variance of the standardized tests is based on the null 
hypothesis. The type I error (alpha) associated with this one-
sided test is 0.025 and the type II error (beta) is <0.1; hence, 
statistical power is > 90%. 
Futility analyses controlled by the Gamma family boundary 
will be performed when 20 and 30 patients have been 
evaluated in cohorts A [Gm(-2)] and B [Gm(-1.5)], 
respectively. If less than four out of 20 patients in Cohort A, 


or less than three patients out of 30 in Cohort B achieve an 
objective response, recruitment to that cohort will be stopped. 
About 110 evaluable patients are expected to be included 
finally in the three cohorts: Cohort A (BRCA+), Cohort A1 
(BRCA+/PARPi), and Cohort B (unselected).
Safety Stopping Rule
In addition to sample size considerations, a decision for early 
study termination due to safety issues will be taken within the 
initial 30 evaluable patients (regardless of the cohort), 
whenever any of the following occurs: 
Two or more eligible patients die due to treatment-
related AEs (>5% of related deaths), or
Ten or more patients need to discontinue treatment 
within the first two cycles due to any grade 4 treatment-
related AEs (NCI-CTCAE v4).
DURATION OF STUDY 
PERIOD (per patient)
Patients will be individually evaluated at scheduled visits 
within three study periods: 
Screening: from signature of the ICF to first infusion of 
PM01183.
Treatment: from the first infusion of PM01183 to end 
of treatment (EOT). EOT is defined as 30 days after 
the date of PM01183 last administration, unless the 
patient starts a new antitumor therapy or dies within 
those 30 days, in which case the date of administration 
of this new antitumor therapy or the date of death will 
be considered as EOT.
Follow-up: after EOT, patients will be followed for any 
ongoing treatment-related AEs every four weeks until 
recovery to grade ≤1, or until symptoms stabilization 
whenever possible. 
Patients will be followed for at least one year after their 
first infusion. Those who discontinued treatment 
without PD will be assessed every two months during 
the first six months after last tumor assessment and 
every three months thereafter, until PD, start of other 
antitumor therapy,
death, or study
completion,
whichever occurs first. 
After documented PD or start of a new antitumor 
therapy, patients will be followed every six months 
until death or study completion, whichever occurs first
(a documented phone contact will be acceptable). 
Patients will be considered to be on-study from the signature 
of the clinical ICF to the end of the follow-up period (or 
screening failure).
Patients will be considered to be on-treatment from the date 
of first infusion until EOT. 


TREATMENT 
DISCONTINUATION
Patients will receive study medication as long as it is 
considered to be in their best interest. Specifically, treatment 
will continue until:
Disease progression.
Unacceptable toxicity (except in case of clear clinical 
benefit, with the Sponsors’ approval), after appropriate 
dose reduction.
Intercurrent illness of sufficient magnitude to preclude 
safe continuation of the study.
Patient refusal and/or noncompliance with study 
requirements.
Investigator’s decision.
Protocol deviation with an effect on the management of 
the patient’s risk/benefit ratio. 
Treatment delay > 3 weeks from the treatment due date 
(except in case of clear clinical benefit, upon Sponsors’
approval).
Requirement of > 2 dose reductions.
REPLACEMENT OF 
PATIENTS
Patients will be replaced if they are not evaluable for the 
primary endpoint of the study (ORR as per RECIST v1.1), 
specifically (any of the following):

They are not eligible.

They have not been treated or have not completed at 
least one PM01183 infusion.

They are not evaluable for ORR as per RECIST v1.1
and they are not categorized as “treatment failures”. 
Treatment failures will not be replaced and are 
defined as patients who: 
o
Discontinue treatment due to any treatment-
related toxicity before an appropriate tumor 
assessment has been performed, or
o
Withdraw PM01183 after more than two 
weeks on treatment without any formal 
evaluation
All replaced patients who received treatment will be included 
in the general safety analysis, if appropriate. 
DURATION OF STUDY 
(as a whole)
The total duration of the study will be approximately 72
months. 
Planned start date (first patient on study): second quarter 
2012 (2Q12).
Planned enrollment period: 60 months.
Planned study completion date (clinical cut-off): nine 
months after the last patient-last treatment visit in the study, 
or 12 months after the last evaluable patient is enrolled 
(whichever occurs first).


SCHEDULE OF ASSESSMENTS AND PROCEDURES
          STUDY PERIODS (1)
PROCEDURES
Screening
(days)
Treatment
Follow-
up (2)
Cycle 1
Cycle 2
Further 
Cycles
End of 
treatment 
(EOT)
D1
D8
D15
D1
D10
D1
Written informed consent 
Before any 
study 
procedure
-
-
-
-
-
-
-
-
Written informed consent 
- PGx substudy (optional
for cohorts A and B)
Before any 
study 
procedure
-
-
-
-
-
-
-
-
Demographic data
-28  to  0
-
-
-
-
-
-
-
-
Primary diagnosis & prior 
treatment(s) 
-28  to  0
-
-
-
-
-
-
-
-
Medical history & prior 
conditions
-14  to  0 
-
-
-
-
-
-
-
-
Assessment of signs and 
symptoms
-7  to  0
-
-
-
-
-
-
-
-
PM01183 administration
NA

-
-

-

-
-
Complete physical 
examination, including 
weight and height (3)
-7  to  0       
-
-
-

-


-
Performance status 
(ECOG)
-7  to  0
-
-
-

-


-
Vital signs (heart rate, 
blood pressure, 
temperature)
-7  to  0
-
-
-

-


-
Coagulation panel
-7  to  0
-
-
-

-


-
Hematology (4)
-7  to  0
-




  (5)

-
Biochemistry A (4)
-7 to  0
-




  (5)

-
Biochemistry B 
-7  to  0
-
-
-

-


-
Pregnancy test (6)
-7  to  0
Repeat if clinically indicated
-
ECG (7)
-7  to  0
Repeat if clinically indicated
-
LVEF by ECHO or MUGA
-28  to  0
Repeat if clinically indicated
-
Radiological and/or clinical 
tumor assessment(8)
-28  to  0
Every 6 weeks until Cycle 6 and 
every 9 weeks thereafter (9)
  (10)
Pharmacokinetics (PK) (11)
-
Immediately before and during Cycles 1 and 2 
only.
-
-
PGx (paraffin 
embedded tumor 
tissue) (12)
From 
available 
prior 
tumor 
samples 
-
-
-
From a 
recent 
biopsy
(cohort 
A1)
After last 
treatment to 0
Intercurrent events, 
concomitant diseases and 
treatments
-14  to  0
Throughout the ”on-treatment period” 
-
Adverse events (AEs)
  NA (13)
Throughout the ”on-treatment period” 
(13)
BRCA1/2 germline 
mutation analysis
(14)
BRCA unknown patients in cohort B:
One blood sample at the time of the response (15)
-
See footnotes on next page


Footnotes refer to table on previous page
1.
A 3-day window will be allowed for laboratory procedures, a 14-day window for radiological procedures (helical CT-scan or 
MRI) and LVEF assessments, a 24-hour window for clinical assessments (ECOG, physical examination, vital signs, ECG, 
weight, BSA, etc.), and a 7-day window for the assessments at end of treatment. 
2.
After documented progression or start of new antitumor therapy, patients will be followed every six months, until death or 
study completion, whichever occurs first.
3.
Height is only required at baseline.
4.
Any patient presenting a grade ≥ 3 treatment-related AE should have all relevant tests re-assessed at least every 48-72 
hours until recovery to grade ≤ 2.
5.
From Cycle 3 onwards Hematology and Biochemistry A tests on Day 10 are to be performed only in patients who experienced 
non-hematological grade ≥3 or hematological grade 4 treatment-related toxicities, or who required any dose adjustments or 
GSF prophylactic therapy, in the preceding cycle. 
6.
In patients of childbearing potential only; if serum human chorionic gonadotropin (HCG) results are abnormally high, 
pregnancy must be clinically discarded by an additional test (i.e. US) before any other study procedure. Pregnancy and 
suspected pregnancy occurring while the patient is on study drug or within six weeks from the patient’s last PM01183 
administration are considered immediately reportable events.
7.
Cardiac rhythm will be identified in ECG intervals of at least 30 seconds of duration, PR interval, QT interval (raw), heart rate 
(HR) and QRS complex.
8.
Contrast enhanced helical CT-scan or MRI as clinically indicated of all measurable sites of disease involvement and of all non-
measurable sites of disease should be done at baseline by appropriate testing (radiological and/or clinical). While on treatment, 
appropriate evaluation of all original sites of disease involvement at baseline, should be done as per RECIST v.1.1. Should be 
repeated at end of treatment visit, if not previously done, and if the reason for treatment discontinuation was other than PD. 
The same initial method must be used throughout the study. 
9.
Patients showing a response must have a confirmatory assessment at least 4 weeks later. Patients with previously known CNS 
involvement at study entry must have documented non-PD by appropriate method at baseline. 
10.
Only patients who discontinued treatment without PD will be assessed radiologically and/or clinically as appropriate. The 
assessments will be performed every two months during the first six months after last tumor assessment and every three 
months thereafter until PD, start of other antitumor therapy, death, or study completion, whichever occurs first. 
11.
In at least 30 treated patients in cohorts A or B.
12.
Prior available stored paraffin-embedded tumor samples from the primary tumor and/or from metastases. For Cohort A1 
patients only: a baseline tumor biopsy must also be available (taken at any time between the end of last antitumor therapy until 
before first study drug infusion). For cohort A1patients whose disease is not amenable to tumor biopsy, approval by the 
Sponsors must be requested prior to inclusion. In any case, the origin of the sample must be specified: diagnosis (primary 
tumor or metastasis) or baseline sample.
13.
From ICF signature to PM01183 treatment only SAEs must be reported. After the end of treatment, all AEs and SAEs 
suspected to be related to PM01183 must be followed-up until recovery to grade ≤ 1 or symptoms stabilization.
14.
To be conducted on patients with unknown germline BRCA mutation status who meet criteria for consideration of BRCA 1/2 
genetic testing, according to the National Comprehensive Cancer Network (NCCN) (see Appendix 3).
15.
In patients included in Cohort B who respond to PM01183 treatment and whose BRCA 1/2 mutation status is unknown at 
study entry, an analysis will be performed in order to confirm or exclude deleterious germline BRCA 1/2 mutation. To this 
end, a blood sample will be collected at the time of response.
Coagulation: PT/INR and PTT.
Hematology: Hemoglobin, platelet counts, and differential WBC including neutrophils, monocytes and lymphocytes.
Biochemistry A: Serum electrolytes (Na+, K+, Cl−), AST, ALT, AP, GGT, total bilirubin (direct bilirubin to be measured only if 
total bilirubin is abnormally high), LDH, creatinine, glucose, and CPK (CPK-MB fraction and troponin T or I should only be 
measured if CPK is abnormally high or if clinically indicated).
Biochemistry B: Total proteins, albumin, CRP, Ca++, phosphorus, Mg++. CA 15-3 or 27.29 will be measured at baseline and 
repeated thereafter only in those patients with abnormally elevated values at baseline. Alpha-1 acid glycoprotein, total cholesterol, 
triglycerides, and LDL will be evaluated at baseline and before Cycle 2 only.
AE(s), adverse event(s); ALT, alanine aminotransferase; AP, alkaline phosphatase; AST, aspartate aminotransferase; CA-15-3 or 
27.29: cancer antigens 15-3 and 27-29 respectively; CNS, central nervous system; CPK, creatinine phosphokinase; CPK-MB, 
creatinine phosphokinase MB isoenzyme; CRP, C-reactive protein; CT, computed tomography; ECG, electrocardiogram; ECHO, 
echocardiogram; ECOG-PS, Eastern Cooperative Oncology Group performance status; EOT, end of treatment; GGT, gamma 
glutamyltransferase; HCG, human chorionic gonadotropin; HR, heart rate; ICF, informed consent form; INR, international 
normalized ratio; LDH, lactate dehydrogenase; LDL, low density lipoprotein; LVEF, left ventricular ejection fraction; MRI, 
magnetic resonance imaging; MUGA, multiple gated acquisition scan; NA, not applicable; NCI-CTCAE, National Cancer Institute 
Common Terminology Criteria for Adverse Events; PD, progressive disease; PGx, pharmacogenomic(s); PK, pharmacokinetic(s); 
PT, pro-thrombin time; PTT, partial thromboplastin time; US, ultrasound; WBC, white blood cells.


LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
5-HT3
Serotonin
ADR
Adverse Drug Reaction
AE(s)
Adverse Event(s)
ALT 
Alanine Aminotransferase
ANC
Absolute Neutrophil Count
AUC
Area Under the Curve 
AUCinf
Area Under the Curve from time zero to infinity
AP
Alkaline Phosphatase
ASCO
American Society of Clinical Oncology
AST 
Aspartate Aminotransferase
AUC
Area Under the Curve
BRCA1/2
Breast Cancer 1 or Breast Cancer 2 Gene
BSA
Body Surface Area
CA 15-3
Cancer Antigen 15.3
CA 19-9
Cancer Antigen 19-9
CA 27.29
Cancer Antigen 27.29
CI
Confidence Interval
CL
Clearance
Cmax
Maximum Plasma Concentration
CNS
Central Nervous System
CPK 
Creatine Phosphokinase
CPK MB
Creatine Phosphokinase Isoenzyme-MB fraction
CR
Complete Response
CRC
Colorectal Cancer
CrCl
Creatinine Clearance
CRF 
Case Report Form
CT
Computed Tomography
DLT
Dose-limiting Toxicity
DNA
Deoxyribonucleic Acid
DP
Drug Product
DR
Duration of Response
DSMB
Data Safety Monitoring Board
DSUR
Development Safety Update Report
ECG 
Electrocardiogram


ECHO
Echocardiogram
ECOG
Eastern Cooperative Oncology Group
EOI
End of Infusion
EOT
End of Treatment
EPO
Erythropoietin
ER
Estrogen Receptor
FD
Flat Dose
FFS
Fast Fact Sheet
GCP
Good Clinical Practice
G-CSF
Granulocyte Colony-stimulating Factor
GGT
Gamma-glutamyltransferase
GMT
Greenwich Meridian Time
Gy
Grays
HBV
Hepatitis B Virus
HCV
Hepatitis C Virus
HCG
Human Chorionic Gonadotropin
HER-2
Human Epidermal Growth Factor Receptor 2
HR
Heart Rate
HIV
Human Immunodeficiency Virus
[I]
Inhibitor Concentration
IB
Investigator’s Brochure
IC50
Half Maximal Inhibitory Concentration
ICF
Informed Consent Form
ICH
International Conference on Harmonisation
IEC
Investigational Ethics Committee
i.v.
Intravenous(ly)
IG50
Half Maximal Growth Inhibition
IHC
Immunohistochemistry
INR
International Normalized Ratio
IRB
Institutional Review Board
k
Terminal Rate Constant
ki
Dissociation Constant for Inhibitor Binding
LDH
Lactate Dehydrogenase
LHRH
Luteinizing hormone-releasing hormone
LVEF
Left Ventricular Ejection Fraction
MAb
Monoclonal Antibody


MBC
Metastatic Breast Cancer
MedDRA
Medical Dictionary for Regulatory Activities
MRI
Magnetic Resonance Imaging
mRNA
Messenger Ribonucleic Acid
MTMD
Multiple Maximum Tolerated Multiple Dose
MUGA
Multiple-gated Acquisition Scan
NCA
Non-compartmental Analysis
NCCN
National Comprehensive Cancer Network
NCI-CTCAE
National Cancer Institute Common Terminology Criteria for Adverse 
Events
NE
Not evaluable
ORR
Overall Response Rate
OS
Overall Survival
PARP
Poly (ADP-ribose) Polymerase
PARPi
Poly (ADP-ribose) Polymerase Inhibitor
PD
Progressive Disease / Pharmacodynamic(s)
PFS
Progression-free Survival
PFS6
Progression-free Survival Rate at Six Months 
PGx
Pharmacogenomics
PhV
Pharmacovigilance
PK
Pharmacokinetics
PR
Partial Response
PRBC
Packed Red Blood Cells
PS
Performance Status
PT
Prothrombin Time
PTT
Partial Thromboplastin Time
q3wk
Every Three Weeks
qRT-PCR
Reverse Transcription Polymerase Chain Reaction
RBC
Red Blood Cell
RD
Recommended Dose
RECIST
Response Evaluation Criteria In Solid Tumors
RNA
Ribonucleic Acid
RT
Radiotherapy
SAE(s)
Serious Adverse Event(s)
SD
Stable Disease
SUAE
Serious Unlisted Associated Adverse Event
SUSAR
Suspected Unexpected Serious Adverse Reaction


t1/2
Half-life
T/C
Therapy Over Control
TMA
Tissue Microarray
TN
Triple Negative
Uk
Unknown
ULN
Upper Limit of Normal
US
Ultrasound
vs.
Versus
WBC
White Blood Cells
Wk
Week(s)
WMA
World Medical Association


1.
INTRODUCTION
1.1.
BREAST CANCER
Breast cancer is the most common cancer in women in western countries. Worldwide, it 
is estimated that more than one million women are diagnosed annually and that more 
than 410,000 will die of the disease (1), thus ranking as second and third cause of 
cancer-related death in women in US and Europe respectively (2, 3).
Despite the many advances that have been achieved in the treatment of breast cancer, 
the prognosis for patients with metastatic breast cancer (MBC) remains poor (4). Breast 
cancer is a heterogeneous disease in which a strong interplay between genetic and 
environmental factors seems crucial to define the disease phenotype and clinical 
behavior. Significant advances have been made in the characterization of different 
breast cancer types according to molecular features and gene expression profile, in 
addition to other existing classifications focused primarily upon cell morphology and 
histology. These findings support that breast cancer is in fact a group of miscellaneous
diseases with possibly different pathogenesis and natural history. Perhaps most 
importantly, this would allow that clinically relevant subgroups to be specifically 
targeted or treated differently depending on the presence or absence of some of these 
characteristics (5, 6).
It is currently estimated that 5-10% of all breast cancers are hereditary due to germline 
mutations in BRCA 1 and/or BRCA 2 genes. The BRCA 1 and BRCA 2 proteins 
participate in deoxyribonucleic acid (DNA) repair and homologous recombination as 
well as other cellular processes (7). There has been a long debate regarding the 
prognosis of hereditary breast cancers as compared to that of sporadic disease. Several 
retrospective trials have failed to demonstrate a worst prognosis in BRCA 1/2 mutated 
breast cancers. However, the fact that disease with both a lack of hormone receptors and 
a lack of human epidermal growth factor receptor 2 (HER-2) overexpression, known as 
triple negative (TN) breast cancer, is more common in BRCA-mutated patients has re-
opened the debate. In particular, BRCA 1-associated hereditary breast cancer might be a 
more aggressive form of disease than sporadic breast cancer, with medullar or atypical 
features, p53 mutations and/or overexpression, high level expression of epithelial 
growth factor (EGF) and Ki-67, and absence of HER-2 overexpression (8). BRCA 2 
mutations are heterogeneous and often present in relatively high grade tumors which 
display substantially less tubule formation (9). Moreover, BRCA 1/2 mutated breast 
cancer has recently come into focus due to the development of new molecules able to 
inhibit the poly (ADP-ribose) polymerase (PARP), a nuclear enzyme responsible for 
signaling in the presence of DNA damage facilitating recognition and repair of DNA by 
specific enzymes such as BRCA 1/2 proteins. Indeed, BRCAness tumors are more 
sensitive to PARP inhibition than wild type tumors, which may escape through 
alternative pathways to such inhibition. Thus, the possibility of selectively target these 
tumors had brought along a lot of interest. Though comparative trials are still pending to 
define a role for these molecules, promising response rates up to 41% were recently 
reported in a phase II trial in advanced breast cancer with a novel oral PARP inhibitor,
olaparib (10).
Metastatic disease at diagnosis is uncommon in breast cancer, occurring in only 6% of 
newly diagnosed cases (11). Nevertheless, approximately 30% of women initially 
diagnosed with early breast cancer will eventually develop recurrent advanced or 
metastatic disease, despite effective adjuvant treatment. In fact, the majority of breast 


cancer patients die as a result of complications from recurrent or metastatic disease. 
Unfortunately, metastatic disease remains incurable, with the goal of therapy being 
tumor control and symptoms palliation with a survival improvement. The median 
survival time of MBC patients is usually between 18 to 30 months.
There is no single standard of care for MBC patients, as treatment plans require an 
individualized approach based on multiple factors. As aforementioned, these include 
both disease and patient-related factors such as: specific tumor biology, disease growth
rate, presence or absence of visceral metastases, history of prior therapy and tumor 
responsiveness, age and menopausal status, specific toxicities risk, and patient 
preferences (4).
A growing pool of treatments have increased the response rates, the progression-free 
survival (PFS), and/or the overall survival (OS) of MBC patients (12). After the 
introduction of taxanes, trastuzumab, vinorelbine and capecitabine in the mid-to-late 
1990s, the last decade has seen the arrival of anastrozole, letrozole, exemestane, 
fulvestrant, gemcitabine, ixabepilone, nanoparticle albumin-bound paclitaxel (nab-
paclitaxel), bevacizumab, and lapatinib to the current available therapeutic arsenal.
Eribulin was approved by EMA in 2011, and the list is continuously growing. Such a 
wide range of available treatment options makes rather difficult to set a unique standard 
above the others, although it seems logical that patients with HER-2 overexpressing 
tumors must have trastuzumab as part of the upfront treatment (13). Apart from 
bevacizumab, these novel agents essentially act at the same level as other previously 
available molecules such as aromatase inhibitors, estrogen receptor (ER) blockers, 
antimicrotubule interactive agents, antimetabolites and HER-2 blockers.
Once the first-line treatment of MBC has failed, management becomes more 
challenging. The likelihood of response subsequently decreases by approximately one 
half with respect to each prior regimen the patient has received. Hence, response rates 
may be as high as 60-80% with first-line treatment in patients, while they may only 
reach between 30%, and 15% in patients who have received two or three regimens 
respectively (14). Hormonal therapy tends to have a lesser role in pretreated progressing 
metastatic patients, as endocrine resistance is common in this setting. The use of 
anthracyclines and taxanes in early settings makes subsequent treatment selection more 
challenging and drug resistance often limits therapeutic options. Drugs with novel 
mechanism of action, likely to lack cross-resistance with other established or commonly 
used agents, are thus needed for pretreated MBC patients, particularly after second-line
failure (15).  
1.2.
INFORMATION ON STUDY DRUGS
1.2.1.
PM01183
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. Chemical structure of PM01183.
1.2.1.1. Non-clinical Data
1.2.1.1.1. Antineoplastic Activity In Vitro
PM01183 is a new chemical entity, structurally related to trabectedin, which also binds 
the deoxyribonucleic acid (DNA) minor groove, leading to the formation of DNA 
double-strand breaks, thus inducing apoptosis and delaying progression through the cell 
cycle S/G2 phase (16). PM01183 has a negative COMPARE analysis (17) when 
compared against other 98 standard anticancer agents in a panel of 36 cell lines. Thus, 
its mechanism of action is likely to differ significantly from theirs. As expected, based 
on preclinical data, PM01183 only showed a positive correlation (S-rank > 0.8) with 
trabectedin (18).
In vitro, PM01183 has shown broad cytotoxic activity against different tumor derived 
cell lines. In breast cancer, cytotoxic activity was observed in BT-474, MCF-7, and 
MDA-MB-231 cell lines (half maximal growth inhibition, IG50: 1.3 10-9 M, 1.7 10-9 M
and 3.5 10-9 M, respectively).
1.2.1.1.2. Antineoplastic Activity In Vivo
The in vivo “Proof of Concept” for PM01183 was accomplished by using a panel of six 
human types, i.e., breast, colon, gastric, ovarian, prostate, and renal. The resulting tumor 
susceptibility was analyzed in xenografts grown in athymic mice, when unformulated 
PM01183 was administered at the maximum tolerated dose (0.3 mg/kg [0.9 mg/m2]) as 
single bolus intravenous (i.v.) injection. Tumor growths in PM01183-treated animals 
were monitored and compared with those of the untreated group. PM01183 
demonstrated a statistically significant antitumor activity (p<0.05) against breast, colon, 
gastric, and kidney xenografts at different time points during the experiment.
The antitumor effectiveness of PM01183 was further analyzed in human derived 
xenografted tumors, namely breast (MAXF 401) and prostate (22RV1), after 
determination of maximum tolerated multiple dose (MTMD) levels in athymic mice. 
Specifically, PM01183 was administered in two different schedules: two doses on Days 
0 and 14, or five consecutive doses repeated on Days 0-4 and 14-18 (qdx5x2); the 
MTMD values were determined as 0.3 mg/kg and 0.06 mg/kg (0.9 and 0.18 mg/m2), 
respectively. Also, the effect of therapy over control (T/C) was assessed. Partial or 
complete remissions of tumors were seen in the MAXF 401 model, showing the 
strongest activity at 0.3 mg/kg (0.9 mg/m2) on Days 0 and 14 (T/C = 0.0 % on Day 35).
PM01183 was further evaluated for in vivo activity in breast (MDA-MB-231 and MX-1 
cell lines) as well as in other xenografted models. PM01183 demonstrated antitumor 


activity in breast, kidney, ovary and lung, but had a more moderate antitumorigenic 
profile against bladder, pancreas and prostate. 
For more information on preclinical PK and safety pharmacology data refer to 
PM01183 Investigator’s Brochure (IB).
1.2.1.2. PM01183 Clinical Data
As of November 2011, the first-in-human clinical study with PM01183 (PM1183-A-
001-08) has been completed. This study was started in March 2009 based on the 
promising preclinical results. Accrual was closed in September 2010, after 31 
relapsed/refractory cancer patients with no available standard therapy had been treated. 
The primary endpoint was to find a safe recommended dose (RD) of PM01183 for 
phase II studies, when administered as a single one-hour i.v. infusion every three weeks 
(q3wk). The RD was defined at 4.0 mg/m2/q3wk; after pharmacokinetic (PK) data 
analysis, PM01183 clearance (CL) was found to be unrelated to body surface area
(BSA) and, consequently, all remaining patients (n=9) at the RD in the expansion cohort 
were treated at an equivalent flat dose (FD) of 7.0 mg q3wk. Overall, 15 patients were
treated at the RD level and only one had a dose-limiting toxicity (DLT), that consisted 
of a grade 4 thrombocytopenia. Preliminary results were presented in 2010 at the 22nd
Annual Symposium on Molecular Targets and Cancer Therapeutics (19).
Toxicity was generally mild and reversible. Standard antiemetic prophylaxis was made
compulsory at the RD to prevent moderate nausea and/or vomiting. Myelosuppression, 
particularly grade 4 non-febrile neutropenia, was the most relevant toxicity (found in
40% of patients treated at the RD). Neutropenia was short-lasting and caused no 
treatment delays at the RD, with nadir generally occurring during the second week (Day 
+13). This hematological event lasted a median of three days without requiring colony-
stimulating factors treatment. The severity of neutropenia correlated more closely with 
the observed PM01183 area under the curve (AUC) than with the dose administrated 
according to body surface. Treatment was very well tolerated by the majority of patients 
and there were no treatment-related deaths in this highly selected patient population. Of 
note, despite patients were eligible with ECOG performance status (PS) between 0 and 
2 and no maximum limit of age was set in this trial, none of the patients treated at the 
RD were PS=2 or over 75 years-old. Therefore caution should be used concerning the 
generalization of the data obtained in this trial. In particular, previous findings may 
apply to younger and less symptomatic patients but not to particularly vulnerable 
populations at greater risk for myelosuppression, such as elderly and highly 
symptomatic cancer patients. 
Regarding the antitumor activity, 14 of the 15 patients treated at the RD were evaluable
for efficacy, and seven among them had been diagnosed with colorectal cancer (CRC). 
This was also the most frequent tumor type in the study, with nearly 60% of all treated 
patients having CRC; it is worth mentioning that none of the 31 treated patients had 
breast cancer in this study. One patient with a progressive, refractory pancreatic 
adenocarcinoma had a confirmed partial response (PR) as per the Response Evaluation 
Criteria in Solid Tumors (RECIST) after three cycles of PM01183, and also had serum 
tumor marker [cancer antigen 19-9 (CA 19-9)] normalization after the fourth cycle.
Three other patients with previously progressing tumors at study entry (one melanoma 
and two soft tissue sarcomas) had clinically meaningful disease stabilizations lasting 
around six months. This finding further supported that clinically active PM01183 


concentrations are achieved at the RD (7.0 mg FD) as one-hour i.v. infusion q3wk, and 
that this dose is safe and tolerable in solid tumor relapsed/refractory patients.
Phase II studies, using this RD, in metastatic pancreatic cancer as second-line treatment 
after gemcitabine-based therapy failure and in platinum-resistant or refractory advanced 
ovarian cancer are currently ongoing.
1.3.
STUDY RATIONALE
Metastatic breast cancer (MBC) is a clinically heterogeneous and an aggressive disease
from which most patients will ultimately die. Unfortunately a cure by the means of 
currently available treatment options still seems
an elusive goal. Cytotoxic 
chemotherapy remains a crucial component of the therapeutic armamentarium and there 
is a need to develop more selective approaches to identify subgroups of patients with 
higher tumor sensitivity that may benefit the most. 
PM01183 is a new chemical entity that induces double-strand DNA breaks through 
binding to the DNA minor groove. Results of the COMPARE analysis (20) revealed 
that is unlikely that this drug shares a similar mechanism of action with any of the other 
98 standard cytotoxic agents compared.
PM01183 has significant in vitro and in vivo wide antitumor activity, particularly in 
several breast cancer models.
PM01183 exposure primarily induces DNA damage, particularly to homologous 
recombinant deficient cells in vitro (see IB); thus, patients with BRCA deleterious 
mutation might be more sensitive to its antitumor effects than other patients. In order to 
test this hypothesis, two cohorts of patients with advanced breast cancer will be 
prospectively evaluated in the trial according to their germline BRCA1/2 mutation 
status: known mutation (BRCA+, Cohort A) vs. unselected (BRCA– or -UK, Cohort B). 
The goal of the trial is, on one hand, to find out whether the presence of a BRCA 1/2 
mutation in Cohort A is associated with a higher response rate in MBC patients; and, on 
the other hand, to explore and benchmark the activity of PM01183 in MBC unselected 
patients. The study design has taken into account the higher sample heterogeneity of 
Cohort B by planning the recruitment of more patients in this group. Also, according to 
the BRCA status in the trial setting, a response rate of 40% or more in Cohort A (sample
of patients with known deleterious BRCA 1/2 mutations) will be considered clinically 
worthy of further research, as well as a response rate of 25% or more in Cohort B. 
The first-in-human phase I clinical trial found a RD of 7.0 mg FD of PM01183 when 
given as a one-hour i.v. infusion q3wk. This dose was safe, tolerable and manageable 
for a highly selected patient population. In particular, PM01183 induced predictable and 
short-lasting non febrile neutropenia as the most relevant toxicity (up to 40% of patients 
treated at the RD). None of the patients treated at the RD were older than 75 years
and/or had PS >1. Therefore, it is uncertain at this time if PM01183 RD is as tolerable 
and safe for a particularly vulnerable and frail population given the degree of 
myelosuppression observed so far. Because toxicity, especially in aging patients, is 
usually an important consideration in order to select the more suitable treatment, it 
seems safer to exclude patients over 75 years old and/or with PS≥2 until more 
information regarding safety and pharmacokinetics of the drug becomes available. 


2.
OVERALL STUDY DESIGN
This is a multicenter, open-label, exploratory, phase II clinical trial evaluating the 
efficacy and safety of PM01183 administration to patients with previously treated MBC, 
as follows.
Two cohorts of MBC patients will be prospectively evaluated in the trial according to 
germline BRCA1/2 status (mutated [cohort A] vs. unselected [cohort B]). A third cohort 
(A1) will include advanced breast cancer patients with deleterious BRAC1/2 mutation 
who received prior treatment with poly (ADP-ribose) polymerase (PARP) inhibitors:

Cohort A (BRCA+ cohort): At least 53 evaluable patients with previously known 
deleterious BRCA1/2 mutation status at study entry.

Cohort A1 (BRCA+/PARPi cohort): 20 evaluable patients with known deleterious 
BRCA1/2 mutation status and prior treatment with PARP inhibitors (PARPi). 

Cohort B (unselected cohort): At least 64 evaluable patients without known 
deleterious BRCA1/2 mutation status at study entry, i.e., either:
o
Patients known to have no deleterious BRCA1/2 mutations (BRCA−), or
o
Patients whose BRCA 1/2 mutation status is unknown (BRCA-UK);
BRCA1/2 germline mutation status will be assessed in PM01183 responding
patients in this subgroup.
The primary efficacy endpoint of the study is the overall response rate (ORR), defined 
as the percentage of patients with a response, either complete (CR) or partial (PR), 
according to RECIST v1.1 (Section 8.1).
An interim analysis based on the primary endpoint (ORR) is planned after 20 and 30 
evaluable patients have been treated in cohorts A and B, respectively (see Section 8.2
for details). No interim analysis is planned for cohort A1. If less than four out of 20 
patients in Cohort A, or less than three out of 30 patients in Cohort B achieve an 
objective confirmed response, recruitment to that cohort will be terminated. Otherwise, 
recruitment will continue until at least 53 and 64 evaluable patients are included in 
cohort A and cohort B, respectively. Sample size and cohort design will be re-evaluated 
at this point in order to estimate the 95% confidence interval (CI) with the desired 
precision. Recruitment to either cohort (e.g., Cohort B) might be halted while interim 
analysis is being performed, if appropriate.
Patients will receive treatment in the absence of progressive disease (PD) or 
unacceptable toxicity for as long as it is considered to be in their own benefit (see 
Section 6.2.1.2 for details).
Patients will be evaluated using clinical and laboratory assessments before each 
treatment cycle (Sections 6.3 and 6.6). Appropriate radiological and/or clinical tumor 
assessments will be done every six weeks until evidence of PD (Section 7.1). Patients 
no longer receiving study treatment will be followed up for survival (Section 6.8).
Any treatment-related AE will be followed until recovery to grade ≤ 1 or stabilization of 
symptoms, whenever possible (Section 7.2). Reasons for dose reduction, treatment 
delays and/or treatment discontinuation will be documented as appropriate.


3.
STUDY OBJECTIVES
3.1.
PRIMARY

To assess the antitumor activity of PM01183 in terms of ORR, according to 
RECIST v1.1, in each cohort of MBC patients.
3.2.
SECONDARY

To further characterize the antitumor activity of PM01183 in terms of duration 
of response (DR), clinical benefit [ORR or stable disease lasting over three 
months (SD > 3 months)], PFS, and one-year overall survival (1y-OS).

To evaluate whether the presence of a known germline mutation in BRCA 1/2 
predicts response to PM01183 in MBC patients.

To explore the activity of PM01183 in specific breast cancer subpopulations 
according to hormonal receptor status, HER-2 overexpression, number and/or 
type of prior therapies, or according to other available histological/molecular 
classifications/parameters.

To evaluate the safety profile of this PM01183 administration schedule (Day 1, 
q3wk) in this patient population.

To analyze the pharmacokinetics (PK) of PM01183 in this patient population.

To explore PK/PD (pharmacokinetic / pharmacodynamic) correlations, if 
applicable.

To evaluate the pharmacogenomic (PGx) expression profile of selected putative 
markers potentially predictive of response to PM01183, in tissues from tumor 
samples.
4.
SELECTION OF PATIENTS
4.1.
INCLUSION CRITERIA
In order to be included into the trial, patients have to fulfill all of the following criteria:
All patients
1.
Women ≥ 18 and ≤ 75 years of age. 
2.
Voluntary signed informed consent form (ICF), obtained from the patient before the 
beginning of any specific study procedure. 
3.
Histologically proven diagnosis of metastatic breast carcinoma. 
4.
No more than three prior chemotherapy-containing regimens for MBC. 
5.
Patients with known HER-2 overexpressing tumors must have failed at least one 
prior trastuzumab-containing regimen for metastatic disease.
6.
Measurable disease as defined by RECIST v1.1.
7.
Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1.
8.
Adequate major organ function:
a.
Hemoglobin ≥ 9 g/dl, prior red blood cell (RBC) transfusions are allowed if 
clinically indicated; absolute neutrophil count (ANC) ≥ 1.5 x 109/l; and platelet 
count ≥ 100 x 109/l.
b. Alanine 
aminotransferase 
(ALT), 
and 
aspartate 
aminotransferase 
(AST) 3.0 x upper limit of normal (ULN).


c.
Total bilirubin 1.5 x ULN or direct bilirubin ULN.
d. Albumin ≥ 3 g/dl.
e.
Serum creatinine ≤ 1.5 x ULN.
f.
Creatine phosphokinase (CPK) ≤ 2.5 x ULN.
9.
Washout periods prior to Day 1 of Cycle 1: 
a.
At least three weeks since the last chemotherapy (six weeks if therapy contained 
nitrosureas or systemic mitomycin C).
b. At least four weeks since the last monoclonal antibody (MAb) containing 
therapy or radiotherapy (RT) > 30 Gy.
c.
At least one week since the last hormonal therapy.
d. At least two weeks since the last biological/investigational therapy (excluding 
MAbs) or palliative RT (≤ 10 fractions or ≤ 30 Gy total dose).
10. Grade ≤ 1 toxicity due to any previous cancer therapy according to the National 
Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE, 
v4). Grade ≤ 2 is allowed in case of alopecia, skin toxicity, asthenia and/or 
peripheral sensory neuropathy.
11. Patients of child-bearing potential must agree to use a medically approved method 
of contraception method until at least six weeks after the last study drug 
administration.
Patients in Cohorts A and A1
12. Known deleterious germline mutation of BRCA1/2.
Patients in Cohort A
13. Prior treatment with PARP inhibitors.
4.2.
EXCLUSION CRITERIA
Patients fulfilling any of the following criteria will not be included into the trial:
All patients
1.
Prior treatment with PM01183 or trabectedin.
2.
Prior RT in more than 35% of the bone marrow.
3.
Prior or concurrent malignant disease unless in complete remission for more than 
five years. Exceptions are contralateral ductal or lobular breast carcinoma, 
adequately treated in situ carcinoma of the cervix, basal or squamous skin cell 
carcinoma, in situ melanoma, and in situ transitional bladder cell carcinoma, which 
are allowed to enter the study.
4.
Histology other than ductal or lobular carcinoma of the breast.
5.
Symptomatic, steroid requiring or progressive central nervous system (CNS) 
involvement. In case of known brain metastasis, clinical stability and lack of 
radiological progression of lesions should be demonstrated for at least the 
immediate six weeks before study entry.
6.
Exclusively bone-limited disease.
7.
Relevant diseases or clinical situations which may increase patient’s risk of serious 
adverse events (AEs) (any of the following):


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 or treatment-requiring arrhythmia.
b. Grade ≥ 3 dyspnea or daily intermittent oxygen requirement.
c.
Active uncontrolled infection.
d. Unhealed wound or presence of any external drainage.
e.
Chronically active hepatitis B virus (HBV) or hepatitis C virus (HCV).
f.
Immunocompromised patients, including those known to be infected by human 
immunodeficiency virus (HIV).
g. Known myopathy or persistent CPK elevations > 2.5 x ULN in two different 
determinations performed one week apart.
8.
Pregnant or breastfeeding women.
9.
Impending need for RT (uncontrolled painful bone metastasis and/or risk of spinal 
cord compression).
10. Limitation of the patient’s ability to comply with the treatment or to follow-up the 
protocol.
Patients in Cohort B
11. Known deleterious germline mutation of BRCA1/2.
5.
TREATMENT
5.1.
STUDY MEDICATIONS
5.1.1.
Study Drug Formulation and Supply
PM01183 drug product (DP) is presented as a lyophilized powder for concentrate for 
solution for infusion with two strengths: 1 mg/vial and 4 mg/vial, which will be 
supplied by the Sponsors for the purposes of this study.
Before use, the 1-mg vial and 4-mg vial should be reconstituted with 2 ml and 8 ml of 
water for injection, respectively, to give a solution containing 0.5 mg/ml of PM01183. 
For administration to patients as an i.v. infusion, reconstituted vials should be diluted 
either 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 1-mg and 4-mg vials and the reconstituted 
solution per ml is summarized in Table 1.
Table 1. Composition of vials.
Component
PM01183
1 mg
PM01183
4 mg
Concentration 
per vial after 
reconstitution
PM01183
1.00 mg
4.00 mg
0.50 mg/ml
Sucrose
200.00 mg
800.00 mg
100.00 mg/ml
Lactic acid
5.52 mg
22.08 mg
2.76 mg/ml
Sodium hydroxide
1.28 mg
5.12 mg
0.64 mg/ml


For instructions regarding drug inventory, handling, reconstitution, dilution, storage and 
disposal, please refer to the Preparation Guide for PM01183 and the PM01183 IB, both 
provided as separate documents.
5.2.
ADMINISTRATION OF STUDY MEDICATIONS
5.2.1.
Route of administration, starting dose, and schedule
Patients included under protocol versions 1.0 and 2.0 will receive PM01183 i.v. as a 
one-hour infusion on Day 1 q3wk at a starting dose of 7.0 mg FD (three weeks = one 
treatment cycle).
Patients included from protocol version 3.0 onward (after implementation of 
amendment no. 2) will receive PM01183 i.v. as a one-hour infusion on Day 1 q3wk at 
a starting dose of 3.5 mg/m2 (three weeks = one treatment cycle). Dose will be capped 
at BSA of 2.0 m2 (i.e., dose will not exceed 7 mg). BSA will be calculated according to 
standard practice at each center.
PM01183 will be administered over a minimum total volume of 100 ml of solution for 
infusion (either on 5% glucose or 0.9% sodium chloride) through a central catheter or 
over a minimum total volume of 250 ml if through a peripheral line, always over one 
hour at a fixed infusion rate.
5.2.2.
Criteria for Treatment Continuation
Before the administration of each dose (re-treatment) on Day 1 of each cycle, patients 
must fulfill all of the criteria defined in Table 2.
Table 2. Criteria for continuation of treatment.
Variable 
Re-treatment
Day 1 
ECOG-PS
≤ 2
Hemoglobin*
8 g/dl
ANC
1.5 x 109/l
Platelets
75 x 109/l
AST/ALT
3.0 x ULN
Total bilirubin or 
direct bilirubin
1.5 x ULN or
x ULN
Albumin
2.7 g/dl
Serum creatinine
≤2.0 x ULN
CPK
Grade ≤ 1
Other non-hematological drug-related AEs (except isolated 
increased GGT and/or AP¥, grade 3 asthenia lasting < 1 week, 
non-optimally treated nausea and/or vomiting) 
Grade ≤ 2
* Patients may receive packed red blood cells (PRBC) transfusion and/or erythropoietin (EPO) treatment, if clinically 
indicated, to increase/maintain adequate hemoglobin levels.
¥ Any grade accepted for non-drug-related increase of GGT and/or AP.
AE(s), adverse event(s); ANC, absolute neutrophil count; AP, alkaline phosphatase; AST/ALT, aspartate 
aminotransferase/alanine aminotransferase; CrCl, creatinine clearance; CPK, creatinine phosphokinase; ECOG, Eastern 
Cooperative Oncology Group; GGT, gamma-glutamyltransferase; PS, performance status; ULN, upper limit of normal.


If a patient does not meet the requirements for re-treatment on Day 1 of any following 
cycle, regardless of the reason, re-assessments will be performed every 48-72 hours. 
Treatment will be then withheld, up to a maximum of three weeks beyond its due date, 
until appropriate recovery.
Patients not meeting re-treatment criteria after a maximum three-week delay the patient 
must be withdrawn from the trial, except in case of objective clinical benefit (upon 
Sponsors’ agreement). 
For any delay lasting more than one week due to treatment-related toxicity (unless 
exclusively due to neutropenia), a dose reduction must be implemented upon recovery
following the rules explained in the next section. Conversely, if the delay was 
exclusively due to neutropenia related to PM01183, treatment may continue without 
dose reduction but with appropriate secondary prophylaxis with granulocyte colony-
stimulating factor (G-CSF).
5.2.3.
Dose Reduction
Study treatment may continue with an appropriate dose reduction (Table 3) if patient 
benefit is perceived by the Investigator (upon Sponsors’ agreement), even after the 
patient experienced any of the following:

Grade ≥ 3 treatment-related non-hematological toxicity. Exceptions are: grade 3 
nausea and/or vomiting not optimally treated, grade 3 asthenia lasting < 1 week, 
grade 3 diarrhea lasting ≤ 2 days or not optimally treated, grade 3-4 hypersensitivity 
and/or extravasation reactions, grade 3 transient ALT/AST elevations which are 
rapidly reversible and not leading to subsequent delays, and/or not clinically 
relevant biochemical abnormalities [i.e., in gamma-glutamyltransferase (GGT), 
lactate dehydrogenase (LDH) and/or alkaline phosphatase (AP) levels], none of 
which require dose reduction to be implemented.

Grade 4 thrombocytopenia or grade 3 thrombocytopenia concomitantly with 
grade ≥3 bleeding.

Frequent or prolonged (>1 week) dose delays due to treatment-related toxicity.
Patients experiencing grade 4 neutropenia or febrile neutropenia during the preceding 
cycle, or treatment delays exclusively due to neutropenia that lasted >1 week, may 
continue treatment without any dose reduction but must receive secondary prophylaxis 
with G-CSF instead. The G-CSF secondary prophylaxis will be administrated 
subcutaneously at 300 μg/day for five consecutive days starting on Day +3 of the 
corresponding cycle. If despite appropriate G-CSF prophylaxis, grade 4 neutropenia or 
febrile neutropenia re-occurs, then dose reduction should be implemented.
Table 3. Guidelines for dose reduction.
Dose reduction level*
PM01183 dose (mg, FD)
Patients included under 
protocol versions 1.0, 2.0
PM01183 dose (mg/m2)
Patients included from 
protocol version 3.0 onward**
  1
7.0
3.5
−1
6.0
2.6
−2
5.0
2.0
* Except for grade ≥ 3 nausea and/or vomiting not optimally treated, grade 3 asthenia lasting < 1 week, grade 3 
diarrhea lasting ≤ 2 days or not optimally treated, grade 3-4 hypersensitivity and/or extravasation reactions, grade 3 
transient ALT/AST elevations which are rapidly reversible and not leading to subsequent delays, and/or isolated not 


clinically relevant biochemical abnormalities (i.e., GGT, LDH and/or AP), none of which require dose reduction to 
be implemented.
**Dose will be capped at BSA of 2.0 m2 (starting dose will not exceed 7 mg). BSA will be calculated according to 
standard practice at each center.
ALT/AST, aspartate aminotransferase/alanine aminotransferase; AP, alkaline phosphatase; FD, flat dose; GGT, 
gamma-glutamyltransferase; LDH, lactate dehydrogenase.
Up to two dose reductions are allowed per patient. 
Once the dose has been reduced for an individual patient, it will not be re-escalated 
under any circumstances.
5.2.4.
Dose Escalation
No dose escalation will be allowed in this clinical trial.
5.3.
CONCOMITANT MEDICATION
5.3.1.
Prophylactic Medications
Patients must receive standard antiemetic prophylactic medication at least 30 minutes 
before the administration of PM01183, as follows:
Corticosteroids (dexamethasone i.v. or equivalent at institutional standard 
antiemetic doses)
Serotonin (5-HT3) antagonists (ondansetron 8 mg i.v. or equivalent)
If necessary and in addition to the above, any of the following could apply:
Administration of 10 mg of metoclopramide (or equivalent) every eight hours 
Extended treatment with 5-HT3 antagonists and/or dexamethasone 
Aprepitant and directly related agents (e.g., fosaprepitant) are forbidden.
An optimal antiemetic prophylaxis is defined, for the purpose of safety evaluations, as 
any of the aforementioned medications at their respectively maximum dosages.
5.3.2.
Allowed Medications/Therapies
The following medications or therapies are allowed to be administered during the study:

Therapies for preexisting and treatment-emergent medical conditions, 
including pain management.

Blood products and transfusions, as clinically indicated.

Bisphosphonates.

In case of nausea or vomiting, secondary prophylaxis and/or symptomatic 
treatment for emesis according to ASCO guidelines.

Erythropoietin (EPO) treatment according to ASCO guidelines.

Granulocyte colony-stimulating factor (G-CSF) for the treatment of grade 4 
neutropenia, any grade febrile neutropenia, or neutropenic infection. After 
Cycle 1, secondary prophylaxis is allowed if applicable.

Anticoagulation therapy for the treatment or secondary prophylaxis of deep 
vein thrombosis. 

Luteinizing hormone-releasing hormone (LHRH) agonists, in women of 
reproductive age.


5.3.3.
Prohibited Medications/Therapies
The following medications or therapies are not allowed to be administered during the 
study:

Concomitant administration of any other antineoplastic therapy, except therapy 
with LHRH agonist if applicable.

Any other investigational agents.

Immunosuppressive therapies other than corticosteroids. 

Primary G-CSF prophylaxis or treatment of non-febrile grade ≤ 3 neutropenia 
with G-CSF (unless previously agreed case-by-case between the Investigator 
and the Sponsor).

Aprepitant, fosaprepitant and directly related compounds.

Radiotherapy (RT), except for bone limited-field bone radiation for pain 
control purposes.
5.3.4.
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 (21) (see 
also Appendix 4).
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. 
5.3.5.
Protein Binding
The plasma protein binding of PM01183 ranged from 88 to 98% in all species tested. In 
human, about 97% of PM01183 was bound to plasma proteins, and this was 
independent of the drug concentration. Caution is therefore recommended when 
concomitant medication known to be highly protein-bound (e.g., warfarin) is 
administered together with PM01183.


5.3.6.
Urinary Excretion
Less than 1% (mean 0.53%, n=13) of the unchanged parent compound was recovered 
from the urine of the patients treated in the PM1183-A-001-08 clinical study; thus, 
urinary excretion is not likely to be a major elimination route for PM01183. 
5.4.
DRUG ACCOUNTABILITY
Proper drug accountability will be done by the clinical trial monitor. Each study site will 
keep records to allow a comparison of quantities of drug received and used at each site. 
The Investigator at each study site will be the person ultimately responsible for drug 
accountability at the site.   
All unused drug supplied by the Sponsors will be properly destroyed at the study site. 
Documentation of this procedure must be provided to the clinical trial monitor. If 
Sponsors agree, unused drug supplies may be returned to the drug repository.
5.5.
TREATMENT COMPLIANCE
The Investigator is responsible for supervising compliance with the instructions 
described in this study protocol.
6.
PLAN OF THE STUDY
6.1.
DURATION OF STUDY (WHOLE POPULATION)
The total duration of the study (including both stages) will be approximately 72 months. 

Planned start date (first patient on study): second quarter 2012 (2Q12).

Planned enrollment period: 60 months.

Planned end-of-study date (clinical cut-off): nine months after the last patient-
last treatment visit in the study, or 12 months after the last evaluable patient is 
enrolled (whichever occurs first).
6.2.
DURATION OF STUDY (PER PATIENT)
Patients will be individually evaluated at scheduled visits in up to three study periods: 
Screening: from signature of the ICF to first infusion of PM01183.
Treatment: from first infusion of PM01183 to end of treatment (EOT). EOT is 
defined as 30 days after the date of PM01183 last administration, unless the patient 
starts a new antitumor therapy or dies within those 30 days, in which case the date of 
administration of this new antitumor therapy or the date of death will be considered 
as EOT.
Follow-up: after EOT, patients will be followed for any ongoing treatment-related 
AEs every four weeks until recovery to grade ≤1, or until symptoms stabilization,
whenever possible.
Patients will be followed for at least one year after their first infusion. Those who 
discontinued treatment without PD will be assessed every two months during the 
first six months after last tumor assessment and every three months thereafter, until 


PD, start of other antitumor therapy, death, or study completion, whichever occurs 
first. 
After documented PD or start of a new antitumor therapy, patients will be followed 
every six months until death or study completion, whichever occurs first. For the 
purpose of collecting information on the patient’s survival exclusively, a 
documented telephone call would be acceptable. 
Patients will be considered to be on-study from the signature of the clinical ICF to the 
end of the follow-up period (or screening failure).
Patients will be considered to be on-treatment from the date of first infusion of 
PM01183 until EOT.
6.2.1.
End of Treatment and Off-study
6.2.1.1. End of Treatment
Treatment discontinuation occurs when an enrolled patient ceases to receive the study 
medication, regardless of the circumstances. By convention, the date of end of treatment 
will be 30 days after the date of last administration of study drug, unless the patient 
starts a new antitumor therapy or dies within those 30 days, 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.
The primary reason for any discontinuation will be recorded on the patient’s Case 
Report Form (CRF).
If a patient discontinues treatment, every effort should be made to complete the 
scheduled assessments.
6.2.1.2. Reasons for End of Treatment
Patients will receive study drug as long as it is considered to be in their best interest. 
Specifically, the assigned treatment will continue until:

Disease progression.

Unacceptable toxicity (except in case of clear clinical benefit, with the Sponsors’
approval), after appropriate dose reduction.

Intercurrent illness of sufficient magnitude to preclude safe continuation of the 
study.

Patient refusal and/or noncompliance with study requirements.

Investigator’s decision.

Protocol deviation with an effect on the management of the patient’s risk/benefit 
ratio. 

Treatment delay > 3 weeks from the treatment due date (except in case of clear 
clinical benefit, upon Sponsors’ approval).

Requirement of > 2 dose reductions.
Regardless of the reason, patients who discontinue the treatment must not be re-treated
at any time.
6.2.1.3. Off-study
Off-study occurs when an enrolled patient ceases to participate in the study, regardless 
of the reason. Patients have the right to withdraw consent at any time; if this is the case, 
no further follow-up should be performed.


The date and reason for study discontinuation will be clearly documented on the 
patient’s CRF. If a patient is lost to follow-up an attempt will be made to collect the 
information on the patient’s survival and date of death (when applicable).
6.2.2.
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/Institutional Review 
Board (IEC/IRB) and Competent Authorities. Therefore, this 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 drug (PM01183) due to not following dose 
adjustment specifications or an incorrect preparation of the medication.

Deviations related to the following of GCP guidelines as described in the 
protocol and regulations in force, such as deviations when obtaining the 
Informed Consent or not following the terms established for reporting serious 
adverse events, etc.
As a general rule, no deviations that may have an effect on the risk/benefit ratio of the 
clinical trial will be authorized. All protocol deviations considered particularly relevant, 
which are related to ethical issues, fulfillment of GCP guidelines and trial procedures, 
will be notified to the pertinent IEC/IRB and, if pertinent, to the relevant authorities as 
established by local regulations.
For those patients in Cohort A1 whose disease is not amenable to biopsy, non-
availability of the biopsy specimen will not be considered a deviation but the patient can 
only be included after Sponsor approval.
6.3.
SCREENING EVALUATIONS
During the screening period, and once the patient has signed the ICF, the Investigator 
will confirm the patient’s eligibility for the study by conducting the assessments 
described in Table 4.
Note that a 3-day window will be allowed for laboratory procedures, a 14-day window 
for radiological procedures [helical computed tomography (CT)-scan or magnetic 
resonance imaging (MRI)] and LVEF assessments, and a 24-hour window for clinical 
assessments [ECOG, physical examination, vital signs, electrocardiogram (ECG), 
weight, BSA, etc.].
Additional information on the collection and processing of pharmacogenomic (PGx)
samples will be provided as a separate document. For details on PGx procedures please 
refer to Section 10.


Table 4. Screening assessments.
SCREENING ASSESSMENT
TIME (1)
1. Medical 
history and 
clinical 
examination
Written informed consent.
Written PGx substudy informed consent
(optional for cohorts A and B).
Prior to any specific study procedures.
Demographic data.
Primary diagnosis and prior treatment(s).
LVEF by ECHO or MUGA.
Within 28 days prior to Day 1 of Cycle 1.
Medical history and prior conditions
Intercurrent events, concomitant diseases 
and treatments.
Within 14 days prior to Day 1 of Cycle 1.
Assessments of signs and symptoms.
Complete physical examination, including 
weight and height.

Performance status (ECOG PS; see 
Appendix 1).
Vital signs: heart rate, blood pressure and 
body temperature.
ECG (2).
Within 7 days prior to Day 1 of Cycle 1.
2. Laboratory 
tests
Coagulation panel: PT/INR and PTT.
Hematology: hemoglobin, platelet counts, 
and 
differential
WBC 
including 
neutrophils, monocytes, and lymphocytes.
Biochemistry A: serum electrolytes (Na+, 
K+, Cl−), AST, ALT, AP, GGT, total 
bilirubin (direct bilirubin to be measured 
only if total bilirubin is abnormally high),
LDH, creatinine, glucose, and CPK (CPK-
MB fraction and troponin T or I should 
only be measured if CPK is abnormally 
high or if clinically indicated). 
Biochemistry B: total proteins, albumin, 
CRP, Ca++, phosphorus, Mg++. CA 15-3 or 
27.29. Alpha-1 acid glycoprotein, total 
cholesterol, triglycerides, and LDL.
Within 7 days prior to Day 1 of Cycle 1.
3. Pregnancy 
test (3)
In patients of childbearing potential only.
Within 7 days prior to Day 1 of Cycle 1.
4. Radiological 
and/or clinical 
tumor 
assessment
Contrast enhanced helical CT-scan or MRI 
(if indicated) of all measurable sites of 
disease involvement, as per RECIST v.1.1 
(see Appendix 2). 
Appropriate test (radiological or clinical) of 
all non-measurable sites of disease.
Within 28 days prior to Day 1 of Cycle 1 (4).
5. PGx paraffin-
embedded 
tumor tissue (5)

From available prior tumor samples 
(primary tumor and/or metastasis).
For Cohort A1 patients only: a baseline
tumor biopsy.
- Archived biopsy sample from diagnosis.
- Recent biopsy sample taken at any time 
between the end of last antitumor therapy 
until before first study drug infusion.
6. AEs
All events should be graded as per NCI-
CTCAE v4.
SAEs will be collected from the signing of 
the ICF.
7. BRCA1/2 
germline 
mutation 
analysis
To be conducted on patients with unknown 
germline BRCA mutation status, who meet 
criteria for consideration of BRCA 1/2 
genetic testing. (6)
-
1. A 3-day window will be allowed for laboratory procedures, a 14-day window for radiological procedures (contrast enhanced 
helical CT-scan or MRI) and LVEF assessments, a 24-hour window for clinical assessments (ECOG, vital signs, ECG, weight, 
BSA, etc.). 
2. Cardiac rhythm will be identified in ECG intervals of at least 30 seconds of duration, PR interval, QT interval (raw), heart rate 
(HR) and QRS complex.
3. If serum human chorionic gonadotropin (HCG) results are abnormally high, pregnancy must be clinically discarded by an 
additional test (i.e., US) before any other study procedure.


4. Patients with previously known CNS involvement at study entry must have documented non-PD by appropriate method.
5. Prior available stored paraffin-embedded tumor samples from the primary tumor and/or from metastases. For cohort A1 patients 
whose disease is not amenable to tumor biopsy, approval by the sponsor must be requested prior to inclusion. In any case, the 
origin of the sample must be specified: diagnosis (primary tumor or metastasis) or baseline sample.
6. National Comprehensive Cancer Network (NCCN) criteria for consideration of BRCA1/2 genetic testing (see Appendix 3).
AE(s), adverse event(s); ALT, alanine aminotransferase; AP, alkaline phosphatase; AST, aspartate aminotransferase; CA 15-3 or 
27.29, cancer antigen 15-3 or 27.29; CNS, central nervous system; CPK, creatinine phosphokinase; CPK-MB, creatinine 
phosphokinase muscle band; CT, computed tomography; ECG, electrocardiogram; ECHO, echocardiography; ECOG, Eastern 
Cooperative Oncology Group; GGT, gamma-glutamyltransferase; ICF, informed consent form; INR, international normalized 
ratio; LDH, lactic dehydrogenase; LVEF, left ventricular ejection fraction; MRI, magnetic resonance imaging; MUGA, multiple-
gated acquisition scan; NCI-CTCAE, National Cancer Institute Common Terminology Criteria for Adverse Events; PD, 
progressive disease; PS, performance status; PT, prothrombin time; PTT, partial thromboplastin time; RECIST, Response 
Evaluation Criteria In Solid Tumors; RT, radiotherapy; SAE, serious adverse event; WBC, white blood cells.
6.4.
PATIENT REGISTRATION
After the patient has signed the ICF and upon ensuring that she meets all eligibility 
criteria, the patient will be entered into the trial by contacting the clinical trial monitor 
designated by the Sponsors and faxing the completed Patient Registration Form (Fast 
Fact Sheet, FFS). The FFS will be checked and eligibility confirmed by the Sponsors. A 
patient number will be provided to the site of enrollment within one working day. This 
patient number should be used on all future documentation and correspondence 
referring to this patient. Investigators are under no circumstances allowed to treat any 
patient before appropriate reception of the patient registration number, which confirms 
the Sponsors’ agreement. Any patient treated prior to registration without the Sponsors’
agreement and/or before receipt of the appropriate documentation may not be 
considered evaluable for the study and may need to be replaced. 
6.5.
PATIENT RANDOMIZATION
Not applicable.
6.6.
EVALUATIONS DURING TREATMENT
The assessments to be done while the patient is on treatment are shown in Table 5.Note 
that a window of duration similar to that for each of the procedures during the screening 
will be allowed.


Table 5. Evaluations during treatment.
TREATMENT ASSESSMENT
TIME (1)
1. Clinical 
examination
Complete physical examination, including 
weight (height is only required at baseline).
Repeat on Day 1 from Cycle 2 
onwards, always prior to PM01183 
administration.

Performance status (ECOG PS; see 
Appendix 1).
Vital signs: heart rate, blood pressure and 
body temperature.
Intercurrent events, concomitant therapies
and treatments.
Throughout the “on treatment” period 
(i.e., during treatment plus 30 ± 7 days
after the last PM01183 administration).
2. Laboratory tests

Hematology(2):
hemoglobin, 
platelet 
counts, and differential WBC including 
neutrophils, monocytes, and lymphocytes.

Biochemistry
A(2):
serum electrolytes 
(Na+, K+, Cl−), liver function test (AST, 
ALT, AP, GGT, and total bilirubin; direct 
bilirubin to be measured only if total 
bilirubin is abnormally high;), LDH, 
creatinine, 
glucose, 
CPK 
(CPK-MB 
fraction and troponin T or I should only be 
measured if CPK is abnormally high or if
clinically indicated).
Repeat in Cycle 1 (Days 8 and 15) and 
on 
Day 
1 
(prior 
to 
PM01183
administration) and Day 10 of further 
cycles.(3).
Coagulation panel: PT/INR and PTT. 
Biochemistry B: total proteins, albumin, 
CRP, 
and 
serum 
electrolytes 
(Ca++, 
phosphorus, Mg++). CA 15-3 or 27.29 only 
in those patients with abnormally elevated 
values 
at 
baseline.
Alpha-1 
acid 
glycoprotein, 
total 
cholesterol, 
triglycerides, and LDL, before Cycle 2 
only.
Repeat on Day 1 (prior to PM01183 
administration).
3. Pregnancy test (4)
In patients of childbearing potential.
Repeat if clinically indicated.
4. ECG (5)
Repeat if clinically indicated.
5. LVEF
By ECHO or MUGA. The same initial 
method must be used throughout the study.
Repeat if clinically indicated.
6. Radiological 
and/or clinical 
tumor assessment
Contrast enhanced helical CT-scan or MRI 
and/or clinical evaluation if indicated, of all 
original
sites of disease involvement
evaluated at baseline, as per RECIST v.1.1 
(see Appendix 2). Always the same method 
must be used throughout the study.
Every six weeks (starting from first 
treatment administration) up to Cycle 6 
and every 9 weeks thereafter (6).
8. PK
At least 30 treated patients in cohorts A and 
B.
Immediately before and during Cycles 
1 and 2 only.
9. AEs
All events should be graded as per NCI-
CTCAE v4.
Throughout the “on treatment” period 
(i.e., during treatment plus 30 ± 7 days 
after the last PM01183 administration).
10. BRCA1/2 
germline mutation 
analysis
BRCA unknown  patients in cohort B: 
One blood sample at the time of the 
response.
1. A 3-day window will be allowed for laboratory procedures, a 14-day window for radiological procedures (contrast enhanced 
helical CT-scan or MRI) and LVEF assessments, a 24-hour window for clinical assessments (ECOG, physical examination, 
vital signs, ECG, weight, BSA, etc.). 
2. Any patient presenting a grade ≥ 3 treatment-related AE should have all relevant tests re-assessed at least every 48-72 hours 
until recovery to grade ≤ 2.
3. From Cycle 3 onwards Hematology and Biochemistry A tests on Day 10 are to be performed only in patients who 
experienced non-hematological grade ≥3 or hematological grade 4 treatment-related toxicities, or who required any dose 


adjustments or GSF prophylactic therapy, in the preceding cycle. 
4. If serum human chorionic gonadotropin (HCG) results are abnormally high, pregnancy must be clinically discarded by an 
additional test (i.e., US) before any other study procedure. Pregnancy and suspected pregnancy occurring while the patient is 
on study drug are considered immediately reportable events.
5. Cardiac rhythm will be identified in ECG intervals of at least 30 seconds of duration, PR interval, QT interval (raw), heart 
rate (HR) and QRS complex.
6. Patients showing a response must have a confirmatory assessment at least 4 weeks later. 
AE(s), adverse event(s); ALT, alanine aminotransferase; AP, alkaline phosphatase; AST, aspartate aminotransferase; BSA, 
body surface area; CA 15-3 or 27.29, cancer antigen 15-3 or 27.29; CNS, central nervous system; CPK, creatinine 
phosphokinase; CPK MB, creatinine phosphokinase muscle band; CRP, C-reactive protein; CT, computed tomography; ECG, 
electrocardiogram; ECHO, echocardiography; ECOG, Eastern Cooperative Oncology Group; EOT, end of treatment; GGT, 
gamma-glutamyltransferase; HR, heart rate; ICF, informed consent form; INR, international normalized ratio; LDH, lactic 
dehydrogenase; LDL, low-density lipoprotein; LVEF, Left ventricular ejection fraction; MRI, magnetic resonance imaging; 
MUGA, multiple-gated acquisition scan; NCI-CTCAE, National Cancer Institute Common Terminology Criteria for Adverse 
Events; PD, progressive disease; PK, pharmacokinetics, PR, partial response; PS, performance status; PT, prothrombin time; 
PTT, partial thromboplastin time; RECIST, Response Evaluation Criteria In Solid Tumors; SAE, serious adverse event; US, 
ultrasound; WBC, white blood cells.
6.7.
EVALUATIONS AT END OF TREATMENT
The EOT visit will be scheduled at 30 days after the last dose of study treatment (a 
window of ± 7 days is allowed), unless the patient starts a new antitumor therapy or dies 
within those 30 days from the last dose, in which case the date of administration of this 
new antitumor therapy or the date of death will be considered as EOT.
For treated patients, regardless of the reason for discontinuation, if no recent data are 
available (i.e., within last 10 days prior to the EOT visit) or if the last data available 
show a grade ≥ 2 alteration, the following work-up will have to be done at this EOT 
visit:

Complete physical examination, including weight (height only at baseline).

ECOG performance status.

Vital signs (heart rate, blood pressure, body temperature).

Coagulation panel.

Hematology.

Biochemistry A.

Biochemistry B.

Pregnancy test, if clinically indicated.

Electrocardiogram (ECG), if clinically indicated.

LVEF by echocardiography (ECHO) or MUGA, if clinically indicated.

Radiological and/or clinical tumor assessment (if not previously done and if the 
reason for treatment discontinuation was other than PD). 

Intercurrent events, concomitant diseases and treatments.

Safety assessment (AEs).
Adverse events (AEs) and serious adverse events (SAEs) must be reported until 30 days 
after the last PM01183 administration (for safety reporting see Section 11.2).
The Sponsors will evaluate all safety information that is spontaneously reported by an 
Investigator beyond the time frame specified in the protocol.
Patients of childbearing potential who use adequate contraception methods while on 
study should be reminded to continue adequate contraception for a period of six weeks 
after last study drug administration.


6.8.
FOLLOW-UP AFTER END-OF-TREATMENT VISIT
The date and reason of the end of study will be recorded on the patient’s CRF. 
After the end of treatment, all AEs and SAEs suspected to be related to PM01183 must 
be followed-up until recovery to grade ≤ 1 or symptoms stabilization whenever possible
(for safety reporting see Section 11.2). Pregnancy and suspected pregnancy occurring 
within six weeks from the patient’s last PM01183 administration are considered 
immediately reportable events.
Additionally, radiological and/or clinical tumor assessments will be done during the 
follow-up only to those patients who discontinue treatment without documented disease 
progression. Patients will be followed every two months during the first six months 
after last tumor assessment and every three months thereafter until PD, start of other 
antitumor therapy, death, or study completion (clinical cut-off), whichever occurs first.
After documented progression or start of a new antitumor therapy, patients will be 
followed every six months, until death or study completion (clinical cut-off), whichever 
occurs first. For this purpose of collecting information on the patient’s survival 
exclusively, a documented telephone call would be acceptable and no visits to the 
hospital will be required.
Patients who withdraw consent will not be followed with any study procedures. 
6.9.
STUDY COMPLETION (AS A WHOLE - CLINICAL CUT-OFF)
The planned study completion date (clinical cut-off) will be nine months after the last 
patient-last treatment visit in the study, or 12 months after the last evaluable patient is 
enrolled (whichever occurs first).
All patients on active treatment at the date of study completion will be offered to 
continue to receive treatment off-study according to the Investigator criteria and upon 
Sponsors’ agreement.
6.10.
REPLACEMENT OF PATIENTS
Patients will be replaced if they are not evaluable for the primary endpoint of the study 
(ORR as per RECIST v1.1), specifically (any of the following):

They are not eligible.

They have not been treated or have not completed at least one PM01183 
infusion.

They are not evaluable for ORR as per RECIST v1.1 and they are not 
categorized as “treatment failures”. Treatment failures will not be replaced and 
are defined as patients who:  
o
Discontinue treatment due to any treatment-related toxicity before an 
appropriate tumor assessment has been performed, or
o
Withdraw PM01183 after more than two weeks on treatment without 
any formal evaluation
All replaced patients will be included in the general safety analysis, if appropriate. 


7.
STUDY EVALUATIONS
7.1.
EFFICACY
For patients to be evaluable for efficacy they must be eligible, have at least one 
complete infusion of PM01183, and either have at least one assessment (as per RECIST 
v1.1) or be categorized as “treatment failure”.
Antitumor activity will be assessed using RECIST v1.1, on a set of measurable lesions 
identified at baseline as target lesions and non-target lesions (if any) identified at 
baseline as non-target lesions and followed until PD by an appropriate method (contrast 
enhanced helical CT-scan, MRI, and/or clinical assessment). 
Radiological and/or clinical (whenever appropriate) tumor assessment will be
performed at baseline and every six weeks (two cycles) until Cycle 6 or evidence of PD. 
After Cycle 6, tumor assessment will be performed every nine weeks (three cycles) until 
evidence of PD. If an objective response is observed, according to RECIST v1.1, it must 
be confirmed by the same method at least four weeks after the date of the first 
documentation of response.
The date of response, the date of clinical or radiological PD, and the date of death will 
be registered and documented as appropriate.
A copy of the imaging tests conducted on the patients during this clinical trial may be 
requested by the Sponsor for evaluation. In addition, an independent radiological review 
committee may be set up, upon Sponsors’ request, to review tumor assessment 
performed for all responding patients (partial or complete response) after study 
completion.
Patients will be categorized as “treatment failures” if they: 

Discontinue treatment due to any treatment-related toxicity before an 
appropriate tumor assessment has been performed, or

Withdraw PM01183 after more than two weeks on treatment without any 
formal evaluation.
These data will be included as non-evaluable (NE) in the analysis of objective response 
as per RECIST v1.1, although these patients will not need to be replaced as they will 
be considered evaluable for efficacy. 
BRCA1/2 germline mutation analysis
In patients included in Cohort B who respond to PM01183 treatment and whose BRCA 
1/2 mutation status is unknown at study entry, an analysis will be performed in order to 
confirm or exclude deleterious germline BRCA 1/2 mutation. To this end, a blood 
sample will be collected at the time of response. If a BRCA 1/2 mutation is found in her
sample then the patient will be analyzed along with patients included in Cohort A.
7.2.
SAFETY
Patients will be evaluable for safety if they received at least one partial or complete 
infusion of PM01183.
All adverse events (AEs) will be graded according to NCI-CTCAE v4.


The safety profile of patients will be monitored throughout the treatment and up to 30 
days after the last treatment infusion (EOT) or until the date of death, whichever occurs 
first.
Treatment delays, dose reduction requirements, G-CSF and/or transfusions
requirements, and reason for treatment discontinuation will be monitored throughout the 
study.
Any treatment-related AEs will be followed until recovery to grade ≤ 1 or stabilization 
of symptoms, whenever possible. 
8.
STATISTICAL METHODS
The statistical analysis will be done by the Sponsors or under the Sponsors’ authority.
8.1.
ENDPOINTS
8.1.1.
Primary Endpoint
The primary evaluation endpoint for this phase II study is the ORR in the population 
evaluable for efficacy. 
The ORR is defined as the percentage of patients with a confirmed response, either CR 
or PR, according to RECIST v1.1.
8.1.2.
Secondary Endpoints
Duration of response (DR), defined as the time between the date when the response 
criteria (PR or CR, whichever is first reached) are fulfilled to the first date when PD, 
recurrence or death is documented.
Clinical benefit, defined as the percentage of patients with ORR or SD > 3 months, 
according to RECIST v1.1.
Progression-free survival (PFS), defined as the period of time from the date of first 
infusion to the date of PD, death (due to any cause), or last tumor evaluation.
Overall survival rate at one year (1y-OS), defined as the Kaplan-Meier estimate of 
the probability of patients to remain alive at one year. Overall survival (OS) will be 
defined as time from the date of first infusion to the date of death or last contact
Treatment safety: AEs, SAEs, and laboratory abnormalities will be graded according 
to the NCI-CTCAE (v4), reasons for treatment discontinuation, dose reduction 
and/or treatment delays.
PK descriptive analysis and PK/PD correlation, if applicable.
PGx expression profile of selected putative markers potentially predictive of 
response to PM01183, in tissues from tumor samples.
8.2.
SAMPLE SIZE
The primary endpoint for this phase II study is to evaluate ORR.

Cohort A (BRCA+):
At least 53 evaluable patients will be recruited to test the null hypothesis that ORR is 
20% or less (p 0.20) vs. the alternative hypothesis that 40% or more patients have 
objective response (p ≥ 0.4). With these assumptions, if the number of evaluable 
patients with objective response is ≥ 17, then this would allow the rejection of the 


null hypothesis.

Cohort A1 (BRAC+/PARPi):
At least 20 evaluable patients will be for an exploratory analysis: if the number of 
patients responding is ≥ 4 (20%), the lower limit of the exact binomial 95% 
confidence interval will be higher than 5% and lack of activity in this subpopulation 
will be ruled out.

Cohort B (unselected):
At least 64 evaluable patients will be recruited to test the null hypothesis that ORR is 
10% or less (p 0.10) vs. the alternative hypothesis that 25% or more patients have 
objective response (p ≥ 0.25). With these assumptions, if the number of evaluable 
patients with objective response is ≥ 12, then this would allow the rejection of the 
null hypothesis.
The variance of the standardized tests is based on the null hypothesis. The type I error 
(alpha) associated with this one-sided test is 0.025 and the type II error (beta) is <0.1; 
hence, statistical power is > 90%. 
Futility analyses controlled by the Gamma family boundary will be performed when 20 
and 30 patients have been evaluated in cohorts A [Gm(-2)] and B [Gm(-1.5)], 
respectively. If less than four out of 20 patients in Cohort A, or less than three patients 
out of 30 in Cohort B achieve an objective response, recruitment to that cohort will be 
stopped. About 110 evaluable patients are expected to be included finally in the three 
cohorts: Cohort A (BRCA+), Cohort A1 (BRCA+/PARPi), and Cohort B (unselected).
8.2.1.
Randomization 
Not applicable.
8.3.
STATISTICAL ANALYSIS
Frequency tables will be prepared by cohort for categorical variables, whereas 
continuous variables will be described by means of summary tables that will include the 
median, minimum, and maximum of each variable. 
8.3.1.
Efficacy Analyses
For the primary endpoint (ORR) the exact binomial estimator and its 95% CI will be 
used.
The time-to-event variables (DR, PFS and OS) and their set time estimates (e.g., PFS3, 
PFS6 and 1y-OS) will be analyzed according to the Kaplan-Meier method.
Exploratory comparison of the efficacy results between the two study cohorts will be 
performed by means of Fisher analysis and logistic regression (ORR), and of log-rank 
test/Cox regression (time-to-event variables). Additionally, if clinically appropriate, the 
two cohorts might be pooled into one, whenever differences between cohorts are 
considered not relevant. In such case, the point estimates and their 95% CIs will be also 
reassessed in order to obtain more accurate calculations.
Exploratory subgroup analyses (e.g., triple negative, hormonal receptor status, HER-2
overexpression, etc.) will be also performed depending on the sample sizes of each 
subgroup, if appropriate.


8.3.2.
Safety Analyses
The safety analyses will consider AEs and SAEs according to their relationship with 
study treatment, as well as analytical results, deaths and the reasons for treatment 
discontinuations, delays and/or dose reductions. 
All AEs and SAEs will be graded according to the NCI-CTCAE, v4. 
8.3.3.
Safety Stopping Rule
In addition to sample size considerations, a decision for early study termination due to 
safety issues will be taken within the initial 30 evaluable patients (regardless of the 
cohort), whenever any of the following occurs: 

Two or more eligible patients die due to treatment-related AEs (>5% of related 
deaths), or

Ten or more patients need to discontinue PM01183 treatment within the first two 
cycles due to any grade 4 treatment-related AEs (NCI-CTCAE v4).
9.
PHARMACOKINETICS
PK parameters of plasma PM01183 will be evaluated immediately before and during the 
first two cycles with a limited sampling schedule of ten samples in at least 30 treated 
patients in cohorts A and B. The sampling schedule during each cycle will be as shown 
Table 6. All sample collection dates and times will be recorded on the CRF.
The infusion rate will be predetermined to ensure that the total drug dose is infused in 
60 minutes 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 to reflect it on the CRF and PK sheet, writing 
clearly the time of the beginning and the end of the infusion. 
Table 6. Sampling schedule for the determination of PM01183 PKs
Sample
Day
Time
# 1
1
Before infusion
# 2
1
5 min before the end of the infusion (EOI)
# 3
1
15 minutes after EOI
# 4
1
1 hour after EOI
# 5
1
2 hours after EOI
# 6
1
4 hours after EOI
# 7*
1
5 hours and 30 min after EOI
# 8**
2
24 hours after EOI
# 9***
4
72 hours after EOI
# 10****
8
168 hours after EOI
*
There is a 30-minute window (before and after the stated point) in the sampling time.
**
There is a two-hour window (before and after the stated point) in the sampling time.
***
There is a two-hour window before the stated point, or until 24 hours after the stated point in 
the sampling time (this sample must be collected within Day 4 or 5).
**** Preferred time; if weekends or other reasons make the sampling on time difficult, it may be 
obtained with a 24-hour window before or after the stated time. In any case, the sampling time 
should differ by at least 24 hours from the prior sample.
EOI, End of Infusion; h, hour(s); min, minute(s).
The accurate recording of actual dosing and sampling times is much more important than 
the strict adherence to the scheduled times. Therefore, as a result of information obtained 


during sample evaluation, sampling times may be changed (as long as the total number 
and volume of samples is maintained or decreased) in order to improve the schedule.
Blood samples for PK analysis will be obtained through a peripheral vein located in the 
contralateral side to that of the infusion, whenever possible. In any case, the sampling 
vein has to be different to that in which drugs are infused. Even the last sample must 
never be collected from the catheter used for drug infusion. 
If the blood sample is obtained from a catheter, the first milliliter of blood will be 
discarded to avoid dilution of the sample with the solution used to keep it clean. Heparin 
(10 U/ml in normal saline solution) or a slow drip of normal saline solution (10 ml/h) 
can be used to keep the catheter permeable between extractions.
A total of 20 samples of about 4 ml of whole blood will be collected along the first two 
cycles (about 80 ml of whole blood) at the predefined times depicted Table 6. The 
Instruction Manual for Collection, Labeling, Storage and Shipment of Pharmacokinetic 
Samples describes in detail the required procedures. Please read it carefully before PK 
sampling. In short, after collection each sample will be centrifuged and the resulting 
plasma layer transferred into a new tube for the determination of PM01183
concentration. The tubes containing plasma will be stored frozen until their shipment to 
the Central Laboratory for Pharmacokinetic Samples (see Study Contacts). All the 
material for PK procedures will be provided by the Sponsors. 
Once all samples from a patient’s cycle have been collected, they should be shipped for 
analysis to the Central Laboratory for Pharmacokinetic Samples as soon as possible, 
ideally on the next shipping day. If the same center has samples from several patients, 
the samples can be sent in the same shipment. However, the time span between the 
obtainment of the last PK sample from a patient and the shipment of all the 
samples from this patient to the Central Laboratory should not exceed one month.
Sampling PK sheets should be sent together with the samples, but never in contact with 
dry ice. Samples will be identified with the following data: protocol code, drug, patient 
number, sample number, and date and time of collection. The confidentiality of 
patients’ data will be maintained at all times. Samples will be destroyed following the 
appropriate laboratory procedures, after the approval of the final analytical study report 
by the Sponsors.
9.1.
EVALUATION OF PHARMACOKINETICS
Pharmacokinetic parameters will be elucidated using standard non-compartmental 
analysis (NCA). The following parameters will be calculated: AUC, Cmax, CL, and half-
life (t1/2). 
The area under the plasma concentration-time curve (AUCinf) will be determined using 
the log-linear trapezoidal method with extrapolation to infinity using the terminal rate 
constant k (Clast/k, where Clast is the last measured analyte concentration). The Cmax will 
be derived directly from the experimental data. The terminal rate constant (k) will be 
estimated by log linear regression analysis of the terminal phase of the plasma 
concentration vs. time curve. The t1/2 will be calculated from the equation 0.693/k; total 
plasma CL will be determined by dividing the total administered dose by the AUCinf.
If considered appropriate by the Sponsor, compartmental analysis on the study results 
will also be performed, and population PK analysis will be made in pooled results of the 
different studies. If applicable, PK/PD parameters will be correlated.


9.2.
PHARMACOKINETIC STATISTICAL METHODS
PK parameters will be tabulated and selected parameters will be graphically displayed. 
The dose-exposure relationships for Cmax and AUC will be evaluated.
The potential influence on selected PK parameters of selected demographic and clinical 
dichotomous variables (gender, laboratory test results above/below selected cut-off 
values, etc.) will be evaluated by Student’s t test or Mann-Whitney’s U test as 
appropriate.
For multinomial variables, analysis of variance will be used. For selected continuous 
demographic and clinical variables (age, laboratory test results, etc.), relationship with 
selected PK parameters will be graphically explored and assessed using correlation and 
regression methods.
Other tests may be applied if the results of the above evaluations suggest that they may 
yield additional relevant information.
10.
PHARMACOGENOMIC SUBSTUDY
The main objective of the PGx study (optional for cohorts A and B, required for cohort 
A1) is the identification of potential biomarkers of sensitivity or resistance to PM01183 
and whose expression might be predictive of the clinical outcome after treatment with 
PM01183.
Requirements

PM01183-treated patients with prior paraffin-embedded tumor samples, if 
available.

For cohorts A and B, patients who voluntarily sign the ICF for the PGx study will 
participate (refusal will not affect patient participation in the clinical study 
PM1183-B-003-11).

For cohort A1, availability of a baseline (taken at any time between the end of last 
antitumor therapy and before first study drug infusion) tumor biopsy is also 
required. For those patients whose disease is not amenable to tumor biopsy, 
approval by the Sponsors must be requested prior to inclusion.
Potential biomarkers of PM01183 activity will be evaluated on paraffin-embedded 
tumor samples obtained at baseline. Additionally, if archived tumor samples are 
available from the primary tumor and/or from metastases, analyses will be also 
performed in both. Samples will be labeled according to its origin: diagnosis (primary 
tumor or metastasis) or baseline sample. 
The expression levels and subcellular localization of selected molecules involved in 
different DNA repair mechanisms, such as nucleotide excision repair (e.g., XPG), 
homologous recombination repair (e.g., RAD51), among others, will be analyzed. 
Specifically, mRNA and protein from tumor samples will be subjected to quantitative 
reverse transcription polymerase chain reaction (qRT-PCR) and immunohistochemistry 
(IHC) in tissue microarrays (TMA), and immunofluorescence in whole tumor sections.
The polymorphisms and mutational status of genes involved in DNA repair mechanisms 
or related to the mechanism of action of PM01183 or to the disease might also be 
analyzed, if relevant.


All PGx analyses will be performed in central reference laboratories selected by the 
Sponsors (see Study Contacts). Tissue blocks or sections will be shipped at room 
temperature to Pharma Mar S.A. who will coordinate the shipments and will cover all 
the costs. A manual describing the procedures for collection, shipping and handling of 
the samples will be provided as a separate document.
11.
ADVERSE EVENTS
11.1.
DEFINITIONS
11.1.1. 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 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 test 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, 
and/or
The test result is considered to be an AE by the Investigator.
Tumor progression or appearance of new tumor lesions, or any sign or symptom clearly 
related with this circumstance is NOT required to be reported as AEs.
11.1.2. 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 whether expedited 
reporting is appropriate in other situations such an important medical events that may 
not be immediately life-threatening or result in hospitalization but may jeopardize the 


Patient or may require intervention to prevent one of the outcomes listed in the above 
definition.
Tumor progression or appearance of new tumor lesions is NOT required to be reported 
as a SAE.
11.1.2.1. Death
Death as such is the outcome of a SAE and should not be used as the SAE term itself, 
whenever possible. Instead the cause of death should be recorded as the SAE term.
When available, the autopsy report will be provided to the Sponsors.
11.1.2.2. 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.
11.1.2.3. 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 11.2.2). 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., study drug, administration, protocol-required 
intervention/investigations, etc). However, events requiring hospitalizations or 
prolongation of hospitalization as a result of a complication of therapy 
administration or clinical trial procedures will be reported as SAEs.
b. Hospitalization or prolonged hospitalization for technical, practical or social 
reasons, in absence of an AE.
c.
Pre-planned hospitalizations: any pre-planned surgery or procedure must be 
documented in the source documentation. Only if the pre-planned surgery needs to 
be performed earlier due to a worsening of the condition, should this event 
(worsened condition) be reported as a SAE.
Other situations that MUST NOT be considered as hospitalizations are the following:
d. An emergency visit due to an accident where the patient is treated and discharged.
e.
When the patient is held 24 hours for observation and finally is not admitted.
f.
Planned treatments at sites not associated to a hospital and generally considered as 
minor surgical procedures (i.e., laser eye surgery, arthroscopy, etc).
11.1.3. Unlisted/Unexpected Adverse Event
An AE, the nature or severity of which is not consistent with the applicable reference 
safety information.
The Sponsors will use as the reference safety information for the evaluation of 
listedness/expectedness the most updated IB for PM01183.
11.1.4. Adverse Events Related to Study Drugs
An AE is considered an adverse drug reaction (ADR) if it is related to a study drug, i.e., 
if the Investigator’s assessment of causal relationship to the study drug is “Y (yes)” (see 
Section 11.1.6). 


The Investigator will assess the causal relationship of the study drug to the SAE.
The Sponsors may also consider related to the study drug those events for which the 
Investigator assesses the causal relationship with the study drug as “Uk (unknown)” 
when it cannot rule out a role of the study drug in the event.
11.1.5. Expedited Reporting
The Sponsors are responsible for the appropriate expedited reporting of serious 
unlisted/unexpected and related adverse events (SUSAR/SUAE) to the Competent 
Authorities. The Sponsors will also report all SAEs that are unlisted/unexpected and 
related to the study drug to the Investigators and to the IECs/IRBs according to the 
current legislation, unless otherwise required and documented by the IECs/IRBs.
11.1.6. Assessment of Causal Relationship to the Study Drug
The Investigator must provide an assessment of the causal relationship of the study drug 
to each SAE according to the following scale:
Y
There is a reasonable possibility that the study drug caused the SAE.
N
There is no reasonable possibility that the study drug 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.
11.2.
PROCEDURES
11.2.1. Reporting Adverse Events
The Sponsors will collect AEs until 30 days after administration of the last dose of 
study drug, until the start of new antitumor therapy, or until the date of death, whichever 
occurs first. All AEs suspected to be related to the study drug must be followed-up after 
the time of therapy discontinuation until the event or its sequelae resolve to grade ≤1 or 
stabilize at an acceptable level to the Investigator and the Sponsors.
All AEs 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, 
version 4, and assign a relationship to each study drug; 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 Sponsors 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
Represents a reason for change in study dosing or for discontinuation from the 
study treatment, 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).
11.2.2. Reporting Serious Adverse Events
The Sponsors will collect SAEs from the signing of the ICF until 30 days after 
administration of the last dose of study drug, until the start of 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 study drug will be collected. Nonetheless, the 
Sponsors will evaluate any safety information that is spontaneously reported by an 
Investigator beyond the time frame specified in the protocol.
Exemptions from SAE REPORTING:  Events of “disease progression”, even if they 
fulfill any seriousness criterion (i.e., fatal, requiring hospitalization, etc), are exempted 
from SAE reporting and will only be reported in the applicable CRF page.
All SAEs (as defined above) regardless of relationship to the study drug must be 
reported immediately and always within 24 hours to the Pharma Mar S.A. 
Pharmacovigilance Department: using the paper SAE form by fax (+34 91 846 6004); e-
mail (phv@pharmamar.com) or telephone (+34 91 823 4556) are available if a fax 
cannot be sent. 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.  
The preferred reporting method is by faxing the completed SAE form. An initial report 
by telephone must be followed by a completed “Serious Adverse Event Form” by fax or 
e-mail from the investigational staff within one working day.
All SAEs suspected to be related to the study drug must be followed until the event or 
its sequelae resolves or stabilizes at an acceptable level by the Investigator and the 
clinical monitor or his/her designated representative.
11.2.3. 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 study drug at any 
time during pregnancy is suspected.
Therefore, pregnancy and suspected pregnancy occurring while the patient is on study 
drug or within six weeks from the patient’s last PM01183 administration are considered 
immediately reportable events.
The Investigator will report the following events immediately and always within 
24 hours from first knowledge:
Any occurrence of a pregnancy where any kind of exposure to the study drug is 
suspected.
Possible exposure of a pregnant woman.
All reports of elevated/ questionable or indeterminate beta human chorionic 
gonadotropins (β-HCGs).
Immediately after detecting a case of suspected pregnancy in a female clinical trial 
patient, the decision on her continued participation in the clinical trial will be jointly 
taken by the trial patient, the Investigator and the Sponsors 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 by facsimile 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 by facsimile 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 should also be reported 
to Pharma Mar S.A. Pharmacovigilance by facsimile within 24 hours of the 
Investigators’ knowledge of the event.
11.3.
ADVERSE EVENTS MONITORING
Safety review will be performed at Pharma Mar S.A. once CRFs have been monitored, 
collected and shipped to the Sponsors. 
Periodic safety review of clinical data will be performed; however, no formal Data 
Safety Monitoring Board (DSMB) has been appointed for this trial. AEs will be 
monitored by the Investigators and by the study team at Pharma Mar S.A. The personnel 
in charge of this process are defined in the section “Study Contacts” of the protocol. In 
general, a clinical oncologist, together with a member of the Pharma Mar S.A. 
Pharmacovigilance Department, will review the safety data of this trial on an ongoing 
basis.
SAEs will be collected, assessed and reported as per the applicable Regulations by the 
Pharmacovigilance Department. Periodic safety reviews of SAE reports are to be 
conducted by the Clinical Oncologist every 3-6 months, depending on recruitment.
As per the applicable regulations, Pharma Mar S.A. will report to the IECs/IRBs, 
Investigators and Competent Authorities:
expeditedly: all serious, related, unlisted/unexpected AEs or critical safety 
findings from this and any other clinical trial with PM01183, and 
periodically: all relevant safety information generated in all clinical trials with 
the study drug within the Development Safety Update Report (DSUR).
Non-serious AEs will be assessed during monitoring visits by the monitor, who will 
discuss them with the Investigators. 
Any protocol deviation will also be discussed with the Investigator during monitoring 
visits. 


12.
ADMINISTRATIVE SECTION
12.1.
ETHICS
This clinical trial will be conducted in accordance with the ethical principles that have 
their origin in the World Medical Association (WMA) Declaration of Helsinki (see
Appendix 5) and will be consistent with GCP guidelines and pertinent regulatory 
requirements.
The study personnel involved in conducting this trial will be qualified by education, 
training and experience to perform their respective task(s).
The study will be conducted in compliance with the protocol. The protocol, any 
amendments and the patient informed consent will receive 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 Sponsors
before the beginning of the study.
The Investigator and/or the Sponsors 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 Sponsors 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.
12.2.
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 the Sponsors.
During site visits, the trial monitor should revise original patient records, drug 
accountability records and document retention (study file). Additionally, the trial 
monitor should observe study procedures and will discuss any problems with the 
Investigator.
Adequate time for these visits should be allocated by the Investigator. The Investigator 
should also ensure that the monitor is given direct access [as per International 
Conference on Harmonization (ICH) Topic E6 Guideline for Good Clinical Practice, 
Sections 4.9.7 and 6.10] to source documents (i.e., hospital or private charts, original 
laboratory records, appointment books, etc.) of the patient which support data entered in 
the case report forms, as defined in the ICH Topic E6 Guideline for Good Clinical 
Practice, Sections 1.51 and 1.52.
Systems and procedures will be implemented to ensure the quality of every aspect of the 
trial.
During the course of the trial, the Clinical Quality Assurance Department of the 
Sponsors or external auditors contracted by the Sponsors may conduct an onsite audit 
visit (ICH Topic E6 Guideline for Good Clinical Practice, Section 1.6).
Participation in this trial implies acceptance of potential inspection by national or 
foreign health authorities.


12.3.
PATIENT INFORMED CONSENT FORM
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 cohorts A or B, the Investigator or a person designated by the 
Investigator, must provide the patient with one copy of the ICF and one copy of the ICF
for the PGx substudy. Both copies must provide written full information about the 
clinical trial and the PGx substudy, in a language that is non-technical and easily 
understood. The Investigator should allow the necessary time for the patient or his/her 
legally acceptable representative to inquire about the details of the clinical trial and the 
PGx substudy. 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. In addition, the specific consent for hereditary cancer testing (BRCA 1/2 
germline mutation), annexed to the ICF must be signed by those patients whose
mutation status is unknown at study entry (BRCA-UK).
Cohort A and B patients willing to participate in the PGx study will voluntarily sign the 
PGx ICF (refusal will not affect patient participation in the clinical study PM1183-B-
003-11).
A single ICF will be used for patients to be included in cohort A1 as consent to 
participate in the PGx substudy is obligatory for this cohort.
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 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.
12.4.
CONFIDENTIALITY / IDENTIFICATION OF PATIENTS
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 Sponsors’ 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.


The Sponsors 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.
12.5.
CASE REPORT FORMS
Case report forms (CRFs) will be used to record all data for each patient. It is the 
responsibility of the Investigator to ensure that the CRFs are properly and completely 
filled in. CRFs must be completed for all patients who have given their informed 
consent and have been enrolled into the study.
A patient’s source documentation is the physician's patient records, and as such they 
should be maintained at the study site.
The data collected in the CRF will be entered into the Sponsors’ 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. Baseline and off-study visit should be 
completed for patients registered but never treated.
12.6.
INSURANCE
The Sponsors will provide insurance or indemnity in accordance with applicable 
regulatory requirements.
12.7.
RETENTION OF RECORDS
The Investigator/Institution should maintain trial documents according to Section 8 of 
the ICH Topic E6 Guideline for Good Clinical Practice and as required by applicable 
regulatory requirements.
Essential documents should be retained as per the aforementioned ICH guideline or for 
a longer period of time, if required by the applicable regulations. 
12.8.
USE OF INFORMATION AND PUBLICATIONS
Before the investigators of this study submit a paper or abstract for publication or 
otherwise publicly disclose information concerning the study drug or products, the 
Sponsors 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 the Sponsors determine 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 personnel from the Sponsors who have fully participated in the study 
must be considered for co-authorship of the publication.


13.
REFERENCES
1. Coughlin SS, Ekwueme DU. Breast cancer as a global health concern. Cancer 
Epidemiol. 2009;33(5):315-8.
2. Howlader N NA, Krapcho M, Neyman N, Aminou R, Waldron W, Altekruse SF, 
Kosary CL, Ruhl J, Tatalovich Z, Cho H, Mariotto A, Eisner MP, Lewis DR, Chen HS, 
Feuer EJ, Cronin KA, Edwards BK. SEER Cancer Statistics Review, 1975-2008, 
http://seer.cancer.gov/csr/1975_2008/, 
based 
on 
November 
2010 
SEER 
data 
submission, posted to the SEER web site, 2011. Bethesda, MD: National Cancer 
Institute, 2011.
3. Ferlay J, Autier P, Boniol M, Heanue M, Colombet M, Boyle P. Estimates of the 
cancer incidence and mortality in Europe in 2006. Ann Oncol. 2007;18(3):581-92.
4. Chung CT, Carlson RW. Goals and objectives in the management of metastatic 
breast cancer. Oncologist. 2003;8(6):514-20.
5. Carey LA, Perou CM, Livasy CA, Dressler LG, Cowan D, Conway K, et al. Race, 
breast cancer subtypes, and survival in the Carolina Breast Cancer Study. Jama. 
2006;295(21):2492-502.
6. Sorlie T, Tibshirani R, Parker J, Hastie T, Marron JS, Nobel A, et al. Repeated 
observation of breast tumor subtypes in independent gene expression data sets. Proc 
Natl Acad Sci U S A. 2003;100(14):8418-23.
7. Phillips KA. Immunophenotypic and pathologic differences between BRCA1 and 
BRCA2 hereditary breast cancers. J Clin Oncol. 2000;18(21 Suppl):107S-12S.
8. Arver B, Du Q, Chen J, Luo L, Lindblom A. Hereditary breast cancer: a review. 
Semin Cancer Biol. 2000;10(4):271-88.
9. Johannsson OT, Idvall I, Anderson C, Borg A, Barkardottir RB, Egilsson V, et al. 
Tumour biological features of BRCA1-induced breast and ovarian cancer. Eur J Cancer. 
1997;33(3):362-71.
10. Tutt A, Robson M, Garber JE, Domchek SM, Audeh MW, Weitzel JN, et al. Oral 
poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 
mutations 
and 
advanced 
breast 
cancer: 
a 
proof-of-concept 
trial. 
Lancet. 
2010;376(9737):235-44.
11. O'Shaughnessy J. Extending survival with chemotherapy in metastatic breast cancer. 
Oncologist. 2005;10 Suppl 3:20-9.
12. Giordano SH, Buzdar AU, Smith TL, Kau SW, Yang Y, Hortobagyi GN. Is breast 
cancer survival improving? Cancer. 2004;100(1):44-52.
13. Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, et al. Use of 
chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer 
that overexpresses HER2. N Engl J Med. 2001;344(11):783-92.
14. Jones SE. Metastatic breast cancer: the treatment challenge. Clin Breast Cancer. 
2008;8(3):224-33.
15. Roche H, Vahdat LT. Treatment of metastatic breast cancer: second line and 
beyond. Ann Oncol. 2011;22(5):1000-10.
16. Leal JF, Martinez-Diez M, Garcia-Hernandez V, Moneo V, Domingo A, Bueren-
Calabuig JA, et al. 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.


17. Paull KD, Shoemaker RH, Hodes L, Monks A, Scudiero DA, Rubinstein L, et al. 
Display and analysis of patterns of differential activity of drugs against human tumor 
cell lines: development of mean graph and COMPARE algorithm. J Natl Cancer Inst. 
1989;81(14):1088-92.
18. Kelter G. Final Report. In vitro evaluation of 14 novel marine compounds for anti-
cancer activity in 36 human tumor cell lines in a monolayer assay. Oncotest protocol 
No. P62A. 14 December 2005. Report No.
19. Ratain MJ, Elez ME, Szyldergemajn S, Geary D, Kang SP, Maraculla T, et al., 
editors. PM01183 clinical and pharmacokinetic (PK) preliminary results of the first-in-
man phase I study following an accelerated titration design. 22nd EORTC-NCI-AACR 
Symposium on Molecular Targets and Cancer Therapeutics; 2010 16-19 November 
2010; Berlin, Germany.
20. Schoenfeld DA, Rosenbaum C, Horton J, Wolter JM, Falkson G, DeConti RC. A 
comparison of adriamycin versus vincristine and adriamycin, and cyclophosphamide 
versus vincristine, actinomycin-D, and cyclophosphamide for advanced sarcoma. 
Cancer. 1982;50(12):2757-62.
21. Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana 
University School of Medicine. http://medicine.iupui.edu/clinpharm/ddis/table.asp. 
2007.


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
Reference: Am. J. Clin. Oncol 5:649-655, 1982: Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., 
Davis, T.E., McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative 
Oncology Group. 


Appendix 2. Evaluation of Response. The RECIST
This document summarizes the main information contained in RECIST version 1.1. 
Further details can be found in the original article: Eisenhauer EA, Therasse P, 
Bogaerts J, et al.: New response evaluation criteria in solid tumours: revised RECIST 
guideline (version 1.1). Eur J Cancer 2009; 45(2): 228-247.
LIST OF ABBREVIATIONS
CR
Complete Response
CRF
Case Report Form
CT
Computed Tomography
FDG-PET
Fluorodeoxyglucose-Positron Emission Tomography
MRI
Magnetic Resonance Imaging
NE
Not Evaluable
PD
Progressive Disease
PET
Positron Emission Tomography
PFS
Progression-free Survival
PR
Partial Response
PSA
Prostate-specific Antigen
RECIST
Response Evaluation Criteria in Solid Tumors
SD
Stable Disease
TTP
Time to Progression
LIST OF TABLES
Table 1. Summary of major changes from RECIST 1.0 to RECIST 1.11.
Table 2. Time point response: patients with target (+/–non-target) disease.
Table 3. Time point response: patients with non-target disease only.
                                                
1This table is named Appendix I in the original RECIST 1.1 article.


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) 
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: 
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 


RECIST 1.0
RECIST 1.1
Rationale
How to assess and 
measure lymph nodes 
CR in face of residual 
tissue 
Discussion of 
‘equivocal’ 
progression 
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
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 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 computerized 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 
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.
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.
Computed Tomography (CT), Magnetic Resonance Imaging (MRI): 
CT is the best currently available and reproducible method to measure lesions selected 
for response assessment. This guideline has defined measurability of lesions on CT scan 
based on the assumption that CT slice thickness is 5 mm or less. As is described in 
original article (Appendix II), when CT scans have slice thickness greater than 5 mm, 
the minimum size for a measurable lesion should be twice the slice thickness. MRI is 
also acceptable in certain situations (e.g., for body scans). More details concerning the 
use of both CT and MRI for assessment of objective tumor response evaluation are 
provided in the original article, Appendix II.
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). 
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. 
Lymph nodes merit special mention since they are normal anatomical structures which 
may be visible by imaging even if not involved by tumor. As noted in the previous 
section, pathological nodes which are defined as measurable and may be identified as 
target lesions must meet the criterion of a short axis of ≥ 15 mm by CT scan. Only the 
short axis of these nodes will contribute to the baseline sum. The short axis of the node 
is the diameter normally used by radiologists to judge if a node is involved by solid 
tumor. Nodal size is normally reported as two dimensions in the plane in which the 
image is obtained (for CT scan this is almost always the axial plane; for MRI the plane 
of acquisition may be axial, sagittal or coronal). The smaller of these measures is the 
short axis. For example, an abdominal node which is reported as being 20 mm 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.
2.3.2 Evaluation of Non-target Lesions
This section provides the definitions of the criteria used to determine the tumor response 
for the group of non-target lesions. While some non-target lesions may actually be 
measurable, they need not be measured and instead should be assessed only 
qualitatively at the time points specified in the protocol.
Complete Response (CR):
Disappearance of all non-target lesions and normalization 
of tumor marker level. All lymph nodes must be non-
pathological in size (< 10 mm short axis).
Non-CR/Non-PD:
Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal 
limits. 
Progressive Disease (PD):
Unequivocal progression (see comments below) of 
existing non-target lesions (Note: the appearance of one or 
more new lesions is also considered progression).
2.4 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’.


2.4.1 Time Point Response 
It is assumed that at each protocol speciﬁed time point, a response assessment occurs. 
Table 1 provides a summary of the overall response status calculation at each time point 
for patients who have measurable disease at baseline. 
Table 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. 
When patients have non-measurable (therefore non-target) disease only, Table 2 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 Special Notes on Response Assessment
When nodal disease is included in the sum of target lesions and the nodes decrease to 
‘normal’ size (< 10 mm), they may still have a measurement reported on scans. This 
measurement should be recorded even though the nodes are normal in order not to 
overstate progression should it be based on increase in size of the nodes. As noted 
earlier, this means that patients with CR may not have a total sum of ‘zero’ on the CRF. 
Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
reported as ‘symptomatic deterioration’. Every effort should be made to document 
objective progression even after discontinuation of treatment. Symptomatic 


deterioration is not a descriptor of an objective response: it is a reason for stopping 
study therapy. 
Conditions that deﬁne ‘early progression, early death and inevaluability’ are study 
speciﬁc and should be clearly described in each protocol (depending on treatment 
duration, treatment periodicity). 
2.5 Reporting Best Response Results
2.5.1 Phase II Trials
When response is the primary endpoint, and thus all patients must have measurable 
disease to enter the trial, all patients included in the study must be accounted for in the 
report of the results, even if there are major protocol treatment deviations or if they are 
not evaluable. Each patient will be assigned one of the following categories: 
1. Complete response.
2. Partial response. 
3. Stable disease.
4. Progression.
5. Inevaluable for response: specify reasons [for example: early death, malignant 
disease; early death, toxicity; tumor assessments not repeated/incomplete; other 
(specify)]. 
2.6 Conﬁrmatory Measurement/Duration of Response
2.6.1 Conﬁrmation
In non-randomized trials where response is the primary endpoint, conﬁrmation of PR 
and CR is required to ensure responses identiﬁed are not the result of measurement 
error. This will also permit appropriate interpretation of results in the context of 
historical data where response has traditionally required conﬁrmation in such trials (see 
Bogaerts et al. Eur J Cancer 2009; 45(2): 248-260). However, in all other 
circumstances, i.e., in randomized trials (phase II or III) or studies where stable disease 
or progression are the primary endpoints, conﬁrmation of response is not required since 
it will not add value to the interpretation of trial results. However, elimination of the 
requirement for response conﬁrmation may increase the importance of central review to 
protect against bias, in particular in studies which are not blinded. 
In the case of SD, measurements must have met the SD criteria at least once after study 
entry at a minimum interval (in general not less than 6–8 weeks) that is deﬁned in the 
study protocol.
2.6.2 Duration of Overall Response
The duration of overall response is measured from the time measurement criteria are 
ﬁrst met for CR/PR (whichever is ﬁrst recorded) until the ﬁrst date that recurrent or 
progressive disease is objectively documented (taking as reference for progressive 
disease the smallest measurements recorded on study). 
The duration of overall complete response is measured from the time measurement 
criteria are ﬁrst met for CR until the ﬁrst date that recurrent disease is objectively 
documented. 
2.6.3 Duration of Stable Disease
Stable disease is measured from the start of the treatment (in randomized trials, from 
date of randomization) until the criteria for progression are met, taking as reference the 


smallest sum on study (if the baseline sum is the smallest, this is the reference for 
calculation of PD). 
The clinical relevance of the duration of SD varies in different studies and diseases. If 
the proportion of patients achieving SD for a minimum period of time is an endpoint of 
importance in a particular trial, the protocol should specify the minimal time interval 
required between two measurements for determination of stable disease. 
Note: The duration of response and SD as well as the progression-free survival are 
inﬂuenced by the frequency of follow-up after baseline evaluation. It is not in the scope 
of this guideline to deﬁne a standard follow-up frequency. The frequency should take 
into account many parameters including disease types and stages, treatment periodicity 
and standard practice. However, these limitations of the precision of the measured 
endpoint should be taken into account if comparisons between trials are to be made. 
2.7 Independent Review of Response and Progression
For trials where objective response (CR + PR) is the primary endpoint, and in particular 
where key drug development decisions are based on the observation of a minimum 
number of responders, it is recommended that all claimed responses be reviewed by an 
expert(s) independent of the study. If the study is a randomized trial, ideally reviewers 
should be blinded to treatment assignment. Simultaneous review of the patients’ ﬁles 
and radiological images is the best approach.
Independent review of progression presents some more complex issues: for example, 
there are statistical problems with the use of central-review-based progression time in 
place of investigator-based progression time due to the potential introduction of 
informative censoring when the former precedes the latter. An overview of these factors 
and other lessons learned from independent review is provided in an article by Ford et 
al. Eur J Cancer 2009; 45:268–274.
2.8 Reporting Best Response Results
2.8.1 Phase II Trials
When response is the primary endpoint, and thus all patients must have measurable 
disease to enter the trial, all patients included in the study must be accounted for in the 
report of the results, even if there are major protocol treatment deviations or if they are 
not evaluable. Each patient will be assigned one of the following categories: 
1. Complete response.
2. Partial response. 
3. Stable disease.
4. Progression.
5. Inevaluable for response: specify reasons [for example: early death, malignant 
disease; early death, toxicity; tumor assessments not repeated/incomplete; other 
(specify)].
Normally, all eligible patients should be included in the denominator for the calculation 
of the response rate for phase II trials (in some protocols it will be appropriate to include 
all treated patients). It is generally preferred that 95% two-sided conﬁdence limits are 
given for the calculated response rate. Trial conclusions should be based on the response 
rate for all eligible (or all treated) patients and should not be based on a selected 
‘evaluable’ subset. 


Appendix 3. National Comprehensive Cancer Network (NCCN) criteria 
for consideration of BRCA1/2 genetic testing
A. Individual from a family with a known deleterious BRCA1/BRCA2 mutation
B. Personal history of breast cancer plus one or more of the following:

Diagnosed age ≤45 years 

Diagnosed age ≤50 years with ≥1 first-, second-, or third-degree blood 
relative (on the same side of the family) with breast and/or epithelial 
ovarian/fallopian tube/primary peritoneal cancer at any age, or with a limited 
family historyΔ

Two breast primaries§ when first breast cancer diagnosis occurred ≤50 years 

Diagnosed ≤60 years with a triple negative breast cancer 

Diagnosed ≤50 years with a limited family historyΔ

Diagnosed at any age with ≥1 first-, second-, or third-degree blood relative 
(on the same side of the family) diagnosed with breast and/or epithelial 
ovarian/fallopian tube/primary peritoneal cancer ≤50 years 

Diagnosed at any age with ≥2 first-, second-, or third-degree blood relatives 
(on the same side of the family) with breast and/or epithelial 
ovarian/fallopian tube/primary peritoneal cancer at any age 

Diagnosed at any age with ≥2 first-, second-, or third-degree blood relatives 
(on the same side of the family) with pancreatic cancer or aggressive prostate 
cancer (Gleason score ≥7) at any age 

First-, second-, or third-degree male blood relative (on the same side of the 
family) with breast cancer 

For an individual of ethnicity associated with higher mutation frequency (e.g, 
Ashkenazi Jewish), no additional family history may be required
C. Personal history of epithelial ovarian/fallopian tube/primary peritoneal 
cancer
Δ Individuals with a limited family history, such as fewer than two first- or second-
degree female relatives or female relatives surviving beyond 45 years in either lineage, 
may have an underestimated probability of a familial mutation.
§ Two breast primaries include bilateral (contralateral) disease or two or more clearly 
separate ipsilateral primary tumors either synchronously or asynchronously.
http://www.nccn.org/professionals/physician_gls/pdf/genetics_screening.pdf


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


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)
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.


Appendix 5. Declaration of Helsinki 
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI
Ethical Principles for Medical Research Involving Human Subjects
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964, and 
amended by the:
29th WMA General Assembly, Tokyo, Japan, October 1975
35th WMA General Assembly, Venice, Italy, October 1983
41st WMA General Assembly, Hong Kong, September 1989
48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996
52nd WMA General Assembly, Edinburgh, Scotland, October 2000 
53th WMA General Assembly, Washington 2002 (Note of Clarification on paragraph 
29 added)
55th WMA General Assembly, Tokyo 2004 (Note of Clarification on paragraph 30 
added)
59th WMA General Assembly, Seoul, October 2008
64th WMA General Assembly, Fortaleza, Brazil, October 2013
Preamble
1.
The World Medical Association (WMA) has developed the Declaration of 
Helsinki as a statement of ethical principles for medical research involving 
human subjects, including research on identifiable human material and data.
The Declaration is intended to be read as a whole and each of its constituent 
paragraphs should be applied with consideration of all other relevant paragraphs.
2.
Consistent with the mandate of the WMA, the Declaration is addressed primarily 
to physicians. The WMA encourages others who are involved in medical 
research involving human subjects to adopt these principles.
General Principles
3.
The Declaration of Geneva of the WMA binds the physician with the words, 
“The health of my patient will be my first consideration,” and the International 
Code of Medical Ethics declares that, “A physician shall act in the patient's best 
interest when providing medical care.”
4.
It is the duty of the physician to promote and safeguard the health, well-being 
and rights of patients, including those who are involved in medical research. The 
physician's knowledge and conscience are dedicated to the fulfilment of this 
duty.


5.
Medical progress is based on research that ultimately must include studies 
involving human subjects.
6.
The primary purpose of medical research involving human subjects is to 
understand the causes, development and effects of diseases and improve 
preventive, diagnostic and therapeutic interventions (methods, procedures and 
treatments). Even the best proven interventions must be evaluated continually 
through research for their safety, effectiveness, efficiency, accessibility and 
quality.
7.
Medical research is subject to ethical standards that promote and ensure respect 
for all human subjects and protect their health and rights.
8.
While the primary purpose of medical research is to generate new knowledge, 
this goal can never take precedence over the rights and interests of individual 
research subjects.
9.
It is the duty of physicians who are involved in medical research to protect the 
life, health, dignity, integrity, right to self-determination, privacy, and 
confidentiality of personal information of research subjects. The responsibility 
for the protection of research subjects must always rest with the physician or 
other health care professionals and never with the research subjects, even though 
they have given consent.
10.
Physicians must consider the ethical, legal and regulatory norms and standards 
for research involving human subjects in their own countries as well as 
applicable international norms and standards. No national or international 
ethical, legal or regulatory requirement should reduce or eliminate any of the 
protections for research subjects set forth in this Declaration.
11.
Medical research should be conducted in a manner that minimises possible harm 
to the environment.
12.
Medical research involving human subjects must be conducted only by 
individuals with the appropriate ethics and scientific education, training and 
qualifications. Research on patients or healthy volunteers requires the 
supervision of a competent and appropriately qualified physician or other health 
care professional.
13.
Groups that are underrepresented in medical research should be provided 
appropriate access to participation in research.
14.
Physicians who combine medical research with medical care should involve 
their patients in research only to the extent that this is justified by its potential 
preventive, diagnostic or therapeutic value and if the physician has good reason 
to believe that participation in the research study will not adversely affect the 
health of the patients who serve as research subjects.


15.
Appropriate compensation and treatment for subjects who are harmed as a result 
of participating in research must be ensured.
Risks, Burdens and Benefits
16.
In medical practice and in medical research, most interventions involve risks and 
burdens.
Medical research involving human subjects may only be conducted if the 
importance of the objective outweighs the risks and burdens to the research 
subjects.
17.
All medical research involving human subjects must be preceded by careful 
assessment of predictable risks and burdens to the individuals and groups 
involved in the research in comparison with foreseeable benefits to them and to 
other individuals or groups affected by the condition under investigation.
Measures to minimise the risks must be implemented. The risks must be 
continuously monitored, assessed and documented by the researcher.
18.
Physicians may not be involved in a research study involving human subjects 
unless they are confident that the risks have been adequately assessed and can be
satisfactorily managed.
When the risks are found to outweigh the potential benefits or when there is 
conclusive proof of definitive outcomes, physicians must assess whether to 
continue, modify or immediately stop the study.
Vulnerable Groups and Individuals
19.
Some groups and individuals are particularly vulnerable and may have an 
increased likelihood of being wronged or of incurring additional harm.
All vulnerable groups and individuals should receive specifically considered 
protection.
20.
Medical research with a vulnerable group is only justified if the research is 
responsive to the health needs or priorities of this group and the research cannot 
be carried out in a non-vulnerable group. In addition, this group should stand to 
benefit from the knowledge, practices or interventions that result from the 
research.
Scientific Requirements and Research Protocols
21.
Medical research involving human subjects must conform to generally accepted 
scientific principles, be based on a thorough knowledge of the scientific 


literature, other relevant sources of information, and adequate laboratory and, as 
appropriate, animal experimentation. The welfare of animals used for research 
must be respected.
22.
The design and performance of each research study involving human subjects 
must be clearly described and justified in a research protocol.
The protocol should contain a statement of the ethical considerations involved 
and should indicate how the principles in this Declaration have been addressed. 
The protocol should include information regarding funding, sponsors, 
institutional affiliations, potential conflicts of interest, incentives for subjects and 
information regarding provisions for treating and/or compensating subjects who 
are harmed as a consequence of participation in the research study.
In clinical trials, the protocol must also describe appropriate arrangements for 
post-trial provisions.
Research Ethics Committees
23.
The research protocol must be submitted for consideration, comment, guidance 
and approval to the concerned research ethics committee before the study 
begins. This committee must be transparent in its functioning, must be 
independent of the researcher, the sponsor and any other undue influence and 
must be duly qualified. It must take into consideration the laws and regulations 
of the country or countries in which the research is to be performed as well as 
applicable international norms and standards but these must not be allowed to 
reduce or eliminate any of the protections for research subjects set forth in this 
Declaration.
The committee must have the right to monitor ongoing studies. The researcher 
must provide monitoring information to the committee, especially information 
about any serious adverse events. No amendment to the protocol may be made 
without consideration and approval by the committee. After the end of the study, 
the researchers must submit a final report to the committee containing a 
summary of the study’s findings and conclusions.
Privacy and Confidentiality
24.
Every precaution must be taken to protect the privacy of research subjects and 
the confidentiality of their personal information.
Informed Consent
25.
Participation by individuals capable of giving informed consent as subjects in 
medical research must be voluntary. Although it may be appropriate to consult 
family members or community leaders, no individual capable of giving informed 
consent may be enrolled in a research study unless he or she freely agrees.


26.
In medical research involving human subjects capable of giving informed 
consent, each potential subject must be adequately informed of the aims, 
methods, sources of funding, any possible conflicts of interest, institutional 
affiliations of the researcher, the anticipated benefits and potential risks of the 
study and the discomfort it may entail, post-study provisions and any other 
relevant aspects of the study. The potential subject must be informed of the right 
to refuse to participate in the study or to withdraw consent to participate at any 
time without reprisal. Special attention should be given to the specific 
information needs of individual potential subjects as well as to the methods used 
to deliver the information.
After ensuring that the potential subject has understood the information, the 
physician or another appropriately qualified individual must then seek the 
potential subject’s freely-given informed consent, preferably in writing. If the 
consent cannot be expressed in writing, the non-written consent must be 
formally documented and witnessed.
  
All medical research subjects should be given the option of being informed 
about the general outcome and results of the study.
27.
When seeking informed consent for participation in a research study the 
physician must be particularly cautious if the potential subject is in a dependent 
relationship with the physician or may consent under duress. In such situations 
the informed consent must be sought by an appropriately qualified individual 
who is completely independent of this relationship.
28.
For a potential research subject who is incapable of giving informed consent, the 
physician must seek informed consent from the legally authorised representative. 
These individuals must not be included in a research study that has no likelihood 
of benefit for them unless it is intended to promote the health of the group 
represented by the potential subject, the research cannot instead be performed 
with persons capable of providing informed consent, and the research entails 
only minimal risk and minimal burden.
29.
When a potential research subject who is deemed incapable of giving informed 
consent is able to give assent to decisions about participation in research, the 
physician must seek that assent in addition to the consent of the legally 
authorised representative. The potential subject’s dissent should be respected.
30.
Research involving subjects who are physically or mentally incapable of giving 
consent, for example, unconscious patients, may be done only if the physical or 
mental condition that prevents giving informed consent is a necessary 
characteristic of the research group. In such circumstances the physician must 
seek informed consent from the legally authorised representative. If no such 
representative is available and if the research cannot be delayed, the study may 
proceed without informed consent provided that the specific reasons for 
involving subjects with a condition that renders them unable to give informed 
consent have been stated in the research protocol and the study has been 
approved by a research ethics committee. Consent to remain in the research must 
be obtained as soon as possible from the subject or a legally authorised 
representative.


31.
The physician must fully inform the patient which aspects of their care are 
related to the research. The refusal of a patient to participate in a study or the 
patient’s decision to withdraw from the study must never adversely affect the 
patient-physician relationship.
32.
For medical research using identifiable human material or data, such as research 
on material or data contained in biobanks or similar repositories, physicians 
must seek informed consent for its collection, storage and/or reuse. There may 
be exceptional situations where consent would be impossible or impracticable to 
obtain for such research. In such situations the research may be done only after 
consideration and approval of a research ethics committee.
Use of Placebo
33.
The benefits, risks, burdens and effectiveness of a new intervention must be 
tested against those of the best proven intervention(s), except in the following 
circumstances:
Where no proven intervention exists, the use of placebo, or no intervention, is 
acceptable; or
Where for compelling and scientifically sound methodological reasons the use of 
any intervention less effective than the best proven one, the use of placebo, or no 
intervention is necessary to determine the efficacy or safety of an intervention
and the patients who receive any intervention less effective than the best proven 
one, placebo, or no intervention will not be subject to additional risks of serious 
or irreversible harm as a result of not receiving the best proven intervention.
Extreme care must be taken to avoid abuse of this option.
Post-Trial Provisions
34.
In advance of a clinical trial, sponsors, researchers and host country 
governments should make provisions for post-trial access for all participants 
who still need an intervention identified as beneficial in the trial. This 
information must also be disclosed to participants during the informed consent 
process.
Research Registration and Publication and Dissemination of Results
35.
Every research study involving human subjects must be registered in a publicly 
accessible database before recruitment of the first subject.
36.
Researchers, authors, sponsors, editors and publishers all have ethical 
obligations with regard to the publication and dissemination of the results of 
research. Researchers have a duty to make publicly available the results of their 
research on human subjects and are accountable for the completeness and 


accuracy of their reports. All parties should adhere to accepted guidelines for 
ethical reporting. Negative and inconclusive as well as positive results must be 
published or otherwise made publicly available. Sources of funding, institutional 
affiliations and conflicts of interest must be declared in the publication. Reports 
of research not in accordance with the principles of this Declaration should not 
be accepted for publication.
Unproven Interventions in Clinical Practice
37.
In the treatment of an individual patient, where proven interventions do not exist 
or other known interventions have been ineffective, the physician, after seeking 
expert advice, with informed consent from the patient or a legally authorised 
representative, may use an unproven intervention if in the physician's judgement 
it offers hope of saving life, re-establishing health or alleviating suffering. This 
intervention should subsequently be made the object of research, designed to 
evaluate its safety and efficacy. In all cases, new information must be recorded 
and, where appropriate, made publicly available.

SAP_001.pdf: 
 
 
 
 
 
 
 
 
 
 
 
PM1183-B-003-11 
        
 
 
A Multicenter Phase II Clinical Trial of PM01183 in BRCA 1/2-
Associated or Unselected Metastatic Breast Cancer 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
 
 
 
NCT Code: 01525589
 
  
 
 
 
 
 
Version: 3.0 
Date: 10-December-2018      
 


 
TABLE OF CONTENTS  
 
1 
STUDY RATIONALE 
6 
2 
STUDY DESIGN 
7 
3 
OBJECTIVES AND ENDPOINTS 
8 
3.1 
Primary Objective 
8 
3.2 
Secondary Objectives 
8 
3.3 
Endpoints 
8 
4 
PATIENTS EVALUABILITY CRITERIA 
9 
4.1 
Included Population 
9 
4.2 
Efficacy Populations 
9 
4.3 
Safety Population 
10 
5 
SAMPLE CONSIDERATIONS 
10 
5.1 
Sample Size 
10 
6 
STATISTICAL METHODOLOGY FOR EFFICACY 
10 
6.1 
Planned Analysis and Definitions 
10 
6.2 
Efficacy Analysis Methods 
11 
6.2.1 
Primary Endpoint 
12 
6.2.2 
Secondary Endpoints 
12 
7 
STATISTICAL METHODOLOGY FOR SAFETY 
13 
7.1.1 
Toxicity and Adverse Events 
13 
7.2 
Clinical Laboratory Evaluation 
13 
7.3 
Vital Signs, Physical Examination, Left Ventricular Ejection Fraction and 
Electrocardiogram Findings 
14 
7.4 
Deaths and Other Serious Adverse Events 
14 
8 
OTHER ANALYSIS 
14 
8.1 
Patient Disposition and Treatment/Study Discontinuation 
14 
8.2 
Protocol Deviations 
14 
8.3 
Baseline and Demographic Data 
14 
8.4 
Treatment Administration 
15 
8.5 
Subsequent Therapy 
16 
8.6 
Pharmacokinetic Analysis 
16 
8.7 
Pharmacogenomic Analysis 
16 
8.8 
Imputation of Incomplete Dates 
16 
8.9 
Subgroup Analysis 
17 
8.10 
Methods for Handling Missing Data 
17 
8.11 
Interim and Group Sequential Analysis 
17 
8.12 
Identification of Fixed or Random Effects Models 
18 
9 
STATISTICAL SOFTWARE 
18 
APPENDIX I 
19 
10 Study Patients 
19 
10.1 
Patient Disposition 
19 
10.2 
Reasons for Treatment Discontinuation 
20 
10.3 
Protocol Deviations 
22 
11 Efficacy Evaluation 
23 


 
11.1 
Demographic and Other Baseline Characteristics 
23 
11.1.1 Patient Characteristics at Baseline 
23 
11.1.2 Disease at Diagnosis and Current Disease 
23 
11.1.3 Prior History 
25 
11.1.4 Prior Anticancer Therapy 
25 
11.1.5 Physical Examination and Performance Status at Baseline 
26 
11.1.6 Vital Signs, Electrocardiogram, LVEF and other tests. 
27 
11.1.7 Hematological Values at Baseline 
28 
11.1.8 Biochemical Values at Baseline 
29 
11.1.9 Coagulation Values at Baseline 
30 
11.1.10 
Signs and Symptoms at Baseline 
30 
11.1.11 
Concomitant Therapy and Procedures at Baseline 
31 
11.2 
Measurements of Treatment Compliance 
34 
11.3 
Efficacy Analysis 
35 
11.3.1 Primary Analysis 
35 
11.3.2 Secondary Analysis 
36 
11.3.3 Exploratory Multivariate Analysis 
39 
12 Safety Analysis 
41 
12.1 
Extent of Exposure 
41 
12.1.1 
Treatment Administration 
41 
12.1.2 Cycle Delays 
41 
12.1.3 Dose Reductions 
43 
12.1.4 Infusions Temporarily Interrupted 
45 
12.1.5 Prophylactic Medication Administration 
45 
12.2 
Adverse Events 
45 
12.2.1 Adverse Events 
45 
12.2.2 Display of Adverse Events 
46 
12.2.3 Evolution of signs and symptoms during the treatment 
48 
12.3 
Serious Adverse Events and Deaths. 
48 
12.3.1 Serious Adverse Events 
48 
12.3.2 Deaths 
49 
12.4 
Clinical Laboratory Evaluation 
49 
12.4.1 Hematological Abnormalities 
50 
12.4.2 Biochemical Abnormalities 
50 
12.4.3 Coagulation Abnormalities 
52 
12.4.4 Laboratory Values Over Time 
53 
12.5 
Physical Findings, PS, LVEF, ECG and Other Tests Related to Safety 
64 
12.5.1 Physical Findings and PS (ECOG) 
64 
12.5.2 LVEF, ECG and Other Related Tests 
64 
12.6 
Concomitant Therapy / Procedures According to the ATC Classification. 
65 
13 DB Listings 
67 
14 SAP Version History 
68 
 


 
ABBREVIATIONS AND GLOSSARY 
AE(s) 
Adverse Event(s) 
ALT  
Alanine Aminotransferase 
AP 
Alkaline Phosphatase 
AST  
Aspartate Aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
BL 
Baseline 
BRCA1/2 
Breast Cancer 1 or Breast Cancer 2 Susceptibility Gene 
BSA 
Body Surface Area 
C 
Cycle 
CI 
Confidence Interval 
CPK  
Creatine Phosphokinase 
CR 
Complete Response 
CRF 
Case Report Form 
CTCAE 
Common Terminology Criteria for Adverse Events 
DB 
Database 
DR 
Duration of Response 
DNA 
Deoxyribonucleic Acid 
ECG 
Electrocardiogram 
ECHO 
Echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
FD 
Flat Dose 
G-CSF 
Granulocyte-Colony Stimulating Factor 
GGT 
Gamma-glutamyltransferase 
HER-2 
Human Epidermal Growth Factor Receptor 2 
IB 
Investigator’s Brochure 
i.v. 
Intravenous(ly) 
K 
Potassium 
LDH 
Lactate Dehydrogenase 
LVEF 
Left Ventricular Ejection Fraction 
MBC 
Metastatic Breast Cancer 
MedDRA 
Medical Dictionary for Regulatory Activities 
MUGA 
Multiple-gated Acquisition Scan 
NA 
Sodium / Not applicable 
NCI 
National Cancer Institute 
NCI-CTC 
National Cancer Institute Common Toxicity Criteria 
NCI-CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 


 
NE 
Not Evaluable 
NOS 
Not Otherwise Specified 
ORR 
Overall Response Rate 
OS 
Overall Survival 
PARPi 
Poly ADP Ribose Polymerase inhibitor 
PD 
Progressive Disease 
PFS 
Progression-free Survival 
PGx 
Pharmacogenomics 
PK/PD 
Pharmacokinetics/Pharmacodynamic 
PR 
Partial Response 
PS 
Performance Status 
PT 
Prothrombin Time/Preferred Term 
PTT 
Partial Thromboplastin Time 
q3wk 
Every Three Weeks 
RD 
Recommended Dose 
RECIST 
Response Evaluation Criteria In Solid Tumors 
SAE(s) 
Serious Adverse Event(s) 
SD 
Stable Disease 
SOC 
System Organ Class 
ULN 
Upper Limit of Normal 
UK 
Unknown 
vs. 
Versus 
WBC 
White Blood Cells 
WHO 
World Health Organization 
Wk(s) 
Week(s) 
y 
Year 


 
1 STUDY RATIONALE 
Metastatic breast cancer (MBC) is a clinically heterogeneous and an aggressive disease 
from which most patients will ultimately die. Unfortunately a cure by the means of 
currently available treatment options still seems an elusive goal. Cytotoxic chemotherapy 
remains a crucial component of the therapeutic armamentarium and there is a need to 
develop more selective approaches to identify subgroups of patients with higher tumor 
sensitivity that may benefit the most. 
PM01183 is a new chemical entity that induces double-strand DNA breaks through binding 
to the DNA minor groove. Results of the COMPARE analysis (see protocol reference 20) 
revealed that is unlikely that this drug shares a similar mechanism of action with any of the 
other 98 standard cytotoxic agents compared. 
PM01183 has significant in vitro and in vivo wide antitumor activity, particularly in several 
breast cancer models. 
PM01183 exposure primarily induces DNA damage, particularly to homologous 
recombinant deficient cells in vitro (see IB); thus, patients with BRCA deleterious mutation 
might be more sensitive to its antitumor effects than other patients. In order to test this 
hypothesis, two Cohorts of patients with advanced breast cancer will be prospectively 
evaluated in the trial according to their germline BRCA1/2 mutation status: known 
mutation (BRCA+, Cohort A) vs. unselected (BRCA– or -UK, Cohort B). 
The goal of the trial is, on one hand, to find out whether the presence of a BRCA 1/2 
mutation in Cohort A is associated with a higher response rate in MBC patients; and, on the 
other hand, to explore and benchmark the activity of PM01183 in MBC unselected patients. 
The study design has taken into account the higher sample heterogeneity of Cohort B by 
planning the recruitment of more patients in this group. Also, according to the BRCA status 
in the trial setting, a response rate of 40% or more in Cohort A (sample of patients with 
known deleterious BRCA 1/2 mutations) will be considered clinically worthy of further 
research, as well as a response rate of 25% or more in Cohort B. 
The first-in-human phase I clinical trial found a RD of 7.0 mg FD of PM01183 when given 
as a one-hour i.v. infusion q3wk. This dose was safe, tolerable and manageable for a highly 
selected patient population. In particular, PM01183 induced predictable and short-lasting 
non-febrile neutropenia as the most relevant toxicity (up to 40% of patients treated at the 
RD). None of the patients treated at the RD were older than 75 years and/or had PS >1. 
Therefore, it is uncertain at this time if PM01183 RD is as tolerable and safe for a 
particularly vulnerable and frail population given the degree of myelosuppresion observed 
so far. Because toxicity, especially in aging patients, is usually an important consideration 
in order to select the more suitable treatment, it seems safer to exclude patients over 75 
years old and/or with PS≥2 until more information regarding safety and pharmacokinetics 
of the drug becomes available. 
 


 
2 STUDY DESIGN 
This is a multicenter, open-label, exploratory, phase II clinical trial evaluating the efficacy 
and safety of PM01183 administration to patients with previously treated MBC, as follows. 
 
Two Cohorts of MBC patients will be prospectively evaluated in the trial according to 
germline BRCA1/2 status (mutated [Cohort A] vs. unselected [Cohort B]). A third Cohort 
(Cohort A1) will include advanced breast cancer patients with deleterious BRCA1/2 
mutation status who received prior treatment with poly (ADP-ribose) polymerase (PARP) 
inhibitors: 
 
• Cohort A (BRCA+ Cohort): At least 53 evaluable patients with previously known 
deleterious BRCA1/2 mutation status at study entry.  
• Cohort A1 (BRCA+/PARPi Cohort): 20 evaluable patients with known deleterious 
BRCA1/2 mutation status and prior treatment with PARP inhibitors (PARPi).  
• Cohort B (unselected Cohort): At least 64 evaluable patients without known 
deleterious BRCA1/2 mutation status at study entry, i.e., either: 
o Patients known to have no deleterious BRCA1/2 mutations (BRCA−), or 
o Patients whose BRCA 1/2 mutation status is unknown (BRCA-UK); 
BRCA1/2 germline mutation status will be assessed in PM01183 responding 
patients in this subgroup. 
In patients included in Cohort B who respond to PM01183 treatment and whose BRCA 1/2 
mutation status is unknown at study entry, an analysis will be performed in order to confirm 
or exclude deleterious germline BRCA 1/2 mutation. To this end, a blood sample will be 
collected at the time of response. If a BRCA 1/2 mutation is found in her sample then the 
patient will be analyzed along with patients included in Cohort A. 
The primary efficacy endpoint of the study is the overall response rate (ORR), defined as 
the percentage of patients with a response, either complete (CR) or partial (PR), according 
to RECIST v1.1 (protocol section 8.1). 
An interim analysis based on the primary endpoint (ORR) is planned after 20 and 30 
evaluable patients have been treated in Cohorts A and B, respectively (see protocol section 
8.2 for details). No interim analysis is planned for Cohort A1. If less than four out of 20 
patients in Cohort A, or less than three out of 30 patients in Cohort B achieve an objective 
confirmed response, recruitment to that Cohort will be terminated. Otherwise, recruitment 
will continue until at least 53 and 64 evaluable patients are included in Cohort A and 
Cohort B, respectively. Sample size and Cohort design will be re-evaluated at this point in 
order to estimate the 95% confidence interval (CI) with the desired precision. Recruitment 
to either Cohort (e.g., Cohort B) might be halted while interim analysis is being performed, 
if appropriate.  
Patients will receive treatment in the absence of progressive disease (PD) or unacceptable 
toxicity for as long as it is considered to be in their own benefit (see protocol section 6.2.1.2 
for details). 
Patients will be evaluated using clinical and laboratory assessments before each treatment 
cycle (protocol sections 6.3 and 6.6). Appropriate radiological and/or clinical tumor 


 
assessments will be done every six weeks until evidence of PD (protocol section 7.1). 
Patients no longer receiving study treatment will be followed up for survival (protocol 
section 6.8). 
Any treatment-related AE will be followed until recovery to grade ≤ 1 or stabilization of 
symptoms, whenever possible (protocol section 7.2). Reasons for dose reduction, treatment 
delays and/or treatment discontinuation will be documented as appropriate. 
 
3 OBJECTIVES AND ENDPOINTS 
3.1 
Primary Objective 
• To assess the antitumor activity of PM01183 in terms of ORR, according to 
RECIST v1.1, in each Cohort of MBC patients. 
3.2 
Secondary Objectives 
• To further characterize the antitumor activity of PM01183 in terms of duration of 
response (DR), clinical benefit [ORR or stable disease lasting over three months 
(SD > 3 months)], PFS, and one-year overall survival (1y-OS). 
• To evaluate whether the presence of a known germline mutation in BRCA1/2 
predicts response to PM01183 in MBC patients. 
• To explore the activity of PM01183 in specific breast cancer subpopulations 
according to hormonal receptor status, HER-2 overexpression, number and/or type 
of prior therapies, or according to other available histological/molecular 
classifications. 
• To evaluate the safety profile of this PM01183 administration schedule (Day 1, 
q3wk) in this patient population. 
• To analyze the pharmacokinetics (PK) of PM01183 in this patient population. 
• To explore PK/PD (pharmacokinetic / pharmacodynamic) correlations, if 
applicable. 
• To evaluate the pharmacogenomic (PGx) expression profile of selected putative 
markers potentially predictive of response to PM01183, in tissues from archived 
tumor samples. 
3.3 
 Endpoints 
Primary endpoint:  
• Overall response rate (ORR) in the population evaluable for efficacy, according to 
RECIST v1.1. 
Secondary endpoints:  
• Duration of response (DR). 


 
• Clinical benefit, defined as the percentage of patients with ORR or SD > 3 months, 
according to RECIST v1.1. 
• Progression-free survival (PFS). 
• Overall survival rate at one year (1y-OS). 
• Treatment safety: AEs, serious AEs (SAEs) and laboratory abnormalities will be 
graded according to the NCI-CTCAE (v4). 
• PK analysis and PK/PD correlation, if applicable. 
• PGx expression profile, in tissues from archived tumor samples. 
4 PATIENTS EVALUABILITY CRITERIA 
The study population will include patients with MBC histologically proven. 
Analysis sets definitions: 
° “All Included Patients” analysis set is defined as all patients recorded in the database 
who are included in the trial, independently of whether they have received the study 
drug or not. 
° “All Treated Patients” analysis set is defined as all included patients who have 
received at least part of one infusion of PM01183. 
° “All Evaluable Patients” analysis set is defined as all eligible patients who have at 
least one complete infusion of PM01183, and either have at least one assessment (as 
per RECIST v1.1) or have been categorized as “treatment failures”. Patients  who 
discontinue treatment due to any treatment-related toxicity before an appropriate tumor 
assessment has been performed or those withdrawn after more than two weeks on 
treatment without any formal evaluation will be defined as “treatment failures”. These 
patients will be included as inevaluable for response in the analysis of objective 
response as per RECIST v1.1, although they will not need to be replaced as they will 
be considered evaluable for efficacy. 
° “All Responder Patients” analysis set is defined as all evaluable patients who have had 
CR or PR as overall best response according to the RECIST v1.1 criteria. 
4.1 
Included Population 
The “All Included Patients” data set will be used for the descriptive analysis of baseline 
characteristics. 
4.2 
Efficacy Populations 
The “All Evaluable Patients” analysis set will be used for the primary endpoint analysis of 
ORR and for the secondary endpoints of PFS, 1y-OS and clinical benefit rate. 
The “All Responder Patients” set will be used for the secondary endpoint analysis of DR. 


 
4.3 
Safety Population 
The safety analysis for the secondary endpoint will be based on the “All Treated Patients” 
analysis set. 
 
5 SAMPLE CONSIDERATIONS  
5.1 
Sample Size 
The primary endpoint for this phase II study is to evaluate ORR. 
• Cohort A (BRCA+): 
At least 53 evaluable patients will be recruited to test the null hypothesis that ORR is 
20% or less (p ≤ 0.20) vs. the alternative hypothesis that 40% or more patients have 
objective response (p ≥ 0.4). With these assumptions, if the number of evaluable 
patients with objective response is ≥ 17, then this would allow the rejection of the null 
hypothesis. 
• Cohort A1 (BRCA+/PARPi): 
At least 20 evaluable patients will be recruited for an exploratory analysis: if the number 
of patients responding is ≥ 4 (20%), the lower limit of the exact binomial 95% 
confidence interval will be higher than 5% and thus lack of activity in this 
subpopulation will be ruled out. 
• Cohort B (unselected): 
At least 64 evaluable patients will be recruited to test the null hypothesis that ORR is 
10% or less (p ≤ 0.10) vs. the alternative hypothesis that 25% or more patients have 
objective response (p ≥ 0.25). With these assumptions, if the number of evaluable 
patients with objective response is ≥ 12, then this would allow the rejection of the null 
hypothesis. 
The variance of the standardized tests is based on the null hypothesis. The type I error 
(alpha) associated with this one-sided test is 0.025 and the type II error (beta) is <0.1; 
hence, statistical power is > 90%.  
Futility analysis controlled by the Gamma family boundary will be performed when 20 and 
30 patients have been evaluated in Cohorts A [Gm(-2)] and B [Gm(-1.5)], respectively. If 
less than four out of 20 patients in Cohort A, or less than three patients out of 30 in Cohort 
B achieve an objective response, recruitment to that Cohort will be stopped. About 110 
evaluable patients are finally expected to be included in the three Cohorts: Cohort A 
(BRCA+), Cohort A1 (BRCA+/PARPi), and Cohort B (unselected). 
6 STATISTICAL METHODOLOGY FOR EFFICACY 
Frequency tables will be performed for categorical variables, whereas continuous variables 
will be described by means of summary tables that will include the median, minimum, and 
maximum of each variable. 
6.1 
Planned Analysis and Definitions 
Primary endpoint  


 
The primary study analysis will be based on the ORR in the “All Evaluable Patients” 
analysis set. 
Overall response rate (ORR) is calculated as the number of patients who have had CR or 
PR as overall best response according to the RECIST v1.1 criteria, divided by the number 
of patients in the “All Evaluable Patients” analysis set.  
 
Secondary endpoint  
The following time-related parameters would be analyzed according to available follow-up 
data: 
Duration of response (DR) is defined as time from first observation of response to the date 
of disease progression, recurrence of death. Other causes will be censored. Although the 
responses have to be confirmed according to RECIST v1.1 criteria, the first documentation, 
not the confirmation, will be taken into account to calculate DR. Patients who progress or 
die will be considered to have had an event, except if this event occurs after the start of 
subsequent antitumor therapy, in which case the patient will be censored at the time of last 
disease assessment prior to or on the first day of the first subsequent antitumor therapy. 
Clinical benefit rate is calculated as the number of patients who have had CR or PR or SD 
≥ 3 months as overall best response according to the RECIST v1.1 criteria, divided by the 
number of patients in the “All Evaluable Patients” analysis set.  
Progression-free survival (PFS) is defined as the time from start of treatment to the date of 
documented progressive disease (PD) by RECIST v1.1 criteria or death (regardless of the 
cause of death), whichever comes first. Patients who progress or die will be considered to 
have had an event, except if this event occurs after the start of subsequent antitumor 
therapy, in which case the patient will be censored at the time of last disease assessment 
prior to or on the first day of the first subsequent antitumor therapy. If the patient is lost for 
the assessment of progression during the follow-up period, or has more than one missing 
follow-up between the date of last tumor assessment and the date of progression, death or 
further antitumor therapy, the PFS will be censored at the date of last valid disease 
assessment before the missing evaluations. 
Overall survival (OS) is defined as the time from the date of start of treatment to the date of 
death or last contact. 1 year overall survival (1y-OS) is defined as the Kaplan-Meier 
estimate of the probability of patients alive after 12 months from the date of start of 
treatment.  
 
6.2 
Efficacy Analysis Methods 
Continuous variables will be tabulated by Cohort and presented with summary statistics 
(i.e., median and range). Categorical variables will be summarized by Cohort in frequency 
tables by means of counts and percentages. 


 
6.2.1 Primary Endpoint 
Exact binomial estimates with 95% confidence intervals (CIs) will be calculated for the 
analysis of the main endpoint (ORR according to RECIST v1.1 criteria). 
6.2.2 Secondary Endpoints  
Time-to-event endpoints (DR, PFS and OS) and their set time estimates (i.e. PFS3, PFS6 
and 1y-OS) will be analyzed according to the Kaplan-Meier method. 
A log-rank test or Cox regression for time-to-event endpoints could be performed as 
supportive analysis to compare both Cohorts. 
If relevant, efficacy parameters versus baseline covariates will be analyzed and appropriate 
test will be used (i.e., the Fisher exact test and logistic regression for categorical variables, 
the log-rank test or Cox regression for time-to-event variables, etc.). 
If appropriate, exploratory multivariate models (main effects or including interaction terms, 
if appropriate) will include all prognostic factors/covariates widely reported and recognized 
by oncologists: Cohort (BRCA (+) vs. BRCA (-) or unknown), BRCA (1 vs. 2  in cohorts A 
and A1), initial dose (7 mg FD vs 3.5 mg/m2), age, age at diagnosis, race (Caucasian vs. 
other), baseline Eastern Cooperative Oncology Group performance status (ECOG PS) (0 
vs. >0), histology type (Ductal vs. lobular carcinoma), histology grade (poorly vs. other), 
stage at diagnosis, primary tumor site (unilateral breast vs. bilateral), hormone receptor 
positive  (estrogen or progesterone receptor +, or both +) vs. triple negative, HER-2 
receptor (positive vs. negative), site of current disease such as liver metastases (yes vs. no), 
CNS metastases (yes vs. no), lung metastases (yes vs. no),  non-visceral (including bone, 
skin, subcutaneous and lymph node vs. other),  number of prior metastatic sites (1 vs. >1), 
body mass index (BMI), height, weight, body surface area (BSA), time from diagnosis to 
first infusion, prior surgery (yes vs. no), prior radiotherapy (yes vs. no), prior advanced 
treatment lines, prior advanced chemotherapy lines (0-1 vs. 2-3), prior anthracyclines (yes 
vs. no), prior taxane (yes vs. no), prior platinum (yes vs. no), prior PARPi (yes vs. no),  last 
prior therapy PFS, first advanced chemotherapy PFS, last advanced chemotherapy PFS, 
PFS for anthracycline, taxane and platinum therapy, hormonotherapy (yes vs no), 
adjuvant/neoadjuvant therapy (yes vs no), platinum-free interval (in months), presence of 
any bulky (< 50 mm vs. ≥ 50 mm) lesion, albumin at baseline, CA-15.3 or 27.29 at 
baseline, any relevant concomitant medication at baseline (to be determinate by the 
oncologist) (yes vs. no) and the sum of all target lesion diameters. 
All variables with a good percentage of valid cases (approximately ≥ 90%) and with a p-
value lower than 0.10 in the univariate analysis will be included in the exploratory 
multivariate analysis. Within the multivariate stepwise Logistic/Cox regression analysis, 
the chosen significance level for entering an explanatory variable into the model will be 
0.05 (for all variables not in the model, the one with the smallest p-value is entered if the p-
value is less than or equal to the specified significance level). The significance level for 
removing an explanatory variable from the model is 0.05 (for all variables in the model, the 
one with the largest p-value will be removed if the p-value exceeds the specified 
significance level). The parameter estimates, hazard ratios and p-values for hazard ratios of 
the variables retained in the model will be presented.  


 
If appropriate, multivariate analysis will be produced for a relevant subgroup of patients 
(e.g. by cohort).  
 
7 STATISTICAL METHODOLOGY FOR SAFETY 
The safety analysis for the secondary endpoints will be based on the “All Treated Patients” 
analysis set. 
Patients will be evaluable for safety if they received at least one partial or complete 
infusion of PM01183. 
7.1.1 Toxicity and Adverse Events  
All the adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). 
The toxicity evaluation will be coded with the National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI-CTCAE), version 4. 
As far as all the toxicities are concerned, the NCI-CTCAE grade will be used wherever an 
NCI-CTCAE grading exists. Otherwise, the severity will be noted. As a convention, the 
term «Grade» will always be used. Toxicities will be described according to the worst NCI-
CTCAE grade or, for toxicities which do not form the subject of NCI-CTCAE 
classification, according to the worst severity. 
Summary of overall AEs will be done by System Organ Class (SOC) and Preferred Term 
(PT), by severity (worst toxicity grade), by relationship to the study drug and by AE 
outcome. Tables will be sorted by SOC/PT coded with MedDRA. 
A frequency table will be made for the AEs leading to cycle delay, dose reduction or 
withdrawal of study medication. Adverse events with outcome of death will also be 
presented by relationship to the study drugs. 
7.2 
Clinical Laboratory Evaluation 
Laboratory results will be classified according to the NCI-CTCAE version 4.  
The following hematological values (worst grade per patient and per cycle during 
treatment) will be displayed: white blood cells (WBC) count, neutrophil count, lymphocyte 
count, platelet count and hemoglobin.  
Overall cross tabulation will be presented for the worst grade during treatment versus the 
baseline toxicity grading of anemia, lymphopenia, neutropenia, leukopenia and 
thrombocytopenia. 
If a grade 3-4 neutropenia or thrombocytopenia increase occur during a cycle of treatment, 
the first day it reached the onset value (counting from the start of the cycle) and the 
duration of the abnormality (until recovery to grade ≤ 2), will be tabulated. 
Similarly, the following biochemical values (worst grade per patient and per cycle during 
treatment) will be displayed: alanine aminotransferase (ALT), aspartate aminotransferase 
(AST), total bilirubin, alkaline phosphatase (AP), creatine phosphokinase (CPK), 


 
creatinine, gamma-glutamyltransferase (GGT), calcium (corrected by albumin levels), 
potassium (K), sodium (NA), magnesium, glucose, phosphorus, triglycerides and albumin. 
If a grade 3-4 AST or ALT increase occur during a cycle of treatment, both the day it 
peaked (counting from the start of the cycle) and the duration of the abnormality (until 
recovery to grade ≤ 2), will be tabulated. 
Overall cross tabulation will be presented for the worst grade during treatment versus the 
baseline toxicity grading of biochemical abnormalities. 
7.3 
Vital Signs, Physical Examination, Left Ventricular Ejection Fraction and 
Electrocardiogram Findings 
Tabulation will be made summarizing the performance status, body weight, left ventricular 
ejection fraction (LVEF) and electrocardiogram (ECG) abnormalities at baseline and during 
the treatment, if appropriate, for each patient. 
7.4 
Deaths and Other Serious Adverse Events 
Deaths and other SAEs will be tabulated. 
 
8 OTHER ANALYSIS 
Continuous variables will be tabulated and presented with summary statistics (i.e., median 
and range).  
Categorical variables will be summarized in frequency tables by means of counts and 
percentages. Percentages in the summary tables will be rounded and may therefore not 
always add up to exactly 100%. 
8.1 
Patient Disposition and Treatment/Study Discontinuation 
The number of patients included in the study, the number of patients treated and the number 
of patients evaluable for the main endpoint, will be shown. Also, accrual by center and 
country and the main dates of the study will be displayed. Reasons for treatment 
discontinuation and for study discontinuation will be tabulated. 
8.2 
Protocol Deviations 
Analysis of inclusion/exclusion criteria deviations, retreatment restrictions, concomitant 
medication and clinically relevant discontinuations, among others, will be done as 
described in Appendix I.   
8.3 
Baseline and Demographic Data 
Baseline data such as demographics, cancer history, prior therapy, prior relevant history, 
signs and symptoms, electrocardiogram, LVEF, physical examination, vital signs, 
laboratory values and concomitant medication, coded according to the Word Health 
Organization (WHO) Anatomical Therapeutic Chemical (ATC) classification system, will 
be described following standard tables detailed in Appendix I.  


 
Age, baseline weight, height, and body surface area (BSA) will be summarized 
descriptively.  
Age will be calculated based on the date of birth and the date of informed consent.  
Baseline weight and height are recorded on the CRF.  
Baseline BSA will be calculated using the Dubois & Dubois formula: 
725
.0
425
.0
2
)
(
)
(
007184
.0
)
(
cm
height
kg
weight
m
BSA
×
×
=
 
Age categories and race will be summarized with frequency counts. 
Baseline Eastern Cooperative Oncology Group (ECOG) performance status (PS) will be 
summarized with frequency counts. 
For the cancer history: time from initial diagnosis, time from metastatic disease and time 
from last progression before the study entry will be summarized. This time calculations will 
be shown in months and summarized descriptively. Histology and characteristics of the 
current disease will be tabulated. 
Previous relevant medical history (other than cancer) will be listed. 
A frequency tabulation of the number of patients with and the different types of previous 
surgery, radiotherapy, or therapy (number of lines) will be given. 
Signs and symptoms at baseline will be displayed by tabulation of frequencies according to 
NCI-CTCAE version 4 toxicity grades. Signs and symptoms will be listed. 
In case of pre-treatment characteristics with multiple measurements per subject before the 
start of treatment (laboratory assessments, vital signs) the baseline measurement will be 
considered the last value prior to or on the first day of treatment. 
Baseline and demography characteristics in different subgroups of analysis (i.e. cohorts) 
will be compared by means of Fisher’s exact test (categorical variables) and Mann-
Whitney-Wilcoxon (continuous variables). 
8.4 
Treatment Administration 
Total cumulative dose, dose intensity and relative dose intensity, time on treatment, cycle 
delays and dose reductions will be described following standard tables detailed in Appendix 
I. 
Total cumulative dose, expressed in mg, is the sum of all the study drug doses from the first 
cycle until last cycle, including the dose received in last cycle. 
Patients will be considered to be on-treatment for the duration of their treatment and 30 
days following the last treatment dose. If the patient starts any new antitumor therapy 
outside this clinical trial or dies within 30 days of last treatment dose, the date of 
administration of this new therapy or the date of death will be considered the date of 
treatment discontinuation. 
However, as a convention, the duration of the last cycle is considered to be 21 days (instead 
of 30 days) for dose intensity calculation purposes.  


 
Intended dose intensity (mg/m2) is the planned dose per cycle divided by the planned 
number of weeks per cycle. 
Absolute dose intensity (mg) is the actual cumulative dose divided by the number of weeks 
of treatment. Relative dose intensity (%) is the ratio of absolute dose intensity divided by 
the intended dose intensity. 
The item of the case report form (CRF) «Infusion delayed: yes/no» will be used to calculate 
the delayed cycles. For those cycles considered as delayed by the investigator, the delay 
will be calculated as: 
Delay:  Date of current drug administration – Date of previous drug administration – 21.  
The infusion of the first cycle will be excluded from all calculations regarding cycle delays 
and modifications. 
8.5 
Subsequent Therapy 
A table summarizing the subsequent therapies received after treatment discontinuation will 
be shown. 
8.6 
Pharmacokinetic Analysis 
This analysis will be detailed in a separate document. 
8.7 
Pharmacogenomic Analysis 
This analysis will be detailed in a separate document. 
8.8 
Imputation of Incomplete Dates 
The dates of certain historical or current clinical activities are key component for statistical 
analysis. An incomplete date results from a missing day, month or year; in that case, the 
missing figure can be imputed allowing for the calculation of variables, such duration and 
time to certain event. However, when all of them, day, month and year, are missing no 
imputation will be done.  
Before registration 
If the day of a month is unknown, then the imputed day will be the 15th of the month; if the 
month is also unknown, then the imputed date will be the 1st of July. This assumption will 
only be valid if the imputed date occurs earlier than the first dose administration date; 
otherwise the imputed date will be the first day of the first dose administration month date 
(i.e. 01/ first dose administration month date/year). 
Between treatment start and end of treatment 
All date variables during treatment where information is needed and is not fully available, 
for example adverse events or concomitant medications, will be subject of imputation by 
means of SAS programming. If the day of a date is unknown then the imputed day will be 
1, if the month and/or year is also unknown then the imputed date will 1/January (this 
assumption will be valid if the imputed date is not earlier than the treatment start date; 
otherwise, the imputed date will be the treatment start date). 


 
After end of treatment 
To ensure the most conservative approach for the time-to-event variables (i.e., DR, PFS and 
OS), which can be affected by missing values, the following rules will be implemented: if 
the day of a date is unknown then the imputed day will be the 1st; if the month is also 
unknown, then the imputed date will be the 1st of July. This assumption will be valid if the 
imputed date occurs later than the last drug administration date; otherwise the imputed date 
will be the date of the last drug administration plus the predefined cycle length (i.e., 21 
days if PM01183), except if the patient dies before, in which case the date of death minus 1 
will be used. 
8.9 
Subgroup Analysis 
The analysis will be done by Cohort and additionally, if clinically appropriate, the Cohorts 
might be pooled into one, whenever differences between Cohorts are considered not 
relevant. In such case, the point estimates and their 95% CIs will be also reassessed in order 
to obtain more accurate calculations.  
Efficacy subgroup analysis will be performed in Cohort A according to prior treatment with 
platinum (Yes vs. No), BRCA status (BRCA1 vs. BRCA2), hormonal status (Triple 
negative vs. HR+), number of  advanced chemotherapy lines , prior PARPi (Yes vs. No)and 
starting dose (7 mg FD vs. 3.5 mg/m2). 
Additional efficacy subgroup analysis will be performed in Cohorts A+A1 according to 
prior PARPi (Yes vs. No). Safety subgroup analysis will be performed according to starting 
dose (7 mg FD vs. 3.5 mg/m2), these analysis include laboratory abnormalities and adverse 
events. 
If clinically relevant, other subgroup analysis may be performed in order to explore the 
activity of PM01183 in specific breast cancer subpopulations. 
No differentiation by center is planned. 
8.10 Methods for Handling Missing Data 
Missing values will be tabulated with their frequency but they will not be included in the 
calculation of percentages. 
8.11 Interim and Group Sequential Analysis 
An interim analysis based on the primary endpoint (ORR) is planned after 20 and 30 
evaluable patients have been treated in Cohorts A and B, respectively. If less than four out 
of 20 patients in Cohort A, or less than three out of 30 patients in Cohort B achieve an 
objective confirmed response (CR or PR according to RECIST v1.1), recruitment to that 
Cohort will be terminated. Otherwise, recruitment will continue until at least 53 and 64 
evaluable patients are included in Cohort A and Cohort B, respectively. Sample size and 
Cohort design will be re-evaluated at this point in order to estimate the 95% confidence 
interval (CI) with the desired precision. For further analysis details, see section 5.1 Sample 
size. 


 
8.12 Identification of Fixed or Random Effects Models 
Not applicable 
 
9 STATISTICAL SOFTWARE 
Medidata Rave® EDC will be used for data entry and clinical data management. 
EAST v.5.4 has been used to calculate sample size. SAS version 9 will be used for all 
statistical analysis outputs. 
 


 
APPENDIX I 
Every output will be displayed by Cohort and/or total and they will be clearly identified 
with a label. To maintain simplicity, nested categories are not presented. 
 
10 Study Patients 
10.1 Patient Disposition  
Main characteristics concerning inclusion in the study, withdrawal from the study and 
protocol deviations will be displayed in this section. 
 
Table 10.1.1 Number of patients included, treated and evaluable for the main endpoint. 
 
N 
% 
Included patients 
 
 
Eligible patients* 
 
 
Treated patients 
 
 
Evaluable patients for efficacy 
 
 
(*)Patients meeting all inclusion criteria and not meeting any exclusion criteria. 
Listing 10.1.2 Patients who do not meet all the inclusion criteria. 
Patient id. 
Criteria number(s) and description 
 
 
Listing 10.1.3 Patients who meet any exclusion criteria. 
Patient id. 
Criteria number(s) and description 
 
 
Listing 10.1.4 Non-evaluable patients for efficacy analysis. 
Patient id. 
Reason 
 
 
 
Listing 10.1.5 Non-evaluable patients for safety (Non-treated patients). 
Patient id. 
Reason 
 
 
 


 
Table 10.1.6 Patients accrual by institution 
 
 
 
N 
% 
No. of patients included 
Country 1 
Institution 1 
 
 
… 
 
 
Total 
 
 
… 
Institution 1 
 
 
… 
 
 
Total 
 
 
Total 
Institution 1 
 
 
… 
 
 
Total 
 
 
No. of patients treated 
Country 1 
Institution 1 
 
 
… 
 
 
Total 
 
 
… 
Institution 1 
 
 
… 
 
 
Total 
 
 
Total 
Institution 1 
 
 
… 
 
 
Total 
 
 
Table 10.1.7 Study dates 
 
Total 
Date of first registration 
 
Date of first dose of the first patient 
 
Date of last registration 
 
Date of first dose of the last patient 
 
Date of last dose 
 
Date of last follow-up* 
 
(*) Last follow-up, exam or procedure before clinical cut-off or study closure 
 
10.2 Reasons for Treatment Discontinuation 
 
Table 10.2.1 Treatment discontinuation 
Reason 
N 
% 
Progressive disease 
 
 
Treatment related adverse event 
 
 
Non Treatment related adverse event 
 
 
Patient refusal to treatment 
 
 
Death (due to toxicity)* 
 
 
Death (non-treatment-related)** 
 
 
Investigator’s decision*** 
 
 
Other *** 
 
 
Total 
 
 
(*) Cause of death = Study drug related Adverse Event; (**) Cause of death = Malignant disease, Non-study drug related 
AE or Other; (***) See Listing 10.2.2  
Listing 10.2.2 Reasons for treatment discontinuation other than progressive disease. 
Patient id. 
Reason 
Last cycle 
Comments  
 
 
 
 
 


 
Table 10.2.3 Reasons for treatment discontinuation by cycles received 
Reason 
Last cycle 
1 
2 
… 
Total 
Progressive disease 
 
 
 
 
Treatment related adverse event 
 
 
 
 
Non Treatment related adverse event 
 
 
 
 
Patient refusal to treatment 
 
 
 
 
Death (due to toxicity)* 
 
 
 
 
Death (non-treatment-related)** 
 
 
 
 
Investigator’s decision*** 
 
 
 
 
Other *** 
 
 
 
 
Total 
 
 
 
 
(*) Cause of death = Study drug related Adverse Event; (**) Cause of death = Malignant disease, Non study drug related 
AE or Other; (***) See Listing 10.2.2  
 
When the reason for discontinuation is a study treatment-related adverse event or study 
treatment-related death, identify patients and describe them in depth here. 
 
Listing 10.2.4 Treatment discontinuation due to AEs 
Patient id. 
Last 
Cycle 
Preferred  
term code 
Adverse event 
reported 
(verbatim) 
Grade  
Relationship  
Onset 
date 
Resolved 
date 
Seriousness criteria 
 
 
  
 
 
 
 
 
 
Table 10.2.5 Study discontinuation 
Reason 
N 
% 
Never treated* 
 
 
Study termination (clinical cut-off) 
 
 
Patient's follow-up completed 
 
 
Patient's refusal 
 
 
Death (due to toxicity)** 
 
 
Death (non-treatment-related)*** 
 
 
Lost to follow-up 
 
 
Other **** 
 
 
Total 
 
 
(*) See Listing 10.2.6;  (**) Cause of death = Study drug related Adverse Event; (***) Cause of death = Malignant 
disease, Non study drug related AE or Other; (****) Specify (see listing 10.2.7) 
Listing 10.2.6 Patients included but not treated 
Patient id. 
Off-study reason 
 
 
Listing 10.2.7 Study discontinuation due to other reason 
Patient id. 
Specify 
 
 
 


 
10.3 Protocol Deviations  
 
Listing 10.3.1 Protocol deviations 
Patient id. 
Deviation type 
Description 
 
 
 
 
 
 


 
11 Efficacy Evaluation 
11.1 Demographic and Other Baseline Characteristics 
11.1.1 Patient Characteristics at Baseline 
Table 11.1.1.1 Baseline characteristics: Age at treatment registration 
 
N 
Median 
Min 
Max 
Age (years) 
 
 
 
 
Table 11.1.1.2 Baseline characteristics: Age grouped 
 
N 
% 
18-XX 
X 
XX.X 
XX-YY 
 
 
≥65 
 
 
Total 
 
 
Table 11.1.1.3 Baseline characteristics: Race 
 
N 
% 
Caucasian 
X 
XX.X 
Asian 
 
 
Black 
 
 
Other* 
 
 
Total 
 
 
(*) See Listing 11.1.1.4;   
Listing 11.1.1.4 Other race, specify 
Patient id. 
Specify 
 
 
 
11.1.2 Disease at Diagnosis and Current Disease 
Table 11.1.2.1 Time from first diagnosis to registration 
 
N 
Median 
Min 
Max 
Time from diagnosis to randomization 
(months) 
 
 
 
 
Table 11.1.2.2 Site of disease at diagnosis 
 
N 
% 
Right breast 
X 
XX.X 
Left breast 
 
 
Bilateral 
 
 
Total 
 
 
Table 11.1.2.3 Histology type at diagnosis 
 
N 
% 
Ductal Carcinoma 
X 
XX.X 
Lobular Carcinoma 
 
 
Total 
 
 


 
Table 11.1.2.4 Histology grade at diagnosis 
 
N 
% 
Well differentiated 
X 
XX.X 
Moderately differentiated 
 
 
Poorly differentiated 
 
 
Unknown 
 
 
Total 
 
 
 
Table 11.1.2.5 Stage at diagnosis 
 
N 
% 
… 
X 
XX.X 
… 
 
 
Total 
 
 
 
Table 11.1.2.6 BRCA in Arm A and Arm A1 (deletereous mutation). 
 
N 
% 
BRCA 1 
X 
XX.X 
BRCA 2 
 
 
Both 
 
 
 
Table 11.1.2.7 BRCA in Arm B. 
 
N 
% 
Negative 
X 
XX.X 
Unknown 
 
 
 
Table 11.1.2.8 Receptor status. Current disease. 
 
Positive 
Negative 
N 
% 
N 
% 
Estrogen receptor 
X 
XX.X 
X 
XX.X 
Progesterone receptor 
 
 
 
 
HER-2 Receptor 
 
 
 
 
 
Table 11.1.2.9 Hormonal status 
 
N 
% 
Triple negative 
X 
XX.X 
ER and/or PR positive + HER2 negative 
 
 
ER and/or PR positive + HER2 positive 
 
 
ER and PR negative + HER2 positive 
 
 
Total 
 
 
 
Table 11.1.2.10 Time from Metastatic disease to registration 
 
N 
Median 
Min 
Max 
Time from metastatic disease (months) 
 
 
 
 
Table 11.1.2.11 Time from last progression before the study entry 
 
N 
Median 
Min 
Max 
Time from last PD  (weeks)  
 
 
 
 


 
Table 11.1.2.12 Sites of metastatic disease. Current disease. 
 
N 
% 
Lymph node 
X 
XX.X 
Bone 
 
 
Lung 
 
 
Liver 
 
 
Pleura 
 
 
… 
 
 
Table 11.1.2.13 Number of sites at baseline 
No. of sites 
N 
% 
1 
X 
XX.X 
2 
 
 
... 
 
 
Total 
 
 
Median (Range) 
 
 
 
11.1.3 Prior History 
Table  11.1.3.1 Prior history  
SOC 
Preferred Term 
N 
% 
Gastrointestinal disorders 
Constipation 
 
 
Diarrhea NOS 
 
 
… 
 
 
… 
… 
 
 
Listing 11.1.3.2 Prior history (Ongoing events) 
Patient id. 
Description (Literal) 
SOC 
PT 
Onset date 
 
 
 
 
 
 
 
11.1.4 Prior Anticancer Therapy 
Table 11.1.4.1 Patients with prior sugery 
Prior surgery 
N 
% 
Yes 
X 
X.X 
No 
 
 
Total 
 
 
Table 11.1.4.2 Patients with prior radiotherapy 
Prior radiotherapy 
N 
% 
Yes 
X 
X.X 
No 
 
 
Total 
 
 
 


 
Table 11.1.4.3 Number of lines of prior therapy 
No. of systemic lines 
N 
% 
1 
X 
XX.X 
... 
 
 
Total 
 
 
Median (Range) 
 
 
Setting 
N 
% 
Adjuvant 
X 
XX.X 
Neoadjuvant 
 
 
Both 
 
 
Advanced 
 
 
No. of advanced chemotherapy lines 
N 
% 
1 
X 
XX.X 
... 
 
 
Total 
 
 
Median (Range) 
 
 
Prior chemotherapy regimens 
N 
% 
Anthracycline and taxane 
X 
XX.X 
Anthracycline, taxane and capecitabine 
 
 
Platinum 
 
 
No. of hormone* therapy lines 
N 
% 
1 
X 
XX.X 
... 
 
 
Total 
 
 
Median (Range) 
 
 
(*) Hormone therapy will be identified by the oncologist;   
Table 11.1.4.4 Prior anticancer agents 
Antineoplastic and immunomodulating agents (ATC-class.) 
N 
% 
Antineoplastic agents (L01) 
X 
XX.X 
     Alkylating agents 
 
 
           Nitrogen mustard analogues 
 
 
           Alkyl sulphonates 
 
 
           …. 
 
 
 
11.1.5 Physical Examination and Performance Status at Baseline  
Table 11.1.5.1 Baseline physical examination 
 
N 
% 
Normal 
X 
X.X 
Abnormal 
 
 
Total 
 
 
Table 11.1.5.2 Baseline physical examination: BSA, Weight and Height 
 
N 
Median 
Min 
Max 
BSA (m2) 
 
 
 
 
Weight (Kg) 
X 
X.X 
X.X 
X.X 
Height (cm) 
 
 
 
 
 


 
Table 11.1.5.3 Baseline characteristics: ECOG Performance Status 
PS (ECOG) 
N 
% 
0 
X 
XX.X 
1 
 
 
2 
 
 
Total 
 
 
 
11.1.6 Vital Signs, Electrocardiogram, LVEF and other tests. 
For vital signs, electrocardiogram, LVEF and other tests, the last examination available 
before treatment will be described in the following tables. 
Table 11.1.6.1 Baseline characteristics: Vital signs 
Parameter 
N 
Median 
Min 
Max 
Heart rate (beats/min) 
 
 
 
 
Systolic blood pressure (mmHg) 
 
 
 
 
Diastolic blood pressure (mmHg) 
 
 
 
 
Temperature (ºC) 
 
 
 
 
Table 11.1.6.2 Baseline characteristics: Electrocardiogram result 
ECG 
N 
% 
Normal 
X 
XX.X 
Abnormal* 
 
 
Total 
 
 
(*)See listing 11.1.6.4 for details 
Table 11.1.6.3 Baseline characteristics: Electrocardiogram values 
Parameter 
N 
Median 
Min 
Max 
PR interval (msec) 
 
 
 
 
Heart rate (bpm) 
 
 
 
 
QT interval (msec) 
 
 
 
 
QRS complex (msec) 
 
 
 
 
QTc Fridericia 
 
 
 
 
Listing 11.1.6.4 Patients with abnormal electrocardiogram 
Patient 
id. 
Abnormality 
Details* 
Reason for 
clinically 
indicated 
repeat 
PR interval 
(msec) 
Heart rate 
(bpm) 
QT interval 
(msec) 
QRS 
complex 
(msec) 
QTc 
Fridericia 
 
 
 
 
 
 
 
 
 
(*)For non-significant abnormalities, for further details see prior medical history or Signs and symptoms   
Table 11.1.6.5 Baseline characteristics: Left Ventricular Ejection Fraction (LVEF) 
LVEF 
N 
% 
Normal 
X 
XX.X 
Abnormal* 
 
 
Total 
 
 
 (*)See listing 11.1.6.7 for details 


 
Table 11.1.6.6 Baseline characteristics: LVEF values. 
LVEF (%) by Method 
N 
Median 
Min 
Max 
ECHO 
 
 
 
 
MUGA 
 
 
 
 
Both 
 
 
 
 
Listing 11.1.6.7 Patients with abnormal LVEF 
Patient 
id. 
Abnormality 
Details* 
Reason for 
clinically 
indicated repeat 
Method 
LVEF (%) 
Institution 
normal range 
 
 
 
 
 
 
 
(*)For non-significant abnormalities, for further details see prior medical history or Signs and symptoms;  
Table 11.1.6.8  Baseline characteristics: Pregnancy test 
Pregnancy test 
N 
% 
Positive 
X 
XX.X 
Negative 
 
 
NA* 
 
 
Total 
 
 
(*) Specify reasons 
Table 11.1.6.9 Baseline characteristics: Adequate contraception 
Adequate birth control 
N 
% 
Yes 
X 
XX.X 
No 
 
 
NA* 
 
 
Total 
 
 
(*) Specify reasons 
 
11.1.7 Hematological Values at Baseline 
Table 11.1.7.1 Hematological abnormalities at baseline   
 
N 
Grade  
1 
… 
Grade  
4 
All* 
N 
% 
… 
N 
% 
N 
% 
Leukopenia 
 
 
 
 
 
 
 
 
Anemia 
 
 
 
 
 
 
 
 
Thrombocytopenia  
 
 
 
 
 
 
 
 
Neutropenia 
 
 
 
 
 
 
 
 
Lymphopenia  
 
 
 
 
 
 
 
 
(*)Any grade 
 
Table 11.1.7.2 Hematology values at baseline 
 
N 
Median 
Min 
Max 
Hemoglobin (g/dL) 
 
 
 
 
Platelets (109/L) 
 
 
 
 
WBC (109/L) 
 
 
 
 
Neutrophils (109/L) 
 
 
 
 
Lymphocytes (109/L) 
 
 
 
 
Monocytes  (109/L) 
 
 
 
 
 


 
Listing 11.1.7.3 Hematological tests not assessed at baseline 
Patient id. 
Lab. test 
 
 
Listing 11.1.7.4 Hematological abnormalities at baseline. Grade ≥ 2 
Patient id 
Parameter 
Value 
Units 
Grade 
 
 
 
 
 
 
11.1.8 Biochemical Values at Baseline 
 
Table 11.1.8.1 Biochemical abnormalities at baseline 
 
N 
Grade  
1 
… 
Grade  
4 
All* 
N 
% 
… 
N 
% 
N 
% 
AST increased 
 
 
 
 
 
 
 
 
ALT increased 
 
 
 
 
 
 
 
 
Total bilirubin increase 
 
 
 
 
 
 
 
 
AP increased 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
Hyperglycemia  
 
 
 
 
 
 
 
 
Hypoglycemia  
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
(*)Any grade 
 
Table 11.1.8.2 Biochemical values at baseline 
 
N 
Median 
Min 
Max 
AST (xULN) 
 
 
 
 
ALT (IU/L) 
 
 
 
 
Direct bilirubin (xULN) 
 
 
 
 
Total bilirubin (xULN) 
 
 
 
 
AP (xULN) 
 
 
 
 
LDH (xULN) 
 
 
 
 
CPK (xULN) 
 
 
 
 
GGT (xULN) 
 
 
 
 
Creatinine (xULN) 
 
 
 
 
Troponin T (ng/mL) 
 
 
 
 
… 
 
 
 
 
Listing 11.1.8.3 Biochemical tests not assessed at baseline 
Patient id. 
Lab. test 
… 
 
Listing 11.1.8.4 Biochemical abnormalities at baseline. Grade ≥ 2 
Patient id 
Parameter 
Value 
Units 
Grade 
 
 
 
 
 


 
 
11.1.9  Coagulation Values at Baseline 
Table 11.1.9.1 Coagulation abnormalities at baseline   
 
N 
Grade  
1 
… 
Grade  
4 
All* 
N 
% 
… 
N 
% 
N 
% 
INR increased 
 
 
 
 
 
 
 
 
PTT prolonged 
 
 
 
 
 
 
 
 
(*)Any grade 
 
Table 11.1.9.2 Coagulation values at baseline 
 
N 
Median 
Min 
Max 
INR  
 
 
 
 
PT (sec) 
 
 
 
 
PTT (sec) 
 
 
 
 
Listing 11.1.9.3 Coagulation tests not assessed at baseline 
Patient id. 
Lab. test 
… 
 
 
Listing 11.1.9.4 Coagulation abnormalities at baseline. Grade ≥ 2 
Patient id 
Parameter 
Value 
Units 
Grade 
 
 
 
 
 
 
11.1.10 Signs and Symptoms at Baseline 
Table 11.1.10.1 Patients with signs and symptoms at baseline 
 
N 
% 
No. signs and symptoms per patient 
 
 
0 
1 
2 
 
 
≥ 3 
 
 
Median (Range) 
 
 
Table 11.1.10.2 Patients with disease related signs and symptoms at baseline 
 
N 
% 
No. of disease related signs and symptoms per patient 
 
 
0 
1 
2 
 
 
≥ 3 
 
 
Median (Range) 
 
 


 
Table 11.1.10.3 Signs and symptoms at baseline  
SOC 
Preferred Term 
N 
Grade  
1 
… 
Grade  
4 
All* 
 
 
N 
N 
% 
… 
N 
% 
N 
% 
Gastrointestinal disorders 
Constipation 
 
 
 
 
 
 
 
 
Diarrhea NOS 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
… 
… 
 
 
 
 
 
 
 
 
(*)Any grade 
Listing 11.1.10.4 Signs and Symptoms at baseline 
Patient id. 
Sign/symptom 
Grade* 
Onset date 
Relationship 
… 
 
 
 
 
 (*)Those events with grade ≥ 2 or with relationship=’Prior study disease treatment’ will be highlighted. 
 
 
11.1.11 Concomitant Therapy and Procedures at Baseline 
Concomitant medication at baseline according to the ATC classification. 
Table 11.1.11.1 Concomitant medication at baseline (ATC1/ATC2/ATC4/PN) 
Concomitant medication at baseline 
N 
% 
Alimentary tract and metabolism 
 
 
   Antacids 
 
 
      Magnesium compounds 
 
 
          Magnesium adipate 
 
 
… 
 
 
Blood and blood forming organs 
 
 
   Antithrombotic agents 
 
 
      Vitamin K antagonists 
 
 
          Acenocoumarol 
 
 
… 
 
 
 
Table 11.1.11.2 Summary of concomitant medication at baseline 
 
N 
% 
No. of systems at BL (ATC1 level) 
 
 
0 
 
 
1 
 
 
2 
 
 
≥ 3 
 
 
  Median (range) 
 
 
No. of indications at BL (ATC2 level) 
 
 
0 
 
 
1 
 
 
2 
 
 
≥ 3 
 
 
  Median (range) 
 
 
No. of agent families at BL (ATC4 level) 
 
 
0 
 
 
1 
 
 
2 
 
 
≥ 3 
 
 
  Median (range) 
 
 


 
 
N 
% 
No. of agents at BL (PN level) 
 
 
      0 
 
 
1 
 
 
2 
 
 
   ≥ 3 
 
 
  Median (range) 
 
 
Listing 11.1.11.3 Concomitant therapy 
Patient 
Type 
Agent/Procedure Route 
Daily 
dose 
Units 
Start 
date 
Reason Indication 
Details 
Start date of 
study drug 
administration 
 
 
 
 
 
 
 
 
 
 
 
 
If there is a relevant number of patients receiving the same concomitant medication, a table 
summarizing this information might be added. 
 
11.1.12Baseline and demographic characteristic comparisons 
Table 11.1.12.1 Baseline and demographic characteristic comparisons by cohorts 
 
N 
Cohort A 
Cohort A1 
Cohort B 
p-value* 
Age 
Median (range) 
X 
X.X (XX-XX) 
X.X (XX-XX) 
X.X (XX-XX) 
X.XXXX 
PS (ECOG) 
0 
X 
X ( XX.X %) 
X ( XX.X %) 
X ( XX.X %) 
X.XXXX 
 
1 
. 
X ( XX.X %) 
X ( XX.X %) 
X ( XX.X %) 
 
BSA 
Median (range) 
 
 
 
 
BRCA mutation 
1 
 
 
 
 
 
2 
 
 
 
 
Receptor status 
Triple negative 
 
 
 
 
 
HR+ / HER2 - 
 
 
 
 
 
HER2 + 
 
 
 
 
Liver metastases 
Yes 
 
 
 
 
 
No 
 
 
 
 
CNS metastases 
Yes 
 
 
 
 
 
No 
 
 
 
 
Sites involvement 
<3 sites 
 
 
 
 
 
≥ 3 sites 
 
 
 
 
Advanced lines 
Median (range) 
 
 
 
 
Advanced CT lines 
Median (range) 
 
 
 
 
Prior Platinum 
Yes 
 
 
 
 
 
No 
 
 
 
 
Prior Anthracyclines 
Yes 
 
 
 
 


 
 
N 
Cohort A 
Cohort A1 
Cohort B 
p-value* 
 
No 
 
 
 
 
Prior Taxanes 
Yes 
 
 
 
 
 
No 
 
 
 
 
Prior Capecitabine 
Yes 
 
 
 
 
 
No 
 
 
 
 
Prior PARP Inhibitor 
Yes 
 
 
 
 
 
No 
 
 
 
 
*Fisher's exact test (categorical variables);Mann-Whitney-Wilcoxon (continuous variables) 
Table 11.1.12.2 Baseline and demographic characteristic comparisons: Platinum Yes/No in 
Cohort A 
 
N 
Prior platinum  
Yes 
Prior platinum  
No 
p-value* 
Age 
Median (range) 
X 
X.X (XX-XX) 
X.X (XX-XX) 
X.XXXX 
PS (ECOG) 
0 
X 
X ( XX.X %) 
X ( XX.X %) 
X.XXXX 
 
1 
. 
X ( XX.X %) 
X ( XX.X %) 
 
… 
… 
 
 
 
 
*Fisher's exact test (categorical variables);Mann-Whitney-Wilcoxon (continuous variables). For the complete list of 
covarites, see table 11.1.12.1  
Table 11.1.12.3 Baseline and demographic characteristic comparisons: BRCA 1 vs 2 in 
Cohort A 
 
N 
BRCA 1 
BRCA 2 
p-value* 
Age 
Median (range) 
X 
X.X (XX-XX) 
X.X (XX-XX) 
X.XXXX 
PS (ECOG) 
0 
X 
X ( XX.X %) 
X ( XX.X %) 
X.XXXX 
 
1 
. 
X ( XX.X %) 
X ( XX.X %) 
 
… 
… 
 
 
 
 
*Fisher's exact test (categorical variables);Mann-Whitney-Wilcoxon (continuous variables). For the complete list of 
covarites, see table 11.1.12.1  
Table 11.1.12.4 Baseline and demographic characteristic comparisons: Prior PARPi 
Yes/No in Cohorts A+A1 
 
N 
Prior PARPi  
Yes 
Prior PARPi  
No 
p-value* 
Age 
Median (range) 
X 
X.X (XX-XX) 
X.X (XX-XX) 
X.XXXX 
PS (ECOG) 
0 
X 
X ( XX.X %) 
X ( XX.X %) 
X.XXXX 
 
1 
. 
X ( XX.X %) 
X ( XX.X %) 
 
… 
… 
 
 
 
 


 
*Fisher's exact test (categorical variables);Mann-Whitney-Wilcoxon (continuous variables). For the complete list of 
covarites, see table 11.1.12.1  
Table 11.1.12.5 Baseline and demographic characteristic comparisons: Initial dose 7 mg FD 
vs 3.5 mg/m2 in Cohort A 
 
N 
7 mg FD 
3.5 mg/m2 
p-value* 
Age 
Median (range) 
X 
X.X (XX-XX) 
X.X (XX-XX) 
X.XXXX 
PS (ECOG) 
0 
X 
X ( XX.X %) 
X ( XX.X %) 
X.XXXX 
 
1 
. 
X ( XX.X %) 
X ( XX.X %) 
 
… 
… 
 
 
 
 
*Fisher's exact test (categorical variables);Mann-Whitney-Wilcoxon (continuous variables). For the complete list of 
covarites, see table 11.1.12.1  
 
Table 11.1.12.6 Baseline and demographic characteristic comparisons: Hormonal status 
triple negative vs Other  
 
N 
Triple negative 
Yes 
Triple negative 
No 
p-value* 
Age 
Median (range) 
X 
X.X (XX-XX) 
X.X (XX-XX) 
X.XXXX 
PS (ECOG) 
0 
X 
X ( XX.X %) 
X ( XX.X %) 
X.XXXX 
 
1 
. 
X ( XX.X %) 
X ( XX.X %) 
 
… 
… 
 
 
 
 
*Fisher's exact test (categorical variables);Mann-Whitney-Wilcoxon (continuous variables). For the complete list of 
covarites, see table 11.1.12.1  
Table 11.1.12.7 Baseline and demographic characteristic comparisons: Advanced 
chemotherapy lines 
 
N 
0-1 lines 
>1 lines 
p-value* 
Age 
Median (range) 
X 
X.X (XX-XX) 
X.X (XX-XX) 
X.XXXX 
PS (ECOG) 
0 
X 
X ( XX.X %) 
X ( XX.X %) 
X.XXXX 
 
1 
. 
X ( XX.X %) 
X ( XX.X %) 
 
… 
… 
 
 
 
 
*Fisher's exact test (categorical variables);Mann-Whitney-Wilcoxon (continuous variables). For the complete list of 
covarites, see table 11.1.12.1  
 
 
11.2 Measurements of Treatment Compliance 
Compliance of individual patients with the treatment regimen under study will be measured 
and tabulated in section 12.1 and listed in appendix 16.2.5 (ICH listings). 


 
 
11.3 Efficacy Analysis 
Efficacy analysis will be carried out on the “All Evaluable Patients” population.  
Subgroup analysis will be performed in Cohort A according to prior treatment with 
platinum, BRCA status (BRCA1 vs. BRCA2), hormonal status (Triple negative vs. HR+), 
number of advanced chemotherapy lines , prior PARPi (Yes vs. No) and starting dose (7 
mg FD vs. 3.5 mg/m2).  
Subgroup analysis will be performed in Cohorts A+A1 according to prior PARPi (Yes vs. 
No).  
 
The tables included in each subgroup analysis are the following:  
Table 11.3.1.1 Response rate 
Table 11.3.1.2 Overall response rate 
Table 11.3.2.1 Duration of response 
Table 11.3.2.2 Progression-free survival (PFS) 
Table 11.3.2.3 Overall survival (OS) 
The tables will be annotated by adding a letter as suffix: 
- 
BRCA status: a 
- 
Prior platinum: b 
- 
Hormonal status: c 
- 
Advanced chemotherapy lines: d 
- 
Starting dose: e 
- 
Prior PARPi (Cohort A): f 
- 
Prior PARPi (Cohorts A+A1): g 
If any other disease characteristic is sufficiently represented and clinically relevant, 
subgroup analysis may be performed, and their corresponding tables will also be annotated 
by adding a letter to the table’s name. 
11.3.1 Primary Analysis 
 
Table 11.3.1.1 Response rate  
Response 
N 
% 
Complete response (CR) 
 
 
Partial response (PR) 
 
 
Stable disease (SD) 
 
 
Progressive disease (PD) 
 
 
Inevaluable for efficacy* 
 
 
(*) Treatment failures 


 
Table 11.3.1.2 Overall response rate 
 
Proportion 
Lower 95% limit 
Upper 95% limit 
Response rate* 
 
 
 
(*) CR + PR 
Binomial exact estimator and 95% CI 
 
11.3.2 Secondary Analysis 
Table 11.3.2.1  Duration of response (DR) 
  
DR 
N 
 
Events 
 
Censored 
 
Median DR 
 
DR at 6 months 
 
DR at 12 months 
 
Kaplan-Meier plot will be also shown (Figure 11.3.2.1)  
Table 11.3.2.2  Progression-free survival (PFS) 
  
PFS 
N 
 
Events 
 
Censored 
 
Median PFS 
 
PFS at 3 months 
 
PFS at 6 months 
 
PFS at 12 months 
 
Kaplan-Meier plot will be also shown (Figure 11.3.2.2)  
Table 11.3.2.3  Overall survival (OS) 
  
OS 
N 
 
Events 
 
Censored 
 
Median OS 
 
OS at 12 months 
 
OS at 18 months 
 
Kaplan-Meier plot will be also shown (Figure 11.3.2.3)  
 
Table 11.3.2.4 Clinical benefit rate 
 
Proportion 
Lower 95% limit 
Upper 95% limit 
Clinical benefit rate* 
 
 
 
(*) CR + PR + SD > 3 months 
Binomial exact estimator and 95% CI 
 
Listing 11.3.2.5 Characteristics of patients with clinical benefit*.  
Patient 
PS / 
Age 
BRCA 
status 
Histology 
Type 
Histology 
Grade 
Hormonal  
Status 
 
Sites 
No. 
of 
prior 
lines 
No. of 
advanced 
CT lines 
Prior 
Platinum 
(Y/N) 
Best 
response 
Prior 
platinum 
Prior last therapy 
Agents 
Best 
response 
PFS 
(months
(*) CR + PR + SD > 3 months 


 
 
Patient 
 
Initial dose 
Cycles received 
Best response 
PFS 
(months) 
OS 
(months) 
DR 
(months) 
(*) CR + PR + SD > 3 months 
 
Table 11.3.2.6 Median follow-up* 
Follow-up 
Median 
95% CI 
PFS 
 
 
OS 
 
 
*Calculated using the Kaplan-Meier method reversing the censoring values. 
 
Figure 11.3.2.7 “Waterfall plot” ΔSum of lesions from BL 
 


 
Figure 11.3.2.8 “Swimmer plot” PFS in Cohort A 
 
 
Figure 11.3.2.9 “Swimmer plot” PFS in Cohort A1 
 
 
Figure 11.3.2.10 “Swimmer plot” PFS in Cohort B 


 
 
 
 
11.3.3 Exploratory Univariate and Multivariate Analyses 
 
Table 11.3.3.1 Univariate analysis of response rate  
Variable 
label 
Variable 
values 
DF Estimate Standard 
error 
Wald chi-
square 
Pr > ChiSq 
Odds ratio 
estimate 
95% Odds Ratio 
confidence 
limits 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(See list of covariates in section 6.2.2). 
 
Table 11.3.3.2 Multivariate analysis of response rate  
Analysis of Maximum Likelihood Estimates 
Variable 
label 
Variable 
values 
DF Estimate Standard 
error 
Wald chi-
square 
Pr > ChiSq 
Odds ratio 
estimate 
95% Odds Ratio 
confidence 
limits 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(See list of covariates in section 6.2.2. Only those covariates with a p-value < 0.10 in univariate analysis and 
with a 90% of valid observations will be included). 
 
Table 11.3.3.3 Univariate analysis of PFS  
Variable label Variable values DF Parameter 
estimate 
Standard 
error 
Chi-square Pr > ChiSq Hazard 
ratio 
95% Hazard ratio confidence 
limits 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(See list of covariates in section 6.2.2). 
 
Table 11.3.3.4 Multivariate analysis of PFS  


 
Analysis of Maximum Likelihood Estimates 
Variable label Variable values DF Parameter 
estimate 
Standard 
error 
Chi-square Pr > ChiSq Hazard 
ratio 
95% Hazard ratio confidence 
limits 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(See list of covariates in section 6.2.2. Only those covariates with a p-value < 0.10 in univariate analysis and 
with a 90% of valid observations will be included). 
 
Table 11.3.3.5 Univariate analysis of OS  
Variable label Variable values DF Parameter 
estimate 
Standard 
error 
Chi-square Pr > ChiSq Hazard 
ratio 
95% Hazard ratio confidence 
limits 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(See list of covariates in section 6.2.2). 
 
Table 11.3.3.6 Multivariate analysis of OS  
Analysis of Maximum Likelihood Estimates 
Variable label Variable values DF Parameter 
estimate 
Standard 
error 
Chi-square Pr > ChiSq Hazard 
ratio 
95% Hazard ratio confidence 
limits 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(See list of covariates in section 6.2.2. Only those covariates with a p-value < 0.10 in univariate analysis and 
with a 90% of valid observations will be included). 
 
 
 


 
 
12 Safety Analysis 
Safety analysis will be carried out on the “All Treated Patients” population.  
12.1 Extent of Exposure 
 
Subgroup analysis will be performed according to starting dose (7 mg FD vs. 3.5 mg/m2). 
The tables will be annotated by adding a letter as suffix. 
The tables included in the subgroup analysis are the following: 
Table 12.1.1.1 Number of cycles administered and dose intensity 
Table 12.1.2.1.3 Number of patients and cycles with dosing delay according to relationship 
Table 12.1.3.3 Number of patient and cycles with dose reduction according to relationship 
 
12.1.1 Treatment Administration 
 
Table 12.1.1.1  Number of cycles administered and dose intensity 
No. of cycles administered per patient 
N 
% 
1 
 
 
2 
 
 
3 
 
 
… 
 
 
Median (range) 
 
 Time on treatment* (weeks) 
Median  
Range 
 
PM01183 cumulative dose (mg) 
 
Median 
Range 
PM01183 dose intensity (mg/wk) 
 
Median 
Range 
PM01183 relative dose intensity (%)  
 
Median 
Range 
(*)Time on treatment: defined as last infusion date plus 30 days, or date of death or subsequent therapy (whichever comes 
first) minus first infusion date.   
12.1.2 Cycle Delays  
12.1.2.1 Number of Patients and Cycles with Dosing Delay, Any Relationship 
Listing 12.1.2.1.1 Delays 
Patient id. 
Delayed 
cycle  
Delayed 
cycle start 
date 
Previous cycle Previous cycle 
start date 
Dose Delay 
calculated. (days) 
Reason for 
dose delay 
Dose Delay 
Spec. 
 
 
 
 
 
 
 
 
 
Table 12.1.2.1.2 Number of patients and cycles with dosing delay, any relationship 


 
 
N 
% 
No. of patients treated 
 
 
No. of patients susceptible to have any dose delayed 
 
 
No. of patients with any dose delayed 
 
 
No. of cycles administered 
 
 
No. of cycles susceptible to be delayed* 
 
 
No. of cycles with dosing delay** 
 
 
No. of patients with  
 
 
No cycles delayed 
 
 
1 cycle delayed  
 
 
2 cycles delayed 
 
 
≥ 3 cycles delayed 
 
 
(*) All cycles excluding first cycle. (**) Denominator= Number of cycles susceptible to be delayed  
 
Table 12.1.2.1.3 Number of patients and cycles with dosing delay according to the 
relationship 
 
Treatment-related** 
Non-treatment-related 
N 
% 
N 
% 
No. of patients with  
 
 
 
 
1 cycle delayed  
 
 
 
 
2 cycles delayed 
 
 
 
 
≥ 3 cycles delayed 
 
 
 
 
No. of cycles with 
dosing delay* 
 
 
 
 
(*) Denominator= Number of cycles susceptible to be delayed. (**)Hematological reason, non-hematological reason or 
both 
 
Table 12.1.2.1.4 Number of patients and cycles with dosing delay according to the 
relationship 
Reasons for delays 
N 
% 
Cycles 
No. of cycles with dosing delays* 
 
Treatment-related 
X 
XX.X 
Hematological 
 
 
Non-hematological 
 
 
Both 
 
 
Non-treatment-related 
 
 
Patients 
No. of patients with dosing delays* 
 
Treatment-related 
X 
XX.X 
Hematological 
 
 
Non-hematological 
 
 
Both 
 
 
Non-treatment-related 
 
 
 (*) Denominator= Number of patient/cycles susceptible to have a delay.  
 
 
Table 12.1.2.1.5 Length of dosing delay. 
 
Treatment-related** 
Non-treatment-related 
Total 
Length of delay  
Median (range) 
 
 
 
Length of delay* 
N 
% 
N 
% 
N 
% 
<= 7 days 
 
 
 
 
 
 
>7 days and <=14 days 
 
 
 
 
 
 
> 14 days 
 
 
 
 
 
 
(*) Denominator= Number of cycles susceptible to be delayed. (**)Hematological reason, Non-hematological reason or 
both 


 
 
12.1.2.2 Number of Delays According to Cycle Number 
 
Table 12.1.2.2.1 Number and reasons of delays according to cycle number 
 
No. of 
patients 
No. of 
delays 
Treatment-
related* 
 
 
Treatment-related 
 
Non-
treatment-
related* 
Hematological 
reason 
Non-
hematological 
reason 
Both 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
 
 
 
Cycle 2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cycle 6 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(*) Denominator= Number of cycles susceptible to be delayed. 
 
Table 12.1.2.2.2 Dose reduction in cycles delayed 
 
Reduction 
Yes 
No 
N 
% 
N 
% 
 
 
 
Cycle 2 
 
 
 
 
… 
 
 
 
 
Cycle 6 
 
 
 
 
 
… 
 
 
 
 
 
Total 
 
 
 
 
 
The distribution of delays according to the cycle administered will be studied by means of 
counts and percentages. The reasons for cycle delay will be detailed, specifying how many 
were due to treatment or not.  
 
Listing 12.1.2.2.3 Cycle delays due to AEs 
Patient 
id. 
Cycle 
Preferred 
term code 
Adverse 
event 
reported 
(verbatim) 
Grade Relationship Onset 
date 
Resolved 
date 
No. of days 
with delay 
Action taken Significant 
consequences 
 
 
  
 
 
 
 
 
 
 
AEs with action = ‘Dose delayed’ or ‘Reduced and delayed’. 
 
12.1.3 Dose Reductions 
All dose reductions should be considered and described, specifying the reason for 
reduction (hematological toxicity, non-hematological toxicity or other causes).  
Listing 12.1.3.1 Dose reductions 
Patient id. 
Cycle 
Day 
Cycle start date Previous dose Reduced dose 
Reason for 
dose 
reduction 
Dose 
reduction 
Spec. 
 
 
 
 
 
 
 
 
 


 
 
Table 12.1.3.2 Number of patients and cycles with dose reduction, any relationship 
 
N 
% 
No. of patients treated 
X 
XX.X 
No. of patients susceptible to have a dose reduced 
 
 
No. of patients with any dose reduced 
 
 
No. of patients with: 
 
 
No PM01183 reduction 
 
 
1 cycle with PM01183 dose reduced  
 
 
2 cycles with PM01183 dose reduced 
 
 
No. of cycles administered 
 
 
No. of cycles susceptible to have any dose reduced*  
 
 
No. of cycles with PM01183 dose reduced ** 
 
 
No. of cycles with PM01183 dose reduced (Treatment-related)** 
 
 
(*) All cycles excluding first cycle. (**) Denominator= Number of cycles susceptible to have a dose reduction  
 
Table 12.1.3.3 Number of patients and cycles with dose reduction according to the 
relationship 
Reasons for reductions 
N 
% 
Cycles 
No. of cycles with dose reductions* 
 
Treatment-related 
X 
XX.X 
Hematological 
 
 
Non-hematological 
 
 
Both 
 
 
Non-treatment-related 
 
 
Patients 
No. of patients with dose reductions* 
 
Treatment-related 
X 
XX.X 
Hematological 
 
 
Non-hematological 
 
 
Both 
 
 
Non-treatment-related 
 
 
 (*) Denominator= Number of patient/cycles susceptible to have a dose reduction.  
 
Table 12.1.3.4 Number and reasons of reductions according to cycle number 
 
No. of 
patients 
No. of 
cycles 
with 
reduction 
Treatment-
related* 
 
 
Treatment-related 
 
Non-
treatment-
related* 
Hematological 
reason 
Non-
hematological 
reason 
Both 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
 
Cycle 1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cycle 2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cycle 6 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(*) Denominator= Number of cycles susceptible to be reduced. 
 
Listing  12.1.3.5 Dose reductions due to AEs 
Patient 
id. 
Total 
no. of 
cycles 
Cycle Preferred  
term code 
Adverse 
event 
reported 
(verbatim) 
Grade Relationship Onset 
date 
Resolved 
date 
Action taken 
Significant 
consequences 
 
 
 
  
 
 
 
 
 
 
AEs with action = ‘Dose reduced/adjusted’ or ‘Reduced and delayed’. 


 
 
12.1.4 Infusions Temporarily Interrupted  
A listing of the patients who had infusions temporarily interrupted with the corresponding 
reasons will be provided. 
Listing  12.1.4.1 Interrupted infusion listing. 
Patient id. 
Cycle 
Reason 
 
 
 
 
12.1.5 Prophylactic Medication Administration  
A listing of the patients who have not received corticosterioids, 5-HT antagonists, 
prokinetics and other antiemetics or equivalents with the corresponding reasons will be 
reported. 
Listing  12.1.5.1 Patients and cycles with prophylactic medication not taken per protocol 
Patient id. 
Cycle 
Prophylactic medication not 
taken* 
Reason 
… 
 
No 
 
(*) Corticosterioids, 5-HT antagonists, prokinetics and other antiemetics. 
12.2 Adverse Events 
12.2.1 Adverse Events 
As far as all the toxicities are concerned, the NCI-CTC grade will be used wherever an 
NCI-CTC grading exists. Otherwise, the severity will be noted. As a convention, the term 
«Grade» will always be used. Toxicities will be described according to the worst NCI-CTC 
grade or, for toxicities which do not form the subject of NCI-CTC classification, according 
to the worst severity. 
Adverse events will be described in this section; treatment-related events (stated as related 
to the study drug or of unknown relationship) will be tabulated.  
Type of toxicity and worst grade or severity by cycle and by patient will be summarized 
according to the Preferred Term coded with MedDRA. Tables will be organized per 
category of events using System Organ Class of MedDRA. 
Subgroup analysis will be performed according to starting dose (7 mg FD vs. 3.5 mg/m2) 
and Cohort.  
The groups will include: 
- 
Patient treated at 7 mg FD Cohort B 
- 
Patient treated at 7 mg FD Cohort A 
- 
Patient treated at 7 mg FD any Cohort  
- 
Patient treated at 3.5 mg/m2 Cohort A 
- 
Patient treated at 3.5 mg/m2 Cohort A1 
- 
Patient treated at 3.5 mg/m2 any Cohort  
 
The tables will be annotated by adding a letter as suffix. 


 
The tables included in the subgroup analysis are the following: 
Table 12.2.2.2 Treatment related AEs. Worst grade by patient 
Table 12.2.2.3 Treatment related AEs. Worst grade by cycle 
Table 12.2.2.4 Adverse events regardless of relationship. Worst grade by patient 
Table 12.2.2.5 Adverse events regardless of relationship. Worst grade by cycle 
 
If clinically relevant the outputs could be split by initial dose or any other characteristic. 
 
12.2.2 Display of Adverse Events 
 
Table 12.2.2.1 Summary of AEs. 
Category 
N 
% 
Patients with at least one AE regardless relationship 
 
 
Any treatment-related AE 
 
 
Any grade 3/4 AE 
 
 
Any grade 3/4 treatment-related AE 
 
 
Any SAE in DB 
 
 
Any treatment-related SAE  
 
 
Any grade 3/4 SAE  
 
 
Any grade 3/4 treatment-related SAE  
 
 
AEs leading to death 
 
 
AEs treatment-related leading to death 
 
 
AEs leading to dose delay 
 
 
AEs leading to dose reduction 
 
 
AEs leading to treatment discontinuation 
 
 
AEs treatment-related leading to treatment discontinuation 
 
 
 
Table 12.2.2.2 Treatment-related AEs. Worst grade by patient 
SOC 
Preferred Term 
Grade  
1 
… 
Grade  
4 
All* 
 
 
N 
% 
… 
N 
% 
N 
% 
Blood and lymphatic 
system disorders 
Anemia NOS 
 
 
 
 
 
 
 
... 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
Cardiac disorders 
Arrhythmia NOS 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
(*) Any grade 
 
Table 12.2.2.3 Treatment-related AEs. Worst grade by cycle 
 SOC 
Preferred Term 
Grade  
1 
… 
Grade  
4 
All* 
 
 
N 
% 
… 
N 
% 
N 
% 
Blood and lymphatic 
system disorders 
Anemia NOS 
 
 
 
 
 
 
 
... 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
Cardiac disorders 
Arrhythmia NOS 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
* Any grade 
 
Table 12.2.2.4 Adverse Events regardless of relationship. Worst grade by patient 


 
SOC 
Preferred Term 
Grade  
1 
… 
Grade  
4 
All* 
 
 
N 
% 
… 
N 
% 
N 
% 
Blood and lymphatic 
system disorders 
Anemia NOS 
 
 
 
 
 
 
 
... 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
Cardiac disorders 
Arrhythmia NOS 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
(*) Any grade 
 
Table 12.2.2.5 Adverse Events regardless of relationship. Worst grade by cycle 
SOC 
Preferred Term 
Grade  
1 
… 
Grade  
4 
All* 
 
 
N 
% 
… 
N 
% 
N 
% 
Blood and lymphatic 
system disorders 
Anemia NOS 
 
 
 
 
 
 
 
... 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
Cardiac disorders 
Arrhythmia NOS 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
(*) Any grade 
 
Listing 12.2.2.6 Treatment-related grade 3-4 AEs. Worst grade per patient 
Patient id. 
SOC Name 
Preferred term 
Grade 
 
 
 
 
 
Listing 12.2.2.7 Treatment-related grade 3-4 AEs. Worst grade by cycle 
Patient id. 
Cycle 
SOC Name 
Preferred term 
Grade 
 
 
 
 
 
 
Listing 12.2.2.8 Adverse Events grade 3-4 regardless of relationship. Worst grade per 
patient 
Patient id. 
SOC Name 
Preferred term 
Grade 
 
 
 
 
 
Listing 12.2.2.9 Adverse Events grade 3-4 regardless of relationship. Worst grade by cycle 
Patient id. 
Cycle 
SOC Name 
Preferred term 
Grade 
 
 
 
 
 
 
Table 12.2.2.10 Treatment-related SAEs. Worst grade by patient 
SOC 
Preferred Term 
Grade  
1 
… 
Grade  
4 
All* 
 
 
N 
% 
… 
N 
% 
N 
% 
Blood and lymphatic 
system disorders 
Anemia NOS 
 
 
 
 
 
 
 
... 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
Cardiac disorders 
Arrhythmia NOS 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
(*) Any grade 
 
Table 12.2.2.11 Treatment-related SAEs. Worst grade by cycle 
 SOC 
Preferred Term 
Grade  
1 
… 
Grade  
4 
All* 
 
 
N 
% 
… 
N 
% 
N 
% 
Blood and lymphatic 
system disorders 
Anemia NOS 
 
 
 
 
 
 
 
... 
 
 
 
 
 
 
 


 
… 
 
 
 
 
 
 
 
Cardiac disorders 
Arrhythmia NOS 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
* Any grade 
 
Table 12.2.2.12 SAEs regardless of relationship. Worst grade by patient 
SOC 
Preferred Term 
Grade  
1 
… 
Grade  
4 
All* 
 
 
N 
% 
… 
N 
% 
N 
% 
Blood and lymphatic 
system disorders 
Anemia NOS 
 
 
 
 
 
 
 
... 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
Cardiac disorders 
Arrhythmia NOS 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
(*) Any grade 
 
Table 12.2.2.13 SAEs regardless of relationship. Worst grade by cycle 
SOC 
Preferred Term 
Grade  
1 
… 
Grade  
4 
All* 
 
 
N 
% 
… 
N 
% 
N 
% 
Blood and lymphatic 
system disorders 
Anemia NOS 
 
 
 
 
 
 
 
... 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
Cardiac disorders 
Arrhythmia NOS 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
(*) Any grade 
 
At the time of the analysis, if appropriate, grouping of similar or clinically related items 
will be made. 
12.2.3 Evolution of signs and symptoms during the treatment 
Worst grade signs and symptoms present during treatment and at baseline regardless of 
relationship will be shown. 
 
Table 12.2.3.1 Shift of signs and symptoms during the treatment 
MedDRA PT 
Baseline grade 
Worst grade per patient during treatment  
Grade  
1 
Grade  
2 
Grade  
3 
Grade  
4 
N 
% 
N 
% 
N 
% 
N 
% 
Constipation 
1 
 
 
 
 
 
 
 
 
 
2 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
Diarrhea 
1 
 
 
 
 
 
 
 
 
 
2 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
12.3 Serious Adverse Events and Deaths.  
12.3.1 Serious Adverse Events 
Listing 12.3.1.1 SAEs 
Patient id. 
Preferred  
term code 
Adverse event 
reported 
(verbatim) 
Grade 
Relationship 
Onset 
date 
Resolved 
date 
Action 
Serious criteria 
 
  
 
 
 
 
 
 


 
 
The Pharmacovigilance Department will provide the narratives of the SAEs from the 
Pharmacovigilance Database (DB). 
12.3.2 Deaths 
 
Table 12.3.2.1 Cause of death 
Reason* 
N 
% 
Malignant disease 
 
 
Study drug related adverse event  
 
 
Non-study drug related AE 
 
 
Other  
 
 
Total 
 
 
(*) Denominator=Number of patients who died 
 
Listing 12.3.2.2 Deaths 
Patient 
id. 
Death 
date 
Cause 
Comments 
Autopsy 
Number of 
cycles 
administered  
Last 
infusion 
date  
Time on 
treatment* 
Time from 
Last dose** 
 
 
 
 
 
 
 
 
 
(*)Time on treatment: defined as last infusion date plus 30 days, or date of death or subsequent therapy (whichever comes 
first) minus first infusion date.  (**)Time from last dose defined as death date minus last infusion date.  
 
Listing 12.3.2.3 AEs with outcome death 
Patient id. 
Cycle 
Preferred  
term code 
Adverse event 
reported 
(verbatim) 
Grade 
Relationship 
Onset 
date  
Date of death 
Action 
 
 
  
 
 
 
 
 
12.4 Clinical Laboratory Evaluation 
Subgroup analysis will be performed according to starting dose (7 mg FD vs. 3.5 mg/m2) 
and Cohort.  
The groups will include: 
- 
Patient treated at 7 mg FD Cohort B 
- 
Patient treated at 7 mg FD Cohort A 
- 
Patient treated at 7 mg FD any Cohort  
- 
Patient treated at 3.5 mg/m2 Cohort A 
- 
Patient treated at 3.5 mg/m2 Cohort A1 
- 
Patient treated at 3.5 mg/m2 any Cohort  
 
The tables will be annotated by adding a letter as suffix. 
The tables included in the subgroup analysis are the following: 
Table 12.4.1.1  Hematological abnormalities during treatment, worst grade per patient 
Table 12.4.1.2  Hematological abnormalities during treatment, worst grade per cycle 
Table 12.4.2.1  Biochemical abnormalities during treatment, worst grade per patient 
Table 12.4.2.2  Biochemical abnormalities during treatment, worst grade per cycle 
Table 12.4.3.1  Coagulation abnormalities during treatment, worst grade per patient 
Table 12.4.3.2  Coagulation abnormalities during treatment, worst grade per cycle 
 


 
12.4.1 Hematological Abnormalities 
Hematological toxicities classified according to the NCI-CTC will be calculated for all 
cycles. The worst grade reached by each patient during treatment will be also calculated. 
If serious toxicities happen, special follow-up, with descriptives and graphs (boxplots, line 
plots), will be made to find out the pattern of thrombocytopenia and neutropenia within and 
between the different cycles. 
Table 12.4.1.1 Hematological abnormalities during treatment, worst grade per patient 
 
N 
Grade  
1 
… 
Grade  
4 
All* 
N 
% 
… 
N 
% 
N 
% 
Leukopenia 
 
 
 
 
 
 
 
 
Anemia 
 
 
 
 
 
 
 
 
Thrombocytopenia 
 
 
 
 
 
 
 
 
Neutropenia 
 
 
 
 
 
 
 
 
Lymphopenia 
 
 
 
 
 
 
 
 
(*) Any grade 
 
Table 12.4.1.2 Hematological abnormalities during treatment, worst grade per cycle 
 
N 
Grade  
1 
… 
Grade  
4 
All* 
N 
% 
… 
N 
% 
N 
% 
Leukopenia 
 
 
 
 
 
 
 
 
Anemia 
 
 
 
 
 
 
 
 
Thrombocytopenia 
 
 
 
 
 
 
 
 
Neutropenia 
 
 
 
 
 
 
 
 
Lymphopenia 
 
 
 
 
 
 
 
 
(*) Any grade 
 
 
Listing 12.4.1.3 Grade 3-4 hematological abnormalities during treatment. Worst grade per 
patient 
Patient id. 
Cycle 
Test 
Grade 
 
 
 
 
 
Listing 12.4.1.4 Grade 3-4 hematological abnormalities during treatment. Worst grade per 
cycle 
Patient id. 
Cycle 
Test 
Grade 
 
 
 
 
Listing 12.4.1.5 Hematological tests not assessed by patient and cycle 
Patient id. 
Cycle 
Lab. test 
 
 
 
  
12.4.2 Biochemical Abnormalities 
Grades of liver toxicity and intercycle pattern of creatinine, CPK, bilirubin, transaminases 
increase and alkaline phosphatase increase during a cycle will be calculated, as it is 
explained in the section 7.2 for biochemical toxicities. 
 
Table 12.4.2.1 Biochemical abnormalities during treatment, worst grade per patient 
 
N 
Grade  
… 
Grade  
All* 


 
1 
4 
N 
% 
… 
N 
% 
N 
% 
AST increased 
 
 
 
 
 
 
 
 
ALT increased 
 
 
 
 
 
 
 
 
Total bilirubin increased 
 
 
 
 
 
 
 
 
AP increased 
 
 
 
 
 
 
 
 
Hyperglycemia 
 
 
 
 
 
 
 
 
Hypoglycemia 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
(*) Any grade 
 
Table 12.4.2.2 Biochemical abnormalities during treatment, worst grade per cycle 
 
N 
Grade  
1 
… 
Grade  
4 
All* 
N 
% 
… 
N 
% 
N 
% 
AST increased 
 
 
 
 
 
 
 
 
ALT increased 
 
 
 
 
 
 
 
 
Total bilirubin increased 
 
 
 
 
 
 
 
 
AP increased 
 
 
 
 
 
 
 
 
Hyperglycemia 
 
 
 
 
 
 
 
 
Hypoglycemia 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
(*) Any grade 
 
Listing 12.4.2.3 Grade 3-4 biochemical abnormalities during treatment. Worst grade per 
patient 
Patient id. 
Cycle 
Test 
Grade 
 
 
 
 
 


 
 
Listing 12.4.2.4 Grade 3-4 biochemical abnormalities during treatment. Worst grade per 
cycle 
Patient id. 
Cycle 
Test 
Grade 
 
 
 
 
Listing 12.4.2.5 Biochemical tests not assessed by patient and cycle 
Patient id. 
Cycle 
Lab. test 
 
 
 
 
12.4.3 Coagulation Abnormalities 
 
Table 12.4.3.1 Coagulation abnormalities during treatment, worst grade per patient 
 
N 
Grade  
1 
… 
Grade  
3 
All* 
N 
% 
… 
N 
% 
N 
% 
INR increased 
 
 
 
 
 
 
 
 
APTT prolonged 
 
 
 
 
 
 
 
 
(*) Any grade 
 
Table 12.4.3.2 Coagulation abnormalities during treatment, worst grade per cycle 
 
N 
Grade  
1 
… 
Grade  
3 
All* 
N 
% 
… 
N 
% 
N 
% 
INR increased 
 
 
 
 
 
 
 
 
APTT prolonged 
 
 
 
 
 
 
 
 
(*) Any grade 
 
Listing 12.4.3.3 Grade 3 coagulation abnormalities during treatment. Worst grade per 
patient 
Patient id. 
Cycle 
Test 
Grade 
 
 
 
 
 
Listing 12.4.3.4 Grade 3 coagulation abnormalities during treatment. Worst grade per cycle 
Patient id. 
Cycle 
Test 
Grade 
 
 
 
 
Listing 12.4.3.5 Coagulation tests not assessed by patient and cycle 
Patient id. 
Cycle 
Lab. test 
 
 
 
 


 
 
12.4.4 Laboratory Values Over Time 
In this section, grades 3-4 hematological and liver enzyme abnormalities will be displayed 
according to the cycle in which they occurred. 
Table 12.4.4.1 Evolution of hematological abnormalities from baseline, worst case per 
patient. 
 
 
Baseline grade* 
 
Worst grade per patient 
Total 
0 
1 
… 
N 
% 
N 
% 
N 
% 
N 
% 
Baseline 
Neutropenia  
Grade 0 
 
 
 
 
 
 
 
 
Grade 1 
 
 
 
 
 
 
 
 
…… 
 
 
 
 
 
 
 
 
Thrombocytopenia 
Grade 0 
 
 
 
 
 
 
 
 
Grade 1 
 
 
 
 
 
 
 
 
…… 
 
 
 
 
 
 
 
 
…. 
Grade 0 
 
 
 
 
 
 
 
 
Grade 1 
 
 
 
 
 
 
 
 
…… 
 
 
 
 
 
 
 
 
*Defined as the last value recorded before or on the date of first infusion. 
Table 12.4.4.2 Evolution of hematological abnormalities from baseline, worst case in the 
first cycle per patient. 
 
 
Baseline grade* 
 
Worst grade in the first cycle per patient 
Total 
0 
1 
… 
N 
% 
N 
% 
N 
% 
N 
% 
Baseline 
Neutropenia  
Grade 0 
 
 
 
 
 
 
 
 
Grade 1 
 
 
 
 
 
 
 
 
…… 
 
 
 
 
 
 
 
 
Thrombocytopenia 
Grade 0 
 
 
 
 
 
 
 
 
Grade 1 
 
 
 
 
 
 
 
 
…… 
 
 
 
 
 
 
 
 
…. 
Grade 0 
 
 
 
 
 
 
 
 
Grade 1 
 
 
 
 
 
 
 
 
…… 
 
 
 
 
 
 
 
 
*Defined as the last value recorded before or on the date of first infusion. 
Table 12.4.4.3 Evolution of hematological abnormalities from baseline, worst case in the 
last cycle per patient. 
 
 
Baseline grade* 
 
Worst grade in the last cycle per patient 
Total 
0 
1 
… 
N 
% 
N 
% 
N 
% 
N 
% 
Baseline 
Neutropenia  
Grade 0 
 
 
 
 
 
 
 
 
Grade 1 
 
 
 
 
 
 
 
 
…… 
 
 
 
 
 
 
 
 
Thrombocytopenia 
Grade 0 
 
 
 
 
 
 
 
 
Grade 1 
 
 
 
 
 
 
 
 
…… 
 
 
 
 
 
 
 
 
…. 
Grade 0 
 
 
 
 
 
 
 
 
Grade 1 
 
 
 
 
 
 
 
 
…… 
 
 
 
 
 
 
 
 
*Defined as the last value recorded before or on the date of first infusion. 


 
 
Table 12.4.4.4 Evolution of biochemical abnormalities from baseline, worst case per 
patient. 
 
 
Baseline grade* 
 
Worst grade per patient 
Total 
0 
1 
… 
N 
% 
N 
% 
N 
% 
N 
% 
Baseline 
AST increase 
Grade 0 
 
 
 
 
 
 
 
 
Grade 1 
 
 
 
 
 
 
 
 
…… 
 
 
 
 
 
 
 
 
ALT increase 
Grade 0 
 
 
 
 
 
 
 
 
Grade 1 
 
 
 
 
 
 
 
 
…… 
 
 
 
 
 
 
 
 
… 
Grade 0 
 
 
 
 
 
 
 
 
Grade 1 
 
 
 
 
 
 
 
 
…… 
 
 
 
 
 
 
 
 
*Defined as the last value recorded before or on the date of first infusion. 
 
Table 12.4.4.5 Evolution of biochemical abnormalities from baseline, worst case in the first 
cycle per patient. 
 
 
Baseline grade* 
 
Worst grade in first cycle per patient 
Total 
0 
1 
… 
N 
% 
N 
% 
N 
% 
N 
% 
Baseline 
AST increase 
Grade 0 
 
 
 
 
 
 
 
 
Grade 1 
 
 
 
 
 
 
 
 
…… 
 
 
 
 
 
 
 
 
ALT increase 
Grade 0 
 
 
 
 
 
 
 
 
Grade 1 
 
 
 
 
 
 
 
 
…… 
 
 
 
 
 
 
 
 
… 
Grade 0 
 
 
 
 
 
 
 
 
Grade 1 
 
 
 
 
 
 
 
 
…… 
 
 
 
 
 
 
 
 
*Defined as the last value recorded before or on the date of first infusion. 
 
 
Table 12.4.4.6 Evolution of biochemical abnormalities from baseline, worst case in last 
cycle per patient. 
 
 
Baseline grade* 
 
Worst grade in last cycle per patient 
Total 
0 
1 
… 
N 
% 
N 
% 
N 
% 
N 
% 
Baseline 
AST increase 
Grade 0 
 
 
 
 
 
 
 
 
Grade 1 
 
 
 
 
 
 
 
 
…… 
 
 
 
 
 
 
 
 
ALT increase 
Grade 0 
 
 
 
 
 
 
 
 
Grade 1 
 
 
 
 
 
 
 
 
…… 
 
 
 
 
 
 
 
 
… 
Grade 0 
 
 
 
 
 
 
 
 
Grade 1 
 
 
 
 
 
 
 
 
…… 
 
 
 
 
 
 
 
 
*Defined as the last value recorded before or on the date of first infusion. 
 


 
 
Table 12.4.4.7 Grade 3-4 laboratory abnormalities in the first cycle and in all other cycles 
Laboratory  
abnormalities 
Cycle 1 
Cycle>1 
No. of cycles evaluated 
No. of cycles 
grade 3-4 
% 
No. of cycles evaluated 
No. of cycles 
grade 3-4 
% 
Thrombocytopenia  
 
 
 
 
 
 
AP  
 
 
 
 
 
 
Total bilirubin  
 
 
 
 
 
 
AST  
 
 
 
 
 
 
ALT  
 
 
 
 
 
 
CPK 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
Listing 12.4.4.8 Summary of grade 4 neutropenia and G-CSF administration 
Patient  Total number of cycles 
received 
Cycle numbers with grade 4 
neutropenia  
Cycle numbers with G-CSF 
administration  
Cycle numbers with 
dose reduction 
 
 
 
 
 
 
 
 
 
 
 
Listing 12.4.4.9 Summary of grade 4 thrombocytopenia and platelets transfusions 
Patient Total number of cycles 
received 
Cycle numbers with grade 4 
thrombocytopenia  
Cycle numbers with platelets 
transfusions  
Cycle numbers with 
dose reduction 
 
 
 
 
 
 
 
 
 
 
 
Listing 12.4.4.10 Summary of grade 4 anemia and EPO/transfusions 
Patient Total number of 
cycles received 
Cycle numbers with 
grade 4 anemia  
Cycle numbers with EPO 
administration 
Cycle numbers with RBC 
transfusions 
Cycle 
numbers with 
dose reduction 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 12.4.4.11 Platelet count time course pattern (summary) 
 
Dose received 
Total 
7 mg FD / 3.5 
mg/m2 
6 mg FD / 2.6 
mg/m2 
5 mg FD/ 2.0 
mg/m2 
N 
Median 
(range) 
N 
Median 
(range) 
N 
Median 
(range) 
N 
Median 
(range) 
Platelet transfusion=Yes 
 Baseline grade 0 
1st cycle 
   Onset day grade 4  
 
 
 
 
 
 
 
 
   ... 
 
 
 
 
 
 
 
 
2nd cycle, 3rd cycle …. 
   Onset day grade 4 
 
 
 
 
 
 
 
 
   ... 
 
 
 
 
 
 
 
 
Total 
   Onset day grade 4  
 
 
 
 
 
 
 
 
   ... 
 
 
 
 
 
 
 
 
 Baseline grade 1, 2 .... 
   ... 
 
 
 
 
 
 
 
 


 
 
Dose received 
Total 
7 mg FD / 3.5 
mg/m2 
6 mg FD / 2.6 
mg/m2 
5 mg FD/ 2.0 
mg/m2 
N 
Median 
(range) 
N 
Median 
(range) 
N 
Median 
(range) 
N 
Median 
(range) 
Platelet transfusion=No 
… 
Total 
 Total 
1st cycle 
   Onset day grade 4 
 
 
 
 
 
 
 
 
   ... 
 
 
 
 
 
 
 
 
2nd cycle, 3rd cycle …. 
   Onset day grade 4  
 
 
 
 
 
 
 
 
   ... 
 
 
 
 
 
 
 
 
Total 
   Onset day grade 4  
 
 
 
 
 
 
 
 
   Nadir day grade 4  
 
 
 
 
 
 
 
 
   Nadir value grade 4 
 
 
 
 
 
 
 
 
   Recovery day to grade ≤ 3 
 
 
 
 
 
 
 
 
   Duration in days to grade 3 
 
 
 
 
 
 
 
 
Recovery day to grade ≤ 2  
 
 
 
 
 
 
 
 
   Duration in days to grade 2 
 
 
 
 
 
 
 
 
Recovery day to grade ≤ 1  
 
 
 
 
 
 
 
 
   Duration in days to grade 1 
 
 
 
 
 
 
 
 
 
 
Table 12.4.4.12 Platelet count time course pattern (freqs) 
 
Dose received 
Total 
7 mg FD / 3.5 
mg/m2 
6 mg FD / 2.6 
mg/m2 
5 mg FD/ 2.0 
mg/m2 
N 
% 
N 
% 
N 
% 
N 
% 
Platelet transfusion=Yes 
 Baseline grade 0 
1st cycle 
   Onset day grade 4 
      ≤ 7 
       8-14 
      ≥ 15 
 
 
 
 
 
 
 
 
   ... 
 
 
 
 
 
 
 
 
2nd cycle, 3rd cycle …. 
   Onset day grade 4 
      ≤ 7 
       8-14 
      ≥ 15 
 
 
 
 
 
 
 
 
   ... 
 
 
 
 
 
 
 
 
Total 
   Onset day grade 4 
      ≤ 7 
       8-14 
      ≥ 15 
 
 
 
 
 
 
 
 
   ... 
 
 
 
 
 
 
 
 
 Baseline grade 1, 2 .... 
   ... 
 
 
 
 
 
 
 
 
Platelet transfusion=No 
… 
Total 
 Total 
1st cycle 


 
 
Dose received 
Total 
7 mg FD / 3.5 
mg/m2 
6 mg FD / 2.6 
mg/m2 
5 mg FD/ 2.0 
mg/m2 
N 
% 
N 
% 
N 
% 
N 
% 
   Onset day grade 4 
      ≤ 7 
       8-14 
      ≥ 15 
 
 
 
 
 
 
 
 
   ... 
 
 
 
 
 
 
 
 
2nd cycle, 3rd cycle …. 
   Onset day grade 4 
      ≤ 7 
       8-14 
      ≥ 15 
 
 
 
 
 
 
 
 
   ... 
 
 
 
 
 
 
 
 
Total 
   Onset day grade 4 
      ≤ 7 
       8-14 
      ≥ 15 
 
 
 
 
 
 
 
 
   Nadir day grade 4 
      ≤ 7 
       8-14 
      ≥ 15  
 
 
 
 
 
 
 
 
   Recovery day to grade ≤ 3 
      ≤ 22 
       23-28 
      ≥ 29 
 
 
 
 
 
 
 
 
   Duration in days to grade 3 
      ≤ 5 
       6-10 
      ≥ 11 
 
 
 
 
 
 
 
 
Recovery day to grade ≤ 2  
      ≤ 22 
       23-28 
     ≥ 29 
 
 
 
 
 
 
 
 
   Duration in days to grade 2 
      ≤ 5 
       6-10 
      ≥ 11 
 
 
 
 
 
 
 
 
Recovery day to grade ≤ 1  
      ≤ 22 
       23-28 
     ≥ 29 
 
 
 
 
 
 
 
 
   Duration in days to grade 1 
      ≤ 5 
       6-10 
      ≥ 11 
 
 
 
 
 
 
 
 
 
Table 12.4.4.13 Neutrophil count time course pattern (summary) 
 
Dose received 
Total 
7 mg FD / 3.5 
mg/m2 
6 mg FD / 2.6 
mg/m2 
5 mg FD/ 2.0 
mg/m2 
N 
Median 
(range) 
N 
Median 
(range) 
N 
Median 
(range) 
N 
Median 
(range) 
G-CSF=Yes 
 Baseline grade 0 
1st cycle 
   Onset day grade 4  
 
 
 
 
 
 
 
 
   ... 
 
 
 
 
 
 
 
 


 
 
Dose received 
Total 
7 mg FD / 3.5 
mg/m2 
6 mg FD / 2.6 
mg/m2 
5 mg FD/ 2.0 
mg/m2 
N 
Median 
(range) 
N 
Median 
(range) 
N 
Median 
(range) 
N 
Median 
(range) 
2nd cycle, 3rd cycle …. 
   Onset day grade 4 
 
 
 
 
 
 
 
 
   ... 
 
 
 
 
 
 
 
 
Total 
   Onset day grade 4  
 
 
 
 
 
 
 
 
   ... 
 
 
 
 
 
 
 
 
 Baseline grade 1, 2 .... 
   ... 
 
 
 
 
 
 
 
 
G-CSF=No 
… 
Total 
 Total 
1st cycle 
   Onset day grade 4 
 
 
 
 
 
 
 
 
   ... 
 
 
 
 
 
 
 
 
2nd cycle, 3rd cycle …. 
   Onset day grade 4  
 
 
 
 
 
 
 
 
   ... 
 
 
 
 
 
 
 
 
Total 
   Onset day grade 4  
 
 
 
 
 
 
 
 
   Nadir day grade 4  
 
 
 
 
 
 
 
 
   Nadir value grade 4 
 
 
 
 
 
 
 
 
   Recovery day to grade ≤ 3 
 
 
 
 
 
 
 
 
   Duration in days to grade 3 
 
 
 
 
 
 
 
 
Recovery day to grade ≤ 2  
 
 
 
 
 
 
 
 
   Duration in days to grade 2 
 
 
 
 
 
 
 
 
Recovery day to grade ≤ 1  
 
 
 
 
 
 
 
 
   Duration in days to grade 1 
 
 
 
 
 
 
 
 
 
 
Table 12.4.4.14 Neutrophil count time course pattern (freqs) 
 
Dose received 
Total 
7 mg FD / 3.5 
mg/m2 
6 mg FD / 2.6 
mg/m2 
5 mg FD/ 2.0 
mg/m2 
N 
% 
N 
% 
N 
% 
N 
% 
G-CSF=Yes 
 Baseline grade 0 
1st cycle 
   Onset day grade 4 
      ≤ 7 
       8-14 
      ≥ 15 
 
 
 
 
 
 
 
 
   ... 
 
 
 
 
 
 
 
 
2nd cycle, 3rd cycle …. 
   Onset day grade 4 
      ≤ 7 
       8-14 
      ≥ 15 
 
 
 
 
 
 
 
 
   ... 
 
 
 
 
 
 
 
 
Total 
   Onset day grade 4 
      ≤ 7 
       8-14 
      ≥ 15 
 
 
 
 
 
 
 
 


 
 
Dose received 
Total 
7 mg FD / 3.5 
mg/m2 
6 mg FD / 2.6 
mg/m2 
5 mg FD/ 2.0 
mg/m2 
N 
% 
N 
% 
N 
% 
N 
% 
   ... 
 
 
 
 
 
 
 
 
 Baseline grade 1, 2 .... 
   ... 
 
 
 
 
 
 
 
 
G-CSF=No 
… 
Total 
 Total 
1st cycle 
   Onset day grade 4 
      ≤ 7 
       8-14 
      ≥ 15 
 
 
 
 
 
 
 
 
   ... 
 
 
 
 
 
 
 
 
2nd cycle, 3rd cycle …. 
   Onset day grade 4 
      ≤ 7 
       8-14 
      ≥ 15 
 
 
 
 
 
 
 
 
   ... 
 
 
 
 
 
 
 
 
Total 
   Onset day grade 4 
      ≤ 7 
       8-14 
      ≥ 15 
 
 
 
 
 
 
 
 
   Nadir day grade 4 
      ≤ 7 
       8-14 
      ≥ 15  
 
 
 
 
 
 
 
 
   Recovery day to grade ≤ 3 
      ≤ 22 
       23-28 
      ≥ 29 
 
 
 
 
 
 
 
 
   Duration in days to grade 3 
      ≤ 5 
       6-10 
      ≥ 11 
 
 
 
 
 
 
 
 
Recovery day to grade ≤ 2  
      ≤ 22 
       23-28 
     ≥ 29 
 
 
 
 
 
 
 
 
   Duration in days to grade 2 
      ≤ 5 
       6-10 
      ≥ 11 
 
 
 
 
 
 
 
 
Recovery day to grade ≤ 1  
      ≤ 22 
       23-28 
     ≥ 29 
 
 
 
 
 
 
 
 
   Duration in days to grade 1 
      ≤ 5 
       6-10 
      ≥ 11 
 
 
 
 
 
 
 
 
 
 
Table 12.4.4.15 AST time course pattern (summary) 
 
Dose received 
Total 


 
7 mg FD / 3.5 
mg/m2 
6 mg FD / 2.6 
mg/m2 
5 mg FD/ 2.0 
mg/m2 
N 
Median 
(range) 
N 
Median 
(range) 
N 
Median 
(range) 
N 
Median 
(range) 
Baseline grade 0 
1st cycle 
   Onset day grade 3/4  
 
 
 
 
 
 
 
 
   ... 
 
 
 
 
 
 
 
 
2nd cycle, 3rd cycle …. 
   Onset day grade 3/4 
 
 
 
 
 
 
 
 
   ... 
 
 
 
 
 
 
 
 
Total 
   Onset day grade 3/4  
 
 
 
 
 
 
 
 
   ... 
 
 
 
 
 
 
 
 
Baseline grade 1, 2 .... 
   ... 
 
 
 
 
 
 
 
 
Total 
1st cycle 
   Onset day grade 3/4 
 
 
 
 
 
 
 
 
   ... 
 
 
 
 
 
 
 
 
2nd cycle, 3rd cycle …. 
   Onset day grade 3/4  
 
 
 
 
 
 
 
 
   ... 
 
 
 
 
 
 
 
 
Total 
   Onset day grade 3/4  
 
 
 
 
 
 
 
 
   Peak day grade 3/4  
 
 
 
 
 
 
 
 
   Peak value grade 3/4 
 
 
 
 
 
 
 
 
   Recovery day to grade ≤ 2 
 
 
 
 
 
 
 
 
   Duration in days to grade 2 
 
 
 
 
 
 
 
 
Recovery day to grade ≤ 1  
 
 
 
 
 
 
 
 
   Duration in days to grade 1 
 
 
 
 
 
 
 
 
 
 
 
Table 12.4.4.16 AST time course pattern (freqs) 
 
Dose received 
Total 
7 mg FD / 3.5 
mg/m2 
6 mg FD / 2.6 
mg/m2 
5 mg FD/ 2.0 
mg/m2 
N 
% 
N 
% 
N 
% 
N 
% 
Baseline grade 0 
1st cycle 
   Onset day grade 3/4 
      ≤ 7 
       8-14 
      ≥ 15 
 
 
 
 
 
 
 
 
   ... 
 
 
 
 
 
 
 
 
2nd cycle, 3rd cycle …. 
   Onset day grade 3/4 
      ≤ 7 
       8-14 
      ≥ 15 
 
 
 
 
 
 
 
 
   ... 
 
 
 
 
 
 
 
 
Total 
   Onset day grade 3/4 
      ≤ 7 
       8-14 
      ≥ 15 
 
 
 
 
 
 
 
 
   ... 
 
 
 
 
 
 
 
 
Baseline grade 1, 2 .... 


 
 
Dose received 
Total 
7 mg FD / 3.5 
mg/m2 
6 mg FD / 2.6 
mg/m2 
5 mg FD/ 2.0 
mg/m2 
N 
% 
N 
% 
N 
% 
N 
% 
   ... 
 
 
 
 
 
 
 
 
Total 
1st cycle 
   Onset day grade 3/4 
      ≤ 7 
       8-14 
      ≥ 15 
 
 
 
 
 
 
 
 
   ... 
 
 
 
 
 
 
 
 
2nd cycle, 3rd cycle …. 
   Onset day grade 3/4 
      ≤ 7 
       8-14 
      ≥ 15 
 
 
 
 
 
 
 
 
   ... 
 
 
 
 
 
 
 
 
Total 
   Onset day grade 3/4 
      ≤ 7 
       8-14 
      ≥ 15 
 
 
 
 
 
 
 
 
   Peak day grade 3/4 
      ≤ 7 
       8-14 
      ≥ 15  
 
 
 
 
 
 
 
 
   Recovery day to grade ≤ 2 
      ≤ 22 
       23-28 
      ≥ 29 
 
 
 
 
 
 
 
 
   Duration in days to grade 2 
      ≤ 5 
       6-10 
      ≥ 11 
 
 
 
 
 
 
 
 
Recovery day to grade ≤ 1  
      ≤ 22 
       23-28 
      ≥ 29 
 
 
 
 
 
 
 
 
   Duration in days to grade 1 
      ≤ 5 
       6-10 
      ≥ 11 
 
 
 
 
 
 
 
 
 
Table 12.4.4.17 ALT time course pattern (summary) 
 
Dose received 
Total 
7 mg FD / 3.5 
mg/m2 
6 mg FD / 2.6 
mg/m2 
5 mg FD/ 2.0 
mg/m2 
N 
Median 
(range) 
N 
Median 
(range) 
N 
Median 
(range) 
N 
Median 
(range) 
Baseline grade 0 
1st cycle 
   Onset day grade 3/4  
 
 
 
 
 
 
 
 
   ... 
 
 
 
 
 
 
 
 
2nd cycle, 3rd cycle …. 
   Onset day grade 3/4 
 
 
 
 
 
 
 
 
   ... 
 
 
 
 
 
 
 
 
Total 
   Onset day grade 3/4  
 
 
 
 
 
 
 
 
   ... 
 
 
 
 
 
 
 
 


 
 
Dose received 
Total 
7 mg FD / 3.5 
mg/m2 
6 mg FD / 2.6 
mg/m2 
5 mg FD/ 2.0 
mg/m2 
N 
Median 
(range) 
N 
Median 
(range) 
N 
Median 
(range) 
N 
Median 
(range) 
Baseline grade 1, 2 .... 
   ... 
 
 
 
 
 
 
 
 
Total 
1st cycle 
   Onset day grade 3/4 
 
 
 
 
 
 
 
 
   ... 
 
 
 
 
 
 
 
 
2nd cycle, 3rd cycle …. 
   Onset day grade 3/4  
 
 
 
 
 
 
 
 
   ... 
 
 
 
 
 
 
 
 
Total 
   Onset day grade 3/4  
 
 
 
 
 
 
 
 
   Peak day grade 3/4  
 
 
 
 
 
 
 
 
   Peak value grade 3/4 
 
 
 
 
 
 
 
 
   Recovery day to grade ≤ 2 
 
 
 
 
 
 
 
 
   Duration in days to grade 2 
 
 
 
 
 
 
 
 
Recovery day to grade ≤ 1  
 
 
 
 
 
 
 
 
   Duration in days to grade 1 
 
 
 
 
 
 
 
 
 
Table 12.4.4.18 ALT time course pattern (freqs) 
 
Dose received 
Total 
7 mg FD / 3.5 
mg/m2 
6 mg FD / 2.6 
mg/m2 
5 mg FD/ 2.0 
mg/m2 
N 
% 
N 
% 
N 
% 
N 
% 
Baseline grade 0 
1st cycle 
   Onset day grade 3/4 
      ≤ 7 
       8-14 
      ≥ 15 
 
 
 
 
 
 
 
 
   ... 
 
 
 
 
 
 
 
 
2nd cycle, 3rd cycle …. 
   Onset day grade 3/4 
      ≤ 7 
       8-14 
      ≥ 15 
 
 
 
 
 
 
 
 
   ... 
 
 
 
 
 
 
 
 
Total 
   Onset day grade 3/4 
      ≤ 7 
       8-14 
      ≥ 15 
 
 
 
 
 
 
 
 
   ... 
 
 
 
 
 
 
 
 
Baseline grade 1, 2 .... 
   ... 
 
 
 
 
 
 
 
 
Total 
1st cycle 
   Onset day grade 3/4 
      ≤ 7 
       8-14 
      ≥ 15 
 
 
 
 
 
 
 
 
   ... 
 
 
 
 
 
 
 
 
2nd cycle, 3rd cycle …. 
   Onset day grade 3/4 
      ≤ 7 
       8-14 
 
 
 
 
 
 
 
 


 
 
Dose received 
Total 
7 mg FD / 3.5 
mg/m2 
6 mg FD / 2.6 
mg/m2 
5 mg FD/ 2.0 
mg/m2 
N 
% 
N 
% 
N 
% 
N 
% 
      ≥ 15 
   ... 
 
 
 
 
 
 
 
 
Total 
   Onset day grade 3/4 
      ≤ 7 
       8-14 
      ≥ 15 
 
 
 
 
 
 
 
 
   Peak day grade 3/4 
      ≤ 7 
       8-14 
      ≥ 15  
 
 
 
 
 
 
 
 
   Recovery day to grade ≤ 2 
      ≤ 22 
       23-28 
      ≥ 29 
 
 
 
 
 
 
 
 
   Duration in days to grade 2 
      ≤ 5 
       6-10 
      ≥ 11 
 
 
 
 
 
 
 
 
Recovery day to grade ≤ 1  
      ≤ 22 
       23-28 
      ≥ 29 
 
 
 
 
 
 
 
 
   Duration in days to grade 1 
      ≤ 5 
       6-10 
      ≥ 11 
 
 
 
 
 
 
 
 
 


 
12.5 Physical Findings, PS, LVEF, ECG and Other Tests Related to Safety 
12.5.1 Physical Findings and PS (ECOG) 
 
Table 12.5.1.1 ECOG performance status during the study 
(*) Worst ECOG PS of the cycle determinations. 
 
Table 12.5.1.2 Physical examination during the study 
(*) Worst result per cycle. 
 
Table 12.5.1.3 Weight by patient per cycle 
(*) % of changes respect to baseline 
 
12.5.2 LVEF, ECG and Other Related Tests 
Listing 12.5.2.1 LVEF evolution during the study. 
Patient id. 
LVEF(%) 
Baseline* 
Minimun*  
End of treatment* 
 
 
 
 
Median(Range) 
 
 
 
(*) LVEF (%) value and method 
Listing 12.5.2.2 Electrocardiogram results. Evolution during the study. 
(*) Worst result of the cycle determinations. 
  
Cycle/PS* 
  
0 
1 
2 
3 
4 
… 
EOT 
Patient id. 
  
… 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
  
Cycle/Physical examination result* 
  
0 
1 
2 
3 
4 
… 
EOT 
Patient id. 
  
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
Cycle/Weight 
  
0 
(kg) 
1* 
(%) 
2* 
(%) 
3* 
(%) 
4* 
(%) 
…* 
(%) 
EOT* 
(%) 
Patient id. 
  
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
Cycle/ECG result* 
  
0 
1 
2 
3 
4 
… 
EOT 
Patient id. 
  
… 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 


 
 Listing 12.5.2.3 Troponin I and Troponin T values. Evolution during the study. 
Patient id. 
Cycle 
Test 
Value 
ULN 
 
 
 
 
 
 
12.6 Concomitant Therapy / Procedures According to the ATC Classification. 
Table 12.6.1 Concomitant medication during treatment (ATC1, ATC2 and ATC4 levels) 
Concomitant medication at baseline 
N 
% 
Alimentary tract and metabolism 
 
 
   Antacids 
 
 
          Magnesium adipate 
 
 
… 
 
 
Blood and blood forming organs 
 
 
   Antithrombotic agents 
 
 
          Acenocoumarol 
 
 
… 
 
 
 
Table 12.6.2 Summary of concomitant medication during treatment 
 
N 
% 
No. of systems  (ATC1 level) 
 
 
0 
1 
2 
 
 
≥ 3 
 
 
Median (range) 
 
 
No. of indications (ATC2 level) 
 
 
0 
1 
2 
 
 
≥ 3 
 
 
Median (range) 
 
 
No. of agent families (ATC4 level) 
 
 
0 
1 
2 
 
 
≥ 3 
 
 
Median (range) 
 
 
No. of agents (PN level) 
 
 
0 
1 
2 
 
 
≥ 3 
 
 
Median (range) 
 
 
Listing  12.6.3 Patients with any transfusion during treatment 
Patient 
Cycle 
PM1183 
dose in the 
previous 
cycle 
Platelets / 
RBC 
Date first 
transfusion 
Date last transfusion 
No. of units required* 
 
 
 
 
 
 
 
(*) No. of transfusions for platelets or no. of packed for RBC transfusions. 


 
Listing  12.6.4 Patients with G-CSF during treatment 
Patient 
Cycle 
Agent 
PT 
Dose 
Start date 
End date 
 
 
 
 
 
 
 
Table 12.6.5 Transfusions and G-CSF by dose 
 
7 mg FD 
3.5 mg/m2 
Total 
 
N 
% 
N 
% 
N 
% 
Transfusions 
 
 
 
 
 
 
  RBC 
 
 
 
 
 
 
  Platelets 
 
 
 
 
 
 
G-CSF 
 
 
 
 
 
 
Table 12.6.6 Subsequent therapy 
 
N 
% 
Type 
 
 
  Chemotherapy 
 
 
   … 
 
 
Subsequent chemotherapy agents (ATC) 
 
 
  … 
 
 
   … 
 
 
Table 12.6.7 Subsequent therapy. Best response (if available). 
Best response 
Subsequent therapy 
CR 
PR 
SD 
PD 
NE 
PM01183 
CR 
 
 
 
 
 
PR 
 
 
 
 
 
SD 
 
 
 
 
 
PD 
 
 
 
 
 
NE 
 
 
 
 
 
(*) If a low number of best response to the subsequent therapy is available, a listing, instead of this table, will be provided. 
 


 
 APPENDIX II 
13 DB Listings 
 
CRF Listings. 
 
-Listing 13.1.1: Investigator comments 
-Listing 13.1.2: Study registration 
-Listing 13.1.3: Demography 
-Listing 13.1.4: Pregnancy test and adequate contraception 
-Listing 13.1.5: Prior medical history 
-Listing 13.1.6: Cancer history 
-Listing 13.1.7: Prior surgery 
-Listing 13.1.8: Prior radiotherapy 
-Listing 13.1.9: Prior medical therapy 
-Listing 13.1.10: Hematological laboratory values 
-Listing 13.1.11: Biochemical laboratory values 
-Listing 13.1.12: Coagulation laboratory values 
-Listing 13.1.13: Physical examination 
-Listing 13.1.14: Performance status 
-Listing 13.1.15: Vital signs 
-Listing 13.1.16: Electrocardiogram 
-Listing 13.1.17: LVEF 
-Listing 13.1.18: Prophylactic medication 
-Listing 13.1.19: Drug administration 
-Listing 13.1.20: Adverse events (including signs and symptoms) 
-Listing 13.1.21: Concomitant therapy/procedures 
-Listing 13.1.22: Tumor assessment 
-Listing 13.1.23: Evaluation of response by cycle 
-Listing 13.1.24: Best study overall response 
-Listing 13.1.25: End of treatment 
-Listing 13.1.26: Follow up 
-Listing 13.1.27: Death report form 
-Listing 13.1.28: Off study 
-Listing 13.1.29: BRCA 1/2 germline mutation 
 
ICH Listings. 
 
-Listing 16.2.1 Discontinued patients 
-Listing 16.2.2 Protocol deviations 
-Listing 16.2.3 Patients excluded from the efficacy analysis 
-Listing 16.2.4 Demographic data 
-Listing 16.2.5 Compliance and-or Drug Concentration Data 
-Listing 16.2.6 Individual Efficacy Response data 
-Listing 16.2.7 Adverse event listings 
-Listing 16.2.8 Individual laboratory measurements 


 
14 SAP Version History  
14.1 From version 1.0 to version 2.0 
After the first version of the statistical plan was approved, some new protocol "substantial 
amendments No. 1 (Nov2013), No. 2 (Oct2014) and No. 3 (Feb2016)" were implemented. 
The Statistical Analysis Plan has been updated (changes are highlighted in italic bold) in 
accordance with the currently available version of the protocol (i.e., version 4) as follows: 
 
Section 2 Study Design 
 
Original text: 
 
This is a multicenter, open-label, exploratory, phase II clinical trial evaluating the efficacy 
and safety of PM01183 administration to patients with previously treated MBC, as follows. 
Two Cohorts of MBC patients will be prospectively evaluated in the trial, initially 
according to germline BRCA1/2 status (mutated vs. unselected): 
• Cohort A (BRCA+ Cohort): At least 53 evaluable patients with previously known 
deleterious BRCA1/2 mutation status at study entry. 
• Cohort B (unselected Cohort): At least 64 evaluable patients without known 
deleterious BRCA1/2 mutation status at study entry, i.e., either: 
o Patients known to have no deleterious BRCA1/2 mutations (BRCA−), or 
o Patients whose BRCA 1/2 mutation status is unknown (BRCA-UK); 
BRCA1/2 germline mutation status will be assessed in PM01183 responding 
patients in this subgroup. 
[…] 
An interim analysis based on the primary endpoint (ORR) is planned after 20 and 30 
evaluable patients have been treated in Cohorts A and B, respectively (see Section ¡Error! 
No se encuentra el origen de la referencia. for details). If less than four out of 20 patients 
in Cohort A, or less than three out of 30 patients in Cohort B achieve an objective 
confirmed response, recruitment to that Cohort will be terminated. 
 
Changed to: 
 
This is a multicenter, open-label, exploratory, phase II clinical trial evaluating the efficacy 
and safety of PM01183 administration to patients with previously treated MBC, as follows. 
 
Two Cohorts of MBC patients will be prospectively evaluated in the trial according to 
germline BRCA1/2 status (mutated [Cohort A] vs. unselected [Cohort B]). A third Cohort 
(Cohort A1) will include advanced breast cancer patients with deleterious BRCA1/2 
mutation status who received prior treatment with poly (ADP-ribose) polymerase (PARP) 
inhibitors: 


 
• Cohort A (BRCA+ Cohort): At least 53 evaluable patients with previously known 
deleterious BRCA1/2 mutation status at study entry.  
• Cohort A1 (BRCA+/PARPi Cohort): 20 evaluable patients with known deleterious 
BRCA1/2 mutation status and prior treatment with PARP inhibitors (PARPi).  
• Cohort B (unselected Cohort): At least 64 evaluable patients without known deleterious 
BRCA1/2 mutation status at study entry, i.e., either: 
o Patients known to have no deleterious BRCA1/2 mutations (BRCA−), or 
o Patients whose BRCA 1/2 mutation status is unknown (BRCA-UK); BRCA1/2 
germline mutation status will be assessed in PM01183 responding patients in 
this subgroup. 
 
[….] 
An interim analysis based on the primary endpoint (ORR) is planned after 20 and 30 
evaluable patients have been treated in Cohorts A and B, respectively (see Section ¡Error! 
No se encuentra el origen de la referencia. for details). No interim analysis is planned 
for Cohort A1. If less than four out of 20 patients in Cohort A, or less than three out of 30 
patients in Cohort B achieve an objective confirmed response, recruitment to that Cohort 
will be terminated. 
 
Section 5.1 Sample Size 
 
Original text 
The primary endpoint for this phase II study is to evaluate ORR. 
• Cohort A (BRCA+): At least 53 evaluable patients will be recruited to test the null 
hypothesis that ORR is 20% or less (p ≤ 0.20) vs. the alternative hypothesis that 
40% or more patients have objective response (p ≥ 0.4). With these assumptions, if 
the number of evaluable patients with objective response is ≥ 17, then this would 
allow the rejection of the null hypothesis. 
• Cohort B (unselected): At least 64 evaluable patients will be recruited to test the 
null hypothesis that ORR is 10% or less (p ≤ 0.10) vs. the alternative hypothesis that 
25% or more patients have objective response (p ≥ 0.25). With these assumptions, if 
the number of evaluable patients with objective response is ≥ 12, then this would 
allow the rejection of the null hypothesis. 
The variance of the standardized tests is based on the null hypothesis. The type I error 
(alpha) associated with this one-sided test is 0.025 and the type II error (beta) is <0.1; 
hence, statistical power is > 90%. Futility analysis controlled by the Gamma family 
boundary will be performed when 20 and 30 patients have been evaluated in Cohorts A 
[Gm(-2)] and B [Gm(-1.5)], respectively. If less than four out of 20 patients in Cohort A, or 
less than three patients out of 30 in Cohort B achieve an objective response, recruitment to 
that Cohort will be stopped. Therefore, between 50 and at least 117 evaluable patients will 
be included in this study. 
 
Changed to: 


 
 
The primary endpoint for this phase II study is to evaluate ORR. 
• Cohort A (BRCA+): 
At least 53 evaluable patients will be recruited to test the null hypothesis that ORR is 
20% or less (p ≤ 0.20) vs. the alternative hypothesis that 40% or more patients have 
objective response (p ≥ 0.4). With these assumptions, if the number of evaluable 
patients with objective response is ≥ 17, then this would allow the rejection of the null 
hypothesis. 
• Cohort A1 (BRCA+/PARPi): 
At least 20 evaluable patients will be included for an exploratory analysis: if the 
number of patients responding is ≥ 4 (20%), the lower limit of the exact binomial 95% 
confidence interval will be higher than 5% and thus lack of activity in this 
subpopulation will be ruled out. 
• Cohort B (unselected): 
At least 64 evaluable patients will be recruited to test the null hypothesis that ORR is 
10% or less (p ≤ 0.10) vs. the alternative hypothesis that 25% or more patients have 
objective response (p ≥ 0.25). With these assumptions, if the number of evaluable 
patients with objective response is ≥ 12, then this would allow the rejection of the null 
hypothesis. 
 
The variance of the standardized tests is based on the null hypothesis. The type I error 
(alpha) associated with this one-sided test is 0.025 and the type II error (beta) is <0.1; 
hence, statistical power is > 90%.  
Futility analysis controlled by the Gamma family boundary will be performed when 20 and 
30 patients have been evaluated in Cohorts A [Gm(-2)] and B [Gm(-1.5)], respectively. If 
less than four out of 20 patients in Cohort A, or less than three patients out of 30 in Cohort 
B achieve an objective response, recruitment to that Cohort will be stopped. Therefore, 
between 50 and at least 117 evaluable patients will be included in this study. About 110 
evaluable patients are finally expected to be included in the three Cohorts: Cohort A 
(BRCA+), Cohort A1 (BRCA+/PARPi), and Cohort B (unselected). 
 
Section 6.2.2 Secondary Endpoints 
 
Original text: 
[…] 
A log-rank test or Cox regression for time-to-event endpoints could be performed as 
supportive analysis to compare both Cohorts. 
[…] 
If appropriate, exploratory multivariate models (main effects or including interaction terms, 
if appropriate) will include all prognostic factors/covariates widely reported and recognized 
by oncologists: Cohort (BRCA (+) vs. BRCA (-) or unknown), BRCA (1 vs. 2 vs. both vs. 
negative/unkown), age, age at diagnosis, race (Caucasian vs. other), baseline Eastern 
Cooperative Oncology Group performance status (ECOG PS) (0 vs. >0), histology type 
(Ductal vs. lobular carcinoma), histology grade (poorly vs. other), stage at diagnosis, 


 
primary tumor site (unilateral breast vs. bilateral), estrogen receptor (positive vs. negative), 
progesterone receptor (positive vs. negative), HER-2 receptor (positive vs. negative), site of 
current disease (CNS vs. liver vs. lung vs. non-visceral (including bone, skin, subcutaneous 
and lymph node) vs. other), liver metastases (yes vs. no), CNS metastases (yes vs. no), 
number of prior metastatic sites (1 vs. >1), body mass index (BMI), height, weight, body 
surface area (BSA), time from diagnosis to first infusion, prior surgery (yes vs. no), prior 
radiotherapy (yes vs. no), prior advanced treatment lines, prior advanced chemotherapy 
lines (1 vs. >1), prior anthracyclines (yes vs. no), prior taxane (yes vs. no), prior platinum 
(yes vs. no), anthracycline cumulative dose, last prior therapy PFS, first advanced 
chemotherapy PFS, last advanced chemotherapy PFS; PFS for anthracycline, taxane and 
platinum therapy, hormonotherapy (yes vs no), adjuvant/neoadjuvant therapy (yes vs no), 
presence of any bulky (< 50 mm vs. ≥ 50 mm) lesion, albumin at baseline, CA-15.3 or 
27.29 at baseline, any relevant concomitant medication at baseline (to be determinate by the 
oncologist) (yes vs. no) and the sum of all target lesion diameters. 
[…] 
 
Changed to: 
[…] 
A log-rank test or Cox regression for time-to-event endpoints could be performed as 
supportive analysis to compare both Cohorts between different cohorts and /or defined 
groups. 
[…] 
If appropriate, exploratory multivariate models (main effects or including interaction terms, 
if appropriate) will include all prognostic factors/covariates widely reported and recognized 
by oncologists: Cohort (BRCA (+) vs. BRCA (-) or unknown), BRCA (1 vs. 2 vs. both vs. 
negative/unkown), initial dose (7 mg FD vs 3.5 mg/m2), age, age at diagnosis, race 
(Caucasian vs. other), baseline Eastern Cooperative Oncology Group performance status 
(ECOG PS) (0 vs. >0), histology type (Ductal vs. lobular carcinoma), histology grade 
(poorly vs. other), stage at diagnosis, primary tumor site (unilateral breast vs. bilateral), 
hormone receptor positive  (estrogen or progesterone receptor +, or both +) vs. triple 
negative, HER-2 receptor (positive vs. negative), site of current disease (CNS vs. liver vs. 
lung vs. non-visceral (including bone, skin, subcutaneous and lymph node) vs. other), liver 
metastases (yes vs. no), CNS metastases (yes vs. no), number of prior metastatic sites (1 vs. 
>1), body mass index (BMI), height, weight, body surface area (BSA), time from diagnosis 
to first infusion, prior surgery (yes vs. no), prior radiotherapy (yes vs. no), prior advanced 
treatment lines, prior advanced chemotherapy lines (0-1 vs. 2-3), prior anthracyclines (yes 
vs. no), prior taxane (yes vs. no), prior platinum (yes vs. no), prior PARPi (yes vs. no), 
anthracycline cumulative dose, last prior therapy PFS, first advanced chemotherapy PFS, 
last advanced chemotherapy PFS; PFS for anthracycline, taxane and platinum therapy, 
hormonotherapy (yes vs no), adjuvant/neoadjuvant therapy (yes vs no), presence of any 
bulky (< 50 mm vs. ≥ 50 mm) lesion, albumin at baseline, CA-15.3 or 27.29 at baseline, 
any relevant concomitant medication at baseline (to be determinate by the oncologist) (yes 
vs. no) and the sum of all target lesion diameters. 
[…] 


 
Section 8.9 Subgroup Analysis 
 
Original Text: 
 
The analysis will be done by Cohort and additionally, if clinically appropriate, the two 
Cohorts might be pooled into one, whenever differences between Cohorts are considered 
not relevant. In such case, the point estimates and their 95% CIs will be also reassessed in 
order to obtain more accurate calculations.  
No other specific subgroup analysis is being planned for the analysis. However, if any of 
the disease characteristics is sufficiently represented and clinically relevant, subgroup 
analysis may be performed in order to explore the activity of PM01183 in specific breast 
cancer subpopulations according to hormonal receptor status, HER-2 overexpression, 
number 
and/or 
type 
of 
prior 
therapies, 
or 
according 
to 
other 
available 
histological/molecular classifications. 
 
Changed to: 
The analysis will be done by Cohort and additionally, if clinically appropriate, the two 
Cohorts might be pooled into one, whenever differences between Cohorts are considered 
not relevant. In such case, the point estimates and their 95% CIs will be also reassessed in 
order to obtain more accurate calculations.  
 
Efficacy subgroup analysis will be performed in Cohort A according to prior treatment 
with platinum, BRCA status (BRCA1 vs. BRCA2), hormonal status (Triple negative vs 
HR+), number of  advanced chemotherapy lines (0-1 vs. 2-3) and starting dose (7 mg FD 
vs. 3.5 mg/m2). 
 
Safety subgroup analysis will be performed according to starting dose (7 mg FD vs. 3.5 
mg/m2), these analysis include laboratory abnormalities and adverse events. 
No other specific subgroup analysis is being planned for the analysis. However, if any of 
the disease characteristics is sufficiently represented and clinically relevant,  If clinically 
relevant, other subgroup analysis may be performed in order to explore the activity of 
PM01183 in specific breast cancer subpopulations. according to hormonal receptor status, 
HER-2 overexpression, number and/or type of prior therapies, or according to other 
available histological/molecular classifications. 


 
Section 11.3 Efficacy Analysis 
 
Original text: 
Efficacy analysis will be carried out on the “All Evaluable Patients” population.  
If any of the disease characteristics is sufficiently represented and clinically relevant, 
subgroup analysis may be performed in order to explore the activity of PM01183 in specific 
breast cancer subpopulations according to hormonal receptor status, HER-2 overexpression, 
number 
and/or 
type 
of 
prior 
therapies, 
or 
according 
to 
other 
available 
histological/molecular classifications. 
 
Changed to: 
Efficacy analysis will be carried out on the “All Evaluable Patients” population.  
Subgroup analysis will be performed in Cohort A according to prior treatment with 
platinum, BRCA status (BRCA1 vs. BRCA2), hormonal status (Triple negative vs. HR+), 
number of advanced chemotherapy lines (0-1 vs. 2-3) and starting dose (7 mg FD vs. 3.5 
mg/m2).  
The tables included in each subgroup analysis are the following:  
Table 11.3.1.1 Response rate 
Table 11.3.1.2 Overall response rate 
Table 11.3.2.1 Duration of response 
Table 11.3.2.2 Progression-free survival (PFS) 
Table 11.3.2.3 Overall survival (OS) 
The tables will be annotated by adding a letter as suffix: 
- 
BRCA status: a 
- 
Prior platinum: b 
- 
Hormonal status: c 
- 
Advanced chemotherapy lines: d 
- 
Starting dose: e 
If any of the other disease characteristics is sufficiently represented and clinically 
relevant, subgroup analysis may be performed, and their corresponding tables will also 
be annotated by adding a letter to the table’s name. according to hormonal receptor status, 
HER-2 overexpression, number and/or type of prior therapies, or according to other 
available histological/molecular classifications. 


 
Section 12.1 Extent of Exposure 
 
Added text: 
 
Subgroup analysis will be performed according to starting dose (7 mg FD vs. 3.5 mg/m2). 
The tables will be annotated by adding a letter as suffix. 
The tables included in the subgroup analysis are the following: 
Table 12.1.1.1 Number of cycles administered and dose intensity 
Table 12.1.2.1.3 Number of patients and cycles with dosing delay according to 
relationship 
Table 12.1.3.3 Number of patient and cycles with dose reduction according to 
relationship 
 
 
Section 12.2.1 Adverse Events 
 
Added text: 
Subgroup analysis will be performed according to starting dose (7 mg FD vs. 3.5 mg/m2) 
and Cohort.  
The groups will include: 
- 
Patient treated at 7 mg FD Cohort B 
- 
Patient treated at 7 mg FD Cohort A 
- 
Patient treated at 7 mg FD any Cohort  
- 
Patient treated at 3.5 mg/m2 Cohort A 
- 
Patient treated at 3.5 mg/m2 Cohort A1 
- 
Patient treated at 3.5 mg/m2 any Cohort  
 
The tables will be annotated by adding a letter as suffix. 
The tables included in the subgroup analysis are the following: 
Table 12.2.2.2 Treatment related AEs. Worst grade by patient 
Table 12.2.2.3 Treatment related AEs. Worst grade by cycle 
Table 12.2.2.4 Adverse events regardless of relationship. Worst grade by patient 
Table 12.2.2.5 Adverse events regardless of relationship. Worst grade by cycle 
 


 
Section 12.4 Clinical Laboratory Evaluation 
 
Added text: 
Subgroup analysis will be performed according to starting dose (7 mg FD vs. 3.5 mg/m2) 
and Cohort.  
The groups will include: 
- 
Patient treated at 7 mg FD Cohort B 
- 
Patient treated at 7 mg FD Cohort A 
- 
Patient treated at 7 mg FD any Cohort  
- 
Patient treated at 3.5 mg/m2 Cohort A 
- 
Patient treated at 3.5 mg/m2 Cohort A1 
- 
Patient treated at 3.5 mg/m2 any Cohort  
 
The tables will be annotated by adding a letter as suffix. 
The tables included in the subgroup analysis are the following: 
Table 12.4.1.1  Hematological abnormalities during treatment, worst grade per patient 
Table 12.4.1.2  Hematological abnormalities during treatment, worst grade per cycle 
Table 12.4.2.1  Biochemical abnormalities during treatment, worst grade per patient 
Table 12.4.2.2  Biochemical abnormalities during treatment, worst grade per cycle 
Table 12.4.3.1  Coagulation abnormalities during treatment, worst grade per patient 
Table 12.4.3.2  Coagulation abnormalities during treatment, worst grade per cycle 
 
14.2 From version 2.0 to version 3.0 
The Statistical Analysis Plan has been updated (changes are highlighted in italic bold) in 
order to include some relevant analysis according to the medical responsible, to clarify 
some of the analyses and to correct several typos found in the previous SAP version. 
 
Section 5.1 Sample size 
 
Original text: 
 
[…] 
• Cohort A1 (BRCA+/PARPi): 
At least 20 evaluable patients will be for an exploratory analysis: if the number of 
patients responding is ≥ 4 (20%), the lower limit of the exact binomial 95% confidence 
interval will be higher than 5% and thus lack of activity in this subpopulation will be 
ruled out. 
 
Changed to: 
[…] 
• Cohort A1 (BRCA+/PARPi): 
At least 20 evaluable patients will be recruited for an exploratory analysis: if the 
number of patients responding is ≥ 4 (20%), the lower limit of the exact binomial 95% 
confidence interval will be higher than 5% and thus lack of activity in this 


 
subpopulation will be ruled out. 
 
Section 6.2.2 Secondary Endpoints 
 
Original text: 
[…] 
If relevant, efficacy parameters versus baseline covariates will be analyzed and appropriate 
test will be used (i.e., the Fisher exact test and logistic regression for categorical variables, 
the log-rank test or Cox regression for time-to-event variables, etc.). 
If appropriate, exploratory multivariate models (main effects or including interaction terms, 
if appropriate) will include all prognostic factors/covariates widely reported and recognized 
by oncologists: Cohort (BRCA (+) vs. BRCA (-) or unknown), BRCA (1 vs. 2 vs. both vs. 
negative/unkown), initial dose (7 mg FD vs 3.5 mg/m2), age, age at diagnosis, race 
(Caucasian vs. other), baseline Eastern Cooperative Oncology Group performance status 
(ECOG PS) (0 vs. >0), histology type (Ductal vs. lobular carcinoma), histology grade 
(poorly vs. other), stage at diagnosis, primary tumor site (unilateral breast vs. bilateral), 
hormone receptor positive  (estrogen or progesterone receptor +, or both +) vs. triple 
negative, HER-2 receptor (positive vs. negative), site of current disease (CNS vs. liver vs. 
lung vs. non-visceral (including bone, skin, subcutaneous and lymph node) vs. other), liver 
metastases (yes vs. no), CNS metastases (yes vs. no), number of prior metastatic sites (1 vs. 
>1), body mass index (BMI), height, weight, body surface area (BSA), time from diagnosis 
to first infusion, prior surgery (yes vs. no), prior radiotherapy (yes vs. no), prior advanced 
treatment lines, prior advanced chemotherapy lines (0-1 vs. 2-3), prior anthracyclines (yes 
vs. no), prior taxane (yes vs. no), prior platinum (yes vs. no), prior PARPi (yes vs. no), 
anthracycline cumulative dose, last prior therapy PFS, first advanced chemotherapy PFS, 
last advanced chemotherapy PFS; PFS for anthracycline, taxane and platinum therapy, 
hormonotherapy (yes vs no), adjuvant/neoadjuvant therapy (yes vs no), presence of any 
bulky (< 50 mm vs. ≥ 50 mm) lesion, albumin at baseline, CA-15.3 or 27.29 at baseline, 
any relevant concomitant medication at baseline (to be determinate by the oncologist) (yes 
vs. no) and the sum of all target lesion diameters. 
All variables with a good percentage of valid cases (approximately ≥ 90%) will be included 
in the exploratory multivariate analysis. […] 
 
Changed to: 
[…] 
If appropriate, exploratory multivariate models (main effects or including interaction terms, 
if appropriate) will include all prognostic factors/covariates widely reported and recognized 
by oncologists: Cohort (BRCA (+) vs. BRCA (-) or unknown), BRCA (1 vs. 2 vs. both vs. 
negative/unknown in cohorts A and A1), initial dose (7 mg FD vs 3.5 mg/m2), age, age at 
diagnosis, race (Caucasian vs. other), baseline Eastern Cooperative Oncology Group 
performance status (ECOG PS) (0 vs. >0), histology type (Ductal vs. lobular carcinoma), 
histology grade (poorly vs. other), stage at diagnosis, primary tumor site (unilateral breast 
vs. bilateral), hormone receptor positive  (estrogen or progesterone receptor +, or both +) 


 
vs. triple negative, HER-2 receptor (positive vs. negative), site of current disease such as 
liver metastases (yes vs. no), CNS metastases (yes vs. no), lung metastases (yes vs. no),  
(CNS vs. liver vs. non-visceral (including bone, skin, subcutaneous and lymph node) vs. 
other),  liver metastases (yes vs. no), CNS metastases (yes vs. no), number of prior 
metastatic sites (1 vs. >1), body mass index (BMI), height, weight, body surface area 
(BSA), time from diagnosis to first infusion, prior surgery (yes vs. no), prior radiotherapy 
(yes vs. no), prior advanced treatment lines, prior advanced chemotherapy lines (0-1 vs. 2-
3), prior anthracyclines (yes vs. no), prior taxane (yes vs. no), prior platinum (yes vs. no), 
prior PARPi (yes vs. no), anthracycline cumulative dose, last prior therapy PFS, first 
advanced chemotherapy PFS, last advanced chemotherapy PFS, PFS for anthracycline, 
taxane and platinum therapy, hormonotherapy (yes vs no), adjuvant/neoadjuvant therapy 
(yes vs no), platinum-free interval (in months), presence of any bulky (< 50 mm vs. ≥ 50 
mm) lesion, albumin at baseline, CA-15.3 or 27.29 at baseline, any relevant concomitant 
medication at baseline (to be determinate by the oncologist) (yes vs. no) and the sum of all 
target lesion diameters. 
All variables with a good percentage of valid cases (approximately ≥ 90%) and with a p-
value lower than 0.10 in the univariate analysis will be included in the exploratory 
multivariate analysis. […] 
If appropriate, multivariate analysis will be produced for a relevant subgroup of patients 
(e.g. by cohort).  
 
Section 8.3 Baseline and Demographic Data 
 
Original text 
[…] 
In case of pre-treatment characteristics with multiple measurements per subject before the 
start of treatment (laboratory assessments, vital signs) the baseline measurement will be 
considered the last value prior to or on the first day of treatment. 
 
Changed to: 
[…] 
In case of pre-treatment characteristics with multiple measurements per subject before the 
start of treatment (laboratory assessments, vital signs) the baseline measurement will be 
considered the last value prior to or on the first day of treatment. 
Baseline and demography characteristics in different subgroups of analysis (i.e. cohorts) 
will be compared by means of Fisher’s exact test (categorical variables) and Mann-
Whitney-Wilcoxon (continuous variables). 
 
Section 8.8 Imputation of incomplete dates 
 
Added: 
Between treatment start and end of treatment 


 
All date variables during treatment where information is needed and is not fully 
available, for example adverse events or concomitant medications, will be subject of 
imputation by means of SAS programming. If the day of a date is unknown then the 
imputed day will be 1, if the month and/or year is also unknown then the imputed date 
will 1/January (this assumption will be valid if the imputed date is not earlier than the 
treatment start date; otherwise, the imputed date will be the treatment start date). 
 
 
Section 8.9 Subgroup Analysis 
 
Original text: 
[…] 
Efficacy subgroup analysis will be performed in Cohort A according to prior treatment with 
platinum (Yes Vs No), BRCA status (BRCA1 vs. BRCA2), hormonal status (Triple 
negative vs. HR+), number of  advanced chemotherapy lines (0-1 vs. 2-3) and starting dose 
(7 mg FD vs. 3.5 mg/m2).  
 
Changed to: 
[…] 
Efficacy subgroup analysis will be performed in Cohort A according to prior treatment with 
platinum (Yes vs. Vs No), BRCA status (BRCA1 vs. BRCA2), hormonal status (Triple 
negative vs. HR+), number of  advanced chemotherapy lines (0-1 vs. 2-3), prior PARPi 
(Yes vs. No) and starting dose (7 mg FD vs. 3.5 mg/m2). 
Additional efficacy subgroup analysis will be performed in Cohorts A+A1 according to 
prior PARPi (Yes vs. No).  
 
Table 11.1.4.3 Number of lines of prior therapy 
 
Typo correction: Antracycline has been corrected to Anthracycline. 
 
Table 11.1.6.3 Baseline characteristics: Electrocardiogram values 
 
Original table: 
Parameter 
N 
Median 
Min 
Max 
PR interval (msec) 
 
 
 
 
Heart rate (bpm) 
 
 
 
 
QT interval (msec) 
 
 
 
 
QRS complex (msec) 
 
 
 
 
QTc Bazett’s* 
 
 
 
 
(*) QTc (Bazett’s)  =  QT interval / √(60/Heart rate) 
 
Changed to: 
Parameter 
N 
Median 
Min 
Max 
PR interval (msec) 
 
 
 
 
Heart rate (bpm) 
 
 
 
 
QT interval (msec) 
 
 
 
 
QRS complex (msec) 
 
 
 
 
QTc Fridericia Bazett’s* 
 
 
 
 


 
(*) QTc (Bazett’s)  =  QT interval / √(60/Heart rate) 
 
Listing 11.1.6.4 Patients with abnormal electrocardiogram 
 
Original listing: 
Patient 
id. 
Abnormality 
Details* 
Reason for 
clinically 
indicated 
repeat 
PR interval 
(msec) 
Heart rate 
(bpm) 
QT interval 
(msec) 
QRS 
complex 
(msec) 
QTc 
Bazett’s** 
 
 
 
 
 
 
 
 
 
(*)For non-significant abnormalities, for further details see prior medical history or Signs and symptoms;  (**) QTc 
(Bazett’s)  =  QT interval / √(60/Heart rate) 
 
Changed to: 
Patient 
id. 
Abnormality 
Details* 
Reason for 
clinically 
indicated 
repeat 
PR 
interval 
(msec) 
Heart rate 
(bpm) 
QT 
interval 
(msec) 
QRS 
complex 
(msec) 
QTc  
FridericiaBazett’s** 
 
 
 
 
 
 
 
 
 
(*)For non-significant abnormalities, for further details see prior medical history or Signs and symptoms;  (**) QTc 
(Bazett’s)  =  QT interval / √(60/Heart rate) 
 
 
Listing 11.1.10.4 Signs and Symptoms at baseline 
 
Original listing: 
Patient id. 
Sign/symptom 
Grade* 
Onset date 
Relationship 
Treated* 
… 
 
 
 
 
 
 
Changed to: 
Patient id. 
Sign/symptom 
Grade* 
Onset date 
Relationship 
Treated* 
… 
 
 
 
 
 
 
 
Section 11.1.12 Baseline and demographic characteristic comparisons 
 
Section added: 
Table 11.1.12.1 Baseline and demographic characteristic comparisons by cohorts 
 
N 
Cohort A 
Cohort A1 
Cohort B 
p-value* 
Age 
Median (range) 
X 
X.X (XX-XX) 
X.X (XX-XX) 
X.X (XX-XX) 
X.XXXX 
PS (ECOG) 
0 
X 
X ( XX.X %) 
X ( XX.X %) 
X ( XX.X %) 
X.XXXX 
 
1 
. 
X ( XX.X %) 
X ( XX.X %) 
X ( XX.X %) 
 
BSA 
Median (range) 
 
 
 
 
BRCA mutation 
1 
 
 
 
 
 
2 
 
 
 
 
Receptor status 
Triple negative 
 
 
 
 
 
HR+ / HER2 - 
 
 
 
 


 
 
N 
Cohort A 
Cohort A1 
Cohort B 
p-value* 
 
HER2 + 
 
 
 
 
Liver metastases 
Yes 
 
 
 
 
 
No 
 
 
 
 
CNS metastases 
Yes 
 
 
 
 
 
No 
 
 
 
 
Sites involvement 
<3 sites 
 
 
 
 
 
≥ 3 sites 
 
 
 
 
Advanced lines 
Median (range) 
 
 
 
 
Advanced CT lines 
Median (range) 
 
 
 
 
Prior Platinum 
Yes 
 
 
 
 
 
No 
 
 
 
 
Prior Anthracyclines 
Yes 
 
 
 
 
 
No 
 
 
 
 
Prior Taxanes 
Yes 
 
 
 
 
 
No 
 
 
 
 
Prior Capecitabine 
Yes 
 
 
 
 
 
No 
 
 
 
 
Prior PARP Inhibitor 
Yes 
 
 
 
 
 
No 
 
 
 
 
*Fisher's exact test (categorical variables);Mann-Whitney-Wilcoxon (continuous variables) 
Table 11.1.12.2 Baseline and demographic characteristic comparisons: Platinum Yes/No 
in Cohort A 
 
N 
Prior platinum  
Yes 
Prior platinum  
No 
p-value* 
Age 
Median (range) 
X 
X.X (XX-XX) 
X.X (XX-XX) 
X.XXXX 
PS (ECOG) 
0 
X 
X ( XX.X %) 
X ( XX.X %) 
X.XXXX 
 
1 
. 
X ( XX.X %) 
X ( XX.X %) 
 
… 
… 
 
 
 
 
*Fisher's exact test (categorical variables);Mann-Whitney-Wilcoxon (continuous variables). For the complete list of 
covarites, see table 11.1.12.1  
Table 11.1.12.3 Baseline and demographic characteristic comparisons: BRCA 1 vs 2 in 
Cohort A 
 
N 
BRCA 1 
BRCA 2 
p-value* 
Age 
Median (range) 
X 
X.X (XX-XX) 
X.X (XX-XX) 
X.XXXX 
PS (ECOG) 
0 
X 
X ( XX.X %) 
X ( XX.X %) 
X.XXXX 


 
 
N 
BRCA 1 
BRCA 2 
p-value* 
 
1 
. 
X ( XX.X %) 
X ( XX.X %) 
 
… 
… 
 
 
 
 
*Fisher's exact test (categorical variables);Mann-Whitney-Wilcoxon (continuous variables). For the complete list of 
covarites, see table 11.1.12.1  
Table 11.1.12.4 Baseline and demographic characteristic comparisons: Prior PARPi 
Yes/No in Cohorts A+A1 
 
N 
Prior PARPi  
Yes 
Prior PARPi  
No 
p-value* 
Age 
Median (range) 
X 
X.X (XX-XX) 
X.X (XX-XX) 
X.XXXX 
PS (ECOG) 
0 
X 
X ( XX.X %) 
X ( XX.X %) 
X.XXXX 
 
1 
. 
X ( XX.X %) 
X ( XX.X %) 
 
… 
… 
 
 
 
 
*Fisher's exact test (categorical variables);Mann-Whitney-Wilcoxon (continuous variables). For the complete list of 
covarites, see table 11.1.12.1  
Table 11.1.12.5 Baseline and demographic characteristic comparisons: Initial dose 7 mg 
FD vs 3.5 mg/m2 in Cohort A 
 
N 
7 mg FD 
3.5 mg/m2 
p-value* 
Age 
Median (range) 
X 
X.X (XX-XX) 
X.X (XX-XX) 
X.XXXX 
PS (ECOG) 
0 
X 
X ( XX.X %) 
X ( XX.X %) 
X.XXXX 
 
1 
. 
X ( XX.X %) 
X ( XX.X %) 
 
… 
… 
 
 
 
 
*Fisher's exact test (categorical variables);Mann-Whitney-Wilcoxon (continuous variables). For the complete list of 
covarites, see table 11.1.12.1  
 
 
Table 11.1.12.6 Baseline and demographic characteristic comparisons: Hormonal status 
triple negative vs Other  
 
N 
Triple negative 
Yes 
Triple negative 
No 
p-value* 
Age 
Median (range) 
X 
X.X (XX-XX) 
X.X (XX-XX) 
X.XXXX 
PS (ECOG) 
0 
X 
X ( XX.X %) 
X ( XX.X %) 
X.XXXX 
 
1 
. 
X ( XX.X %) 
X ( XX.X %) 
 
… 
… 
 
 
 
 
*Fisher's exact test (categorical variables);Mann-Whitney-Wilcoxon (continuous variables). For the complete list of 
covarites, see table 11.1.12.1  


 
Table 11.1.12.7 Baseline and demographic characteristic comparisons: Advanced 
chemotherapy lines  
 
N 
0-1 lines 
>1 lines 
p-value* 
Age 
Median (range) 
X 
X.X (XX-XX) 
X.X (XX-XX) 
X.XXXX 
PS (ECOG) 
0 
X 
X ( XX.X %) 
X ( XX.X %) 
X.XXXX 
 
1 
. 
X ( XX.X %) 
X ( XX.X %) 
 
… 
… 
 
 
 
 
*Fisher's exact test (categorical variables);Mann-Whitney-Wilcoxon (continuous variables). For the complete list of 
covarites, see table 11.1.12.1  
 
Section 11.3 Efficacy Analysis 
 
Original text: 
Efficacy analysis will be carried out on the “All Evaluable Patients” population.  
Subgroup analysis will be performed in Cohort A according to prior treatment with 
platinum, BRCA status (BRCA1 vs. BRCA2), hormonal status (Triple negative vs. HR+), 
number of advanced chemotherapy lines (0-1 vs. 2-3) and starting dose (7 mg FD vs. 3.5 
mg/m2).  
The tables included in each subgroup analysis are the following:  
[…] 
- 
Prior PARPi: f 
 
Changed to: 
Efficacy analysis will be carried out on the “All Evaluable Patients” population.  
Subgroup analysis will be performed in Cohort A according to prior treatment with 
platinum, BRCA status (BRCA1 vs. BRCA2), hormonal status (Triple negative vs. HR+), 
number of advanced chemotherapy lines (0-1 vs. 2-3), prior PARPi (Yes vs. No) and 
starting dose (7 mg FD vs. 3.5 mg/m2).  
Subgroup analysis will be performed in Cohorts A+A1 according to prior PARPi (Yes vs. 
No).  
 
The tables included in each subgroup analysis are the following:  
[…] 
- 
Prior PARPi (Cohort A): f 
- 
Prior PARPi (Cohorts A+A1): g 
 


 
 
Listing 11.3.2.5  Characteristics of patients with clinical benefit* 
 
Original listing: 
Patient 
PS / 
Age 
Histology 
Type 
Histology 
Grade 
Hormonal  
Status 
(ER +/-; PR 
+/-; HER2 
+/-) 
No. 
of 
prior 
lines 
No. of 
advanced 
prior lines 
Prior last therapy 
Agents 
Best 
response 
PFS 
(months) 
 
Patient 
Cycles received 
Best response 
PFS 
(months) 
OS 
(months) 
DR 
(months) 
 
 
Changed to: 
Patient 
PS / 
Age 
BRCA 
status 
Histology 
Type 
Histology 
Grade 
Hormonal  
Status  
(ER +/-; 
PR +/-; 
HER2 +/-
) 
Sites 
No. 
of 
prior 
lines 
No. of 
advanced 
CT prior 
lines 
Prior 
Platinum 
(Y/N) 
Best 
response 
Prior 
platinum 
Prior last therapy 
Agents 
Best 
response 
PFS 
(month
 
Patient 
 
Initial dose 
Cycles received 
Best response 
PFS 
(months) 
OS 
(months) 
DR 
(months) 
 
 
Section 11.3.2 Secondary analyses 
 
Added: 
 
Figure 11.3.2.8 “Swimmer plot” PFS in Cohort A 


 
 
 
Figure 11.3.2.9 “Swimmer plot” PFS in Cohort A1 
 
 
Figure 11.3.2.10 “Swimmer plot” PFS in Cohort B 


 
 
 
 
Section 11.3.3 Exploratory Multivariate Analysis 
 
Section title has been modified. 
 
Original title: 
 
11.3.3 Exploratory Multivariate Analysis 
 
Changed to: 
 
11.3.3 Exploratory Univariate and Multivariate Analyses 
 
Original section: 
 
Table 11.3.3.1 Multivariate analysis of response rate  
Analysis of Maximum Likelihood Estimates 
Variable 
label 
Variable 
values 
DF Estimate Standard 
error 
Wald chi-
square 
Pr > ChiSq 
Odds ratio 
estimate 
95% Wald 
confidence 
limits 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(See list of covariates in section 6.2.2). 
 
Table 11.3.3.2 Multivariate analysis of PFS  
Analysis of Maximum Likelihood Estimates 
Variable label Variable values DF Parameter 
estimate 
Standard 
error 
Chi-square Pr > ChiSq Hazard 
ratio 
95% Hazard ratio confidence 
limits 
 
 
 
 
 
 
 
 
 


 
Analysis of Maximum Likelihood Estimates 
Variable label Variable values DF Parameter 
estimate 
Standard 
error 
Chi-square Pr > ChiSq Hazard 
ratio 
95% Hazard ratio confidence 
limits 
 
 
 
 
 
 
 
 
 
(See list of covariates in section 6.2.2). 
 
Table 11.3.3.3 Multivariate analysis of OS  
Analysis of Maximum Likelihood Estimates 
Variable label Variable values DF Parameter 
estimate 
Standard 
error 
Chi-square Pr > ChiSq Hazard 
ratio 
95% Hazard ratio confidence 
limits 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(See list of covariates in section 6.2.2). 
 
 
Changed to: 
 
Table 11.3.3.1 Univariate analysis of response rate  
Variable 
label 
Variable 
values 
DF Estimate Standard 
error 
Wald chi-
square 
Pr > ChiSq 
Odds ratio 
estimate 
95% Odds 
Ratio 
confidence 
limits 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(See list of covariates in section 6.2.2). 
 
Table 11.3.3.1 11.3.3.2 Multivariate analysis of response rate  
Analysis of Maximum Likelihood Estimates 
Variable 
label 
Variable 
values 
DF Estimate Standard 
error 
Wald chi-
square 
Pr > ChiSq 
Odds ratio 
estimate 
95% Wald Odds 
Ratio 
confidence limits 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(See list of covariates in section 6.2.2. Only those covariates with a p-value < 0.10 in univariate analysis and 
with a 90% of valid observations will be included). 
 
Table 11.3.3.3 Univariate analysis of PFS  
Variable 
label 
Variable 
values 
DF Parameter 
estimate 
Standard 
error 
Chi-
square 
Pr > ChiSq Hazard 
ratio 
95% Hazard ratio 
confidence 
limits 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(See list of covariates in section 6.2.2). 
 
Table 11.3.3.2 11.3.3.4 Multivariate analysis of PFS  
Analysis of Maximum Likelihood Estimates 


 
Variable label Variable values DF Parameter 
estimate 
Standard 
error 
Chi-square Pr > ChiSq Hazard 
ratio 
95% Hazard ratio confidence 
limits 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(See list of covariates in section 6.2.2. Only those covariates with a p-value < 0.10 in univariate analysis and 
with a 90% of valid observations will be included). 
 
Table 11.3.3.5 Univariate analysis of OS  
Variable 
label 
Variable 
values 
DF Parameter 
estimate 
Standard 
error 
Chi-
square 
Pr > ChiSq Hazard 
ratio 
95% Hazard ratio 
confidence 
limits 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(See list of covariates in section 6.2.2). 
 
Table 11.3.3.3 11.3.3.6 Multivariate analysis of OS  
Analysis of Maximum Likelihood Estimates 
Variable label Variable values DF Parameter 
estimate 
Standard 
error 
Chi-square Pr > ChiSq Hazard 
ratio 
95% Hazard ratio confidence 
limits 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(See list of covariates in section 6.2.2. Only those covariates with a p-value < 0.10 in univariate analysis and 
with a 90% of valid observations will be included). 
 
Table 12.1.2.1.2 Number of patients and cycles with dosing delay, any relationship 
 
Original table: 
 
N 
% 
No. of patients treated 
 
 
No. of patients with any dose delay 
 
 
No. of cycles administered 
 
 
No. of cycles susceptible to be delayed* 
 
 
No. of cycles with dosing delay** 
 
 
No. of patients with  
 
 
No cycles delayed 
 
 
1 cycle delayed  
 
 
2 cycles delayed 
 
 
≥ 3 cycles delayed 
 
 
 
Changed to: 


 
 
N 
% 
No. of patients treated 
 
 
No. of patients susceptible to have any dose delayed 
 
 
No. of patients with any dose delayed 
 
 
No. of cycles administered 
 
 
No. of cycles susceptible to be delayed* 
 
 
No. of cycles with dosing delay** 
 
 
No. of patients with  
 
 
No cycles delayed 
 
 
1 cycle delayed  
 
 
2 cycles delayed 
 
 
≥ 3 cycles delayed 
 
 
 
Table 12.1.2.1.4 Number of patients and cycles with dosing delay according to the 
relationship 
 
Original table: 
Reasons for delays 
N 
% 
No. of cycles with dosing delays* 
 
Treatment-related 
X 
XX.X 
Hematological 
 
 
Non-hematological 
 
 
Both 
 
 
Non-treatment-related 
 
 
(*) Denominator= Number of cycles susceptible to have a delay.  
 
Changed to: 
Reasons for delays 
N 
% 
Cycles 
No. of cycles with dosing delays* 
 
Treatment-related 
X 
XX.X 
Hematological 
 
 
Non-hematological 
 
 
Both 
 
 
Non-treatment-related 
 
 
Patients 
No. of patients with dosing delays* 
 
Treatment-related 
X 
XX.X 
Hematological 
 
 
Non-hematological 
 
 
Both 
 
 
Non-treatment-related 
 
 
(*) Denominator= Number of patient/cycles susceptible to have a delay.  
 
Table 12.1.3.2 Number of patients and cycles with dose reduction, any relationship 
 
Original table: 
 
N 
% 


 
No. of patients treated 
X 
XX.X 
No. of patients with any dose reduced 
 
 
No. of patients with: 
 
 
No PM01183 reduction 
 
 
1 cycle with PM01183 dose reduced  
 
 
2 cycles with PM01183 dose reduced 
 
 
No. of cycles administered 
 
 
No. of cycles susceptible to have any dose reduced*  
 
 
No. of cycles with PM01183 dose reduced ** 
 
 
No. of cycles with PM01183 dose reduced (Treatment-related)** 
 
 
 
Changed to: 
 
N 
% 
No. of patients treated 
X 
XX.X 
No. of patients susceptible to have a dose reduced 
 
 
No. of patients with any dose reduced 
 
 
No. of patients with: 
 
 
No PM01183 reduction 
 
 
1 cycle with PM01183 dose reduced  
 
 
2 cycles with PM01183 dose reduced 
 
 
No. of cycles administered 
 
 
No. of cycles susceptible to have any dose reduced*  
 
 
No. of cycles with PM01183 dose reduced ** 
 
 
No. of cycles with PM01183 dose reduced (Treatment-related)** 
 
 
 
Table 12.1.3.3 Number of patients and cycles with dose reduction according to the 
relationship 
 
Original table: 
Reasons for reductions 
N 
% 
No. of cycles with dose reductions* 
 
Treatment-related 
X 
XX.X 
Hematological 
 
 
Non-hematological 
 
 
Both 
 
 
Non-treatment-related 
 
 
 (*) Denominator= Number of cycles susceptible to have a dose reduction.  
 
Changed to: 
Reasons for reductions 
N 
% 
Cycles 
No. of cycles with dose reductions* 
 
Treatment-related 
X 
XX.X 
Hematological 
 
 
Non-hematological 
 
 
Both 
 
 
Non-treatment-related 
 
 
Patients 
No. of patients with dose reductions* 
 
Treatment-related 
X 
XX.X 
Hematological 
 
 
Non-hematological 
 
 
Both 
 
 
Non-treatment-related 
 
 
 (*) Denominator= Number of patient/cycles susceptible to have a dose reduction.  
 
Section 12.2.2 Display of Adverse Events 


 
Added: 
 
Table 12.2.2.10 Treatment-related SAEs. Worst grade by patient 
SOC 
Preferred Term 
Grade  
1 
… 
Grade  
4 
All* 
 
 
N 
% 
… 
N 
% 
N 
% 
Blood and lymphatic 
system disorders 
Anemia NOS 
 
 
 
 
 
 
 
... 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
Cardiac disorders 
Arrhythmia NOS 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
(*) Any grade 
 
Table 12.2.2.11 Treatment-related SAEs. Worst grade by cycle 
 SOC 
Preferred Term 
Grade  
1 
… 
Grade  
4 
All* 
 
 
N 
% 
… 
N 
% 
N 
% 
Blood and lymphatic 
system disorders 
Anemia NOS 
 
 
 
 
 
 
 
... 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
Cardiac disorders 
Arrhythmia NOS 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
* Any grade 
 
Table 12.2.2.12 SAEs regardless of relationship. Worst grade by patient 
SOC 
Preferred Term 
Grade  
1 
… 
Grade  
4 
All* 
 
 
N 
% 
… 
N 
% 
N 
% 
Blood and lymphatic 
system disorders 
Anemia NOS 
 
 
 
 
 
 
 
... 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
Cardiac disorders 
Arrhythmia NOS 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
(*) Any grade 
 
Table 12.2.2.13 SAEs regardless of relationship. Worst grade by cycle 
SOC 
Preferred Term 
Grade  
1 
… 
Grade  
4 
All* 
 
 
N 
% 
… 
N 
% 
N 
% 
Blood and lymphatic 
system disorders 
Anemia NOS 
 
 
 
 
 
 
 
... 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
Cardiac disorders 
Arrhythmia NOS 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
(*) Any grade 
 
 
Listing 12.2.2.6 Treatment-related grade 3-4 AEs. Worst grade per patient 
 
Original Listing: 
Patient id. 
Cycle 
SOC Name 
Preferred term 
Grade 
 
 
 
 
 
 
Changed to: 
Patient id. 
Cycle 
SOC Name 
Preferred term 
Grade 
 
 
 
 
 


 
 
Listing 12.2.2.8 Adverse Events grade 3-4 regardless of relationship. Worst grade per 
patient 
 
Original Listing: 
Patient id. 
Cycle 
SOC Name 
Preferred term 
Grade 
 
 
 
 
 
 
Changed to: 
Patient id. 
Cycle 
SOC Name 
Preferred term 
Grade 
 
 
 
 
 
 
Listing 12.3.1.1 SAEs 
 
Original Listing: 
Patient 
id. 
Preferred  
term code 
Adverse 
event 
reported 
(verbatim) 
Status 
Grade 
Relationship 
Onset 
date 
Resolved 
date 
Action 
Serious criteria 
 
  
 
 
 
 
 
 
 
 
Changed to: 
Patient 
id. 
Preferred  
term code 
Adverse 
event 
reported 
(verbatim) 
Status Grade 
Relationship 
Onset 
date 
Resolved 
date 
Action 
Serious criteria 
 
  
 
 
 
 
 
 
 
 
 
Section 12.4.4 Laboratory Values Over Time 
 
Tables:  
12.4.4.11 Platelet count time course pattern (summary) 
12.4.4.12 Platelet count time course pattern (freqs) 
12.4.4.13 Neutrophil count time course pattern (summary) 
12.4.4.14 Neutrophil count time course pattern (freqs) 
12.4.4.15 AST time course pattern (summary) 
12.4.4.16 AST time course pattern (freqs) 
12.4.4.17 ALT time course pattern (summary) 
 
 
Original table headers: 
 
Dose received 
Total 
7 mg FD  
6 mg FD 
5 mg FD 
 
Changed to: 
 
Dose received 
Total 
7 mg FD / 3.5 
mg/m2 
6 mg FD / 2.6 
mg/m2 
5 mg FD/ 2.0 
mg/m2 
 


 
 
Table added: 
Table 11.4.4.18 ALT time course pattern (freqs) 
 
Dose received 
Total 
7 mg FD / 3.5 
mg/m2 
6 mg FD / 2.6 
mg/m2 
5 mg FD/ 2.0 
mg/m2 
N 
% 
N 
% 
N 
% 
N 
% 
Baseline grade 0 
1st cycle 
   Onset day grade 3/4 
      ≤ 7 
       8-14 
      ≥ 15 
 
 
 
 
 
 
 
 
   ... 
 
 
 
 
 
 
 
 
2nd cycle, 3rd cycle …. 
   Onset day grade 3/4 
      ≤ 7 
       8-14 
      ≥ 15 
 
 
 
 
 
 
 
 
   ... 
 
 
 
 
 
 
 
 
Total 
   Onset day grade 3/4 
      ≤ 7 
       8-14 
      ≥ 15 
 
 
 
 
 
 
 
 
   ... 
 
 
 
 
 
 
 
 
Baseline grade 1, 2 .... 
   ... 
 
 
 
 
 
 
 
 
Total 
1st cycle 
   Onset day grade 3/4 
      ≤ 7 
       8-14 
      ≥ 15 
 
 
 
 
 
 
 
 
   ... 
 
 
 
 
 
 
 
 
2nd cycle, 3rd cycle …. 
   Onset day grade 3/4 
      ≤ 7 
       8-14 
      ≥ 15 
 
 
 
 
 
 
 
 
   ... 
 
 
 
 
 
 
 
 
Total 
   Onset day grade 3/4 
      ≤ 7 
       8-14 
      ≥ 15 
 
 
 
 
 
 
 
 
   Peak day grade 3/4 
      ≤ 7 
       8-14 
      ≥ 15  
 
 
 
 
 
 
 
 
   Recovery day to grade ≤ 2 
      ≤ 22 
       23-28 
      ≥ 29 
 
 
 
 
 
 
 
 
   Duration in days to grade 2 
      ≤ 5 
       6-10 
      ≥ 11 
 
 
 
 
 
 
 
 
Recovery day to grade ≤ 1  
      ≤ 22 
 
 
 
 
 
 
 
 


 
 
Dose received 
Total 
7 mg FD / 3.5 
mg/m2 
6 mg FD / 2.6 
mg/m2 
5 mg FD/ 2.0 
mg/m2 
N 
% 
N 
% 
N 
% 
N 
% 
       23-28 
      ≥ 29 
   Duration in days to grade 1 
      ≤ 5 
       6-10 
      ≥ 11 
 
 
 
 
 
 
 
 
 
 
Listing 12.5.2.3 Troponin I and Troponin T values. Evolution during the study. 
 
Original listing: 
Patient id. 
Cycle 
Value 
ULN 
 
 
 
 
 
Changed to: 
Patient id. 
Cycle 
Test 
Value 
ULN 
 
 
 
 
 
 
 
Table 12.6.1 Concomitant medication during treatment (ATC1, ATC2 and ATC4 
levels) 
Original table: 
Concomitant medication at baseline 
N 
% 
Alimentary tract and metabolism 
 
 
   Antacids 
 
 
      Magnesium compounds 
 
 
          Magnesium adipate 
 
 
… 
 
 
Blood and blood forming organs 
 
 
   Antithrombotic agents 
 
 
      Vitamin K antagonists 
 
 
          Acenocoumarol 
 
 
… 
 
 
 
Changed to: 
Concomitant medication at baseline 
N 
% 
Alimentary tract and metabolism 
 
 
   Antacids 
 
 
      Magnesium compounds 
 
 
          Magnesium adipate 
 
 
… 
 
 
Blood and blood forming organs 
 
 
   Antithrombotic agents 
 
 
      Vitamin K antagonists 
 
 
          Acenocoumarol 
 
 
… 
 
 
 
 
Table 12.6.2 Summary of concomitant medication during treatment 
 


 
Original table: 
 
N 
% 
No. of systems at BL (ATC1 level) 
 
 
0 
1 
2 
 
 
≥ 3 
 
 
Median (range) 
 
 
No. of indications at BL (ATC2 level) 
 
 
0 
1 
2 
 
 
≥ 3 
 
 
Median (range) 
 
 
No. of agent families at BL (ATC4 level) 
 
 
0 
1 
2 
 
 
≥ 3 
 
 
Median (range) 
 
 
No. of agents at BL (PN level) 
 
 
0 
1 
2 
 
 
≥ 3 
 
 
Median (range) 
 
 
 
Changed to: 
 
N 
% 
No. of systems at BL (ATC1 level) 
 
 
0 
1 
2 
 
 
≥ 3 
 
 
Median (range) 
 
 
No. of indications at BL (ATC2 level) 
 
 
0 
1 
2 
 
 
≥ 3 
 
 
Median (range) 
 
 
No. of agent families at BL (ATC4 level) 
 
 
0 
1 
2 
 
 
≥ 3 
 
 
Median (range) 
 
 
No. of agents at BL (PN level) 
 
 
0 
1 
2 
 
 
≥ 3 
 
 
Median (range) 
 
 
 
Table 12.6.5 Transfurions and G-CSF by dose 
 
Table added: 


 
Table 12.6.5 Transfusions and G-CSF by dose 
 
7 mg FD 
3.5 mg/m2 
Total 
 
N 
% 
N 
% 
N 
% 
Transfusions 
 
 
 
 
 
 
  RBC 
 
 
 
 
 
 
  Platelets 
 
 
 
 
 
 
G-CSF 
 
 
 
 
 
 
 
Rest of tables in this section has been renumbered.  
 
Section 13 DB Listings 
 
Original title: 
 
Listing 13.1.1: Cover 
 
Changed to: 
 
Listing 13.1.1: Investigator comments 
 
 
Added: 
 
ICH Listings. 
 
-Listing 16.2.1 Discontinued patients 
-Listing 16.2.2 Protocol deviations 
-Listing 16.2.3 Patients excluded from the efficacy analysis 
-Listing 16.2.4 Demographic data 
-Listing 16.2.5 Compliance and-or Drug Concentration Data 
-Listing 16.2.6 Individual Efficacy Response data 
-Listing 16.2.7 Adverse event listings 
-Listing 16.2.8 Individual laboratory measurements