Conditions: Endometrial Adenocarcinomas Neuroendocrine Tumors Small-cell Lung Cancer With Less Than 2 Prior Cytotoxic-containing Lines of Therapy
Keywords: lurbinectedin PM01183 tumors cancer Pharma Mar
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 122
Healthy volunteers: no

Brief summary:
Phase I Multicenter, Open-label, Clinical and Pharmacokinetic Study of PM01183 in Combination with Fixed Doxorubicin in Non- Heavily Pretreated Patients with Selected Advanced Solid Tumors to determine the maximum tolerated dose (MTD) and the recommended dose (RD) of PM01183 in combination with doxorubicin, to characterize the safety profile and feasibility of this combination, to characterize the pharmacokinetics (PK) of this combination, to obtain preliminary information on the clinical antitumor activity,to explore the feasibility, safety and efficacy of a potential improvable dose of this combination in selected tumor types \[i.e. small cell lung cancer (SCLC) and endometrial cáncer\] and to evaluate the pharmacogenomics (PGx) in tumor samples of patients exposed to PM01183 and doxorubicin at the RD in order to assess potential markers of response and/or resistance.

Detailed description:
The study has currently met its primary end point and is now recruiting patients to be treated at the RD expansion cohort of selected tumor types, specifically: endometrial adenocarcinomas, neuroendocrine tumors, and small-cell lung cancer (SCLC).

Arms:
arm 1: None

Interventions: intervention 1: lurbinectedin (PM01183) intervention 2: Doxorubicin
Intervention descriptions: intervention 1: lurbinectedin (PM01183) is presented as powder for concentrate for solution for infusion with two strengths, 1-mg and 4-mg vials. intervention 2: Commercially available presentations of vials containing doxorubicin will be provided as appropriate.

Protocol document:
Prot_000.pdf: 
 
 
 
 
SPONSOR 
Pharma Mar S.A., Sociedad Unipersonal 
Avda de los Reyes, 1 
Polígono Industrial “La Mina” 
28770 Colmenar Viejo (Madrid) Spain 
Phone:+ 34 91 846 6000 / Fax:+ 34 91 846 6003 
 
 
 
CLINICAL TRIAL PROTOCOL 
 
 
 
Phase I Multicenter, Open-label, Clinical and Pharmacokinetic Study of PM01183 in 
Combination with Doxorubicin in Non-heavily Pretreated Patients with Selected 
Advanced Solid Tumors 
 
 
INVESTIGATIONAL MEDICINAL PRODUCT: PM01183 
Protocol Code: PM1183-A-003-10 
EudraCT No: 2010-024291-25 
NCT Code: 01970540 
 
Protocol Version 4.0 (includes amendment #1 dated 21 November 2011, amendment #2 
dated 10 July 2013, and amendment #3 dated 17 October 2014) 


CL_0111 4.0
Page 1 of 107
Protocol PM1183-A-003-10
SPONSOR
Pharma Mar S.A., Sociedad Unipersonal
Avda de los Reyes, 1
Polígono Industrial “La Mina”
28770 Colmenar Viejo (Madrid) Spain
Phone:+ 34 91 846 6000 / Fax:+ 34 91 846 6003
CLINICAL TRIAL PROTOCOL
PM1183-A-003-10
Phase I Multicenter, Open-label, Clinical and Pharmacokinetic Study of 
PM01183 in Combination with Doxorubicin in Non-heavily Pretreated Patients 
with Selected Advanced Solid Tumors
INVESTIGATIONAL MEDICINAL PRODUCT: PM01183
Protocol Code: PM1183-A-003-10
EudraCT No: 2010-024291-25
Protocol Version 4.0
(includes amendment #1 dated 21 November 2011, 
amendment #2 dated 10 July 2013, and amendment #3 dated 17 October 2014)   
This study will be conducted in compliance with the protocol, Good Clinical Practice (GCP) 
and the applicable regulatory requirements.
Confidentiality statement
Information and data included in this protocol contain trade secrets and privileged or 
confidential information which is the property of the Sponsor. No person is authorized to make 
it public without written permission of the Sponsor. These restrictions on disclosure will apply 
equally to all future information supplied to you which is indicated as privileged or confidential. 
This material may be disclosed to and used by your staff and associates as it may be necessary 
to conduct the clinical study.


CL_0111 4.0
Page 4 of 107
Protocol PM1183-A-003-10
PRINCIPAL INVESTIGATORS
A full list of investigators will be available as a separate document. 


CL_0111 4.0
Page 5 of 107
Protocol PM1183-A-003-10
TABLE OF CONTENTS
STUDY CONTACTS .................................................................................................................................2
PRINCIPAL INVESTIGATORS..............................................................................................................4
SYNOPSIS ..................................................................................................................................................8
SCHEDULE OF ASSESSMENTS AND PROCEDURES....................................................................27
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS..........................................................29
1.
INTRODUCTION ...........................................................................................................................33
1.1
BACKGROUND ..........................................................................................................................33
1.2
INFORMATION ON STUDY DRUG: PM01183 ...........................................................................33
1.2.1
Name and Chemical Information .......................................................................................33
1.2.2
Non-clinical Data ................................................................................................................34
1.2.3
Clinical Data........................................................................................................................35
1.3
INFORMATION ON STUDY DRUG: DOXORUBICIN....................................................................36
1.4
INFORMATION ON THE COMBINATION OF PM01183 AND DOXORUBICIN..............................37
1.5
STUDY RATIONALE...................................................................................................................37
1.5.1
Pharmacogenomics Rationale.............................................................................................38
2.
STUDY OBJECTIVES ...................................................................................................................39
2.1
PRIMARY ..................................................................................................................................39
2.2
SECONDARY..............................................................................................................................39
3.
OVERALL STUDY DESIGN.........................................................................................................39
3.1
PRIMARY ENDPOINT ................................................................................................................41
3.1.1
Determination of MTD and RD ..........................................................................................41
3.2
SECONDARY ENDPOINTS..........................................................................................................43
3.2.1
Safety....................................................................................................................................43
3.2.2
Pharmacokinetics ................................................................................................................43
3.2.3
Efficacy ................................................................................................................................43
3.2.4
Pharmacogenomics..............................................................................................................43
3.3
DOSE ESCALATION SCHEDULE................................................................................................43
3.3.1
Dose Escalation Meetings ...................................................................................................44
4.
SELECTION OF PATIENTS.........................................................................................................45
4.1
INCLUSION CRITERIA...............................................................................................................45
4.2
EXCLUSION CRITERIA..............................................................................................................47
4.3
PATIENTS FOR THE PHARMACOGENOMIC STUDY...................................................................47
5.
PLAN OF THE STUDY..................................................................................................................48
5.1
DURATION OF THE STUDY (WHOLE POPULATION).................................................................48
5.2
DURATION OF STUDY AND TREATMENT (PER PATIENT) .........................................................48
5.2.1
Discontinuations..................................................................................................................49
5.2.1.1
End of Treatment........................................................................................................................ 49
5.2.1.2
Reasons for End of Treatment.................................................................................................... 49
5.2.1.3
Study Discontinuation................................................................................................................ 50
5.2.2
Protocol Deviations..............................................................................................................50
5.3
REPLACEMENT OF PATIENTS...................................................................................................51
5.4
PRE-TREATMENT ASSESSMENTS..............................................................................................51
5.5
PATIENT REGISTRATION..........................................................................................................53
5.6
PATIENT RANDOMIZATION......................................................................................................53
5.7
EVALUATIONS DURING TREATMENT.......................................................................................53
5.8
EVALUATIONS AT END OF TREATMENT ..................................................................................55
5.9
FOLLOW-UP AFTER END-OF-TREATMENT VISIT....................................................................55


CL_0111 4.0
Page 6 of 107
Protocol PM1183-A-003-10
6.
PHARMACOKINETICS................................................................................................................56
7.
PHARMACOGENOMICS .............................................................................................................58
8.
TREATMENT .................................................................................................................................59
8.1
DESCRIPTION OF TREATMENT.................................................................................................59
8.1.1
Drug Formulation and Supply............................................................................................59
8.1.1.1
PM01183.................................................................................................................................... 59
8.1.1.2
Doxorubicin ............................................................................................................................... 60
8.2
ADMINISTRATION OF STUDY MEDICATION.............................................................................60
8.3
CRITERIA FOR TREATMENT CONTINUATION..........................................................................61
8.4
DOSE REDUCTION ....................................................................................................................62
8.5
CONCOMITANT MEDICATION..................................................................................................63
8.5.1
Prophylactic Medication......................................................................................................63
8.5.2
Allowed Medications/Therapies ..........................................................................................64
8.5.3
Prohibited Medications/Therapies ......................................................................................64
8.5.4
Drug-drug Interactions .......................................................................................................65
8.5.5
Drug Accountability.............................................................................................................65
8.6
TREATMENT COMPLIANCE......................................................................................................65
9.
STUDY EVALUATIONS ...............................................................................................................66
9.1
DETERMINATION OF MTD AND RD ........................................................................................66
9.2
SAFETY .....................................................................................................................................66
9.3
ADVERSE EVENTS DEFINITIONS ..............................................................................................66
9.3.1
Adverse Event (AE)..............................................................................................................66
9.3.2
Serious Adverse Event (SAE)..............................................................................................66
9.3.3
Death....................................................................................................................................67
9.3.4
Life-threatening Event.........................................................................................................67
9.3.5
Hospitalization or Prolongation of Hospitalization............................................................67
9.3.6
Unlisted/Unexpected Adverse Event ...................................................................................68
9.3.7
Adverse Events Related to the Study Drugs........................................................................68
9.3.8
Expedited reporting .............................................................................................................68
9.3.9
Assessment of Causal Relationship to the Study Drug.......................................................68
9.4
ADVERSE EVENTS REPORTING PROCEDURES.........................................................................68
9.4.1
Reporting Adverse Events....................................................................................................68
9.4.2
Reporting Serious Adverse Events ......................................................................................69
9.4.3
Reporting Pregnancy Cases Occurred within the Clinical Trial........................................69
9.5
ADVERSE EVENTS MONITORING .............................................................................................70
9.6
EVALUATION OF PHARMACOKINETICS...................................................................................71
9.7
EFFICACY .................................................................................................................................71
9.7.1
Duration of Overall Response.............................................................................................72
9.7.2
Progression-free Survival....................................................................................................72
9.7.3
Overall Survival ...................................................................................................................73
9.8
EVALUATION OF PHARMACOGENOMICS ................................................................................73
10.
STATISTICAL METHODS.......................................................................................................73
10.1
SAMPLE SIZE ............................................................................................................................73
10.2
STATISTICAL ANALYSIS...........................................................................................................73
10.2.1
Demographics..................................................................................................................73
10.2.2
Safety ...............................................................................................................................74
10.2.3
Efficacy Analysis.............................................................................................................74
10.2.4
Pharmacokinetics............................................................................................................74
10.2.5
Pharmacogenomics .........................................................................................................74
10.3
INTERIM ANALYSIS ..................................................................................................................75
11.
ADMINISTRATIVE SECTION................................................................................................75
11.1
ETHICS......................................................................................................................................75
11.2
MONITORING, AUDITING AND INSPECTING .............................................................................75
11.3
PATIENT INFORMED CONSENT ................................................................................................76


CL_0111 4.0
Page 7 of 107
Protocol PM1183-A-003-10
11.4
CONFIDENTIALITY/ PATIENTS IDENTIFICATION......................................................................76
11.5
CASE REPORT FORMS...............................................................................................................77
11.6
INSURANCE ...............................................................................................................................77
11.7
RETENTION OF RECORDS.........................................................................................................77
11.8
USE OF INFORMATION AND PUBLICATION ..............................................................................77
12.
REFERENCES............................................................................................................................79
13.
APPENDICES .............................................................................................................................83
APPENDIX 1: ECOG PERFORMANCE STATUS ASSESSMENT SCALE .......................................83
APPENDIX 2: EVALUATION OF RESPONSE. THE RECIST. ..........................................................84
APPENDIX 3: GCIG SPECIFIC CRITERIA ........................................................................................96
APPENDIX 4: COCKCROFT AND GAULT’S FORMULA.................................................................97
APPENDIX 5: L IST OF CYP1/CYP2/CYP3 INHIBITORS, INDUCERS AND SUBSTRATES........98
APPENDIX 6: DECLARATION OF HELSINKI.................................................................................101


CL_0111 4.0
Page 8 of 107
Protocol PM1183-A-003-10
SYNOPSIS
TITLE
Phase I Multicenter, Open-label, Clinical and Pharmacokinetic 
Study of PM01183 in Combination with Doxorubicin in Non-
Heavily Pretreated Patients with Selected Advanced Solid 
Tumors.
PROTOCOL CODE
PM1183-A-003-10
INVESTIGATORS / 
TRIAL LOCATION
A full list of investigators will be available as a separate 
document.
NUMBER OF SITES
Seven sites in Spain and the United Kingdom (UK) are expected 
to participate in this study.
STUDY OBJECTIVES 
Primary:

To determine the maximum tolerated dose (MTD) and the 
recommended dose (RD) of PM01183 in combination with 
doxorubicin in patients with selected advanced solid tumors. 
Secondary:

To determine the MTD and the RD of PM01183 in 
combination with doxorubicin with primary prophylaxis
with granulocyte-colony stimulating factor (G-CSF) in 
patients with selected advanced solid tumors [if dose-
limiting toxicities (DLTs) of the combination without G-
CSF prophylaxis are exclusively related to neutropenia].

To characterize the safety profile and feasibility of this 
combination in patients with selected advanced solid 
tumors.

To characterize the pharmacokinetics (PK) of this 
combination and to detect major drug-drug PK interactions.

To obtain preliminary information on the clinical antitumor 
activity of this combination in non-heavily pretreated 
selected solid tumor patients.

Based on promising findings, to explore the feasibility, 
safety and efficacy of a potential improvable dose of this 
combination in selected tumor types [i.e. small cell lung 
cancer (SCLC) and endometrial cancer).

To evaluate the pharmacogenomics (PGx) in tumor samples 
of patients exposed to PM01183 and doxorubicin at the RD 
in order to assess potential markers of response and/or 
resistance.
STUDY DESIGN
Prospective, open-label, dose-ranging, uncontrolled phase I 
study with escalating doses of PM01183 in combination with 
doxorubicin.
Patients will start receiving intravenous (i.v.) doxorubicin 50 
mg/m2 (fixed dose) as bolus followed by PM01183 3.5 mg, flat 


CL_0111 4.0
Page 9 of 107
Protocol PM1183-A-003-10
dose (FD), i.v. over one hour on Day 1 every three weeks 
(q3wk). A cycle is defined as an interval of three weeks.
Cohorts of three to six patients will be included at each dose 
level (DL). If no dose-limiting toxicity (DLT) occurs in more 
than one patient in each cohort, escalation will proceed to the 
next dose level. 
The MTD will be the lowest dose level explored during the dose 
escalation at which more than one evaluable patient experience 
a DLT in Cycle 1. If one among the first three evaluable patients 
experiences a DLT, the dose level should be expanded up to six 
patients. Dose escalation will be terminated once the MTD or 
the last dose level (DL4) is reached, whichever occurs first, 
except if all DLTs occurring at a given dose level are related to 
neutropenia (e.g., febrile neutropenia, grade 4 neutropenia 
lasting more than 7 days or neutropenic sepsis) in which case 
dose escalation may be resumed, starting at the lowest dose 
level at which exclusively neutropenia-related DLTs were 
observed, and will follow the same original schedule but with 
compulsory primary G-CSF prophylaxis. An expansion cohort 
to complete a minimum of nine evaluable patients will be 
recruited at the immediate lower dose level, or at the last dose 
level (DL4) if the MTD is not defined yet. This level will be 
confirmed as the RD if less than one third of the first nine 
evaluable patients experience DLT during Cycle 1.
Further to the finding of encouraging antitumor activity in the 
first 43 evaluable patients (13 responses, including four 
complete responses, with five partial responses in eight patients 
with small cell lung cancer, and one complete and one partial 
response in three patients with endometrial cancer), expansion 
of the cohort treated at the RD has been increased to include 
approximately 30 additional patients, for a total of around 39 
patients.
In addition, a new cohort of 20 evaluable patients with small 
cell lung cancer (SCLC) who failed after first-line standard 
cytotoxic-containing therapy and at least nine evaluable patients 
with endometrial cancer will be included to further define the 
efficacy, safety and feasibility of a doxorubicin dose adaptation 
(doxorubicin 40 mg/m2 and PM01183 2.0 mg/m2).
In the event of DLTs occurring in the first patient at the first 
level, the second and third patients will be included at least two 
weeks apart. Otherwise and/or at subsequent dose levels, all 
patients within a dose level may be treated simultaneously. All 
evaluable patients within a dose level will be followed for at 
least one cycle (i.e., three weeks) before dose escalation may 
proceed.
Intermediate dose levels could be tested on agreement between 
the Investigator and the Sponsor if deemed appropriate. The 
tumor type(s) that will be eligible to be included in the 
expansion cohort at the RD will be chosen according to the 
preliminary efficacy observed among those previously treated 


CL_0111 4.0
Page 10 of 107
Protocol PM1183-A-003-10
during the escalation phase, and will be discussed and agreed 
between the investigators and the Sponsor.
STUDY POPULATION
Inclusion criteria
1)
Voluntarily signed and dated written informed consent prior 
to any specific study procedure.
2)
Age: between 18 and 75 years (both inclusive).
For patients with SCLC and endometrial cancer included in 
the new cohort after implementation of Amendment #3: age 
≥ 18 years.
3)
Eastern Cooperative Oncology Group (ECOG) performance 
status (PS) ≤ 1.
For patients with SCLC and endometrial cancer included in 
the new cohort after implementation of Amendment #3: 
ECOG PS ≤ 2.
4)
Life expectancy ≥3 months.
5)
Patients not previously treated with anthracycline-
containing therapy for advanced disease (Note: adjuvant 
therapy with anthracyclines is allowed provided not more 
than 300 mg/m2 of doxorubicin or an equivalent total 
cumulative dose was administered and they did not have to 
discontinue treatment due to any anthracycline-related 
toxicity, and relapse occurred more than six months after 
the last drug administration). 
6)
No more than two prior lines of cytotoxic-containing 
chemotherapy regimens for advanced disease.
For patients with SCLC included in the new cohort after 
implementation of Amendment #3: no more than one prior 
line of cytotoxic-containing chemotherapy regimens for 
advanced disease.
7)
Patients
with a histologically/cytologically confirmed 
diagnosis of advanced disease of any of the following 
tumors:
a) Breast cancer (non-candidate for hormone therapy alone: 
i.e., 
hormone-sensitive 
patients 
with 
bone-limited 
disease).
b) Soft-tissue sarcoma [excluding gastrointestinal stromal 
tumors (GIST)].
c) Primary bone sarcomas.
d) Epithelial ovarian cancer (including primary peritoneal 
disease 
and/or 
fallopian 
tube 
carcinomas 
and/or 
endometrial adenocarcinomas).
e) Hepatocellular carcinoma (HCC) (non-eligible for liver 
transplantation and Child-Pugh score A only). Elevated 
alpha-fetoprotein (AFP) levels in a patient with known 
risk factors and radiological findings compatible with 
HCC do not require pathological confirmation.


CL_0111 4.0
Page 11 of 107
Protocol PM1183-A-003-10
f) Gastroenteropancreatic neuroendocrine tumors (GEP-
NET).
g) Small cell lung cancer (SCLC).
h) Gastric cancer.
i) Bladder cancer.
j) Adenocarcinoma of unknown primary site (AUKPS).
8)
Expansion cohort at the RD:
All patients must have:
a) Measurable disease according to Response Evaluation 
Criteria In Solid Tumors (RECIST) version 1.1;  or 
b) Evaluable disease by serum markers in the case of 
ovarian cancer [Gynecologic Cancer Intergroup (GCIG) 
specific criteria]; and
c) Documented disease progression during or immediately 
after last therapy according to any of the aforementioned 
criteria.
9)
New cohort after implementation of Amendment #3:
a) Measurable SCLC or endometrial cancer according to 
Response Evaluation Criteria In Solid Tumors (RECIST) 
version 1.1;  and
b) Documented disease progression during or immediately 
after last therapy according to any of the aforementioned 
criteria.
10) At least three weeks since the last anticancer therapy, 
including radiotherapy, and at least six weeks since 
nitrosoureas and mitomycin C (systemic). In the case of 
hormone-sensitive breast cancer progressing while on 
hormone therapy, the latter must be either stopped up to one 
week before or continued without changes during the trial.
11) Adequate bone marrow, renal, hepatic, and metabolic 
function (assessed ≤ 7 days before inclusion in the study):
a) Platelet count ≥ 100 x 109/l, hemoglobin ≥ 9.0 g/dl and 
absolute neutrophil count (ANC) ≥ 1.5 x 109/l.
b) Aspartate 
aminotransferase 
(AST) 
and 
alanine 
aminotransferase (ALT) ≤ 3.0 x the upper limit of normal 
(ULN), independently of the presence of liver metastases.
c) Alkaline phosphatase (AP) ≤ 2.5 x ULN (≤ 5 x ULN if 
disease-related).
d) Total bilirubin ≤ 1.5 x ULN or direct bilirubin ≤ ULN.
e) International Normalized Ratio (INR) < 1.5 (except if 
patient is on oral anticoagulation therapy).
f) Calculated creatinine clearance (CrCl) ≥ 30 ml/minute 
(using Cockcroft and Gault´s formula).
g) Creatine phosphokinase (CPK) ≤ 2.5 x ULN.
h) Albumin ≥ 2.5 g/dl.


CL_0111 4.0
Page 12 of 107
Protocol PM1183-A-003-10
For patients with SCLC and endometrial cancer included 
in the new cohort after implementation of Amendment 
#3: albumin ≥ 3.0 g/dl.
12) Recovery to grade ≤ 1 or to baseline from any adverse event 
(AE) derived from previous treatment (excluding alopecia 
and/or
cutaneous toxicity and/or
peripheral sensory 
neuropathy and/or asthenia, all grade ≤ 2).
13) Left 
ventricular 
ejection 
fraction 
(LVEF) 
by 
echocardiogram (ECHO) or multiple-gated acquisition 
(MUGA) scan within normal range (according to 
institutional standards).
14) Women of childbearing potential must have a negative 
serum pregnancy test before study entry. Both women and 
men must agree to use a medically acceptable method of 
contraception throughout the treatment period and for six 
weeks after discontinuation of treatment. Acceptable 
methods of contraception include intrauterine device (IUD), 
oral contraceptive, subdermal implant and/or double barrier.
Exclusion criteria
1)
Concomitant diseases/conditions:
a) History or presence of unstable angina, myocardial 
infarction, 
congestive 
heart 
failure, 
or 
clinically 
significant valvular heart disease within last year.
b) Symptomatic arrhythmia or any uncontrolled arrhythmia 
requiring ongoing treatment.
c) Ongoing chronic alcohol consumption, or cirrhosis with 
Child-Pugh score B or C.
d) Active uncontrolled infection.
e) Known human immunodeficiency virus (HIV) infection.
f) Myopathy or any clinical situation that causes significant 
and persistent elevation of CPK (> 2.5 x ULN in two 
different determinations performed one week apart).
g) Limitation of the patient’s ability to comply with the 
treatment or follow-up protocol.
h) Any other major illness that, in the Investigator’s 
judgment, will substantially increase the risk associated 
with the patient’s participation in this study.
2)
Symptomatic, 
progressive 
or 
corticosteroids-requiring 
documented brain metastases or leptomeningeal disease
involvement.
3)
Men or women of childbearing potential who are not using 
an effective method of contraception as previously 
described; women who are pregnant or breast feeding.
4)
Patients who have had radiation therapy in more than 35% 
of the bone marrow.
This criterion will not apply to patients with SCLC and 
endometrial cancer included in the new cohort after 


CL_0111 4.0
Page 13 of 107
Protocol PM1183-A-003-10
implementation of Amendment #3.
5)
History of previous bone marrow and/or stem cell 
transplantation.
6)
Treatment with any investigational product in the period of 
≥ 5 half-lives of the investigational compound prior to the 
first infusion.
STUDY POPULATION
Pharmacogenomic 
study criteria
The aim of the PGx component of this study is to identify and 
validate putative molecular markers associated with the clinical 
outcome of patients treated with PM01183 combined with 
doxorubicin. These molecular markers would help to select 
future patients who might preferentially benefit from PM01183 
and doxorubicin treatment, thus contributing to improve health 
care through a more individualized medicine.
Eligibility criteria:
1) Patients with prior available tumor samples who are eligible 
for the trial will also be eligible for the PGx study.
2) Only patients who voluntarily sign the Informed Consent for 
the PGx study will participate. Refusal to participate in the 
PGx study will not affect patient participation in the clinical 
study PM1183-A-003-10.
Expected number of 
patients
The number of patients may vary depending both on the 
tolerability to PM01183 combined with doxorubicin and the 
number of dose levels required to identify the MTD.
Approximately, 100 evaluable patients will participate in this 
study.
STUDY DRUG
Formulation
PM01183: 
PM01183 drug product (DP) will be presented as a lyophilized 
powder for concentrate for solution for infusion, with two 
strengths: 1 mg/vial and 4 mg/vial.
Before use, the 1-mg vial and 4-mg vial should be reconstituted 
with 2 ml and 8 ml of sterile water for injection, respectively, to 
give a solution containing 0.5 mg/ml of PM01183. For 
administration to patients as i.v. infusion, reconstituted vials 
will be diluted with glucose 50 mg/ml (5%) 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 are as follows:
Component
PM01183
1 mg
PM01183
4 mg
Concentration 
per vial after 
reconstitution
PM01183
1.0 mg
4.0 mg
0.5 mg/ml
Sucrose
200 mg
800 mg
100 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


CL_0111 4.0
Page 14 of 107
Protocol PM1183-A-003-10
Doxorubicin:
Commercially available presentations of vials containing 
doxorubicin will be provided as appropriate.
Treatment schedule
Doxorubicin at a fixed dose of 50 mg/m2 administered as an i.v. 
bolus followed by escalating doses of PM01183 as a 1-hour i.v. 
infusion on Day 1 q3wk.
New cohort after implementation of Amendment #3:
Patients with SCLC and endometrial cancer will be treated with
doxorubicin at 40 mg/m2 administered as an i.v. bolus/short 
infusion followed by PM01183 at 2.0 mg/m2 as a 1-hour i.v. 
infusion on Day 1 q3wk.
Administration route 
and dose 
Patients will consecutively receive the following on Day 1 q3wk 
(three weeks = one treatment cycle):

Doxorubicin: i.v. infusion of a total volume of 20 ml 
dilution on 0.9% saline or 5% dextrose, on a short i.v. bolus 
at a dose of 50 mg/m2 (fixed dose), via a central or 
peripheral 
venous 
catheter 
after 
appropriate 
visual 
confirmation of effective venous blood return through the 
line, immediately followed by:

PM01183: i.v. infusion over one hour at a starting dose of 
3.5 mg FD, over a minimum of 100 ml dilution on 5% 
glucose or 0.9% sodium chloride (at a fixed rate) via a 
central line (or a minimum of 250 ml dilution if a peripheral 
line will be used) through a pump device. Then PM01183 
will be escalated as planned according to the respective dose 
levels.
New cohort after implementation of Amendment #3:
Patients with SCLC and endometrial cancer will consecutively 
receive the following on Day 1 q3wk (three weeks = one 
treatment cycle):

Doxorubicin: i.v. bolus/short infusion at a dose of 40 
mg/m2, administered as described above, immediately 
followed by:

PM01183: i.v. infusion over one hour at a dose of 2.0 
mg/m2, administered as described above.
Both doxorubicin and PM01183 doses will be capped at 2.0 m2
of BSA for individuals exceeding this BSA value. Doses will 
have to be recalculated for patients showing a ≥ 10% change in 
total body weight value compared to previous cycle.  
Doses will be rounded to the first decimal.


CL_0111 4.0
Page 15 of 107
Protocol PM1183-A-003-10
Prophylactic medication
All patients must receive the following prophylactic medication 
20-30 minutes before infusion of any study drug:

Dexamethasone 8 mg i.v. or equivalent,

Ondansetron 8 mg i.v. or equivalent, with or without:
- Metoclopramide 10 mg i.v. or equivalent, and/or

Extended oral dexamethasone not exceeding 20 mg/days 
and/or oral ondansetron 4 to 8 mg or equivalent, at the 
investigator’s criteria if required.

Additional antiemetics might be used, if required.

If primary G-CSF prophylaxis is required in specific cohorts 
of patients, it will consist of: 
- G-CSF (non-pegylated filgrastim) at 300 μg/day 
subcutaneously for five consecutive days, starting on 
Day +3.
Allowed medications/
therapies

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 American 
Society of Clinical Oncology (ASCO) guidelines will be 
allowed.

Erythropoietin use according to ASCO guidelines will be 
allowed.

Hormone-responsive breast cancer patients [i.e., those 
whose tumors express estrogen receptor (ER)
and/or 
progestogen receptor (PrR)] may continue receiving their 
same 
prior 
hormonal 
therapy 
without 
interruption 
throughout their study participation.

Luteinizing hormone-releasing hormone (LHRH) agonists 
in women of reproductive age.

Palliative 
local 
radiation 
(excluding 
thorax 
and 
mediastinum) may be applied if needed after the first cycle 
of study treatment is completed. Any lesion within the 
irradiated area will then not be considered an area of 
measurable/evaluable disease. Thorax and mediastinum may 
be irradiated, if required, after a minimum of three weeks of 
doxorubicin discontinuation.

Megestrol acetate for appetite stimulation is also allowed.
Prohibited medications/
therapies

Concomitant administration of any other antineoplastic 
therapy is prohibited,
other than the aforementioned 
hormonal therapy for breast cancer.

Other investigational agents.

Aprepitant 
or 
directly 
related 
substances 
(e.g., 
fosaprepitant).

Immunosuppressive therapies, other than corticosteroids 

Primary prophylaxis and/or treatment with colony-
stimulating factors such as granulocyte colony-stimulating 
factor (G-CSF) and granulocyte/macrophage colony-


CL_0111 4.0
Page 16 of 107
Protocol PM1183-A-003-10
stimulating factor (GM-CSF) during Cycle 1, (except if 
patient(s) is/are treated within an specific cohort resuming 
dose escalation with primary G-CSF prophylaxis, in which 
case use is not only allowed but compulsory). Secondary 
prophylaxis might be allowed, if required, during the 
following cycles, instead of a dose reduction due to 
exclusively hematological reasons
and upon Sponsor
agreement.
Note: G-CSF treatment for non-febrile uncomplicated 
neutropenia during Cycle 1 and primary G-CSF or GM-CSF 
prophylaxis will not be allowed in patients with SCLC and 
endometrial cancer included in the new cohort after 
implementation of Amendment #3.

Thoracic and/or mediastinal irradiation concomitant with 
doxorubicin therapy.
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.
EVALUABILITY OF 
PATIENTS
An evaluable patient for the main objective of the study 
(determination of the MTD and RD) should have received at 
least one complete cycle (including observation period), except 
if early discontinuations or missed doses and/or assessments 
were the consequence of drug-related toxicity (excluding 


CL_0111 4.0
Page 17 of 107
Protocol PM1183-A-003-10
hypersensitivity reactions and/or extravasations).
In the new cohort of patients with SCLC and endometrial cancer 
after implementation of Amendment #3, a patient evaluable for
efficacy should have received at least one complete cycle 
(including observation period) and be evaluable as per RECIST, 
except if non-evaluability is due to treatment failure such as 
drug-related toxicity, death or early unequivocal PD outside the 
central nervous system.  
EVALUATION 
CRITERIA
Primary endpoint
DOSE-LIMITING 
TOXICITIES

Determination of MTD and RD.
o
The MTD will be the lowest dose level explored during 
the dose escalation at which more than one evaluable 
patient experience a DLT in Cycle 1. 
o
The RD will be the highest dose level explored in 
which less than one third of evaluable patients 
experience a DLT during Cycle 1.
If the DLTs of the doxorubicin and PM01183 combination 
without G-CSF prophylaxis are exclusively related to 
neutropenia, the MTD and RD will also be determined with 
primary G-CSF prophylaxis.
DLTs are defined as AEs and laboratory abnormalities related to 
the study treatment during the first cycle of treatment and 
fulfilling at least one of the criteria outlined below.

Grade 4 neutropenia (ANC < 0.5 x 109/l) lasting > 7 days.

Grade ≥ 3 febrile neutropenia of any duration or neutropenic 
sepsis.

Grade 4 thrombocytopenia (platelet count < 25 x 109/l) or 
grade 3 with any major bleeding episode requiring a platelet 
transfusion.

Grade 4 ALT and/or AST increase, or grade 3 lasting > 14 
days. 

Treatment-related grade ≥ 2 ALT or AST increase 
concomitantly with ≥ 2 times ULN total bilirubin increase 
and normal AP. 

Grade ≥ 3 CPK increase.

Any other grade 3/4 non-hematological AE that is suspected 
to be related to study drug(s), except nausea/vomiting 
(unless the patient is receiving an optimal anti-emetic 
regimen), hypersensitivity reactions, extravasations, grade 3 
asthenia lasting less than one week, and non-clinically 
relevant isolated biochemical abnormalities [e.g., isolated 
increase in gamma-glutamyltransferase (GGT)]. In any case, 
the clinical relevance should be discussed between the 
Investigators and Sponsor's representatives.

Delay in the administration of Cycle 2 of the combination 
exceeding 15 days of the theoretical date (i.e., Day 22), due 
to any AEs related to the study drug(s).


CL_0111 4.0
Page 18 of 107
Protocol PM1183-A-003-10

The following circumstances will be discussed between the 
Principal Investigator and the Sponsor, and the final 
consensus will be documented:
o
DLTs with delayed onset (i.e., that occur after Cycle 
1).
Secondary endpoints

Safety: patients will be evaluable for safety if they have 
received at least one partial or complete infusion of 
PM01183. AEs will be graded according to the National 
Cancer Institute Common Terminology Criteria for Adverse 
Events (NCI-CTCAE) version 4.

Pharmacokinetics: PK parameters will be evaluated in 
plasma
by 
standard 
non-compartmental 
methods 
(compartmental modeling may be performed if appropriate).

Efficacy: although it is not the main objective of this study, 
antitumor activity will be measured according to the 
RECIST version 1.1 at least six weeks after treatment 
initiation in all patients with measurable disease, or by 
evaluation of tumor markers if applicable (e.g., ovarian 
cancer). Patients included at the RD in the expansion cohort 
must be evaluable per RECIST version 1.1 or by evaluation 
of tumor markers.
In the new cohort after the implementation of Amendment 
#3, exploratory assessment for progression-free survival
(PFS) and overall survival (OS) will be performed.

Pharmacogenomics: pharmacogenomics will be evaluated 
from available tumor samples previously
obtained at 
diagnosis in order to determine predictive/prognostic 
markers of response and/or resistance to PM01183 and 
doxorubicin in those patients that signed the Informed 
Consent for the PGx study. The expression of XPG RNA 
will be evaluated in paraffin-embedded tumor tissues by 
real-time quantitative reverse transcriptase polymerase chain 
reaction (qRT-PCR) and XPG, topoisomerase IIa (TopoIIa)
and P-glycoprotein (Pgp) by immunohistochemistry (IHC) 
and associated with clinical outcome in patients treated with 
PM01183 and doxorubicin.
REPLACEMENT OF 
PATIENTS
Patients must be replaced if they are not evaluable for the 
assessment of the primary endpoint, i.e. if:

They are withdrawn from the study before receiving at least 
the infusion of both drugs on the first day (Day 1) of the 
first cycle of the scheduled treatment (“evaluable cycle”). 
An evaluable cycle is defined as: doxorubicin followed by 
PM01183 on Day 1 with the corresponding follow-up 
period of three weeks. 

They require radiotherapy (RT) or other therapeutic 
procedure within three weeks after the first dose, unless they 
previously had another drug-related AE included in the 
definition of DLT.

There is a protocol violation resulting in an impossibility of 
concluding anything regarding the safety of the study 


CL_0111 4.0
Page 19 of 107
Protocol PM1183-A-003-10
therapy.
In addition, patients with SCLC and endometrial cancer 
included in the new cohort after implementation of Amendment 
#3 must be replaced if:

They are not evaluable for efficacy as per RECIST for 
reasons other than treatment failure such as drug-related 
toxicity, death or early unequivocal PD outside the central 
nervous system.  
All replaced patients will be included in the general safety 
analysis and in the efficacy analysis (if appropriate).
DOSE ESCALATION 
SCHEDULE
Doxorubicin will be given at 50 mg/m2 as an i.v. bolus, which 
corresponds to 100% of its actual RD when combined with 
other myelosuppressive agents; therefore, the doxorubicin dose 
will not be escalated in this study.
The starting dose (DL1) for PM01183 will be 3.5 mg given as 
FD on Day 1 q3wk, which corresponds to 50% of the RD for 
this schedule when given as single agent. 
The dose escalation schedule is summarized in the following 
table:
DL
No. of 
patients
Relative DI 
(%) of 
doxorubicin  / 
PM01183
Dose of doxorubicin
(mg/m2 ) / PM01183 
(mg FD) on Day 1 
q3wk
DL-1
0-6
100 / 42.85
50 / 3.0
DL1
3-6
100 / 50 
50 / 3.5
DL2
3-6
100 / 71.4
50 / 5.0
DL3
3-6
100 / 85.7
50 / 6.0
DL4
3-6
100 / 100
50 / 7.0
The DL-1 level is to be explored only if DL1 is defined as 
the MTD.
DI, dose intensity; DL, dose level; FD, flat dose.
As shown in the table below, a minimum of three patients will 
be included at each DL. If no patients experience a DLT during 
the first cycle, the dose will be escalated. If one of three patients 
experiences a DLT, three additional patients will be included at 
that level. If >1 evaluable patient during dose escalation at a 
given DL experience a DLT during the first cycle, that level will 
be considered the MTD and dose escalation will be terminated
except if all DLTs occurring at a given dose level are related to 
neutropenia (e.g., febrile neutropenia, grade 4 neutropenia 
lasting more than 7 days or neutropenic sepsis) in which case 
dose escalation may be resumed, starting at the lowest dose 
level where exclusively neutropenia-related DLTs have 
occurred, and will follow the same original schedule but with 
compulsory primary G-CSF prophylaxis. The DL immediately 
below the MTD, or DL4 if the MTD is not reached during dose 
escalation and the last dose level (DL4) is reached, was to be


CL_0111 4.0
Page 20 of 107
Protocol PM1183-A-003-10
initially expanded up to a minimum of nine evaluable patients.
If less than three among the first nine evaluable patients treated 
within the expansion cohort experience a DLT during Cycle 1 
this DL will be the RD. 
Further to the finding of encouraging antitumor activity in the 
first 43 evaluable patients (13 responses, including four 
complete responses, with five partial responses in eight patients 
with small cell lung cancer, and one complete and one partial 
response in three patients with endometrial cancer), expansion 
of the cohort treated at the RD has been increased to include 
approximately 30 additional patients, for a total of around 39 
patients.
No. of  
patients 
evaluable* 
for DLT
No. of patients with 
DLTs in first cycle
Action
3
0
Escalate DL until 
DL4 is reached
1
Add 3 patients
>1
MTD
6
1
Escalate DL until 
DL4 is reached
>1
MTD
DL, dose level; DLT: dose-limiting toxicities; MTD, maximum tolerated 
dose.
* Patients not evaluable for DLT during dose optimization must be 
replaced.
According to the toxicity observed, intermediate dose levels 
may be explored if considered appropriate by the investigators 
and the Sponsor. 
Intra-patient dose escalation will not be allowed under any 
circumstances.
Criteria for treatment 
continuation
Patients will be treated with additional cycles of PM01183 
combined with doxorubicin as long as no unacceptable toxicity 
and/or progression of the disease and/or withdrawal of consent 
occurs.
The administration of a new cycle should be delayed if the 
criteria in the table below are not met on the corresponding Day 1 
of the next administration. Parameters will be reevaluated at 
minimum intervals of 48 hours. The new cycle will be started 
upon recovery of these parameters. A maximum delay of 15 days 
will be allowed for recovery from drug-related adverse events. If 
recovery has not occurred after a 15-day delay, the patient should 
discontinue the treatment, except in case of obvious patient 
benefit at the criteria of the Investigator and upon agreement with 
the Sponsor.
After delaying doses due to drug-related toxicity (except for 
neutropenia exclusively) exceeding the 15-day delay, or in 


CL_0111 4.0
Page 21 of 107
Protocol PM1183-A-003-10
patients who experience a DLT, treatment may continue after 
appropriate dose reduction of PM01183, appropriate secondary 
prophylaxis with G-CSF (when due to neutropenia exclusively), 
or doxorubicin interruption (i.e., due to cardiac toxicity or 
maximal cumulative dose reached). 
Criteria for Treatment Continuation
PM01183
Doxorubicin
Day 1
Day 1 
ANC 
1.5 x 109/l
1.5 x 109/l
Platelets
100 x 109/l
100 x 109/l
Hemoglobin
9 g/dl
9 g/dl
Total bilirubin
(or direct bilirubin)
1.5 x ULN
(ULN)
1.5 x ULN
(ULN)
AST/ALT
3.0 x ULN
3.0 x ULN
Albumin
≥ 3.0 g/dl.
≥ 3.0 g/dl.
ECOG PS
0-2
0-2
Calculated CrCl 
(Cockcroft and Gault’s formula)
≥ 30 ml/min
≥ 30 ml/min 
Muscular toxicity 
(myalgia, muscular weakness, CPK increase)
Grade ≤ 1
Grade ≤ 1
Other non-hematological drug-related AEs 
(except increased GGT, not optimally treated 
nausea and vomiting , alopecia, asthenia 
and/or neuropathy) a
Grade ≤ 1
Grade ≤ 1
Mucositis
Grade ≤ 1
Grade ≤ 1
Signs and/or symptoms of CHF
-
No
Current cumulative doxorubicin-
equivalent dose < 400 mg/m2 b
-
Yes
If a patient does not meet the requirements for treatment continuation (excluding cardiac 
toxicity and/or maximal doxorubicin cumulative dose) on Day 1 of further cycles, both 
drugs (PM01183 and doxorubicin) infusions will be withheld until recovery for a 
maximum of 15 days after the theoretical treatment date. If recovery has not occurred 
after a delay of > 15 days, the patient must be withdrawn from the trial, except in case of 
perceived clinical benefit from the Investigator and upon agreement with the Sponsor.
If a patient does not meet the requirements for treatment continuation due to cardiac 
toxicity and/or maximal doxorubicin cumulative dose, doxorubicin will be permanently 
discontinued and treatment may continue with PM01183 alone at its single-agent RD, 7.0 
mg FD q3wk, without any delay if clinically appropriate.
a
Any grade accepted for increased GGT. Up to grade 2 for alopecia, nausea, vomiting, 
neuropathy and asthenia.
b
The total doxorubicin cumulative dose received by each patient must never reach > 
450 mg/m2.
AEs, adverse event(s); ALT, alanine aminotransferase; ANC, absolute neutrophil count; 
AP, alkaline phosphatase; AST, aspartate aminotransferase; CHF, congestive heart 
failure; 
CPK, 
creatine 
phosphokinase; 
CrCl, 
creatinine 
clearance; 
ECG,
electrocardiogram; ECOG PS, Eastern Cooperative Oncology Group performance status; 
FD, flat dose; GGT, gamma-glutamyltransferase; q3wk, every three weeks; ULN, upper 
limit of normal.
Dose reduction
Treatment after DLT, a treatment-related infusion delay greater 
than 15 days, or toxicity considered as unacceptable by the 
investigators may continue, after appropriate dose reduction, only 
if there is clear evidence of objective patient benefit. This will 
always be discussed with the Sponsor. Under this circumstance, 
and following recovery to pre-specified re-treatment criteria, 
patients will be re-treated at the immediately lowest dose level. If 


CL_0111 4.0
Page 22 of 107
Protocol PM1183-A-003-10
dose reduction beyond DL-1 is required, the dose of PM01183 
may be reduced by an additional 0.5 mg (FD). Up to two 
individual dose reductions will be allowed per patient; any 
patients requiring more than two dose reductions will be
withdrawn from the study. Once the dose has been reduced for an 
individual patient, it will not be re-escalated again under any 
circumstances. 
Patients requiring dose reduction exclusively due to grade 4 
neutropenia or any grade febrile neutropenia that occurred during 
the preceding cycle may receive secondary prophylaxis with G-
CSF instead of a dose reduction. If toxicity re-occurs despite G-
CSF use, dose reduction will then be implemented.
Patients who reach a maximal cumulative dose of 450 mg/m2 of 
doxorubicin or have to discontinue doxorubicin due to a cardiac 
AE may continue receiving treatment with PM01183 (after Cycle 
1) at the single-agent RD (7 mg FD q3wk) if patient benefit is 
perceived. These patients do not need to be replaced.
New cohort after implementation of Amendment #3:
Patients with SCLC and endometrial cancer included in the new 
cohort after implementation of Amendment #3 who require dose 
reduction due to the reasons described above will be re-treated at 
the following dose levels: 

DL-1: Doxorubicin 40 mg/m2 + PM01183 1.5 mg/m2.

DL-2: Doxorubicin 30 mg/m2 + PM01183 1.5 mg/m2.
Up to two sequential dose reductions will be allowed per patient; 
any patients requiring more than two dose reductions will be 
withdrawn from the study, except if there is objective clinical 
benefit or upon the Sponsor’s agreement. Once the dose has been 
reduced for an individual patient, it will not be re-escalated again 
under any circumstances.
Patients included in this cohort who have received ten cycles of 
the doxorubicin/PM01183 combination or have to discontinue 
doxorubicin due to a cardiac AE may continue receiving 
treatment with single-agent PM01183 at 4.0 mg/m2 q3wk if 
patient benefit is perceived. These patients do not need to be 
replaced.
Patients treated with single-agent PM01183 who require dose 
reduction due to the reasons described above will have their dose 
reduced by 25%. Up to two sequential dose reductions will be 
allowed per patient; any patients requiring more than two dose 
reductions will be withdrawn from the study, except if there is 
objective clinical benefit or upon the Sponsor’s agreement.
PHARMACOKINETICS
The plasma PK of doxorubicin and PM01183 will be evaluated 
during Cycle 1 with a schedule of 16 samples. The sampling 
schedule will be as follows, taking as reference the doxorubicin 
administration: 


CL_0111 4.0
Page 23 of 107
Protocol PM1183-A-003-10

Sample #1: before administration.

Sample #2: 5 minutes after administration; sample for 
doxorubicin determination only.

Sample #3: 30 minutes after administration.

Sample #4: 55 minutes after administration [i.e., 5 minutes 
before PM01183 end of infusion (EOI)]. 

Sample #5: 1.5 hours after administration.

Sample #6: 2 hours after administration.  

Sample #7: 2.5 hours after administration. 

Sample #8: 3 hours after administration. 

Sample #9: 4 hours after administration. 

Sample #10: 5 hours after administration.

Sample #11: 6 hours after administration.

Sample #12: 8 hours after administration.

Sample #13: 24 hours after administration.

Sample #14: 48 hours after administration.

Sample #15: 96 hours after administration.

Sample #16: 168 hours after administration; sample for 
PM01183 determination only.
PK parameters will be calculated using non-compartmental 
analysis and population methods if appropriate, after pooling data 
from this study with data obtained during phase I studies to check 
any PK interaction.
PHARMACOGENOMIC
EVALUATIONS
The aim of this investigation is to identify molecular markers 
whose expression may be associated with the clinical outcome of 
patients. These molecular markers might allow the identification 
of those patients who will benefit from PM01183 and 
doxorubicin treatment, thus improving the health care by an 
individualized medicine. 
The following analyses will be done on paraffin-embedded tumor 
tissue samples from consenting patients treated with PM01183 
and doxorubicin: 

Quantitation of XPG mRNA expression by real-time qRT-
PCR and other genes related to the mechanism of action of 
PM01183 and doxorubicin.

Quantitation of XPG, TopoIIa and Pgp expression and other 
proteins related to the mechanism of action of PM01183 and 
doxorubicin by IHC in tumor tissue microarrays constructed 
from the patient’s paraffin-embedded tumor tissue blocks.
In those patients responding to treatment, Myriads Genetics 
Homologous Recombination Deficiency (HRD) assay, including 
analysis of BRCA1 mutation status, will be performed, if 
considered relevant.
STATISTICAL 
METHODS
Demographics:
Descriptive statistics (mean, median, standard deviation and 95% 
confidence interval, range of value, frequencies and percentages) 
will be used. Tables will be displayed by dose level.


CL_0111 4.0
Page 24 of 107
Protocol PM1183-A-003-10
Safety: 
Descriptive statistics will be used to characterize the profiles of 
drug-related AEs, drug-related deaths, serious adverse events 
(SAEs), drug-related delays, dose reductions, and/or treatment 
discontinuations. Tables will be displayed by dose level.
Efficacy analysis:
Response rates (percentage of patients with any response [partial 
response (PR) or complete response (CR): overall response rate], 
percentages for PR and CR separately, as well as percentage of 
patients with prolonged stable disease (SD) ≥ 4 months) will be 
characterized using descriptive statistics (95% exact binomial 
confidence interval). If any particular tumor type is adequately 
represented, time-related parameters (i.e., progression-free 
survival, overall survival) will be analyzed according to the 
Kaplan-Meier method, if appropriate. The characteristics of the 
patients achieving an objective response or SD ≥ 4 months by 
RECIST version 1.1., or a clinically significant improvement as
measured by tumor markers, if applicable, will be displayed.
In addition, patients with SCLC and endometrial cancer included 
in the new cohort after the implementation of Amendment #3 
will be followed for survival for up to 18 months after the first 
study dose.
Pharmacokinetics:
The PK parameters will be tabulated and selected parameters will 
be graphically displayed per dose level. The dose-exposure 
relationships for maximum plasma concentration (Cmax) and area 
under the curve (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 cutoff 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, 
relationship with selected PK parameters will be graphically 
explored and assessed using correlation and regression methods.
Pharmacogenomics:
RNA expression and IHC scoring will be performed blind, and 
clinical data compiled only after all analyses are completed. 
Fisher’s exact test will be used to test whether a specific protein-
expression profile is associated with the clinical outcome after 
treatment with PM01183 and doxorubicin. The prognosis value 
of markers will be explored for objective clinical response, 
progression-free survival and overall survival. In each case, if 
applicable, a multivariate model will be developed by backwards 
elimination, starting with all markers with a p-value lower than 
0.10 in the univariate analysis. If applicable, hazard ratios will be 
calculated with the univariate Cox model, and comparison 
between Kaplan-Meier survival (whenever available) and 
progression-free survival curves will be performed with the log-


CL_0111 4.0
Page 25 of 107
Protocol PM1183-A-003-10
rank test. All tests of statistical significance will be two-sided, 
and significance will be set at 0.05 except in multiple 
comparisons, where it will be set at 0.017 in accordance with the 
Bonferroni correction of type I error.
DURATION OF STUDY 
PERIOD (per patient)
Patients will be evaluated at scheduled visits in three study 
periods:

Pre-treatment: from signature of informed consent to first 
infusion of study drugs.

Treatment: from first infusion of study drugs to end of 
treatment.

Follow-up: after end of treatment, patients will be followed 
every four weeks until resolution to at least grade 1 or 
stabilization of all toxicities, if any. Patients who finish
treatment without disease progression will be followed every 
two months until disease progression, other antitumor 
therapy, death or until the date of study termination (clinical 
cutoff), whichever occurs first. 
In the new cohort after the implementation of Amendment 
#3, patients with SCLC and endometrial cancer will be 
followed every three months until death or the date of study 
termination, whichever occurs first.
Patients will be considered to be on-study from the signature of 
the informed consent to the end of the follow-up period. Patients 
will be considered to be on-treatment for the duration of their 
treatment and until the day of end of treatment. 
End of treatment is defined as 30 days after the treatment 
discontinuation, unless the patient starts a new antitumor therapy 
or dies (whichever occurs first). An end-of-treatment visit will be 
performed within 30 days (± 7
days) after last dose 
administration, unless the patient dies or starts any subsequent 
antitumor therapy, in which case the end-of-treatment visit 
should be performed immediately before the start of the new 
therapy.
Patients will receive the study medications while it is considered 
to be in their best interest. Specifically, treatment will continue 
until:

Disease progression.

Unacceptable toxicity.

Intercurrent illness of sufficient magnitude to preclude
fulfillment of appropriate re-treatment criteria and/or safety 
continuation of the study.

Patient 
refusal 
and/or 
non 
compliance 
with 
study 
requirements.

Treatment delay > 15 days due to toxicity (except clear 
clinical benefit, with the Sponsor’s approval).

Requirement of > 2 dose reductions. 

Specifically, doxorubicin will be continued before a maximal 
total cumulative dose of 450 mg/m2 has been reached. Thus, a 
maximum of ten cycles of the combination will
be 
administered to patients with SCLC and endometrial cancer 


CL_0111 4.0
Page 26 of 107
Protocol PM1183-A-003-10
included in the new cohort after implementation of 
Amendment #3), in absence of disease progression and/or 
unacceptable toxicity. 
Patients discontinuing doxorubicin at any time after Cycle 1 will 
remain on study as long as they continue receiving PM01183.
PLANNED TRIAL 
PERIODS
The total duration of the study will be approximately 72 months, 
including approximately a 54-month enrolment period. 
Consenting patients will be followed until disease progression, 
other antitumor therapy, death or until the date of study 
termination (clinical cutoff), whichever occurs first.
In the new cohort after the implementation of Amendment #3, 
consenting patients with SCLC and endometrial cancer will be 
followed until death or the date of study termination (clinical 
cutoff), whichever occurs first.
Planned start date (first patient on study): Second quarter (Q2) 
2011.
Planned enrolment period: 54 months.
Planned end-of-study date (clinical cutoff): 18 months after the 
first study dose of the last patient or when follow-up of all SCLC 
and endometrial cancer patients included in the cohort after 
implementation of Amendment #3 has been completed, 
whichever occurs first.


CL_0111 4.0
Page 27 of 107
Protocol PM1183-A-003-10
SCHEDULE OF ASSESSMENTS AND PROCEDURES
Assessments and procedures
Screening 
Treatment
Follow-
up 
Cycle 1
Further cycles *
End of 
treatment 
D1
D8
D15
D22 
D10 †
Written informed consent
Before any 
study 
procedures
-
-
-
-
-
-
-
PGx study informed consent
Before any
study 
procedures
-
-
-
-
-
-
-
Demographic data
-14  to  0
-
-
-
-
-
-
-
Medical and cancer history
/ Baseline condition
-14  to  0
-
-
-
-
-
-
-
Assessment of signs and 
symptoms (1)
-14  to  0
-
-
-

-
(3)
-
Complete physical examination, 
including weight and BSA (1,2)
-14  to  0
-
-
-

-
(3)
-
Performance status (ECOG) (2)
-14  to  0

-
-

-
(3)
-
Vital signs (heart rate, blood 
pressure, temperature) (2)
-14  to  0

-
-

-
(3)
-
Hematology (1,2,4)
-7  to  0
-




(3)
-
Biochemistry-A (1,2,4)
-7  to  0
-




(3)
-
Biochemistry-B and coagulation 
(1,2)
-7  to  0
-
-
-

-
(3)
-
Pregnancy test (if applicable) (2,5)
-14  to  0
Repeat if applicable
-
ECG (2,6)
-7  to  0
Repeat at the time of doxorubicin 
discontinuation and whenever is 
clinically indicated (7)
(8)
-
LVEF by ECHO or MUGA (2)
-14  to  0
Repeat at the time of doxorubicin 
discontinuation and whenever is 
clinically indicated (7)
(8)
-
Clinical and radiological tumor 
assessment as per RECIST (2,9)
-28  to  0
Every 6 weeks (±2 weeks) 
(or every 2 cycles prior to infusion) 
-

(10)
Pharmacokinetics 
-
Immediately before treatment and 
during Cycle 1 only
-
Pharmacogenomics, if PGx 
consented (11)
If tumor 
samples are 
available
-
-
Concomitant therapies (2)
-14  to  0
Throughout the “on-treatment” phase 
-
Adverse events
NA
Throughout the “on-treatment” phase 

(12)
* Day 1 = day of treatment start. Day 22 = Day 1 of the next cycle.
† A ±3-day window will be allowed for Day 10 of any further cycle.
1.
Repeat prior to first infusion, if treatment will be administered after more than the pre-specified 
screening period plus the allowed window.
2.
A +3-day window will be allowed for laboratory procedures, a ±2-week window for radiological 
procedures, a +24-hour window for clinical assessments (ECOG, vital signs, ECG, weight, BSA, etc.), a 
+2-week window for LVEF assessments, and a ±7-day window for the assessments at end of treatment. 
3.
To be repeated only for those parameters for which no measurement is available at one week + 3 days 
before the end-of-treatment visit, or for those parameters with values that are out of range in the last 
assessment (grade > 1 according to NCI-CTCAE version 4).
4.
If any suspected or possible treatment-related NCI-CTCAE grade ≥ 3 toxicity occurs, the abnormal 
test(s) should be re-assessed at least every 2-3 days until recovery to at least grade 1. In the event of 
febrile neutropenia of any grade, grade 4 neutropenia and/or grade 4 thrombocytopenia, re-assessment 
should be performed daily until recovery to at least grade 3 and/or until 24 hours after fever resolution, 
if applicable, and then every 2-3 days thereafter until recovery to at least grade 1.
5.
Beta serum hCG.


CL_0111 4.0
Page 28 of 107
Protocol PM1183-A-003-10
6.
It should allow rhythm definition (at least 30 seconds of duration).

PR interval.

RR interval.

QT interval (raw).

QRS complex duration.
7.
To be repeated in patients in no acute distress within three weeks of the last doxorubicin dose ± 1 week.
8.
To be repeated at end of treatment only in patients who did not receive single-agent PM01183 after 
discontinuing doxorubicin.  
9.
Helical contrast-enhanced CT-scan or gadolinium enhanced MRI as appropriate every six weeks 
(method should be always the same throughout the study for each individual patient). In case of 
objective tumor response, a copy of CT-scans or MRIs can be requested by the Sponsor.
10. Patients who discontinued treatment without progression will be followed every two months until 
disease progression, other antitumor therapy, death or until the date of study termination, whichever 
occurs first.
In the new cohort after the implementation of Amendment #3, consenting patients with SCLC and 
endometrial cancer will be followed every three months until death or the date of study termination, 
whichever occurs first.
11.
Tumor samples from patients treated with PM01183 and doxorubicin will be used to analyze the 
expression of putative markers of response/resistance to treatment. Paraffin-embedded tumor tissue 
samples obtained at diagnosis of the disease can be collected at any time during treatment.
12. Patients withdrawn with a drug-related AE should be followed until recovery to baseline or stabilization. 
Beyond 30 days after the last administration of study drug, only those procedures that are relevant to any 
remaining toxicities adverse event need to be performed.
Study termination date is defined as 18 months after the first study dose of the last patient or when 
follow-up of all SCLC and endometrial cancer patients included in the cohort after implementation of 
Amendment #3 has been completed, whichever occurs first.
Hematology: Differential WBC, hemoglobin and platelets.
Biochemistry A: AST, ALT, total bilirubin (and direct, if total is abnormally elevated), AP, LDH, creatinine, 
glucose, CPK (and CPK-MB fraction if total CPK is abnormally high), serum electrolytes (Na+, K+, Cl-).
Biochemistry B and coagulation: total proteins, albumin, Ca++, CRP, coagulation tests (PT/INR, PTT). Only at 
baseline and to be repeated if clinically indicated: alpha-1 acid glycoprotein (AAGP), total cholesterol, LDL, 
triglycerides, Mg++ and amylase. Exploratory/validated serum tumor marker as clinically indicated [CA-125 
(ovarian cancer), CEA and/or CA19-9 (gastric cancer), AFP (HCC), NSE (NET) and/or CA15-3 (breast cancer)]. 
Repeat serum tumor marker assessment only in patients with abnormally elevated values at baseline. No serum 
markers will be evaluated in patients with SCLC and endometrial cancer included in the new cohort after 
implementation of Amendment #3.   
AE, adverse event; AFP, alpha-fetoprotein; ALT, alanine aminotransferase; AP, alkaline phosphatase; AST, 
aspartate aminotransferase; BSA, body surface area; CA19-9 and 15-3, carbohydrate antigen 19-9 and 15-3, 
respectively; CEA, carcinoembryonic antigen; CPK, creatine phosphokinase; CRP, C-reactive protein; CrCl, 
creatinine clearance; CT, computed tomography; ECG, electrocardiogram; ECHO, echocardiography; ECOG, 
Eastern Cooperative Oncology Group; GGT, gamma-glutamyltransferase; HCC, hepatocarcinoma; hCG, human 
chorionic gonadotropin; INR, international normalized ratio; LDH, lactate dehydrogenase; LDL, low density 
lipoprotein; LVEF, left vascular 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; NET, neuroendocrine tumor; NSE, neuron-specific enolase; PGx, pharmacogenomics; PT, 
prothrombin time; PTT, partial thromboplastin time; RECIST, Response Evaluation Criteria in Solid Tumors; 
SCLC, small cell lung cancer; WBC, white blood cell.


CL_0111 4.0
Page 29 of 107
Protocol PM1183-A-003-10
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
AAGP
Alpha-1 Acid Glycoprotein
ABP
Arterial Blood Pressure
ADR
Adverse Drug Reaction
AE(s)
Adverse Event(s)
AFP
Alpha-fetoprotein
ALT
Alanine Aminotransferase
ANC 
Absolute Neutrophil Count
AP
Alkaline Phosphatase
ASCO
American Society of Clinical Oncology
AST
Aspartate Aminotransferase
AUC
Area Under The Curve
AUKPS
Adenocarcinoma of Unknown Primary Site
β-hCGs
Beta Subunit of Human Chorionic Gonadotropins
BSA
Body Surface Area
CA-125
Carbohydrate Antigen-125
CA15-3
Carbohydrate Antigen 15-3
CA19-9
Carbohydrate Antigen 19-9
CEA
Carcinoembryonic Antigen
CHF
Congestive Heart Failure 
CI
Combination Index
CL
Clearance
Cmax
Maximum Plasma Concentration
CPK
Creatine Phosphokinase
CR
Complete Response/Complete Regression
CrCl
Creatinine Clearance
CRF
Case Report Form
CRP
C-reactive Protein
CT-scan
Computed Tomography Scan
d/D
Day(s)
DI
Dose Intensity
DL
Dose Level
DLT
Dose-limiting Toxicity
DNA
Deoxyribonucleic Acid
DSB
Double-strand Breaks
ECG
Electrocardiogram
ECHO
Echocardiography
ECOG
Eastern Cooperative Oncology Group


CL_0111 4.0
Page 30 of 107
Protocol PM1183-A-003-10
EOA
End of Administration
EOI
End of Infusion
ER
Estrogen Receptor
FD
Flat Dose
FUP
Follow-up
G-CSF
Granulocyte Colony-stimulating Factor
GCIG
Gynecologic Cancer Intergroup
GCP
Good Clinical Practice
GEP
Gene Expression Profiling
GEP-NET
Gastroenteropancreatic Neuroendocrine Tumors
GGT
Gamma-glutamyltransferase
GIST
Gastrointestinal Stromal Tumors
GM-CSF
Granulocyte/Macrophage Colony-stimulating Factor
GMT
Greenwich Meridian Time
HCC
Hepatocellular Carcinoma
hCG
Human Chorionic Gonadotropin
HIV
Human Immunodeficiency Virus
HRD
Homologous Recombination Deficiency
HR
Heart Rate; Homologous Recombination
IB
Investigator’s Brochure
IC50
Half Maximal Inhibitory Concentration
ICF
Informed Consent Form
ICH
International Conference on Harmonization
IEC
Independent Ethics Committees
IG50
Concentration that Result in 50% of Cell Growth Inhibition
IHC
Immunohistochemistry
IMP
Investigational Medicinal Product
INR
International Normalized Ratio
IUD
Intrauterine Contraceptive Device
i.v.
Intravenous (intravenously)
k
Terminal Rate Constant
LDH
Lactate Dehydrogenase
LDL
Low Density Lipoprotein
LHRH
Luteinizing Hormone-releasing Hormone
LVEF
Left Ventricular Ejection Fraction
ml
Milliliter
MMR
Mismatch Repair
MRI
Magnetic Resonance Imaging
MTD
Maximum Tolerated Dose


CL_0111 4.0
Page 31 of 107
Protocol PM1183-A-003-10
MUGA
Multiple-gated Acquisition Scan
NCI
National Cancer Institute
NCI-CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
NER
Nucleotide Excision Repair
NET
Neuroendocrine Tumor
NSE
Non-specific Enolase
OS
Overall Survival
PD
Progressive Disease
PFS
Progression-free Survival
Pgp
P-glycoprotein
PGx
Pharmacogenomic(s)
PhV
Pharmacovigilance
PK
Pharmacokinetic(s)
PR
Partial Response
PRE TT
Pre-treatment
PrP
Progesterone Receptor
PS
Performance Status
Pt/Pts
Patient/Patients
PT
Prothrombin Time
PTT
Partial Thromboplastin Time
q3wk
Every 3 Weeks
qRT-PCR
Quantitative Reverse Transcriptase Polymerase Chain Reaction
RD
Recommended Dose
RECIST
Response Evaluation Criteria In Solid Tumors
RNA
Ribonucleic Acid
RT
Radiotherapy
SAE(s)
Serious Adverse Event(s)
SCLC
Small Cell Lung Cancer
SD
Stable Disease
SUSAR
Suspected Unexpected Serious Adverse Reaction
t1/2
Half-life
TGD
Tumor Growth Delay 
TopoIIa
Topoisomerase IIa
TT
Treatment
Uk
Unknown
UK
United Kingdom
ULN
Upper Limit of Normal
Vss
Volume of Distribution at Steady State
Vz
Volume of Distribution Based on the Terminal Half-life


CL_0111 4.0
Page 32 of 107
Protocol PM1183-A-003-10
WBC
White Blood Cells
WMA
World Medical Association


CL_0111 4.0
Page 33 of 107
Protocol PM1183-A-003-10
1.
INTRODUCTION
1.1
BACKGROUND
Despite recent advances in the treatment of cancer, advanced (metastatic) disease 
remains mostly incurable and there is an urgent need for developing new therapeutic 
options for these patients, particularly including investigational drugs with novel 
mechanism of action. The introduction of new combination regimens of non-cross-
resistant chemotherapy agents with acceptable toxicity profiles is a major way to 
improve the outcome of patients with advanced solid tumors.
1.2
INFORMATION ON STUDY DRUG: PM01183
Please refer to the Investigator's Brochure (IB) for full information on PM01183.
1.2.1
Name and Chemical Information
PM01183 is produced by synthesis and has the following chemical properties:
Chemical Name
(1R,6'R,6a'R,7'R,13'S,14'S,16'R)-8',14'-dihydroxy-6,9'-
dimethoxy-4',10',23'-trimethyl-19'-oxo-2,3,4,6',7',9,12',13', 
14',16'-decahydro-6a'H-spiro[ß-carboline-1,20'-
[7,13]epimino[6,16](epithiopropanooxymethano) 
[1,3]dioxolo[7,8]isoquino[3,2-b][3]benzazocin]-5'-yl acetate
Molecular Formula
C41H44N4O10S
Molecular Weight
784.874
The structural and molecular formula of PM01183 are shown in Figure 1: 
Figure 1. Molecular Formula of PM01183: C41H44N4O10 S


CL_0111 4.0
Page 34 of 107
Protocol PM1183-A-003-10
1.2.2
Non-clinical Data
PM01183 is a new chemical entity, structurally related to trabectedin that binds the 
DNA, leading to the formation of DNA double-strand breaks (DSBs), thus inducing 
apoptosis and delaying progression through the cell cycle S/G2 phase. The binding to 
DNA likely occurs in the minor groove region. 
PM01183 has a negative COMPARE analysis when compared against other 98 standard 
anticancer agents in the standard National Cancer Institute (NCI) panel of 36 cell lines. 
Thus, its mechanism of action is likely to differ significantly from the other drugs. It 
only showed a positive correlation (S-rank > 0.8) with trabectedin (1).
In vitro, PM01183 demonstrated cytotoxic effects against a broad selection of tumor 
types with half maximal inhibitory concentration (IC50) values in the low to very low 
nanomolar range (approximately median IC50
of 1-10
M). These PM01183 
concentrations are far achievable, by two or three logarithms, in the plasma of patients 
in the clinical setting at the single-agent recommended dose (RD). Although some 
selectivity was also seen, a clustering of sensitive tumors has not been identified yet. 
PM01183 also exhibits in vivo antitumor activity against different murine models of 
xenografted human-derived tumor types.
The antineoplastic in vitro activity of PM01183 was evaluated in a panel of solid tumor 
cell lines (Table 1), which were exposed to a range of PM01183 concentrations for 72 
hours and then assayed for viability by a MTT short-term assay (2).
Table 1. Selected in vitro activity of PM01183.
Type
Tumor
Cell line
IG50 (M)
Solid
Breast
BT-474
1.3·10-9
MDA-MB-231
3.5·10-9
MCF-7
1.7·10-9
Kidney
Caki-1
1.7·10-9
RXF 393
8.6·10-10
Liver
HepG2
3.1·10-9
SK-HEP-1
3.1·10-9
Lung
A-549
1.3·10-9
NCI-H460
1.6·10-9
NCI-H23
5.4·10-10
Ovarian
A2780
1.6·10-9
IGROV-1
9.8·10-9
Pancreas
MiaPaca-2
1.1·10-9
PANC-1
2.9·10-9
Non-solid
Leukemia
K-562
1.6·10-9
MOLT-4
1.1·10-9
IG50, concentration that results in 50% of cell growth inhibition.
The in vivo “Proof of Concept” for PM01183 was first accomplished by using a panel of 
six human tumor 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. PM01183 demonstrated 
statistically significant antitumor activity (p<0.05) against breast, colon, gastric and 
kidney xenografts at different time points during the experiment (3).


CL_0111 4.0
Page 35 of 107
Protocol PM1183-A-003-10
PM01183 was further evaluated for in vivo activity in bladder, breast, kidney, lung, 
ovary, pancreas and prostate xenografted models (4-11). In summary, PM01183 
demonstrated antitumor activity in breast, kidney, ovary and lung, but had moderate 
antitumor activity against bladder, pancreas and prostate xenografted models. 
Finally, PM01183 was also evaluated for in vivo activity, by using the M5076 sarcoma 
model that spontaneously metastasizes in the liver of tumor-bearing female C57Bl/6 
mice (12). PM01183 was administered i.v. at a dose of 0.2 mg/kg/day (0.6 mg/m2/day) 
for three consecutive weeks. Results showed marginal activity as evaluated by tumor 
growth inhibition. However, PM01183 statistically significantly reduced the number of 
liver metastasis compared to placebo-treated animals.
Toxicology studies in rats and dogs showed that the main target organs were the bone 
marrow and the liver. In particular, the effect of a single bolus injection of PM01183 on 
cardiovascular parameters [arterial blood pressure (ABP), heart rate (HR) and lead II 
electrocardiogram (ECG)] was evaluated in conscious, telemetered dogs for six hours 
(13). This study showed no effects on heart, blood pressure, lead II ECG variables (PR, 
QT, QTcF and QTcV intervals, and QRS duration), ECG gross morphology or rhythm 
in dogs treated with PM01183 at doses up to 0.01 mg/kg (0.2 mg/m2). When the dogs 
received an actual dose of 0.023 mg/kg (0.46 mg/m2), they showed a short-lasting 
tachycardia during the first 30 minutes after administration (mean increase of 89% after
one minute, followed by rapid normalization). Although a direct pharmacological effect 
of PM01183 cannot be ruled out, other factors contributing to an increase in HR should 
be considered, such as vomiting episodes (in three of four animals) and/or increasing 
pain related to PM01183, especially in the sequential, dose-increase design of this 
study. Moreover, two different toxicity studies found no electrophysiological alterations 
in the HR and the ECGs of dogs following single or repeated PM01183 administration 
at doses up to 0.05 mg/kg (1 mg/m2) (14, 15).
1.2.3
Clinical Data
Based on the promising preclinical results described above, the first-in-human phase I 
clinical study with PM01183 was started in March 2009. 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 RD for phase II 
studies of single-agent PM01183 when administered as a 1-hour i.v. infusion on Day 1 
every three weeks (q3wk). The RD was established at 4.0 mg/m2/q3wk; however, 
PM01183 clearance was found to be unrelated to body surface area (BSA), and 
therefore all patients treated at the RD in this study’s expansion cohort were treated at a 
flat dose (FD) of 7.0 mg as a 1-hour i.v. infusion q3wk (16). The median terminal 
plasma half-life at the RD was 62 hours and interindividual variability was high.
One of the 15 patients treated at the RD experienced a dose-limiting toxicity (DLT) 
during their first cycle (grade 4 thrombocytopenia). Toxicity was generally mild and 
reversible. Standard antiemetic prophylaxis was required at the RD in order to avoid 
grade 2 nausea and vomiting. Myelosuppression, particularly non-complicated short-
duration grade 4 neutropenia, was the most relevant toxicity (in up to 40% of the 
patients treated at the RD). It was also predictable and easily manageable; it caused no 
delays and all patients recovered by Day +22. Neutropenia nadir occurred during the 
second week (median on Day +13) and lasted a median of 3 days without granulocyte
colony-stimulating factor (G-CSF) treatment. The severity of the neutropenia correlated 
better with the observed area under the curve (AUC) concentration than with the dose 


CL_0111 4.0
Page 36 of 107
Protocol PM1183-A-003-10
administered. Other drug-related toxicities found at the RD were transient and reversible 
mild transaminase increases, asthenia, diarrhea, mild nausea and anemia. Neither 
treatment-related deaths nor signs of potential cardiac toxicity were observed in this 
population of pretreated patients (a median of 2 prior lines per patient, range, 1-7). In 
conclusion, treatment with PM01183 was very well tolerated by most patients.
Regarding the antitumor clinical activity of PM01183, ten of the 15 patients treated at 
the RD were evaluable for efficacy at the time of the latest clinical cutoff (September 
2010). The majority of these patients had advanced colorectal cancer, and no hints of 
clinical activity were seen in this particular subgroup. Nevertheless, one patient with a 
pancreatic adenocarcinoma showed a confirmed partial response (PR) as per Response 
Evaluation Criteria In Solid Tumors (RECIST) after only three cycles of PM01183; in 
addition, this patient showed normalization of serum tumor marker [carbohydrate 
antigen 19-9 (CA19-9)] levels after the fourth cycle, and was still ongoing at the clinical 
cutoff. Three other patients with progressing tumors (one melanoma and two soft tissue 
sarcomas) at study entry had clinically meaningful disease stabilizations with tumor 
shrinkage lasting more than three months and were still on treatment at the clinical 
cutoff, having received 13+, 6+ and 4+ cycles, respectively. This further reinforces the 
finding that clinically active PM01183 concentrations are achieved at a safe and 
tolerable dose and schedule.
1.3
INFORMATION ON STUDY DRUG: DOXORUBICIN
Doxorubicin (hydroxyldaunorubicin) is one of the anthracyclines most widely used in 
onco-hematology
worldwide. 
Alone 
or, 
more 
frequently,
in 
combinations, 
anthracyclines are commonly used to treat a variety of advanced malignancies, from 
acute leukemias (17) or lymphomas (18, 19), to solid tumors such as breast cancer (20), 
soft-tissue and bone sarcomas (21, 22), ovarian cancer (23), small cell lung cancer (24), 
hepatocellular carcinoma (25), gastric cancer (26), neuroendocrine tumors (27) and 
adenocarcinoma of unknown primary site (AUKPS) (28).
Doxorubicin primarily acts by inhibiting DNA synthesis through intercalation between 
DNA base pairs and forming a complex with topoisomerase II (topoII), one of the 
enzymes responsible for uncoiling the double helix at the early beginning of the S-phase 
of the cell cycle. It also generates free radicals (similarly to ionizing radiation), which 
can also generate direct or indirect DNA damage (29). Several mechanisms of primary 
or acquired tumor resistance have been described for anthracyclines, such as
overexpression of P-glycoprotein (which also confers resistance to many other widely 
used drugs), increased intracellular radicals scavengers such as gluthathione synthesis, 
mutations and/or post-transcriptional changes in its main target (topoII), and also loss of 
other important proteins involved in DNA repair and apoptosis signals such as 
mismatch repair (MMR) deficiency (30); however, the relative clinical relevance of 
each one is difficult to determine. 
The main DLT of doxorubicin is neutropenia, with the nadir occurring between Days 
10-14 and usually recovering by Day 21. To a slight degree, it also induces anemia and 
thrombocytopenia. However, the most characteristic toxicity of anthracyclines is a dose 
cumulative and schedule-dependent cardiac toxicity. In effect, the risk of developing a 
congestive cardiac failure starts to rise steeply, over 10%, after a total cumulative dose 
of over 450 mg/m2 (31). Thus, the strategy to not exceed this dose in a patient during 
his/her lifetime does not remove the risk completely, but it keeps it acceptably low. 


CL_0111 4.0
Page 37 of 107
Protocol PM1183-A-003-10
Alternatively, co-administration with dexrazoxane (a chelating agent), and/or special 
formulations such as liposomal encapsulated has shown some advantages and allows to 
increase (although marginally) the maximal deliverable dose. Other cardiotoxics such as 
ionizing radiation or trastuzumab have been shown to increase doxorubicin 
cardiotoxicity as well, and therefore they are not used concomitantly (32). Other 
common adverse events related to doxorubicin include nausea and vomiting, diarrhea, 
reversible alopecia and mucositis; in addition, it is a highly vesicant agent if 
extravasation occurs.
A dose-response relationship has been shown for anthracyclines in breast cancer 
patients (33); however, no consistent advantage has been observed in the use of 
doxorubicin at doses over 50 mg/m2 per cycle (34) when combined with other agents,
and doses over 60 mg/m2 in combination usually require G-CSF support (35).
1.4
INFORMATION ON THE COMBINATION OF PM01183 AND DOXORUBICIN
The in vivo antitumor activity of PM01183 administered alone and in combination with 
doxorubicin was investigated in mice bearing A2780 xenografted tumors (36). 
Treatments administered were: i) placebo; ii) PM01183 at four different dose levels, i.e. 
the maximum tolerated dose (MTD) (0.180 mg/kg), 0.75·MTD, 0.5·MTD and 
0.25·MTD; iii) doxorubicin at four different dose levels, MTD (8 mg/kg), 0.75·MTD, 
0.5·MTD and 0.25·MTD; and, iv) PM01183 plus doxorubicin, administered with the 
combination at (1+1), (0.75+0.75), (0.50+0.50) and (0.25+0.25) of their respective 
MTDs. Doxorubicin was found to induce modest and dose-dependent antitumor activity 
in A2780-bearing animals; tumors were significantly (P < 0.05) smaller with 
doxorubicin than with placebo in all groups, except at the lowest dose level. The 
highest-dosed cohort also showed modest tumor growth delay (TGD), which was 
calculated as 90.0%. Single therapy of PM01183 in mice bearing A2780 xenografts 
resulted in very modest antitumor activity: only animals dosed at the two highest levels 
had tumors significantly (P < 0.05) smaller than placebo-treated mice. However, the 
combination of PM01183 and doxorubicin showed strong and dose-dependent 
antitumor activity: all groups of animals treated with the combination (except the lower) 
showed a highly significant (P < 0.01) reduction of tumor volume compared to placebo-
treated animals. Of note, the group treated at (1+1)·MTD experienced a TGD of 
184.0%. The antitumor effect induced by any treatment (single-agent or combination) 
was analyzed using the median-effect principle (37). The results suggested a synergistic 
combination index (CI), with values 1, in mice bearing ovarian (A2780) xenografted 
tumors.
1.5
STUDY RATIONALE
PM01183 is a new chemical entity with promising in vitro and in vivo cytotoxic activity 
at clinically achievable concentrations. Its mechanism of action and main target is likely 
different to that of doxorubicin. Evidence of synergistic antitumor activity has been
observed in vivo with the combination. Preclinically, a pattern of cytotoxic activity 
overlaps significantly for both compounds, whereas the clinical toxicity of each 
compound does not seem to overlap completely, according to currently available data. 
Therefore, it is feasible to evaluate the safety and efficacy of a combination of 
PM01183 and doxorubicin in non-heavily pretreated candidate patients with advanced 
cancer. 


CL_0111 4.0
Page 38 of 107
Protocol PM1183-A-003-10
The first phase I clinical study revealed that a RD of 7.0 mg for PM01183 when given 
as single-agent as a 1-hour i.v. infusion q3wk (16) was safe, tolerable and mostly 
induced a predictable, manageable and reversible myelosuppression that correlated to 
the drug’s AUC. Based on these results, a dose equivalent to 50% of this RD was 
chosen as a safe starting dose of PM01183 for its combination with doxorubicin. 
Moreover, the targeted non-heavily pretreated patient population (with no more than 
two prior lines of chemotherapy per patient) will adequately represent the median 
treatment lines of those patients already treated in the first study with PM01183 for 
whom tolerance has been excellent. 
The doxorubicin dose of 50 mg/m2/cycle, which is the standard dose for the drug when 
used in combination schedules, will be fixed throughout the study so as to prevent 
undertreatment of patients at potentially inadequate doses. The decision to not escalate 
doxorubicin is well justified in the literature, as higher doses are unlikely to provide 
additional clinical benefit.
The tumor type selection in this study is based on the standard clinical use of 
doxorubicin in solid tumor patients as well as on preclinical evidence of potential 
activity of PM01183. The higher likelihood of clinical benefit in these patients will 
provide a chance for assessing the tolerability and feasibility of the combination 
regimen both in the short and the median term.
1.5.1
Pharmacogenomics Rationale
The antitumor activity of PM01183 is associated with the following cell events, as 
described in Leal et al. (38):
o
PM01183 binds to the minor groove of DNA. This binding occurs in preferred 
GC-rich trinucleotide sequences, preferably AGC. The binding of PM01183 to 
the DNA produces a stabilization of the DNA duplex. This could account for the 
need of the same DNA repair machinery that usually deals with inter-strand 
cross-links and involves proteins from both homologous recombination (HR) 
and nucleotide excision repair (NER) machineries.
o
PM01183 induces DNA DSBs. In fact, treatment of cells with the drug induces 
the formation of foci of -H2AX, which is indicative of the formation of DSBs. 
In addition, treatment of cells with PM01183 leads to cell cycle delay in the S 
phase, activation of the DNA damage checkpoint, and cell death by apoptosis. 
o
PM01183 interferes with DNA repair. Experimental data reveal that the NER 
system is essential to overcome PM01183-induced DNA damage. When the 
pattern of sensitivity to PM01183 was analyzed in a collection of 5,000 haploid 
deletion mutants of the yeast Saccharomyces cerevisiae, Rad13(orthologue of 
human XPG) haploid deletion mutants were found to be more resistant to 
PM01183 than wild-type cells, therefore indicating the dependence of the 
cytotoxic effect of this compound to a functional NER system. XPG is a member 
of the NER system.
Objective of the Pharmacogenomic Study
The experimental data indicate that PM01183 binds to DNA and interferes with NER 
pathway, inducing DSBs and cell death by apoptosis. Thus, it seems of interest to 
conduct studies correlating the tumor/patient and genes/proteins determinant in the 
efficiency/deficiency of the DNA repair pathways and the outcome of patients exposed 


CL_0111 4.0
Page 39 of 107
Protocol PM1183-A-003-10
to PM01183. The ultimate goal is the characterization of such patients who shall be 
prone to respond to PM01183, in order to implement a customized therapy in the future.
Initially the mRNA expression of XPG will be determined in paraffin-embedded tumor 
tissue blocks from consenting patients treated with PM01183 and doxorubicin. 
Depending on the availability and quality of the samples, the RNA expression analysis 
could be extended to other genes involved in the mechanism of action of PM01183 
and/or doxorubicin. In addition, a tissue microarray containing representative sections 
of the patients’ paraffin-embedded tumor tissue blocks will be constructed and analyzed 
for protein expression of the key suppressor gene Topoisomerase II (TopoIIa) and P-
glycoprotein (Pgp) by immunohistochemistry (IHC) using specific antibodies. As for 
RNA, protein expression analyses could be extended to other proteins involved in the 
mechanism of action of PM01183 and/or doxorubicin.
2.
STUDY OBJECTIVES
2.1
PRIMARY

To determine the MTD and the RD of PM01183 in combination with 
doxorubicin in patients with selected advanced solid tumors.
2.2
SECONDARY

To determine the MTD and the RD of PM01183 in combination with 
doxorubicin and primary prophylaxis with G-CSF in patients with selected 
advanced solid tumors (if DLTs of the combination without G-CSF prophylaxis 
are exclusively related to neutropenia).

To characterize the safety profile and feasibility of this combination in patients 
with selected advanced solid tumors.

To characterize the pharmacokinetics (PK) of this combination and to detect 
major drug-drug PK interactions.

To obtain preliminary information on the clinical antitumor activity of this 
combination in non-heavily pretreated selected solid tumor patients.

Based on promising findings, to explore the feasibility, safety and efficacy of a 
potential improvable dose of this combination in selected tumor types [i.e. small 
cell lung cancer (SCLC) and endometrial cancer).

To evaluate the pharmacogenomics (PGx) in tumor samples of patients exposed 
to PM01183 and doxorubicin at the RD in order to assess potential markers of 
response and/or resistance.
3.
OVERALL STUDY DESIGN
Prospective, open-label, dose-ranging, uncontrolled phase I study with escalating doses 
of PM01183 in combination with fixed doses of doxorubicin (see escalation dose 
scheme in Section 3.3).


CL_0111 4.0
Page 40 of 107
Protocol PM1183-A-003-10
Patients will start receiving i.v. doxorubicin 50 mg/m2 (fixed dose) as bolus followed by 
PM01183 3.5 mg FD i.v. over one hour on Day 1 q3wk. A cycle is defined as an 
interval of three weeks.
Cohorts of three to six patients will be included at each dose level (DL). If no DLT 
occurs in more than one patient within each cohort, escalation will proceed to the 
following dose level. If one of the first three evaluable patients experiences a DLT, the 
dose level should be expanded up to six patients. The MTD will be the lowest dose level 
explored during the dose escalation at which more than one evaluable patient experience 
a DLT in Cycle 1. All evaluable patients within a dose level will be followed for at least 
one cycle (i.e., three weeks) before dose escalation may proceed. Dose escalation will 
be terminated once the MTD or the last dose level (DL4) is reached, whichever occurs 
first, except if all DLTs occurring at a given dose level are related to neutropenia (e.g., 
febrile neutropenia, grade 4 neutropenia lasting more than 7 days or neutropenic sepsis) 
in which case dose escalation may be resumed, starting at the lowest dose level where 
exclusively neutropenia-related DLTs have occurred, and will follow the same original 
schedule but with compulsory primary G-CSF prophylaxis. An expansion cohort to 
complete a minimum of nine evaluable patients will be recruited at the immediate lower 
dose level, or at the last dose level (DL4) if the MTD is not defined yet. This level will 
be confirmed as the RD if less than one third of the first nine evaluable patients 
experience DLT during Cycle 1. 
Further to the finding of encouraging antitumor activity in the first 43 evaluable patients 
(13 responses, including four complete responses, with five partial responses in eight 
patients with small cell lung cancer, and one complete and one partial response in three 
patients with endometrial cancer), expansion of the cohort treated at the RD has been 
increased to include approximately 30 additional patients, for a total of around 39 
patients.
In the event of DLTs occurring in the first patient at the first level, the second and third 
patients will be included at least two weeks apart. Otherwise and/or at subsequent dose 
levels, all patients within a dose level may be treated simultaneously. 
Patients treated at the expansion cohort must be evaluable by the RECIST version 1.1 
and/or by serum markers (carbohydrate antigen-125, CA-125) in the case of ovarian 
cancer, as appropriate [according to the Gynecologic Cancer Intergroup (GCIG) specific 
criteria] (see Section 9.7), and must have documented disease progression according to 
any of these criteria. The tumor type(s) that will be eligible to be included in the 
expansion cohort at the RD will be chosen according to the preliminary efficacy 
observed among those previously treated during the escalation phase, and will be 
discussed and agreed between the investigators and the Sponsor.
Intermediate dose levels could be tested on agreement between the Investigator and the 
Sponsor, if deemed appropriate.
Patients will receive PM01183 and doxorubicin until progression, unacceptable toxicity, 
consent withdrawal or while it is considered to be in their best interest. More 
specifically, doxorubicin will be administered in the absence of disease progression or 
unacceptable toxicity until a maximal total cumulative dose of 450 mg/m2 is reached; 
once this dose has been reached, the patients may continue treatment with PM01183 
alone at the established single-agent RD, 7.0 mg FD q3wk. Tumor assessments will be 
done every six weeks while on treatment. After treatment discontinuation, patients will 
be followed every four weeks until resolution or stabilization of all toxicities, if any. 


CL_0111 4.0
Page 41 of 107
Protocol PM1183-A-003-10
Patients discontinuing treatment without progression will be followed every two months
until disease progression, other antitumor therapy, death or the date of study 
termination, whichever occurs first (see Section 5.9).
Antitumor response will be assessed using the RECIST version 1.1 and/or serum tumor 
markers as appropriate (e.g., ovarian cancer markers).
Patients will be evaluated at scheduled visits on three study periods: Pre-treatment, 
Treatment and Follow-up (see Section 5.2).
In addition, a new cohort of 20 evaluable patients with small cell lung cancer (SCLC) 
who failed after first-line standard cytotoxic-containing therapy and at least nine 
evaluable patients with endometrial cancer will be included to further define the 
efficacy, safety and feasibility of a doxorubicin dose adaptation. These patients will be 
treated with doxorubicin at 40 mg/m2 administered as an i.v. bolus/short infusion
followed by PM01183 at 2.0 mg/m2 as a 1-hour i.v. infusion on Day 1 q3wk. The 
administered doses of both PM01183 and doxorubicin will be capped at 2.0 m2 of body 
surface area (BSA) for any patients exceeding this BSA value. Patients in this cohort 
who have received ten cycles of the doxorubicin/PM01183 combination or have to 
discontinue doxorubicin due to a cardiac AE may continue receiving treatment with 
single-agent PM01183 at 2.0 mg/m2 q3wk if patient benefit is perceived according to 
the Investigator. These patients will be followed every three months until death or the 
date of study termination, whichever occurs first.
3.1
PRIMARY ENDPOINT
3.1.1
Determination of MTD and RD
An evaluable patient for the main objective of the study (i.e., the determination of the 
MTD and RD) should have received at least one complete cycle (including observation 
period), except if early discontinuations or missed doses and/or assessments were the 
consequence of drug-related toxicity (excluding hypersensitivity reactions and/or 
extravasations).
As shown in Table 2, a minimum of three patients will be included at each DL. If no 
patients experience a DLT during Cycle 1, the dose will be escalated. If one of three 
patients experiences a DLT, three additional patients will be included at that level. If >1 
evaluable patient during dose escalation at a given DL experience a DLT during Cycle 
1, that DL will be considered the MTD and dose escalation will be terminated, except if 
all DLTs are related to neutropenia exclusively, in which case dose escalation may be 
resumed as originally planned in a new cohort of patients but with compulsory primary 
G-CSF prophylaxis. The DL immediately below the MTD, or DL4 if the MTD is not 
yet defined during dose escalation before the last DL (i.e., DL4) is reached, was to be 
initially expanded up to a minimum of nine evaluable patients. If less than three among 
the first nine evaluable patients treated within the expansion cohort experience a DLT 
during Cycle 1, this DL will be the RD.
Further to the finding of encouraging antitumor activity in the first 43 evaluable patients 
(13 responses, including four complete responses, with five partial responses in eight 
patients with small cell lung cancer, and one complete and one partial response in three 
patients with endometrial cancer), expansion of the cohort treated at the RD has been 


CL_0111 4.0
Page 42 of 107
Protocol PM1183-A-003-10
increased to include approximately 30 additional patients, for a total of around 39 
patients.
Table 2. Determination of the maximum tolerated dose.
No. of  patients 
evaluable* 
for DLT
No. of patients 
with DLTs 
in first cycle
Action
3
0
Escalate DL until 
DL4 is reached
1
Add 3 patients
>1
MTD
6
1
Escalate DL until 
DL4 is reached 
>1
MTD
DL, dose level; DLT, dose-limiting toxicities; MTD, maximum tolerated dose.
* Patients not evaluable for DLT during dose optimization must be replaced.
Decisions on delayed-onset DLTs (i.e., those DLTs occurring after Cycle 1) will be 
individually discussed between the Investigators and Sponsor, and might end affecting 
the definition of the proposed RD for phase II clinical trials.
In the new cohort of patients with SCLC and endometrial cancer after implementation 
of Amendment #3, a patient evaluable for efficacy should have received at least one 
complete cycle (including observation period) and be evaluable as per RECIST, except 
if non-evaluability is due to treatment failure such as drug-related toxicity, death or 
early unequivocal PD outside the central nervous system.  
Definition of Dose-limiting Toxicities
DLTs are defined as adverse events (AEs) and laboratory abnormalities related to the 
study treatment during the first cycle of treatment and fulfilling at least one of the 
criteria outlined below.

Grade 4 neutropenia [absolute neutrophil count (ANC) < 0.5 x 109/l] lasting > 7 
days.

Grade ≥3 febrile neutropenia of any duration or neutropenic sepsis. 

Grade 4 thrombocytopenia (platelet count < 25 x 109/l) or grade 3 with any major 
bleeding episode requiring a platelet transfusion.

Grade 4 alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST)
increase, or grade 3 lasting > 14 days.

Treatment-related grade ≥ 2 ALT or AST increase concomitantly with ≥ 2 times 
the upper limit of normal (ULN) total bilirubin increase and normal alkaline 
phosphatase (AP). 

Grade ≥ 3 creatine phosphokinase (CPK) increase.

Any other grade 3/4 non-hematological AE that is suspected to be related to study 
drug(s), except nausea/vomiting (unless the patient is receiving an optimal anti-
emetic regimen), hypersensitivity reactions, extravasations, grade 3 asthenia 
lasting less than one week, and non-clinically relevant isolated biochemical 


CL_0111 4.0
Page 43 of 107
Protocol PM1183-A-003-10
abnormalities [e.g., isolated increase in gamma-glutamyltransferase (GGT)]. In 
any case, the clinical relevance should be discussed between the Investigators and 
Sponsor’s representatives.

Delay in the administration of Cycle 2 of the combination exceeding 15 days of 
the theoretical date (i.e., Day 22), due to any AEs related to study drug(s).

The following circumstances will be discussed between the Principal Investigator 
and the Sponsor, and the final consensus will be documented:
o DLTs with delayed onset (i.e., that occur after Cycle 1).
3.2
SECONDARY ENDPOINTS
3.2.1
Safety
Patients will be evaluable for safety if they have received at least one partial or 
complete infusion of PM01183. AEs will be graded according to the National Cancer 
Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.
For further details on safety evaluation see Section 9.2.
3.2.2
Pharmacokinetics
PK analyses will be evaluated in plasma by standard non-compartmental methods 
(population compartmental modeling may be performed if appropriate) (see Section 9.6
for PK evaluation).
3.2.3
Efficacy
Although it is not the main objective of this study, antitumor activity will be measured 
according to the RECIST version 1.1 at least six weeks after treatment initiation in all 
patients with measurable disease, or by evaluation of serum tumor markers if applicable 
(e.g., ovarian cancer markers). Patients included at the RD in the expansion cohort must 
be evaluable per RECIST version 1.1 or by evaluation of tumor markers (see Section 
9.7 for efficacy evaluation).
In the new cohort after the implementation of Amendment #3, exploratory assessment 
for progression-free survival (PFS) and overall survival (OS) will be performed.
3.2.4
Pharmacogenomics
PGx will be evaluated from available tumor samples obtained at diagnosis in order to 
determine predictive/prognostic markers of response and/or resistance to PM01183 and 
doxorubicin in those patients that signed the Informed Consent for the PGx study (see 
Section 9.8 for evaluation of PGx).
3.3
DOSE ESCALATION SCHEDULE
Doxorubicin will be given at 50 mg/m² as an i.v. bolus on Day 1 q3wk, which 
corresponds to 100% of its actual RD when combined with other myelosuppressive 
agents. It will not be escalated in this study.
The starting dose (DL1) for PM01183 will be 3.5 mg given as FD on Day 1 q3wk, 
which corresponds to 50% of the RD for this schedule when given as single agent.
The dose escalation schedule is summarized in Table 3.


CL_0111 4.0
Page 44 of 107
Protocol PM1183-A-003-10
Table 3. Dose escalation schedule.
DL
No. of 
patients
Relative DI (%) of 
doxorubicin  / 
PM01183
Dose of doxorubicin
(mg/m2 ) / PM01183 (mg FD) 
on Day 1 q3wk
DL-1
0-6
100 / 42.85
50 / 3.0
DL1
3-6
100 / 50 
50 / 3.5
DL2
3-6
100 / 71.4
50 / 5.0
DL3
3-6
100 / 85.7
50 / 6.0
DL4
3-6
100 / 100
50 / 7.0
The DL-1 level is to be explored only if DL1 is defined as the MTD.
DI, dose intensity; DL, dose level; FD, flat dose.
According to the toxicity observed, intermediate dose levels may be explored if 
considered appropriate by the investigators and the Sponsor. 
Intra-patient dose escalation will not be allowed under any circumstances.
3.3.1
Dose Escalation Meetings
The Sponsor will organize raw data review and discussion (e.g., a teleconference) with 
the phase I investigators on a regular basis as per protocol requirement (e.g., monthly or 
after first patient enrolled at a given dose level has completed the first cycle or when a
dose level cohort has been completed). Prior to the meeting, all relevant safety and 
laboratory data must be collected and sent by the Investigators to the Sponsor’s 
responsible. Investigators must guarantee the accuracy of the information provided 
against the source documents.
At the dose escalation discussion, the clinical course (safety information, including 
DLTs, all grade ≥ 2 toxicity data during Cycle 1, and available PK data) of each patient 
in the ongoing dose cohort will be described in detail. Updated safety data from other 
ongoing patients, including data collected in later treatment cycles, will be also 
discussed. The final decision to escalate dose will be based primarily, although not 
exclusively, on DLT information, but also on a clinical synthesis of all relevant toxicity 
observed (both DLT and non-DLT), treatment-related dose delays, PK and efficacy 
data, when available. The parties must reach a consensus on whether to further escalate 
the dose, or whether to de-escalate or expand recruitment into particular cohorts.
Finally, available slot assignment for the next cohort of patients to be included will also 
be updated during these discussions. The investigators will be responsible for informing 
the Sponsor of any potential candidate patients on screening at that time. The Sponsor 
will immediately update all investigators on slot availability as soon as a screening 
failure is notified.
The Sponsor will document the final agreement or decision adopted per dose level, 
irrespectively of the type of data review implemented in each particular case, and will 
keep the information and all support documents in the trial master file.


CL_0111 4.0
Page 45 of 107
Protocol PM1183-A-003-10
4.
SELECTION OF PATIENTS
Patients must fulfill all the inclusion/exclusion criteria to be eligible for participate in
the study.
4.1
INCLUSION CRITERIA
1) Voluntarily signed and dated written informed consent prior to any specific study 
procedure.
2) Age: between 18 and 75 years (both inclusive).
For patients with SCLC and endometrial cancer included in the new cohort after 
implementation of Amendment #3: age ≥ 18 years.
3) Eastern Cooperative Oncology Group (ECOG) performance status (PS) of ≤ 1 (see 
APPENDIX 1).
For patients with SCLC and endometrial cancer included in the new cohort after 
implementation of Amendment #3: ECOG PS ≤ 2.
4) Life expectancy ≥ 3 months.
5) Patients not previously treated with anthracycline-containing therapy for advanced 
disease (Note: adjuvant therapy with anthracyclines is allowed provided not more 
than 300 mg/m2 of doxorubicin or an equivalent total cumulative dose was 
administered and they did not have to discontinue treatment due to any 
anthracycline-related toxicity, and relapse occurred more than six months after the 
last drug administration).
6) No more than two prior lines of cytotoxic-containing chemotherapy regimens for 
advanced disease.
For patients with SCLC included in the new cohort after implementation of 
Amendment #3: no more than one prior line of cytotoxic-containing chemotherapy 
regimens for advanced disease.
7) Patients with a histologically/cytologically confirmed diagnosis of advanced disease 
of any of the following tumors:
a) Breast cancer (non-candidate for hormone therapy alone: i.e., hormone-
sensitive patients with bone-limited disease).
b) Soft-tissue sarcoma [excluding gastrointestinal stromal tumors (GIST)].
c) Primary bone sarcomas.
d) Epithelial ovarian cancer (including primary peritoneal disease and/or fallopian 
tube carcinomas and/or endometrial adenocarcinomas).
e) Hepatocellular carcinoma (HCC) (non-eligible for liver transplantation and 
Child-Pugh score A only). Elevated alpha-fetoprotein (AFP) levels in a patient 
with known risk factors and radiological findings compatible with HCC do not 
require pathological confirmation.
f)
Gastroenteropancreatic neuroendocrine tumors (GEP-NET).


CL_0111 4.0
Page 46 of 107
Protocol PM1183-A-003-10
g) Small cell lung cancer (SCLC).
h) Gastric cancer.
i)
Bladder cancer.
j)
Adenocarcinoma of unknown primary site (AUKPS).
8) Expansion cohort at the RD:
All patients must have:
a) Measurable disease according to RECIST version 1.1 (see APPENDIX 2);  or 
b) Evaluable disease by serum markers in the case of ovarian cancer (GCIG 
specific criteria) (see APPENDIX 3); and
c) Documented disease progression during or immediately after last therapy
according to any of the aforementioned criteria.
9) New cohort after implementation of Amendment #3:
a) Measurable SCLC or endometrial cancer according to Response Evaluation 
Criteria In Solid Tumors (RECIST) version 1.1;  and 
b) Documented disease progression during or immediately after last therapy 
according to any of the aforementioned criteria.
10) At least three weeks since the last anticancer therapy, including radiotherapy (RT), 
and at least six weeks since nitrosoureas and mitomycin C (systemic). In the case of 
hormone-sensitive breast cancer progressing while on hormone therapy, the latter 
must be either stopped up to one week before or continued during the trial.
11) Adequate bone marrow, renal, hepatic, and metabolic function (assessed ≤ 7 days 
before inclusion in the study):
a) Platelet count ≥ 100 x 109/l, hemoglobin ≥ 9.0 g/dl and ANC ≥ 1.5 x 109/l.
b) AST and ALT ≤ 3.0 x ULN, independently of the presence of liver metastases.
c) AP ≤ 2.5 x ULN (≤ 5 x ULN if disease-related).
d) Total bilirubin ≤ 1.5 x ULN or direct bilirubin ≤ ULN.
e) International Normalized Ratio (INR) < 1.5 (except if patient is on oral 
anticoagulation therapy).
f)
Calculated creatinine clearance (CrCl) ≥ 30 ml/minute (using Cockcroft and 
Gault´s formula; see APPENDIX 4).
g) CPK ≤ 2.5 x ULN.
h) Albumin ≥ 2.5 g/dl.
For patients with SCLC and endometrial cancer included in the new cohort 
after implementation of Amendment #3: albumin ≥ 3.0 g/dl.
12) Recovery to grade ≤ 1 or to baseline from any AE derived from previous treatment 
(excluding alopecia and/or cutaneous toxicity and/or peripheral sensory neuropathy 
and/or asthenia, all grade ≤ 2).


CL_0111 4.0
Page 47 of 107
Protocol PM1183-A-003-10
13) Left ventricular ejection fraction (LVEF) by echocardiogram (ECHO) or multiple-
gated acquisition (MUGA) scan within normal range (according to institutional 
standards).
14) Women of childbearing potential must have a negative serum pregnancy test before 
study entry. Both women and men must agree to use a medically acceptable method 
of contraception throughout the treatment period and for six weeks after 
discontinuation of treatment. Acceptable methods of contraception include 
intrauterine device (IUD), oral contraceptive, subdermal implant and/or double
barrier.
4.2
EXCLUSION CRITERIA
1) Concomitant diseases/conditions:
a) History or presence of unstable angina, myocardial infarction, congestive heart 
failure, or clinically significant valvular heart disease within last year.
b) Symptomatic arrhythmia or any uncontrolled arrhythmia requiring ongoing 
treatment.
c) Ongoing chronic alcohol consumption, or cirrhosis with Child-Pugh score B or
C.
d) Active uncontrolled infection.
e) Known human immunodeficiency virus (HIV) infection.
f)
Myopathy or any clinical situation that causes significant and persistent 
elevation of CPK (> 2.5 x ULN in two different determinations performed one 
week apart).
g) Limitation of the patient’s ability to comply with the treatment or follow-up 
protocol.
h) Any other major illness that, in the Investigator’s judgment, will substantially 
increase the risk associated with the patient’s participation in this study.
2) Symptomatic, 
progressive 
or 
corticosteroids-requiring 
documented 
brain 
metastases or leptomeningeal disease involvement.
3) Men or women of childbearing potential who are not using an effective method of 
contraception as previously described; women who are pregnant or breast feeding.
4) Patients who have had RT in more than 35% of the bone marrow.
This criterion will not apply to patients with SCLC and endometrial cancer 
included in the new cohort after implementation of Amendment #3.
5) History of previous bone marrow and/or stem cell transplantation.
6) Treatment with any investigational product in the period of ≥ 5 half-lives of the 
investigational compound prior to the first infusion.
4.3
PATIENTS FOR THE PHARMACOGENOMIC STUDY
1) Patients with prior available tumor samples who are eligible for the trial will also 
be eligible for the PGx study.


CL_0111 4.0
Page 48 of 107
Protocol PM1183-A-003-10
2) Only patients who voluntarily sign the Informed Consent for the PGx study will 
participate. Refusal to participate in the PGx study will not affect patient 
participation in the clinical study PM1183-A-003-10.
5.
PLAN OF THE STUDY
5.1
DURATION OF THE STUDY (WHOLE POPULATION)
The total duration of the study will be approximately 72 months, including 
approximately a 54-month enrolment period. Consenting patients will be followed until 
disease progression, other antitumor therapy, death, or until the date of study 
termination (clinical cutoff), whichever occurs first.
In the new cohort after the implementation of Amendment #3, consenting patients with 
SCLC and endometrial cancer will be followed until death or the date of study 
termination (clinical cutoff), whichever occurs first.
Planned start date (first patient on study): second quarter (Q2) 2011.
Planned enrolment period: 54 months.
Planned end-of-study date (clinical cutoff): 18 months after the first study dose of the 
last patient or when follow-up of all SCLC and endometrial cancer patients included in 
the cohort after implementation of Amendment #3 has been completed, whichever 
occurs first.
5.2
DURATION OF STUDY AND TREATMENT (PER PATIENT)
Patients will be evaluated at scheduled visits in three study periods:
Pre-treatment: from signature of informed consent to first infusion of study drugs.
Treatment: from first infusion of study drugs to end of treatment (see Section 
5.2.1).
Follow-up: after end of treatment, patients will be followed every four weeks until 
resolution to at least grade 1 or stabilization of all toxicities, if any. Patients who 
finish treatment without disease progression will be followed every two months until 
disease progression, other antitumor therapy, death or until the date of study 
termination (clinical cutoff), whichever occurs first.
In the new cohort after the implementation of Amendment #3, consenting patients 
with SCLC and endometrial cancer will be followed every three months until death or 
the date of study termination, whichever occurs first.
Patients will be considered to be on-study from the signature of the informed consent to 
the end of the follow-up period. Patients will be considered to be on-treatment for the 
duration of their treatment and until the day of end of treatment. 
End of treatment is defined as 30 days after the day of last dose of study drug 
administration (see Figure 2), unless the patient starts a new antitumor therapy or dies 
(whichever occurs first). 


CL_0111 4.0
Page 49 of 107
Protocol PM1183-A-003-10
Figure 2. Study periods.
FUP, follow-up; ICF, informed consent form; PRE TT, pre-treatment; TT, treatment
Patients may withdraw their consent at any time; under this circumstance, no further 
study activities will be conducted on them.
5.2.1
Discontinuations
5.2.1.1 End of Treatment
Treatment discontinuation occurs when an enrolled patient ceases to receive PM01183
regardless of the circumstances. The primary reason for any treatment discontinuation
will be recorded on the patient’s Case Report Form (CRF). By convention, the date of
end of treatment is defined as 30 days after the day of last dose of study drug 
administration (PM01183 treatment discontinuation), start of a new antitumor therapy 
or death (whichever occurs first). 
An end-of-treatment visit will be performed within 30 days (± 7 days) after last dose 
administration, unless the patient starts any subsequent antitumor therapy, in which case 
the end-of-treatment visit should be performed immediately before the start of the new 
therapy (ideally the day before or the same day).
If a patient discontinues treatment, every effort should be made to complete the 
scheduled assessments.
5.2.1.2 Reasons for End of Treatment
Patients will receive the study medications while it is considered to be in their best 
interest. Specifically, treatment will continue until:

Disease progression.

Unacceptable toxicity.

Intercurrent illness of sufficient magnitude to preclude fulfillment of appropriate 
re-treatment criteria and/or safety continuation of the study.
ICF
Cycle
1
Cycle 
n
Cycle 
n+1
Last
dose
End of treatment
(last dose + 30 d)
4 wks
3 wks
3 wks
3 wks
30 days
TT
PRE 
TT
FUP
“On treatment”
“On study”
(ICF to end of FUP)
ICF
ICF
Cycle
1
Cycle
1
Cycle 
n
Cycle 
n
Cycle 
n+1
Cycle 
n+1
Last
dose
Last
dose
End of treatment
(last dose + 30 d)
End of treatment
(last dose + 30 d)
4 wks
3 wks
3 wks
3 wks
30 days
TT
PRE 
TT
FUP
“On treatment”
“On study”
(ICF to end of FUP)


CL_0111 4.0
Page 50 of 107
Protocol PM1183-A-003-10

Patient refusal and/or non compliance with study requirements.

Treatment delay > 15 days due to toxicity (except clear clinical benefit, with the 
Sponsor’s approval).

Requirement of > 2 dose reductions.

Specifically, doxorubicin will be continued before a maximal total cumulative 
dose of 450 mg/m2 has been reached. Thus, a maximum of ten cycles of the 
combination will be administered to patients with SCLC and endometrial cancer 
included in the new cohort after implementation of Amendment #3), in absence 
of disease progression and/or unacceptable toxicity.
Patients discontinuing doxorubicin at any time after Cycle 1 will remain on study as 
long as they continue receiving PM01183. Patients who are withdrawn for any reasons
must not be re-treated in the context of this study at any time. For follow-up activities,
please refer to Section 5.9.
5.2.1.3 Study Discontinuation
Study discontinuation occurs when an enrolled patient ceases to participate in the study, 
regardless of the reason (as detailed under “Follow-up” in Section 5.2). Patients have 
the right to withdraw consent at any time; if this is the case, no further study procedures
should be performed.
The date and reason for study discontinuation will be clearly documented on the 
patient’s CRF. 
5.2.2
Protocol Deviations
A protocol deviation is defined as any departure from what is described in the protocol 
of a clinical trial approved by an Independent Ethics Committee (IEC) and Competent 
Authorities. Therefore, it applies to deviations related to patient inclusion and clinical 
procedures (e.g., assessments to be conducted or parameters to be determined), and also 
to other procedures described in the protocol that concern the Good Clinical Practice 
(GCP) guidelines or ethical issues (e.g., issues related to obtaining the patients’ 
Informed Consent, data reporting, the responsibilities of the Investigator, etc.).
Deviations with no effects on the risk/benefit ratio of the clinical trial (such as minimal 
delays in assessments or visits) will be distinguished from those that might have an 
effect on this risk/benefit ratio, such as:

Deviations that might affect the clinical trial objectives, such as those involving the 
inclusion/exclusion criteria (which could mean that the patient is not eligible for the 
trial) and those having an effect on patient evaluability.

Deviations that might affect the patient’s well-being and/or safety, such as an 
incorrect dosing of the investigational medicinal product (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.


CL_0111 4.0
Page 51 of 107
Protocol PM1183-A-003-10
The Investigators may suggest to the Sponsor the authorization of certain protocol 
deviations, especially if they are related to the inclusion/exclusion criteria or if they may 
have an effect on the evaluability of the patients. 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 detected during the study will be appropriately documented, and 
those considered particularly relevant (i.e., those related to ethical issues, to fulfillment 
of GCP guidelines and with an effect on the risk/benefit ratio) will be notified to the 
pertinent IEC and, if applicable, to the Competent Authorities as established by local 
regulations.
5.3
REPLACEMENT OF PATIENTS
Patients must be replaced if they are not fully evaluable for the assessment of the 
primary endpoint, i.e. if:

They are withdrawn from the study before receiving at least the infusion of both 
drugs on the first day (Day 1) of the first cycle of the scheduled treatment 
(“evaluable cycle”). An evaluable cycle is defined as: doxorubicin followed by 
PM01183 on Day 1 with the corresponding follow-up period of three weeks.

They require RT or other therapeutic procedure within three weeks after the first 
dose, unless they previously had another drug-related AE included in the definition 
of DLT.

There is a protocol violation resulting in an impossibility of concluding anything 
regarding the safety of the study therapy.
In addition, patients with SCLC and endometrial cancer included in the new cohort after 
implementation of Amendment #3 must be replaced if:

They are not evaluable for efficacy as per RECIST for reasons other than treatment 
failure such as drug-related toxicity, death or early unequivocal PD outside the 
central nervous system.  
All replaced patients will be included in the general safety analysis and in the efficacy 
analysis (if appropriate).
5.4
PRE-TREATMENT ASSESSMENTS
During the pre-treatment period, and once the patient has signed the Informed Consent
Form, the Investigator will confirm the patient’s eligibility for the study by conducting 
the assessments summarized in Table 4.
Table 4. Screening period: pre-treatment assessments.
ASSESSMENT
TIME
1. Written 
informed 
consent
Prior to any specific study procedure 
2. PGx study 
informed 
consent
Prior to any specific study procedure 


CL_0111 4.0
Page 52 of 107
Protocol PM1183-A-003-10
ASSESSMENT
TIME
3. Medical 
history and 
clinical 
examination
Medical and cancer history:
o Demographic data (race/ethnicity, age).
o Date of diagnosis of the primary disease.
o Prior 
treatments 
(surgery, 
radiotherapy, 
chemotherapy, immunotherapy), specifying best 
response and date of PD, when available.
o Signs and symptoms.
Complete physical examination, including weight 
and BSA. 
Performance status (ECOG PS; see APPENDIX 1).
Vital signs: heart rate, blood pressure and body 
temperature
Concomitant therapies.
Within 14 days prior to registration. *
4. Laboratory 
tests
Hematology: differential WBC, hemoglobin and 
platelets.
Biochemistry-A: AST, ALT, total bilirubin (and 
direct bilirubin, if total is abnormally elevated), AP, 
LDH, creatinine, glucose, CPK (and CPK-MB 
fraction if total CPK is abnormally high) and serum 
electrolytes (sodium, potassium, chloride).
Biochemistry-B and coagulation:
o Total proteins, albumin, AAGP, total 
cholesterol, LDL, triglycerides, magnesium, 
calcium, CRP, amylase (only at baseline).
o Coagulation tests: PT/INR, PTT.
o Exploratory/validated serum tumor marker as 
clinically indicated: CA-125 (ovarian cancer), 
CEA and/or CA19-9 (gastric cancer), AFP 
(HCC), NSE (NET) and/or CA15-3 (breast 
cancer). **
Within seven days prior to registration.
*
5. Pregnancy 
test
Measurement of beta serum hCG.
Within 14 days prior to registration, if 
applicable.
6. Cardiac 
assessment
ECG. ***
Within seven days prior to registration.
LVEF assessment by ECHO or MUGA.
Within 14 days prior to registration. *
7. Clinical and 
radiological 
tumor 
assessment
Helical contrast-enhanced CT-scan or gadolinium-
enhanced MRI of all measurable/evaluable sites as 
per RECIST version 1.1 (see APPENDIX 2).
Within 28 days prior to registration. *
8. PGx 
Available archived tissue samples will be taken to 
analyze potential markers of sensitivity or resistance 
to study treatment in consenting patients for the PGx 
study.
-
* A +3-day window will be allowed for laboratory procedures, a ±2-week window for radiological procedures, a +24-
hour window for clinical assessments (ECOG, vital signs, ECG, weight, BSA, etc.), and a +2-week window for 
LVEF assessments.
** The analysis of these exploratory tumor markers will be only descriptive, and formal efficacy evaluation will be 
performed according only to RECIST version 1.1 criteria (see APPENDIX 2), and by GCIG criteria (patients with 
ovarian cancer) when applicable (see APPENDIX 3). The analysis will be repeated before starting a new cycle only 
in those patients with abnormally elevated values at baseline.
*** It should allow rhythm definition (at least 30 seconds of duration), and should include assessment of PR interval, 
RR interval, QT interval (raw) and QRS complex duration.
AAGP, alpha-1 acid glycoprotein; AFP, alpha-fetoprotein; ALT, alanine aminotransferase; AP, alkaline phosphatase; 
AST, aspartate aminotransferase; BSA, body surface area; CA19-9 and 15-3, carbohydrate antigen 19-9 and 15-3 
respectively; CEA, carcinoembryonic antigen; CPK, creatine phosphokinase; CRP, C-reactive protein; CrCl, 
creatinine clearance; CT-scan, computed tomography scan; ECG, electrocardiogram; ECHO, echocardiography; 
ECOG, Eastern Cooperative Oncology Group; GCIG, Gynecologic Cancer Intergroup; GGT, gamma-
glutamyltransferase; HCC, hepatocarcinoma; hCG, human chorionic gonadotropin; ß-hCG, beta subunit of human 
chorionic gonadotropin; 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; NET, neuroendocrine tumor; NSE, neuron-specific enolase; PD, progressive disease; PGx, 
pharmacogenomics; PS, performance status; PT, prothrombin time; PTT, partial thromboplastin time; RECIST, 
Response Evaluation Criteria In Solid Tumors; WBC, white blood cells.


CL_0111 4.0
Page 53 of 107
Protocol PM1183-A-003-10
Additional information on the collection and processing of PGx samples will be 
provided in a separate document (“Guide for identification, packaging and shipment of 
Pharmacogenomic samples”).
5.5
PATIENT REGISTRATION
After ensuring that the patient meets all eligibility criteria and has given written 
informed consent, he/she can be registered into the study by contacting the designated 
trial monitor at the Sponsor location and faxing the completed Registration Form. The 
Registration form will be checked and eligibility confirmed by the Sponsor. A patient 
number will be provided to the site of enrolment within one working day. This patient 
number should be used on all future documentation and correspondence referring this 
patient. Regardless of circumstances, the investigators will not be allowed to treat any 
patient before appropriate receipt of the patient’s registration number that confirms the 
Sponsor’s agreement.
A patient who has been treated prior to registration without the Sponsor’s agreement 
documentation will not be considered evaluable for the study and will need to be 
replaced.
Baseline and off-study visit should be completed for patients registered but never 
treated.
5.6
PATIENT RANDOMIZATION
Not applicable.
5.7
EVALUATIONS DURING TREATMENT
The following assessments will be done while the patient is on treatment (Table 5).
Table 5. Evaluations during treatment.
ASSESSMENT
TIME
1. Clinical 
examination
Complete physical examination, including weight 
and BSA. 
Repeat on Day of 1 of Cycle 2 and 
subsequent cycles (always prior to 
treatment infusion). *
Signs and symptoms. 
Repeat on Day 1 of Cycle 2 and 
subsequent cycles (always prior to 
treatment infusion). *
Performance status (ECOG PS; see APPENDIX 
1).
Repeat on Day 1 of all cycles (always 
prior to treatment infusion). *
Vital signs: heart rate, blood pressure and body 
temperature.
Repeat on Day 1 of all cycles (always 
prior to treatment infusion). *
Concomitant therapies.
Throughout the “on treatment” period. **
2. Laboratory 
tests
Hematology: differential WBC, hemoglobin and 
platelets.
Biochemistry-A: AST, ALT, total bilirubin (and 
direct bilirubin, if total is abnormally elevated), AP, 
LDH, creatinine, glucose, CPK (and CPK-MB 
fraction if total CPK is abnormally high) and serum 
electrolytes (sodium, potassium, chloride).
Repeat on Days 8 and 15 of Cycle 1 and 
on Day 1 (always prior to treatment 
infusion) * and Day 10 (± 3 days) of all 
subsequent cycles 
If any suspected or possible treatment-
related NCI-CTCAE grade ≥ 3 toxicity 
occurs, the abnormal test(s) should be re-
assessed at least every 2-3 days until 
recovery to at least grade 1.


CL_0111 4.0
Page 54 of 107
Protocol PM1183-A-003-10
ASSESSMENT
TIME
In the event of febrile neutropenia of any 
grade, grade 4 neutropenia and/or grade 4 
thrombocytopenia, re-assessment should 
be performed daily until recovery to at 
least grade 3 and/or until 24 hours after 
fever resolution, if applicable, and then 
every 2-3 days thereafter until recovery to 
at least grade 1.
Biochemistry-B and coagulation:
o Total proteins, albumin, calcium, CRP.
o AAGP,  total cholesterol, LDL, triglycerides, 
magnesium, amylase (only if clinically 
indicated).
o Coagulation tests: PT, PTT, INR.
o Repeat only the same serum tumor marker that 
was abnormally elevated at baseline, if
applicable: CA-125 (ovarian cancer), CEA 
and/or CA19-9 (gastric cancer), AFP (HCC), 
NSE (NET) and/or CA15-3 (breast cancer). 
***
Repeat on Day 1 of Cycle 2 and 
subsequent cycles (always prior to 
treatment infusion). *
If any suspected or possible treatment-
related NCI-CTCAE grade ≥ 3 toxicity 
occurs, the abnormal test(s) should be re-
assessed at least every 2-3 days until 
recovery to at least grade 1.
3. Pregnancy 
test
Measurement of beta serum hCG.
Repeat if applicable.
4. Cardiac 
assessment
ECG. ****
LVEF assessment by ECHO or MUGA.
Repeat at the time of doxorubicin 
discontinuation and whenever is clinically 
indicated. *****
5. Clinical and 
radiological 
tumor 
assessment
Helical contrast-enhanced CT-scan or gadolinium-
enhanced MRI of all measurable/evaluable sites as 
per RECIST version 1.1 (see APPENDIX 2).
Every six weeks. *. 
The method should be always the same 
throughout the study for each individual 
patient.
6. PK sampling
As in Section 6.
Immediately before, during and after the 
infusions administered on Day 1 of Cycle 
1.
7. Adverse 
events
As per NCI-CTCAE, version 4.
Throughout the “on treatment” period. **
* A +3-day window will be allowed for laboratory procedures, a ±2-week window for radiological procedures, a +24-
hour window for clinical assessments (ECOG, vital signs, ECG, weight, BSA, etc.), and a +2-week window for 
LVEF assessments. 
** “On treatment period” = from first infusion of study drugs to end of treatment [30 days after the day of last dose of 
study drug administration, unless the patient starts a new antitumor therapy or dies (whichever occurs first), in which 
case the date of administration of this new therapy or the date of death will be considered the date of end of 
treatment].
*** The analysis of these exploratory tumor markers will be only descriptive, and formal disease evaluation will be 
performed according only to RECIST version 1.1 criteria (see APPENDIX 2), and by GCIG criteria (patients with 
ovarian cancer) when applicable (see APPENDIX 3).
**** It should allow rhythm definition (at least 30 seconds of duration), and should include assessment of PR 
interval, RR interval, QT interval (raw) and QRS complex duration.
***** To be repeated in patients in no acute distress within three weeks of the last doxorubicin dose ± 1 week.
AAGP, alpha-1 acid glycoprotein; AFP, alpha-fetoprotein; ALT, alanine aminotransferase; AP, alkaline phosphatase; 
AST, aspartate aminotransferase; BSA, body surface area; CA19-9 and 15-3, carbohydrate antigen 19-9 and 15-3 
respectively; CEA, carcinoembryonic antigen; CPK, creatine phosphokinase; CRP, C-reactive protein; CrCl, 
creatinine clearance; CT-scan, computed tomography scan; ECG, electrocardiogram; ECHO, echocardiography; 
ECOG, Eastern Cooperative Oncology Group; GCIG, Gynecologic Cancer Intergroup; GGT, gamma-
glutamyltransferase; HCC, hepatocarcinoma; hCG, human chorionic gonadotropin; ß-hCG, beta subunit of human 
chorionic gonadotropin; 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; NCI-CTCAE, National Cancer Institute Common Terminology Criteria for Adverse Events; NET, 
neuroendocrine tumor; NSE, neuron-specific enolase; PD, progressive disease; PGx, pharmacogenomics; PK, 
pharmacokinetics; PS, performance status; PT, prothrombin time; PTT, partial thromboplastin time; RECIST, 
Response Evaluation Criteria In Solid Tumors; WBC, white blood cells.


CL_0111 4.0
Page 55 of 107
Protocol PM1183-A-003-10
5.8
EVALUATIONS AT END OF TREATMENT
The end-of-treatment visit will be scheduled within 30 days after the day of last dose of 
study drug administration, unless the patient starts a new antitumor therapy, in which 
case the end-of-treatment visit should be performed immediately before the start of the 
new therapy (ideally the day before or the same day).
Evaluable patients, regardless of the reason for ending the treatment, will have to 
undergo at the end of treatment the same workup conducted before study entry; a ±7-
day window will be allowed to conduct these assessments. These will include the 
following:

Signs and symptoms.

Complete physical examination (including weight and BSA).

ECOG performance status.

Vital signs (heart rate, blood pressure, body temperature).

Concomitant therapies.

Hematology.

Biochemistry-A.

Biochemistry-B and coagulation.

Electrocardiogram (only in patients who did not receive single-agent PM01183 
after discontinuing doxorubicin).

LVEF assessment by ECHO or MUGA (only in patients who did not receive 
single-agent PM01183 after discontinuing doxorubicin). 

Adverse events. 
These evaluations will only have to be repeated for those parameters for which no 
measurement is available at one week + 3 days before the end-of-treatment visit, or for 
those parameters with values that are out of range in the last assessment (grade > 1 
according to NCI-CTCAE version 4).
Adverse events must be reported for 30 days after the last study drug administration. All 
serious adverse events (SAEs) occurring within 30 days of the last study drug 
administration will be reported. Beyond this period of time, only those suspected to be 
treatment-related SAEs will be reported (Section 9.3.2).
The Sponsor will evaluate all safety information that is spontaneously reported by an
Investigator beyond the time frame specified in the protocol.
5.9
FOLLOW-UP AFTER END-OF-TREATMENT VISIT
The date and reason of the study discontinuation will be recorded on the patient’s CRF 
(see Section 5.2.1.1).
Patients who discontinue treatment without disease progression will be followed every 
two months until disease progression, other antitumor therapy, death or until the date of 
study termination, whichever occurs first.


CL_0111 4.0
Page 56 of 107
Protocol PM1183-A-003-10
In the new cohort after the implementation of Amendment #3, patients with SCLC and 
endometrial cancer will be followed every three months until death or the date of study 
termination, whichever occurs first.
The end-of-study date (clinical cutoff) is defined as 18 months after the first study dose 
of the last patient or when follow-up of all SCLC and endometrial cancer patients 
included in the cohort after implementation of Amendment #3 has been completed, 
whichever occurs first.
All AEs suspected to be related to study drugs must be followed after the end of 
treatment until the event or its sequel resolve or stabilize at a level acceptable to the
Investigator and the clinical monitor or his/her designated representative. After the end 
of treatment, patients will be followed every four weeks until resolution or stabilization 
of toxicities, if any.
Patients who withdraw consent will not be followed with any study procedures. 
Additional parameters and/or increased frequency of observations should be performed 
at the Investigator’s discretion and according to the nature of the observed AEs. When 
available, autopsy data should be provided in case of death.
6.
PHARMACOKINETICS
All patients included in the study will be sampled for PK analysis. Before, during and 
after the infusion on Day 1 of the first cycle, 16 blood samples will be collected at the 
time points detailed in Table 6 for the determination in plasma of PM01183 and 
doxorubicin. A total volume of 120 ml of whole blood will be extracted.
Table 6. Sampling schedule for the determination of PM01183 and doxorubicin.
Sample 
number
Day
Absolute time (h)
from the doxorubicin
administration
Sampling time
for doxorubicin
Sampling time 
for PM01183
#1
1
0
Preinfusion
Preinfusion
#2
1
0.0833
5 min after EOA
-
#3
1
0.5
30 min after EOA
30 min before EOI
#4
1
1
55 min after EOA
5 min before EOI
#5
1
1.5
1.5 h after EOA
30 min after EOI
#6
1
2
2 h after EOA
1 h after EOI
#7
1
2.5
2.5 h after EOA
1.5 h after EOI
#8
1
3
3 h after EOA
2 h after EOI
#9
1
4
4 h after EOA
3 h after EOI
#10
1
5
5 h after EOA
4 h after EOI
#11
1
6
6 h after EOA
5 h after EOI
#12
1
8
8 h after EOA
7 h after EOI
#13
2
24*
24 h after EOA
23 h after EOI
#14
3
48*
48 h after EOA
47 h after EOI
#15
5
96**
96 h after EOA
95 h after EOI
#16
8
168**
-
167 h after EOI
EOA: End of administration. EOI: End of infusion. 
* There is a ±3 hour flexibility in sampling times.
** There is a ±24 hour flexibility in sampling times to avoid weekends and sampling on holidays, but the sample 
should be obtained with a difference of at least 24 hours vs. the previous and the next samples.


CL_0111 4.0
Page 57 of 107
Protocol PM1183-A-003-10
The sampling times may be changed while maintaining or decreasing the total number 
and volume of samples, if information obtained during evaluation allows improvement 
of the schedule.
The accurate recording of actual dosing and sampling times is much more important 
than strict adherence to the scheduled times.
Samples intended for the measurement of doxorubicin will have a volume of 4 ml, those 
intended for PM01183 will have a volume of 4 ml, while those intended for both drugs 
will have a volume of 8 ml. All vacuum tubes will have a total volume of 9 ml, 
furthermore they will need to be filled with 4 or 8 ml of blood depending on the drugs to 
be measured.
The exact recording of the time of drug administration and sampling times during 
infusions is crucial. Patients will start receiving i.v. doxorubicin as bolus followed by 
PM01183, i.v. over one hour on Day 1 q3wk. Drugs will be infused at a constant rate 
throughout the corresponding period. In order to obtain reliable PK information, the 
infusion rate should not be modified once infusion begins. If a variation in the infusion 
time eventually occurs, it is very important to record this on the CRF, writing clearly the 
time of the beginning and the end of the infusion. If the infusion needs to be stopped, 
the reason and relationship to study product should be documented on the CRF, as well 
as the time of stopping and re-initiation of infusion if applicable. PK sampling will then 
be modified according to current end of infusion (EOI) time and not to the one 
originally scheduled. The infusion rate should not be changed to maintain the scheduled 
duration of infusion. It is enough to simply record the actual duration on the CRF and 
on the PK sampling sheet.
Blood samples for PK analysis will be obtained through a peripheral vein located in the 
contralateral side to that of the infusion. 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 (ml) 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.
The Instruction Manual for the Collection, Labeling, Storage and Shipment of 
Pharmacokinetic Samples describes in detail the procedures. Please, read carefully all 
the procedures before PK days. In summary, after the collection of each sample, the 
sample will be centrifuged and the plasma layer transferred into a single tube for the 
determination of doxorubicin or PM01183, or split into two tubes for the determination 
of PM01183 and doxorubicin. The plasma tubes will be stored under frozen conditions 
until shipment to the analysis laboratory. All the PK material will be provided by 
Pharma Mar S.A.
Once all samples from a patient have been collected, they should be shipped to the 
central laboratory for PK analysis 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 moment the last PK sample for a 
patient has been collected and the shipment of all the samples from this patient to the 
central laboratories should not exceed one month.


CL_0111 4.0
Page 58 of 107
Protocol PM1183-A-003-10
Sampling PK sheets should be sent at the same time, but never in contact with dry ice. 
Samples will be identified with the following data: study reference, drug, patient 
number, sample number, 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 
Sponsor.
7.
PHARMACOGENOMICS
The objective of this pharmacogenomic study is to evaluate the role of potential markers 
of sensitivity to treatment in a population of advanced cancer patients treated with 
PM01183 combined with doxorubicin.
For those patients who consent to participate in the PGx study, response to therapy will 
be correlated with the RNA/protein expression levels of the selected genes. Tumor 
tissue blocks used for the initial diagnosis of the disease will be collected during his/her 
participation in the associated clinical trial. Provision of samples for such PGx analyses 
will be optional and performed upon patient consent by signing the PGx informed 
consent form (ICF).
These analyses will include the use of transcriptional profiling technologies and other 
molecular biology techniques to identify and validate PGx markers from pre-treatment 
tumor samples. The basal expression levels of these markers will be correlated with the 
patient’s response outcome data. In addition, the experimental data will be analyzed 
with respect to duration of response and time to disease progression.
Experimental Methods
The experimental data indicate that PM01183 binds to DNA and interferes with the 
NER pathway, therefore inducing DSBs and cell death by apoptosis. It seems thus of 
interest to conduct studies correlating the tumor/patient and genes/proteins determinant 
in the efficiency/deficiency of the DNA repair pathways and the outcome of patients 
exposed to PM01183. The ultimate goal is the characterization of such patients who
shall be prone to respond to PM01183 in order to implement a customized therapy in 
the future.
This PGx substudy will be focused on the expression of XPG mRNA (a key gene in the 
NER pathway), which has previously been correlated to the sensitivity/resistance to 
other DNA binders, such as trabectedin and platinum compounds. In addition, a tissue 
microarray containing representative sections of the patients’ paraffin-embedded tumor 
tissue blocks will be constructed and analyzed for protein expression of TopoIIa (a gene 
directly related with the mechanism of action of doxorubicin) and Pgp (MDR1, a 
detoxifying pump responsible for resistance to multiple antitumor drugs).
The mRNA expression of XPG in the patients’ paraffin-embedded tumor tissue will be 
determined by quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR), 
and the p53 protein expression by IHC using the corresponding antibodies.
The analytical methods required for this molecular characterization analysis are 
described in a separate document. Briefly, the required tumor tissue samples are 5-m 
slices of paraffin-embedded tumor tissue from patients treated with PM01183 and 


CL_0111 4.0
Page 59 of 107
Protocol PM1183-A-003-10
doxorubicin and mounted on laser microdissection microscopy slides. The tumor tissue 
will be microdissected, the total RNA will be extracted and the mRNA expression of the 
selected genes will be quantitated by qRT-PCR using gene-specific primers.
In addition, the same samples used in the mRNA expression analysis will be studied at 
the protein level in tissue microarrays for determining the protein expression of TopoIIa 
and Pgp. Briefly, cylinders from the paraffin-embedded tissue blocks will be cut and 
arrayed in a new paraffin block to allow the simultaneous determination of the 
expression of proteins by IHC using adequate antibodies. Hence, the expression of 
several proteins and their histological location may be analyzed and correlated in a 
technical setting more familiar for the Pathology departments. 
Both analyses will be done at the Central Laboratories for PGx samples (see Study 
Contacts). The gene expression profiling (GEP) and IHC analysis will be done at 
baseline conditions, i.e. using the tumor tissue obtained at the diagnosis of the disease.
The level of mRNA expression of these genes and their corresponding protein products 
will be used to evaluate their utility in making clinical predictions. Genes which
expression is most highly correlated to clinical outcome will be considered candidate 
markers. Candidate markers must be validated in at least one independent technology 
and in an independent population in order to be considered potentially useful in making 
clinical decisions. 
In those patients responding to treatment, Myriads Genetics Homologous 
Recombination Deficiency (HRD) assay, including analysis of BRCA1 mutation 
status, will be performed, if considered relevant.
The Sponsor will provide a Charter document detailing the procedures to be followed
for sample collection, labeling and shipment.
8.
TREATMENT
8.1
DESCRIPTION OF TREATMENT
8.1.1
Drug Formulation and Supply
8.1.1.1 PM01183
PM01183 is presented as a lyophilized powder for concentrate for solution for infusion
with two strengths: 1 mg/vial and 4 mg/vial.
Before use, the 1-mg vial and 4-mg vial should be reconstituted with 2 ml and 8 ml of 
sterile water for injection, respectively, to give a solution containing 0.5 mg/ml of
PM01183. For administration to patients as i.v. infusion, reconstituted vials will be 
diluted with glucose 50 mg/ml (5%) solution for infusion or sodium chloride 9 mg/ml 
(0.9%) solution for infusion. 
The full composition of the PM01183 1-mg and 4-mg vials and the reconstituted 
solution per ml are summarized in Table 7.


CL_0111 4.0
Page 60 of 107
Protocol PM1183-A-003-10
Table 7. Composition of PM01183 vials and the reconstituted solution.
Component
PM01183
1 mg
PM01183
4 mg
Concentration per 
vial after 
reconstitution
PM01183
1.0 mg
4.0 mg
0.5 mg/ml
Sucrose
200 mg
800 mg
100 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, 
accountability and disposal, please refer to the Preparation Guide for PM01183 and the 
PM01183 Investigator’s Brochure (IB), both provided as separate documents.
8.1.1.2 Doxorubicin
Commercially available presentations of vials containing doxorubicin will be provided 
as appropriate.
8.2
ADMINISTRATION OF STUDY MEDICATION
Patients will consecutively receive the following on Day 1 q3wk (three weeks = one 
treatment cycle):

Doxorubicin: i.v. infusion of a total volume of 20 ml dilution on 0.9% saline or 
5% dextrose, on a short i.v. bolus at a dose of 50 mg/m2 (fixed dose), via a central 
or peripheral venous catheter after appropriate visual confirmation of effective 
venous blood return through the line, immediately followed by:

PM01183: i.v. infusion over one hour at a starting dose of 3.5 mg (FD), over a 
minimum of 100 ml dilution on 5% glucose or 0.9% sodium chloride via a central 
line (or a minimum of 250 ml dilution if a peripheral line will be used), through a 
pump device.
Information on dose escalation may be found in Section 3.3.
New cohort after implementation of Amendment #3:
Patients with SCLC and endometrial cancer will consecutively receive the following 
on Day 1 q3wk (three weeks = one treatment cycle):

Doxorubicin: i.v. bolus/short infusion at a dose of 40 mg/m2, administered as 
described above, immediately followed by:

PM01183: i.v. infusion over one hour at a dose of 2.0 mg/m2, administered as 
described above.
Both doxorubicin and PM01183 doses will be capped at 2.0 m2 of BSA for individuals 
exceeding this BSA value. Doses will have to be recalculated for patients showing a ≥ 
10% change in total body weight value compared to previous cycle.  
Doses will be rounded to the first decimal.


CL_0111 4.0
Page 61 of 107
Protocol PM1183-A-003-10
8.3
CRITERIA FOR TREATMENT CONTINUATION 
Patients will be treated with additional cycles of PM01183 combined with doxorubicin
as long as no unacceptable toxicity and/or progression of the disease and/or withdrawal 
of consent occurs (see Section 5.2.1). 
Complete blood counts, blood chemistries and other tests will be done prior to starting 
the next infusion (please refer to Section 5.4 and Section 5.7 for the full list of tests to 
be done before first study drug administration and/or further treatment cycles).
Table 8 lists the minimum requirements needed to re-expose the patient to the treatment 
schedule. Other factors might be considered critical by the Investigator. In this case, 
these factors should be appropriately documented in the patient’s record and on the 
CRF, and discussed with the Sponsor. 
The administration of a new cycle should be delayed if the criteria shown in Table 8 are 
not met on the corresponding Day 1 of the next administration, with parameters being 
reevaluated at minimum intervals of 48 hours. The new cycle will start upon recovery of 
these parameters.
A maximum delay of 15 days will be allowed for recovery from drug-related AEs. If 
recovery has not occurred after a 15-day delay, the patient should discontinue the 
treatment, except in case of obvious patient benefit at the criteria of the Investigator and 
upon agreement with the Sponsor.
After delaying doses due to drug-related toxicity (except for neutropenia exclusively) 
exceeding the 15-day delay, or in patients who experience a DLT, treatment may only 
continue after appropriate dose reduction of PM01183, appropriate secondary 
prophylaxis with G-CSF (when due to neutropenia exclusively), or doxorubicin 
interruption (i.e., due to cardiac toxicity or maximal cumulative dose reached) (see 
Section 8.4).
In order to avoid unnecessary administrative delays, patients who undergo radiological 
tumor assessment but the results of which are still pending on the due date of 
retreatment may exceptionally receive their scheduled infusions without any delays, in 
the absence of clinical PD and provided all retreatment criteria are otherwise met. 
However, if PD is observed radiologically once the results are available, treatment will 
be immediately discontinued and the date of PD will be the day when the radiological 
assessment was originally performed.
Table 8. Criteria for continuation of treatment.
Variable
PM01183
Doxorubicin
Day 1
Day 1 
ANC 
1.5 x 109/l
1.5 x 109/l
Platelets
100 x 109/l
100 x 109/l
Hemoglobin
9 g/dl
9 g/dl
Total bilirubin
(or direct bilirubin)
1.5 x ULN
(ULN)
1.5 x ULN
(ULN)
AST/ALT
3.0 x ULN
3.0 x ULN
Albumin
≥ 3.0 g/dl.
≥ 3.0 g/dl.
ECOG PS
0-2
0-2


CL_0111 4.0
Page 62 of 107
Protocol PM1183-A-003-10
Variable
PM01183
Doxorubicin
Day 1
Day 1 
Calculated CrCl 
(Cockcroft and Gault’s formula)
≥ 30 ml/min
≥ 30 ml/min 
Muscular toxicity 
(myalgia, muscular weakness, CPK increase)
Grade ≤ 1
Grade ≤ 1
Other non-hematological drug-related AEs 
(except increased GGT, not optimally treated nausea and 
vomiting, alopecia, asthenia and/or neuropathy) a
Grade ≤ 1
Grade ≤ 1
Mucositis
Grade ≤ 1
Grade ≤ 1
Signs and/or symptoms of CHF
-
No
Current cumulative doxorubicin-equivalent dose 
< 400 mg/m2 b
-
Yes
If a patient does not meet the requirements for treatment continuation (excluding cardiac toxicity 
and/or maximal doxorubicin cumulative dose) on Day 1 of further cycles, both drugs (PM01183 and 
doxorubicin) infusions will be withheld until recovery for a maximum of 15 days after the 
theoretical treatment date. If recovery has not occurred after a delay of > 15 days, the patient must 
be withdrawn from the trial, except in case of perceived clinical benefit from the Investigator and 
upon agreement with the Sponsor.
If a patient does not meet the requirements for treatment continuation due to cardiac toxicity and/or 
maximal doxorubicin cumulative dose, doxorubicin will be permanently discontinued and treatment 
may continue with PM01183 alone at its single-agent RD, 7.0 mg FD q3wk, without any delay if 
clinically appropriate.
a
Any grade accepted for increased GGT. Up to grade 2 for alopecia, nausea, vomiting, 
neuropathy and asthenia. 
b
The total doxorubicin cumulative dose received by each patient must never reach > 450 mg/m2.
AEs, adverse event(s); ALT, alanine aminotransferase; ANC, absolute neutrophil count; AP, 
alkaline phosphatase; AST, aspartate aminotransferase; CHF, congestive heart failure; CPK, 
creatine phosphokinase; CrCl, creatinine clearance; ECG, electrocardiogram; ECOG PS, Eastern 
Cooperative Oncology Group performance status; FD, flat dose; GGT, gamma-glutamyltransferase; 
RD, recommended dose; ULN, upper limit of normal; q3wk, every three weeks.
8.4
DOSE REDUCTION
Patients will continue treatment at the same dose level as long as they did not 
experience a DLT(s) and/or infusion delays due to toxicity during the preceding cycle 
and they continue to meet the criteria for re-treatment. 
Treatment after DLT, a treatment-related infusion delay greater than 15 days, or a 
toxicity considered as unacceptable by the investigators may continue, after appropriate 
dose reduction, only if there is clear evidence of objective patient benefit. This will 
always be discussed with the Sponsor. Under this circumstance, and following recovery 
to pre-specified re-treatment criteria, patients will be re-treated at the immediately 
lowest dose level. If dose reduction beyond DL-1 is required, the dose of PM01183 may 
be reduced by an additional 0.5 mg (FD).
Up to two individual dose reductions will be allowed per patient; any patients requiring 
more than two dose reductions will be withdrawn from the study. Once the dose has 
been reduced for an individual patient, it will not be re-escalated again under any 
circumstances. 
Patients requiring dose reduction exclusively due to grade 4 neutropenia or any grade 
febrile neutropenia that occurred during the preceding cycle may receive secondary 
prophylaxis with G-CSF instead of a dose reduction. If toxicity re-occurs despite G-CSF 
use, dose reduction will then be implemented.


CL_0111 4.0
Page 63 of 107
Protocol PM1183-A-003-10
Patients who reach a maximal cumulative dose of 450 mg/m2 of doxorubicin or have to 
discontinue doxorubicin due to a cardiac AE may continue receiving treatment with 
PM01183 (after Cycle 1) at the single-agent RD (7 mg FD q3wk) if patient benefit is 
perceived. These patients do not need to be replaced.
Patients who may require thoracic RT for pain palliation after Cycle 1 may continue 
treatment with PM01183 alone at its single-agent RD (7.0 mg FD q3wk), after a 
minimum doxorubicin washout period of three weeks and without any dose adjustments 
if patient benefit is perceived; these patients do not need to be replaced.
New cohort after implementation of Amendment #3:
Patients with SCLC and endometrial cancer included in the new cohort after 
implementation of Amendment #3 who require dose reduction due to the reasons 
described above will be re-treated at the following dose levels: 

DL-1: Doxorubicin 40 mg/m2 + PM01183 1.5 mg/m2.

DL-2: Doxorubicin 30 mg/m2 + PM01183 1.5 mg/m2.
Up to two sequential dose reductions will be allowed per patient; any patients requiring 
more than two dose reductions will be withdrawn from the study, except if there is 
objective clinical benefit or upon the Sponsor’s agreement. Once the dose has been 
reduced for an individual patient, it will not be re-escalated again under any 
circumstances.
Patients included in this cohort who have received ten cycles of the 
doxorubicin/PM01183 combination or have to discontinue doxorubicin due to a cardiac 
AE may continue receiving treatment with single-agent PM01183 at 4.0 mg/m2 q3wk if 
patient benefit is perceived. These patients do not need to be replaced.
Patients treated with single-agent PM01183 who require dose reduction due to the 
reasons described above will have their dose reduced by 25%. Up to two sequential 
dose reductions will be allowed per patient; any patients requiring more than two dose 
reductions will be withdrawn from the study, except if there is objective clinical benefit 
or upon the Sponsor’s agreement.
8.5
CONCOMITANT MEDICATION
All tumor-specific prior chemotherapy, radiation therapy and all relevant information 
must be recorded on the patient's CRF.
In addition, reasonable efforts will be made to determine all treatments received by the 
patient during administration of the study drugs. This information must be documented 
in the concomitant therapy Section of the CRF.
8.5.1
Prophylactic Medication
All patients must receive the following prophylactic medication 20-30 minutes before 
infusion of any study drug:
Dexamethasone 8 mg i.v. or equivalent,
Ondansetron 8 mg i.v. or equivalent, with or without:
- Metoclopramide 10 mg i.v. or equivalent, and/or


CL_0111 4.0
Page 64 of 107
Protocol PM1183-A-003-10
Extended oral dexamethasone not exceeding 20 mg/days and/or oral ondansetron 
4 to 8 mg or equivalent, at the investigator’s criteria if required.
Additional antiemetics might be used, if required.
If primary G-CSF prophylaxis is required in specific cohorts of patients, it will 
consist of: 
- G-CSF (non-pegylated filgrastim) at 300 μg/day subcutaneously for five 
consecutive days, starting on Day +3.
8.5.2
Allowed Medications/Therapies
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 American Society of Clinical Oncology 
(ASCO) guidelines (39) will be allowed.
Erythropoietin use according to ASCO guidelines (40) will be allowed.
Hormone-responsive breast cancer patients [i.e., those whose tumors express 
estrogen receptor (ER) and/or progestogen receptor (PrR)] may continue receiving 
their same prior hormonal therapy without interruption throughout their study 
participation.
Luteinizing hormone-releasing hormone (LHRH) agonists in women
of 
reproductive age.
Palliative local radiation (excluding thorax and mediastinum) may be applied if 
needed after the first cycle of study treatment is completed. Any lesion within the 
irradiated area will then not be considered an area of measurable/evaluable 
disease. Thorax and mediastinum may be irradiated, if required, after a minimum 
of three weeks of doxorubicin discontinuation.
Megestrol acetate for appetite stimulation is also allowed.
8.5.3
Prohibited Medications/Therapies
Concomitant administration of any other antineoplastic therapy is prohibited, 
other than the aforementioned hormonal therapy for breast cancer.
Other investigational agents.
Aprepitant or directly related substances (e.g., fosaprepitant).
Immunosuppressive therapies, other than corticosteroids. 
Primary prophylaxis and/or treatment with colony-stimulating factors such as G-
CSF and granulocyte/macrophage colony stimulating factor (GM-CSF) during 
Cycle 1, (except if patient(s) is/are treated within an specific cohort resuming dose 
escalation with primary G-CSF prophylaxis, in which case use is not only allowed 
but compulsory). Secondary prophylaxis might be allowed, if required, during the 
following cycles, instead of a dose reduction due to exclusively hematological 
reasons and upon Sponsor agreement.


CL_0111 4.0
Page 65 of 107
Protocol PM1183-A-003-10
Note: G-CSF treatment for non-febrile uncomplicated neutropenia during Cycle 1 
and primary G-CSF or GM-CSF prophylaxis will not be allowed in patients with 
SCLC and endometrial cancer  included in the new cohort after implementation of 
Amendment #3.
Thoracic and/or mediastinal irradiation concomitant with doxorubicin therapy.
8.5.4
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.
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.
A list of commonly prescribed drugs that are substrates for these enzymes is provided 
in APPENDIX 5.
8.5.5
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 Sponsor will be properly destroyed at the study site. 
Documentation of this procedure must be provided to the clinical trial monitor. If the 
Sponsor agrees, unused drug supplies may be returned to the drug repository.
8.6
TREATMENT COMPLIANCE
The Investigator is responsible for supervising compliance with the instructions 
described in this study protocol.


CL_0111 4.0
Page 66 of 107
Protocol PM1183-A-003-10
9.
STUDY EVALUATIONS
9.1
DETERMINATION OF MTD AND RD
The definition of the MTD and the RD may be found in Section 3.1.1.
9.2
SAFETY
Patients will be evaluable for safety if they have received at least one partial or 
complete infusion of PM01183. AEs will be graded according to the NCI-CTCAE 
version 4.
The evaluation period for individual patients should include observations since start of 
the treatment until 30 days after the last administration of study drug. Any previous 
drug-related AEs must be followed until recovery to at least grade 1 or stabilization, if 
present after end of treatment.
9.3
ADVERSE EVENTS DEFINITIONS
9.3.1
Adverse Event (AE)
An AE is any untoward medical occurrence in a patient or clinical investigation patient 
administered a pharmaceutical product which does not necessarily have a causal 
relationship with this treatment. 
An AE can therefore be any unfavorable and unintended sign, (e.g., an abnormal 
laboratory finding), or a disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product.
Illnesses with onset during the study or exacerbations of pre-existing illnesses, including
but not limited to clinically significant changes in physical examination findings and 
abnormal objective 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
(see definition below), and/or
The test result is considered to be an AE by the Investigator.
9.3.2
Serious Adverse Event (SAE)
A SAE is any adverse experience occurring at any dose that:
Results in death (is fatal),
Is life-threatening,
Requires or prolongs inpatient hospitalization,
Results in persistent or significant disability or incapacity,


CL_0111 4.0
Page 67 of 107
Protocol PM1183-A-003-10
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.
9.3.3
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 by the Sponsor.
9.3.4
Life-threatening Event
Any event in which the patient was at risk of death at the time of the event is considered 
life-threatening; it does not refer to an event which hypothetically might have caused 
death if it were more severe.
9.3.5
Hospitalization or Prolongation of Hospitalization
Any AE requiring hospitalization (or prolongation of hospitalization) that occurs or 
worsens during the course of a patient’s participation in a clinical trial must be reported 
as a SAE unless exempted from SAE reporting (see Section 9.4.2). Prolongation of 
hospitalization is defined as any extension of an inpatient hospitalization beyond the 
stay anticipated/required for the initial admission, as determined by the Investigator or 
treating physician.
Hospitalizations that do not meet criteria for SAE reporting are: 
a. Reasons described in protocol [e.g., investigational medicinal product (IMP) 
administration, protocol-required intervention/investigations, etc]. However, events 
requiring hospitalizations or prolongation of hospitalization as a result of a 
complication of therapy administration or clinical trial procedures will be reported 
as SAEs.
b. Hospitalization or prolonged hospitalization for technical, practical or social 
reasons, in absence of an AE.
c. Pre-planned hospitalizations: any pre-planned surgery or procedure must be 
documented in the source documentation. Only if the pre-planned surgery needs to 
be performed earlier due to a worsening of the condition, should this event 
(worsened condition) be reported as a SAE. 
Other situations that MUST NOT be considered as hospitalizations are the following:
d. An emergency visit due to an accident where the patient is treated and discharged.
e. When the patient is held 24 hours for observation and finally is not admitted.
f. Planned treatments at sites not associated to a hospital and generally considered as 
minor surgical procedures (i.e., laser eye surgery, arthroscopy, etc).


CL_0111 4.0
Page 68 of 107
Protocol PM1183-A-003-10
9.3.6
Unlisted/Unexpected Adverse Event
An AE, the nature or severity of which is not consistent with the applicable reference 
safety information.
The Sponsor will use as the reference safety information for the evaluation of 
listedness/expectedness the most updated IB for PM01183 and the Summary of Product 
Characteristics for doxorubicin.
9.3.7
Adverse Events Related to the Study Drugs
An AE is considered an adverse drug reaction (ADR) if it is related to a study 
drug/IMP, i.e., if the Investigator’s assessment of causal relationship to the IMP(s) is “Y 
(yes)” (see Section 9.3.9). 
The Investigator will assess the causal relationship of the IMP(s) to the SAE.
The Sponsor may also consider related to the study drug(s)/IMP(s) those events for 
which the Investigator assesses the causal relationship with the IMP(s) as “Uk 
(unknown)” when it cannot rule out a role of the IMP(s) in the event.
9.3.8
Expedited reporting
The Sponsor is responsible for the appropriate expedited reporting of serious 
unlisted/unexpected and related adverse events (SUSAR/SUAE) to the Competent
Authorities. The Sponsor will also report all SAEs that are unlisted/unexpected and 
related to the study drug(s) [IMP(s)] to the Investigators and to the IECs according to 
the current legislation, unless otherwise required and documented by the IECs.
9.3.9
Assessment of Causal Relationship to the Study Drug
The Investigator must provide an assessment of the causal relationship of the clinical 
trial IMP(s) to each SAE according to the following scale:
Y
There is a reasonable possibility that the IMP(s) caused the SAE.
N
There is no reasonable possibility that the IMP(s) caused the SAE and 
other causes are more probable.
Uk.
(Unknown). Only to be used in special situations where the Investigator 
has insufficient information (i.e., the patient was not seen at his/her 
center) if none of the above can be used.
9.4
ADVERSE EVENTS REPORTING PROCEDURES
9.4.1
Reporting Adverse Events
The Sponsor will collect AEs until 30 days after administration of the last dose of study 
drug(s)/IMP(s) or until the start of a new antitumor therapy, whichever occurs first. All 
AEs suspected to be related to the study drug/IMP must be followed-up after the time of 
therapy discontinuation until the event or its sequelae resolve or stabilize at an 
acceptable level to the Investigator and the Sponsor.
All AEs 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. 


CL_0111 4.0
Page 69 of 107
Protocol PM1183-A-003-10
Investigators must assess severity (grade) of the event following the NCI-CTCAE 
version 4 and assign a relationship to each study drug(s)/IMP(s); and pursue and obtain 
information adequate both to determine the outcome and to assess whether it meets the 
criteria for classification as a SAE requiring immediate notification to Pharma Mar S.A. 
or its designated representative. The Investigator must provide any relevant information 
as requested by the Sponsor in addition to that on the CRF.
Abnormal laboratory tests occurring during the study should only be recorded in the AE 
section of the CRF if the disorder:
Is associated with clinically significant symptoms, and/or
Leads to a change in study dosing or discontinuation from the study, significant 
additional concomitant drug treatment or other therapy, and/or
Leads to any of the outcomes included in the definition of a SAE.
Otherwise laboratory results should be reported in the corresponding section of the CRF 
(e.g. biochemistry, hematology).
9.4.2
Reporting Serious Adverse Events
The Sponsor will collect SAEs from the signing of the ICF. If the patient is definitively 
included in the study, this information will also be recorded in the AE section of the 
CRF. 
SAEs will be collected until 30 days after administration of the last dose of study 
drug(s)/IMP(s) or until the start of a new antitumor therapy, whichever occurs first. 
Beyond this period of time, only those SAEs suspected to be related to the IMP will be 
collected. Nonetheless, the Sponsor will evaluate any safety information that is 
spontaneously reported by an Investigator beyond the time frame specified in the 
protocol.
All SAEs (as defined above) regardless of relationship to the study drug(s)/IMP(s) must 
be reported immediately and always within 24 hours to the Pharma Mar S.A. 
Pharmacovigilance function by fax (+34 91 846 6004) or telephone (+34 91 823 4556). 
Out of office hours [Greenwich Meridian Time (GMT)], assistance on SAE reporting 
can be obtained by calling the Pharmacovigilance Service 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” from the 
investigational staff within one working day.
All SAEs suspected to be related to the IMP(s) must be followed until the event or its 
sequelae resolves or stabilizes at an acceptable level by the Investigator and the clinical 
monitor or his/her designated representative.
9.4.3
Reporting Pregnancy Cases Occurred within the Clinical Trial
National regulations require that clinical trial Sponsors collect information on 
pregnancies occurring during clinical trials, in which exposure to the IMP(s) at any time 
during pregnancy, via either maternal or paternal exposure, is suspected.
Therefore, pregnancy and suspected pregnancy (including a positive pregnancy test 
regardless of age or disease state) of a female patient or the female partner of a male 
patient occurring while the patient is on study drug, or within 30 days of the patient’s 
discontinuation visit, are considered immediately reportable events.


CL_0111 4.0
Page 70 of 107
Protocol PM1183-A-003-10
The Investigator will report the following events immediately and always within 24 
hours from first knowledge:
Any occurrence of a pregnancy where any kind of exposure to the IMP(s) is 
suspected.
Possible exposure of a pregnant woman [this could involve a partner of a male 
patient or a pregnant female who came in contact with the clinical trial IMP(s)].
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 Sponsor, with the patient’s best 
interest in mind. A decision to continue the pregnancy will require immediate 
withdrawal from the trial. 
Any pregnancy, suspected pregnancy, or positive pregnancy test must be reported to 
Pharma Mar S.A. Pharmacovigilance immediately by facsimile using the Pregnancy 
Report form. In the case of pregnancy of the female partner of a trial patient, the 
Investigator will obtain her informed consent to provide the information by using the 
applicable form provided by the Sponsor who will also advise the Investigator in these 
situations.
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(s)/IMP(s) should also 
be reported to Pharma Mar S.A. Pharmacovigilance by facsimile within 24 hours of the 
Investigators’ knowledge of the event.
9.5
ADVERSE EVENTS MONITORING
Safety review will be performed at Pharma Mar S.A. once CRFs have been monitored, 
collected and shipped to the Sponsor. 
Periodic safety review of clinical data will be performed; however, no formal Data 
Safety Monitoring Board 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 this 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. 


CL_0111 4.0
Page 71 of 107
Protocol PM1183-A-003-10
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, 
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 IMP(s) within an Annual Safety Report.
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.
9.6
EVALUATION OF PHARMACOKINETICS
The PK will be elucidated using standard non-compartmental methods. The following 
parameters will be calculated: Cmax, AUC, volume of distribution based on the terminal 
half-life (Vz), volume of distribution at steady state (Vss), clearance (CL) and half-life 
(t1/2).
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 versus time curve. 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 t1/2 will be calculated from the equation 0.693/k; 
total plasma clearance (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 be also performed, and population kinetic analysis will be made in 
pooled results of the different studies.
9.7
EFFICACY 
The evaluation of antitumor response is not a main objective in phase I trials. However, 
patients entered in this study at the expansion cohort of the RD must have either:

Measurable disease according to the RECIST version 1.1 (41) (see details in
APPENDIX 2), or

Evaluable disease by serum tumor markers, in patients with ovarian cancer.
Response rates will be determined in patients with measurable or evaluable disease. If 
any tumor type is adequately represented, time-related parameters will be also analyzed. 
In patients with measurable disease, tumor assessments will be done every six weeks, 
and tumor response will be evaluated by the RECIST version 1.1 (see details in 
APPENDIX 2). In case of patient objective tumor response, a copy of CT-scans or MRIs 
can be requested by the Sponsor.


CL_0111 4.0
Page 72 of 107
Protocol PM1183-A-003-10
If early progression occurs (i.e., before six weeks since treatment) or if treatment should 
be discontinued due to any treatment-related toxicity before appropriate tumor 
assessments have been performed, the patient’s objective response will be considered as 
a treatment failure or progressive disease (PD); therefore, their data will be included in 
the analysis of objective response as per RECIST version 1.1.
In patients with ovarian cancer, serum tumor marker (CA-125) assessments will be 
obtained before every new cycle (i.e., three weeks) and tumor response will be 
evaluated by GCIG specific criteria (see details in APPENDIX 3).
Analysis of other clinically routinely employed serum markers will be performed for 
individual patients in an exploratory fashion, as clinically indicated. This will include 
baseline measurements of:

Carcinoembryonic antigen (CEA) or carbohydrate antigen 19-9 (CA19-9): for 
patients diagnosed with gastric cancer.

Alpha-fetoprotein (AFP): for patients diagnosed with HCC.

Non-specific enolase (NSE): for patients diagnosed with neuroendocrine tumor 
(NET). 

Carbohydrate antigen 15-3 (CA15-3): for patients diagnosed with breast cancer.
Patients for whom disease diagnostic applies and are found to have elevated baseline 
values, according to the institution reference (which will be also provided), will be 
assessed before treatment on Day 1 of Cycle 2 and all subsequent cycles.
Since formal consensus on response criteria for these markers is lacking, the analysis of 
these markers will be only descriptive in nature. Moreover, no clinical decisions 
regarding treatment continuation or disease progression will be taken based solely on 
these parameters (except for CA-125).
Note: No serum markers will be evaluated in patients with SCLC and endometrial 
cancer included in the new cohort after implementation of Amendment #3.   
9.7.1
Duration of Overall Response 
The duration of overall response will be measured from the time measurement criteria 
are met for complete response (CR)/ PR, whichever is first recorded, until the first date 
in which progressive disease is objectively documented (taking as reference for 
progressive disease the smallest measurements recorded since the treatment started) or 
the date of death. In absence of disease progression or death, the duration of response 
will be censored on the date of last tumor evaluation. 
9.7.2
Progression-free Survival 
Progression-free survival (PFS) is defined as the time from the date of first infusion of 
study treatment to the date of progression or death (due to any cause). If progression or 
death has not occurred at the time of the analysis, the PFS will be censored on the date 
of last tumor evaluation.


CL_0111 4.0
Page 73 of 107
Protocol PM1183-A-003-10
9.7.3
Overall Survival 
Overall survival (OS) is defined as the time from the date of first infusion of study 
treatment to the date of death (due to any cause). Patients with no documented death 
will be censored at the last date they are known to be alive.
9.8
EVALUATION OF PHARMACOGENOMICS
Provision of samples for PGx analyses will be optional and performed upon patient 
consent by signing the PGx ICF (see Section 4.3). 
For those patients who consent to participate in the PGx study, available tumor tissue 
blocks obtained at diagnosis of the disease will be collected during his/her participation 
in the associated clinical trial (see Section 5.4, Table 4). 
The following analyses will be done on samples from consenting patients treated with 
PM01183 and doxorubicin: 

Quantitation of XPG mRNA expression in paraffin-embedded tumor tissue by 
real-time qRT-PCR and other genes related to the mechanism of action of 
PM01183 and doxorubicin.

Quantitation of XPG, TopoIIa and Pgp expression and other proteins related to 
the mechanism of action of PM01183 and doxorubicin by IHC in tumor tissue 
microarrays constructed from the patient’s paraffin-embedded tumor tissue 
blocks.
In those patients responding to treatment, Myriads Genetics Homologous 
Recombination Deficiency (HRD) assay, including analysis of BRCA1 mutation 
status, will be performed, if considered relevant.
If possible, expression levels of the different markers should be correlated with the 
patient’s clinical outcome.
10. STATISTICAL METHODS
10.1 SAMPLE SIZE
The number of patients may vary depending both on the tolerability to PM01183 
combined with doxorubicin and the number of dose levels required to identify the MTD.
Approximately, 100 evaluable patients will participate in this study.
10.2 STATISTICAL ANALYSIS
10.2.1 Demographics
Descriptive statistics (mean, median, standard deviation and 95% confidence interval, 
range of value, frequencies and percentages) will be used. Tables will be displayed by 
dose level.


CL_0111 4.0
Page 74 of 107
Protocol PM1183-A-003-10
10.2.2 Safety 
Descriptive statistics will be used to characterize the profiles of drug-related AEs, drug-
related deaths, SAEs, drug-related delays, dose reductions
and/or treatment 
discontinuations. Tables will be displayed by dose level.
10.2.3 Efficacy Analysis
Response rates [percentage of patients with any response (PR or CR: overall response 
rate), percentages for PR and CR separately, as well as percentage of patients with 
prolonged stable disease (SD) ≥ 4 months] will be characterized using descriptive 
statistics (95% exact binomial confidence interval).
If any particular tumor type is adequately represented, time-related parameters (i.e., 
progression-free survival, overall survival) will be analyzed according to the Kaplan-
Meier method, if appropriate.
The characteristics of the patients achieving an objective response or SD ≥ 4 months by 
RECIST version 1.1, or a clinically significant improvement as measured by tumor 
markers, if applicable, will be displayed.
In addition, patients with SCLC and endometrial cancer included in the new cohort after 
the implementation of Amendment #3 will be followed for survival for up to 18 months 
after the first study dose.
10.2.4 Pharmacokinetics 
The PK parameters will be tabulated and selected parameters will be graphically 
displayed per dose level. The dose-exposure relationships for Cmax and AUC will be 
evaluated and any potential PK interaction between doxorubicin and PM01183 will be 
explored.
The potential influence on selected PK parameters of selected demographic and clinical 
dichotomous variables (gender, laboratory test results above/below selected cutoff 
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…), relationship with 
selected pharmacokinetic 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.
10.2.5 Pharmacogenomics
RNA expression and IHC scoring will be performed blind, and clinical data compiled 
only after all analyses are completed. Fisher’s exact test will be used to test whether a 
specific protein-expression profile is associated with the clinical outcome after 
treatment with PM01183 and doxorubicin.
The prognosis value of markers will be explored for objective clinical response, 
progression-free survival and overall survival. In each case, if applicable, a multivariate 


CL_0111 4.0
Page 75 of 107
Protocol PM1183-A-003-10
model will be developed by backwards elimination, starting with all markers with a p-
value lower than 0.10 in the univariate analysis. 
If applicable, hazard ratios will be calculated with the univariate Cox model, and 
comparison between Kaplan-Meier survival (whenever available) and progression-free 
survival curves will be performed with the log-rank test. All tests of statistical 
significance will be two-sided, and significance will be set at 0.05 except in multiple 
comparisons, where it will be set at 0.017 in accordance with the Bonferroni correction 
of type I error.
10.3 INTERIM ANALYSIS
The patient’s safety will be assessed on a regular basis prior to each dose escalation 
upon completion of a cohort. No formal interim analyses are planned.
11. ADMINISTRATIVE SECTION
11.1 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 6) 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 approval/favorable 
opinion prior to initiation, according to pertinent regulations.
The decision of the IEC concerning the conduct of the study will be made in writing to 
the Investigator, and a copy of this decision will be provided to the Sponsor before the 
beginning of the study.
The Investigator and/or the Sponsor is/are responsible for keeping the IEC informed of 
any significant new information about the study drug.
All protocol amendments will be agreed upon by the Sponsor and the Investigator.
Administrative changes of the protocol are minor corrections and/or clarifications that 
have no impact on the way the study is to be conducted.
11.2 MONITORING, AUDITING AND INSPECTING
The study will be monitored by regular site visits and telephone calls to the Investigator 
by the clinical trial monitor designated by Pharma Mar S.A.
During site visits, the trial monitor should revise original patient records, drug 
accountability records and document retention (study file). Additionally, the trial 
monitor should observe study procedures and will discuss any problems with the 
Investigator.


CL_0111 4.0
Page 76 of 107
Protocol PM1183-A-003-10
Adequate time for these visits should be allocated by the Investigator. The Investigator 
should also ensure that the monitor is given direct access [as per International 
Conference on Harmonization (ICH) Topic E6 (R1) Guideline for Good Clinical 
Practice, Sections 4.9.7 and 6.10] to source documents (i.e., hospital or private charts, 
original laboratory records, appointment books, etc.) of the patient which support data 
entered in the case report forms, as defined in the ICH Topic E6 (R1) Guideline for 
Good Clinical Practice, Sections 1.51 and 1.52.
Systems and procedures will be implemented to ensure the quality of every aspect of the 
trial.
During the course of the trial, the Clinical Quality Assurance Department of Pharma 
Mar S.A. or external auditors contracted by the Sponsor may conduct an onsite audit 
visit (ICH Topic E6 (R1) Guideline for Good Clinical Practice, Section 1.6).
Participation in this trial implies acceptance of potential inspection by national or 
foreign Competent Authorities.
11.3 PATIENT INFORMED CONSENT
The rights, safety and well-being of the trial patients are the most important 
considerations and should prevail over interests of science and society.
The ICFs will include all elements required by ICH, GCP and applicable regulatory 
requirements.
Prior to inclusion into the trial, the Investigator or a person designated by the 
Investigator, must provide the patient with one copy of the ICF for the clinical trial and 
one copy of the ICF for the PGx study, if applicable. Both copies must provide written 
full information about the clinical trial and the PGx study, 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 study; then, both ICFs must be freely signed and 
personally dated by the patient and by the person who conducted the Informed Consent 
discussion before the beginning of the study. The patient should receive a copy of both 
signed ICFs and any other written information provided to study patients prior to 
participation in the trial.
During a patient's participation in the trial, any updates to the consent forms and any 
updates to the written information will be provided to him/her.
If there is a need to obtain new consent from the patients, the Investigator or a person 
designated by the Investigator should inform the patients of any new information 
relevant to the patients’ willingness to continue participation in the study, before 
obtaining the written consent.
11.4 CONFIDENTIALITY/ PATIENTS IDENTIFICATION
The collection and processing of personal data from the patients enrolled in this clinical 
trial will be limited to those data that are necessary to investigate the efficacy, safety, 
quality and usefulness of the study drug used in this trial.
It is the Investigator’s responsibility that sufficient information on the identity of the 
patients will be retained.


CL_0111 4.0
Page 77 of 107
Protocol PM1183-A-003-10
The trial monitor, the Sponsor’s auditor, the IECs and the Competent Authorities should 
have direct access to all requested trial-related records, and agree to keep the identity of 
study patients confidential.
The data must be collected and processed with adequate precautions to ensure 
confidentiality and compliance with applicable data privacy protection laws and 
regulations.
Explicit consent for the processing of personal data will be obtained from the 
participating patient before data collection, if applicable, and this consent should also 
address the transfer of the data to other entities and countries.
Pharma Mar S.A. shall comply with the Directive 95/46/EEC of the European 
Parliament and of the Council of 24 October 1995 on the protection of individuals with 
regard to the processing of personal data and on the free movement of such data.
11.5 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, in English. 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 Pharma Mar S.A. 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. 
11.6 INSURANCE
The Sponsor will provide insurance or indemnity in accordance with the applicable 
regulatory requirements.
11.7 RETENTION OF RECORDS
The Investigator/Institution should maintain trial documents according to Section 8 of 
the ICH Topic E6 (R1) Guideline for Good Clinical Practice and as required by 
applicable regulatory requirements.
Essential documents should be retained as per the aforementioned ICH guideline or for 
a longer period of time, if required by the applicable regulations. 
11.8 USE OF INFORMATION AND PUBLICATION
Before the investigators of this study submit a paper or abstract for publication or 
otherwise publicly disclose information concerning the study drug or products, Pharma 
Mar S.A. must be provided with at least 60 days to revise and approve the proposed 
publication or disclosure to ensure that confidential and proprietary data are protected.
If Pharma Mar S.A. determines that patentable patient matter is disclosed in the 
proposed publication or disclosure, the publication or disclosure will be withheld for a 


CL_0111 4.0
Page 78 of 107
Protocol PM1183-A-003-10
period of time considered convenient. If the study is part of a multicenter study, the first 
publication of the study shall be made in conjunction with the presentation of a joint, 
multicenter publication of the study results with the investigators and the institutions 
from all appropriate sites that are contributing data, analysis and comments. However, if 
such a multicenter publication is not submitted within 12 months after conclusion, 
abandonment or termination of the study at all sites, the present study may be published 
individually in accordance with the procedure established above.
The order of the coauthors will reflect the relative contribution of each one to study 
development and analysis. In general, the first author will be the investigator who 
recruits the highest number of patients with information finally available for data 
analysis. Relevant Pharma Mar S.A. personnel who have fully participated in the study 
must be considered for co-authorship of the publication.


CL_0111 4.0
Page 79 of 107
Protocol PM1183-A-003-10
12. REFERENCES
1.
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.
2.
Moneo V. Study No. BCCP08001. Colmenar Viejo (Madrid), Spain: 
PharmaMar S.A.U. 2008.
3.
Elices M. Comparison of the antitumor profiles of sacidin analogs PM00104 and 
PM01183. PUSA-SR012. . Cambridge, MA, U.S.A.: PharmaMar USA, Inc.; 2004.
4.
Baush N. Antitumor activity of 4 compounds (PM00104, PM00113, PM01183 
and Yondelis) in vivo. Study No. P62K. Germany: Oncotest GmbH; 2008.
5.
Guillen MJ. Efficacy of Zalypsis (PM00104), Met-4 (PM02734), PM00113 and 
PM01183 as single agents against human bladder, UM-UC-3 and human gastric 
xenograft, Hs746T. PUSA00662. Cambridge, MA, USA.: PharmaMar USA, Inc.; 2008.
6.
Guillen MJ. Efficacy of PM00104, PM02734, PM00113 and PM01183 as single 
agents against MRI-H-121, subcutaneous human renal xenograft model. PUSA00705. 
Cambridge, MA, USA.: PharmaMar USA, Inc.; 2008.
7.
Guillen MJ. Efficacy of PM00104, PM02734, PM00113 and PM01183 
administered as single agents against Capan-1, subcutaneous human pancreatic 
xenograft model. PUSA00735. Cambridge, MA, USA.: PharmaMar USA, Inc.; 2008.
8.
Guillen MJ. Response of PM01183 and Yondelis® as a monotherapy and 
Zalypsis® administered as a monotherapy and in combination with SOC agents:  
Torisel® and Avastin® (bevacizumab) against the subcutaneous implanted human 
breast xenograft model, MDA-MB-231. PUSA00851. 2008. Cambridge, MA, USA.: 
PharmaMar USA, Inc.; 2008.
9.
Guillen MJ. Response of Yondelis®, Zalypsis®, PM01183 and PM070311 
administered as a monotherapy against the subcutaneously implanted human ovarian 
xenograft mouse model, A2780. PUSA00881. Cambridge, MA, USA.: PharmaMar 
USA, Inc.; 2008.
10.
Guillen MJ. Response of Yondelis®, Zalypsis®, PM01183, PM050458, 
PM070311, PM070020 and PM070266 administered as a monotherapy in the 
subcutaneously implanted human prostate xenograft mouse model, PC-3. PUSA00894. 
Cambridge, MA, USA.: PharmaMar USA, Inc.; 2008.
11.
Guillen MJ. Response of Yondelis®, Zalypsis®, PM01183, PM050458, 
PM070311, PM070020 administered as a monotherapy in the subcutaneous implanted 
human breast xenograft model, MX-1. PUSA00898. Cambridge, MA, USA.: 
PharmaMar USA, Inc.; 2008.
12.
D'Incalci M, Frapolli R. D´Incalci M and Frapolli R. Antitumor activity of 
trabectedin analogs. In vivo studies. CPU-ACT-08-04. Milano, Italy: Instituto di 
Recerche Farmacologiche MARIO NEGRI.; 2008.
13.
Sutton A. Cardiovascular effects of PM01183 in conscious, telemetered Beagle 
dogs. 2008. ZNA14886.005. Edinburgh, UK: Aptuit Ltd.; 2008. Report No.: 
ZNA14886.005.


CL_0111 4.0
Page 80 of 107
Protocol PM1183-A-003-10
14.
Salerno D. Single Dose Intravenous Toxicity Study of PM01183 in Dogs (with a 
14 Day Treatment-Free Period). Rome, Italy: Research Toxicology Centre S.p.A.; 2008. 
Report No.: RTC 64720.
15.
Salerno D. Multiple-Cycle Toxicity Study Following 4 Cycles of Administration 
by Intravenous Route to Dogs (with a 3 Week Treatment-Free Period). Rome, Italy: 
Research Toxicology Centre S.p.A.; 2008. Report No.: RTC 73520.
16.
Ratain MJ, Elez ME, Szyldergemajn S, Geary D, Kang SP, Maraculla T, et al. 
PM01183 clinical and pharmacokinetic (PK) preliminary results of the first-in-man 
phase I study following an accelerated titration design. In: 22nd EORTC-NCI-AACR 
Symposium on Molecular Targets and Cancer Therapeutics; 2010 16-19 November 
2010; Berlin, Germany; 2010.
17.
Rai KR, Holland JF, Glidewell OJ, Weinberg V, Brunner K, Obrecht JP, et al. 
Treatment of acute myelocytic leukemia: a study by cancer and leukemia group B. 
Blood 1981;58(6):1203-12.
18.
Canellos GP, Anderson JR, Propert KJ, Nissen N, Cooper MR, Henderson ES, 
et al. Chemotherapy of advanced Hodgkin's disease with MOPP, ABVD, or MOPP 
alternating with ABVD. N Engl J Med 1992;327(21):1478-84.
19.
Bjorkholm M, Osby E, Hagberg H, Andersson H, Kvaloy S, Teerenhovi L, et al. 
Randomized trial of r-metHu granulocity-colony- stimulating factors (G-CSF) as 
adjunct to CHOP or CNOP treatment of elderly patients with aggressive non-Hodgkin’ 
s lymphoma. Blood 1999;94:599a (Abstract #2665).
20.
Stewart DJ, Evans WK, Shepherd FA, Wilson KS, Pritchard KI, Trudeau ME, et 
al. Cyclophosphamide and fluorouracil combined with mitoxantrone versus doxorubicin 
for breast cancer: superiority of doxorubicin. J Clin Oncol 1997;15(5):1897-905.
21.
Schutte J, Mouridsen HT, Stewart W, Santoro A, van Oosterom AT, Somers R, 
et al. Ifosfamide plus doxorubicin in previously untreated patients with advanced soft 
tissue sarcoma. The EORTC Soft Tissue and Bone Sarcoma Group. Eur J Cancer 
1990;26(5):558-61.
22.
Bacci G, Ferrari S, Bertoni F, Ruggieri P, Picci P, Longhi A, et al. Long-term 
outcome for patients with nonmetastatic osteosarcoma of the extremity treated at the 
istituto ortopedico rizzoli according to the istituto ortopedico rizzoli/osteosarcoma-2 
protocol: an updated report. J Clin Oncol 2000;18(24):4016-27.
23.
Gordon AN, Fleagle JT, Guthrie D, Parkin DE, Gore ME, Lacave AJ. Recurrent 
epithelial ovarian carcinoma: a randomized phase III study of pegylated liposomal 
doxorubicin versus topotecan. J Clin Oncol 2001;19(14):3312-22.
24.
Fukuoka M, Furuse K, Saijo N, Nishiwaki Y, Ikegami H, Tamura T, et al. 
Randomized trial of cyclophosphamide, doxorubicin, and vincristine versus cisplatin 
and etoposide versus alternation of these regimens in small-cell lung cancer. J Natl 
Cancer Inst 1991;83(12):855-61.
25.
Leung TW, Patt YZ, Lau WY, Ho SK, Yu SC, Chan AT, et al. Complete 
pathological remission is possible with systemic combination chemotherapy for 
inoperable hepatocellular carcinoma. Clin Cancer Res 1999;5(7):1676-81.
26.
Wils JA, Klein HO, Wagener DJ, Bleiberg H, Reis H, Korsten F, et al. 
Sequential high-dose methotrexate and fluorouracil combined with doxorubicin--a step 


CL_0111 4.0
Page 81 of 107
Protocol PM1183-A-003-10
ahead in the treatment of advanced gastric cancer: a trial of the European Organization 
for Research and Treatment of Cancer Gastrointestinal Tract Cooperative Group. J Clin 
Oncol 1991;9(5):827-31.
27.
Bukowski RM, Johnson KG, Peterson RF, Stephens RL, Rivkin SE, Neilan B, et 
al. A phase II trial of combination chemotherapy in patients with metastatic carcinoid 
tumors. A Southwest Oncology Group Study. Cancer 1987;60(12):2891-5.
28.
Goldberg RM, Smith FP, Ueno W, Ahlgren JD, Schein PS. 5-fluorouracil, 
adriamycin, and mitomycin in the treatment of adenocarcinoma of unknown primary. J 
Clin Oncol 1986;4(3):395-9.
29.
Malone H, Atassi G. DNA topoisomerasa targeting drugs: mechanisms of 
actions and perspectives. Anticancer Drugs 1997;8:811-22.
30.
Lage H, Dietel M. Involvement of the DNA mismatch repair system in 
antineoplastic drug resistance. J Cancer Res Clin Oncol 1999;125(3-4):156-65.
31.
Von Hoff DD, Layard MW, Basa P, Davis HL, Jr., Von Hoff AL, Rozencweig 
M, et al. Risk factors for doxorubicin-induced congestive heart failure. Ann Intern Med 
1979;91(5):710-7.
32.
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.
33.
Piccart MJ, Di Leo A, Beauduin M, Vindevoghel A, Michel J, Focan C, et al. 
Phase III trial comparing two dose levels of epirubicin combined with 
cyclophosphamide with cyclophosphamide, methotrexate, and fluorouracil in node-
positive breast cancer. J Clin Oncol 2001;19(12):3103-10.
34.
Fisher B, Anderson S, Wickerham DL, DeCillis A, Dimitrov N, Mamounas E, et 
al. Increased intensification and total dose of cyclophosphamide in a doxorubicin-
cyclophosphamide regimen for the treatment of primary breast cancer: findings from 
National Surgical Adjuvant Breast and Bowel Project B-22. J Clin Oncol 
1997;15(5):1858-69.
35.
Patel SR, Vadhan-Raj S, Burgess MA, Plager C, Papadopolous N, Jenkins J, et 
al. Results of two consecutive trials of dose-intensive chemotherapy with doxorubicin 
and ifosfamide in patients with sarcomas. Am J Clin Oncol 1998;21(3):317-21.
36.
Guillen MJ. Antitumor activity of PM01183 in combination with doxorubicin in 
mice bearing human ovarian tumor (A2780) xenografts. Colmenar Viejo (Madrid), 
Spain: PharmaMar, S.A.U.; 2010. Report No.: PMAR10-NC033.
37.
Chou TC. Theoretical basis, experimental design, and computerized simulation 
of synergism and antagonism in drug combination studies. Pharmacol Rev 
2006;58(3):621-81.
38.
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;161(5):1099-110.
39.
Kris MG, Hesketh PJ, Somerfield MR, Feyer P, Clark-Snow R, Koeller JM, et 
al. American Society of Clinical Oncology guideline for antiemetics in oncology: 
update 2006. J Clin Oncol 2006;24(18):2932-47.


CL_0111 4.0
Page 82 of 107
Protocol PM1183-A-003-10
40.
Rizzo JD, Somerfield MR, Hagerty KL, Seidenfeld J, Bohlius J, Bennett CL, et 
al. Use of epoetin and darbepoetin in patients with cancer: 2007 American Society of 
Clinical Oncology/American Society of Hematology clinical practice guideline update. 
J Clin Oncol 2008;26(1):132-49.
41.
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. 
New response evaluation criteria in solid tumours: revised RECIST guideline (version 
1.1). Eur J Cancer 2009;45(2):228-47.


CL_0111 4.0
Page 83 of 107
Protocol PM1183-A-003-10
13. APPENDICES
APPENDIX 1: ECOG PERFORMANCE STATUS ASSESSMENT SCALE 
Grade
ECOG PS*
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light house work, office work
2
Ambulatory and capable of all self-care but unable to carry out any work 
activities. Up and about more than 50% of waking hours
3
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours
4
Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair
5
Dead
*As published in Am. J. Clin. Oncol 5:649-655, 1982: Oken, M.M., Creech, R.H., Tormey, D.C., Horton, 
J., Davis, T.E., McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern 
Cooperative Oncology Group. 


CL_0111 4.0
Page 84 of 107
Protocol PM1183-A-003-10
APPENDIX 2: EVALUATION OF RESPONSE. THE RECIST.
This document summarizes the main information contained in RECIST version 1.1. 
Further details can be found in the original article: Eisenhauer EA, Therasse P, 
Bogaerts J, et al.: New response evaluation criteria in solid tumours: revised RECIST 
guideline (version 1.1). Eur J Cancer 2009; 45(2): 228-247.2
LIST OF ABBREVIATIONS
CR
Complete Response
CRF
Case Report Form
CT
Computed Tomography
FDG-PET
Fluorodeoxyglucose-Positron Emission Tomography
MRI
Magnetic Resonance Imaging
NE
Not Evaluable
PD
Progressive Disease
PET
Positron Emission Tomography
PFS
Progression-free Survival
PR
Partial Response
PSA
Prostate-specific Antigen
RECIST
Response Evaluation Criteria in Solid Tumors
SD
Stable Disease
TTP
Time to Progression
LIST OF TABLES
Table 1. Summary of major changes from RECIST 1.0 to RECIST 1.13.
Table 2. Time point response: patients with target (+/–non-target) disease.
Table 3. Time point response: patients with non-target disease only.
Table 4.  Best overall response when confirmation of complete response (CR) and 
partial response (PR) is  required.
                                                
2 A summary of major changes from RECIST 1.0 to RECIST 1.1 can be found at the beginning of this 
document (Table 1).
3This table is named Appendix I in the original RECIST 1.1 article.


CL_0111 4.0
Page 85 of 107
Protocol PM1183-A-003-10
The main changes from RECIST 1.0 to RECIST 1.1 are shown in the following table.
Table 1. Summary of major changes from RECIST 1.0 to RECIST 1.1.
RECIST 1.0
RECIST 1.1
Rationale
Minimum size 
measurable 
lesions 
CT: 10 mm spiral 
20 mm non-spiral 
CT 10 mm; delete 
reference to 
spiral scan 
Most scans used have 5 mm or 
less slice thickness. Clearer to 
give instruction based on slice 
interval if it is greater than 5 mm 
Clinical: 20 mm 
Clinical: 10 mm 
(must be 
measurable with 
calipers) 
Caliper measurement will make 
this reliable 
Lymph node: not 
mentioned 
CT: 
≥ 15 mm short
axis for target 
≥ 10–<15 mm for 
non-target 
< 10 mm is non-
pathological 
Since nodes are normal 
structure need to define 
pathological enlargement. Short 
axis is most sensitive 
Special 
considerations on 
lesion 
measurability 
–
Notes included on 
bone lesions, cystic 
lesions 
Clarify frequently asked 
questions 
Overall tumor 
burden 
10 lesions (5 per 
organ) 
5 lesions (2 per 
organ) 
Data warehouse analysis 
shows no loss of information if 
lesion number reduced from 10 
to 5. A maximum of 2 lesions 
per organ yields sufficient 
representation per disease site 
Response criteria 
target 
disease 
CR lymph node not 
mentioned 
CR lymph nodes 
must be <10 mm 
short axis 
In keeping with normal size of 
nodes 
PD 20% increase 
over smallest sum on 
study or new lesions 
PD 20% increase 
over smallest sum 
on study (including 
baseline if that is 
smallest) and 
at least 5 mm 
increase or new 
lesions 
Clarification that if baseline 
measurement is smaller than 
any on study measurement, it is 
reference against which PD is 
assessed 5 mm absolute 
increase to guard against over  
calling PD when total sum is 
very small and 20% increase is 
within measurement error 
Response criteria 
non-target 
disease 
‘Unequivocal 
progression’ 
considered as PD 
More detailed 
description of 
‘unequivocal 
progression’ to 
indicate that it 
should not normally 
trump target 
disease 
status. It must be 
representative of 
overall disease 
status change, not 
a single lesion 
increase 
Confusion with RECIST 1.0 
where some were considering 
PD if ‘increase’ in any non-
target lesion, even when target 
disease is stable or responding 


CL_0111 4.0
Page 86 of 107
Protocol PM1183-A-003-10
RECIST 1.0
RECIST 1.1
Rationale
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: 
How to assess and 
measure lymph 
nodes 
CR in face of 
residual tissue 
Discussion of 
‘equivocal’ 
progression 
To account for the fact that 
RECIST criteria are now being 
used in trials where PFS is the 
endpoint and not all patients 
have measurable (target) 
disease at baseline 
Frequently asked questions on 
these topics 
Confirmatory 
measure 
For CR and PR: 
criteria 
must be met again 4 
weeks after initial 
documentation 
Retain this 
requirement ONLY 
for non-randomized 
trials with  primary 
endpoint of 
response 
Data warehouse shows that 
response rates rise when 
confirmation is eliminated, but 
the only circumstance where 
this is important is in trials 
where there is no concurrent 
comparative control and where 
this measure is the primary 
endpoint 
Progression-free 
survival 
General comments 
only 
More specific 
comments on 
use of PFS (or 
proportion 
progression-free) 
as 
phase II endpoint 
Greater detail on 
PFS 
assessment in 
phase III trials 
Increasing use of PFS in phase 
III trials requires guidance on 
assessment of PD in patients 
with non-measurable disease 
Reporting of 
response 
results 
9 categories 
suggested for 
reporting phase II 
results 
Divided into phase 
II and phase III 
9 categories 
collapsed into 5 
In phase III, 
guidance given 
about reporting 
response 
Simplifies reporting and clarifies 
how to report phase II and III 
data consistently 
Response in 
phase III 
trials 
More relaxed 
guidelines
possible if protocol 
specified 
This section 
removed and 
referenced in 
section 
above: no need to 
have different 
criteria for phase II 
and III 
Simplification of response 
assessment by reducing 
number of lesions and 
eliminating need for 
confirmation in randomized 
studies where response is not 
the primary endpoint makes 
separate ‘rules’ unnecessary 


CL_0111 4.0
Page 87 of 107
Protocol PM1183-A-003-10
RECIST 1.0
RECIST 1.1
Rationale
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 computed tomography (CT) scan (irrespective of scanner type) 
and magnetic resonance imaging (MRI) (no less than double the slice 
thickness and a minimum of 10 mm).

10 mm caliper measurement by clinical exam (when superficial). 

20 mm by chest X-ray (if clearly defined and surrounded by aerated lung).
Malignant Lymph Nodes:
To be considered pathologically enlarged and measurable, a lymph node must be ≥ 15 
mm in short axis when assessed by CT scan (CT scan slice thickness recommended to 
be no greater than 5 mm). At baseline and in follow-up, only the short axis will be 
measured and followed (see Schwartz et al. Eur J Cancer. 2009; 45(2):261-267). See 
also notes below on ‘Baseline documentation of target and non-target lesions’ for 
information on lymph node measurement. 
1.1.2 Non-measurable
All other lesions, including small lesions (longest diameter < 10 mm or pathological 
lymph nodes with ≥ 10 to < 15 mm short axis) as well as lesions considered truly non-


CL_0111 4.0
Page 88 of 107
Protocol PM1183-A-003-10
measurable. Lesions considered truly non-measurable include: leptomeningeal disease, 
ascites, pleural or pericardial effusion, inflammatory breast disease, lymphangitic 
involvement of skin or lung, and abdominal masses/abdominal organomegaly identified 
by physical exam that is not measurable by reproducible imaging techniques. 
1.1.3 Special Considerations Regarding Lesion Measurability
Bone lesions, cystic lesions, and lesions previously treated with local therapy require 
particular comment:
Bone Lesions:

Bone scan, positron emission tomography (PET) scan or plain films are not 
considered adequate imaging techniques to measure bone lesions. However, 
these techniques can be used to confirm the presence or disappearance of bone 
lesions. 

Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, that can be evaluated by cross sectional imaging techniques such as 
CT or MRI can be considered as measurable lesions if the soft tissue component
meets the definition of measurability described above.

Blastic bone lesions are non-measurable.
Cystic Lesions:

Lesions that meet the criteria for radiographically defined simple cysts should 
not be considered as malignant lesions (neither measurable nor non-measurable) 
since they are, by definition, simple cysts.

‘Cystic lesions’ thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the definition of measurability described above. 
However, if non-cystic lesions are present in the same patient, these are 
preferred for selection as target lesions.
Lesions with Prior Local Treatment:

Tumor lesions situated in a previously irradiated area, or in an area subjected to 
other loco-regional therapy, are usually not considered measurable unless there 
has been demonstrated progression in the lesion. Study protocols should detail 
the conditions under which such lesions would be considered measurable.
1.2. Specifications by Methods of Measurement
1.2.1 Measurement of Lesions
All measurements should be recorded in metric notation, using calipers if clinically 
assessed. All baseline evaluations should be performed as close as possible to the 
treatment start and never more than four weeks before the beginning of the treatment.
1.2.2 Method of Assessment
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. Imaging based 
evaluation should always be done rather than clinical examination unless the lesion(s) 
being followed cannot be imaged but are assessable by clinical exam.


CL_0111 4.0
Page 89 of 107
Protocol PM1183-A-003-10
Clinical Lesions: 
Clinical lesions will only be considered measurable when they are superficial and ≥ 10 
mm diameter as assessed using calipers (e.g., skin nodules). For the case of skin lesions, 
documentation by color photography including a ruler to estimate the size of the lesion 
is suggested. As noted above, when lesions can be evaluated by both clinical exam and 
imaging, imaging evaluation should be undertaken since it is more objective and may 
also be reviewed at the end of the study.
Chest X-Ray: 
Chest CT is preferred over chest X-ray, particularly when progression is an important 
endpoint, since CT is more sensitive than X-ray, particularly in identifying new lesions. 
However, lesions on chest X-ray may be considered measurable if they are clearly 
defined and surrounded by aerated lung. See original article, Appendix II, for more 
details.
Computed Tomography (CT), Magnetic Resonance Imaging (MRI):
CT is the best currently available and reproducible method to measure lesions selected 
for response assessment. This guideline has defined measurability of lesions on CT scan 
based on the assumption that CT slice thickness is 5 mm or less. As is described in 
original article (Appendix II), when CT scans have slice thickness greater than 5 mm, 
the minimum size for a measurable lesion should be twice the slice thickness. MRI is 
also acceptable in certain situations (e.g., for body scans). More details concerning the 
use of both CT and MRI for assessment of objective tumor response evaluation are 
provided in the original article, Appendix II.
Ultrasound:
Ultrasound is not useful in assessment of lesion size and should not be used as a method 
of measurement. Ultrasound examinations cannot be reproduced in their entirety for 
independent review at a later date and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken from one 
assessment to the next (described in greater detail in the original article, Appendix II). If 
new lesions are identified by ultrasound in the course of the study, confirmation by CT 
or MRI is advised. If there is concern about radiation exposure at CT, MRI may be used 
instead of CT in selected instances.
Endoscopy, Laparoscopy: 
The use of these techniques for objective tumor evaluation is not advised. However, 
they can be useful to confirm complete pathological response when biopsies are 
obtained or to determine relapse in trials where recurrence following complete response 
or surgical resection is an endpoint.
Tumor Markers: 
Tumor markers alone cannot be used to assess objective tumor response. If markers are
initially above the upper normal limit, however, they must normalize for a patient to be 
considered in complete response (CR). Because tumor markers are disease specific, 
instructions for their measurement should be incorporated into protocols on a disease 
specific basis. Specific guidelines for both CA-125 response (in recurrent ovarian 
cancer) have been published (Rustin et al. J Natl Cancer Inst 2004; 96:487–488).


CL_0111 4.0
Page 90 of 107
Protocol PM1183-A-003-10
2. TUMOR RESPONSE EVALUATION
2.1 Assessment of Overall Tumor Burden and Measurable Disease
To assess objective response or future progression, it is necessary to estimate the overall 
tumor burden at baseline and use this as a comparator for subsequent measurements. 
Only patients with measurable disease at baseline should be included in protocols where 
objective tumor response is the primary endpoint. Measurable disease is defined by the 
presence of at least one measurable lesion (as detailed above in Section 1. Measurability 
of tumor at baseline). In studies where the primary endpoint is tumor progression (either 
time to progression or proportion with progression at a fixed date), the protocol must 
specify if entry is restricted to those with measurable disease or whether patients having 
non-measurable disease only are also eligible.
2.2 Baseline Documentation of “Target” and “Non-target” Lesions
When more than one measurable lesion is present at baseline, all lesions up to a 
maximum of ﬁve lesions total (and a maximum of two lesions per organ) representative 
of all involved organs should be identiﬁed as target lesions and will be recorded and 
measured at baseline (this means in instances where patients have only one or two organ 
sites involved that a maximum of two and four lesions will be recorded, respectively). 
For evidence to support the selection of only ﬁve target lesions, see analyses on a large 
prospective database in the article by Bogaerts et al. Eur J Cancer 2009;45:248–260. 
Target lesions should be selected on the basis of their size (lesions with the longest 
diameter), be representative of all involved organs, but in addition should be those that 
lend themselves to reproducible repeated measurements. It may be the case that, on 
occasion, the largest lesion does not lend itself to reproducible measurement, in which 
circumstance the next largest lesion which can be measured reproducibly should be 
selected. To illustrate this point see the example in the original article, Figure 3 of 
Appendix II. 
Lymph nodes merit special mention since they are normal anatomical structures which 
may be visible by imaging even if not involved by tumor. As noted in the previous 
section, pathological nodes which are defined as measurable and may be identified as 
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, saggital 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 


CL_0111 4.0
Page 91 of 107
Protocol PM1183-A-003-10
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 Special Notes on the Assessment of Target Lesions
Lymph Nodes:
Lymph nodes identified as target lesions should always have the actual short axis 
measurement recorded (measured in the same anatomical plane as the baseline 
examination), even if the nodes regress to below 10 mm on study. This means that when 
lymph nodes are included as target lesions, the ‘sum’ of lesions may not be zero even if 
complete response criteria are met, since a normal lymph node is defined as having a 
short axis of < 10 mm. Case report forms (CRFs) or other data collection methods may 
therefore be designed to have target nodal lesions recorded in a separate section where, 
in order to qualify for CR, each node must achieve a short axis < 10 mm. For PR, SD 
and PD, the actual short axis measurement of the nodes is to be included in the sum of 
target lesions.
Target Lesions that Become ‘Too Small to Measure’:
While on study, all lesions (nodal and non-nodal) recorded at baseline should have their 
actual measurements recorded at each subsequent evaluation, even when very small 
(e.g., 2 mm). However, sometimes lesions or lymph nodes which are recorded as target 


CL_0111 4.0
Page 92 of 107
Protocol PM1183-A-003-10
lesions at baseline become so faint on CT scan that the radiologist may not feel 
comfortable assigning an exact measure and may report them as being ‘too small to 
measure’. When this occurs it is important that a value be recorded on the CRF. If it is 
the opinion of the radiologist that the lesion has likely disappeared, the measurement 
should be recorded as 0 mm. If the lesion is believed to be present and is faintly seen 
but too small to measure, a default value of 5 mm should be assigned (Note: It is less 
likely that this rule will be used for lymph nodes since they usually have a definable 
size when normal and are frequently surrounded by fat such as in the retroperitoneum; 
however, if a lymph node is believed to be present and is faintly seen but too small to 
measure, a default value of 5 mm should be assigned in this circumstance as well). This 
default value is derived from the 5 mm CT slice thickness (but should not be changed 
with varying CT slice thickness). The measurement of these lesions is potentially non-
reproducible, therefore providing this default value will prevent false responses or 
progressions based upon measurement error. To reiterate, however, if the radiologist is 
able to provide an actual measure, that should be recorded, even if it is below 5 mm.
Lesions that Split or Coalesce on Treatment:
As noted in the original article, Appendix II, when non-nodal lesions ‘fragment’, the 
longest diameters of the fragmented portions should be added together to calculate the 
target lesion sum. Similarly, as lesions coalesce, a plane between them may be 
maintained that would aid in obtaining maximal diameter measurements of each 
individual lesion. If the lesions have truly coalesced such that they are no longer 
separable, the vector of the longest diameter in this instance should be the maximal 
longest diameter for the ‘coalesced lesion’.
2.3.3 Evaluation of Non-target Lesions
This section provides the definitions of the criteria used to determine the tumor response 
for the group of non-target lesions. While some non-target lesions may actually be 
measurable, they need not be measured and instead should be assessed only 
qualitatively at the time points specified in the protocol.
Complete Response (CR):
Disappearance of all non-target lesions and normalization 
of tumor marker level. All lymph nodes must be non-
pathological in size (< 10 mm short axis).
Non-CR/Non-PD:
Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal 
limits. 
Progressive Disease (PD):
Unequivocal progression (see comments below) of 
existing non-target lesions (Note: the appearance of one 
or more new lesions is also considered progression).
2.3.4 Special Notes on Assessment of Progression of Non-target Disease
The concept of progression of non-target disease requires additional explanation as 
follows:
When the Patient Also Has Measurable Disease:
In this setting, to achieve ‘unequivocal progression’ on the basis of the non-target 
disease, there must be an overall level of substantial worsening in non-target disease 
such that, even in presence of SD or PR in target disease, the overall tumor burden has 


CL_0111 4.0
Page 93 of 107
Protocol PM1183-A-003-10
increased sufficiently to merit discontinuation of therapy (see examples in the original 
article, Appendix II and further details below). A modest ‘increase’ in the size of one or 
more non-target lesions is usually not sufficient to quality for unequivocal progression 
status. The designation of overall progression solely on the basis of change in non-target 
disease in the face of SD or PR of target disease will therefore be extremely rare.
When the Patient Has only Non-measurable Disease:
This circumstance arises in some phase III trials when it is not a criterion of study entry 
to have measurable disease. The same general concepts apply here as noted above, 
however, in this instance there is no measurable disease assessment to factor into the 
interpretation of an increase in non-measurable disease burden. Because worsening in 
non-target disease cannot be easily quantified (by definition: if all lesions are truly non-
measurable) a useful test that can be applied when assessing patients for unequivocal 
progression is to consider if the increase in overall disease burden based on the change 
in non-measurable disease is comparable in magnitude to the increase that would be 
required to declare PD for measurable disease: i.e., an increase in tumor burden 
representing an additional 73% increase in ‘volume’ (which is equivalent to a 20% 
increase diameter in a measurable lesion). Examples include an increase in a pleural 
effusion from ‘trace’ to ‘large’, an increase in lymphangitic disease from localized to 
widespread, or may be described in protocols as ‘sufficient to require a change in 
therapy’. Some illustrative examples are shown in the original article, Figures 5 and 6 of 
Appendix II. If ‘unequivocal progression’ is seen, the patient should be considered to 
have had overall PD at that point. While it would be ideal to have objective criteria to 
apply to non-measurable disease, the very nature of that disease makes it impossible to 
do so, therefore the increase must be substantial.
2.3.5 New Lesions
The appearance of new malignant lesions denotes disease progression; therefore, some 
comments on detection of new lesions are important. There are no speciﬁc criteria for 
the identiﬁcation of new radiographic lesions; however, the ﬁnding of a new lesion 
should be unequivocal: i.e., not attributable to differences in scanning technique, change 
in imaging modality or ﬁndings thought to represent something other than tumor (for 
example, some ‘new’ bone lesions may be simply healing or ﬂare of pre-existing 
lesions). This is particularly important when the patient’s baseline lesions show PR or 
CR. For example, necrosis of a liver lesion may be reported on a CT scan report as a 
‘new’ cystic lesion, which it is not. 
A lesion identiﬁed on a follow-up study in an anatomical location that was not scanned 
at baseline is considered a new lesion and will indicate disease progression. An example 
of this is the patient who has visceral disease at baseline and while on study has a CT or 
MRI brain ordered which reveals metastases. The patient’s brain metastases are 
considered to be evidence of PD even if he/she did not have brain imaging at baseline. 
If a new lesion is equivocal, for example because of its small size, continued therapy 
and follow-up evaluation will clarify if it represents truly new disease. If repeat scans 
conﬁrm there is deﬁnitely a new lesion, then progression should be declared using the 
date of the initial scan. 
2.4 Evaluation of Best Overall Response
The best overall response is the best response recorded from the start of the study 
treatment until the end of treatment taking into account any requirement for 


CL_0111 4.0
Page 94 of 107
Protocol PM1183-A-003-10
conﬁrmation. On occasion a response may not be documented until after the end of 
therapy so protocols should be clear if post-treatment assessments are to be considered 
in determination of best overall response. Protocols must specify how any new therapy 
introduced before progression will affect best response designation. The patient’s best 
overall response assignment will depend on the ﬁndings of both target and non-target 
disease and will also take into consideration the appearance of new lesions. 
Furthermore, depending on the nature of the study and the protocol requirements, it may 
also 
require 
conﬁrmatory 
measurement 
(see 
Section 
2.6. 
Confirmatory 
Measurement/Duration of Response). Speciﬁcally, in non-randomized trials where 
response is the primary endpoint, conﬁrmation of PR or CR is needed to deem either 
one the ‘best overall response’. This is described further below. 
2.4.1 Time Point Response 
It is assumed that at each protocol speciﬁed time point, a response assessment occurs. 
Table 2 provides a summary of the overall response status calculation at each time point 
for patients who have measurable disease at baseline. 
Table 2. Time point response: patients with target (+/–non-target) disease.
Target lesions
Non-target lesions
New
lesions
Overall
response
CR
CR
No
CR
CR
Non-CR/non-PD
No
PR
CR
Not evaluated
No
PR
PR
Non-PD or not all evaluated
No
PR
SD
Non-PD or not all evaluated
No
SD
Not all evaluated
Non- PD
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
CR, complete response; NE, inevaluable; PD, progressive disease; PR, partial 
response; SD, stable disease. 
When patients have non-measurable (therefore non-target) disease only, Table 3 is to be 
used. 
Table 3. Time point response: patients with non-target disease only.
Non-target lesions
New lesions
Overall response
CR
No
CR
Non-CR/non-PD
No
Non-CR/non-PDa
Not all evaluated
No
NE
Unequivocal PD
Yes or No
PD
Any
Yes
PD
CR, complete response, NE, inevaluable; PD, progressive disease. 
a ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease 
since SD is increasingly used as endpoint for assessment of efficacy in 
some trials; so, to assign this category when no lesions can be measured is 
not advised.
2.4.2 Missing Assessments and Inevaluable Designation
When no imaging/measurement is done at all at a particular time point, the patient is not 
evaluable (NE) at that time point. If only a subset of lesion measurements are made at 
an assessment, usually the case is also considered NE at that time point, unless a 


CL_0111 4.0
Page 95 of 107
Protocol PM1183-A-003-10
convincing argument can be made that the contribution of the individual missing 
lesion(s) would not change the assigned time point response. This would be most likely 
to happen in the case of PD. For example, if a patient had a baseline sum of 50 mm with 
three measured lesions and at follow-up only two lesions were assessed, but those gave 
a sum of 80 mm, the patient will have achieved PD status, regardless of the contribution 
of the missing lesion.
2.4.3 Best Overall Response: All Time Points 
The best overall response is determined once all the data for the patient is known.
Best Response Determination in Trials Where Conﬁrmation of Complete or Partial 
Response IS NOT Required: 
Best response in these trials is deﬁned as the best response across all time points (for 
example, a patient who has SD at ﬁrst assessment, PR at second assessment, and PD on 
last assessment has a best overall response of PR). When SD is believed to be best 
response, it must also meet the protocol speciﬁed minimum time from baseline. If the 
minimum time is not met when SD is otherwise the best time point response, the 
patient’s best response depends on the subsequent assessments. For example, a patient 
who has SD at ﬁrst assessment, PD at second and does not meet minimum duration for 
SD, will have a best response of PD. The same patient lost to follow-up after the ﬁrst 
SD assessment would be considered inevaluable. 
Best Response Determination in Trials Where Conﬁrmation of Complete or Partial 
Response IS Required: 
Complete or partial responses may be claimed only if the criteria for each are met at a 
subsequent time point as speciﬁed in the protocol (generally four weeks later). In this 
circumstance, the best overall response can be interpreted as in Table 4. 
Table 4.  Best overall response when confirmation of complete response (CR) and partial 
response (PR) is  required.
Overall response.
First time point
Overall response.
Subsequent time point
BEST overall response
CR
CR
CR
CR
PR
SD, PD or PRa
CR
SD
SD provided minimum criteria for SD duration met, 
otherwise, PD
CR
PD
SD provided minimum criteria for SD duration met, 
otherwise, PD
CR
NE
SD provided minimum criteria for SD duration met, 
otherwise NE
PR
CR
PR
PR
PR
PR
PR
SD
SD
PR
PD
SD provided minimum criteria for SD duration met, 
otherwise, PD
PR
NE
SD provided minimum criteria for SD duration met, 
otherwise NE
NE
NE
NE
CR, complete response; NE, inevaluable; PD, progressive disease; PR, partial response; SD, stable disease. 
a If a CR is truly met at first time point, then any disease seen at a subsequent time point, even disease meeting PR 
criteria relative to baseline, makes the disease PD at that point (since disease must have reappeared after CR). Best 
response would depend on whether minimum duration for SD was met. However, sometimes ‘CR’ may be claimed 
when subsequent scans suggest small lesions were likely still present and in fact the patient had PR, not CR at the 
first time point. Under these circumstances, the original CR should be changed to PR and the best response is PR. 


CL_0111 4.0
Page 96 of 107
Protocol PM1183-A-003-10
APPENDIX 3: GCIG SPECIFIC CRITERIA
GCIC-Rustin-modified Criteria for CA-125 Response4
Patients will be scored as having attained a CA-125 response if they meet the GCIG-
Rustin-modified criteria which require that there is at least a 50% reduction in CA-125 
levels from a pre-treatment sample. The response must be confirmed and maintained for 
at least 28 days. Patients can be evaluated according to CA-125 only if they have a pre-
treatment sample that is at least twice the upper limit of normal and within two weeks 
prior to starting treatment. In addition, CA-125 levels in samples obtained after 
administration of mouse antibodies or within four weeks after surgery or paracentesis 
should not be taken into account. 
Definition of Progression free survival and duration of response by CA-125
PFS based on CA-125 will be defined as the time from first study drug infusion until the 
GCIC-Rustin-modified criteria of progression are met, or until the date of death (with or 
without disease progression).Duration of CA-125 response will be defined as the time 
between when the CA-125 was first documented to have decreased by 50% in a patient 
who meets all the GCIG-Rustin-modified criteria for a CA-125 response, and the time 
the CA-125 is first documented to have risen to the point where the patient meets GCIG 
criteria of disease progression.
GCIC-Rustin-modified definition of progressive disease according to CA-125 criteria
Definition of progression
Date of progression
Patients with elevated CA-125 before 
treatment and normalization of CA-125 
during treatment
CA-125 2 X ULN 
documented on 2 occasions*
Date CA-125 is first 
elevated to 2 X ULN
Patients with elevated CA-125 pretreatment 
that never normalizes
CA-125 2 X nadir value on 
2 occasions*
Date CA-125 is first 
elevated to 2 X nadir 
value
Patients with CA-125 in normal range 
pretreatment
CA-125 2 X ULN 
documented on 2 occasions*
Date CA-125 is first 
elevated to 2 X ULN
*Repeat CA-125 anytime but normally not less than one week after the first elevated CA-125 level. CA-
125 levels in samples obtained after administration of mouse antibodies or within four weeks after 
surgery or paracentesis should not be taken into account.
In patients for whom response to treatment is evaluated by both RECIST and CA-125 
criteria, the date of response and progression will be the earliest date of the two 
methods.
                                                
4 Rustin GJ, Quinn M, Thigpen T, du Bois A, Pujade-Lauraine E, Jakobsen A, et al. Re: New guidelines to evaluate 
the response to treatment in solid tumors (ovarian cancer). J Natl Cancer Inst 2004;96(6):487-8.


CL_0111 4.0
Page 97 of 107
Protocol PM1183-A-003-10
APPENDIX 4: COCKCROFT AND GAULT’S FORMULA
For calculating creatinine clearance: 
[(140-age (years)) x weight (Kg)]
Creatinine clearance (ml/min)  =      
x G1
72 x serum creatinine (mg/dl)
[(140-age (years)) x weight (Kg)]
Creatinine clearance (ml/min)  =      
x G1
72 x serum creatinine (mol/l) x 0.0113
1G(Gender)= 0.85 if Female; 1 if Male.
Reference:
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. 
Nephron. 1976;16(1):31-41.


CL_0111 4.0
Page 98 of 107
Protocol PM1183-A-003-10
APPENDIX 5: L IST 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.


CL_0111 4.0
Page 99 of 107
Protocol PM1183-A-003-10
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, 
Alfentanil, astemizole, (7) 
cisapride, (7) cyclosporine, 
dihydroergotamine, ergotamine, 


CL_0111 4.0
Page 100 of 107
Protocol PM1183-A-003-10
CYP
enzymes
Sensitive substrates (2)
Substrates with
narrow therapeutic range (3)
lopinavir, lovastatin, lurasidone, maraviroc, midazolam, 
nisoldipine, quetiapine, saquinavir, sildenafil, simvastatin, 
sirolimus, tolvaptan, tipranavir, triazolam, vardenafil
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/DrugInteractionsLab
eling/ucm080499.htm.
2.
Sensitive CYP substrates refers to drugs whose plasma AUC values have been shown to increase 5-
fold or higher when co-administered with a known CYP inhibitor.
3.
CYP substrates with narrow therapeutic range refers to drugs whose exposure-response relationship 
indicates that small increases in their exposure levels by the concomitant use of CYP inhibitors may 
lead to serious safety concerns (e.g., Torsades de Pointes).
4.
The AUC of these substrates were not increased by 5-fold or more with a CYP2B6 inhibitor, but they 
represent the most sensitive substrates studied with available inhibitors evaluated to date.
5.
Repaglinide is also a substrate for OATP1B1, and it is only suitable as a CYP2C8 substrate if the 
inhibition of OATP1B1 by the investigational drug has been ruled out.  
6.
Because a number of CYP3A substrates (e.g., darunavir, maraviroc) are also substrates of P-gp, the 
observed increase in exposure could be due to inhibition of both CYP3A and P-gp.
7.
Withdrawn from the United States market because of safety reasons.


CL_0111 4.0
Page 101 of 107
Protocol PM1183-A-003-10
APPENDIX 6: DECLARATION OF HELSINKI
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI
Ethical Principles for Medical Research Involving Human Subjects
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964
and amended by the:
29th WMA General Assembly, Tokyo, Japan, October 1975
35th WMA General Assembly, Venice, Italy, October 1983
41st WMA General Assembly, Hong Kong, September 1989
48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996
52nd WMA General Assembly, Edinburgh, Scotland, October 2000
53rd WMA General Assembly, Washington DC, USA, October 2002 (Note of 
Clarification added)
55th WMA General Assembly, Tokyo, Japan, October 2004 (Note of Clarification 
added)
59th WMA General Assembly, Seoul, Republic of Korea, October 2008
64th WMA General Assembly, Fortaleza, Brazil, October 2013
Preamble
1.
The World Medical Association (WMA) has developed the Declaration of 
Helsinki as a statement of ethical principles for medical research involving 
human subjects, including research on identifiable human material and data.
The Declaration is intended to be read as a whole and each of its constituent 
paragraphs should be applied with consideration of all other relevant paragraphs.
2.
Consistent with the mandate of the WMA, the Declaration is addressed 
primarily to physicians. The WMA encourages others who are involved in 
medical research involving human subjects to adopt these principles.
General Principles
3.
The Declaration of Geneva of the WMA binds the physician with the words, 
“The health of my patient will be my first consideration,” and the International 
Code of Medical Ethics declares that, “A physician shall act in the patient's best 
interest when providing medical care.”
4.
It is the duty of the physician to promote and safeguard the health, well-being 
and rights of patients, including those who are involved in medical research. The 
physician's knowledge and conscience are dedicated to the fulfilment of this 
duty.


CL_0111 4.0
Page 102 of 107
Protocol PM1183-A-003-10
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 


CL_0111 4.0
Page 103 of 107
Protocol PM1183-A-003-10
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.


CL_0111 4.0
Page 104 of 107
Protocol PM1183-A-003-10
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.


CL_0111 4.0
Page 105 of 107
Protocol PM1183-A-003-10
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 


CL_0111 4.0
Page 106 of 107
Protocol PM1183-A-003-10
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.


CL_0111 4.0
Page 107 of 107
Protocol PM1183-A-003-10
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.
Disclaimer: ©2013 World Medical Association, Inc. All Rights Reserved. All intellectual property rights 
in the Declaration of Helsinki are vested in the World Medical Association. Previous permissions granted 
to publish or reproduce otherwise WMA policy don’t apply to this version of the Declaration of Helsinki 
until January 1st, 2014. For further questions, please contact the WMA secretariat at secretariat@wma.net

SAP_001.pdf: 
 
1
 
 
PM1183-A-003-10 (NCT01970540) 
Phase I Multicenter, Open-label, Clinical and Pharmacokinetic Study of 
PM01183 in Combination with Doxorubicin in Non-heavily Pretreated 
Patients with Selected Advanced Solid Tumors 
STATISTICAL ANALYSIS PLAN 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Version
Date
 
V4.0 
12Feb2018 
 
 


 
2
Table of Contents 
 
List of Abbreviations .................................................................................................................. 5 
1. 
Introduction. ...................................................................................................................... 7 
2. 
Study Objectives. ................................................................................................................ 7 
2.1. 
Primary Objective. ................................................................................................................7 
2.2. 
Secondary Objectives. ..........................................................................................................7 
3. 
Study Design. ..................................................................................................................... 8 
4. 
Sample Size and Dose Escalation. .................................................................................... 9 
4.1. 
Sample Size. ...........................................................................................................................9 
4.2. 
Dose Escalation Schedule. ..................................................................................................10 
5. 
Population and Endpoints. .............................................................................................. 10 
5.1. 
Patient Evaluability Criteria. .............................................................................................11 
5.2. 
Endpoints. ............................................................................................................................11 
5.2.1. 
Primary Endpoint. .......................................................................................................................... 11 
5.2.1.1. 
Determination of MTD and RD. .......................................................................................... 12 
5.2.1.2. 
DLT Criteria. ........................................................................................................................ 13 
5.2.2. 
Secondary Endpoints. .................................................................................................................... 13 
5.2.2.1. 
Safety. .................................................................................................................................. 13 
5.2.2.2. 
Efficacy. ............................................................................................................................... 14 
5.2.2.3. 
Pharmacokinetics. ................................................................................................................ 14 
5.2.2.4. 
Pharmacogenomics. ............................................................................................................. 15 
6. 
General analysis methods. ............................................................................................... 15 
6.1. 
Statistical Software. ............................................................................................................15 
6.2. 
Data Analysis Conventions. ...............................................................................................15 
7. 
Statistical analysis. ........................................................................................................... 15 
7.1. 
Patient Disposition and Protocol Deviations. ...................................................................15 
7.2. 
Baseline Characteristics. ....................................................................................................16 
7.2.1. 
Demographics. ............................................................................................................................... 16 
7.3. 
Statistical Analysis for Safety. ...........................................................................................17 
7.3.1. 
Treatment Administration and Exposure. ...................................................................................... 17 
7.3.2. 
Cycle Delays and Omissions. ........................................................................................................ 18 
7.3.3. 
Dose Reductions. ........................................................................................................................... 18 
7.3.4. 
Adverse Events. ............................................................................................................................. 18 
7.3.5. 
Serious Adverse Events (SAEs). ................................................................................................... 19 
7.3.6. 
Laboratory Evaluations. ................................................................................................................. 19 
7.3.6.1. 
Hematology. ......................................................................................................................... 19 
7.3.6.2. 
Serum Biochemistry and Coagulation Tests. ....................................................................... 20 
7.3.7. 
Physical Examination. ................................................................................................................... 20 
7.3.8. 
ECG / LVEF. ................................................................................................................................. 20 
7.3.9. 
Vital Signs. .................................................................................................................................... 20 
7.3.10. 
Concomitant Medication. .......................................................................................................... 21 
7.4. 
Statistical analysis for efficacy. ..........................................................................................21 


 
3
7.4.1. 
Exploratory Analysis of Antitumor Activity. ................................................................................ 21 
7.4.2. 
Level of Significance. .................................................................................................................... 21 
8. 
Other statistical analysis. ................................................................................................. 21 
8.1. 
Stratification and Covariate Analysis. ..............................................................................22 
8.2. 
Multivariate Analysis. ........................................................................................................22 
8.3. 
Subgroup Analysis. .............................................................................................................22 
8.4. 
Interim Analysis. .................................................................................................................22 
8.5. 
Missing Values Management. ............................................................................................22 
8.6. 
Decimals Places. ..................................................................................................................23 
9. 
Tables, Listings and Figures. .......................................................................................... 23 
10. 
Appendix I. Patients Disposition. ................................................................................ 33 
10.1. 
General Characteristics. .....................................................................................................34 
10.1.1. 
Patients Treated, Eligible and Evaluable. ................................................................................. 34 
10.1.2. 
Treatment Discontinuations. ..................................................................................................... 35 
10.1.3. 
Protocol Deviations. .................................................................................................................. 36 
10.2. 
Patient Characteristics. ......................................................................................................36 
10.2.1. 
Patient Characteristics at Baseline. ........................................................................................... 36 
10.2.2. 
Cancer History. ......................................................................................................................... 40 
10.2.3. 
Sites Involved. .......................................................................................................................... 41 
10.2.4. 
Previous Treatment Summary. .................................................................................................. 42 
10.2.5. 
Previous Surgery. ...................................................................................................................... 43 
10.2.6. 
Previous Radiotherapy. ............................................................................................................. 43 
10.2.7. 
Previous Anticancer Medical Therapy. ..................................................................................... 43 
10.2.8. 
Hematological Evaluation at Baseline. ..................................................................................... 46 
10.2.9. 
Biochemical Evaluation at Baseline. ........................................................................................ 47 
10.2.10. 
Coagulation Evaluations at Baseline. ........................................................................................ 48 
10.2.11. 
Other Metabolic Evaluations at Baseline. ................................................................................. 48 
10.2.12. 
Signs and Symptoms at Baseline. ............................................................................................. 49 
10.2.13. 
Concomitant and Prophylactic Medication Starting Pre-Study. ............................................... 50 
11. 
Appendix II. Safety Evaluation. .................................................................................. 52 
11.1. 
Extent of Exposure..............................................................................................................52 
11.1.1. 
Cumulative Dose, Dose Intensity and Relative Dose Intensity................................................. 52 
11.1.2. 
Cycle Delays and Omissions. ................................................................................................... 54 
11.1.3. 
Dose Reductions. ...................................................................................................................... 57 
11.1.4. 
Dose Interruption and Re-administration. ................................................................................. 58 
11.2. 
Dose-Limiting Toxicities. ....................................................................................................58 
11.2.1. 
Dose-Limiting Toxicities. ......................................................................................................... 58 
11.3. 
Adverse Events (AEs). ........................................................................................................59 
11.3.1. 
Display of Adverse Events........................................................................................................ 59 
11.4. 
Deaths and Other Serious Adverse Events. ......................................................................60 
11.4.1. 
Deaths. ...................................................................................................................................... 60 
11.4.2. 
Serious Adverse Events. ........................................................................................................... 61 
11.5. 
Clinical Laboratory Evaluation. ........................................................................................61 
11.5.1. 
Hematological Abnormalities. .................................................................................................. 61 
11.5.2. 
Biochemical Abnormalities. ..................................................................................................... 67 
11.5.3. 
Other Metabolic Abnormalities. ............................................................................................... 70 
11.5.4. 
Coagulation Abnormalities. ...................................................................................................... 72 


 
4
11.6. 
Vital Signs, Physical Findings, ECG, LVEF and Pregnancy tests. ................................74 
11.6.1. 
Vital Signs and Physical Findings. ........................................................................................... 74 
11.6.2. 
Electrocardiogram. .................................................................................................................... 75 
11.6.3. 
LVEF. ....................................................................................................................................... 77 
11.7. 
Concomitant and Prophylactic Medication. .....................................................................78 
11.7.1. 
Concomitant and Prophylactic Medication During Study. ....................................................... 78 
12. 
Appendix III. Efficacy Evaluation. ............................................................................. 81 
12.1. 
Efficacy Analysis. ................................................................................................................81 
12.1.1. 
Response. .................................................................................................................................. 81 
13. 
Figures. ........................................................................................................................ 84 
14. 
Database Listings. ........................................................................................................ 93 
15. 
SAP Version History. ................................................................................................... 95 
15.1. 
SAP Version History v1. .....................................................................................................95 
15.2. 
SAP Version History v2. ...................................................................................................102 
15.3. 
SAP Version History v3. ...................................................................................................104 
 


 
5
 
List of Abbreviations 
AE(s) 
Adverse Event(s) 
AFP 
Alpha-fetoprotein 
ALT 
Alanine Aminotransferase 
ANC  
Absolute Neutrophil Count 
AP 
Alkaline phosphatase 
ASCO 
American Society of Clinical Oncology 
AST 
Aspartate Aminotransferase 
BSA 
Body Surface Area 
BPD 
Blood Diastolic Pressure 
BPS 
Blood Systolic Pressure 
CA-125 
Carbohydrate Antigen-125 
CA15-3 
Carbohydrate Antigen 15-3 
CA19-9 
Carbohydrate Antigen 19-9 
CEA 
Carcinoembryonic Antigen 
CI 
Confidence Interval 
CL 
Clearance 
Cmax 
Maximum Plasma Concentration 
CPK 
Creatine Phosphokinase 
CPK-MB 
Creatine Phosphokinase Muscle-Brain (serum CPK isoenzymes found in 
cardiac muscle) 
CR 
Complete Response/Complete Regression 
CrCl 
Creatinine Clearance 
CRF 
Case Report Form 
CTFI                  Chemotheraphy Free-Interval       
CT-scan 
Computed Tomography Scan 
DAC                   Data Analysis Conventions 
d/D 
Day(s) 
DI 
Dose Intensity 
DL 
Dose Level  
DLT 
Dose-Limiting Toxicity 
ECG 
Electrocardiogram 
ECHO 
Echocardiography 
ECOG-PS 
Performance Status according to Eastern Cooperative Oncology Group 
FD 
Flat Dose 
FUP 
Follow-up 
G-CSF 
Granulocyte Colony-stimulating Factor 
CSF 
Colony-stimulating Factor 
GCIG 
Gynecologic Cancer Intergroup 
GCP 
Good Clinical Practice 
GGT                   Gama-glutamyltransferasa 
HR 
Heart Rate 
i.v. 
Intravenous (intravenously) 
IB 
Investigator's Brochure 


 
6
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committees 
INR 
International Normalized Ratio 
LDH 
Lactate Dehydrogenase 
LVEF 
Left Ventricular Ejection Fraction 
min 
Minutes 
ml 
Milliliter 
MRI 
Magnetic Resonance Imaging 
MTD 
Maximum Tolerated Dose 
MUGA 
Multiple-gated Acquisition Scan 
NCI 
National Cancer Institute 
NCI-CTCAE 
National Cancer Institute - Common Terminology Criteria for Adverse 
Events (version 4 will be used for this trial) 
NSCLC 
Non-small Cell Lung Cancer 
OS 
Overall Survival 
PFS                    Progression Free Survival 
PD 
Progressive Disease 
PGx 
Pharmacogenomic(s) 
PK 
Pharmacokinetic(s) 
PR 
Partial Response 
PS 
Performance Status 
PT 
Prothrombin Time 
PTT 
Partial Thromboplastin Time 
q3wk 
Every 3 Weeks 
RD 
Recommended Dose 
QT 
QT Interval (measure of the time between the start of the Q wave and the 
end of the T wave in the heart's electrical cycle) 
QTcF 
Louis Sigurd Fridericia's formula for the correction of the QT interval 
RECIST 
Response Evaluation Criteria In Solid Tumors (version 1.1 will be used for 
this trial) 
RT 
Radiotherapy 
SAE(s) 
Serious Adverse Event(s) 
SAP                    Statistical Analysis Plan 
Sec                      Seconds 
SD 
Stable Disease 
TA 
Tumor Assessment 
STD                    Standard Deviation 
TFI                     Systemic Chemotheraphy Free Interval    
TTP 
Time to Progression 
ULN 
Upper Limit of Normal 
WBC 
White Blood Cells 
WHO 
World Health Organization 


 
7
 
1. 
Introduction. 
This document [Statistical Analysis Plan (SAP)] explains in detail the statistical analyses that 
will be carried out for the PharmaMar PM1183-A-003-10 study. 
The analyses described in this SAP are based upon and supplement those described in the 
study protocol version 1.0, version 2.0 and version 3.0 and the protocol amendments 
No.1, dated 21 November 2011, No.2, dated 10 July 2013, No.3, dated 17 October 2014 and 
No.1 Non substantial amendment, dated 30 January 2015. 
 
2. 
Study Objectives. 
The clinical trial protocol states the following: 
2.1. Primary Objective. 
• To determine the maximum tolerated dose (MTD) and the recommended dose (RD) 
of PM01183 in combination with doxorubicin in patients with selected advanced 
solid tumors.  
2.2. Secondary Objectives. 
• To determine the MTD and the RD of PM01183 in combination with doxorubicin 
with primary prophylaxis with granulocyte-colony stimulating factor (G-CSF) in 
patients with selected advanced solid tumors [if dose-limiting toxicities (DLTs) of the 
combination without G-CSF prophylaxis are exclusively related to neutropenia]. 
• To characterize the safety profile and feasibility of this combination in patients with 
selected advanced solid tumors. 
• To characterize the pharmacokinetics (PK) of this combination and to detect major 
drug-drug PK interactions. 
• To obtain preliminary information on the clinical antitumor activity of this 
combination in non-heavily pretreated selected solid tumor patients. 
• Based on promising findings, to explore the feasibility, safety and efficacy of a 
potential improvable dose of this combination in selected tumor types [i.e. small cell 
lung cancer (SCLC) and endometrial cancer). 
• To evaluate the pharmacogenomics (PGx) in tumor samples of patients exposed to 
PM01183 and doxorubicin at the RD in order to assess potential markers of response 
and/or resistance. 
 
 


 
8
3. 
Study Design. 
Prospective, open-label, dose-ranging, uncontrolled phase I study with escalating doses of 
PM01183 in combination with fixed doses of doxorubicin (see escalation dose scheme in 
section 4.2). 
Patients will start receiving intravenous (i.v). doxorubicin 50 mg/m2 (fixed dose) as bolus 
followed by PM01183 3.5 mg flat dose (FD) i.v. over one hour on Day 1 q3wk. A cycle is 
defined as an interval of three weeks. 
Cohorts of three to six patients will be included at each dose level (DL). If no DLT occurs in 
more than one patient within each cohort, escalation will proceed to the following dose level. 
If one of the first three evaluable patients experiences a DLT, the dose level should be 
expanded up to six patients.  
The MTD will be the lowest dose level explored during the dose escalation at which more 
than one evaluable patient experience a DLT in Cycle 1. All evaluable patients within a dose 
level will be followed for at least one cycle (i.e., three weeks) before dose escalation may 
proceed. Dose escalation will be terminated once the MTD or the last dose level (DL4) is 
reached, whichever occurs first, except if all DLTs occurring at a given dose level are related 
to neutropenia (e.g., febrile neutropenia, grade 4 neutropenia lasting more than seven days or 
neutropenic sepsis) in which case dose escalation may be resumed, starting at the lowest dose 
level where exclusively neutropenia-related DLTs have occurred, and will follow the same 
original schedule but with compulsory primary G-CSF prophylaxis. An expansion cohort to 
complete a minimum of nine evaluable patients will be recruited at the immediate lower dose 
level, or at the last dose level (DL4) if the MTD is not defined yet. This level will be 
confirmed as the RD if less than one third of the first nine evaluable patients experience DLT 
during Cycle 1. 
Further to the finding of encouraging antitumor activity in the first 43 evaluable patients (13 
responses, including four complete responses, with five partial responses in eight patients 
with small cell lung cancer, and one complete and one partial response in three patients with 
endometrial cancer), expansion of the cohort treated at the RD has been increased to include 
approximately 30 additional patients, for a total of around 39 patients. 
In addition, a new cohort B of 20 evaluable patients with small cell lung cancer (SCLC) who 
failed treatment after first-line standard cytotoxic-containing therapy and at least nine 
evaluable patients with endometrial cancer will be included to further define the efficacy, 
safety and feasibility of a doxorubicin dose adaptation (doxorubicin 40 mg/m2 and PM01183 
2.0 mg/m2). The administered doses of both PM01183 and doxorubicin will be capped at 2.0 
m2 of body surface area (BSA) for any patients exceeding this BSA value. Patients in this 
cohort who have received ten cycles of the doxorubicin/PM01183 combination or have to 
discontinue doxorubicin due to a cardiac AE may continue receiving treatment with single-
agent PM01183 at 4.0 mg/m2 q3wk if patient benefit is perceived according to the 
Investigator. These patients will be followed every three months until death or the date of 
study termination, whichever occurs first. 
Patients will be divided into two cohorts. Cohort A will consist of all patients included before 
the implementation of protocol amendment #3, and Cohort B will consist of all patients 
included after the implementation of protocol amendment #3. 


 
9
In the event of DLTs occurring in the first patient at the first level, the second and third 
patients will be included at least two weeks apart. Otherwise and/or at subsequent dose levels, 
all patients within a dose level may be treated simultaneously.  
Patients treated at the expansion cohort must be evaluable by RECIST v.1.1 and/or by serum 
markers (carbohydrate antigen-125, CA-125) in the case of ovarian cancer, as appropriate 
[according to the Gynecologic Cancer Intergroup (GCIG) specific criteria] (see study 
protocol, section 9.7), and must have documented disease progression according to any of 
these criteria. The tumor type(s) that will be eligible to be included in the expansion cohort at 
the RD will be chosen according to the preliminary efficacy observed among those previously 
treated during the escalation phase, and will be discussed and agreed between the 
investigators and the Sponsor.  
Intermediate dose levels could be tested on agreement between the Investigator and the 
Sponsor, if deemed appropriate. 
Patients will receive PM01183 and doxorubicin until progression, unacceptable toxicity, 
consent withdrawal or while it is considered to be in their best interest. More specifically, 
doxorubicin will be administered in the absence of disease progression or unacceptable 
toxicity before a maximal total cumulative dose of 450 mg/m2 is reached. Thus, a maximum 
of ten cycles of the combination will be administered to patients with SCLC and endometrial 
cancer included in the new cohort B. Once this dose has been reached, the patients may 
continue treatment with PM01183 alone at the established single-agent RD, 7.0 mg FD q3wk 
and for patients included in the new cohort B they may continue treatment with PM01183 
alone at 4.0 mg/m2 q3wk.    
Tumor assessments will be done every six weeks while on treatment. After treatment 
discontinuation, patients will be followed every four weeks until resolution or stabilization of 
all toxicities, if any. Patients discontinuing treatment without progression will be followed 
every two months until disease progression, other antitumor therapy, death or the date of 
study termination, whichever occurs first (see study protocol, section 5.9). 
In the new cohort B, patients with SCLC and endometrial cancer will be followed every three 
months until death or the date of study termination, whichever occurs first. Antitumor 
response will be assessed using the RECIST v.1.1 and/or serum tumor markers as appropriate 
(e.g., ovarian cancer markers). 
No serum markers will be evaluated in patients with SCLC and endometrial cancer included 
in the new cohort B. Patients will be evaluated at scheduled visits on three study periods: Pre-
treatment, Treatment and Follow-up (see study protocol, section 5.2). 
 
4. 
Sample Size and Dose Escalation. 
4.1. Sample Size. 
The number of patients may vary depending both on the tolerability to PM01183 combined 
with doxorubicin and the number of dose levels required to identify the MTD. Approximately, 
100 evaluable patients will participate in this study. 


 
10
 
4.2. Dose Escalation Schedule. 
Doxorubicin will be given at 50 mg/m² as an i.v. bolus on Day 1 q3wk, which corresponds to 
100% of its actual RD when combined with other myelosuppressive agents. It will not be 
escalated in this study.  
The starting dose (DL1) for PM01183 will be 3.5 mg given as FD on Day 1 q3wk, which 
corresponds to 50% of the RD for this schedule when given as single agent. 
The dose escalation schedule is summarized in the following table: 
Dose escalation schedule (cohort A). 
DL 
No. of  
patients 
Relative DI (%) of 
doxorubicin  / 
PM01183 
Dose of doxorubicin 
(mg/m2 ) / PM01183 (mg FD)  
on Day 1 q3wk 
DL-1 
0-6 
100 / 42.85 
50 / 3.0 
DL1 
3-6 
100 / 50 
50 / 3.5 
DL2 
3-6 
100 / 71.4 
50 / 5.0 
DL3 
3-6 
100 / 85.7 
50 / 6.0 
DL4 
3-6 
100 / 100 
50 / 7.0 
The DL-1 level is to be explored only if DL1 is defined as the MTD. 
DI, dose intensity; DL, dose level; FD, flat dose. 
 
According to the toxicity observed, intermediate dose levels may be explored if considered 
appropriate by the investigators and the Sponsor.  
Intra-patient dose escalation will not be allowed under any circumstances. 
New cohort (cohort B) after implementation of protocol amendment #3 (Cohort B): 
Patients with SCLC and endometrial cancer will consecutively receive the following on Day 1 
q3wk (three weeks = one treatment cycle): 
• Doxorubicin: i.v. bolus/short infusion at a dose of 40 mg/m2, administered as 
described above, immediately followed by: 
• PM01183: i.v. infusion over one hour at a dose of 2.0 mg/m2, administered as 
described above. 
Both doxorubicin and PM01183 doses will be capped at 2.0 m2 of BSA for individuals 
exceeding this BSA value. Doses will have to be recalculated for patients showing a ≥ 10% 
change in total body weight value compared to previous cycle. 
PM01183 doses will be rounded to the first decimal, if necessary. Doxorubicin doses will be 
rounded according to institutional guidelines/standard practices. 
5. 
Population and Endpoints. 
Patients must fulfill all the inclusion/exclusion criteria to be eligible for admission to the 
study. See clinical trial protocol, sections 4.1 Inclusion Criteria and 4.2 Exclusion Criteria. 


 
11
5.1. Patient Evaluability Criteria. 
The analysis sets are defined as follows:  
The "All Included Patients" analysis set is defined as all patients who are included in the 
study, regardless of whether they have received any study drug or not.  
The "All Treated Patients" analysis set is defined as all included patients who have received at 
least part of one infusion of PM01183.  
The "All Evaluable Patients for the Assessment of the Primary Endpoint" analysis set is 
defined as all included patients who have received at least one complete cycle (including 
observation period), except if early discontinuations or missed doses or delays and/or 
assessments were the consequence of drug-related toxicity (excluding hypersensitivity 
reactions and/or extravasations). 
The "All Evaluable for Efficacy Patients" analysis set is defined as all evaluable patients 
measured according to the RECIST v.1.1 at least six weeks after treatment initiation in all 
patients with measurable disease, and/or by CA-125 levels if applicable, i.e. ovarian cancer 
with at least 2 x upper limit of normal (ULN) at baseline [according to the Gynecologic 
Cancer Intergroup (GCIG/Rustin) specific criteria]. No serum markers will be evaluated in 
patients with SCLC and endometrial cancer included in the new cohort B.    
If early progression occurs (i.e., before six weeks since treatment) or if treatment should be 
discontinued due to any treatment-related toxicity before appropriate tumor assessments have 
been performed, the patient’s objective response will be considered as a treatment failure or 
progressive disease (PD); therefore, their data will be included in the analysis of objective 
response as per RECIST v.1.1. 
In the new cohort B of patients with SCLC and endometrial cancer, a patient evaluable for 
efficacy should have received at least one complete cycle (including observation period) and 
be evaluable as per RECIST, except if non-evaluability is due to treatment failure such as 
drug-related toxicity, death or early unequivocal PD outside the central nervous system. 
All analyses will be performed as per protocol rather than on an intention-to-treat-basis. Any 
departure from the planned treatment according to the study schedule will be listed and 
documented in the clinical study report. 
 
5.2. Endpoints. 
5.2.1. Primary Endpoint. 
• 
The MTD will be the lowest dose level explored during the dose escalation at which 
more than one evaluable patient experience a DLT in Cycle 1.  
• 
The RD will be the highest dose level explored in which less than one third of evaluable 
patients experience a DLT during Cycle 1. 
 


 
12
If the DLTs of the doxorubicin and PM01183 combination without G-CSF prophylaxis are 
exclusively related to neutropenia, the MTD and RD will also be determined with primary G-
CSF prophylaxis. 
5.2.1.1. Determination of MTD and RD. 
A minimum of three patients will be included at each dose level. If no patients experience a 
DLT during the first cycle, the dose will be escalated. If one of three patients experiences a 
DLT, three additional patients will be included at that level. If >1 evaluable patient during 
dose escalation at a given dose level experience a DLT during the first cycle, that level will be 
considered the MTD and dose escalation will be terminated except if all DLTs occurring at a 
given dose level are related to neutropenia (e.g., febrile neutropenia, grade 4 neutropenia 
lasting more than 7 days or neutropenic sepsis) in which case dose escalation may be 
resumed, starting at the lowest dose level where exclusively neutropenia-related DLTs have 
occurred, and will follow the same original schedule but with compulsory primary G-CSF 
prophylaxis The DL immediately below the MTD, or DL4 if the MTD is not reached during 
dose escalation and the last dose level (DL4) is reached, was to be initially expanded up to a 
minimum of nine evaluable patients. If less than three among the first nine evaluable patients 
treated within the expansion cohort experience a DLT during Cycle 1 this DL will be the RD.  
Further to the finding of encouraging antitumor activity in the first 43 evaluable patients (13 
responses, including four complete responses, with five partial responses in eight patients 
with SCLC, and one complete and one partial response in three patients with endometrial 
cancer), expansion of the cohort treated at the RD has been increased to include 
approximately 30 additional patients, for a total of around 39 patients. 
 
 
Determination of the maximum tolerated dose. 
No. of  patients 
evaluable*  
for DLT 
No. of patients  
with DLTs  
in Cycle 1 
Action 
3 
0 
Escalate DL until DL4 is reached 
1 
Add 3 patients 
>1 
MTD 
6 
1 
Escalate DL until DL4 is reached 
>1 
MTD 
DL, dose level; DLT, dose-limiting toxicities; MTD, maximum tolerated dose. 
* Patients not evaluable for DLT during dose optimization must be replaced. 
** For replacement of patients and replacement of patients after implementation 
of Amendment #3 (see Protocol section 5.3).
 
Decisions on delayed-onset DLTs (i.e., those DLTs occurring after Cycle 1) will be 
individually discussed between the Investigators and Sponsor, and might end affecting the 
definition of the proposed RD for phase II clinical trials. 
In the new cohort B of patients with SCLC and endometrial cancer, a patient evaluable for 
efficacy should have received at least one complete cycle (including observation period) and 
be evaluable as per RECIST, except if non-evaluability is due to treatment failure such as 
drug-related toxicity, death or early unequivocal PD outside the central nervous system. 


 
13
 
5.2.1.2. DLT Criteria. 
DLTs are defined as adverse events (AEs) and laboratory abnormalities related to the study 
treatment during the first cycle of treatment and fulfilling at least one of the criteria outlined 
below. 
• 
Grade 4 neutropenia [absolute neutrophil count (ANC) < 0.5 x 109/l] lasting > 7 days. 
• 
Grade ≥ 3 febrile neutropenia of any duration or neutropenic sepsis.  
• 
Grade 4 thrombocytopenia (platelet count < 25 x 109/l) or grade 3 with any major 
bleeding episode requiring a platelet transfusion. 
• 
Grade 4 alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) 
increase, or grade 3 lasting > 14 days. 
• 
Treatment-related grade ≥ 2 ALT or AST increase concomitantly with ≥ 2 xULN total 
bilirubin increase and normal alkaline phosphatase (AP).  
• 
Grade ≥ 3 creatine phosphokinase (CPK) increase. 
• 
Any other grade 3/4 non-hematological AE that is suspected to be related to study 
drug(s), except nausea/vomiting (unless the patient is receiving an optimal anti-emetic 
regimen), hypersensitivity reactions, extravasations, grade 3 asthenia lasting less than 
one week, and non-clinically relevant isolated biochemical abnormalities [e.g., isolated 
increase in gamma-glutamyltransferase (GGT)]. In any case, the clinical relevance 
should be discussed between the Investigators and Sponsor’s representatives. 
• 
Delay in the administration of Cycle 2 of the combination exceeding 15 days of the 
theoretical date (i.e., Day 22), due to any AEs related to study drug(s). 
• 
The following circumstances will be discussed between the Principal Investigator and 
the Sponsor, and the final consensus will be documented: 
o DLTs with delayed onset (i.e., that occur after Cycle 1). 
 
5.2.2. Secondary Endpoints. 
5.2.2.1. Safety. 
Safety parameters include: 
• Adverse events. 
• Hematology. 
• Clinical chemistry.  
• Coagulation tests. 
• Vital signs. 
• Electrocardiogram (ECG) and Left Ventricular Ejection Fraction (LVEF). 
• Physical examinations. 
• Delays and reductions. 
• Withdrawals. 


 
14
 
AEs will be graded according to the National Cancer Institute-Common Terminology Criteria 
for Adverse Events (NCI-CTCAE) v.4 and coded using the Medical Dictionary for 
Regulatory Activities (MedDRA). 
5.2.2.2. Efficacy. 
Although it is not the main objective of this study, antitumor activity will be measured 
according to the RECIST v.1.1 at least six weeks after treatment initiation in all patients with 
measurable disease, or by evaluation of tumor markers if applicable (e.g., ovarian cancer). 
Patients included at the RD in the expansion cohort must be evaluable per RECIST v.1.1 or 
by evaluation of tumor markers (see Section 7.4 for efficacy evaluation). 
No serum markers will be evaluated in patients with SCLC and endometrial cancer included 
in the new cohort B.   
If any particular tumor type is adequately represented, time-related parameters [i.e., 
progression-free survival (PFS), overall survival (OS)] will be analyzed according to the 
Kaplan-Meier method, if appropriate. 
In the new cohort B, exploratory assessment for progression-free survival (PFS) and overall 
survival (OS) will be performed. 
The best overall response is defined as the best response achieved during the study according 
to RECIST v.1.1 and/or GCIG, whenever is applicable, before disease progression, 
administration of subsequent anticancer treatment or study discontinuation. 
The response rate is defined as the ratio of patients with any response [complete response 
(CR) or partial response (PR)] by the total number of patients included in the efficacy 
population. The number of patients with stable disease SD ≥ 3 and/or 4 months will also be 
shown. 
Duration of response (DR), defined as the time between the date when the response criteria 
(PR or CR, the first that is reached) are fulfilled and the first date when disease progression, 
recurrence or death is objectively documented (taking the smallest measurements documented 
since the treatment started as reference for progressive disease).  
Progression-free survival (PFS), defined as the time from the first day of study treatment to 
the day of negative assessment (progression or death) or last tumor evaluation. 
In addition, patients with SCLC and endometrial cancer included in the cohort B will be 
followed for survival for up to 18 months after the first study dose. 
 
5.2.2.3. Pharmacokinetics. 
Pharmacokinetic (PK) analyses will be described and reported in a different document out of 
the scope of this SAP. 
 


 
15
5.2.2.4. Pharmacogenomics. 
Pharmacogenomic (PGx) analyses will be described and reported in a different document out 
of the scope of this SAP. 
6. 
General analysis methods. 
6.1. Statistical Software. 
Oracle Clinical will be used for double data entry and clinical data management. 
SAS® Software v.9.2 or higher will be used for all statistical analyses. 
 
6.2. Data Analysis Conventions. 
All data analysis conventions, derived data calculations and grouping needed to perform the 
statistical analysis will come in separate document not included in this SAP.  
 
7. 
Statistical analysis. 
7.1. Patient Disposition and Protocol Deviations. 
Patients and dose levels will be summarized and listed by the populations used in the study: 
• All Included Patients. 
• All Treated Patients. 
• All Evaluable Patients for the Assessment of the Primary Endpoint. 
• All Evaluable for Efficacy Patients. 
 
Reasons for not belonging to any population will be detailed. 
The accrual and study discontinuation details will be presented descriptively. 
Reasons for treatment discontinuation by number of cycles received will be described by 
counts and percentages. Reasons of treatment discontinuation other than disease progression 
will be detailed. 
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, it applies to deviations related to patient 
inclusion and clinical procedures (e.g., assessments to be conducted or parameters to be 


 
16
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.). 
Protocol deviations will be categorized by the PharmaMar's responsible physician and 
summarized for all patients. A summary table with the number of patients with 
inclusion/exclusion deviations will be presented per criterion. These patients will be listed 
with the unmet criteria. 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. 
A summary including but not necessarily restricted to the following categories will be 
presented: 
• Ineligible patients as per protocol. 
• Patient not withdrawn as per protocol. 
• Excluded concomitant medication. 
• Incorrect dose or schedule, including patients not meeting re-treatment criteria on Day 
1 of subsequent cycles. 
 
7.2. Baseline Characteristics. 
7.2.1. Demographics. 
Demographics and baseline characteristics will be summarized for all treated patients. All 
patient characteristics will be described by dose level (or most adequate dose 
grouping/cohort/Tumor type or other clinical relevant variable). 
Continuous variables will be summarized and presented with summary statistics, i.e., mean, 
median, range and standard deviation. 
Categorical variables will be summarized in frequency tables. Percentages in the summary 
tables will be rounded and may therefore not always add up to exactly 100%. 
In case of pre-treatment characteristics with multiple measurements per patient 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 Eastern Cooperative Oncology Group (ECOG) performance status will be 
summarized with frequency counts. 
For the cancer history, histologic diagnosis, time from diagnosis, number of baseline lesions, 
and involvement in the different sites will be summarized. Time from initial diagnosis to the 
start of study treatment and time from the latest disease progression to the start of study 
treatment will be calculated in months and summarized descriptively. If incomplete dates are 
recorded, the rules described in section 8.5 will be used for imputation. 
The primary tumor sites and baseline lesions will be recoded by PharmaMar's physicians in 
order to categorize them accurately in the analysis. 


 
17
The previous relevant medical history (other than cancer) will be listed by dose level (or most 
adequate dose grouping/cohort/Tumor type or other clinical relevant variable) and patient. 
A frequency tabulation of the different types of previous oncologic surgery (excluding only 
diagnostic or palliative procedures), radiotherapy, or anticancer systemic therapy (number of 
lines for advanced and number of agents) will be given. Chemotherapy agents and lines will 
be recoded by PharmaMar's physicians in order to categorize them accurately in the analysis. 
The signs and symptoms, hematology and serum biochemistry abnormalities at baseline will 
be displayed by tabulation of frequencies according to NCI-CTCAE v.4.0 toxicity grades. The 
signs and symptoms and laboratory abnormalities of grade ≥2 at baseline will be listed by 
dose level (or most adequate dose grouping/cohort/Tumor type or other clinical relevant 
variable) and patient. 
7.3. Statistical Analysis for Safety. 
All analysis of safety variables will be descriptive. Data retrieved at both scheduled and 
unscheduled visits will be tabulated and listed. 
The safety population is composed by all patients that receive at least part of a PM01183 
infusion. The safety patient population will be used for the general safety presentations. 
The "All Evaluable Patients for the Assessment of the Primary Endpoint" population will be 
used for primary analysis. 
For the evaluation of the main endpoint, the total number of patients included, the number of 
patients evaluable for determination of DLTs, and the number of patients with any DLT (and 
their categorization) will be summarized by dose level (or most adequate dose 
grouping/cohort/Tumor type or other clinical relevant variable). The toxicities meeting the 
DLT criteria in Cycle 1 and toxicities in subsequent cycles, if any, will be listed separately, 
and the description of laboratory abnormalities (hematology/ biochemistry) will be supported 
by graphs depicting the evolution in time of laboratory values (including nadir calculation and 
median time to recovery from baseline values). 
7.3.1. Treatment Administration and Exposure. 
Exposure to each treatment will be described by dose level (or most adequate dose 
grouping/cohort/tumor type or other clinical relevant variable) for all patients who have 
received at least one of the study treatments. 
Total cumulative dose, expressed in mg for PM01183 and in mg for doxorubicin and defined 
as the sum of all the product doses from the 1st dose received until the last dose received. 
Intended dose intensity is the planned dose of the cycle divided by planned duration of a cycle 
in weeks. 
Absolute dose intensity: is the total cumulative dose divided by the duration of the treatment. 
As a convention, the duration of the last cycle is considered to be 21 days (planed cycle 
duration).  
Relative dose intensity (%): is the ratio of absolute dose intensity divided by the intended dose 
intensity. 


 
18
Time on treatment: is the interval expressed in weeks, between the first infusion date and the 
last infusion date plus 30 days or start of new treatment or date of death (whichever occurs 
first). 
The number of cases, median, standard deviations, 95% confidence interval (CI), minimum 
and maximum values for the parameters defined above will be tabulated by dose level (or 
most adequate dose grouping/cohort/Tumor type or other clinical relevant variable) and drug 
(PM01183 and doxorubicin). 
7.3.2. Cycle Delays and Omissions. 
The item "Infusion delayed: No/Yes" in the case report from (CRF) will be used to calculate 
the delay. For doses considered as delayed by the investigator, the delay will be calculated as: 
Delay (in days) will be equal to the date of start of current cycle minus the date of start of 
previous cycle minus 21 days (planed cycle duration, in days). 
Dose delay is defined by a delay in the administration of the first infusion of one cycle (Day 1 
infusion).  
Cycle 1 will be excluded from all calculations of cycle delay (and the denominator used for 
calculations will be equal to the number of cycles susceptible to be delayed). 
The distribution of delays according to the infusion administered will be studied by means of 
counts and percentages. The reasons for infusion delay will be detailed, specifying how many 
were due to treatment-related toxicity and how many were not (administrative reasons will be 
analyzed separately and additional tables will be prepared after exclusion of these delays). 
Within delays attributable to treatment, hematological and/or non-hematological reasons will 
be outlined, and the specific reasons will be detailed, if possible. 
Skipped dose or dose omission is defined as every doxorubicin infusion not administrated on 
Day 1 of the cycle. The distribution of skipped doses will be studied by means of counts and 
percentages (the denominator used for calculations will be equal to the number of 
patients/cycles susceptible to have an omission) and a detailed listing of patients with skipped 
dose and reason will be showed. Also reasons for dose omission will be detailed, specifying 
how many were due to treatment, how many were not and how many reached a maximal total 
cumulative dose of 450 mg/m2. 
All cycles in which a maximal total cumulative dose of 450 mg/m2 is not reached are 
susceptible of doxorubicin omission (the denominator used for calculations will be equal to 
the number of cycles susceptible to be omitted). 
7.3.3. Dose Reductions. 
All dose reductions will be considered and described (per cycle and patient), specifying the 
magnitude and the reason(s) for reduction treatment-related (hematological toxicity, non-
hematological toxicity or both), or if any, other causes unrelated to treatment. 
7.3.4. Adverse Events. 
All adverse events will be coded using the MedDRA coding dictionary. 


 
19
The toxicity evaluation will be made according to the National Cancer Institute- Common 
Toxicity Criteria (NCI-CTCAE) v.4 and the events will be coded and classified using the 
MedDRA dictionary. 
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. 
Descriptive statistics will be used for the evaluation of safety. The incidence and grade of 
adverse events and laboratory abnormalities will be calculated considering the most severe 
grade per patient and cycle and will be displayed in frequency tables using counts and 
percentages. 
The shift of severity grades from baseline to the worst occurrence during treatment will be 
tabulated. 
Deaths, serious adverse events and events resulting in study discontinuation will be tabulated. 
Additional safety analyses may be determined at any time, in order to most clearly enumerate 
rates of toxicities and to further define the safety profile of PM01183 in combination with 
doxorubicin. In order to categorize accurately the safety information, additional classifications 
other than system organ class (SOC)/preferred term (PT) could be populated in order to 
understand better the safety drug profile. 
7.3.5. Serious Adverse Events (SAEs). 
Database listings of deaths and serious adverse events will be provided, including at least date 
of onset and resolution (if applicable), severity, relationship to study drug, most important 
significant consequence and main action taken. 
7.3.6. Laboratory Evaluations. 
7.3.6.1. Hematology. 
Hematological toxicities classified according to the NCI-CTCAE v.4 will be calculated in all 
cycles by dose level (or most adequate dose grouping/cohort/Tumor type or other clinical 
relevant variable). Separate analyses will be carried out for the first cycle of treatment. The 
worst grade reached by each patient during treatment and Cycle 1 will also be determinated. 
If serious toxicities occur, a special follow-up will be done to determine the pattern of 
thrombocytopenia and neutropenia within and between the different cycles. This follow-up 
will include the calculation of median and the range of nadir values and of the median time to 
recovery to baseline values and also descriptive tables. 
If appropriate, these tables might be complemented with graphic representations of the nadir 
of neutrophil and platelets count by cycle during treatment by dose level (or most adequate 
dose grouping/cohort/Tumor type or other clinical relevant variable). Furthermore, graphs of 
the inter-cycle time course of neutropenia, thrombocytopenia or any other considered 


 
20
parameter will be provided. If applicable, graphs comparing the time course of these 
parameters during the first and second cycles will be created. 
7.3.6.2. Serum Biochemistry and Coagulation Tests. 
The non-hematological laboratory abnormalities (i.e., NCI-CTCAE grades) of transaminases, 
creatinine, CPK, bilirubin, AP, etc. will be calculated by patient and cycle as explained for 
hematological toxicities. Separate analyses will be carried out for the first cycle of treatment. 
The worst grade reached by each patient during treatment and Cycle 1 will also be calculated. 
If serious toxicities occur, a special follow-up that will include calculation of median and 
range of peak values and of median time to recovery to baseline values and, together with 
descriptive tables will be done to determine the pattern of these toxicities within and between 
cycles. 
If appropriate, these tables might be complemented with boxplots for the peaks of 
transaminases, creatinine, CPK, bilirubin, AP, etc. by cycle along the treatment by dose level 
(or most adequate dose grouping/cohort/Tumor type or other clinical relevant variable). 
Furthermore, graphs of the inter-cycle time course of any considered parameter will be 
provided. If applicable, graphs comparing the time course during the first and second cycles 
will be created. 
7.3.7. Physical Examination.  
The evaluation of physical examination (i.e., normal/abnormal) will be summarized with 
frequency counts. All data will be listed by dose level (or most adequate dose 
grouping/cohort/Tumor type or other clinical relevant variable). 
7.3.8. ECG / LVEF. 
Baseline ECG evaluation (normal/abnormal) will be summarized with frequency counts. 
Continuous variables (PR Interval, QT Interval, QRS Complex, Ventricular Rate, LVEF and 
LVEF Normal Range) will be summarized and summary statistics will be provided (i.e., 
mean, standard deviation, median and range). Baseline values and their evolution during 
treatment will be tabulated with summary statistics. 
3 RR
QT
QTcF =
 
 
QTcF (Fridericia's formula) will be graded using the NCI-CTCAE v.4 
7.3.9. Vital Signs. 
PS and weight gain / loss during the study will be summarized by frequency tabulation. 


 
21
7.3.10.  Concomitant Medication. 
Concomitant therapies will be coded using the World Health Organization Anatomical 
Therapeutic Chemical (WHO-ATC) classification system dictionary and categorized 
according to the ATC (levels 1, 2 and 4) class. The number of patients receiving each type of 
therapy will be tabulated in two separated frequency tables: one for therapies that started pre-
study, and for those administrated during the study. The accompanying listing will include all 
concomitant therapies. 
Additional listings for patients taking prohibited medications / therapies according to protocol 
will be provided. 
7.4. Statistical analysis for efficacy. 
7.4.1. Exploratory Analysis of Antitumor Activity. 
The "All Evaluable for Efficacy Patients" population will be used for the analysis of the 
efficacy and also "All Treated Patients" population will be used for the overall response 
analysis.  
Response rates will be characterized using descriptive statistics (95% confidence interval). If 
applicable, overall response rate (percentage of patients with PR or CR), percentages for PR 
or CR separately and percentage of patients with SD ≥ 4 months will be analyzed. 
Time-related parameters (DR and PFS) will be analyzed according to the Kaplan-Meier 
methodology, if applicable. 
The characteristics of the patients achieving an objective response or SD ≥ 4 months by 
RECIST v.1.1, or a clinically significant improvement measured by tumor markers, will be 
displayed. 
In addition, patients with SCLC and endometrial cancer included in the new cohort B will be 
followed for survival for up to 18 months after the first study dose.  
7.4.2. Level of Significance. 
Confidence intervals will be constructed using the 95% level. No formal statistical tests are 
defined, but if needed, all will be done at a significance level of 5% and will be considered 
exploratory. 
 
8. 
Other statistical analysis. 


 
22
8.1. Stratification and Covariate Analysis. 
No stratification by prognostic factors or tumor types is planned. If a disease is adequately 
represented, response rates might be analyzed descriptively, and time-related parameters 
might be analyzed according to the Kaplan-Meier method. Efficacy parameters could also be 
subjected to further analysis (if appropriate), considering correlation with factors of known 
prognostic value such as patient ECOG performance status at entry, disease burden, prior 
therapies, other disease-specific known prognostic factor, or population characteristics, etc. 
using the appropriate test (Fisher's exact test, Spearman test, etc.). 
8.2. Multivariate Analysis. 
Exploratory Cox regression for multivariate analysis will be used for time-dependent efficacy 
parameters, and logistic regression for the evaluation of covariates associated with best 
overall response, if appropriate. 
8.3. Subgroup Analysis. 
If any cancer subtype or any other baseline characteristics of patients are adequately 
represented, a separate analysis by tumor type and efficacy as per RECIST v.1.1, will be 
performed.  
If there is a representative number of patients who receive a maximal total cumulative dose of 
450 mg/m2 of doxorubicin and continue treatment with PM01183 alone, a separate analysis 
will be performed and tables, listings and graphic representations for this population will be 
provided when applicable. 
 
8.4. Interim Analysis. 
Non-scheduled interim analyses might be performed exclusively for enhancing patient’s 
safety. 
8.5. Missing Values Management. 
Missing laboratory values will be subtracted from the denominator of the tables. 
Imputation of incomplete dates 
Dates before randomization 
If the day of a date is unknown, the imputed day will be 15. If the month is also unknown, the 
imputed date will 01/July/year. This assumption will be valid if the imputed date is earlier 
than the informed consent's date; otherwise the imputed date will be the first day of the 
informed consent's month date (i.e., 01/ informed consent's month date/year). 
Dates after end of treatment 


 
23
To ensure the most conservative approach for the efficacy time-to-event variables (i.e., PFS) 
that 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 01; if the month is also unknown, then the 
imputed date will be 01/July/year. This assumption will be valid if the imputed date occurs 
later than the last drug administration date; otherwise, the imputed date will be the last drug 
administration date plus the planed cycle duration (21 days) or the last day of the reported 
month, whichever occurs first. 
 
8.6. Decimals Places. 
By default, all numeric results will be rounded to one decimal, except in the case where 
variables are integer; in that case, they will be reported without decimals, for example, age in 
years, number of sites, etc. 
9. 
Tables, Listings and Figures. 
After the implementation of protocol amendment #3, a new cohort B of patients with SCLC 
and endometrial cancer has been included. All statistical outputs will be displayed according 
to dose level (grouped)/cohort/tumor type or primary site/ CSF use or not/other relevant 
clinical variable, whenever applicable and if an adequate number of patients is represented. 
Summary tables will have source data footnotes that will refer to the relevant listings. The 
tables' layout may change to adequately accommodate cohort/group size as appropriate. 
If the number of categories or items would not yield appropriate tabular or graphic 
representations, detailed listings will be shown instead. 
 
The abbreviation DL shown in the mock tables might refer to dose level (grouped <RD, RD, 
etc…)/cohort (i.e. Cohort A and B)/tumor type or primary site (i.e. Ovarian, SCLC (2nd line), 
etc…)/CSF use or not/other clinical relevant variable).The following is a list of tables, listings 
and figures that will be produced: 
 
Table 10.1.1.1  Patient Accrual by Institution and Dose Level. ............................................ 34 
Table 10.1.1.2  Disposition of Patients. .................................................................................. 34 
Table 10.1.1.3  Time on Treatment by Dose Level. ................................................................ 34 
Table 10.1.1.4  Number of Patients Evaluable for Analysis. ................................................. 34 
Table 10.1.1.5  Listing of Not Evaluable Patients. ................................................................. 34 
Table 10.1.2.1  Treatment Discontinuation by Dose Level*. ................................................. 35 
Table 10.1.2.2  Treatment Discontinuation Details. .............................................................. 35 
Table 10.1.2.3  Reasons for Treatment Discontinuations by Cycle and Dose Level. ............ 35 
Table 10.1.2.4  Listing of patients with Discontinuation with PM01183 alone. ................... 35 


 
24
Table 10.1.2.5  Treatment Discontinuation Due to Adverse Events. ..................................... 36 
Table 10.1.2.6  Reasons for Treatment Discontinuation Other than Progressive Disease. . 36 
Table 10.1.2.7  Reasons for Study Discontinuation by Dose Level. ...................................... 36 
Table 10.1.3.1  Supportive Listing Relevant Protocol Deviations. ........................................ 36 
Table 10.2.1.1  Age at Entry by Dose Level. ........................................................................... 36 
Table 10.2.1.2  Age Median and Range by Dose Level. ......................................................... 37 
Table 10.2.1.3  Gender by Dose Level. .................................................................................... 37 
Table 10.2.1.4  Race by Dose Level. ........................................................................................ 37 
Table 10.2.1.5  Pregnancy Tests by Dose Level. ..................................................................... 37 
Table 10.2.1.6  Physical Examination Result by Dose Level. ................................................ 37 
Table 10.2.1.7  Physical Examination Parameters by Dose Level......................................... 38 
Table 10.2.1.8  ECOG Performance Status by Dose Level at Baseline. ................................ 38 
Table 10.2.1.9  Vital Signs Parameters by Dose Level. .......................................................... 38 
Table 10.2.1.10  ECG Result by Dose Level. .......................................................................... 39 
Table 10.2.1.11  ECG Parameters by Dose Level. .................................................................. 39 
Table 10.2.1.12  Median LVEF for Patients with Previous Treatment with Anthracyclines 
by Dose Level. .......................................................................................................................... 40 
Table 10.2.2.1  Time from Diagnosis to First Infusion. ......................................................... 40 
Table 10.2.2.2  Time from last PD to First Infusion. ............................................................. 40 
Table 10.2.2.3  TTP of Last Prior Therapy. ............................................................................ 40 
Table 10.2.2.4  Tumor type by Dose Level. ............................................................................. 41 
Table 10.2.2.5  Summary of Cancer History per Patient and Tumor type. ........................... 41 
Table 10.2.3.1  No of Sites Involved by Tumor type and Dose Level. ................................... 41 
Table 10.2.3.2  Summary Statistics. No of Sites Involved by Tumor type Dose Level. ......... 41 
Table 10.2.3.3  Frequency of Patients Classified by Sites Involved by Tumor type and Dose 
Level. ........................................................................................................................................ 42 
Table 10.2.3.4  Listing of Sites per Patient. ............................................................................ 42 
Table 10.2.3.5  Bulky disease by Tumor type and Dose Level. .............................................. 42 
Table 10.2.3.6  Median sum of diameter of target lesions (mm). .......................................... 42 
Table 10.2.4.1  Previous Treatment Summary by Dose Level. .............................................. 42 
Table 10.2.4.2  Previous Systemic Therapy by Dose Level/Tumor type. ............................... 42 
Table 10.2.5.1  Previous Surgery by Dose Level (Curative/Palliative). ................................. 43 
Table 10.2.6.1  Previous Radiotherapy by Dose Level. .......................................................... 43 
Table 10.2.7.1  Agents of Previous Anticancer Therapy (ATC level 1 & 4) by Dose 
Level/Tumor type. .................................................................................................................... 43 


 
25
Table 10.2.7.2  No of Lines of Prior Anticancer Therapy for Advanced Disease by Dose 
Level/Tumor type. .................................................................................................................... 43 
Table 10.2.7.3  Summary Statistics. No of Lines of Prior Anticancer Therapy by Dose 
Level/Tumor type. .................................................................................................................... 44 
Table 10.2.7.4  No of Agents of Prior Anticancer Therapy by Dose Level/Tumor type. ...... 44 
Table 10.2.7.5  No of Agents of Last Prior Anticancer Therapy before PM01183 treatment 
by Dose Level/Tumor type. ...................................................................................................... 44 
Table 10.2.7.6  Summary Statistics. No of Agents of Prior Anticancer Therapy by Dose 
Level/Tumor type. .................................................................................................................... 44 
Table 10.2.7.7  Listing of Agents of Prior Anticancer Therapy by Dose Level. .................... 45 
Table 10.2.7.8  Agents of Prior Anticancer Therapy by Dose Level/Tumor type. ................ 45 
Table 10.2.7.9  CTFI by Dose Level/Cohort/Tumor type ....................................................... 45 
Table 10.2.7.10  Summary Statistics: CTFI by Dose Level/Cohort/Tumor type. .................. 45 
Table 10.2.7.11  Patients Previously Treated with Anthracyclines by Dose Level. ............... 45 
Table 10.2.7.12  Summary Statistics: Cumulative Dose in Patients Previously Treated with 
Anthracyclines by Dose Level. ................................................................................................ 45 
Table 10.2.8.1  Hematological Abnormalities at Baseline by Dose Level. ............................ 46 
Table 10.2.8.2  Median and Range for Hematological Parameters at Baseline by Dose 
Level. ........................................................................................................................................ 46 
Table 10.2.8.3  Supportive Listing: Patients with grade >1 Hematological Abnormalities at 
Baseline. ................................................................................................................................... 46 
Table 10.2.8.4 Patients with Missing Hematological Evaluations at Baseline. .................... 46 
Table 10.2.9.1  Biochemical Abnormalities at Baseline by Dose Level. ................................ 47 
Table 10.2.9.2  Median and Range for Biochemical Parameters at Baseline by Dose Level.
 .................................................................................................................................................. 47 
Table 10.2.9.3  Supportive Listing: Patients with Grade >1 Biochemical Abnormalities at 
Baseline. ................................................................................................................................... 47 
Table 10.2.9.4  Patients with Missing Biochemical Evaluations at Baseline. ...................... 47 
Table 10.2.10. 1  Coagulation Abnormalities at Baseline by Dose Level. ............................. 48 
Table 10.2.10. 2  Median and Range for Coagulation Parameters at Baseline by Dose 
Level. ........................................................................................................................................ 48 
Table 10.2.10. 3  Supportive Listing: Patients with Grade >1 Coagulation Abnormalities at 
Baseline. ................................................................................................................................... 48 
Table 10.2.10. 4  Patients with Missing Coagulation Evaluations at Baseline. .................... 48 
Table 10.2.11. 1  Metabolic Abnormalities at Baseline by Dose Level. ................................. 48 
Table 10.2.11. 2  Median and Range for Metabolic Parameters at Baseline by Dose Level.
 .................................................................................................................................................. 49 


 
26
Table 10.2.11. 3  Supportive Listing: Patients with grade >1 Metabolic Abnormalities at 
Baseline. ................................................................................................................................... 49 
Table 10.2.11. 4  Patients with Missing Metabolic Evaluations at Baseline. ........................ 49 
Table 10.2.12. 1  Signs and Symptoms by Dose Level. ........................................................... 49 
Table 10.2.12. 2  Listing of Adverse Events at Baseline Grade >1. ....................................... 49 
Table 10.2.13. 1  Concomitant Medication Starting Pre-Study (ATC Levels 1 and 4) by 
Dose Level. ............................................................................................................................... 50 
Table 10.2.13. 2   Concomitant Medication Starting Pre-Study (RBC and Platelet 
transfusions/EPO). .................................................................................................................. 50 
Table 10.2.13. 3   Supportive Listing: RBC and Platelet transfusions/EPO (Pre-Study). .... 50 
Table 10.2.13. 4 No of patients with Opioids Treatment at Baseline by Dose Level. ............ 50 
Table 10.2.13. 5 Median number of No of Opioids per patient by Dose Level. .................... 50 
Table 10.2.13. 6 No of patients with Steroids treatment at baseline by dose Level ............... 50 
Table 10.2.13. 7 Known CYP 3A4 Inducers/Inhibitors/Substrates Concomitant Therapies at 
BL. ............................................................................................................................................ 51 
Table 10.2.13. 8 Listing of CYP 3A4 Inducers/Inhibitors/Substrates Concomitant Therapies 
at BL. ........................................................................................................................................ 51 
Table 11.1.1.1  No of Cycles Administered by Dose Level. .................................................... 52 
Table 11.1.1.2  Median and Range of Cycles Administered by Dose Level. ......................... 52 
Table 11.1.1.3  Cumulative Dose by Dose Level. .................................................................... 53 
Table 11.1.1.4  Dose Intensity by Dose Level. ........................................................................ 53 
Table 11.1.1.5  Relative Dose Intensity by Dose Level. .......................................................... 53 
Table 11.1.1.6  Drug Administration: Patients that Reached the Maximal Cumulative Dose 
of 450 mg/m2. ........................................................................................................................... 54 
Table 11.1.2.1  No of Patients with Delayed Cycles by Dose Level. ...................................... 54 
Table 11.1.2.2  No of Patients with Dose Delayed by Dose Level According to Relationship.
 .................................................................................................................................................. 54 
Table 11.1.2.3  No of Cycles Delayed Per Patient by Dose Level. ......................................... 54 
Table 11.1.2.4  No of Cycles Delayed Per Patient by Dose Level. Summary Statistics. ....... 54 
Table 11.1.2.5  Number of Cycles with Drug Related Delay per Patient by Dose Level....... 55 
Table 11.1.2.6 Number of Cycles with Drug Related Delay per Patient by Dose Level. 
Summary Statistics. ................................................................................................................. 55 
Table 11.1.2.7  Length of Delay According to relationship by Dose Level. Summary 
Statistics. .................................................................................................................................. 55 
Table 11.1.2.8  Listing of Patient with Dose Delays. .............................................................. 56 
Table 11.1.2.9  Supportive Listing: Dose Delays Excluding Administrative Reasons. ......... 56 


 
27
Table 11.1.2.10  No. of Patients with Doxorubicin Omissions by Dose Level. ..................... 56 
Table 11.1.2.11  No of Patients with Doxorubicin Cycles Omission by Dose Level. ............ 56 
Table 11.1.2.12  Listing of Doxorubicin Dose Omissions. ..................................................... 56 
Table 11.1.2.13  Listing of Cycles Delays due to Hematological Abnormalities................... 56 
Table 11.1.2.14  Listing of Cycles Delays due to Non-Hematological Adverse Events. ....... 57 
Table 11.1.3.1  No of Patients with PM01183 Dose Reduction by Dose Level. .................... 57 
Table 11.1.3.2  No of Patients with PM01183 Cycles Dose Reduction by Dose Level. ........ 57 
Table 11.1.3.3  Reasons for PM01183 Dose Reduction by Dose Level. ................................ 57 
Table 11.1.3.4  Listing of PM01183 Dose Reductions. .......................................................... 57 
Table 11.1.3.5  Listing of Dose Reductions due to Hematological Abnormalities. ............... 58 
Table 11.1.3.6  Listing of Dose Reductions due to Non-Hematological Adverse Events. .... 58 
Table 11.1.4. 1  Listing of Patients with Dose Interruption and Re-administration. ............ 58 
Table 11.2.1.1  Summary of Patients with DLT by Dose Level. ............................................ 58 
Table 11.2.1.2  Characteristics of Patients with DLT by Dose Level..................................... 58 
Table 11.3.1.1  Combination (PM01183-Doxorubicin) Related (or Relationship Unknown) 
Adverse Events. Worst Grade by Patient and Dose Level. ..................................................... 59 
Table 11.3.1.2  PM01183-Only Related (or Relationship Unknown) Adverse Events. Worst 
Grade by Patient and Dose Level. ........................................................................................... 59 
Table 11.3.1.3  Doxorubicin-Only Related (or Relationship Unknown) Adverse Events. 
Worst Grade by Patient and Dose Level. ................................................................................ 59 
Table 11.3.1.4  Combination (PM01183-Doxorubicin) Related (or Relationship Unknown) 
Adverse Events in the First Cycle by Patient and Dose Level. .............................................. 59 
Table 11.3.1.5  PM01183-Only Related (or Relationship Unknown) Adverse Events in the 
First Cycle by Patient and Dose Level. ................................................................................... 59 
Table 11.3.1.6  Doxorubicin-Only Related (or Relationship Unknown) Adverse Events in 
the First Cycle by Patient and Dose Level. ............................................................................. 59 
Table 11.3.1.7  Combination (PM01183-Doxorubicin) Related (or Relationship Unknown) 
Adverse Events. Worst Grade Per Cycle by Dose Level. ........................................................ 59 
Table 11.3.1.8  PM01183-Only Related (or Relationship Unknown) Adverse Events. Worst 
Grade Per Cycle by Dose Level. .............................................................................................. 59 
Table 11.3.1.9  Doxorubicin-Only Related (or Relationship Unknown) Adverse Events. 
Worst Grade Per Cycle by Dose Level. ................................................................................... 59 
Table 11.3.1.10  Combination (PM01183-Doxorubicin) Related (or Relationship Unknown) 
Adverse Events Observed in ≥10% of Patients Treated by Dose Level.................................. 59 
Table 11.3.1.11  PM01183-Only Related (or Relationship Unknown) Adverse Events 
Observed in ≥10% of Patients Treated by Dose Level. ........................................................... 59 


 
28
Table 11.3.1.12  Doxorubicin-Only Related (or Relationship Unknown) Adverse Events 
Observed in ≥10% of Patients Treated by Dose Level. ........................................................... 59 
Table 11.3.1.13  Combination (PM01183-Doxorubicin) Related (or Relationship Unknown) 
Adverse Events Observed in ≥ 10% of Patients Treated. Worst grade per Cycle by Dose 
Level. ........................................................................................................................................ 59 
Table 11.3.1.14  PM01183-Only Related (or Relationship Unknown) Adverse Events 
Observed in ≥10% of Patients Treated. Worst grade per Cycle by Dose Level. .................... 59 
Table 11.3.1.15  Doxorubicin-Only Related (or Relationship Unknown) Adverse Events 
Observed in ≥10% of Patients Treated. Worst grade per Cycle by Dose Level. .................... 59 
Table 11.3.1.16  Adverse Events Regardless of Relationship. Worst Grade by Patient by 
Dose Level. ............................................................................................................................... 59 
Table 11.3.1.17  Adverse Events Regardless of Relationship in the First Cycle by Patient 
and Dose Level. ........................................................................................................................ 59 
Table 11.3.1.18  Adverse Events Regardless of Relationship. Worst Grade per Cycle by 
Dose Level. ............................................................................................................................... 59 
Table 11.3.1.19  Adverse Events Observed in ≥ 10% of Patients Treated by Dose Level. .... 59 
Table 11.3.1.20  Adverse Events Observed in ≥ 10% of Patients Treated. Worst grade per 
Cycle by Dose Level. ................................................................................................................ 59 
Table 11.3.1.21  Supportive Listing: Drug Related (or Relationship Unknown) Adverse 
Events Grade 3-4 by Dose Level. ............................................................................................. 60 
Table 11.3.1.22 Time to course to Alopecia Grade >1. .......................................................... 60 
Table 11.4.1.1  Patients who Died While on Treatment. ........................................................ 60 
Table 11.4.1.2  Patients Who Died Within 30 Days of Last Drug Administration. .............. 60 
Table 11.4.1.3  Listing of All Deaths. ..................................................................................... 60 
Table 11.4.2.1  All SAEs. ......................................................................................................... 61 
Table 11.5.1.1  Hematological Abnormalities: Worst Grade per Patient by Dose Level. ..... 61 
Table 11.5.1.2  Hematological Abnormalities: Worst Grade per Cycle by Dose Level. ........ 61 
Table 11.5.1.3  Hematological Abnormalities: Worst Grade per patient in the First Cycle by 
Dose Level. ............................................................................................................................... 61 
Table 11.5.1.4  Supportive Listing: Patients with Grade 4 Hematological Abnormalities. .. 61 
Table 11.5.1.5  Patients with Missing Hematological Evaluations. ...................................... 61 
Table 11.5.1.6  Shift of Hematological Abnormalities. Baseline Grade vs. Worst Grade on 
First Cycle. ............................................................................................................................... 62 
Table 11.5.1.7  Shift of Hematological Abnormalities. Baseline Grade vs. Worst Grade on 
Treatment. ................................................................................................................................ 62 
Table 11.5.1.8 Listing of Patients with Hematological Abnormalities >G2 and Experience 
Grade Increase (wpp) from Baseline. ..................................................................................... 63 
Table 11.5.1.9  Summary of Characteristics of wpp Hematological Abnormailities G3-4. .. 63 


 
29
Table 11.5.1.10  Summary of Hematological Abnormalities Grade 4 and specific 
Transfusions/treatment. .......................................................................................................... 63 
Table 11.5.1.11  Anemia wpp/wpc and Use of EPO per Dose Level in Cycle >1. ................. 63 
Table 11.5.1.12   Patients with Anemia Grade 3/4 and Use of EPO in Cycle >1. ................. 63 
Table 11.5.1.13   Platelet Count Time Course Pattern (summary). ....................................... 63 
Table 11.5.1.14   Platelet Count Time Course Pattern. .......................................................... 64 
Table 11.5.1.15  Thrombocytopenia wpp/wpc and Use of Transfusions per Dose Level in 
Cycle>1. .................................................................................................................................... 65 
Table 11.5.1.16  Patients with Thrombocytopenia Grade 3/4 and Use of Transfusions in 
Cycle >1. ................................................................................................................................... 65 
Table 11.5.1.17  Summary of Hematological Abnormalities Grade 4 and Specific 
Transfusions. ........................................................................................................................... 65 
Table 11.5.1.18  Neutrophil Count Time Course Pattern (summary). .................................. 66 
Table 11.5.1.19  Platelet Count Time Course Pattern. ........................................................... 66 
Table 11.5.1.20  Neuthropenia wpp/wpc and Use of Prophylactic CSF per Dose Level in 
Cycle>1. .................................................................................................................................... 67 
Table 11.5.1.21  Patients with Neutrophenia Grade 3/4 and Use of Prophylactic CSF in 
Cycle >1. ................................................................................................................................... 67 
Table 11.5.2.1  Biochemical Abnormalities: Worst Grade per Patient by Dose Level. ........ 67 
Table 11.5.2.2  Biochemical Abnormalities: Worst Grade per Cycle by Dose Level. ........... 67 
Table 11.5.2.3  Biochemical Abnormalities: Worst Grade per Patient in the first Cycle by 
Dose Level. ............................................................................................................................... 67 
Table 11.5.2.4  Patients with Missing Biochemical Evaluation. ........................................... 68 
Table 11.5.2.5  Shift of Biochemical Abnormalities. Baseline Grade vs. Worst Grade on 
First Cycle. ............................................................................................................................... 68 
Table 11.5.2.6  Shift of Biochemical Abnormalities. Baseline Grade vs. Worst Grade on 
Treatment. ................................................................................................................................ 68 
Table 11.5.2.7  Listing of patients with Biochemical Abnormalities >G2 and Experience 
Grade Increase (wpp) from Baseline. ..................................................................................... 69 
Table 11.5.2.8 Summary of Characteristics of wpp Biochemical Abnormalities G3-4. ....... 69 
Table 11.5.2.9  AST/ALT Count Time Course Pattern (summary). ...................................... 69 
Table 11.5.2.10  AST/ALT Count Time Course Pattern. ....................................................... 70 
Table 11.5.3. 1  Other Metabolic Abnormalities: Worst Grade per Patient by Dose Level. . 70 
Table 11.5.3. 2  Other Metabolic Abnormalities: Worst Grade per Cycle by Dose Level. .... 70 
Table 11.5.3. 3  Other Metabolic Abnormalities: Worst Grade per Patient in the first Cycle 
by Dose Level. .......................................................................................................................... 70 
Table 11.5.3. 4  Patients with missing Metabolic Evaluations. ............................................. 71 


 
30
Table 11.5.3. 5  Shift of Metabolic Abnormalities. Baseline Grade vs. Worst Grade on First 
Cycle. ........................................................................................................................................ 71 
Table 11.5.3. 6  Shift of Metabolic Abnormalities. Baseline Grade vs. Worst Grade on 
Treatment. ................................................................................................................................ 71 
Table 11.5.3. 7  Listing of Patients with Metabolic Abnormailities >G2 and Experience 
Grade Increase (wpp) from Baseline. ..................................................................................... 72 
Table 11.5.3. 8  Supportive Listing: Patients with Grade ≥3 Metabolic Abnormalities........ 72 
Table 11.5.4. 1  Coagulation Abnormalities: Worst Grade per Patient by Dose Level. ........ 72 
Table 11.5.4. 2  Coagulation Abnormalities: Worst Grade per Cycle by Dose Level. .......... 72 
Table 11.5.4. 3  Coagulation Abnormalities: Worst Grade per Patient in the first Cycle by 
Dose Level. ............................................................................................................................... 72 
Table 11.5.4. 4  Shift of Coagulation Abnormalities. Baseline Grade vs. Worst Grade on 
First Cycle. ............................................................................................................................... 72 
Table 11.5.4. 5  Shift of Coagulation Abnormalities. Baseline Grade vs. Worst Grade on 
Treatment. ................................................................................................................................ 73 
Table 11.5.4. 6 Listing of Patients with Coagulation Abnormalities >G2 and Experience 
Grade Increase from Baseline. ............................................................................................... 73 
Table 11.5.4. 7  Patients with missing Metabolic Evaluations. ............................................. 73 
Table 11.6.1.1  Physical examination during the Study by Cycle and Dose Level. .............. 74 
Table 11.6.1.2  Performance Status during the Study by Cycle and Dose Level. ................. 74 
Table 11.6.1.3  Weight Change during the Study by Dose Level. .......................................... 74 
Table 11.6.2 1 ECG during the Study by Dose Level. ............................................................ 75 
Table 11.6.2 2  ECG during the Study by Dose Level. ........................................................... 75 
Table 11.6.2 3  QTcF Values during the Study by Dose Level. ............................................. 76 
Table 11.6.2 4  QTcF (msec) Change per Patient during the Study by Dose Level. ............. 76 
Table 11.6.2 5  Shift of QTc. Baseline Grade vs. Worst Grade on Treatment. ..................... 76 
Table 11.6.2 6  QTcF Values during the Study by Doxorubicin Cumulative Dose. ............. 76 
Table 11.6.2 7  Listing of Patients with Grade ≥ 2 QTc Interval Prolonged. ........................ 77 
Table 11.6.3 1  LVEF (%) Change per Patient during the Study by Dose Level. ................. 77 
Table 11.6.3 2  Median LVEF Values (%) during the Study by Doxorubicin Cumulative 
Dose. ......................................................................................................................................... 77 
Table 11.6.3 3  Shift of LVEF. Baseline vs. Worst Grade on Treatment. ............................. 77 
Table 11.6.3 4  Listing of Patients with Grade ≥ 2 LVEF Decrease...................................... 78 
Table 11.7.1.1  Concomitant Medication during Study (ATC Level 1 and 4) by Dose Level.
 .................................................................................................................................................. 78 
Table 11.7.1.2 EPO/RBC and PlateletsTransfusions/CSF. ................................................... 78 


 
31
Table 11.7.1.3 Patients with EPO/RBC and Platelets Transfusions/CSF. ............................ 78 
Table 11.7.1.4  Prophylactic Medication during Study. ......................................................... 79 
Table 11.7.1.5  Patients with Nausea and /or Vomiting G3/4 and Use of Antiemetics in 
Cycle >1. ................................................................................................................................... 79 
Table 11.7.1.6 No of Patients with Opioids Treatment During Treatment by Dose Level. .. 79 
Table 11.7.1.7 Median Number of No of Opioids per Patient During Treatment by Dose 
Level. ........................................................................................................................................ 79 
Table 11.7.1.8 No of Patients with Steroids Treatment During Treatment by Dose Level. .. 80 
Table 11.7.1.9 Known CYP 3A4 Inducers/Inhibitors/Substrates Concomitant Therapies at 
BL. ............................................................................................................................................ 80 
Table 11.7.1.10 Listing of CYP 3A4 Inducers/Inhibitors/Substrates Concomitant Therapies 
During Treatment. ................................................................................................................... 80 
Table 12.1.1.1  Overall response by Dose Level: Treated Patients. ....................................... 81 
Table 12.1.1.2  Overall response by Tumor type and Dose Level: Treated Patients. ............ 81 
Table 12.1.1.3  Overall response by Dose Level: Evaluable Patients. ................................... 82 
Table 12.1.1.4  Overall Response by Tumor type and Dose Level: Evaluable Patients. ....... 82 
Table 12.1.1.5  SD ≥ 4 months by Dose Level: Evaluable Patients. ...................................... 82 
Table 12.1.1.6  Tumor Marker Evolution During Study. ...................................................... 82 
Table 12.1.1.7  Characteristics of Patients with Clinical Benefit*. ....................................... 82 
Table 12.1.1.8  Characteristics of Patients with Clinical Benefit based on any Specific 
Tumor Marker Criteria. .......................................................................................................... 83 
Table 12.1.1.9  Progression-Free Survival: Evaluable Patients. ........................................... 83 
Table 12.1.1.10  Duration of Response. .................................................................................. 83 
Table 12.1.1.11  Overall survival. ........................................................................................... 83 
Figure 13.1 1 Pattern of Hematological/non Hematological DLTs in Individual Patients. 84 
Figure 13.1 2 Transaminase Series in Individual Patients. .................................................. 84 
Figure 13.1 3 Barcharts of Adverse Events or Laboratory Abnormalities by Dose 
Level/Cohort. ............................................................................................................................ 85 
Figure 13.1 4 Barcharts of Adverse Events or Laboratory Abnormalities by Dose 
Level/Cohort/Tumor type/ or Other Clinical Relevant Variable............................................ 85 
Figure 13.1 5 Hematology/Transaminase Worst Severity by Cycle. ..................................... 86 
Figure 13.1 6 LVEF/QTcF Boxplot by Dose Level. ............................................................... 86 
Figure 13.1 7 Boxplot QTcF Worst Value by Cycle. .............................................................. 87 
Figure 13.1 8 Duration of Response. ...................................................................................... 87 
Figure 13.1 9 Progression-free Survival by Dose level/Cohort/Tumor type/ or Other 
Clinical Relevant Variable. ..................................................................................................... 88 


 
32
Figure 13.1 10 Overall Survival. ............................................................................................. 88 
Figure 13.1 11 Waterfall Graphs. ........................................................................................... 89 
Figure 13.1 12 Spider plot: Evolution of RECIST v.1.1 Assessments. .................................. 89 
Figure 13.1 13 Best RECIST v.1.1 Efficacy Assessment in Evaluable pts per Tumour Type.
 .................................................................................................................................................. 90 
Figure 13.1 14 Treatment Exposure and Reasons for Discontinuation per Tumour Type. 90 
Figure 13.1 15 Best RECIST v.1.1 Response According to Line of Treatment. ................... 90 
Figure 13.1 16 Last Prior Treatment Response (TTP) vs PM001183/Combo response 
(TTP). ....................................................................................................................................... 91 
Figure 13.1 17 Number of Cycles, Reason for Treatment Discontinuation for Patients with 
Response or Clinical Benefit. .................................................................................................. 91 
Figure 13.1 18 Efficacy and Individual TTP in Selected Patients by BSA/CTFI and 
Treatment Discontinuation. .................................................................................................... 92 
Figure 13.1 19 Number of Cycles, Reason for Treatment Discontinuation and Response in 
Patients who Received PM001183 Alone................................................................................ 92 
Listing 14.1  Patient Registration. ........................................................................................... 93 
Listing 14.2  Demography. ...................................................................................................... 93 
Listing 14.3  Patient Disposition. ............................................................................................ 93 
Listing 14.4  Protocol Deviations. ........................................................................................... 93 
Listing 14.5  Patient Populations. ........................................................................................... 93 
Listing 14.6  Selection Criteria. ............................................................................................... 93 
Listing 14.7  Medical History. ................................................................................................. 93 
Listing 14.8  Cancer History. .................................................................................................. 93 
Listing 14.9  Current Disease. ................................................................................................. 93 
Listing 14.10  Prior Surgery. ................................................................................................... 93 
Listing 14.11  Prior Radiotherapy. .......................................................................................... 93 
Listing 14.12  Prior Anticancer Therapy. ............................................................................... 93 
Listing 14.13  Signs and Symptoms. ....................................................................................... 93 
Listing 14.14  Tumor Assessment (Target Lesions). .............................................................. 93 
Listing 14.15  Tumor Assessment (Non - Target Lesions). .................................................... 93 
Listing 14.16  Tumor Assessment (New Lesions). .................................................................. 93 
Listing 14.17  Radiological Response (RECIST v.1.1). ......................................................... 93 
Listing 14.18  Clinical Evaluation Response. ......................................................................... 93 
Listing 14.19  Tumor Marker Evaluation Response. ............................................................. 93 
Listing 14.20  Overall Cycle Response. ................................................................................... 93 


 
33
Listing 14.21  Treatment Exposure. ........................................................................................ 93 
Listing 14.22  Hematology Laboratory Results. ..................................................................... 93 
Listing 14.23  Clinical Chemistry and Coagulation Laboratory Results. ............................. 93 
Listing 14.24  Physical Examination and Performance Status (PS). .................................... 93 
Listing 14.25  Vital Signs. ....................................................................................................... 93 
Listing 14.26  ECG Results. .................................................................................................... 93 
Listing 14.27  Left Ventricular Ejection Fraction (LVEF) Results. ..................................... 93 
Listing 14.28  Other Tests and Procedures Results. ............................................................... 93 
Listing 14.29  Adverse Events. ................................................................................................ 93 
Listing 14.30  Concomitant Therapy. ..................................................................................... 93 
Listing 14.31  End of Treatment. ............................................................................................ 94 
Listing 14.32  Follow-up. ........................................................................................................ 94 
Listing 14.33  Follow-up: Antitumor therapy. ........................................................................ 94 
Listing 14.34  Death Report. ................................................................................................... 94 
Listing 14.35  Best Study Overall Response. .......................................................................... 94 
Listing 14.36  Off Study. .......................................................................................................... 94 
Listing 14.37  Signature Report. ............................................................................................. 94 
A footnote has been added. .................................................................................................... 115 
Table 10.2.1.1. Age at Entry by Dose Level. ......................................................................... 115 
Table 10.2.7.9 CTFI by Dose Level/Cohort/Tumor type ...................................................... 115 
Table 10.2.7.10 Summary Statistics: CTFI by Dose Level/Cohort/Tumor type. ................. 116 
Table12.1.1.10 Duration of Response. .................................................................................. 117 
Table 12.1.1.11 Overall survival. .......................................................................................... 118 
 
 
 
 
 
10. Appendix I. Patients Disposition. 
All statistical outputs will be displayed according to Dose level (grouped)/Cohort/Cancer type 
or primary site/CSF use or not/other clinical relevant variable, whenever applicable and if an 
adequate number of patients is represented. Summary tables will have source data footnotes 
that will refer to the relevant listings. The tables' layout may change to adequately 
accommodate cohort/group size as appropriate. 


 
34
10.1. General Characteristics. 
10.1.1. Patients Treated, Eligible and Evaluable. 
Table 10.1.1.1  Patient Accrual by Institution and Dose Level. 
 
DL I 
DL II 
· · · 
DL  n 
Total 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
Institution 1 
 
 
 
 
 
 
 
 
 
 
Institution 2 
 
 
 
 
 
 
 
 
 
 
· · · 
 
 
 
 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
Note: Percentages based on number of patients by dose level. 
 
Table 10.1.1.2  Disposition of Patients. 
Date information 
Date of first consent 
 
Date of first dose 
 
Date of last consent 
 
Date of first dose of last patient 
 
Date of last dose 
 
Date of last follow up* 
 
Note: (*) Last follow up date, examination date or procedure before study closure. 
 
Table 10.1.1.3  Time on Treatment by Dose Level. 
Median and Range of Time on 
treatment (weeks) 
DL I 
DL II 
· · · 
DL n 
Total 
N 
 
 
 
 
 
Mean 
 
 
 
 
 
Median 
 
 
 
 
 
Min 
 
 
 
 
 
Max 
 
 
 
 
 
STD 
 
 
 
 
 
 
Table 10.1.1.4  Number of Patients Evaluable for Analysis. 
Number of included 
patients 
Treated Patients 
Evaluable for DLT  
Evaluable for Safety 
Evaluable for  
Efficacy* 
Yes 
No 
Yes 
No 
Yes 
No 
Yes 
No 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
DL I 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
· · · 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DL n 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Notes: (*) Efficacy by RECIST. A listing of patients not-evaluable by RECIST v.1.1 will be provided. 
 
Table 10.1.1.5  Listing of Not Evaluable Patients. 
Not Evaluable for 
Dose level  
Patient 
Reason(s) 
DLT 
 
 
 
Safety 
 
 
 
Efficacy 
 
 
 


 
35
Not Evaluable for 
Dose level  
Patient 
Reason(s) 
· · · 
 
 
 
 
10.1.2. Treatment Discontinuations. 
Table 10.1.2.1  Treatment Discontinuation by Dose Level*. 
 
DL I 
DL II 
· · · 
DL n 
Total 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
Progressive disease 
 
 
 
 
 
 
 
 
 
 
Treatment non-related AE 
 
 
 
 
 
 
 
 
 
 
Treatment  related AE 
 
 
 
 
 
 
 
 
 
 
Patient refusal 
 
 
 
 
 
 
 
 
 
 
Death 
 
 
 
 
 
 
 
 
 
 
Investigator’s decision 
 
 
 
 
 
 
 
 
 
 
Other ** 
 
 
 
 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
Notes: Percentages based on number of patients by dose level. (*)  Reasons for treatment discontinuation for patients who discontinued while the combination or PM 
alone will be provided, if required. (**) If applicable, a supporting listing 10.1.2.1.a will be provided and reasons for treatment discontinuation may suffer re-
categorization after clinical review. 
 
Table 10.1.2.2  Treatment Discontinuation Details. 
Dose  level 
Patient No 
Last cycle infused 
Treatment discontinuation reason 
Details 
 
 
 
 
 
 
 
 
 
 
 
Table 10.1.2.3  Reasons for Treatment Discontinuations by Cycle and Dose Level. 
Treatment discontinuation 
DL I 
DL II 
· · · 
DL  n 
Total 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
Progressive disease 
Cycle 1  
 
 
 
 
 
 
 
 
 
 
Cycles 2-3 
 
 
 
 
 
 
 
 
 
 
Cycles ≥4 
 
 
 
 
 
 
 
 
 
 
Patient refusal  
Cycle 1  
 
 
 
 
 
 
 
 
 
 
Cycles 2-3 
 
 
 
 
 
 
 
 
 
 
Cycles ≥4 
 
 
 
 
 
 
 
 
 
 
Non treatment-related AE Cycle 1  
 
 
 
 
 
 
 
 
 
 
Cycles 2-3 
 
 
 
 
 
 
 
 
 
 
Cycles ≥4 
 
 
 
 
 
 
 
 
 
 
…..* 
Cycle 1  
 
 
 
 
 
 
 
 
 
 
Cycles 2-3 
 
 
 
 
 
 
 
 
 
 
Cycles ≥4 
 
 
 
 
 
 
 
 
 
 
Total 
Cycle 1  
 
 
 
 
 
 
 
 
 
 
Cycles 2-3 
 
 
 
 
 
 
 
 
 
 
Cycles ≥4 
 
 
 
 
 
 
 
 
 
 
Notes: Percentages based on number of patients by dose level. Cycle grouping is only shown as an example. 
 
Table 10.1.2.4  Listing of patients with Discontinuation with PM01183 alone. 
Dose  level 
Patient No 
Last cycle infused 
Treatment discontinuation reason 
Details 
 
 
 
 
 
 
 
 
 
 
 


 
36
 
Table 10.1.2.5  Treatment Discontinuation Due to Adverse Events. 
Dose  level 
Patient 
SOC / Group 
Event 
…* 
 
 
 
 
 
 
 
 
 
 
Note: (*) Adverse event, Cycle, Grade, NCI-CTCAE v.4., Relationship, Action taken, Seriousness criteria, Prior PM01183 dose reduction.  
 
Table 10.1.2.6  Reasons for Treatment Discontinuation Other than Progressive Disease. 
Dose  level   Patient No 
Last cycle infused 
Off Study reason 
Specify 
 
 
 
 
 
 
 
 
 
  
 
Table 10.1.2.7  Reasons for Study Discontinuation by Dose Level. 
Treatment discontinuation 
DL I 
DL II 
· · · 
DL  n 
Total 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
Study completion 
 
 
 
 
 
 
 
 
 
 
Patient follow-up completed 
 
 
 
 
 
 
 
 
 
 
Patient refusal  
 
 
 
 
 
 
 
 
 
 
Death 
 
 
 
 
 
 
 
 
 
 
Never treated 
 
 
 
 
 
 
 
 
 
 
Lost to follow up 
 
 
 
 
 
 
 
 
 
 
Other* 
 
 
 
 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
Notes:  Percentages based on number of patients by dose level. (*) If applicable, a supporting listing 10.1.2.6.a will be showed. 
 
10.1.3. Protocol Deviations. 
Table 10.1.3.1  Supportive Listing Relevant Protocol Deviations. 
Dose level   Patient No 
Protocol deviation type 
Specify 
 
 
 
 
 
 
 
 
 
 
 
 
 
10.2. Patient Characteristics. 
All statistical outputs will be displayed according to Dose level (grouped)/Cohort/Cancer type 
or primary site/CSF use or not/other clinical relevant variable, whenever applicable and if an 
adequate number of patients is represented. Summary tables will have source data footnotes 
that will refer to the relevant listings. The tables' layout may change to adequately 
accommodate cohort/group size as appropriate. 
10.2.1. Patient Characteristics at Baseline. 
Table 10.2.1.1  Age at Entry by Dose Level. 
Age at entry 
DL I 
DL II 
· · · 
DL  n 
Total 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 


 
37
Age at entry 
DL I 
DL II 
· · · 
DL  n 
Total 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
18-45 years 
 
 
 
 
 
 
 
 
 
 
46-55 years  
 
 
 
 
 
 
 
 
 
 
· · · 
 
 
 
 
 
 
 
 
 
 
< 76* years  
 
 
 
 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
Note:  Percentages based on number of patients by dose level. (*) Example categories. 
 
Table 10.2.1.2  Age Median and Range by Dose Level. 
Age median and range 
DL I 
DL II 
· · · 
DL  n 
Total 
N 
 
 
 
 
 
Median 
 
 
 
 
 
Min 
 
 
 
 
 
Max 
 
 
 
 
 
STD 
 
 
 
 
 
 
Table 10.2.1.3  Gender by Dose Level. 
Gender 
DL I 
DL II 
· · · 
DL  n 
Total 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
Male  
 
 
 
 
 
 
 
 
 
 
Female 
 
 
 
 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
Note:  Percentages based on number of patients by dose level. 
 
Table 10.2.1.4  Race by Dose Level. 
Gender 
DL I 
DL II 
· · · 
DL  n 
Total 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
Caucasian 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
Note:  Percentages based on number of patients by dose level. 
 
Table 10.2.1.5  Pregnancy Tests by Dose Level. 
Result 
DL I 
DL II 
· · · 
DL  n 
Total 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
Not applicable* 
 
 
 
 
 
 
 
 
 
 
Negative 
 
 
 
 
 
 
 
 
 
 
Positive 
 
 
 
 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
Note:  Percentages based on number of premenopausal patients by dose level. (*) A supporting listing 10.1.2.5.a with  reasons will be showed. 
 
Table 10.2.1.6  Physical Examination Result by Dose Level. 
Physical Examination 
DL I 
DL II 
· · · 
DL  n 
Total 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
Normal  
 
 
 
 
 
 
 
 
 
 
Abnormal 
 
 
 
 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
Notes Percentages based on number of patients by dose level. 
 


 
38
Table 10.2.1.7  Physical Examination Parameters by Dose Level. 
 
DL I 
DL II 
· · · 
DL  n 
Total 
Weight (kg). 
 
 
 
 
 
N 
 
 
 
 
 
Mean 
 
 
 
 
 
Median 
 
 
 
 
 
Min 
 
 
 
 
 
Max 
 
 
 
 
 
STD 
 
 
 
 
 
……* 
 
 
 
 
 
N 
 
 
 
 
 
Mean 
 
 
 
 
 
Median 
 
 
 
 
 
Min 
 
 
 
 
 
Max 
 
 
 
 
 
STD 
 
 
 
 
 
Notes: (*) Height (cm) and body surface area (BSA) (DuBois formula) . 
 
Table 10.2.1.8  ECOG Performance Status by Dose Level at Baseline. 
PS (ECOG) 
DL I 
DL II 
· · · 
DL  n 
Total 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
0 
 
 
 
 
 
 
 
 
 
 
1 
 
 
 
 
 
 
 
 
 
 
· · · 
 
 
 
 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
Note: Percentages based on number of patients by dose level. 
 
Table 10.2.1.9  Vital Signs Parameters by Dose Level. 
Vital signs 
DL I 
DL II 
· · · 
DL  n 
Total 
Heart rate  (beats / minute)  
 
 
 
 
N 
 
 
 
 
 
Mean 
 
 
 
 
 
Median 
 
 
 
 
 
Min 
 
 
 
 
 
Max 
 
 
 
 
 
STD 
 
 
 
 
 
 
 
 
 
 
 
   BPS (mmHg) 
 
 
 
 
 
N 
 
 
 
 
 
Median 
 
 
 
 
 
Min 
 
 
 
 
 
Max 
 
 
 
 
 
STD 
 
 
 
 
 
   BPD (mmHg) 
 
 
 
 
 
N 
 
 
 
 
 
Mean 
 
 
 
 
 
Median 
 
 
 
 
 
Min 
 
 
 
 
 
Max 
 
 
 
 
 
STD 
 
 
 
 
 
   Temperature  (ºC) 
 
 
 
 
 
N 
 
 
 
 
 
Mean 
 
 
 
 
 


 
39
Vital signs 
DL I 
DL II 
· · · 
DL  n 
Total 
Median 
 
 
 
 
 
Min 
 
 
 
 
 
Max 
 
 
 
 
 
STD 
 
 
 
 
 
 
Table 10.2.1.10  ECG Result by Dose Level. 
Physical Examination 
DL I 
DL II 
· · · 
DL  n 
Total 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
Normal  
 
 
 
 
 
 
 
 
 
 
Abnormal* 
 
 
 
 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
Notes: Percentages based on number of patients by dose level. (*) If abnormal, a supportive listing will show detailed information. 
 
Table 10.2.1.11  ECG Parameters by Dose Level. 
ECG 
DL I 
DL II 
· · · 
DL  n 
Total 
PR  interval  (msec) 
 
 
 
 
 
N 
 
 
 
 
 
Mean 
 
 
 
 
 
Median 
 
 
 
 
 
Min 
 
 
 
 
 
Max 
 
 
 
 
 
STD 
 
 
 
 
 
QT interval  (msec) 
 
 
 
 
 
N 
 
 
 
 
 
Mean 
 
 
 
 
 
Median 
 
 
 
 
 
Min 
 
 
 
 
 
Max 
 
 
 
 
 
STD 
 
 
 
 
 
RR interval  (msec) 
 
 
 
 
 
N 
 
 
 
 
 
Mean 
 
 
 
 
 
Median 
 
 
 
 
 
Min 
 
 
 
 
 
Max 
 
 
 
 
 
STD 
 
 
 
 
 
QRS interval  (msec) 
 
 
 
 
 
N 
 
 
 
 
 
Mean 
 
 
 
 
 
Median 
 
 
 
 
 
Min 
 
 
 
 
 
Max 
 
 
 
 
 
STD 
 
 
 
 
 
QTcF * (msec) 
 
 
 
 
 
N 
 
 
 
 
 
Mean 
 
 
 
 
 
Median 
 
 
 
 
 
Min 
 
 
 
 
 
Max 
 
 
 
 
 
STD 
 
 
 
 
 
Note: (*) Fridericia method. 


 
40
 
Table 10.2.1.12  Median LVEF for Patients with Previous Treatment with Anthracyclines by Dose Level. 
LVEF 
DL I 
DL II 
· · · 
DL  n 
Total 
          Anthracyclines 
 
 
 
 
 
N 
 
 
 
 
 
Mean 
 
 
 
 
 
Median 
 
 
 
 
 
Min 
 
 
 
 
 
Max 
 
 
 
 
 
STD 
 
 
 
 
 
Non Anthracyclines 
 
 
 
 
 
N 
 
 
 
 
 
Mean 
 
 
 
 
 
Median 
 
 
 
 
 
Min 
 
 
 
 
 
Max 
 
 
 
 
 
STD 
 
 
 
 
 
         Total 
 
 
 
 
 
N 
 
 
 
 
 
Mean 
 
 
 
 
 
Median 
 
 
 
 
 
Min 
 
 
 
 
 
Max 
 
 
 
 
 
STD 
 
 
 
 
 
 
10.2.2. Cancer History. 
Table 10.2.2.1  Time from Diagnosis to First Infusion. 
Time from Diagnosis to First Infusion 
(years) 
DL I 
DL II 
· · · 
DL n 
Total 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
N 
 
 
 
 
 
 
 
 
 
 
Mean 
 
 
 
 
 
 
 
 
 
 
Median 
 
 
 
 
 
 
 
 
 
 
Min 
 
 
 
 
 
 
 
 
 
 
Max 
 
 
 
 
 
 
 
 
 
 
STD 
 
 
 
 
 
 
 
 
 
 
 
Table 10.2.2.2  Time from last PD to First Infusion. 
Time from Last PD to First Infusion 
(months) 
DL I 
DL II 
· · · 
DL n 
Total 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
N 
 
 
 
 
 
 
 
 
 
 
Mean 
 
 
 
 
 
 
 
 
 
 
Median 
 
 
 
 
 
 
 
 
 
 
Min 
 
 
 
 
 
 
 
 
 
 
Max 
 
 
 
 
 
 
 
 
 
 
STD 
 
 
 
 
 
 
 
 
 
 
 
Table 10.2.2.3  TTP of Last Prior Therapy. 
TTP in months of last Prior Therapy  
DL I 
DL II 
· · · 
DL n 
Total 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 


 
41
TTP in months of last Prior Therapy  
DL I 
DL II 
· · · 
DL n 
Total 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
N 
 
 
 
 
 
 
 
 
 
 
Mean 
 
 
 
 
 
 
 
 
 
 
Median 
 
 
 
 
 
 
 
 
 
 
Min 
 
 
 
 
 
 
 
 
 
 
Max 
 
 
 
 
 
 
 
 
 
 
STD 
 
 
 
 
 
 
 
 
 
 
 
Table 10.2.2.4  Tumor type by Dose Level. 
Tumor type* 
DL I 
DL II 
· · · 
DL  n 
Total 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
Breast 
 
 
 
 
 
 
 
 
 
 
· · · * 
 
 
 
 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
Notes:  Percentages based on number of patients by dose level. (*) CRF categories will be shown and categories will be susceptible of clinical coding, if requested. A 
supportive table 10.2.2.6.a will be provided for subcategories. (e.g: sarcomas). 
 
Table 10.2.2.5  Summary of Cancer History per Patient and Tumor type. 
Dose 
level 
Patient 
No 
Primary tumor 
site 
Histology 
 
  …….* 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Notes: (*)  Stage at diagnosis,  Histology grade ,  Date of first diagnosis, Current  stage  (date),  date  of  last PD before  study entry, TTP to prior therapy, best response to 
last prior therapy. Also characteristics of patients by specific tumor type, e.g: smoker, etc… If required, tabulations for specific categories will be shown as Supportive 
tables. 
 
10.2.3. Sites Involved. 
Table 10.2.3.1  No of Sites Involved by Tumor type and Dose Level. 
Tumor Type* No of Sites 
DL I 
DL II 
· · · 
DL n 
Total 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
Breast 
1  Sites 
 
 
 
 
 
 
 
 
 
 
 
2  Sites 
 
 
 
 
 
 
 
 
 
 
 
> 2 
 
 
 
 
 
 
 
 
 
 
…..* 
1  Sites 
 
 
 
 
 
 
 
 
 
 
 
2  Sites 
 
 
 
 
 
 
 
 
 
 
 
> 2 
 
 
 
 
 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
Notes:  Percentages based on number of patients by dose level. (*) Coded tumor types. 
 
Table 10.2.3.2  Summary Statistics. No of Sites Involved by Tumor type Dose Level. 
Tumor Type* 
Median, range and STD for 
No. of sites involved 
DL I 
DL II 
· · · 
DL n 
Total 
Breast 
N** 
 
 
 
 
 
……* 
 
 
 
 
 
 
Notes: (*) Coded tumor types.  (**)  N, mean, STD, median and range. 


 
42
 
Table 10.2.3.3  Frequency of Patients Classified by Sites Involved by Tumor type and Dose Level. 
Tumor Type* 
Site** 
DL I 
DL II 
· · · 
DL  n 
Total 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
Breast 
CNS 
 
 
 
 
 
 
 
 
 
 
 
Liver 
 
 
 
 
 
 
 
 
 
 
…..* 
.... 
 
 
 
 
 
 
 
 
 
 
Notes:  Percentages based on number of patients by dose level. (* and **) Coded tumor types and sites will be recoded, if required. 
 
Table 10.2.3.4  Listing of Sites per Patient. 
Dose 
level 
Patient 
No 
Tumor type* 
Target/Non target 
Method 
Diameter (mm) 
 
 
 
 
 
 
 
 
 
 
 
 
Note: (*) Coded tumor types. 
 
Table 10.2.3.5  Bulky disease by Tumor type and Dose Level. 
Tumor type* 
Maximum 
diameter 
DL I 
DL II 
· · · 
DL  n 
Total 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
Breast 
≥ 50 mm 
 
 
 
 
 
 
 
 
 
 
 
< 50 mm 
 
 
 
 
 
 
 
 
 
 
...... 
 
 
 
 
 
 
 
 
 
 
 
Notes:  Percentages based on number of patients by dose level. (*) Coded tumor types. 
 
Table 10.2.3.6  Median sum of diameter of target lesions (mm). 
Tumor type* 
Median and range for sum of 
target lesions (mm) 
DL I 
DL II 
· · · 
DL n 
Total 
Breast 
N** 
 
 
 
 
 
…… 
 
 
 
 
 
 
Notes: (*) Coded tumor types (**) N, mean, STD, median and range. 
 
10.2.4. Previous Treatment Summary. 
Table 10.2.4.1  Previous Treatment Summary by Dose Level. 
Previous Treatment 
DL I 
DL II 
· · · 
DL  n 
Total 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
Systemic Therapy 
 
 
 
 
 
 
 
 
 
 
Surgery* 
 
 
 
 
 
 
 
 
 
 
Radiotherapy 
 
 
 
 
 
 
 
 
 
 
Systemic Therapy + Surgery* 
 
 
 
 
 
 
 
 
 
 
Systemic Therapy + Radiotherapy 
 
 
 
 
 
 
 
 
 
 
Systemic Therapy + Surgery*+ 
Radiotherapy  
 
 
 
 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
Notes:  Percentages based on number of patients by dose level. (*)  Curative / Palliative. 
 
Table 10.2.4.2  Previous Systemic Therapy by Dose Level/Tumor type. 
Tumor  type 
Previous Treatment 
DL I 
DL II 
· · · 
DL  n 
Total 


 
43
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
Breast 
Chemotherapy  
 
 
 
 
 
 
 
 
 
 
Biological therapy  
 
 
 
 
 
 
 
 
 
 
Hormonal therapy  
 
 
 
 
 
 
 
 
 
 
….…  
 
 
 
 
 
 
 
 
 
….. 
Total 
 
 
 
 
 
 
 
 
 
 
Note: (*)Adjuvant and /or neoadjuvant therapies are not included in this table, if required a supportive table for this therapies will be shown. 
 
 
10.2.5. Previous Surgery. 
Table 10.2.5.1  Previous Surgery by Dose Level (Curative/Palliative). 
Previous Surgery 
DL I 
DL II 
· · · 
DL  n 
Total 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
No  
 
 
 
 
 
 
 
 
 
 
Yes  
 
 
 
 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
Note: Percentages based on number of patients by dose level. 
 
10.2.6. Previous Radiotherapy. 
Table 10.2.6.1  Previous Radiotherapy by Dose Level. 
Previous 
Radiotherapy 
DL I 
DL II 
· · · 
DL  n 
Total 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
No  
 
 
 
 
 
 
 
 
 
 
Yes  
 
 
 
 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
Note:  Percentages based on number of patients by dose level. 
 
10.2.7. Previous Anticancer Medical Therapy. 
Table 10.2.7.1  Agents of Previous Anticancer Therapy (ATC level 1 & 4) by Dose Level/Tumor type. 
Medication* 
DL I 
DL II 
· · · 
DL n 
Total 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
ATC level 1 
 
 
 
 
 
 
 
 
 
 
 
ATC level 4 
 
 
 
 
 
 
 
 
 
 
 
· · · 
 
 
 
 
 
 
 
 
 
 
 
ATC level 4 
 
 
 
 
 
 
 
 
 
 
Notes:  Percentages based on number of patients by dose level. (*) A supportive table of Agents of Previous Chemotherapy will be displayed. Adjuvant and/or 
neoadjuvant therapies are not included in this table; if required, a supportive table for these therapies will be shown. 
 
Table 10.2.7.2  No of Lines of Prior Anticancer Therapy for Advanced Disease by Dose Level/Tumor type. 
No of lines* 
DL I 
DL II 
· · · 
DL n 
Total 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
0 lines 
 
 
 
 
 
 
 
 
 
 
1 line 
 
 
 
 
 
 
 
 
 
 
….. 
 
 
 
 
 
 
 
 
 
 
≥ N lines 
 
 
 
 
 
 
 
 
 
 


 
44
No of lines* 
DL I 
DL II 
· · · 
DL n 
Total 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
Total 
 
 
 
 
 
 
 
 
 
 
Notes: Percentages based on number of patients by dose level. (*) Adjuvant and /or neoadjuvant therapies are not included in this table and a supportive table of 
Agents of Previous Chemotherapy-containing Therapies for Advanced Disease will be displayed. 
 
Table 10.2.7.3  Summary Statistics. No of Lines of Prior Anticancer Therapy by Dose Level/Tumor type. 
Median and range for No of 
lines* 
DL I 
DL II 
· · · 
DL n 
Total 
N 
 
 
 
 
 
Mean 
 
 
 
 
 
Median 
 
 
 
 
 
Min 
 
 
 
 
 
Max 
 
 
 
 
 
STD 
 
 
 
 
 
Note: (*) Adjuvant and /or neoadjuvant therapies are not included in this table and a supportive table of Agents of Previous Chemotherapy-containing Therapies for 
Advanced Disease will be displayed. 
 
Table 10.2.7.4  No of Agents of Prior Anticancer Therapy by Dose Level/Tumor type. 
No of agents 
DL I 
DL II 
· · · 
DL  n 
Total 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
0 agents 
 
 
 
 
 
 
 
 
 
 
1 agent 
 
 
 
 
 
 
 
 
 
 
2 agents 
 
 
 
 
 
 
 
 
 
 
…. 
 
 
 
 
 
 
 
 
 
 
≥ N agents 
 
 
 
 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
Note: Percentages based on number of patients by dose level. Any agents used more than once will only add 1 to the total. 
 
Table 10.2.7.5  No of Agents of Last Prior Anticancer Therapy before PM01183 treatment by Dose Level/Tumor 
type. 
No of agents 
DL I 
DL II 
· · · 
DL  n 
Total 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
0 agents 
 
 
 
 
 
 
 
 
 
 
1 agent 
 
 
 
 
 
 
 
 
 
 
2 agents 
 
 
 
 
 
 
 
 
 
 
…. 
 
 
 
 
 
 
 
 
 
 
≥ N agents 
 
 
 
 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
Note: Percentages based on number of patients by dose level. Any agents used more than once will only add 1 to the total. 
 
Table 10.2.7.6  Summary Statistics. No of Agents of Prior Anticancer Therapy by Dose Level/Tumor type. 
Median and range for No of 
agents 
DL I 
DL II 
· · · 
DL  n 
Total 
N 
 
 
 
 
 
Mean 
 
 
 
 
 
Median 
 
 
 
 
 
Min 
 
 
 
 
 
Max 
 
 
 
 
 
STD 
 
 
 
 
 
 


 
45
Table 10.2.7.7  Listing of Agents of Prior Anticancer Therapy by Dose Level. 
Dose  level  Patient No Setting Type 
  …….* 
 Progression date 
 
 
 
 
 
 
 
 
 
 
 
 
(*)  Dose and units; Schedule, Start –End date and Best Response. 
 
Table 10.2.7.8  Agents of Prior Anticancer Therapy by Dose Level/Tumor type. 
Agents* 
DL I 
DL II 
· · · 
DL  n 
Total 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
Platinum 
 
 
 
 
 
 
 
 
 
 
…. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Notes: Percentages based on number of patients by dose level or by tumor type. Any agents used more than once will only add 1 to the total. (*)  Indicated by clinical 
request e.g: Anti-EGFR targeted therapies, Taxanes, Other investigational drugs, etc… 
 
Table 10.2.7.9  CTFI by Dose Level/Cohort/Tumor type 
CTFI/TFI* 
DL I 
DL II 
· · · 
DL  n 
Total 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
Resistant 
 
 
 
 
 
 
 
 
 
 
Sensitive 
 
 
 
 
 
 
 
 
 
 
…. 
 
 
 
 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
Note: (*) CTFI (Chemotheraphy Free Interval)/for SCLC patients and TFI (Systemic Chemotherapy Free Interval) for Endometrial patients. Calculated from the last 
therapy previous therapy with ATC coded ”L01XA”  and calculated  as the difference from the end of  therapy to the PD, e.g: for SCLC patients Categories  R 
(resistant) and S (sensitive).  
 
Table 10.2.7.10  Summary Statistics: CTFI by Dose Level/Cohort/Tumor type. 
Tumor type*/Median and 
range  
DL I 
DL II 
· · · 
DL  n 
Total 
N 
 
 
 
 
 
Mean 
 
 
 
 
 
Median 
 
 
 
 
 
Min 
 
 
 
 
 
Max 
 
 
 
 
 
STD 
 
 
 
 
 
Note: (*) Tumor type, if apply  
 
Table 10.2.7.11  Patients Previously Treated with Anthracyclines by Dose Level. 
Anthracyclines* 
DL I 
DL II 
· · · 
DL  n 
Total 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
Yes 
 
 
 
 
 
 
 
 
 
 
No 
 
 
 
 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
Note: (*) For those patients previously treated with anthracyclines a supportive listing 10.2.7.7.a will be given. 
 
Table 10.2.7.12  Summary Statistics: Cumulative Dose in Patients Previously Treated with Anthracyclines by 
Dose Level. 
Median and range  
DL I 
DL II 
· · · 
DL  n 
Total 
N 
 
 
 
 
 
Mean 
 
 
 
 
 
Median 
 
 
 
 
 
Min 
 
 
 
 
 
Max 
 
 
 
 
 


 
46
Median and range  
DL I 
DL II 
· · · 
DL  n 
Total 
STD 
 
 
 
 
 
 
 
10.2.8. Hematological Evaluation at Baseline. 
Table 10.2.8.1  Hematological Abnormalities at Baseline by Dose Level. 
Abnormality* 
DL I 
DL II 
· · · 
DL  n 
Total 
Anemia 
 
 
 
 
 
Grade 1 - 4, n (%) 
 
 
 
 
 
Grade 1 
 
 
 
 
 
Grade 2 
 
 
 
 
 
Grade 3 
 
 
 
 
 
Grade 4 
 
 
 
 
 
……* 
 
 
 
 
 
Grade 1 - 4, n (%) 
 
 
 
 
 
Grade 1 
 
 
 
 
 
Grade 2 
 
 
 
 
 
Grade 3 
 
 
 
 
 
Grade 4 
 
 
 
 
 
Notes: Baseline values obtained from last value recorded before or on the date of first infusion .Percentages based on number of patients by dose level/cohort. (*) Also 
Leukopenia, Lymphopenia, Neutropenia, and Thrombocytopenia. 
 
Table 10.2.8.2  Median and Range for Hematological Parameters at Baseline by Dose Level. 
Parameters* 
DL I 
DL II 
· · · 
DL  n 
Total 
Hemoglobin (g/dL) 
 
 
 
 
 
N 
 
 
 
 
 
Mean 
 
 
 
 
 
Median 
 
 
 
 
 
Min 
 
 
 
 
 
Max 
 
 
 
 
 
STD 
 
 
 
 
 
…..* 
 
 
 
 
 
Notes: Baseline values obtained from last value recorded before or on the date of first infusion.  Percentage based on number of patients by dose level. (*) Also 
Lymphocytes, WBC, Neutrophils, Platelets in 109 /L. 
 
Table 10.2.8.3  Supportive Listing: Patients with grade >1 Hematological Abnormalities at Baseline. 
 
Dose  level 
 
Patient 
Lab. test 
Cycle 
Examination date 
Std. value 
Grade NCI-
CTCAE v.4 
 
 
 
 
 
 
 
 
Table 10.2.8.4 Patients with Missing Hematological Evaluations at Baseline. 
Dose  level 
Patient 
Lab. test 
 
 
 
 
 
 
 


 
47
10.2.9. Biochemical Evaluation at Baseline. 
Table 10.2.9.1  Biochemical Abnormalities at Baseline by Dose Level. 
Abnormality* 
DL I 
DL II 
· · · 
DL  n 
Total 
AP increase 
 
 
 
 
 
Grade 1 - 4, n (%) 
 
 
 
 
 
Grade 1 
 
 
 
 
 
Grade 2 
 
 
 
 
 
Grade 3 
 
 
 
 
 
Grade 4 
 
 
 
 
 
……* 
 
 
 
 
 
Grade 1 - 4, n (%) 
 
 
 
 
 
Grade 1 
 
 
 
 
 
Grade 2 
 
 
 
 
 
Grade 3 
 
 
 
 
 
Grade 4 
 
 
 
 
 
Notes:  Baseline values obtained from last value recorded before or on the date of first infusion. Percentages based on number of patients by dose level. (*) All 
biochemical abnormalities susceptible to be graded with NCI-CTCAE v.4.   
 
Table 10.2.9.2  Median and Range for Biochemical Parameters at Baseline by Dose Level. 
Parameters* 
DL I 
DL II 
· · · 
DL  n 
Total 
AP  
 
 
 
 
 
N 
 
 
 
 
 
Mean 
 
 
 
 
 
Median 
 
 
 
 
 
Min 
 
 
 
 
 
Max 
 
 
 
 
 
STD 
 
 
 
 
 
….. * 
 
 
 
 
 
N 
 
 
 
 
 
Mean 
 
 
 
 
 
Median 
 
 
 
 
 
Min 
 
 
 
 
 
Max 
 
 
 
 
 
STD 
 
 
 
 
 
Note: (*) Baseline values obtained from last value recorded before or on the date of first infusion AP, AST, ALT, LDH, CPK, CPK MB and Amylase in IU/L. Total 
and direct bilirubin, creatinine, Alpha-1 acid glycoprotein, and LDL in mg/dl. Total proteins in g/dl and C-reactive protein in mg/l. 
 
Table 10.2.9.3  Supportive Listing: Patients with Grade >1 Biochemical Abnormalities at Baseline. 
Dose  level 
Patient 
Lab. test 
Cycle 
Examination date 
Std. value 
Grade NCI-
CTCAE v.4 
 
 
 
 
 
 
 
 
Table 10.2.9.4  Patients with Missing Biochemical Evaluations at Baseline. 
Dose  level 
Patient 
Lab. test 
 
 
 
 
 
 
 


 
48
10.2.10. 
Coagulation Evaluations at Baseline. 
Table 10.2.10. 1  Coagulation Abnormalities at Baseline by Dose Level. 
Abnormality 
DL I 
DL II 
· · · 
DL  n 
Total 
INR increase 
 
 
 
 
 
Grade 1 - 4, n (%) 
 
 
 
 
 
Grade 1 
 
 
 
 
 
Grade 2 
 
 
 
 
 
Grade 3 
 
 
 
 
 
Grade 4 
 
 
 
 
 
PTT 
 
 
 
 
 
Grade 1 - 4, n (%) 
 
 
 
 
 
Grade 1 
 
 
 
 
 
Grade 2 
 
 
 
 
 
Grade 3 
 
 
 
 
 
Grade 4 
 
 
 
 
 
Note:  Baseline values obtained from last value recorded before or on the date of first infusion. Percentages based on number of patients by dose level.  
 
Table 10.2.10. 2  Median and Range for Coagulation Parameters at Baseline by Dose Level. 
Parameters* 
DL I 
DL II 
· · · 
DL  n 
Total 
INR 
 
 
 
 
 
N 
 
 
 
 
 
Mean 
 
 
 
 
 
Median 
 
 
 
 
 
Min 
 
 
 
 
 
Max 
 
 
 
 
 
STD 
 
 
 
 
 
….. * 
 
 
 
 
 
Notes: (*) Baseline values obtained from last value recorded before or on the date of first infusion . INR: no units. PTT and  PT in seconds. 
 
Table 10.2.10. 3  Supportive Listing: Patients with Grade >1 Coagulation Abnormalities at Baseline. 
Dose  level 
Patient 
Lab. test 
Cycle 
Examination date 
Std. value 
Grade NCI-
CTCAE v.4 
 
 
 
 
 
 
 
 
Table 10.2.10. 4  Patients with Missing Coagulation Evaluations at Baseline. 
Dose  level 
Patient 
Lab. test 
 
 
 
 
 
 
 
10.2.11. 
Other Metabolic Evaluations at Baseline. 
 
Table 10.2.11. 1  Metabolic Abnormalities at Baseline by Dose Level. 
Abnormality* 
DL I 
DL II 
· · · 
DL  n 
Total 
Hypercalcemia 
 
 
 
 
 
Grade 1 - 4, n (%) 
 
 
 
 
 
Grade 1 
 
 
 
 
 
Grade 2 
 
 
 
 
 


 
49
Abnormality* 
DL I 
DL II 
· · · 
DL  n 
Total 
Grade 3 
 
 
 
 
 
Grade 4 
 
 
 
 
 
…..* 
 
 
 
 
 
Grade 1 - 4, n (%) 
 
 
 
 
 
Grade 1 
 
 
 
 
 
Grade 2 
 
 
 
 
 
Grade 3 
 
 
 
 
 
Grade 4 
 
 
 
 
 
Notes: Baseline values obtained from last value recorded before or on the date of first infusion. Percentages based on number of patients by dose level. (*)  All 
metabolic abnormalities susceptible to be graded with the NCI-CTCAE v.4. 
 
Table 10.2.11. 2  Median and Range for Metabolic Parameters at Baseline by Dose Level. 
Parameters* 
DL I 
DL II 
· · · 
DL  n 
Total 
Calcium 
 
 
 
 
 
N 
 
 
 
 
 
Mean 
 
 
 
 
 
Median 
 
 
 
 
 
Min 
 
 
 
 
 
Max 
 
 
 
 
 
STD 
 
 
 
 
 
….. * 
 
 
 
 
 
Notes:  (*)  Baseline values obtained from last value recorded before or on the date of first infusion. Sodium, potassium, chloride, glucose, magnesium and calcium in 
mmol/l., triglycerides and total cholesterol in mg/dL and albumin in g/dL. 
 
 Table 10.2.11. 3  Supportive Listing: Patients with grade >1 Metabolic Abnormalities at Baseline. 
Dose  level/ 
Patient 
Lab. test 
Cycle 
Examination date 
Std. value 
Grade NCI-
CTCAE v.4 
 
 
 
 
 
 
 
 
Table 10.2.11. 4  Patients with Missing Metabolic Evaluations at Baseline. 
Dose  level 
Patient 
Lab. test 
 
 
 
 
 
 
 
10.2.12. 
Signs and Symptoms at Baseline. 
Table 10.2.12. 1  Signs and Symptoms by Dose Level. 
MedDRA System 
Organ Class 
Preferred Term 
DL I 
· · · 
Total 
Gr. 1* 
Gr. 2 
Gr. 3 
Gr. 4 
Gr. 1 
Gr. 2 
Gr. 3 
Gr. 4 
Gr. 1 
Gr. 2 
Gr. 3 
Gr. 4 
n %
n %
n %
n % n %
n %
n %
n % n %
n % n % n % 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Notes: Percentages based on number of patients by dose level. (*) Grades may suffer modification (e.g. G 1 and G > 1), if requested. 
 
Table 10.2.12. 2  Listing of Adverse Events at Baseline Grade >1. 
Dose  level Patient No
Literal 
MedDRA 
Preferred Term 
NCI-CTCAE 
v.4 grade 
Start date Relationship Treated


 
50
Dose  level Patient No
Literal 
MedDRA 
Preferred Term 
NCI-CTCAE 
v.4 grade 
Start date Relationship Treated
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
10.2.13. 
Concomitant and Prophylactic Medication Starting Pre-Study. 
Table 10.2.13. 1  Concomitant Medication Starting Pre-Study (ATC Levels 1 and 4) by Dose Level. 
Medication Term 
(ATC level 1) 
Medication Term
(ATC level 2) 
Medication Term
(ATC level 4) 
DL I 
DL II 
· · · 
DL  n 
Total 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: Percentages based on number of patients by dose level. 
 
Table 10.2.13. 2   Concomitant Medication Starting Pre-Study (RBC and Platelet transfusions/EPO). 
Medication Term 
(ATC level 1) 
Medication Term
(ATC level 2) 
Medication Term
(ATC level 4) 
DL I 
DL II 
· · · 
DL n 
Total 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
Platelet transfusion  
 
 
 
 
 
 
 
 
 
 
 
RBC transfusion 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
Note: Percentages based on number of patients by dose level. 
 
Table 10.2.13. 3   Supportive Listing: RBC and Platelet transfusions/EPO (Pre-Study). 
Dose 
Level 
Patient No Cycle 
Type 
Literal Term 
ATC4 ATC2 ATC1 Route
…. 
Start 
date 
End 
date 
Reason for 
Use 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 10.2.13. 4 No of patients with Opioids Treatment at Baseline by Dose Level. 
Opioids*  
DL I 
DL II 
· · · 
DL n 
Total 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
…. 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
Note: (*) ATC classification including opioids and terms will be selected and provided by clinical request. 
 
Table 10.2.13. 5 Median number of No of Opioids per patient by Dose Level. 
Opioids* 
DL I 
DL II 
· · · 
DL  n 
Total 
N 
 
 
 
 
 
Mean 
 
 
 
 
 
Median 
 
 
 
 
 
Min 
 
 
 
 
 
Max 
 
 
 
 
 
STD 
 
 
 
 
 
(*)  The ATC classification including opioids and terms will be selected and provided by clinical request. 
 
Table 10.2.13. 6 No of patients with Steroids treatment at baseline by dose Level 
Steroids*  
DL I 
DL II 
· · · 
DL n 
Total 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
…. 
 
 
 
 
 
 
 
 
 
 


 
51
Steroids*  
DL I 
DL II 
· · · 
DL n 
Total 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
… 
 
 
 
 
 
 
 
 
 
 
Note: (*)  The ATC classification, including steroids and terms, will be selected and provided by clinical request. 
 
Table 10.2.13. 7 Known CYP 3A4 Inducers/Inhibitors/Substrates Concomitant Therapies at BL. 
CYP 3A4*  
DL I 
DL II 
· · · 
DL n 
Total 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
Inhibitor 
 
 
 
 
 
 
 
 
 
 
…. 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
Notes: (*) Also the possibility of displaying one table for each category Inducers/Inhibitors or substrates. Some medication will be excluded by clinical request (e.g. 
Dexamethasone). 
 
Table 10.2.13. 8 Listing of CYP 3A4 Inducers/Inhibitors/Substrates Concomitant Therapies at BL. 
Dose 
Level  
Patno 
Type* 
Literal Term 
ATC4 ATC2 ATC1
… 
Start 
date 
End 
date 
Reason for Use SS/AE Specify
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Notes: (*) Also the possibility of display onetable for each category Inducers/Inhibitors or substrates. Some medication will be excluded by clinical request (e.g. 
Dexamethasone). 


 
52
 
11. Appendix II. Safety Evaluation. 
All statistical outputs in this section, whenever applicable, will be displayed according to the 
discontinuation of the combination treatment. Treatment exposure, delays, omissions and 
reductions will be shown considering the whole study treatment and/or before and after 
discontinuation, if appropriate. 
Dose level may suffer categorization (e.g: RD ≤ or RD, Cohorts/Cancer type or primary 
site/CSF use or not/other clinical relevant variable), if required and if an adequate number of 
patients is represented. 
Each specific table and listing will have a comprehensive header identifying the group/cohort 
of treatment, whenever necessary. 
Summary tables will have source data footnotes that will refer to the relevant listings. The 
tables' layout may change to adequately accommodate cohort/group size as appropriate. 
11.1. Extent of Exposure. 
11.1.1. Cumulative Dose, Dose Intensity and Relative Dose Intensity. 
Table 11.1.1.1  No of Cycles Administered by Dose Level. 
  
Patients 
Dose level  
No. of 
cycles infused 
No. of patients  
with PM01183+Doxo 
No. of patients  
with PM01183 alone 
I 
1 Cycle 
 
 
2 Cycles 
 
 
…. 
 
 
II 
… 
1 Cycle 
 
 
2 Cycles 
 
 
… 
 
 
N 
1 Cycle 
 
 
2 Cycles 
 
 
… 
 
 
Total 
1 Cycle 
 
 
2 Cycles 
 
 
…. 
 
 
N Cycles 
 
 
 
Table 11.1.1.2  Median and Range of Cycles Administered by Dose Level. 
Drug 
Median range and STD of 
cycles administered 
DL I 
DL II 
· · · 
DL  n 
Total 
PM01183 + Doxorubicin 
N* 
 
 
 
 
 
PM01183 alone 
N* 
 
 
 
 
 
Total 
N* 
 
 
 
 
 
Note: (*) N, median, mean, range, and STD. 


 
53
 
Table 11.1.1.3  Cumulative Dose by Dose Level. 
Drug 
Cumulative dose  
DL I 
DL II 
· · · 
DL  n 
Total 
PM01183  
(mg) 
N 
 
 
 
 
 
Mean 
 
 
 
 
 
Median 
 
 
 
 
 
Min 
 
 
 
 
 
Max 
 
 
 
 
 
STD 
 
 
 
 
 
Doxorubicin 
(mg/m²) 
N 
 
 
 
 
 
Mean 
 
 
 
 
 
Median 
 
 
 
 
 
Min 
 
 
 
 
 
Max 
 
 
 
 
 
STD 
 
 
 
 
 
 
Table 11.1.1.4  Dose Intensity by Dose Level. 
Drug 
Dose  intensity  
DL I 
DL II 
· · · 
DL  n 
Total 
PM01183* 
 (mg/week) 
N 
 
 
 
 
 
Mean 
 
 
 
 
 
Median 
 
 
 
 
 
Min 
 
 
 
 
 
Max 
 
 
 
 
 
STD 
 
 
 
 
 
PM01183* 
 (mg/m²/week) 
N 
 
 
 
 
 
Mean 
 
 
 
 
 
Median 
 
 
 
 
 
Min 
 
 
 
 
 
Max 
 
 
 
 
 
STD 
 
 
 
 
 
Doxorubicin 
(mg/m²/week) 
N 
 
 
 
 
 
Mean 
 
 
 
 
 
Median 
 
 
 
 
 
Min 
 
 
 
 
 
Max 
 
 
 
 
 
STD 
 
 
 
 
 
(*) Results of dose intensity maybe grouped and presented in mg/m²/week for patients treated in the Cohort A, if appropriate.   
 
Table 11.1.1.5  Relative Dose Intensity by Dose Level. 
Drug 
Relative dose 
intensity (%) 
DL I 
DL II 
· · · 
DL  n 
Total 
PM01183 
N 
 
 
 
 
 
Mean 
 
 
 
 
 
Median 
 
 
 
 
 
Min 
 
 
 
 
 
Max 
 
 
 
 
 
STD 
 
 
 
 
 
Doxorubicin 
N 
 
 
 
 
 
Mean 
 
 
 
 
 
Median 
 
 
 
 
 
Min 
 
 
 
 
 
Max 
 
 
 
 
 
STD 
 
 
 
 
 


 
54
 
Table 11.1.1.6  Drug Administration: Patients that Reached the Maximal Cumulative Dose of 450 mg/m2. 
Dose level 
Patient No 
No. of Cycles 
PM01183 
No. of Cycles 
Doxorubicin 
Delay 
Delay specify
…..* 
 
 
 
 
 
 
 
Note: (*) Delays, omissions, reductions and specify. 
 
11.1.2. Cycle Delays and Omissions. 
Table 11.1.2.1  No of Patients with Delayed Cycles by Dose Level. 
No of patients with delayed 
cycles 
DL I 
DL II 
· · · 
DL  n 
Total 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
No  
 
 
 
 
 
 
 
 
 
 
Yes 
 
 
 
 
 
 
 
 
 
 
    Any DR* 
 
 
 
 
 
 
 
 
 
 
    All NDR** 
 
 
 
 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
Notes: Percentages based on number of patients by dose level. (*)  Drug related (**) Non -drug related. 
 
Table 11.1.2.2  No of Patients with Dose Delayed by Dose Level According to Relationship. 
No of cycles delayed 
DL I 
DL II 
· · · 
DL  n 
Total 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
No  
 
 
 
 
 
 
 
 
 
 
 
Yes 
Drug Related 
 
 
 
 
 
 
 
 
 
 
Hematological 
 
 
 
 
 
 
 
 
 
 
Non Hematological 
 
 
 
 
 
 
 
 
 
 
Both 
 
 
 
 
 
 
 
 
 
 
Non Drug Related 
 
 
 
 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
Note: Percentages based on number of cycles susceptible of delay by dose level. 
 
Table 11.1.2.3  No of Cycles Delayed Per Patient by Dose Level. 
No patients with : 
DL I 
DL II 
· · · 
DL  n 
Total 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
No cycle delayed 
 
 
 
 
 
 
 
 
 
 
01 cycle delayed 
 
 
 
 
 
 
 
 
 
 
02 cycles delayed 
 
 
 
 
 
 
 
 
 
 
· · · 
 
 
 
 
 
 
 
 
 
 
N cycles delayed 
 
 
 
 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
Note: Percentages based on number of patients by dose level. 
 
Table 11.1.2.4  No of Cycles Delayed Per Patient by Dose Level. Summary Statistics. 
No patients with delays
DL I 
DL II 
· · · 
DL  n 
Total 
N 
 
 
 
 
 
Median 
 
 
 
 
 
Min 
 
 
 
 
 
Max 
 
 
 
 
 
STD 
 
 
 
 
 
 


 
55
Table 11.1.2.5  Number of Cycles with Drug Related Delay per Patient by Dose Level. 
No cycles with : 
DL I 
DL II 
· · · 
DL  n 
Total 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
No cycle delayed 
 
 
 
 
 
 
 
 
 
 
01 cycle delayed 
 
 
 
 
 
 
 
 
 
 
02 cycles delayed 
 
 
 
 
 
 
 
 
 
 
· · · 
 
 
 
 
 
 
 
 
 
 
N cycles delayed 
 
 
 
 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
 
Table 11.1.2.6 Number of Cycles with Drug Related Delay per Patient by Dose Level. Summary Statistics. 
No cycles with delays 
DL I 
DL II 
· · · 
DL  n 
Total 
N 
 
 
 
 
 
Median 
 
 
 
 
 
Min 
 
 
 
 
 
Max 
 
 
 
 
 
STD 
 
 
 
 
 
 
Table 11.1.2.7  Length of Delay According to relationship by Dose Level. Summary Statistics. 
Relationship 
DL I 
DL II 
· · · 
DL  n 
Total 
Hematological 
 
 
 
 
 
N 
 
 
 
 
 
Mean 
 
 
 
 
 
Median 
 
 
 
 
 
Min 
 
 
 
 
 
Max 
 
 
 
 
 
STD 
 
 
 
 
 
Non Hematological 
 
 
 
 
 
N 
 
 
 
 
 
Mean 
 
 
 
 
 
Median 
 
 
 
 
 
Min 
 
 
 
 
 
Max 
 
 
 
 
 
STD 
 
 
 
 
 
Both 
 
 
 
 
 
N 
 
 
 
 
 
Mean 
 
 
 
 
 
Median 
 
 
 
 
 
Min 
 
 
 
 
 
Max 
 
 
 
 
 
STD 
 
 
 
 
 
Total 
 
 
 
 
 
N 
 
 
 
 
 
Mean 
 
 
 
 
 
Median 
 
 
 
 
 
Min 
 
 
 
 
 
Max 
 
 
 
 
 
STD 
 
 
 
 
 
 


 
56
Table 11.1.2.8  Listing of Patient with Dose Delays. 
Dose  level
Patient No 
Cycle 
Date 
 
Intended dose 
 
 
Total dose 
 
Length of 
Delay 
Delay 
Reason 
Delay specify 
 
 
 
 
 
 
 
 
 
 
Table 11.1.2.9  Supportive Listing: Dose Delays Excluding Administrative Reasons. 
Dose level
Patient No 
Cycle 
Date 
 
Intended dose 
 
 
Total dose 
 
Length of 
Delay 
Delay 
Reason 
Delay specify 
 
 
 
 
 
 
 
 
 
Note: (*) Excluding administrative reasons. 
 
Table 11.1.2.10  No. of Patients with Doxorubicin Omissions by Dose Level. 
No of patients with any dosage 
omitted 
DL I 
DL II 
· · · 
DL  n 
Total 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
Omitted 
 
 
 
 
 
 
 
 
 
 
Maintained 
 
 
 
 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
Note:  Percentages based on number of patients by dose level. 
 
Table 11.1.2.11  No of Patients with Doxorubicin Cycles Omission by Dose Level. 
No of patients with cycles 
omitted 
DL I 
DL II 
· · · 
DL  n 
Total 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
No omission 
 
 
 
 
 
 
 
 
 
 
1 cycle 
 
 
 
 
 
 
 
 
 
 
2 cycles 
 
 
 
 
 
 
 
 
 
 
· · · 
 
 
 
 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
Note:  Percentages based on number of patients by dose level. 
 
Table 11.1.2.12  Listing of Doxorubicin Dose Omissions. 
Dose level  
Patient No 
Cycle 
DA Start 
 Date 
DA infusion omitted?
DA Omission   
reason 
Specify 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 11.1.2.13  Listing of Cycles Delays due to Hematological Abnormalities. 
Dose level  
Patient No 
Total number of 
cycles received 
Cycle numbers 
with dose delay 
due to …* 
Cycle numbers with dose 
delay not due to …* 
Cycle  numbers  with 
…** 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Notes: (*/**) Also Leukopenia /CSF, Anemia / EPO, Thrombocytopenia / platelet transfusions. Narratives with the information contained in the tables will be 
provided instead of tables only if a low number of dose delays occur. 
 


 
57
Table 11.1.2.14  Listing of Cycles Delays due to Non-Hematological Adverse Events. 
Dose level  
Patient No 
Total number of 
cycles received 
Cycle numbers 
with dose delays 
due to …* 
Cycle numbers with dose 
delays not due to …* 
Cycle numbers without 
adequate prophylaxis 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Notes: (*)Adverse event. Narratives with the information contained in the tables will be provided instead of tables only if a low number of dose delays are found. 
 
11.1.3. Dose Reductions. 
Table 11.1.3.1  No of Patients with PM01183 Dose Reduction by Dose Level. 
No of patients with any dose 
modified 
DL I 
DL II 
· · · 
DL  n 
Total 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
Reduced 
 
 
 
 
 
 
 
 
 
 
No reduced 
 
 
 
 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
Note:  Percentages based on number of patients by dose level. 
 
Table 11.1.3.2  No of Patients with PM01183 Cycles Dose Reduction by Dose Level. 
No of patients with cycles 
reduced 
DL I 
DL II 
· · · 
DL  n 
Total 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
1 reduction 
 
 
 
 
 
 
 
 
 
 
2 reductions 
 
 
 
 
 
 
 
 
 
 
· · · 
 
 
 
 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
Note:  Percentages based on number of patients by dose level. 
 
Table 11.1.3.3  Reasons for PM01183 Dose Reduction by Dose Level. 
No of patients with cycles reduced
DL I 
DL II 
· · · 
DL  n 
Total 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
No dose  reduction 
 
 
 
 
 
 
 
 
 
 
Hematological 
 
 
 
 
 
 
 
 
 
 
Non-hematological 
 
 
 
 
 
 
 
 
 
 
Both (hematological and non-
hematological) 
 
 
 
 
 
 
 
 
 
 
Other 
 
 
 
 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
Note: Percentages based on number of patients by dose level. 
 
Table 11.1.3.4  Listing of PM01183 Dose Reductions. 
Dose level  
Patient No 
Cycle 
DA Start 
 Date 
DA infusion 
reduced? 
% of reduction 
DA Reduce  
reason 
Specify 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
58
Table 11.1.3.5  Listing of Dose Reductions due to Hematological Abnormalities. 
Dose level  
Patient No 
Total number of 
cycles received 
Cycle numbers 
with dose 
reduction due to 
…* 
Cycle numbers with dose 
reduction not due to …* Cycle numbers with …**
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Notes: (*/**) Also Leukopenia/CSF, Anemia / EPO, Thrombocytopenia / platelet transfusions. 
 
Table 11.1.3.6  Listing of Dose Reductions due to Non-Hematological Adverse Events. 
Dose level  
Patient No 
Total number of 
cycles received 
Cycle numbers 
with dose 
reduction due to 
…* 
Cycle numbers with dose 
reduction not due to …*
Cycle numbers  without 
adequate prophylaxis 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: (*) Adverse event. 
 
11.1.4. Dose Interruption and Re-administration. 
Table 11.1.4. 1  Listing of Patients with Dose Interruption and Re-administration. 
Dose level Patient No Cycle 
Infusion Day 
1/Day 8 
Drug 
Was infusion  
interrupted? 
Reason  
               
Date Intended dose
Total dose 
Total Volume
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
11.2. Dose-Limiting Toxicities. 
11.2.1. Dose-Limiting Toxicities. 
Table 11.2.1.1  Summary of Patients with DLT by Dose Level. 
G-CSF factors 
Dose  level  
N 
Patients with DLT 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 11.2.1.2  Characteristics of Patients with DLT by Dose Level. 
G-CSF factors
Dose  level  
Patient 
Id 
Cycle 
DLT Description
NCI-CTCAE v.4.0 
Grade 
……..* 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: (*) Onset –Resolved date, Relation (Specify), Action taken and Main Consequences. 


 
59
11.3. Adverse Events (AEs). 
11.3.1. Display of Adverse Events. 
All adverse events tables will be listed by cohort and dose level (or most adequate dose 
grouping/tumor type/other clinical relevant variable or according to the discontinuation of the 
combination treatment, if required). 
Table 11.3.1.1  Combination (PM01183-Doxorubicin) Related (or Relationship Unknown) Adverse Events. 
Worst Grade by Patient and Dose Level. 
Table 11.3.1.2  PM01183-Only Related (or Relationship Unknown) Adverse Events. Worst Grade by Patient and 
Dose Level. 
Table 11.3.1.3  Doxorubicin-Only Related (or Relationship Unknown) Adverse Events. Worst Grade by Patient 
and Dose Level. 
Table 11.3.1.4  Combination (PM01183-Doxorubicin) Related (or Relationship Unknown) Adverse Events in the 
First Cycle by Patient and Dose Level. 
Table 11.3.1.5  PM01183-Only Related (or Relationship Unknown) Adverse Events in the First Cycle by Patient 
and Dose Level. 
Table 11.3.1.6  Doxorubicin-Only Related (or Relationship Unknown) Adverse Events in the First Cycle by 
Patient and Dose Level. 
Table 11.3.1.7  Combination (PM01183-Doxorubicin) Related (or Relationship Unknown) Adverse Events. 
Worst Grade Per Cycle by Dose Level. 
Table 11.3.1.8  PM01183-Only Related (or Relationship Unknown) Adverse Events. Worst Grade Per Cycle by 
Dose Level. 
Table 11.3.1.9  Doxorubicin-Only Related (or Relationship Unknown) Adverse Events. Worst Grade Per Cycle 
by Dose Level. 
Table 11.3.1.10  Combination (PM01183-Doxorubicin) Related (or Relationship Unknown) Adverse Events 
Observed in ≥10% of Patients Treated by Dose Level. 
Table 11.3.1.11  PM01183-Only Related (or Relationship Unknown) Adverse Events Observed in ≥10% of 
Patients Treated by Dose Level. 
Table 11.3.1.12  Doxorubicin-Only Related (or Relationship Unknown) Adverse Events Observed in ≥10% of 
Patients Treated by Dose Level. 
Table 11.3.1.13  Combination (PM01183-Doxorubicin) Related (or Relationship Unknown) Adverse Events 
Observed in ≥ 10% of Patients Treated. Worst grade per Cycle by Dose Level. 
Table 11.3.1.14  PM01183-Only Related (or Relationship Unknown) Adverse Events Observed in ≥10% of 
Patients Treated. Worst grade per Cycle by Dose Level. 
Table 11.3.1.15  Doxorubicin-Only Related (or Relationship Unknown) Adverse Events Observed in ≥10% of 
Patients Treated. Worst grade per Cycle by Dose Level. 
Table 11.3.1.16  Adverse Events Regardless of Relationship. Worst Grade by Patient by Dose Level. 
Table 11.3.1.17  Adverse Events Regardless of Relationship in the First Cycle by Patient and Dose Level. 
Table 11.3.1.18  Adverse Events Regardless of Relationship. Worst Grade per Cycle by Dose Level. 
Table 11.3.1.19  Adverse Events Observed in ≥ 10% of Patients Treated by Dose Level. 
Table 11.3.1.20  Adverse Events Observed in ≥ 10% of Patients Treated. Worst grade per Cycle by Dose Level. 
 


 
60
Tables 11.3.1.1-.20 will have the following pattern but DL and Grade column might be grouped if required. 
MedDRA System Organ 
Class 
Preferred Term 
DL I 
· · · 
DL n 
Total 
Gr. 1 Gr. 2 Gr. 3 Gr. 4 Gr. 1 Gr. 2 Gr. 3 Gr. 4 Gr. 1 Gr. 2 Gr. 3 Gr. 4 Gr. 1 Gr. 2 Gr. 3 Gr. 4
n % n % n % n % n % n % n % n % n % n % n % n % n % n % n % n %
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Note: Percentages based on number of patients/cycles by dose level. 
 
Table 11.3.1.21  Supportive Listing: Drug Related (or Relationship Unknown) Adverse Events Grade 3-4 by 
Dose Level. 
Dose level Patient 
SOC 
MedDRA 
Preferred 
Term 
Literal 
term 
Grade 
SAE  
(Y/N) 
Onset 
Date 
Resolved 
Date 
Relationship 
to Study 
Drug 
Action 
Taken 
Main 
Consequence
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 11.3.1.22 Time to course to Alopecia Grade >1. 
Dose level  
Patient 
Grade at 
Baseline 
Grade 
Onset Date 
Resolved 
Date 
Time in days * Action Taken
Main 
Consequence 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(*) Time in days calculated as the difference between Onset date and DA first drug administration. 
 
11.4. Deaths and Other Serious Adverse Events. 
11.4.1. Deaths. 
Table 11.4.1.1  Patients who Died While on Treatment. 
Dose 
level 
Patient 
No 
Last cycle 
received 
Last infusion 
date 
Death 
date 
Time from last 
infusion date (days)
Cause 
Comments 
Time on treatment 
(weeks) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: Patients with death reported as end of treatment reason. 
 
Table 11.4.1.2  Patients Who Died Within 30 Days of Last Drug Administration. 
Dose 
level 
Patient 
No 
Last cycle 
received 
Last infusion 
date 
Death 
date 
Time from last 
infusion date (days)
Cause 
Comments 
Time on treatment 
(weeks) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 11.4.1.3  Listing of All Deaths. 
Dose 
level 
Patient 
No 
Last cycle 
received
Last 
infusion 
date 
Death date
Cause 
Comments 
Autopsy 
Time on  
treatment 
(weeks) 
Time from last 
infusion date 
(days) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
61
11.4.2. Serious Adverse Events. 
All serious adverse events will be listed only for the purpose of reconciliation with the 
database of pharmacovigilance. The listings provided by the Product Safety department will 
be used for the clinical study report. 
  
Table 11.4.2.1  All SAEs. 
Dose 
level Patient Cycle
MedDRA 
System Organ 
Class 
Preferred 
Term 
Grade
AE 
Status 
AE 
relationship
AE 
consequences SAE
Onset 
date 
Resolved 
date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
11.5. Clinical Laboratory Evaluation. 
11.5.1. Hematological Abnormalities. 
Table 11.5.1.1  Hematological Abnormalities: Worst Grade per Patient by Dose Level. 
Table 11.5.1.2  Hematological Abnormalities: Worst Grade per Cycle by Dose Level. 
Table 11.5.1.3  Hematological Abnormalities: Worst Grade per patient in the First Cycle by Dose Level. 
Tables 11.5.1.1-.3 will have the following pattern but DL and Grade columns might be grouped if required. 
Abnormality* 
DL I 
DL II 
· · · 
DL  n 
Total 
Anemia 
 
 
 
 
 
Grade 1 - 4, n (%) 
 
 
 
 
 
Grade 1 
 
 
 
 
 
Grade 2 
 
 
 
 
 
Grade 3 
 
 
 
 
 
Grade 4 
 
 
 
 
 
…..* 
 
 
 
 
 
Grade 1 - 4, n (%) 
 
 
 
 
 
Grade 1 
 
 
 
 
 
Grade 2 
 
 
 
 
 
Grade 3 
 
 
 
 
 
Grade 4 
 
 
 
 
 
Notes:  Percentage s based on number of patients by dose level. (*) Also Leukopenia, Lymphopenia, Neutropenia, and Thrombocytopenia. 
 
Table 11.5.1.4  Supportive Listing: Patients with Grade 4 Hematological Abnormalities. 
Dose level 
Patient 
Lab. test 
Cycle 
Examination  
date 
…….* 
 
 
 
 
 
 
 
 
 
 
 
 
Notes: (*)  Include the following: Value at BL, Grade at BL, Onset day, Onset grade, Nadir day, Nadir value, Nadir grade, Recovery day, Recovery value, Recovery 
grade, Days Grade 4. 
 
Table 11.5.1.5  Patients with Missing Hematological Evaluations. 
Dose level/CSF 
Patient 
Cycle  
Lab. test 


 
62
Dose level/CSF 
Patient 
Cycle  
Lab. test 
 
 
 
 
 
 
 
 
 
Table 11.5.1.6  Shift of Hematological Abnormalities. Baseline Grade vs. Worst Grade on First Cycle. 
Dose level/Parameter* 
Baseline Grade 
Worst Grade on First Cycle 
Gr. 1 
Gr. 2 
Gr. 3 
Gr. 4 
N 
% 
N 
% 
N 
% 
N 
% 
DL I 
Anemia 
0 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
4 
 
 
 
 
 
 
 
 
…… 
0 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
4 
 
 
 
 
 
 
 
 
… 
Anemia 
0 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
4 
 
 
 
 
 
 
 
 
… 
0 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
4 
 
 
 
 
 
 
 
 
Total 
Anemia 
0 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
4 
 
 
 
 
 
 
 
 
… 
 
0 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
4 
 
 
 
 
 
 
 
 
Notes: Percentages based on number of patients by dose level. (*) Also Leukopenia, Lymphopenia, Neutropenia and Thrombocytopenia. 
 
Table 11.5.1.7  Shift of Hematological Abnormalities. Baseline Grade vs. Worst Grade on Treatment. 
Dose level/Parameter* 
Baseline Grade 
Worst Grade during on Treatment 
Gr. 1 
Gr. 2 
Gr. 3 
Gr. 4 
N 
% 
N 
% 
N 
% 
N 
% 
DL I 
Anemia 
0 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
4 
 
 
 
 
 
 
 
 
…… 
0 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
4 
 
 
 
 
 
 
 
 
… 
Anemia 
0 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
4 
 
 
 
 
 
 
 
 
… 
0 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
4 
 
 
 
 
 
 
 
 
Total 
Anemia 
0 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
4 
 
 
 
 
 
 
 
 
… 
 
0 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
4 
 
 
 
 
 
 
 
 


 
63
Notes:  Percentages based on number of patients by dose level. (**) Leukopenia, Lymphopenia, Neutropenia and Thrombocytopenia. 
 
Table 11.5.1.8 Listing of Patients with Hematological Abnormalities >G2 and Experience Grade Increase (wpp) 
from Baseline. 
Dose level 
Patient 
Event* 
NCI-CTCAE v.4  
at baseline 
NCI-CTCAE v.4 
at Cycle 
Cycle 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 11.5.1.9  Summary of Characteristics of wpp Hematological Abnormailities G3-4.  
Dose Level 
Parameter 
N/(%)* 
Mean** 
Median** 
Range** 
 
 
 
 
 
 
 
 
 
 
 
 
Notes: (*) Percentages based on number of patients by dose level with grade 3-4. (**) Cycle occurrence. 
 
Table 11.5.1.10  Summary of Hematological Abnormalities Grade 4 and specific Transfusions/treatment. 
Dose level 
Patient 
Cycles 
received 
Cycle number with 
hematological abnormality 
* 
grade 4 
Cycle numbers  with  
….** 
Cycle  numbers  with 
dose reduction 
 
 
 
 
 
 
Note: (*) Neutropenia/CSF administration. Thrombocytopenia / Platelets transfusion and Anemia / EPO. 
 
Table 11.5.1.11  Anemia wpp/wpc and Use of EPO per Dose Level in Cycle >1. 
EPO/Dose Level 
Worst Grade on Treatment*/Cycle* 
Gr. 1-2 
Gr. 3 
Gr. 4 
Total 
N 
% 
N 
% 
N 
% 
N 
% 
EPO 
DL I 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
…… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
No EPO 
DL I 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
…… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 11.5.1.12   Patients with Anemia Grade 3/4 and Use of EPO in Cycle >1. 
Dose Level 
Tumor type 
Patno 
Cycle 
Prophylaxis CSF (Y/N) 
* 
 
 
 
 
 
 
 
 
 
 
 
 
Notes: (*) Grade, nadir day to grade 3/4, recovery day to grade ≤3,** duration in days to grade 3**, (**) Grade 2 or 1 also if clinically indicated (***) Numeric 
intervals in days might change upon request. 
 
Table 11.5.1.13   Platelet Count Time Course Pattern (summary). 
Parameter* 
DL I 
 · · · 
DL  n 


 
64
Parameter* 
DL I 
 · · · 
DL  n 
Platelet  transfusion 
 
 N   Median   Range 
N   Median   Range 
N   Median   Range 
 Baseline grade  0 
Onset day grade 4 
1st cycle 
 
 
 
 Cycle >1 
 
 
 
Total 
 
 
 
Baseline grade  > 0 
Onset day grade 4 
1st cycle 
 
 
 
 Cycle >1 
 
 
 
Total 
 
 
 
No  Platelet transfusion 
 
 N   Median   Range 
N   Median   Range 
N   Median   Range 
 Baseline grade  0 
Onset day grade 4 
1st cycle 
 
 
 
 Cycle >1 
 
 
 
Total 
 
 
 
Baseline grade  > 0 
Onset day grade 4 
1st cycle 
 
 
 
 Cycle >1 
 
 
 
Total 
 
 
 
Totals 
 
 N   Median   Range 
N   Median   Range 
N   Median   Range 
 Baseline grade  0 
Onset day grade 4 
1st cycle 
 
 
 
 Cycle >1 
 
 
 
Total 
 
 
 
Baseline grade  > 0 
Onset day grade 4 
1st cycle 
 
 
 
 Cycle >1 
 
 
 
Total 
 
 
 
Notes: (*) Also 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 and duration in days to grade 1. Grade limits may change under request. 
 
Table 11.5.1.14   Platelet Count Time Course Pattern. 
Parameter* 
DL I 
 · · · 
DL  n 
Platelet transfusion 
                                                                Onset day grade 4 
 N                % 
N                % 
N                % 
 Baseline grade  0 
1st cycle 
≤ 7*** 
 
 
 
8-14 
 
 
 
≥ 15 
 
 
 
Cycle >1 
≤ 7 
 
 
 
8-14 
 
 
 
≥ 15 
 
 
 
Baseline grade  > 0 
1st cycle 
≤ 7 
 
 
 
8-14 
 
 
 
≥ 15 
 
 
 
Cycle >1 
≤ 7 
 
 
 
8-14 
 
 
 
≥ 15 
 
 
 
No Platelet transfusion 
                                                                Onset day grade 4 
N                % 
N                % 
N                % 
 …… 
 
….. 
≤ 7 
 
 
 
8-14 
 
 
 
≥ 15 
 
 
 


 
65
Parameter* 
DL I 
 · · · 
DL  n 
….. 
≤ 7 
 
 
 
8-14 
 
 
 
≥ 15 
 
 
 
Totals 
                                                                 Onset day grade 4 
N                % 
N                % 
N                % 
 …… 
….. 
≤ 7 
 
 
 
8-14 
 
 
 
≥ 15 
 
 
 
….. 
≤ 7 
 
 
 
8-14 
 
 
 
≥ 15 
 
 
 
…….* 
 
 
 
Note: (*) Also nadir day to grade 4, recovery day to grade ≤3**, duration in days to grade 3**, (**) Grade 2 or 1 also if clinically indicated, (***) Numeric intervals in 
days might change upon request. 
 
Table 11.5.1.15  Thrombocytopenia wpp/wpc and Use of Transfusions per Dose Level in Cycle>1. 
Tansfusion/Dose Level 
Worst Grade on Treatment*/Cycle* 
Gr. 1-2 
Gr. 3 
Gr. 4 
Total 
N 
% 
N 
% 
N 
% 
N 
% 
Transfusion 
DL I 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
…… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
No Transfusion 
DL I 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
…… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 11.5.1.16  Patients with Thrombocytopenia Grade 3/4 and Use of Transfusions in Cycle >1. 
Dose Level 
Tumor type 
Patno 
Cycle 
Prophylaxis CSF (Y/N) 
* 
 
 
 
 
 
 
 
 
 
 
 
 
Notes:  (*) Grade, nadir day to grade 3/4, recovery day to grade ≤3, (**) duration in days to grade 3**, (**) Grade 2 or 1 also if clinically indicated (***) Numeric 
intervals in days might change upon request. 
 
Table 11.5.1.17  Summary of Hematological Abnormalities Grade 4 and Specific Transfusions. 
Dose level 
Patient 
Cycles received 
Cycle number with 
hematological 
abnormality * 
grade 4 
Cycle numbers  with  
….** 
Cycle  numbers  with 
dose reduction 
 
 
 
 
 
 
 
 
 
 
 
 
Note: (*) Also Neutropenia,/CSF administration. Thrombocytopenia/ Platelets transfusion and Anemia / EPO transfusions. 
 


 
66
Table 11.5.1.18  Neutrophil Count Time Course Pattern (summary). 
Parameter* 
DL I 
 · · · 
DL  n 
CSF use 
 
 N   Median   Range  
N   Median   Range 
N   Median   Range 
 Baseline grade  0 
Onset day grade 4 1st cycle 
 
 
 
 Cycle >1 
 
 
 
Total 
 
 
 
Baseline grade  > 0 
Onset day grade 4 1st cycle 
 
 
 
 Cycle >1 
 
 
 
Total 
 
 
 
No CSF 
 
 N   Median   Range 
N   Median   Range 
N   Median   Range 
 Baseline grade  0 
Onset day grade 4 
1st cycle 
 
 
 
 Cycle >1 
 
 
 
Total 
 
 
 
Baseline grade  > 0 
Onset day grade 4 
1st cycle 
 
 
 
 Cycle >1 
 
 
 
Total 
 
 
 
Totals 
 
 N   Median   Range 
N   Median   Range 
N   Median   Range 
 Baseline grade  0 
Onset day grade 4 
1st cycle 
 
 
 
 Cycle >1 
 
 
 
Total 
 
 
 
Baseline grade  > 0 
Onset day grade 4 
1st cycle 
 
 
 
 Cycle >1 
 
 
 
Total 
 
 
 
Note: (*) Also 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 and duration in days to grade 1.
 
Table 11.5.1.19  Platelet Count Time Course Pattern. 
Parameter* 
DL I 
 · · · 
DL  n 
Platelet transfusion 
Onset day grade 4 
 N                % 
N                % 
N                % 
 Baseline grade  0 
1st cycle 
≤ 7*** 
 
 
 
8-14 
 
 
 
≥ 15 
 
 
 
Cycle >1 
≤ 7 
 
 
 
8-14 
 
 
 
≥ 15 
 
 
 
Baseline grade  > 0 
1st cycle 
≤ 7 
 
 
 
8-14 
 
 
 
≥ 15 
 
 
 
Cycle >1 
≤ 7 
 
 
 
8-14 
 
 
 
≥ 15 
 
 
 
No Platelet transfusion 
Onset day grade 4 
N                % 
N                % 
N                % 
 …… 
 
….. 
≤ 7 
 
 
 
8-14 
 
 
 
≥ 15 
 
 
 


 
67
Parameter* 
DL I 
 · · · 
DL  n 
….. 
≤ 7 
 
 
 
8-14 
 
 
 
≥ 15 
 
 
 
Totals 
 …… 
…. 
≤ 7 
 
 
 
8-14 
 
 
 
≥ 15 
 
 
 
…. 
≤ 7 
 
 
 
8-14 
 
 
 
≥ 15 
 
 
 
…….* 
Notes: (*) Also nadir day to grade 4, recovery day to grade ≤3**, duration in days to grade 3**, (**) Grade 2 or 1 also if clinically indicated, (***) Numeric intervals in 
days might change upon request. 
 
Table 11.5.1.20  Neuthropenia wpp/wpc and Use of Prophylactic CSF per Dose Level in Cycle>1. 
Tansfusion/Dose Level 
Worst Grade on Treatment*/Cycle* 
Gr. 1-2 
Gr. 3 
Gr. 4 
Total 
N 
% 
N 
% 
N 
% 
N 
% 
CSF 
DL I 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
…… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
No CSF 
DL I 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
…… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 11.5.1.21  Patients with Neutrophenia Grade 3/4 and Use of Prophylactic CSF in Cycle >1. 
Dose Level 
Tumor type 
Patno 
Cycle 
Prophylaxis CSF (Y/N) 
* 
 
 
 
 
 
 
 
 
 
 
 
 
(*) Grade, nadir day to grade 3/4, recovery day to grade ≤3, (**) duration in days to grade 3**, (**) Grade 2 or 1 also if clinically indicated (***) Numeric intervals in 
days might change upon request. 
 
11.5.2. Biochemical Abnormalities. 
Table 11.5.2.1  Biochemical Abnormalities: Worst Grade per Patient by Dose Level. 
Table 11.5.2.2  Biochemical Abnormalities: Worst Grade per Cycle by Dose Level. 
Table 11.5.2.3  Biochemical Abnormalities: Worst Grade per Patient in the first Cycle by Dose Level. 
Tables 11.5.2.1-.3 will have the following pattern but Grade column might be grouped if required. 
Abnormality* 
DL I 
DL II 
· · · 
DL  n 
Total 
AP 
 
 
 
 
 


 
68
Abnormality* 
DL I 
DL II 
· · · 
DL  n 
Total 
Grade 1 - 4, n  (%) 
 
 
 
 
 
Grade 1 
 
 
 
 
 
Grade 2 
 
 
 
 
 
Grade 3 
 
 
 
 
 
Grade 4 
 
 
 
 
 
….* 
 
 
 
 
 
Grade 1 - 4, n  (%) 
 
 
 
 
 
Grade 1 
 
 
 
 
 
Grade 2 
 
 
 
 
 
Grade 3 
 
 
 
 
 
Grade 4 
 
 
 
 
 
Notes: Percentages based on number of patients by dose level. (*) All biochemical abnormalities susceptible to be graded with NCI-CTCAE v.4. 
 
Table 11.5.2.4  Patients with Missing Biochemical Evaluation. 
Dose level 
Patient 
Cycle  
Lab. test 
 
 
 
 
 
 
 
 
 
Table 11.5.2.5  Shift of Biochemical Abnormalities. Baseline Grade vs. Worst Grade on First Cycle. 
Dose level/Parameter 
Baseline Grade 
Worst Grade on Cycle 1 
Gr. 1 
Gr. 2 
Gr. 3 
Gr. 4 
N 
% 
N 
% 
N 
% 
N 
% 
DL I 
AP increase 
0 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
4 
 
 
 
 
 
 
 
 
…… 
0 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
4 
 
 
 
 
 
 
 
 
… 
AP increase 
0 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
4 
 
 
 
 
 
 
 
 
… 
0 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
4 
 
 
 
 
 
 
 
 
Total 
AP increase 
0 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
4 
 
 
 
 
 
 
 
 
… 
 
0 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
4 
 
 
 
 
 
 
 
 
Notes:  Percentages based on number of patients by dose level. (*) All biochemical abnormalities susceptible to be graded with NCI-CTCAE v.4.  
 
Table 11.5.2.6  Shift of Biochemical Abnormalities. Baseline Grade vs. Worst Grade on Treatment. 
Dose level/Parameter 
Baseline Grade 
Worst Grade on Treatment 
Gr. 1 
Gr. 2 
Gr. 3 
Gr. 4 
N 
% 
N 
% 
N 
% 
N 
% 
DL I 
AP increase 
0 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
4 
 
 
 
 
 
 
 
 
…… 
0 
 
 
 
 
 
 
 
 


 
69
… 
 
 
 
 
 
 
 
 
4 
 
 
 
 
 
 
 
 
… 
AP increase 
0 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
4 
 
 
 
 
 
 
 
 
… 
0 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
4 
 
 
 
 
 
 
 
 
Total 
AP increase 
0 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
4 
 
 
 
 
 
 
 
 
… 
 
0 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
4 
 
 
 
 
 
 
 
 
Notes:  Percentages based on number of patients by dose level. (*) All biochemical abnormalities susceptible to be graded with NCI-CTCAE v.4.  
 
Table 11.5.2.7  Listing of patients with Biochemical Abnormalities >G2 and Experience 
Grade Increase (wpp) from Baseline. 
Dose level 
Patient 
Event* 
NCI-CTCAE v4 at 
baseline 
NCI-CTCAE v4 
at Cycle 
Cycle 
 
 
 
 
 
 
 
 
 
 
 
 
Note: (*) For nausea and vomiting events, other table will be provided and use or not of antiemetic will be added. 
 
Table 11.5.2.8 Summary of Characteristics of wpp Biochemical Abnormalities G3-4.  
Dose Level 
Parameter 
N* 
Mean** 
Median** 
Range** 
 
 
 
 
 
 
 
 
 
 
 
 
Notes: (*) Percentages based on number of patients by dose level. with grade 3-4. (**)  Cycle occurrence. 
 
Table 11.5.2.9  AST/ALT Count Time Course Pattern (summary). 
Parameter* 
DL I 
 · · · 
DL  n 
 
 N   Median   Range 
N   Median   Range 
N   Median   Range 
 Baseline grade  0 
Onset day  
grade 3-4 
1st cycle 
 
 
 
 Cycle >1 
 
 
 
Total 
 
 
 
Baseline grade  > 0 
Onset day  
grade 3-4 
1st cycle 
 
 
 
 Cycle >1 
 
 
 
Total 
 
 
 
Totals 
 
 N   Median   Range 
N   Median   Range 
N   Median   Range 
 Baseline grade  0 
Onset day  
grade 3-4 
1st cycle 
 
 
 
 Cycle >1 
 
 
 
Total 
 
 
 
Baseline grade  > 0 
Onset day  
grade 3-4 
1st cycle 
 
 
 
 Cycle >1 
 
 
 
Total 
 
 
 
Note: (*) Also 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. Grade limits may change under request. 
 


 
70
Table 11.5.2.10  AST/ALT Count Time Course Pattern. 
Parameter 
DL I 
 · · · 
DL  n 
Onset day 
grade 3-4 
 N                % 
N                % 
N                % 
 Baseline grade  0 
1st cycle 
≤ 7*** 
 
 
 
8-14 
 
 
 
≥ 15 
 
 
 
Cycle >1 
≤ 7 
 
 
 
8-14 
 
 
 
≥ 15 
 
 
 
Baseline grade  > 0 
1st cycle 
≤ 7 
 
 
 
8-14 
 
 
 
≥ 15 
 
 
 
Cycle >1 
≤ 7 
 
 
 
8-14 
 
 
 
≥ 15 
 
 
 
Totals 
Onset day grade 3-4 
N                % 
N                % 
N                % 
 …… 
….. 
≤ 7 
 
 
 
8-14 
 
 
 
≥ 15 
 
 
 
….. 
≤ 7 
 
 
 
8-14 
 
 
 
≥ 15 
 
 
 
Notes: (*) Also Peak day to grade 3-4, recovery day to grade ≤2**, duration in days to grade 2**, (**) Grade 1 also if clinically indicated (***) Numeric intervals in 
days might change upon request. 
  
11.5.3. Other Metabolic Abnormalities. 
Table 11.5.3. 1  Other Metabolic Abnormalities: Worst Grade per Patient by Dose Level. 
Table 11.5.3. 2  Other Metabolic Abnormalities: Worst Grade per Cycle by Dose Level. 
Table 11.5.3. 3  Other Metabolic Abnormalities: Worst Grade per Patient in the first Cycle by Dose Level. 
Tables 11.5.3.1-.3 will have the following pattern but Grade column might be grouped if required. 
Abnormality* 
DL I 
DL II 
· · · 
DL  n 
Total 
Metabolic abnormality 
 
 
 
 
 
Grade 1 - 4, n  (%) 
 
 
 
 
 
Grade 1 
 
 
 
 
 
Grade 2 
 
 
 
 
 
Grade 3 
 
 
 
 
 
Grade 4 
 
 
 
 
 
…..* 
 
 
 
 
 
Grade 1 - 4, n  (%) 
 
 
 
 
 
Grade 1 
 
 
 
 
 
Grade 2 
 
 
 
 
 
Grade 3 
 
 
 
 
 
Grade 4 
 
 
 
 
 
Notes:  Percentages based on number of patients by dose level. (*) All biochemical abnormalities susceptible to be graded with NCI-CTCAE v.4.  


 
71
 
Table 11.5.3. 4  Patients with missing Metabolic Evaluations. 
Dose level 
Patient 
Cycle  
Lab. test 
 
 
 
 
 
 
 
 
 
Table 11.5.3. 5  Shift of Metabolic Abnormalities. Baseline Grade vs. Worst Grade on First Cycle. 
Dose level/Parameter 
Baseline Grade 
Worst Grade on Cycle 1 
Gr. 1 
Gr. 2 
Gr. 3 
Gr. 4 
N 
% 
N 
% 
N 
% 
N 
% 
DL I 
Hypercalcemia 
0 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
4 
 
 
 
 
 
 
 
 
…… 
0 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
4 
 
 
 
 
 
 
 
 
… 
Hypercalcemia 
0 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
4 
 
 
 
 
 
 
 
 
… 
0 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
4 
 
 
 
 
 
 
 
 
Total 
Hypercalcemia 
0 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
4 
 
 
 
 
 
 
 
 
… 
 
0 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
4 
 
 
 
 
 
 
 
 
Notes:  Percentages based on number of patients by dose level. (*) All metabolic abnormalities susceptible to be graded with NCI-CTCAE v.4.  
 
Table 11.5.3. 6  Shift of Metabolic Abnormalities. Baseline Grade vs. Worst Grade on Treatment. 
Dose level/Parameter 
Baseline Grade 
Worst Grade on Treatment 
Gr. 1 
Gr. 2 
Gr. 3 
Gr. 4 
N 
% 
N 
% 
N 
% 
N 
% 
DL I 
Hypercalcemia 
0 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
4 
 
 
 
 
 
 
 
 
…… 
0 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
4 
 
 
 
 
 
 
 
 
… 
Hypercalcemia 
0 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
4 
 
 
 
 
 
 
 
 
… 
0 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
4 
 
 
 
 
 
 
 
 
Total 
Hypercalcemia 
0 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
4 
 
 
 
 
 
 
 
 
… 
0 
 
 
 
 
 
 
 
 


 
72
 
… 
 
 
 
 
 
 
 
 
4 
 
 
 
 
 
 
 
 
Notes:  Percentages based on number of patients by dose level. (*) All metabolic abnormalities susceptible to be graded with NCI-CTCAE v.4.  
 
Table 11.5.3. 7  Listing of Patients with Metabolic Abnormailities >G2 and Experience 
Grade Increase (wpp) from Baseline. 
Dose level 
Patient 
Event 
NCI-CTCAE v.4 at 
baseline 
NCI-CTCAE v.4 
at Cycle 
Cycle 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 11.5.3. 8  Supportive Listing: Patients with Grade ≥3 Metabolic Abnormalities 
Dose level 
Patient 
Lab. test 
Cycle 
Examination  
date 
…….* 
 
 
 
 
 
 
 
 
 
 
 
 
Note: (*)  It will include the following: Value at BL, Grade at BL, Onset day, Onset grade, Nadir day, Nadir value, Nadir grade, Recovery day, Recovery value, 
Recovery grade, Days Grade 3-4. 
 
11.5.4. Coagulation Abnormalities. 
Table 11.5.4. 1  Coagulation Abnormalities: Worst Grade per Patient by Dose Level. 
Table 11.5.4. 2  Coagulation Abnormalities: Worst Grade per Cycle by Dose Level. 
Table 11.5.4. 3  Coagulation Abnormalities: Worst Grade per Patient in the first Cycle by Dose Level. 
 
Tables 11.5.4.1-.3 will have the following pattern but Grade column might be grouped if required. 
Abnormality 
DL I 
DL II 
· · · 
DL  n 
Total 
INR 
 
 
 
 
 
Grade 1 - 4, n (%) 
 
 
 
 
 
Grade 1 
 
 
 
 
 
Grade 2 
 
 
 
 
 
Grade 3 
 
 
 
 
 
Grade 4 
 
 
 
 
 
PTT 
 
 
 
 
 
Grade 1 - 4, n (%) 
 
 
 
 
 
Grade 1 
 
 
 
 
 
Grade 2 
 
 
 
 
 
Grade 3 
 
 
 
 
 
Grade 4 
 
 
 
 
 
 
Table 11.5.4. 4  Shift of Coagulation Abnormalities. Baseline Grade vs. Worst Grade on First Cycle. 
Dose level/Parameter* 
Baseline Grade 
Worst Grade on Treatment 
Gr. 1 
Gr. 2 
Gr. 3 
N 
% 
N 
% 
N 
% 
DL I 
INR increase 
0 
 
 
 
 
 
 
… 
 
 
 
 
 
 
3 
 
 
 
 
 
 


 
73
…… 
0 
 
 
 
 
 
 
… 
 
 
 
 
 
 
3 
 
 
 
 
 
 
… 
INR increase 
0 
 
 
 
 
 
 
… 
 
 
 
 
 
 
3 
 
 
 
 
 
 
… 
0 
 
 
 
 
 
 
… 
 
 
 
 
 
 
3 
 
 
 
 
 
 
Total 
INR increase 
0 
 
 
 
 
 
 
… 
 
 
 
 
 
 
3 
 
 
 
 
 
 
… 
 
0 
 
 
 
 
 
 
… 
 
 
 
 
 
 
3 
 
 
 
 
 
 
Notes:  Percentages based on number of patients by dose level. (*)  INR and PTT. If data available. 
 
Table 11.5.4. 5  Shift of Coagulation Abnormalities. Baseline Grade vs. Worst Grade on Treatment. 
Dose level/Parameter* 
Baseline Grade 
Worst Grade on Treatment 
Gr. 1 
Gr. 2 
Gr. 3 
N 
% 
N 
% 
N 
% 
DL I 
INR increase 
0 
 
 
 
 
 
 
… 
 
 
 
 
 
 
3 
 
 
 
 
 
 
…… 
0 
 
 
 
 
 
 
… 
 
 
 
 
 
 
3 
 
 
 
 
 
 
… 
INR increase 
0 
 
 
 
 
 
 
… 
 
 
 
 
 
 
3 
 
 
 
 
 
 
… 
0 
 
 
 
 
 
 
… 
 
 
 
 
 
 
3 
 
 
 
 
 
 
Total 
INR increase 
0 
 
 
 
 
 
 
… 
 
 
 
 
 
 
3 
 
 
 
 
 
 
… 
 
0 
 
 
 
 
 
 
… 
 
 
 
 
 
 
3 
 
 
 
 
 
 
Notes:  Percentages based on number of patients by dose level. (*)  INR and PTT. If data available. 
 
Table 11.5.4. 6 Listing of Patients with Coagulation Abnormalities >G2 and Experience Grade Increase from 
Baseline. 
Dose level 
Patient 
Event 
NCI-CTCAE v4 at 
baseline 
NCI-CTCAE v4 
at Cycle 
Cycle 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 11.5.4. 7  Patients with missing Metabolic Evaluations. 
Dose level 
Patient 
Cycle  
Lab. test 


 
74
Dose level 
Patient 
Cycle  
Lab. test 
 
 
 
 
 
 
 
 
 
 
11.6. Vital Signs, Physical Findings, ECG, LVEF and Pregnancy tests. 
All statistical outputs in this section, whenever applicable, will be displayed according to 
assignment to prophylactic CSF use or not as well as per Dose level/Dose group or by cancer 
type or primary site if adequate number of patients is represented. Total numbers will be 
displayed independently, if applicable. 
11.6.1. Vital Signs and Physical Findings.  
Table 11.6.1.1  Physical examination during the Study by Cycle and Dose Level. 
 
Baseline 
Cycle 1 
Cycle 2 
· · · 
Cycle N 
Dose 
level 
Patient 
No 
Normal/Abnormal Normal/Abnormal Normal/Abnormal Normal/Abnormal Normal/Abnormal 
I 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
· · · 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
N 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 11.6.1.2  Performance Status during the Study by Cycle and Dose Level. 
 
Baseline 
Cycle 1 
Cycle 2 
· · · 
Cycle N 
Dose 
level 
Patient 
No 
PS 
PS 
PS 
PS 
PS 
I 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
· · · 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
N  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 11.6.1.3  Weight Change during the Study by Dose Level. 
Dose 
level 
Patient 
No 
Weight at baseline 
(kg) 
Cycle 1 
Cycle 2 
· · · 
Cycle N 
% 
change 
% 
change 
% 
change 
% 
change 
I 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
75
Dose 
level 
Patient 
No 
Weight at baseline 
(kg) 
Cycle 1 
Cycle 2 
· · · 
Cycle N 
% 
change 
% 
change 
% 
change 
% 
change 
· · · 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
N 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
11.6.2. Electrocardiogram. 
Table 11.6.2 1 ECG during the Study by Dose Level.     
 
Baseline 
Cycle 1 
Cycle 2 
· · · 
Cycle N 
Dose 
level 
Patient 
No 
Normal/Abnormal Normal/Abnormal Normal/Abnormal Normal/Abnormal Normal/Abnormal 
I 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
· · · 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
N 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 11.6.2 2  ECG during the Study by Dose Level.      
 
No cycles with 
delays 
DL I 
DL II 
· · · 
DL  n 
Total 
PR interval 
N 
 
 
 
 
 
Mean 
 
 
 
 
 
Median 
 
 
 
 
 
Min 
 
 
 
 
 
Max 
 
 
 
 
 
STD 
 
 
 
 
 
QT interval 
N 
 
 
 
 
 
Mean 
 
 
 
 
 
Median 
 
 
 
 
 
Min 
 
 
 
 
 
Max 
 
 
 
 
 
STD 
 
 
 
 
 
….* 
N 
 
 
 
 
 
Mean 
 
 
 
 
 
Median 
 
 
 
 
 
Min 
 
 
 
 
 
Max 
 
 
 
 
 
STD 
 
 
 
 
 
Note: (*) Also RR interval, QRS interval, QTcF. 
 


 
76
 Table 11.6.2 3  QTcF Values during the Study by Dose Level.      
Dose 
level 
Patient 
No 
Baseline 
QTcF (msec) 
Cycle 1 
Cycle 2 
· · · 
Cycle N 
% 
change 
% 
change 
% 
change 
% 
change 
I 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
· · · 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
N 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 11.6.2 4  QTcF (msec) Change per Patient during the Study by Dose Level. 
 
Baseline 
Cycle 1 
Cycle 2 
· · · 
Cycle N 
Dose 
level 
Patient 
No 
QTcF (msec) 
QTcF (msec) 
QTcF (msec) 
QTcF (msec) 
QTcF (msec) 
I 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
· · · 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
N  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 11.6.2 5  Shift of QTc. Baseline Grade vs. Worst Grade on Treatment. 
Dose level/Parameter 
Baseline Grade 
Worst Grade on Treatment. 
Gr. 1 
Gr. 2 
Gr. 3 
Gr. 4 
N 
% 
N 
% 
N 
% 
N 
% 
DL I 
QTc corrected 
0 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
4 
 
 
 
 
 
 
 
 
… 
QTc corrected 
0 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
4 
 
 
 
 
 
 
 
 
Total 
QTc corrected 
0 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
4 
 
 
 
 
 
 
 
 
     
Table 11.6.2 6  QTcF Values during the Study by Doxorubicin Cumulative Dose. 
 
QTcF (msec) 
0-xx (mg/m2) 
xx-xx      xx-xx 
xx-xx 
xx-450 (mg/m2) 
Total 
Previous to 
treatment or at BL
N 
 
 
 
 
 
Mean 
 
 
 
 
 
Median 
 
 
 
 
 
Min 
 
 
 
 
 
Max 
 
 
 
 
 
STD 
 
 
 
 
 


 
77
 
QTcF (msec) 
0-xx (mg/m2) 
xx-xx      xx-xx 
xx-xx 
xx-450 (mg/m2) 
Total 
Accumulated 
during treatment 
N 
 
 
 
 
 
Mean 
 
 
 
 
 
Median 
 
 
 
 
 
Min 
 
 
 
 
 
Max 
 
 
 
 
 
STD 
 
 
 
 
 
 
Table 11.6.2 7  Listing of Patients with Grade ≥ 2 QTc Interval Prolonged. 
Dose level 
Patient 
Cycle QTc value (msec) Grade NCI-
CTC v.4 
QTc at 
Baseline 
% of increase 
from BL 
Total cumulative dose 
of anthracyclines 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
11.6.3. LVEF. 
Table 11.6.3 1  LVEF (%) Change per Patient during the Study by Dose Level. 
 
Baseline 
Cycle 1 
Cycle 2 
· · · 
Cycle N 
Dose 
level 
Patient 
No 
Normal/Abnormal Normal/Abnormal Normal/Abnormal Normal/Abnormal Normal/Abnormal 
I 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
· · · 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
N  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
. 
 
. 
 
 
Table 11.6.3 2  Median LVEF Values (%) during the Study by Doxorubicin Cumulative Dose. 
 
QTcF (msec) 
0-xx (mg/m2) 
xx-xx      xx-xx 
xx-xx 
xx-450 (mg/m2) 
Total 
Previous to 
treatment or at BL 
N 
 
 
 
 
 
Mean 
 
 
 
 
 
Median 
 
 
 
 
 
Min 
 
 
 
 
 
Max 
 
 
 
 
 
STD 
 
 
 
 
 
Accumulated 
during 
 treatment 
N 
 
 
 
 
 
Mean 
 
 
 
 
 
Median 
 
 
 
 
 
Min 
 
 
 
 
 
Max 
 
 
 
 
 
STD 
 
 
 
 
 
 
Table 11.6.3 3  Shift of LVEF. Baseline vs. Worst Grade on Treatment. 
Dose level 
Baseline Grade 
Worst Grade on Treatment. 
Gr. 1 
               Gr. 2 
Gr. 3 


 
78
N 
 % 
N 
% 
N 
% 
DL I 
0 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
…    
0 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Total 
0 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 11.6.3 4  Listing of Patients with Grade ≥ 2 LVEF Decrease. 
Dose level 
Patient 
Cycle 
LVEF  
value (%) 
Grade NCI-
CTCAE v.4 
LVEF at 
Baseline 
% of decrease from BL
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
11.7. Concomitant and Prophylactic Medication. 
11.7.1. Concomitant and Prophylactic Medication During Study. 
Table 11.7.1.1  Concomitant Medication during Study (ATC Level 1 and 4) by Dose Level. 
Medication Term 
(ATC level 1) 
Medication Term
(ATC level  2) 
Medication Term
(ATC level 4) 
DL I 
DL II 
· · · 
DL  n 
Total 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: Percentages based on number of patients by dose level. 
 
Table 11.7.1.2 EPO/RBC and PlateletsTransfusions/CSF.  
Medication Term 
(ATC level 1) 
Medication 
Term 
(ATC level 2) 
Medication 
Term 
(ATC level 4) 
DL I 
DL II 
· · · 
DL  n 
Total 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
EPO 
 
 
 
 
 
 
 
 
 
 
 
 
RBC transfusion 
 
 
 
 
 
 
 
 
 
 
 
 
Platelet transfusion   
 
 
 
 
 
 
 
 
 
 
 
CSF*  
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
Notes: Percentages based on number of patients by dose level. (*) Non-prophylactic CSF use. 
 
Table 11.7.1.3 Patients with EPO/RBC and Platelets Transfusions/CSF. 
Dose 
Level
Patient 
No 
Cycle Not 
done
Type* 
Literal 
Route Specify 
of route Dose Unit
Start 
date 
(text)
Start date 
ongoing
End 
date 
(text)
End date 
ongoing
Reason 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
Note: (*) Non-prophylactic CSF use. 
 


 
79
Table 11.7.1.4  Prophylactic Medication during Study. 
Medication Term 
(ATC level 1)* 
DL I 
DL II 
· · · 
DL  n 
Total 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
Cycle 1 
Steroids 
 
 
 
 
 
 
 
 
 
 
5-HT antagonist 
 
 
 
 
 
 
 
 
 
 
Prokinetics 
 
 
 
 
 
 
 
 
 
 
Aprepitant 
 
 
 
 
 
 
 
 
 
 
Other 
 
 
 
 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
Cycle >1 
Steroids 
 
 
 
 
 
 
 
 
 
 
5-HT antagonist 
 
 
 
 
 
 
 
 
 
 
Prokinetics 
 
 
 
 
 
 
 
 
 
 
Aprepitant 
 
 
 
 
 
 
 
 
 
 
Other 
 
 
 
 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
All 
Steroids 
 
 
 
 
 
 
 
 
 
 
5-HT antagonist 
 
 
 
 
 
 
 
 
 
 
Prokinetics 
 
 
 
 
 
 
 
 
 
 
Aprepitant 
 
 
 
 
 
 
 
 
 
 
Other 
 
 
 
 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
Notes: Percentages based on number of patients by dose level. (*) Antiemetic use may include more categories as extended and extensive, or a frequency table just for 
antiemetic medication will be added, if clinically indicated. 
 
Table 11.7.1.5  Patients with Nausea and /or Vomiting G3/4 and Use of Antiemetics in Cycle >1. 
Dose Level 
Tumor 
type 
Patno
Cycle 
AE prefered 
Term 
NCI-CTCAE v.4 Antiemetics* 
(Y/N) 
Medication Term 
…** 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Notes:(*) Antiemetics  e.g : Dexamethasone + 5HT3. (**) AE onset date/resolved date. Antiemetics dates, etc… 
 
 
Table 11.7.1.6 No of Patients with Opioids Treatment During Treatment by Dose Level. 
Opioids*  
DL I 
DL II 
· · · 
DL n 
Total 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
…. 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
(*) The ATC classification including opioids and terms will be selected and provided by clinical request. 
 
Table 11.7.1.7 Median Number of No of Opioids per Patient During Treatment by Dose Level. 
Opioids* 
DL I 
DL II 
· · · 
DL  n 
Total 
N 
 
 
 
 
 
Mean 
 
 
 
 
 
Median 
 
 
 
 
 
Min 
 
 
 
 
 
Max 
 
 
 
 
 
STD 
 
 
 
 
 
(*) The ATC classification including opioids and terms will be selected and provided by clinical request. 
 


 
80
Table 11.7.1.8 No of Patients with Steroids Treatment During Treatment by Dose Level. 
Steroids*  
DL I 
DL II 
· · · 
DL n 
Total 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
…. 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
(*) The ATC classification including steroids and terms will be selected and provided by clinical request. 
 
Table 11.7.1.9 Known CYP 3A4 Inducers/Inhibitors/Substrates Concomitant Therapies at BL. 
CYP 3A4*  
DL I 
DL II 
· · · 
DL n 
Total 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
Inhibitor 
 
 
 
 
 
 
 
 
 
 
…. 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
Note: (*) Also the possibility of displaying one table for each category of Inducers/Inhibitors or substrates. Some medication will be excluded by clinical request (e.g. 
Dexamethasone). 
 
Table 11.7.1.10 Listing of CYP 3A4 Inducers/Inhibitors/Substrates Concomitant Therapies During Treatment. 
Dose 
Level  
Pat No 
Type* 
Literal Term 
ATC4 ATC2 ATC1
… 
Start 
date 
End 
date 
Reason for Use SS/AE Specify
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Note: (*) Also the possibility of displaying one table for each category of Inducers/Inhibitors or substrates. Some medication will be excluded by clinical request (e.g. 
Dexamethasone). 
 
 


 
81
 
12. Appendix III. Efficacy Evaluation. 
All statistical outputs will be displayed according to Dose level (grouped)/Cohort/Cancer type 
or primary site/CSF use or not/other clinical relevant variable (e.g. 2nd line SCLC by CTFI), 
whenever applicable and if an adequate number of patients is represented. Summary tables 
will have source data footnotes that will refer to the relevant listings. The tables' layout may 
change to adequately accommodate cohort/group size as appropriate. 
12.1. Efficacy Analysis. 
12.1.1. Response. 
Table 12.1.1.1  Overall response by Dose Level: Treated Patients. 
Overall response 
DL I 
DL II 
· · · 
DL  n 
Total 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
RECIST  v.1.1 
 
 
 
 
 
 
 
 
 
 
CR 
 
 
 
 
 
 
 
 
 
 
PR 
 
 
 
 
 
 
 
 
 
 
SD < 4 months  
 
 
 
 
 
 
 
 
 
 
SD ≥ 4 months  
 
 
 
 
 
 
 
 
 
 
PD 
 
 
 
 
 
 
 
 
 
 
NE 
 
 
 
 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
Other evaluation criteria  (if 
needed) 
 
 
 
 
 
 
 
 
 
 
CR 
 
 
 
 
 
 
 
 
 
 
PR 
 
 
 
 
 
 
 
 
 
 
SD < 4 months  
 
 
 
 
 
 
 
 
 
 
SD ≥ 4 months  
 
 
 
 
 
 
 
 
 
 
PD 
 
 
 
 
 
 
 
 
 
 
NE 
 
 
 
 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
Note:  Percentages based on number of patients by dose level. 
 
Table 12.1.1.2  Overall response by Tumor type and Dose Level: Treated Patients. 
Tumor type 
Overall response 
DL I 
DL II 
· · · 
DL  n 
Total 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
Breast 
CR 
 
 
 
 
 
 
 
 
 
 
 
PR 
 
 
 
 
 
 
 
 
 
 
 
SD < 4 months  
 
 
 
 
 
 
 
 
 
 
 
SD ≥ 4 months  
 
 
 
 
 
 
 
 
 
 
 
PD 
 
 
 
 
 
 
 
 
 
 
……* 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
…… 
Total 
 
 
 
 
 
 
 
 
 
 
Notes:  Percentages based on number of patients by dose level. (*) Coded tumor types. 
 


 
82
Table 12.1.1.3  Overall response by Dose Level: Evaluable Patients. 
Overall response 
DL I 
DL II 
· · · 
DL  n 
Total 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
CR 
 
 
 
 
 
 
 
 
 
 
PR 
 
 
 
 
 
 
 
 
 
 
SD < 4 months  
 
 
 
 
 
 
 
 
 
 
SD ≥ 4 months  
 
 
 
 
 
 
 
 
 
 
PD 
 
 
 
 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
Note:  Percentages based on number of evaluable patients by dose level. 
 
Table 12.1.1.4  Overall Response by Tumor type and Dose Level: Evaluable Patients. 
Tumor type 
Overall response 
DL I 
DL II 
· · · 
DL  n 
Total 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
Breast 
CR 
 
 
 
 
 
 
 
 
 
 
 
PR 
 
 
 
 
 
 
 
 
 
 
 
SD < 4 months  
 
 
 
 
 
 
 
 
 
 
 
SD ≥ 4 months  
 
 
 
 
 
 
 
 
 
 
 
PD 
 
 
 
 
 
 
 
 
 
 
……* 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
…… 
Total 
 
 
 
 
 
 
 
 
 
 
Notes:  Percentages based on number of evaluable patients by dose level. (*) Coded tumor types. 
 
Table 12.1.1.5  SD ≥ 4 months by Dose Level: Evaluable Patients. 
SD ≥ 4 months 
DL I 
DL II 
· · · 
DL  n 
Total 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
No  
 
 
 
 
 
 
 
 
 
 
Yes 
 
 
 
 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
Note:  Percentages based on number of evaluable patients by dose level. 
 
Table 12.1.1.6  Tumor Marker Evolution During Study. 
 
Baseline  
Cycle 1 
· · · 
Cycle N 
Dose 
level 
Patient 
No 
Tumor type/ 
Tumor marker* 
Tumor marker  
value 
Tumor marker  
value / (%) change 
from BL 
Tumor marker  
value / (%) change 
from BL 
Tumor marker  
value / (%) change 
from BL 
I 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
· · · 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
N 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(*) If available data  
 
Table 12.1.1.7  Characteristics of Patients with Clinical Benefit*. 
Dose 
level 
Patient 
No 
Sex/
Age/
Tumor 
type 
Number 
of 
Agents 
(previous 
Best 
Response 
TTP 
Previous 
Cycles 
Received 
Overall 
Response
TTP 
(months)
OS 
(months)
Treatment 
Discontinuation 


 
83
PS 
lines of 
previous 
treatment
treatment) Previous 
CT 
CT 
PM01183
Reason 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: (*) "Evidence of Clinical Benefit" when response is CR, PR or SD≥4 months and/or no evidence of PD with increase tumor markers, if non-evaluable as per 
RECIST v.1.1.  
 
Table 12.1.1.8  Characteristics of Patients with Clinical Benefit based on any Specific Tumor Marker Criteria. 
Dose 
level 
Patient  
No 
Sex/ 
Age/ 
PS 
Tumor 
type 
Number of 
lines of 
previous 
treatment 
Agents 
(previous 
treatment) 
Best 
Response 
Previous CT
TTP 
Previous  
CT 
Cycles 
Received 
PM01183 
Overall 
Response   
for tumor 
marker  
…..* 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Notes: (*Also overall response by RECIST v1.1, TTP, OS, Treatment discontinuation reason, e.g: CA-125 value at BL, Nadir value CA-125.  In patients for whom 
response to treatment are evaluated by both RECIST v.1.1 and any specific tumor marker criteria, the date of response and progression will be the earliest date of the 
two methods. 
 
Table 12.1.1.9  Progression-Free Survival: Evaluable Patients. 
Summary* 
N=XX 
Events X (XX.X%) 
Censored X (XX.X%) 
Median X.X 95% CI (X.X-X.X) 
PFS  at 3 months XX.X% 95% CI XX.X%-XX.X%) 
PFS  at 6 months XX.X% 95% CI XX.X%-XX.X%) 
Note: (*) If any particular tumor type or any other clinically relevant variable is adequately represented and PFS at 12, and 24 months also if available data.  
 
Table 12.1.1.10  Duration of Response. 
Summary* 
N=XX 
Events X (XX.X%) 
Censored X (XX.X%) 
Median X.X 95% CI (X.X-X.X) 
Duration  of  Response  at 3 months XX.X% 95% CI XX.X%-XX.X%) 
Duration  of  Response  at  6 months XX.X% 95% CI XX.X%-XX.X%) 
(*) If any particular tumor type or any other clinically relevant variable is adequately represented and DR at 12 and 24 months also if available data. 
 
Table 12.1.1.11  Overall survival. 
Summary* 
N=XX 
Events X (XX.X%) 
Censored X (XX.X%) 
Median X.X 95% CI (X.X-X.X) 
OS  at  6 months XX.X% 95% CI XX.X%-XX.X%) 
OS  at 12 months XX.X% 95% CI XX.X%-XX.X%) 
OS  at 18 months XX.X% 95% CI XX.X%-XX.X%) 
(*) Only for Cohort B but if requested also for cohort A. 


 
84
 
13. Figures. 
All statistical outputs will be displayed according to Dose level (grouped)/Cohort/Cancer type 
or primary site/CSF use or not/other clinical relevant variable (e.g. 2nd line SCLC by CTFI), 
whenever applicable and if an adequate number of patients is represented. The figures' layout 
may change to adequately accommodate cohort/group size as appropriate 
 
Figure 13.1 1 Pattern of Hematological/non Hematological DLTs in Individual Patients. 
 
Also if applicable pattern for Neutropenia for patients with prophylactic CSF vs. No CSF. 
Figure 13.1 2 Transaminase Series in Individual Patients. 
 
 


 
85
Figure 13.1 3 Barcharts of Adverse Events or Laboratory Abnormalities by Dose Level/Cohort. 
 
 
Figure 13.1 4 Barcharts of Adverse Events or Laboratory Abnormalities by Dose Level/Cohort/Tumor type/ or 
Other Clinical Relevant Variable. 
 
 
 


 
86
Figure 13.1 5 Hematology/Transaminase Worst Severity by Cycle. 
 
 
Figure 13.1 6 LVEF/QTcF Boxplot by Dose Level. 
 


 
87
 
Figure 13.1 7 Boxplot QTcF Worst Value by Cycle. 
 
 
 
Figure 13.1 8 Duration of Response. 
 
Kaplan-Meier curve of duration of response (If any response is observed). 
 
 


 
88
Figure 13.1 9 Progression-free Survival by Dose level/Cohort/Tumor type/ or Other Clinical Relevant Variable. 
 
Figure 13.1 10 Overall Survival. 
 
 
 


 
89
 
Figure 13.1 11 Waterfall Graphs. 
 
Waterfall graphs will be displayed in measurable lesions by RECIST v.1.1Also graphs for each tumor 
type/cohort and for responders. 
 
Figure 13.1 12 Spider plot: Evolution of RECIST v.1.1 Assessments. 
 
Spider plot will be displayed individually for each tumor type/cohort / or Other clinical relevant variable, if 
required. 
 
 


 
90
Figure 13.1 13 Best RECIST v.1.1 Efficacy Assessment in Evaluable pts per Tumour Type. 
 
 
Figure 13.1 14 Treatment Exposure and Reasons for Discontinuation per Tumour Type. 
 
 
Figure 13.1 15 Best RECIST v.1.1 Response According to Line of Treatment. 
 
 


 
91
 
Figure 13.1 16 Last Prior Treatment Response (TTP) vs PM001183/Combo response (TTP). 
 
Figure 13.1 17 Number of Cycles, Reason for Treatment Discontinuation for Patients with Response or Clinical 
Benefit. 
 
 
 
 
 
 


 
92
Figure 13.1 18 Efficacy and Individual TTP in Selected Patients by BSA/CTFI and Treatment Discontinuation. 
 
Figure 13.1 19 Number of Cycles, Reason for Treatment Discontinuation and Response in Patients who 
Received PM001183 Alone. 
 
 
 
 
 
 


 
93
14. Database Listings. 
Listing 14.1  Patient Registration. 
Listing 14.2  Demography. 
Listing 14.3  Patient Disposition. 
Listing 14.4  Protocol Deviations. 
Listing 14.5  Patient Populations. 
Listing 14.6  Selection Criteria. 
Listing 14.7  Medical History. 
Listing 14.8  Cancer History. 
Listing 14.9  Current Disease. 
Listing 14.10  Prior Surgery. 
Listing 14.11  Prior Radiotherapy. 
Listing 14.12  Prior Anticancer Therapy. 
Listing 14.13  Signs and Symptoms. 
Listing 14.14  Tumor Assessment (Target Lesions). 
Listing 14.15  Tumor Assessment (Non - Target Lesions). 
Listing 14.16  Tumor Assessment (New Lesions). 
Listing 14.17  Radiological Response (RECIST v.1.1). 
Listing 14.18  Clinical Evaluation Response. 
Listing 14.19  Tumor Marker Evaluation Response. 
Listing 14.20  Overall Cycle Response. 
Listing 14.21  Treatment Exposure. 
Listing 14.22  Hematology Laboratory Results. 
Listing 14.23  Clinical Chemistry and Coagulation Laboratory Results. 
Listing 14.24  Physical Examination and Performance Status (PS). 
Listing 14.25  Vital Signs. 
Listing 14.26  ECG Results. 
Listing 14.27  Left Ventricular Ejection Fraction (LVEF) Results. 
Listing 14.28  Other Tests and Procedures Results. 
Listing 14.29  Adverse Events. 
Listing 14.30  Concomitant Therapy. 
 


 
94
Listing 14.31  End of Treatment. 
Listing 14.32  Follow-up. 
Listing 14.33  Follow-up: Antitumor therapy. 
Listing 14.34  Death Report. 
Listing 14.35  Best Study Overall Response. 
Listing 14.36  Off Study. 
Listing 14.37  Signature Report. 


 
95
 
15. SAP Version History. 
15.1. SAP Version History v1. 
After the first version of the SAP was approved by the responsible physician, the medical 
writer and the biostatistics manager, a new protocol "substantial amendment No. 1" was 
included; therefore the SAP has been updated (highlighted in italic bold) in accordance with 
the new version (version 2) of the protocol as follows: 
•  Changes in Study design/dose escalation and G-CSF/CSF primary prophylaxis and MTD 
definition has been rephrased in order to maintain consistency between DLT and MTD 
definitions. 
•  Changes in Inclusion/exclusion criteria have been done: a maximum age limit of 75 years 
old has been set and the inclusion of patients with mesothelioma has been allowed. 
•  Some minor changes and corrections have been done in the text and the mock shells to 
allow a clear and unambiguous communication of the science and statistics of the trial. 
 
Summary of proposed changes from section 2.1 to 8: 
Section 2.1 Primary Objective: 
Original text: 
• To determine the maximum tolerated dose (MTD) and the recommended dose (RD) of 
PM01183 in combination with doxorubicin in patients with selected advanced solid 
tumors. 
Change to: 
• To determine the MTD and the RD of PM01183 in combination with doxorubicin 
with primary prophylaxis with G-CSF in patients with selected advanced solid 
tumors (if DLTs of the combination without G-CSF prophylaxis are exclusively 
related to neutropenia). 
 
Section 3. Study design: 
Original text: 
….. All evaluable patients within a dose level will be followed for at least one cycle (i.e., 
three weeks) before dose escalation may proceed. Dose escalation will be terminated once the 
MTD or the last dose level (DL4) is reached, whichever occurs first. 
Change to: 
… All evaluable patients within a dose level will be followed for at least one cycle (i.e., three 
weeks) before dose escalation may proceed. Dose escalation will be terminated once the 
MTD or the last dose level (DL4) is reached, whichever occurs first, except if all DLTs 


 
96
occurring at a given dose level are related to neutropenia (e.g., febrile neutropenia, grade 4 
neutropenia lasting more than 7 days or neutropenic sepsis) in which case dose escalation 
may be resumed, starting at the lowest dose level where exclusively neutropenia-related 
DLTs have occurred, and will follow the same original schedule but with compulsory 
primary G-CSF prophylaxis. 
 
Section 5.2.1.1 Determination of MTD and RD 
Original text: 
…….If >1 evaluable patient during dose escalation at a given DL experience a DLT during 
Cycle 1, that DL will be considered the MTD and dose escalation will be terminated. The DL 
immediately below the MTD, or DL4 if the MTD is not yet defined during dose escalation 
before the last DL (i.e., DL4) is reached, will be expanded up to a minimum of nine evaluable 
patients. If less than three among the first nine evaluable patients treated within the expansion 
cohort experience a DLT during Cycle 1, this DL will be the RD. 
 
Change to: 
……..If >1 evaluable patient during dose escalation at a given DL experience a DLT 
during the first cycle, that level will be considered the MTD and dose escalation will be 
terminated except if all DLTs occurring at a given dose level are related to neutropenia 
(e.g., febrile neutropenia, grade 4 neutropenia lasting more than 7 days or neutropenic 
sepsis) in which case dose escalation may be resumed, starting at the lowest dose level 
where exclusively neutropenia-related DLTs have occurred, and will follow the same 
original schedule but with compulsory primary G-CSF prophylaxis. 
 
Section 8.1 Stratification and Covariate Analysis: 
Original text: 
No stratification by prognostic factors or tumor types is planned. If a disease is adequately 
represented, response rates might be analyzed descriptively, and time-related parameters 
might be analyzed according to the Kaplan-Meier method. Efficacy parameters could also be 
subjected to further analysis (if appropriate), considering correlation with factors of probable 
prognostic value such as subject PS at entry, disease burden, prior therapies, other disease-
specific known prognostic factor, or population characteristics, etc. using the appropriate test 
(Fisher's exact test, Spearman test, etc.). 
Change to: 
No stratification by prognostic factors or tumor types is planned. If a disease is adequately 
represented, response rates might be analyzed descriptively, and time-related parameters 
might be analyzed according to the Kaplan-Meier method. Efficacy parameters could also be 
subjected to further analysis (if appropriate), considering correlation with factors of known 
prognostic value such as subject PS at entry, disease burden, prior therapies, other disease-
specific known prognostic factor, or population characteristics, etc. using the appropriate test 
(Fisher's exact test, Spearman test, etc.). 
Section 8.3 Subgroups Analysis: 


 
97
Original text: 
If any cancer groups of patients are sufficiently represented, a separate analysis by tumor type 
and evaluation criteria (RECIST, GCIC) will be performed.  
If there is a representative number of patients who receive a maximal total cumulative dose of 
450 mg/m2 of doxorubicine and continue treatment with PM01183 alone at the recommended 
dose as a single agent, a separate analysis will be performed and tables, listings and graphic 
representations for this population will be provided when applicable. 
Exploratory safety and efficacy analyses considering the three groups (below RD, RD and 
over RD) will be performed if appropriate. 
Change to: 
If any cancer subtype or any other baseline characteristics of patients are adequately 
represented, a separate analysis by tumor type and efficacy as per RECIST v1.1, will be 
performed.  
If there is a representative number of patients who receive a maximal total cumulative dose of 
450 mg/m2 of doxorubicin and continue treatment with PM01183 alone, a separate analysis 
will be performed and tables, listings and graphic representations for this population will be 
provided when applicable. 
 
Summary of changes in Section 9. Tables, Listings and Graphs: 
 
The following new paragraphs have been added,  
Original text: 
Statistical outputs, whenever is applicable, will be displayed according to assignment to 
prophylactic G-CSF factors use or not as well as per Dose level. Totals numbers will be 
displayed independently, if applicable. Summary tables will have source data footnotes that 
will refer to the relevant listings. The tables' layout may change to adequately accommodate 
cohort size as appropriate.  
Patients included and treated over 75 yrs old will be excluded from all tables, listings and 
graphs in this SAP. Detailed narratives of these patients will be shown in the CSR. 
If the number of categories or items would not yield appropriate tabular or graphic 
representations, detailed listings will be shown instead. 
Change to: 
 
Statistical outputs, whenever is applicable, will be displayed according to assignment to 
prophylactic CSF factors use or not as well as per Dose level/Dose group or by cancer type 
or primary site if adequate number of patients is represented. Totals numbers will be 
displayed independently, if applicable. Summary tables will have source data footnotes that 
will refer to the relevant listings. The tables' layout may change to adequately accommodate 
cohort size as appropriate.  
If the number of categories or items would not yield appropriate tabular or graphic 
representations, detailed listings will be shown instead. 


 
98
Patients included and treated over 75 years old will be excluded from all tables, listings and 
graphs in this SAP. Detailed narratives of these patients will be shown in the clinical study 
report CSR. 
 
Summary of changes in Section 10. Appendix I. Patients disposition: 
New tables and variables have been included after clinical request and some minor changes 
and corrections have been done in the text and the mock shells to allow a clear 
and unambiguous communication of the science and statistics of the trial.  
 
Section 10.1.1 Patients Treated, Elegible, and Evaluable: 
In Table 10.1.1.4 Number of Patients Evaluable for the Analysis, a footnote has been 
added and categories have been reordered. Note:(*) Efficacy by RECIST v.1.1. A listing of 
patient non evaluable by RECIST v.1.1 will be provided. 
 
Section 10.1.2 Treatment discontinuation:  
Table 10.1.2.1 Treatment Discontinuation by Dose Level adds two more tables and the 
possibility of include other reasons for treatment discontinuation not included in the CRF 
categories and added, after clinical review. Notes:(*) Reasons for treatment discontinuation 
for patients who discontinued while the combination or PM alone will be provided, if 
required. (**) If applicable, a supporting listing 10.1.2.1.a will be provided and reasons for 
treatment discontinuation may suffer re-categorization after clinical review. A new table have 
been added Table 10.1.2.4 Listing of patients with Discontinuation after cycle 9. All tables 
have been renumbered. 
 
Table 10.1.2.1 Treatment Discontinuation by Dose Level adds the following Note:(*) If 
applicable, a supporting listing 10.1.2.1.a will be provided and reasons for treatment 
discontinuation may suffer re-categorization after clinical review. 
 
Table 10.1.2.4 Listing of patients with Discontinuation with PM01183 alone has been 
included. 
 
Section 10.2.1 Patients Characteristics at Baseline: 
Table 10.2.1.1 Age at Entry by Dose Level: categories of age are between 18 and 75 years 
(both inclusive). 
 
Tables 
from 
Previous 
Section 
10.2.9 
Physical 
Examination, 
Vital 
Sings, 
Electrocardiogram and Other Tests have been moved to Section 10.2.1 Patient 
Characteristics at Baseline. 
Table 10.2.1.8 has been renamed to Demographic Parameters by Dose level and added the  
footnote Note: (*) Height (cm) and BSA (DuBois formula). 
 
Section 10.2.2 Cancer History: 
New tables have been added. Table 10.2.2.3 TTP Last Prior Therapy. 


 
99
Table 10.2.2.4 Stage at Diagnosis by Dose Level and Table 10.2.2.5 Tumor Type by Dose 
level have been deleted by clinical indication and 10.2.2.4 Tumor type by dose level include 
the following footnote: Note: (*) CRF categories will be shown and a supportive table 
10.2.2.6.a will be provided for subcategories (e.g. sarcomas). 
New variables have been added to Table 10.2.2.7. See footnote as last TTP prior therapy and 
best response to prior therapy. 
 
Section 10.2.3  Sites involved: 
All tables included in this section will be shown by dose level and/or tumor type, if required. 
Two new tables have been included: Table 10.2.3.5 Bulky Disease and Dose Level. Table 
10.2.3.6 Median Sum of Diameter of Target Lesions (mm). 
 
Section 10.2.4 Previous Treatment Summary.  
Table 10.2.4.2 Previous systemic therapy type by dose level/tumor type has been added. 
 
Section 10.2.7 Previous Anticancer Medical History. 
All tables of this section have now the possibility of being displayed by Tumor type, if 
required.  In addition, tables from Tables 10.2.7.1 Agents of Previous Anticancer Therapy 
(ATC level 1&4) by Dose Level/Tumor Type to Table 10.2.7.3 Summary Statistics. No of 
Lines of Prior Anticancer Therapy by Dose Level/Tumor Type will show only therapies with 
chemotherapy containing and excluding hormonal therapy. 
A new table has been added: Table 10.2.7.5 No of Agents of Last Prior Anticancer Therapy 
before PM01183 treatment by Dose Level/Tumor type. 
 
Section 10.2.8 to 10.2.11: All statistical outputs, whenever applicable, will be displayed 
according to assignment to prophylactic G-CSF factors use or not as well as per Dose level. 
Totals numbers will be displayed independently, if applicable.  
 
Section 10.2.12 Signs and Symptoms at Baseline: 
Table 10.2.12.2 has been renamed to Listing of Adverse events Grade > 1. 
 
Section 10.2.13 Concomitant and Prophylactic Medication Starting Pre-Study: 
New tables have been added: Table 10.2.13.4 No of Patients with Opioids Treatment at 
Baseline by Dose Level, Table 10.2.13.5 Median Number of No of Opioids at Baseline per 
patient by Dose Level. Table 10.2.13.6 No of patients with Steroids Treatment at Baseline by 
Dose Level. Table 10.2.13.7 Known CYP 3A4 Inducers/Inhibitors/Substrates Concomitant 
Therapies at BL and Listing 10.2.13.8 Known CYP 3A4 Inducers/ Inhibitors/Substrates) 
Concomitant Therapies at BL. 
In addition, tables 10.2.13.4 and 10.3.5 have been renumbered to 10.2.13.7 and 10.2.13.8 
and the following footnote has been added: Note: (*) Also the possibility of display one table 
for each category Inducers/Inhibitors or substrates. Some medication will be excluded by 
clinical request (e.g: Dexamethasone) 


 
100
 
Summary of changes in Section 11. Appendix II Safety Evaluation:  
All statistical outputs in this section, whenever applicable, will be displayed according to the 
discontinuation of the combination treatment. Treatment exposure, delays, omissions and 
reductions will be shown before and after discontinuation. Dose level may suffer 
categorization (e.g: RD≤ or RD), if required. 
Each specific table and listing will have a comprehensive header identifying the group/cohort 
of treatment and/or the specific study drug, whenever necessary. 
New tables and variables have been included after clinical request and some minor changes 
and corrections have been done in the text and the mock shells to allow a clear and 
unambiguous communication of the science and statistics of the trial. 
 
Section 11.1.1 Cumulative Dose, Dose Intensity and Relative Dose Intensity:  
Table 11.1.2.12 Reasons for Doxorubicin Dose reduction by Dose Level has been deleted 
because any dose reductions of doxorubicin will be a deviation and will be described in 
the Protocol Deviation section. 
Tables 11.1.2.14 and 11.1.3.6 Listing of Cycles Delays/Reductions due to Nausea/Vomiting 
have been renamed to Listing of Cycles Delays due to Non-Hematological Adverse Events. 
 
Section 11.2.1 Dose-Limiting Toxicities: 
A new table has been added: Table 11.2.1.1 Summary of patients with DLT by Dose Level.  
 
Section 11.3.1 Display of Adverse Events:  
All statistical outputs, whenever applicable, will be displayed according to assignment to 
prophylactic CSF use or not as well as per Dose level. Total numbers will be displayed 
independently, if applicable.  
 
Section 11.4.2 Serious Adverse Events: 
The following text has been added. All serious adverse events will be listed only for the 
purpose of reconciliation with the database of pharmacovigilance. The listings provided by 
the Product Safety department will be used for the clinical study report. 
 
Section 11.5.1 Hematological abnormalities: 
New tables have been added: Table 11.5.1.6 Shift of Hematological Abnormalities. Baseline 
Grade vs. Worst Grade on First Cycle. and Table 11.5.1.8 Listing of patients with 
Biochemical Abnormalities >G2 and Experience Grade Increase (wpp) from Baseline and 
11.5.1.9 Summary of Characteristics of Wpp Hematological Abnormalities G3-4. 
 
Section 11.5.2 Biochemical Abnormalities: 


 
101
New tables have been included: Table 11.5.2.7 Listing of patients with Biochemical 
Abnormalities >G2 and Experience Grade Increase (wpp) from Baseline and 11.5.2.8 
Summary of Characteristics of Wpp Biochemical Abnormalities G3-4. 
 
Section 11.5.3 MetabolicAbnormalities: 
New tables have been added in this section: Table 11.5.3.5 Shift of Metabolic Abnormalities. 
Baseline Grade vs Worst Grade on First Cycle. Table 11.5.3.6 Shift of Metabolic 
Abnormalities. Baseline Grade vs Worst Grade on Treatment. Table 11.5.3.7 Listing of 
Patients with Metabolic Abnormalities >G2 and Experience Grade Increase (wpp) from 
Baseline. Table 11.5.3.8 Supportive Listing: Patients with Grade ≥ 3 Metabolic 
Abnormalities. 
 
Section 11.5.4 Coagulation Abnormalities: 
New tables have been added in this section: Table 11.5.4.4 Shift of Coagulation 
Abnormalities. Baseline Grade vs Worst Grade on First Cycle. Table 11.5.4.5 Shift of 
Coagulation Abnormalities. Baseline Grade vs Worst Grade on Treatment. Table 11.5.4.6 
Listing of Patients with Metabolic Abnormalities >G2 and Experience Grade Increase (wpp) 
from Baseline. 
 
Section 11.6.2 Electrocardiogram. 
Tables of this section have been renumbered and new tables added. Table 11.6.2.5 Shift of 
QTc. Baseline Grade vs. Worst Grade on Treatment. Table 11.6.2.7 Listing of Patients with 
Grade ≥ 2 QTc Interval Prolonged. 
 
Section 11.6.3 LVEF. 
Tables of this section have been renumbered and new tables added. Table 11.6.3.3 Shift of 
LVEF. Baseline Grade vs. Worst Grade on Treatment. Table 11.6.3.4 Listing of Patients with 
Grade ≥ 2 LVEF Decrease.  
 
Section 11.6.4 Pregnancy Test and Adequate Contraception.  
Table 11.6.4.1 Patients with Positive Pregnancy Test and Not Adequate Contraception 
Method has been deleted. If any patients are positive for the pregnancy test or are not using an 
adequate contraception method, they will be reported in the Protocol Deviation section. 
 
Section 11.7 Concomitant and Prophylactic Medication: 
The titles of Tables 11.7.1.2 and 11.7.1.3 have been modified to EPO/RBC and Platelets 
transfusions/CSF. Also, the following footonote has been added: Note: (*) Non-prophylactic 
CSF use. 
New tables have been added: Table 11.7.1.5 Known CYP 3A4 Inducers/Inhibitors/Substrates 
Concomitant Therapies During Study and Table 11.7.1.6. are renamed and depending on the 
number of observations will be shown separately and include the footnote Note: (*) Also the 
possibility of display one table for each category Inducers/Inhibitors or substrates. Some 
medication will be excluded by clinical request (e.g: Dexamethasone) 


 
102
 
New tables have been included in this section, and therefore all tables have been renumbered. 
Table 11.1.7.5 No of Patients with Opioids Treatment During Treatment by Dose Level, 
Table 11.1.7.6 Median Number of No of Opioids During Treatment per Patient by Dose 
Level. Table 11.1.7.7 No of Patients with Steroids Treatment During Treatment by Dose 
Level.   
 
Section 11.7.1 Concomitant and Prophylactic Medication During Study. 
This subsection includes new Table 11.7.1.5 Known CYP 3A4 Inducers/Inhibitors/Substrates 
Concomitant Therapies During Study and Table 11.7.1.6 Listing of CYP 3A4 Inducers or 
Inhibitors (or Substrates) Concomitant Therapies During Study. 
 
Summary of changes in Section 12. Appendix III Efficacy Evaluation: 
The Clinical Benefit criterion has been changed from when response is CR, PR or SD≥3 
months to when response is CR, PR or SD≥4 months. In addition, the possibility of 
calculating time-to-event parameters PFS and DR at 12 and/or 24 months has been added. 
Some other minor changes and corrections have been done in the text and the mock shells to 
allow a clear and unambiguous communication of the science and statistics of the trial. 
 
Summary of changes in Section Figures 13.  
A new Figure 13.6 Boxplot QTcF worst value by cycle has been included. 
 
Section 15 SAP Version History has been included in order to be consistent with the 
Protocol amendment No. 1 of this study and due to the inclusion of new TLGs for the cancer 
subgroups that could be adequately represented in accordance with PharmaMar’s SOPs. 
 
15.2. SAP Version History v2. 
Some other changes were implemented in a new version of the SAP (v.3) for adequate 
representation of cancer subgroups (highlighted in italic bold) and a summary of changes are 
shown at the end of this section. 
 
Summary of changes implemented in SAP (v.3).  
 
• All TLGs detailed in Section 9 will be represented per Dose level or Dose group (RD<, 
etc..) and/or also per cancer type or primary site if an adequate number of patients is 
represented. 
• The granulocyte colony-stimulating factor may be abbreviated indistinctively as CSF or as 
G-CSF in the tables and text detailed in Section 9. 


 
103
• Some minor changes and corrections have been done in the text and the mock shells in 
order to provide a clear and unambiguous communication of the science and statistics of 
the trial. 
• In addition to these changes, minor typographic corrections have been done throughout 
the document. 
 
Summary of proposed changes by section: 
   
Section 10.2.2 Cancer History 
 
Table 10.2.2.5 has been renamed to 10.2.2.5 Summary of Cancer History per Patient and 
Tumor Type. A footnote has been added to this listing to include the possibility of displaying 
any specific characteristics of previous Patient History for each Tumor type. If required, 
tabulations for specific categories will be shown as Supportive tables.  
 
Section 10.2.7  Previous Systemic Therapies 
 
New tables have been included: Table 10.2.7.7 Agents of Prior Anticancer Therapy by 
Tumor Type/Dose Level and Table 10.2.7.9 Platinum-Free Survival by Tumor Type/Dose 
level 
 
Section 11.5 Clinical Laboratory Evaluation 
 
New tables have been included: Table 11.5.1.10 Anemia wpp/wpc and Use of EPO per Dose 
Level, 11.5.1.11 Patients with Anemia Grade 3/4 in Cycle >1 and Use of EPO. , Table 
11.5.1.14 Thrombocytopenia wpp/wpc and Use of Transfusions per Dose Level in Cycle>1., 
Table 11.5.1.15 Patients with Thrombocytopenia Grade 3/4 in Cycle >1 and Use of 
Transfusions; Table 11.5.18 Neuthropenia wpp/wpc and Use of Prophylactic CSF per Dose 
Level in Cycle>1, 11.5.13.19 Patients with Neutrophenia Grade 3/4 in Cycle >1 and Use of 
Prophylactic CSF. 
 
Section 11.7 Concomitant and Prophylactic Medication 
 
A new table has been included: Table 11.7.1.5 Patients with Nausea and /or Vomiting G3/4 
and Use of Antiemetics in Cycle >1. 
 
In Figure 13.1, the possibility of drawing pattern for Neutropenia for patients with 
prophylactic CSF vs. No CSF has been added. 
 
New Figures 13.10 and 13.15 have been included for graphic representation of the subgroup 
populations and specific characteristics. 
 
 
 


 
104
15.3. SAP Version History v3. 
Two substantial protocol amendments “No. 2 and No. 3” and one “non-substancial protocol 
amendment “No.1” have been implemented after the approval of SAP v3; therefore, the SAP 
has been updated (highlighted in italic bold) in accordance with the current version of the 
protocol (version 4.0) as follows: 
• Dose escalation began at PM01183 3.0 mg FD and DOX 50.0 mg/m2 q3wk. Patients 
received DOX capped at 2.0 m² of BSA up to a maximum cumulative dose (MCD) of 450 
mg/m². After DOX withdrawal, PM01183 administration could continue alone at its full 
single-agent RD (7.0 mg FD or 4.0 mg/m² on D1 q3wk). A first amendment to the 
protocol set a maximum age of 75 years for patients enrolled in the study and allowed 
primary G-CSF prophylaxis during dose escalation to explore the potential of this 
approach to reach a higher RD. However, DLTs occurred at the same dose level 
regardless of primary G-CSF prophylaxis, and they included grade 3/4 FN, grade 4 
thrombocytopenia and grade 4 septic shock. Based on these results, the MTD was defined 
at PM01183 5.0 mg FD and DOX 50.0 mg/m² regardless of G-CSF support. The 
immediately lower DL (PM01183 4.0 mg and DOX 50.0 mg/m²) was then expanded, and 
DLTs were found in none of three patients with G-CSF and in one of ten (10%) patients 
without G-CSF (FN). Thus, PM01183 4.0 mg FD and DOX 50.0 mg/m² was defined as 
the RD for this combination, and was not further expanded with primary G-CSF 
prophylaxis. 
Objective antitumor activity was found in more than one third of patients across most 
tumor types at all DLs explored. It was particularly promising in small cell lung cancer 
(SCLC) patients treated as second-line after chemotherapy failure and in endometrial 
cancer patients. Hence, the RD was further expanded to confirm the preliminary antitumor 
activity observed in these settings. All DLTs found after RD expansion were 
myelosuppression-related. Three of 14 patients with endometrial cancer had DLTs. Less 
than one third of second-line SCLC patients had DLTs, but more than 20% of them had 
FN, thus suggesting further dose adjustment was also required in this subsetting.  
Following these findings, the initial RD underwent a 20% reduction in the DOX dose to 
40 mg/m². In addition, the PM01183 dose was adapted to a BSA-based dose of 2.0 mg/m², 
after a logistic regression analysis of pooled data from phase II clinical trials with single-
agent PM01183 in several solid tumors had suggested that patients with the lowest BSA 
values could have a greater risk of developing grade 3/4 thrombocytopenia. 
• In the new cohort B, exploratory assessment for progression-free survival (PFS) and 
overall survival (OS) will be performed and patients will be followed for survival for up to 
18 months after the first study dose. 
• All TLGs described by DL will be also done by most adequate dose 
grouping/cohort/tumor type or other clinical relevant variable where appropriate. The 
tables' layout and headings may change to adequately accommodate cohort/group as 
appropriate. 
• Some minor changes (e.g. clarify dose level grouping to dose level/cohort/Tumor type or 
other clinical relevant variable) and corrections in the text and in the mock shells have 
been done in order to achieve a clear, unambiguous communication of the science and 
statistics of the trial. 


 
105
 
Summary of changes implemented in SAP (v.4).  
 
Section 2.1 Primary Objective: 
Original text: 
• To determine the maximum tolerated dose (MTD) and the recommended dose (RD) of 
PM01183 in combination with doxorubicin with primary prophylaxis with granulocyte 
colony-stimulating factor (G-CSF) in patients with selected advanced solid tumors [if 
dose-limiting toxicities (DLTs) of the combination without G-CSF prophylaxis are 
exclusively related to neutropenia]. 
Changes to: 
• To determine the maximum tolerated dose (MTD) and the recommended dose (RD) 
of PM01183 in combination with doxorubicin in patients with selected advanced 
solid tumors.  
 
Section 2.1 Secondary Objectives: 
Original text: 
• To characterize the safety profile and feasibility of this combination in patients with 
selected advanced solid tumors. 
• To characterize the pharmacokinetics (PK) of this combination and to detect major 
drug-drug PK interactions. 
• To obtain preliminary information on the clinical antitumor activity of this 
combination in non-heavily pretreated selected solid tumor patients. 
• To evaluate the pharmacogenomics (PGx) in tumor samples of patients exposed to 
PM01183 and doxorubicin at the RD in order to assess potential markers of response 
and/or resistance. 
 
Changes to: 
• To determine the MTD and the RD of PM01183 in combination with doxorubicin 
with primary prophylaxis with granulocyte-colony stimulating factor (G-CSF) in 
patients with selected advanced solid tumors [if dose-limiting toxicities (DLTs) of 
the combination without G-CSF prophylaxis are exclusively related to neutropenia]. 
• To characterize the safety profile and feasibility of this combination in patients with 
selected advanced solid tumors. 
• To characterize the pharmacokinetics (PK) of this combination and to detect major 
drug-drug PK interactions. 
• To obtain preliminary information on the clinical antitumor activity of this 
combination in non-heavily pretreated selected solid tumor patients. 
• Based on promising findings, to explore the feasibility, safety and efficacy of a 
potential improvable dose of this combination in selected tumor types [i.e. small cell 
lung cancer (SCLC) and endometrial cancer). 


 
106
• To evaluate the pharmacogenomics (PGx) in tumor samples of patients exposed to 
PM01183 and doxorubicin at the RD in order to assess potential markers of response 
and/or resistance. 
 
Section 3 Study design: 
Original text: 
…… 
Cohorts of three to six patients will be included at each dose level (DL). If no DLT occurs in 
more than one patient within each cohort, escalation will proceed to the following dose level. 
If one of the first three evaluable patients experiences a DLT, the dose level should be 
expanded up to six patients. The MTD will be the lowest dose level explored during the dose 
escalation at which more than one evaluable patient experience a DLT in Cycle 1. All 
evaluable patients within a dose level will be followed for at least one cycle (i.e., three weeks) 
before dose escalation may proceed. Dose escalation will be terminated once the MTD or the 
last dose level (DL4) is reached, whichever occurs first, except if all DLTs occurring at a 
given dose level are related to neutropenia (e.g., febrile neutropenia, grade 4 neutropenia 
lasting more than 7 days or neutropenic sepsis) in which case dose escalation may be 
resumed, starting at the lowest dose level where exclusively neutropenia-related DLTs have 
occurred, and will follow the same original schedule but with compulsory primary G-CSF 
prophylaxis. 
In the event of DLTs occurring in the first patient at the first level, the second and third 
patients will be included at least two weeks apart. Otherwise and/or at subsequent dose levels, 
all patients within a dose level may be treated simultaneously.  
Patients treated at the expansion cohort must be evaluable by the RECIST version 1.1 and/or 
by serum markers (carbohydrate antigen-125, CA-125) in the case of ovarian cancer, as 
appropriate [according to the Gynecologic Cancer Intergroup (GCIG) specific criteria] (see 
study protocol, section 9.7), and must have documented disease progression according to any 
of these criteria. The tumor type(s) that will be eligible to be included in the expansion cohort 
at the RD will be chosen according to the preliminary efficacy observed among those 
previously treated during the escalation phase, and will be discussed and agreed between the 
investigators and the Sponsor. 
Intermediate dose levels could be tested on agreement between the Investigator and the 
Sponsor, if deemed appropriate. 
Patients will receive PM01183 and doxorubicin until progression, unacceptable toxicity, 
consent withdrawal or while it is considered to be in their best interest. More specifically, 
doxorubicin will be administered in the absence of disease progression or unacceptable 
toxicity until a maximal total cumulative dose of 450 mg/m² is reached; once this dose has 
been reached, the patients may continue treatment with PM01183 alone at the established 
single-agent RD, 7.0 mg FD q3wk.    
Tumor assessments will be done every six weeks while on treatment. After treatment 
discontinuation, patients will be followed every four weeks until resolution or stabilization of 
all toxicities, if any. Patients discontinuing treatment without progression will be followed 
every two months until disease progression, other antitumor therapy, death or the date of 
study termination, whichever occurs first (see study protocol, section 5.9). 


 
107
Antitumor response will be assessed using the RECIST version 1.1 and/or serum tumor 
markers as appropriate (e.g., ovarian cancer markers). 
Patients will be evaluated at scheduled visits on three study periods: Pre-treatment, Treatment 
and Follow-up (see study protocol, section 5.2). 
 
Changes to: 
….. 
Cohorts of three to six patients will be included at each dose level (DL). If no DLT occurs in 
more than one patient within each cohort, escalation will proceed to the following dose level. 
The MTD will be the lowest dose level explored during the dose escalation at which more 
than one evaluable patient experience a DLT in Cycle 1. All evaluable patients within a dose 
level will be followed for at least one cycle (i.e., three weeks) before dose escalation may 
proceed. Dose escalation will be terminated once the MTD or the last dose level (DL4) is 
reached, whichever occurs first, except if all DLTs occurring at a given dose level are related 
to neutropenia (e.g., febrile neutropenia, grade 4 neutropenia lasting more than seven days or 
neutropenic sepsis) in which case dose escalation may be resumed, starting at the lowest dose 
level where exclusively neutropenia-related DLTs have occurred, and will follow the same 
original schedule but with compulsory primary G-CSF prophylaxis. An expansion cohort to 
complete a minimum of nine evaluable patients will be recruited at the immediate lower 
dose level, or at the last dose level (DL4) if the MTD is not defined yet. This level will be 
confirmed as the RD if less than one third of the first nine evaluable patients experience 
DLT during Cycle 1. 
Further to the finding of encouraging antitumor activity in the first 43 evaluable patients 
(13 responses, including four complete responses, with five partial responses in eight 
patients with small cell lung cancer, and one complete and one partial response in three 
patients with endometrial cancer), expansion of the cohort treated at the RD has been 
increased to include approximately 30 additional patients, for a total of around 39 patients. 
In addition, a new cohort B of 20 evaluable patients with small cell lung cancer (SCLC) 
who failed treatment after first-line standard cytotoxic-containing therapy and at least nine 
evaluable patients with endometrial cancer will be included to further define the efficacy, 
safety and feasibility of a doxorubicin dose adaptation (doxorubicin 40 mg/m2 and 
PM01183 2.0 mg/m2). Patients in this cohort who have received ten cycles of the 
doxorubicin/PM01183 combination or have to discontinue doxorubicin due to a cardiac AE 
may continue receiving treatment with single-agent PM01183 at 4.0 mg/m2 q3wk if patient 
benefit is perceived according to the Investigator. These patients will be followed every 
three months until death or the date of study termination, whichever occurs first. 
Patients will be divided into two cohorts. Cohort A will consist of all patients included 
before the implementation of protocol amendment #3, and Cohort B will consist of all 
patients included after the implementation of protocol amendment #3. 
 
…… 
Patients will receive PM01183 and doxorubicin until progression, unacceptable toxicity, 
consent withdrawal or while it is considered to be in their best interest. More specifically, 


 
108
doxorubicin will be administered in the absence of disease progression or unacceptable 
toxicity before a maximal total cumulative dose of 450 mg/m2 is reached. Thus, a maximum 
of ten cycles of the combination will be administered to patients with SCLC and 
endometrial cancer included in the new cohort B. Once this dose has been reached, the 
patients may continue treatment with PM01183 alone at the established single-agent RD, 7.0 
mg FD q3wk and for patients included in the new cohort B they may continue treatment 
with PM01183 alone at 4.0 mg/m2 q3wk.   
Tumor assessments will be done every six weeks while on treatment. After treatment 
discontinuation, patients will be followed every four weeks until resolution or stabilization of 
all toxicities, if any. Patients discontinuing treatment without progression will be followed 
every two months until disease progression, other antitumor therapy, death or the date of 
study termination, whichever occurs first (see study protocol, section 5.9). 
In the new cohort B, patients with SCLC and endometrial cancer will be followed every 
three months until death or the date of study termination, whichever occurs first. Antitumor 
response will be assessed using the RECIST v.1.1 and/or serum tumor markers as appropriate 
(e.g., ovarian cancer markers). 
No serum markers will be evaluated in patients with SCLC and endometrial cancer 
included in the new cohort B. Patients will be evaluated at scheduled visits on three study 
periods: Pre-treatment, Treatment and Follow-up (see study protocol, section 5.2). 
In addition, a new cohort B of 20 evaluable patients with small cell lung cancer (SCLC) 
who failed treatment after first-line standard cytotoxic-containing therapy and at least nine 
evaluable patients with endometrial cancer will be included to further define the efficacy, 
safety and feasibility of a doxorubicin dose adaptation. These patients will be treated with 
doxorubicin at 40 mg/m2 administered as an i.v. bolus/short infusion followed by PM01183 
at 2.0 mg/m2 as a 1-hour i.v. infusion on Day 1 q3wk. The administered doses of both 
PM01183 and doxorubicin will be capped at 2.0 m2 of body surface area (BSA) for any 
patients exceeding this BSA value. Patients in this cohort who have received ten cycles of 
the doxorubicin/PM01183 combination or have to discontinue doxorubicin due to a cardiac 
AE may continue receiving treatment with single-agent PM01183 at 4.0 mg/m2 q3wk if 
patient benefit is perceived according to the Investigator. These patients will be followed 
every three months until death or the date of study termination, whichever occurs first. 
 
Section 4.1 Sample size: 
Original text: 
The number of patients may vary depending both on the tolerability to PM01183 combined 
with doxorubicin and the number of dose levels required to identify the MTD. Approximately 
between four and 27 evaluable patients will participate in this study. 
Changes to: 
The number of patients may vary depending both on the tolerability to PM01183 combined 
with doxorubicin and the number of dose levels required to identify the MTD. Approximately, 
100 evaluable patients will participate in this study. 
 
Section 4.2 Dose escalation: 


 
109
Original text: 
The dose escalation schedule is summarized in the following table: 
Dose escalation schedule 
DL 
No. of  
patients 
Relative DI (%) of 
doxorubicin 
 
/ 
PM01183 
Dose of doxorubicin 
(mg/m2 ) / PM01183 (mg FD)  
on Day 1 q3wk 
DL-1 
0-6 
100 / 42.85 
50 / 3.0 
DL1 
3-6 
100 / 50 
50 / 3.5 
DL2 
3-6 
100 / 71.4 
50 / 5.0 
DL3 
3-6 
100 / 85.7 
50 / 6.0 
DL4 
3-6 
100 / 100 
50 / 7.0 
The DL-1 level is to be explored only if DL1 is defined as the MTD. 
DI, dose intensity; DL, dose level; FD, flat dose. 
…. 
Intra-patient dose escalation will not be allowed under any circumstances. 
Changes to: 
The dose escalation schedule is summarized in the following table: 
Dose escalation schedule (cohort A). 
DL 
No. of  
patients 
Relative DI (%) of 
doxorubicin 
 
/ 
PM01183 
Dose of doxorubicin 
(mg/m2 ) / PM01183 (mg FD)  
on Day 1 q3wk 
DL-1 
0-6 
100 / 42.85 
50 / 3.0 
DL1 
3-6 
100 / 50 
50 / 3.5 
DL2 
3-6 
100 / 71.4 
50 / 5.0 
DL3 
3-6 
100 / 85.7 
50 / 6.0 
DL4 
3-6 
100 / 100 
50 / 7.0 
The DL-1 level is to be explored only if DL1 is defined as the MTD. 
DI, dose intensity; DL, dose level; FD, flat dose. 
…. 
Intra-patient dose escalation will not be allowed under any circumstances. 
New cohort after implementation of protocol amendment #3 (Cohort B): 
Patients with SCLC and endometrial cancer will consecutively receive the following on Day 
1 q3wk (three weeks = one treatment cycle): 
• Doxorubicin: i.v. bolus/short infusion at a dose of 40 mg/m2, administered as 
described above, immediately followed by: 
• PM01183: i.v. infusion over one hour at a dose of 2.0 mg/m2, administered as 
described above. 
Both doxorubicin and PM01183 doses will be capped at 2.0 m2 of BSA for individuals 
exceeding this BSA value. Doses will have to be recalculated for patients showing a ≥ 10% 
change in total body weight value compared to previous cycle.   


 
110
PM01183 doses will be rounded to the first decimal, if necessary. Doxorubicin doses will be 
rounded according to institutional guidelines/standard practices. 
 
Section 5.1 Patient evaluability criteria: 
Original text: 
…. 
The "All Evaluable for Efficacy Patients" analysis set is defined as all evaluable patients 
measured according to the RECIST v.1.1 at least six weeks after treatment initiation in all 
patients with measurable disease, and/or by CA-125 levels if applicable, i.e. ovarian cancer 
with at least 2 x upper limit of normal (ULN) at baseline [according to the Gynecologic 
Cancer Intergroup (GCIG/Rustin) specific criteria]. 
If early progression occurs (i.e., before six weeks since treatment) or if treatment should be 
discontinued due to any treatment-related toxicity before appropriate tumor assessments have 
been performed, the patient’s objective response will be considered as a treatment failure or 
progressive disease (PD); therefore, their data will be included in the analysis of objective 
response as per RECIST v.1.1. 
All analyses will be performed as per protocol rather than on an intention-to-treat-basis. Any 
departure from the planned treatment according to the study schedule will be listed and 
documented in the clinical study report. 
Changes to: 
…. 
The "All Evaluable for Efficacy Patients" analysis set is defined as all evaluable patients 
measured according to the RECIST v.1.1 at least six weeks after treatment initiation in all 
patients with measurable disease, and/or by CA-125 levels if applicable, i.e. ovarian cancer 
with at least 2 x upper limit of normal (ULN) at baseline [according to the Gynecologic 
Cancer Intergroup (GCIG/Rustin) specific criteria]. No serum markers will be evaluated in 
patients with SCLC and endometrial cancer included in the new cohort B.    
If early progression occurs (i.e., before six weeks since treatment) or if treatment should be 
discontinued due to any treatment-related toxicity before appropriate tumor assessments have 
been performed, the patient’s objective response will be considered as a treatment failure or 
progressive disease (PD); therefore, their data will be included in the analysis of objective 
response as per RECIST v.1.1. 
In the new cohort B of patients with SCLC and endometrial cancer, a patient evaluable for 
efficacy should have received at least one complete cycle (including observation period) and 
be evaluable as per RECIST, except if non-evaluability is due to treatment failure such as 
drug-related toxicity, death or early unequivocal PD outside the central nervous system. 
All analyses will be performed as per protocol rather than on an intention-to-treat-basis. Any 
departure from the planned treatment according to the study schedule will be listed and 
documented in the clinical study report. 
 
Section 5.2.1.1 Determination of MTD and RD: 


 
111
Original text: 
A minimum of three patients will be included at each dose level. If no patients experience a 
DLT during the first cycle, the dose will be escalated. If one of three patients experiences a 
DLT, three additional patients will be included at that level. If >1 evaluable patient during 
dose escalation at a given dose level experience a DLT during the first cycle, that level will be 
considered the MTD and dose escalation will be terminated except if all DLTs occurring at a 
given dose level are related to neutropenia (e.g., febrile neutropenia, grade 4 neutropenia 
lasting more than 7 days or neutropenic sepsis) in which case dose escalation may be 
resumed, starting at the lowest dose level where exclusively neutropenia-related DLTs have 
occurred, and will follow the same original schedule but with compulsory primary G-CSF 
prophylaxis  
 
Determination of the maximum tolerated dose. 
No. of  patients 
evaluable*  
for DLT 
No. of patients  
with DLTs  
in Cycle 1 
Action 
3 
0 
Escalate DL until DL4 is reached 
1 
Add 3 patients 
>1 
MTD 
6 
1 
Escalate DL until DL4 is reached  
>1 
MTD 
DL, dose level; DLT, dose-limiting toxicities; MTD, maximum tolerated dose. 
* Patients not evaluable for DLT during dose optimization must be replaced. 
 
Decisions on delayed-onset DLTs (i.e., those DLTs occurring after Cycle 1) will be 
individually discussed between the Investigators and Sponsor, and might end affecting the 
definition of the proposed RD for phase II clinical trials. 
Changes to: 
A minimum of three patients will be included at each dose level. If no patients experience a 
DLT during the first cycle, the dose will be escalated. If one of three patients experiences a 
DLT, three additional patients will be included at that level. If >1 evaluable patient during 
dose escalation at a given dose level experience a DLT during the first cycle, that level will be 
considered the MTD and dose escalation will be terminated except if all DLTs occurring at a 
given dose level are related to neutropenia (e.g., febrile neutropenia, grade 4 neutropenia 
lasting more than 7 days or neutropenic sepsis) in which case dose escalation may be 
resumed, starting at the lowest dose level where exclusively neutropenia-related DLTs have 
occurred, and will follow the same original schedule but with compulsory primary G-CSF 
prophylaxis The DL immediately below the MTD, or DL4 if the MTD is not reached during 
dose escalation and the last dose level (DL4) is reached, was to be initially expanded up to a 
minimum of nine evaluable patients. If less than three among the first nine evaluable 
patients treated within the expansion cohort experience a DLT during Cycle 1 this DL will 
be the RD.  
Further to the finding of encouraging antitumor activity in the first 43 evaluable patients 
(13 responses, including four complete responses, with five partial responses in eight 
patients with SCLC, and one complete and one partial response in three patients with 


 
112
endometrial cancer), expansion of the cohort treated at the RD has been increased to 
include approximately 30 additional patients, for a total of around 39 patients. 
 
Determination of the maximum tolerated dose. 
No. of  patients 
evaluable*  
for DLT 
No. of patients  
with DLTs  
in Cycle 1 
Action 
3 
0 
Escalate DL until DL4 is reached 
1 
Add 3 patients 
>1 
MTD 
6 
1 
Escalate DL until DL4 is reached  
>1 
MTD 
DL, dose level; DLT, dose-limiting toxicities; MTD, maximum tolerated dose. 
* Patients not evaluable for DLT during dose optimization must be replaced. 
** For replacement of patients and replacement of patients after 
implementation of Amendment #3 (see Protocol section 5.3).
 
Decisions on delayed-onset DLTs (i.e., those DLTs occurring after Cycle 1) will be 
individually discussed between the Investigators and Sponsor, and might end affecting the 
definition of the proposed RD for phase II clinical trials. 
In the new cohort B of patients with SCLC and endometrial cancer, a patient evaluable for 
efficacy should have received at least one complete cycle (including observation period) and 
be evaluable as per RECIST, except if non-evaluability is due to treatment failure such as 
drug-related toxicity, death or early unequivocal PD outside the central nervous system. 
 
Section 5.2.2.2 Efficacy: 
Original text: 
Although it is not the main objective of this study, antitumor activity will be measured 
according to the RECIST v.1.1 at least six weeks after treatment initiation in all patients with 
measurable disease, or by evaluation of tumor markers if applicable (e.g., ovarian cancer). 
Patients included at the RD in the expansion cohort must be evaluable per RECIST v.1.1 or 
by evaluation of tumor markers (see Section 7.4 for efficacy evaluation). 
If any particular tumor type is adequately represented, time-related parameters [i.e., 
progression-free survival (PFS), overall survival (OS)] will be analyzed according to the 
Kaplan-Meier method, if appropriate. 
….. 
Changes to: 
Although it is not the main objective of this study, antitumor activity will be measured 
according to the RECIST v.1.1 at least six weeks after treatment initiation in all patients with 
measurable disease, or by evaluation of tumor markers if applicable (e.g., ovarian cancer). 
Patients included at the RD in the expansion cohort must be evaluable per RECIST v.1.1 or 
by evaluation of tumor markers (see Section 7.4 for efficacy evaluation). 
No serum markers will be evaluated in patients with SCLC and endometrial cancer 
included in the new cohort B.   


 
113
If any particular tumor type is adequately represented, time-related parameters [i.e., 
progression-free survival (PFS), overall survival (OS)] will be analyzed according to the 
Kaplan-Meier method, if appropriate. 
In the new cohort B, exploratory assessment for progression-free survival (PFS) and 
overall survival (OS) will be performed. 
In addition, patients with SCLC and endometrial cancer included in the new cohort B will 
be followed for survival for up to 18 months after the first study dose. 
..... 
 
Section 7.3.1 Treatment Administration and Exposure 
Original text: 
Exposure to each treatment will be described by dose level (or most adequate dose grouping) 
for all patients who have received at least one of the study treatments. 
….. 
The number of cases, median, standard deviations, 95% confidence interval (CI), minimum 
and maximum values for the parameters defined above will be tabulated by dose level (or 
most adequate dose grouping) and drug (PM01183 and doxorubicin). 
Changes to: 
…. 
Exposure to each treatment will be described by dose level (or most adequate dose 
grouping/cohort/tumor type or other clinical relevant variable) for all patients who have 
received at least one of the study treatments. 
… 
The number of cases, median, standard deviations, 95% confidence interval (CI), minimum 
and maximum values for the parameters defined above will be tabulated by dose level (or 
most adequate dose grouping/cohort/tumor type or other clinical relevant variable) and 
drug (PM01183 and doxorubicin). 
 
Section 7.4.1. Exploratory Analysis of Antitumor Activity: 
Original text: 
…. 
Response rates will be characterized using descriptive statistics (95% confidence interval). If 
applicable, overall response rate (percentage of patients with PR or CR), percentages for PR 
or CR separately and percentage of patients with SD ≥3 and/or 4 months will be analyzed. 
… 
The characteristics of the patients achieving an objective response or SD ≥ 3 and/or 4 months 
by RECIST v.1.1, or a clinically significant improvement measured by tumor markers, will be 
displayed. 
Changes to: 


 
114
…. 
Response rates will be characterized using descriptive statistics (95% confidence interval). If 
applicable, overall response rate (percentage of patients with PR or CR), percentages for PR 
or CR separately and percentage of patients with SD ≥ 4 months will be analyzed. 
…. 
The characteristics of the patients achieving an objective response or SD ≥ 4 months by 
RECIST v.1.1, or a clinically significant improvement measured by tumor markers, will be 
displayed. 
In addition, patients with SCLC and endometrial cancer included in the new cohort B will 
be followed for survival for up to 18 months after the first study dose. 
 
Section 9. Tables, Listings and Figures: 
Original text: 
Statistical outputs, whenever is applicable, will be displayed according to assignment to 
prophylactic CSF use or not as well as per Dose level/Dose group or by cancer type or 
primary site if adequate number of patients is represented. Totals numbers will be displayed 
independently, if applicable. Summary tables will have source data footnotes that will refer to 
the relevant listings. The tables' layout may change to adequately accommodate cohort size as 
appropriate.  
If the number of categories or items would not yield appropriate tabular or graphic 
representations, detailed listings will be shown instead. 
Patients included and treated over 75 years old will be excluded from all tables, listings and 
graphs in this SAP. Detailed narratives of these patients will be shown in the clinical study 
report CSR. 
…. 
Changes to: 
After the implementation of Amendment #3, a new cohort B of patients with SCLC and 
endometrial cancer has been included. All statistical outputs will be displayed according to 
dose level (grouped)/cohort/tumor type or primary site/CSF use or not/other relevant 
clinical variable, whenever applicable and if an adequate number of patients is represented. 
Summary tables will have source data footnotes that will refer to the relevant listings. The 
tables' layout may change to adequately accommodate cohort/group size as appropriate. 
If the number of categories or items would not yield appropriate tabular or graphic 
representations, detailed listings will be shown instead. 
Patients included and treated over 75 years old will be excluded from all tables, listings and 
graphs in this SAP. Detailed narratives of these patients will be shown in the clinical study 
report (CSR).  
The abbreviation DL shown in the mock tables might refer to dose level (grouped <RD, RD, 
etc…)/cohort (i.e. Cohort A and B)/tumor type or primary site (i.e. Ovarian, SCLC (2nd 
line), etc…)/CSF use or not/ other clinical relevant variable ….. 
 


 
115
Sections 10.2.8 Hematological Evaluation at Baseline to 10.2.11 Other Metabolic 
Evaluations at Baseline ; 11.3.1 Display of Adverse Events; 11.5 Clinical Laboratory 
Evaluations; 11.6 Vital Signs, Physical findings and Pregnancy tests, ECG,LVEF; 
Appendix III 12.1 Efficacy Analysis 
The following paragraph has been removed from the aforementioned sections:  
“All statistical outputs in this section, whenever applicable, will be displayed according to 
assignment to prophylactic CSF use or not as well as per Dose level/Dose group or by cancer 
type or primary site if adequate number of patients is represented. Total numbers will be 
displayed independently, if applicable.” 
 
And the following text replaces the removed paragraph in the following sections: 10. 
Appendix I. Patients Characteristics; 11. Appendix II. Safety Evaluation; 12. Appendix 
III. Efficacy Evaluation. 
“All statistical outputs will be displayed according to dose level (grouped)/cohort/tumor type 
or primary site/ CSF use or not/other relevant clinical variable, whenever applicable and if 
an adequate number of patients is represented. Summary tables will have source data 
footnotes that will refer to the relevant listings. The tables' layout may change to adequately 
accommodate cohort/group size as appropriate.”  
 
Section 10.2.1 Patients Characteristics at Baseline 
A footnote has been added. 
Table 10.2.1.1. Age at Entry by Dose Level. 
Age at entry 
DL I 
DL II 
· · · 
DL  n 
Total 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
18-45 years 
 
 
 
 
 
 
 
 
 
 
46-55 years  
 
 
 
 
 
 
 
 
 
 
· · · 
 
 
 
 
 
 
 
 
 
 
< 76* years  
 
 
 
 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
Note:  Percentages based on number of patients by dose level. (*) Example categories. 
 
Section 10.2.7 Previous Anticancer Medical Therapy 
New tables have been included: 
Table 10.2.7.9 CTFI by Dose Level/Cohort/Tumor type 
CTFI/TFI* 
DL I 
DL II 
· · · 
DL  n 
Total 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
Resistant 
 
 
 
 
 
 
 
 
 
 
Sensitive 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
Note: (*) CTFI  (chemotheraphy free interval)/for SCLC patients and TFI (Systemic chemotherapy free interval) for Endometrial patients. Calculated from the last 
therapy previous therapy with ATC coded ”L01XA”  and calculated  as the difference from the end of  therapy to the PD, e.g: for SCLC patients Categories  R 
(resistant) and S (sensitive). 


 
116
Table 10.2.7.10 Summary Statistics: CTFI by Dose Level/Cohort/Tumor type. 
Tumor 
type*/Median 
and 
range  
DL I 
DL II 
· · · 
DL  n 
Total 
N 
 
 
 
 
 
Mean 
 
 
 
 
 
Median 
 
 
 
 
 
Min 
 
 
 
 
 
Max 
 
 
 
 
 
STD 
 
 
 
 
 
Note: (*) Tumor type, if apply  
 
Section 11. Safety Evaluation. 
Original: 
All statistical outputs in this section, whenever applicable, will be displayed according to the 
discontinuation of the combination treatment. Treatment exposure, delays, omissions and 
reductions will be shown before and after discontinuation. 
Changes to: 
All statistical outputs in this section, whenever applicable, will be displayed according to the 
discontinuation of the combination treatment. Treatment exposure, delays, omissions and 
reductions will be shown considering the whole study treatment and/or before and after 
discontinuation, if appropriate. 
Table 11.1.1.4. Dose Intensity by Dose Level: 
Original table: 
Drug 
Dose  intensity  
DL I 
DL II 
· · · 
DL  n 
Total 
PM01183 
 (mg/week) 
N 
 
 
 
 
 
Mean 
 
 
 
 
 
Median 
 
 
 
 
 
Min 
 
 
 
 
 
Max 
 
 
 
 
 
Doxorubicin 
(mg/m²/week) 
N 
 
 
 
 
 
Mean 
 
 
 
 
 
Median 
 
 
 
 
 
Min 
 
 
 
 
 
Max 
 
 
 
 
 
Changes to: 
Drug 
Dose  intensity  
DL I 
DL II 
· · · 
DL  n 
Total 
PM01183* 
 (mg/week) 
N 
 
 
 
 
 
Mean 
 
 
 
 
 
Median 
 
 
 
 
 
Min 
 
 
 
 
 
Max 
 
 
 
 
 
STD 
 
 
 
 
 
PM01183* 
 (mg/m²/week) 
N 
 
 
 
 
 
Mean 
 
 
 
 
 
Median 
 
 
 
 
 
Min 
 
 
 
 
 
Max 
 
 
 
 
 


 
117
Drug 
Dose  intensity  
DL I 
DL II 
· · · 
DL  n 
Total 
STD 
 
 
 
 
 
Doxorubicin 
(mg/m²/week) 
N 
 
 
 
 
 
Mean 
 
 
 
 
 
Median 
 
 
 
 
 
Min 
 
 
 
 
 
Max 
 
 
 
 
 
STD 
 
 
 
 
 
(*) Results of dose intensity maybe grouped and presented in mg/m²/week for patients treated in the Cohort A, if appropriate.   
 
Section 11.3.1 Display of Adverse Events. 
The following paragraph is added: 
All adverse events tables will be listed by cohort and dose level (or most adequate dose 
grouping/tumor type/other clinical relevant variable or according to the discontinuation of 
the combination treatment, if required). 
 
Section 12. Efficacy Evaluation. 
Original: 
All statistical outputs will be displayed according to Dose level (grouped)/Cohort/Cancer type 
or primary site/CSF use or not/other clinical relevant variable, whenever applicable and if an 
adequate number of patients is represented. Summary tables will have source data footnotes 
that will refer to the relevant listings. The tables' layout may change to adequately 
accommodate cohort/group size as appropriate. 
Changes to:  
All statistical outputs will be displayed according to Dose level (grouped)/Cohort/Cancer type 
or primary site/CSF use or not/other clinical relevant variable (e.g. 2nd line SCLC by CTFI), 
whenever applicable and if an adequate number of patients is represented. Summary tables 
will have source data footnotes that will refer to the relevant listings. The tables' layout may 
change to adequately accommodate cohort/group size as appropriate. 
 
Section 12.1.1 Response. 
Table 12.1.1.9 add the following footnote: 
Note: (*) If any particular tumor type or any other clinically relevant variable is adequately represented and PFS at 12, and 24 months also if available data.  
The following category has been added to Table 12.1.1.10.  
Table12.1.1.10 Duration of Response. 
Summary* 
N=XX 
Events X (XX.X%) 
Censored X (XX.X%) 
Median X.X 95% CI (X.X-X.X) 
Duration  of  Response  at 3 months XX.X% 95% CI XX.X%-XX.X%) 
Duration  of  Response  at  6 months XX.X% 95% CI XX.X%-XX.X%) 
 (*) If any particular tumor type or any other clinically relevant variable is adequately represented and DR at 12 and 24 months also if available data. 
 


 
118
The following new Table 12.1.1.11 has been added.  
Table 12.1.1.11 Overall survival. 
Summary* 
N=XX 
Events X (XX.X%) 
Censored X (XX.X%) 
Median X.X 95% CI (X.X-X.X) 
OS  at  6 months XX.X% 95% CI XX.X%-XX.X%) 
OS  at 12 months XX.X% 95% CI XX.X%-XX.X%) 
OS  at 18 months XX.X% 95% CI XX.X%-XX.X%) 
(*) Only for Cohort B but if requested also for cohort A.  
 
Section 13. Figures. 
 
The following paragraph is added: 
All statistical outputs will be displayed according to Dose level (grouped)/Cohort/Cancer 
type or primary site/CSF use or not/other clinical relevant variable (e.g. 2nd line SCLC by 
CTFI), whenever applicable and if an adequate number of patients is represented. The 
figures' layout may change to adequately accommodate cohort/group size as appropriate. 
Figures from this section have changed table numbering due to the inclusion of new graphs 
and the modification of others.  
 
Original graph: 
Figure 13.1.3 Barcharts of Hematological/Biochemical Abnormalities by Dose level 
 
Changes to: 
Figure 13.1.3 Barcharts of Adverse Events or Laboratory Abnormalities 


 
119
 
Figure 13.1.3 Barcharts of Adverse Events or Laboratory Abnormalities by Dose 
Level/Cohort/Tumor type/or Other Clinical Relevant Variable. 
 
The following graphics representations have been included: 
Figure 13.1.9 Waterfall Graphs change to 13.1.11 and change layout to allow grouping 
graphical representations.  
 
Figure 13.1.10  Overall Survival 


 
120
 
Figure 13.1.12 Spider plot: Evolution of RECIST v1.1 Assessments.  
 
Figure 13.1.18 Efficacy and individual TTP in Selected Patients by BSA/CTFI and Treatment 
Discontinuation. 
 


 
121
Figure 13.1.19 Number of Cycles, Reason for Treatment Discontinuation and Response in 
Patients who Received PM001183 alone.