Clinical trial NCT00900562
Conditions: Uterine Cervical Cancer Endometrial Cancer
Keywords: Zalypsis Cancer Endometrial Uterine Cervical PharmaMar
Sponsor: PharmaMar
Start date: 2009-08-01; Completion date: 2011-09-01
Enrollment: 19 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This study is a phase II clinical and pharmacokinetic trial of PM00104 (Zalypsis®) in patients with advanced and/or metastatic endometrial or cervical cancer previously treated with one line of systemic chemotherapy to evaluate the antitumor activity and to determine the safety profile, the pharmacokinetic profile and the pharmacogenomic profile.

Detailed description:

Arms: arm 1: Zalypsis (PM00104)
Interventions: intervention 1: Zalypsis ( PM00104)
Intervention descriptions: intervention 1: Zalypsis (PM00104) (2.5 mg/vial) is provided as a powder for concentrate for solution for infusion

Protocol documents:
Prot_000.pdf: 
 
 
 
SPONSOR 
 
Pharma Mar, S.A. 
Avda de los Reyes, 1 
 
Polígono Industrial “La Mina” 
28770 Colmenar Viejo (Madrid), Spain 
Phone: + 34 918 466 000  
Fax:  
+ 34 918 466 003 
 
 
Pharma Mar USA, Inc. 
One Liberty Plaza, 23rd floor, suite 2335 
New York, NY 10006, USA 
 
Phone: +1 212 201 6770 
Fax: +1 212 201 6771 
 
 
 
 
CLINICAL TRIAL PROTOCOL 
 
Phase II Clinical and Pharmacokinetic Trial of PM00104 (Zalypsis®) in Patients with 
Advanced and/or Metastatic Endometrial or Cervical Cancer Previously Treated with 
One Line of Systemic Chemotherapy 
 
 
INVESTIGATIONAL MEDICINAL PRODUCTS: PM00104 (Zalypsis®) 
Protocol No.: PM104-B-001-09 
NCT Code: 00900562 
 
 
 
Version 2.0 including Amendment #1 – 30 September 2010 
 


SPONSOR
Pharma Mar S.A., Sociedad Unipersonal 
Pharma Mar USA, Inc.
Avda de los Reyes, 1
One Liberty Plaza, 23rd floor, suite 2335
Polígono Industrial “La Mina” 
New York, NY 10006, USA
28770 Colmenar Viejo, Madrid, Spain
Phone: + 34 91 846 6000 
Phone: +1 212 201 6770
Fax: + 34 91 846 6003 
Fax: +1 212 201 6771
CLINICAL TRIAL PROTOCOL
PM104-B-001-09
Phase II Clinical and Pharmacokinetic Trial of PM00104 (Zalypsis®) in Patients 
with Advanced and/or Metastatic Endometrial or Cervical Cancer Previously 
Treated with One Line of Systemic Chemotherapy
INVESTIGATIONAL MEDICINAL PRODUCT:
PM00104 (Zalypsis®)
Protocol No.:
      PM104-B-001-09
Final Version 1.0 – 27 January 2009
Version 2.0 including Amendment #1 – 30 September 2010 
This study will be conducted in compliance with the protocol, Good Clinical Practice (GCP) and 
the applicable regulatory requirements.
Confidentiality Statement
The information and data included in this protocol contain trade secrets and privileged or 
confidential information which is the property of the 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.


STUDY 
CONTACTS
NAME AND ADDRESS
PHONE AND FAX 
NUMBER AND E-
MAIL ADDRESS
Pharma Mar USA, 
Inc.
One Liberty Plaza, 23rd floor, suite 
2335.
New York, NY 10006, USA.
Phone: + 1 212 201 6770
Fax:     + 1 212 201 6771
Pharma Mar S.A.
Sociedad 
Unipersonal1
Avda. de los Reyes, 1.
Polígono Industrial “La Mina-Norte”.
28770 Colmenar Viejo (Madrid), Spain.
Phone: + 34 91 846 6000
Fax:
+ 34 91 846 6003
PharmaMar
Responsible 
Physician
Carmen Kahatt.
Clinical Oncology.
Clinical Development.
PharmaMar S.A.
Phone:
+ 34 91 846 6030
Fax:
+ 34 91 823 4504
e-mail: ckahatt@pharmamar.com
PharmaMar
Project Manager 
Manuel Luque Ibañes.
Clinical Operations.
Project Management.
Clinical Development.
PharmaMar S.A.
Phone:
+ 34 91 823 4548
Fax:        + 34 91 846 60 03
e-mail: mluque@pharmamar.com
Clinical Trial 
Monitor
To be determined.
PharmaMar
Pharmacovigilance 
Contact
María Isabel Ibarra Cabo.
Pharmacovigilance.
Clinical Development.
PharmaMar S.A.
Phone: + 34 91 846 6081
Phone: + 34 91 846 6054
Fax:      + 34 91 846 6004
e-mail: iibarra@pharmamar.com
Outside office hours (GMT):
Elena Roy Berroya.
Pharmacovigilance.
Clinical Development.
PharmaMar S.A.
Phone: + 34 91 823 4749
Clinical 
Pharmacology 
Contact
Arturo Soto Matos-Pita.
Clinical Pharmacology.
Clinical Development.
PharmaMar S.A.
Phone: + 34 91 846 6053
Fax:
+ 34 91 823 4504
E-mail: asoto@pharmamar.com
                                                
1 Abbreviated as PharmaMar S.A. in the rest of the protocol.


Central Laboratory 
for 
Pharmacokinetic 
Samples
Icon Development Solutions.
Manchester Bioanalytical Laboratory.
Parkway One, Parkway Business Centre.
300 Princess Road, Manchester, M14 
7QU
(United Kingdom).
Phone: + 44 (0) 161 232 2815
Fax:
+ 44 (0) 161 227 6625
E-mail: 
sally.hannam@iconpcl.com
Pharmacogenomics 
Contact
Juan Carlos Tercero López.
Scientific Development.
PharmaMar S.A.
Phone: + 34 91 846 6023
Fax:     + 34 91 846 6001
e-mail:
jctercero@pharmamar.com
Pharmacogenomic 
RNA and SNP 
analyses 
(laboratory 1)
Molecular Oncology Lab.
Pangaea Biotech S.A.
USP Institut Universitari Dexeus.
c/ Sabino Arana, 5.
Consultas Externas. Planta -1 (-1.7).
08028 Barcelona, Spain.
Responsible:
Miquel Tarón Roca.
Head of Molecular Biology Laboratory 
Pangaea Biotech S.A.
Phone: + 34 93 497 8925
Fax:     + 34 93 497 8950
Pharmacogenomic 
Protein analyses 
(laboratory 2)
Centro Nacional de Investigaciones 
Oncológicas (CNIO).
c/ Melchor Fernández Almagro, 3.
28029, Madrid, Spain.
Responsible:
Miguel Angel Piris.
Director Molecular Pathology Program, 
CNIO.
Phone: + 34 91 224 6900
Fax:     + 34 91 224 6980


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


TABLE OF CONTENTS
STUDY CONTACTS ............................................................................................................................ 2
INVESTIGATORS................................................................................................................................ 4
TABLE OF CONTENTS...................................................................................................................... 5
SYNOPSIS ............................................................................................................................................. 8
SCHEDULE OF ASSESSMENTS AND PROCEDURES............................................................... 19
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS..................................................... 21
1.
INTRODUCTION .................................................................................................................. 23
1.1.
Endometrial Cancer ...................................................................................................... 23
1.1.1.
Treatment of Advanced/Metastatic Endometrial Cancer......................................................... 24
1.2.
Cervical Cancer............................................................................................................. 26
1.2.1.
Treatment of Advanced/Metastatic Cervical Cancer............................................................... 27
1.3.
PM00104 (Zalypsis®) .................................................................................................... 29
1.3.1.
Chemical Structure and Formulation....................................................................................... 29
1.3.2.
Mechanism of Action .............................................................................................................. 29
1.3.3.
Preclinical Data ....................................................................................................................... 30
1.3.4.
Metabolism.............................................................................................................................. 32
1.3.5.
Clinical Data............................................................................................................................ 32
1.3.5.1.
Clinical Safety Data...................................................................................................... 33
1.3.5.2.
Results of PM104-A-004-05 trial.................................................................................. 34
1.3.5.3.
Clinical Efficacy Data................................................................................................... 34
1.3.5.4.
Evidence for Antitumor Activity against Endometrial Cancer and Cervical Cancer in 
the Phase I Clinical Development of PM00104 ................................................................................. 35
1.3.5.4.1.
Endometrial Cancer.................................................................................................. 35
1.3.5.4.2.
Cervical Cancer ........................................................................................................ 36
1.3.5.5.
Pharmacokinetic Data................................................................................................... 37
1.3.5.5.1.
Renal Function and PM00104 Clearance.................................................................. 37
1.3.5.5.2.
PK/PD Analysis of Neutropenia Associated to Treatment with PM00104............... 37
1.3.6.
Pharmacogenomic Data........................................................................................................... 41
1.3.6.1.
Rationale for the Pharmacogenomic Substudy Associated to PM104-B-001-09.......... 42
1.4.
Rationale for this Phase II Exploratory Trial of PM00104 in Endometrial and Cervical 
Cancer 43
2.
STUDY OBJECTIVES........................................................................................................... 44
2.1.
Primary.......................................................................................................................... 44
2.2.
Secondary...................................................................................................................... 44
3.
OVERALL STUDY DESIGN................................................................................................. 45
4.
SELECTION OF PATIENTS ................................................................................................. 45
4.1.
Inclusion Criteria .......................................................................................................... 45
4.2.
Exclusion Criteria ......................................................................................................... 47
4.3.
Patients for the Pharmacogenomic Substudy (Only for Patients Included in Sites 
Located in the U.S.) ..................................................................................................................... 48
4.3.1.
Inclusion Criteria..................................................................................................................... 48
4.3.2.
Exclusion Criteria.................................................................................................................... 48
5.
PLAN OF THE STUDY.......................................................................................................... 48
5.1.
Duration of Study (Whole Population).......................................................................... 48
5.2.
Duration of Study and Treatment (Per Patient) ............................................................ 49
5.2.1.
Discontinuations...................................................................................................................... 50
5.2.1.1.
Treatment Discontinuation............................................................................................ 50
5.2.1.2.
Reasons for Treatment Discontinuation........................................................................ 50
5.2.1.3.
Study Discontinuation................................................................................................... 51
5.2.2.
Protocol Deviations ................................................................................................................. 51
5.3.
Replacement of Patients ................................................................................................ 52


5.4.
Study Termination (Clinical Cutoff).............................................................................. 52
5.5.
Screening Evaluation..................................................................................................... 52
5.6.
Patient Registration....................................................................................................... 53
5.7.
Evaluations During Treatment ...................................................................................... 53
5.8.
Evaluation at End of Treatment..................................................................................... 55
5.9.
Follow-up after End-of-treatment Visit ......................................................................... 55
6.
PHARMACOKINETICS........................................................................................................ 56
6.1.
Sample Collection, Storage, And Shipping Of The Pharmacokinetic Samples.............. 56
7.
TREATMENT ........................................................................................................................ 57
7.1.
Description of Treatment............................................................................................... 58
7.2.
Administration of Study Medication.............................................................................. 58
7.2.1.
Dose Schedule......................................................................................................................... 58
7.2.2.
Criteria for Treatment Continuation........................................................................................ 58
7.2.3.
Dose Reduction ....................................................................................................................... 60
7.2.3.1.
Hematological Toxicity ................................................................................................ 60
7.2.3.2.
Non-hematological Toxicity ......................................................................................... 60
7.2.4.
Dose Escalation....................................................................................................................... 61
7.3.
Concomitant Medication ............................................................................................... 61
7.3.1.
Prophylactic Antiemetic Treatment......................................................................................... 61
7.3.2.
Concomitant Medication Permitted......................................................................................... 61
7.3.3.
Concomitant Medication Prohibited........................................................................................ 62
7.4.
Packaging and Labeling................................................................................................ 62
7.5.
Drug Accountability ...................................................................................................... 62
7.6.
Treatment Compliance .................................................................................................. 62
8.
STUDY EVALUATIONS ...................................................................................................... 62
8.1.
Efficacy.......................................................................................................................... 62
8.1.1.
Primary Endpoint: Overall Response Rate per RECIST.......................................................... 63
8.1.2.
Secondary Endpoints of Efficacy ............................................................................................ 63
8.2.
Safety ............................................................................................................................. 64
8.3.
Central Cardiological Review....................................................................................... 64
8.4.
Pharmacogenomic Substudy (Only on Samples Collected in the U.S.)......................... 64
9.
ADVERSE EVENTS REPORTING....................................................................................... 65
9.1.
Definitions ..................................................................................................................... 65
9.1.1.
Adverse Event ......................................................................................................................... 65
9.1.2.
Serious Adverse Event (SAE) ................................................................................................. 66
9.1.2.1.
Death............................................................................................................................. 66
9.1.2.2.
Life-Threatening Event................................................................................................. 66
9.1.2.3.
Hospitalization or Prolongation of Hospitalization....................................................... 66
9.1.3.
Unlisted/Unexpected Adverse Event....................................................................................... 67
9.1.4.
Adverse Events Related to Study Drug/s (IMP)...................................................................... 67
9.1.5.
Expedited Reporting................................................................................................................ 67
9.1.6.
Assessment of Causal Relationship to the Study Drug/IMP.................................................... 67
9.2.
Procedures..................................................................................................................... 68
9.2.1.
Reporting Adverse Events....................................................................................................... 68
9.2.2.
Reporting Serious Adverse Events.......................................................................................... 68
9.2.3.
Reporting Pregnancy Cases Occurred within the Clinical Trial .............................................. 69
10.
STATISTICAL METHODS .............................................................................................. 70
10.1.
Sample Size.................................................................................................................... 70
10.2.
Endpoints....................................................................................................................... 71
10.2.1.
Primary Endpoint ............................................................................................................... 71
10.2.2.
Secondary Endpoints.......................................................................................................... 71
10.3.
Statistical Analysis......................................................................................................... 72
10.3.1.
Efficacy Analysis ............................................................................................................... 72
10.3.2.
Safety Analysis .................................................................................................................. 72
10.3.3.
Pharmacokinetic Analysis.................................................................................................. 72
10.3.4.
Pharmacogenomic Analysis ............................................................................................... 73
11.
ADMINISTRATIVE SECTION........................................................................................ 73
11.1.
Ethics............................................................................................................................. 73
11.2.
Monitoring, Auditing and Inspecting............................................................................. 73


11.3.
Patient Informed Consent Form.................................................................................... 74
11.4.
Confidentiality / Identification of Patients..................................................................... 74
11.5.
Case Report Forms........................................................................................................ 75
11.6.
Insurance....................................................................................................................... 75
11.7.
Retention of Records...................................................................................................... 75
11.8.
Use of Information and Publications............................................................................. 75
12.
REFERENCES................................................................................................................... 77
APPENDIX 1. SAMPLES, METHODOLOGY AND TECHNIQUES OF THE 
PHARMACOGENOMIC SUBSTUDY (ONLY ON SAMPLES COLLECTED IN THE U.S.) .. 84
1. PGX STUDY DESIGN.................................................................................................................... 84
APPENDIX 2. ECOG PERFORMANCE STATUS ASSESSMENT SCALE ............................... 89
APPENDIX 3. COCKCROFT AND GAULT FORMULA ............................................................. 90
APPENDIX 4. EVALUATION OF RESPONSE. THE RECIST.................................................... 91
APPENDIX 5. DECLARATION OF HELSINKI ............................................................................ 94
APPENDIX 5. DECLARATION OF HELSINKI ............................................................................ 94


SYNOPSIS
TITLE
Phase II Clinical and Pharmacokinetic Trial of PM00104 
(Zalypsis®) in Patients with Advanced and/or Metastatic 
Endometrial or Cervical Cancer Previously Treated with One 
Line of Systemic Chemotherapy.
PROTOCOL CODE
PM104-B-001-09
INVESTIGATORS / 
TRIAL LOCATION
About 10 centers worldwide will participate in this trial.
A full list of investigators will be available as a separate 
document.
STUDY OBJECTIVES
Primary

To evaluate the antitumor activity of PM00104 administered 
as a 1-hour intravenous (i.v.) infusion on Day 1, 8 and 15 
every four weeks (d1, d8 and d15; q4wk) to patients with 
advanced and/or metastatic endometrial or cervical cancer 
previously treated with one line of systemic chemotherapy.
Secondary

To determine the safety profile of this PM00104 regimen in 
these patients.

To determine the pharmacokinetic (PK) profile of this 
PM00104 regimen in these patients.

To determine the pharmacogenomic (PGx) profile of this 
PM00104 regimen in these patients. Hypothesis-generating 
exploratory PGx analyses will be conducted to correlate the 
molecular parameters found in the tumor and blood samples 
of the patients with the clinical results achieved with 
PM00104.
STUDY DESIGN
Multicenter, open label, phase II clinical trial with single-agent 
PM00104 given as a 1-hour i.v. infusion on d1, d8 and d15 
q4wk to patients with advanced and/or metastatic endometrial or 
cervical cancer in progression.
The primary endpoint of the study is the overall response rate 
(ORR), defined as the percentage of patients with objective 
response (OR; complete or partial response) as defined by the 
Response Evaluation Criteria in Solid Tumors (RECIST).
Treatment will be administered in the absence of disease 
progression and/or unacceptable toxicity. In case of obtaining a 
complete response, two additional cycles will be administered 
and then the treatment will be stopped.


STUDY POPULATION
Adult female patients with endometrial or cervical cancer 
progressing after one previous line of systemic chemotherapy 
are eligible for this trial.
To be included in the study, patients have to fulfill all inclusion 
criteria and none of the exclusion criteria.
INCLUSION CRITERIA 1.
Voluntary written informed consent, obtained from the 
patient before the beginning of any specific study 
procedures. 
2.
Group 1 (endometrial cancer): histologically confirmed 
advanced and/or metastatic endometrial cancer (any grade, 
including endometroid, clear cell, serous and mixed types) 
with documented disease progression as per RECIST at 
study entry.
Group 2 (cervical cancer): histologically confirmed 
advanced and/or metastatic cervical cancer with documented
disease progression as per RECIST at study entry.
3.
Group 1 (endometrial cancer): patients must have failed one 
prior systemic chemotherapy line for advanced/metastatic 
disease (excluding chemosensitizing chemotherapy); prior 
hormone therapy and biological therapy are allowed.               
Group 2 (cervical cancer): patients must have failed one 
prior systemic chemotherapy line for advanced/metastatic 
disease (excluding chemosensitizing chemotherapy); prior 
hormone therapy and biological therapy are allowed.
4.
Complete recovery from the effects of prior radiotherapy 
and from any drug-related adverse events (AEs) derived 
from previous treatments, excluding alopecia and grade 1 
peripheral neuropathy according to the National Cancer 
Institute Common Terminology Criteria for Adverse Events 
(NCI-CTCAE, v. 3.0).
5.
At least one measurable lesion (“target lesion” according to 
the RECIST), located in a non-irradiated area and 
adequately measured less than four weeks before study 
entry. Tumors within a previously irradiated field will be 
designated as "non-target" lesions unless progression is 
clearly documented or biopsy proven.
6.
Age 18 years.
7.
Eastern Cooperative Oncology Group (ECOG) Performance 
Status (PS)  1.
8.
Life expectancy  3 months.
9.
Appropriate bone marrow reserve, renal and hepatic 
functions.
a.
Platelet count  100 x 109/l, hemoglobin  9 g/dl and 
absolute neutrophil count (ANC)  1.5 x 109/l.
b.
Alkaline phosphatase (AP)  2.5 x upper limit of 
normality (ULN) (≤ 5 x ULN in case of extensive bone 
metastases).
c.
Alanine 
aminotransferase 
(ALT), 
aspartate 


aminotransferase (AST) ≤ 2.5 x ULN ( 5 x ULN in 
case of hepatic metastases). 
d.
Total bilirubin  1.5 x ULN, unless due to Gilbert’s 
syndrome.
e.
Renal function: patients with calculated creatinine 
clearance (using Cockcroft and Gault formula)  30 
ml/min.
f.
Albumin ≥ 2.5 g/dl.
10. Left ventricular ejection fraction (LVEF) within normal 
limits (LVEF of at least 50%).
11. Women of childbearing potential must have a negative 
serum pregnancy test before study entry. In case of 
childbearing potential, the patients and their partners must 
agree to use a medically acceptable method of contraception 
throughout the treatment period and for three months after 
discontinuation of treatment. Acceptable methods of 
contraception include complete abstinence, intrauterine 
contraceptive device (IUD), oral contraceptive, subdermal 
implant and double barrier (condom with a contraceptive 
sponge or contraceptive suppository).
EXCLUSION 
CRITERIA
1.
Prior therapy with PM00104.
2.
Uterine sarcomas, adenosarcoma, and malignant Mullerian 
tumors.
3.
Cervical neuroendocrine or small cell carcinomas, non-
epithelial cervical neoplasms such as sarcomas.
4.
Patients who have isolated recurrences (vaginal, pelvic or 
para-aortic) potentially curative with radiation therapy or 
surgery.
5.
Pregnant or lactating women, or in case of childbearing 
potential, women not using an appropriate contraceptive 
method.
6.
Less than three weeks from prior radiation therapy, 
biological therapy or chemotherapy. Less than six weeks 
from 
prior 
nitrosourea, 
mitomycin 
C, 
high-dose 
chemotherapy or radiotherapy involving the whole pelvis or 
over 50% of the spine, provided that acute effects of 
radiation treatment have resolved. Hormonal therapy and 
palliative radiation therapy (i.e., for control of pain from 
bone metastases) must be discontinued before study entry.
7.
Group 1 (endometrial cancer): more than one line of prior 
systemic chemotherapy for advanced/metastatic disease
(excluding chemosensitizing chemotherapy).  
Group 2 (cervical cancer): more than one line of prior 
systemic chemotherapy for advanced/metastatic disease
(excluding chemosensitizing chemotherapy.  
8.
Patients with a prior invasive malignancy (except non-
melanoma skin cancer) who have had any evidence of 
disease within the last five years or whose prior malignancy 
treatment contraindicates the current protocol therapy.


9.
Patients with serious non-healing wound, ulcer, or bone 
fracture.  This includes history of abdominal fistula,
gastrointestinal perforation or intra-abdominal abscess for 
which an interval of three to six months must pass before 
study entry. In addition, the patient must have undergone 
correction (or spontaneous healing) of the perforation/fistula 
and/or the underlying process causing the fistula/perforation. 
Patients with granulating incisions healing by secondary 
intention with no evidence of fascial dehiscence or infection 
are eligible but require weekly wound examinations.
10. Evidence of progressive or symptomatic central nervous 
system (CNS) metastases or leptomeningeal metastases.
11. Other diseases or serious conditions:
a.
Increased cardiac risk as defined by:

Unstable angina or myocardial infarction within 12 
months before inclusion in the study.

New York Heart Association (NYHA) grade II or 
greater congestive heart failure. 

Symptomatic arrhythmia or any arrhythmia requiring 
ongoing treatment. 

Abnormal electrocardiogram (ECG), i.e., patients with 
the following are excluded: QT prolongation - QTc > 
480 
msec; 
signs 
of 
cardiac 
enlargement 
or 
hypertrophy; bundle branch block; partial blocks; 
signs of ischemia or necrosis, and Wolff Parkinson 
White patterns.

History or presence of valvular heart disease.

Uncontrolled arterial hypertension despite optimal 
medical therapy.

Previous mediastinal radiotherapy.

Previous treatment with doxorubicin at cumulative 
doses exceeding 400 mg/m2.
b.
History of significant neurological or psychiatric 
disorders.
c.
Active infection requiring systemic treatment.
d.
Significant non-neoplastic liver disease (e.g., cirrhosis, 
active chronic hepatitis).
e.
Immunocompromised patients, including those known 
to be infected with the human immunodeficiency virus 
(HIV).
f.
Uncontrolled (i.e., requiring relevant changes in 
medication within the last month or hospital admission 
within the last three months) endocrine diseases (e.g., 
diabetes mellitus, hypo- or hyperthyroidism, adrenal 
disorder).
12. Any other major illness that, in the Investigator’s judgment, 
will substantially increase the risk associated with the 
patient’s participation in the study. The investigator should 
feel free to consult the Study Coordinator or the Sponsor for 


uncertainty in this regard.
13. Limitation of the patient’s ability to comply with the 
treatment or to follow-up at a participating center. Patients 
enrolled into this trial must be treated and followed at a 
participating center.
14. Treatment with any investigational product within 30 days 
prior to inclusion in the study.
15. Known hypersensitivity to any component of PM00104.
No. of patients
A total of 62 evaluable patients are expected to participate in the 
study:
30 patients in Group 1 (endometrial cancer), and 
32 patients in Group 2 (cervical cancer).
No. of sites
About 10 sites.
STUDY DRUG
Formulation
Zalypsis(PM00104).
PM00104 is provided as a lyophilized powder for concentrate 
for solution for infusion in strength of 2.5 mg/vial. 
Route of administration
Intravenous as a 1-h infusion by central catheter.
Administered dose
2 mg/m2.
Treatment schedule
A treatment cycle consists of the drug administration on Day 1, 
8 and 15 and all the study evaluations done before the next 
cycle. Treatment cycles will be repeated every four weeks.
Concomitant medication 
Antiemetic prophylaxis: patients will receive prophylactic 
treatment for emesis consisting of dexamethasone 8 mg i.v. and 
5-HT3 antagonists (ondansetron 8 mg i.v. or granisetron 1 mg 
i.v. or tropisetron 5 mg i.v.) before the infusion of PM00104 and 
according to the American Society for Clinical Oncology 
(ASCO) guidelines for drugs with moderate emetic risk.
If necessary, in addition to the above, 10 mg of metoclopramide 
orally every 8 hours may be administered, or the duration of 
treatment with 5-HT3 antagonists and/or dexamethasone can be 
extended.
Secondary prophylaxis with colony-stimulating factors such as 
granulocyte (G-CSF) or granulocyte-macrophage (GM-CSF) 
colony-stimulating factors are allowed according to the ASCO 
guidelines. 


Criteria for continuation 
of treatment and for re-
treatment
In order to be re-treated on Day 1 of a new cycle, the patients 
will have to fulfill the same criteria as at study entry.
If these criteria are not met on Day 1 of a new cycle, treatment 
administration should be delayed up to two weeks and 
reevaluated weekly. The new cycle will start upon recovery of 
these parameters, according to these same criteria.
A maximum delay of two weeks is allowed for recovery from 
drug-related AEs. If toxicities have not recovered after a 
maximum delay of two weeks, the patient should discontinue the 
treatment. In the event of obvious clinical benefit, the patient 
will remain on treatment only after having discussed and agreed 
upon the case with the Sponsor, and upon recovery of all 
parameters according to the aforementioned criteria.
In order to be re-treated on Day 8 and Day 15 of each cycle, the 
patients will have to fulfill the following criteria: 
a)
Platelet count  75 x 109/l, hemoglobin  9 g/dl and 
ANC  1.0 x 109/l.
b)
ALT and AST ≤ 2.5 x ULN (≤ 5 x ULN in case of 
hepatic metastases).
c)
Other non-hematological toxicities, including renal 
function,  grade 1 ( grade 2 in case of asthenia). 
If these criteria are not met on Day 8 or Day 15, the respective 
infusion will be skipped. If both Day 8 and Day 15 infusions 
cannot be administered for any reason, the patient should 
discontinue the treatment, except in the event of obvious clinical 
benefit, in which case the patient will be allowed to remain on 
treatment only after having discussed and agreed upon the case 
with the Sponsor, and upon subsequent recovery of all 
parameters according to the aforementioned criteria.
Dose reduction
Dose reductions will take place based on the worst drug-related 
toxicity found since the last dose administration.
No more than two dose reductions per patient (from 2 mg/m2 to 
1.6 mg/m2 and then to 1.3 mg/m2) will be allowed during the 
study. Patients requiring more than two dose reductions should 
discontinue the treatment, except in the event of obvious clinical 
benefit, in which case the patient could be allowed to remain on 
treatment after having discussed and agreed upon the case with 
the Sponsor.
No dose escalations will be allowed in this study.
EFFICACY 
EVALUATIONS
To be evaluable for efficacy, patients must have:

Received at least four of the six infusions in the first two 
cycles (i.e., two infusions in each cycle, or three infusions in 
Cycle 1 and one infusion in Cycle 2), and

At least one disease measurement recorded not less than six 
weeks after treatment onset. 


In addition, any eligible patient who receive at least two of the 
three infusions in one treatment cycle and experience disease 
progression or die due to progressive disease (PD) prior to 
response evaluation will be considered evaluable for the main 
endpoint (ORR) and will be categorized as an “early 
progression”.
Patients withdrawn due to toxicity without any tumor 
assessment after the start of study treatment will be considered 
as “treatment failures” and will not be replaced.
Patients withdrawn due to significant clinical deterioration of 
unknown reason, hypersensitivity reactions, refusal to continue 
on study for any reason or unrelated AEs without any tumor 
assessment after the start of study treatment will be considered 
not evaluable for efficacy and will be replaced.
Assessment of efficacy will be done using the RECIST and will 
be essentially based on a set of measurable lesions identified at 
baseline as target lesions and followed until disease progression. 
A comprehensive workup will be performed at baseline and 
every other cycle (± 1 week) until evidence of PD. The same 
procedure will be used to evaluate each identified lesion both at 
baseline and throughout the treatment period.
In case of detection of an objective response (complete or partial 
response), a confirmation assessment has to be performed four 
weeks after the first documentation of the response.
SAFETY 
EVALUATIONS
Patients will be evaluable for safety if they have received at least 
one total or partial infusion of PM00104. 
Safety will be evaluated using clinical examinations, which will 
comprise vital signs analysis, clinical assessment of AEs, 
changes 
in 
laboratory 
parameters 
(hematological 
and 
biochemical, including liver function tests) and any other 
analyses that may be considered necessary.
All AEs will be classified according to the NCI-CTCAE, v. 3.0.
PHARMACOKINETIC 
EVALUATIONS
The PK of plasma PM00104 will be evaluated during the first 
two infusions of the first cycle with a limited sampling schedule 
of eight samples. The schedule of sampling per each infusion 
will be as follows: 
T0 (before infusion).
T1 [5 min before the end of the infusion (EOI)].
T1.5 (1.5 hours after the EOI).
T3 (3 hours after EOI). 
T7 (7 hours after EOI). 
T24 (24 hours after EOI). 
T48 (48 hours after EOI). 
T168 (168 hours after EOI).


PK parameters will be calculated using population methods, 
after pooling data from this study with data obtained during 
phase I studies.
PHARMACOGENOMIC 
EVALUATIONS (only 
on samples collected in 
the U.S.)
Inclusion criteria for the PGx substudy:
All patients included in trial PM104-B-001-09 will be 
eligible.
Only those patients with available tissue samples that 
voluntarily sign the Informed Consent Form for the PGx 
substudy will participate.
Exclusion criteria for the PGx substudy:

Patients who do not consent to participate in this substudy. 
Refusal to participate in the PGx substudy will not affect 
participation in the main trial PM104-B-001-09.
The aim of this investigation is to identify and validate 
molecular markers whose expression may be associated with the 
clinical outcome of patients treated with PM00104. These 
molecular markers might allow the identification of those 
patients who will benefit from the treatment with PM00104, thus 
improving the health care by an individualized medicine. 
The following analyses will be done on tumor and blood 
samples from consenting patients treated with PM00104: 
 Quantitation of mRNA expression in paraffin-embedded 
tumor tissue by real-time quantitative reverse transcriptase 
polymerase chain reaction (PCR) of genes identified during 
in vitro studies as potential biomarkers of response to 
PM00104. These genes will be selected from BRCA1, 
ERCC1, XPG, RAD51, TOP2A and TOP1 and other genes 
related to the mechanism of action of PM00104.
 Quantitation of protein expression by immunohistochemistry 
in tissue microarrays constructed from the patient’s paraffin-
embedded tumor tissue blocks. The proteins to be 
determined include XPG, ERCC1, XPA, BRCA1, RAD51, 
BRCA2, ATM, CDK7, CHK1, MDM2, DNApola, CHK2, 
DNA-PK, p16, p21, p53, and other proteins related to the 
mechanism of action of PM00104.
 Analysis of single nucleotide polymorphisms (SNP) at the 
gene XPG will be done, including those at positions 1104, 
1080 and 1053 and SNPs of other genes related to the 
mechanism of action of PM00104.
STATISTICAL 
METHODS
Primary Endpoint:
Overall response rate (ORR), defined as the percentage of 
patients with confirmed objective response (OR), either 
complete (CR) or partial (PR) response according to the 
RECIST.


Secondary Endpoints:
Progression-free survival rate at four months (PFS4), 
defined as the percentage of patients who are alive and with 
no evidence of disease progression at four months after the 
first study drug administration.
Progression-free survival rate at six months (PFS6), defined 
as the percentage of patients who are alive and with no 
evidence of disease progression at six months after the first 
study drug administration.
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.
Overall survival (OS), defined as the time from the first day 
of treatment to the date of death (or the last day when the 
patient is known to be alive). Survival will be followed for 
up to six months after the treatment discontinuation of the 
last patient.
Safety profile.
PK profile.
PGx profile.
Sample Size Considerations:
In this phase II trial, efficacy of PM00104 will be evaluated in 
two different groups of patients with endometrial or cervical 
cancer.
Group 1 (endometrial cancer): patients with endometrial cancer 
who have received one previous systemic chemotherapy line for 
advanced/metastatic 
disease 
(excluding 
chemosensitizing 
chemotherapy). A Simon two-stage design will be adopted in 
this group to test the null hypothesis that the ORR by 
RECIST is ≤10% versus the alternative that ORR ≥ 30% (two-
sided test; alpha=0.1 and beta=0.1). A maximum of 30 evaluable 
patients will be included in this group. In a first stage, 10 
evaluable patients will be recruited. If one or more (≥ 1) patients
achieve an objective response, the accrual in this group will be 
expanded with 20 additional evaluable patients. If the total 
number of patients with objective response is 6 or more (≥ 6) in 
30 evaluable patients (i.e., an ORR in the whole study of at least 
20%), the null hypothesis will be rejected and PM00104 will be 
considered for further clinical development in endometrial 
cancer.


Group 2 (cervical cancer): patients with cervical cancer who 
have received one previous systemic chemotherapy line for 
advanced/metastatic 
disease 
(excluding 
chemosensitizing 
chemotherapy). A Simon two-stage design will be adopted in 
this group to test the null hypothesis that the ORR by 
RECIST is ≤5% versus the alternative that ORR ≥ 20% (two-
sided test; alpha=0.1 and beta=0.1). A maximum of 32 evaluable 
patients will be included in this group. In a first stage, 18 
evaluable patients will be recruited. If one or more (≥ 1) patients 
achieve an objective response, the accrual in this group will be 
expanded with 14 additional evaluable patients. If the total 
number of patients with objective response is 4 or more (≥ 4) in 
32 evaluable patients (i.e., an ORR in the whole study of at least 
12.5%), the null hypothesis will be rejected and PM00104 will 
be considered for further clinical development in cervical 
cancer.
Methods of Analysis:
Binomial estimates with exact 95% confidence intervals will be 
calculated for the analysis of the main endpoint (ORR) and 
PFS4 and PFS6 rates.
Time-to-event endpoints (DR, PFS and OS) will be analyzed 
according to the Kaplan-Meier method. 
If relevant, efficacy parameters versus baseline covariates will 
be analyzed and appropriate test will be used (i.e., the Fisher 
exact test for categorical variables, the log-rank test or Cox 
regression for time to event variables, etc.).
Baseline characteristics, AEs, serious adverse events (SAEs), 
laboratory evaluations, deaths and the reason for study 
discontinuations will be analyzed. Continuous variables will be 
tabulated and presented with summary statistics (i.e., mean, 
standard deviation, median and range). Categorical variables 
will be summarized in frequency tables by means of counts and 
percentages.
DURATION OF STUDY 
PERIOD (per patient)
Patients will be evaluated at scheduled visits in up to three study 
periods:
Pre-treatment: from signature of informed consent to the 
first infusion of PM00104.
Treatment: from the first infusion of PM00104 to treatment 
discontinuation plus 30 days. 
Follow-up: after treatment discontinuation, patients will be 
followed until all toxicities or their sequelae resolve or 
stabilize at a level acceptable to the Investigator and the 
Sponsor. Patients who discontinue treatment without 
progression will be followed every three months until 
disease progression, other antitumor therapy or death or until 
the date of study termination, whichever occurs first. After 


disease progression or after other antitumor therapy, patients 
will be followed every three months until death or until 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 follow-up period. Patients 
will be considered to be on-treatment for the duration of their 
treatment and in the first 30 days following treatment 
discontinuation. Treatment discontinuation is defined as the 
day of the last study drug dose administration.
Patients will receive PM00104 while it is considered to be in 
their best interest. Specifically, treatment will continue until:
Disease progression.
Unacceptable toxicity (including any toxicity leading to the 
need for a third dose reduction or severe hypersensitivity 
reactions).
Patient refusal.
Intercurrent serious illness. 
Protocol deviation with an effect on the risk/benefit ratio of 
the clinical trial.
Treatment delay > two weeks or impossibility to administer 
both Day 8 and Day 15 dose on a given cycle (except in case 
of clear clinical benefit, with the Sponsor’s approval).
Any subsequent therapies for the patients may be provided off-
study according to the Investigator’s criteria.
REPLACEMENT OF 
PATIENTS
Patients must be replaced if they are considered not evaluable 
for efficacy, i.e., if they are withdrawn from the study due to 
significant 
clinical 
deterioration 
of 
unknown 
reason, 
hypersensitivity reactions, patient refusal or unrelated AEs 
without any tumor assessments after the start of study treatment.
PLANNED TRIAL 
PERIODS
The total duration of the study will be approximately 33 months, 
including approximately 24 months of active enrolment. 
Consenting patients will be followed until death, or until the date 
of study termination, whichever occurs first. 
Planned start date (first patient on study): 3Q09.
Planned enrolment period: 24 months.
Planned study termination (clinical cutoff): six months after 
the last treatment visit of the last evaluable patient included 
in the study or nine months after the last patient is included, 
whichever occurs first.


SCHEDULE OF ASSESSMENTS AND PROCEDURES
Screening
Treatment
(cycle 1 and further cycles)
Follow-
up (1)
Study day
D–28 to D1
D1
D8
D15
D22
D28
(=D1 of the 
next cycle)
End of 
treatment
(last dose 
+ 30 
days)
Study visit window
Within 2 days of pre-specified day
Written informed 
consent
Before any 
study  
procedure
Medical history

Complete physical 
examination


Repeat if clinically indicated

(9)
ECOG PS


Repeat if clinically indicated

(9)
Vital signs 





(9)
Weight and height

Repeat if clinically indicated

Repeat if clinically 
indicated
Hematology  
(2)
(2)
 (7)
 (7)
 (7)


Biochemistry A  
(2)
(2)
 (7)
 (7)
 (7)


Biochemistry B 
(2)
Repeat if clinically indicated
 (7)


Calculated 
creatinine 
clearance
(2)
Repeat if clinically indicated

Repeat if clinically 
indicated
Pregnancy test 
(3)
Repeat if clinically indicated
ECG
(10)
Repeat if clinically indicated



LVEF (cardiac 
ultrasound)
 (10)
Repeat if clinically indicated
 (8)


Intercurrent 
events, 
concomitant 
disease and 
treatments

Throughout the “on treatment” period
(1,9)
Adverse events
NA
Throughout the “on treatment” period
(1)
Tumor assessment 
(4)
Every other cycle (± 1 week) until PD

(9)
Other tests 

When indicated, according to the clinical and laboratory 
context
(9)
Pharmacokinetics
(5)
(5)
PGx substudy, if 
patient consented
(6)
1. Patients withdrawn with PM00104-related ongoing AEs should be followed with the appropriate tests until their 
resolution. Beyond 30 days after the last administration of study drug, only those procedures that are relevant to 
any remaining toxicities need to be performed.


2. Within one week prior to the first administration of PM00104. Repeat on Day 1 of Cycle 1 prior to treatment 
with PM00104, if the treatment is administered more than one week after the screening test.
Hematology: differential WBC (neutrophils, lymphocytes), hemoglobin and platelets.
Biochemistry A: liver function test (ALT, AP, AST, LDH, total and direct bilirubin), creatinine, CPK, troponin 
I , glucose and serum electrolytes (Na+, Cl-, K+, Ca++, Mg++).
Biochemistry B: total protein, albumin, amylase and lipase. CPK-MB fraction to be analyzed if CPK and/or 
troponin I are abnormal. In the case of grade  3 increase in serum cardiac troponin I, an ECG and cardiac 
ultrasound will be performed as soon as possible. 
3. Pregnancy test, if applicable, within two weeks prior to registration
4. CT-scan or MRI of all measurable/evaluable sites of disease, as per RECIST. Within four weeks prior to the 
first dose of PM00104. Documentation of PD is mandatory.
5. First two infusions of the first cycle only.
6. Tissue block collection. Additionally, one blood sample will be taken prior to the first infusion of PM00104.
7. To be performed within the two prior days. If NCI-CTCAE grade  3 occurs, the appropriate chemistry test(s) 
should be done at least every 2-3 days until recovery.
8. To be performed every other cycle.
9. After discontinuation, patients taken off study without PD should be monitored every three months until PD, 
death, other antitumor therapy or the predefined date for study termination. After PD, patients should be 
monitored every three months until death or the predefined date for study termination.
10. All ECGs and LVEFs (ultrasound) will be reviewed by an external cardiologist.
AE, adverse event; ALT, alanine aminotransferase; AP, alkaline phosphatase; AST, aspartate aminotransferase; 
CPK, creatine phosphokinase; CPK-MB, creatine phosphokinase-fraction MB; CT, computed tomography; ECG, 
electrocardiogram; ECOG, Eastern Cooperative Oncology Group Performance Status; LDH, lactate 
dehydrogenase; LVEF, left ventricular ejection fraction; MRI, magnetic resonance imaging; NA, not applicable; 
NCI-CTCAE, National Cancer Institute Common Terminology Criteria for Adverse Events; PD, progressive 
disease; RECIST, Response Evaluation Criteria In Solid Tumors; WBC, white blood cells.


LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
T/C
% Ratio of Treated versus Control Tumor Volumes
AE(s)
Adverse Event(s)
ALT 
Alanine Aminotransferase
ANC
Absolute Neutrophil Count
AP
Alkaline Phosphatase
ASCO
American Society of Clinical Oncology
AST 
Aspartate Aminotransferase
AUC
Area Under the Curve
βhCGs
Beta Human Chorionic Gonadotrophins
BSA
Body Surface Area
Cmax
Maximum Plasma Concentration
CNIO
Centro Nacional de Investigaciones Oncológicas (Spain)
CNS
Central Nervous System
Cp
Plasma Concentrations
CPK 
Creatine Phosphokinase
CPK-MB
Creatine Phosphokinase-Fraction MB
CR
Complete Response
CRF 
Case Report Form
CT
Computerized Tomography
CTRT
Chemoradiotherapy
d
Day
DLT
Dose-limiting Toxicity
DNA
Deoxyribonucleic Acid
DR
Duration of Response
ECG 
Electrocardiogram
ECHO
Echocardiography
ECOG
Eastern Cooperative Oncology Group
EGFR
Epidermal Growth Factor Receptor
EOI
End of Infusion
EVA
Ethylene Vinyl Acetate
FDA
Food and Drug Administration (United States)
FUP
Follow-up
G-CSF
Granulocyte Colony Stimulating Factor
GCP
Good Clinical Practice
GM-CSF
Granulocyte-macrophage Colony Stimulating Factor
GMT
Greenwich Meridian Time
Hb
Hemoglobin
HIV
Human Immunodeficiency Virus
hERG
Human ERG Potassium Channel
HR
Homologous Recombination
i.v.
Intravenous
IB
Investigator’s Brochure
IC50
Half-maximal Inhibitory Concentration
ICF
Informed Consent Form
ICH
International Conference on Harmonization
IEC
Investigational Ethics Committee
IMP
Investigational Medicinal Product
IRB
Institutional Review Board
IUD
Intrauterine Device
LD
Longest Diameter
LDH
Lactate Dehydrogenase
LVEF
Left Ventricular Ejection Fraction


MedDRA
Medical Dictionary for Regulatory Activities
MRI
Magnetic Resonance Imaging
mRNA
Messenger Ribonucleic Acid
MTD
Maximum Tolerated Dose
NA
Non Available-Non Applicable
NCI
National Cancer Institute
NCI-
CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
NCCN
National Comprehensive Cancer Network
NER
Nucleotide Excision Repair
NYHA
New York Heart Association
OR
Objective Response
ORR
Overall Response Rate
OS
Overall Survival
PCR
Polymerase Chain Reaction
PD
Progressive Disease
PE
Polyethylene
PFS
Progression-free Survival
PFS4
Progression-free Survival Rate at Four Months
PFS6
Progression-free Survival Rate at Six Months
PGx
Pharmacogenomic(s)
PK
Pharmacokinetics
PK/PD
Pharmacokinetic/Pharmacodynamic
PM00104
Zalypsis
PP
Polypropylene
PR
Partial Response
PRE TT
Pre-treatment
PS
Performance Status
PTEN
Phosphatase and Tensin Homolog
PU
Polyurethane
PVC
Polyvinyl Chloride
q3wk
Every Three Weeks
q4wk
Every Four Weeks
q.d.
Every Day
q.s.
Quantum Sufficit
RD
Recommended Dose
RECIST
Response Evaluation Criteria In Solid Tumors
RNA
Ribonucleic Acid
SAE(s)
Serious Adverse Event(s)
SNP
Single Nucleotide Polymorphism
SOI
Start of Infusion
SPC
Summary of Product Characteristics
STR
Serious Toxicity Rate
TT
Treatment
ULN
Upper Limit of Normality
UPSC
Uterine Papillary Serous Carcinoma
US
Ultrasound
USPI
United States Package Insert
U.S./USA
United States/United States of America
vs.
Versus
WBC
White Blood Cells
Wk(s)
Week(s)
WMA
World Medical Association
XPG
Xeroderma Pigmentosum, Complementation group G


1.
INTRODUCTION
1.1.
ENDOMETRIAL CANCER
Uterine corpus cancer includes endometrial carcinoma (90%) and mixed histology 
(10%) 
(1). 
The 
75-80% 
of 
endometrial 
carcinomas 
are 
endometrioid 
adenocarcinomas, with variants such as adenosquamous, villoglandular, ciliated and 
secretory subtypes. Rare cell types, including uterine papillary serous carcinoma
(UPSC), clear cell carcinoma, papillary endometroid carcinoma, and mucinous 
carcinoma have a later age of onset, greater risk for extrauterine metastases, and 
poorer prognosis compared with typical low grade adenocarcinomas. 
Table 1 outlines the incidence and mortality figures for uterine corpus cancer in the 
USA and Europe (no statistics are available for endometrial cancer alone). In 2008, it 
was estimated that 40,100 new cases of uterine corpus cancer will be found in the 
USA and 7,470 deaths will occur due to this disease (2). Thus, uterine corpus is the 
first genital cancer in females with respect to estimated new cases in the USA (6% of 
all cancer cases), and the second cause of gynecologic cancer mortality (3% of deaths 
due to cancer), immediately after ovarian cancer.
Table 1.  Incidence and mortality due to cancer of the uterus (corpus and 
cervix)§.
Incidence*
Mortality**
Uterine corpus cancer
USA†
40,100
7,470
European Union ††
82,230
25,740
Uterine cervix cancer
USA†
11,070
3,870
European Union ††
30,560
13,650
*Number of new cases per year.
 **Number of deaths per year.
†Source: Jemal et al. Cancer statistics, 2008. CA Cancer J Clin. 58:71-96 (2008) (2).
††Source: Arbyn et al. Burden of cervical cancer in Europe: estimates for 2004 Ann Oncol 18:1708-
1715 (2007) (3).
§In both statistical analyses/databases, no data for endometrial cancer alone are provided. They are 
included with other types of cancer characteristic of uterine corpus cancer (uterine sarcoma, etc.).
Cancer of the uterus is among the cancers for which survival has not improved 
substantially over the past 25 years (Figure 1), making its treatment an important 
public health issue. The 5-year survival rates are drastically reduced in those patients 
with regional disease at diagnosis (56%) or with distant disease (17%) (2). Therefore, 
patients with metastatic disease have a dismal survival. 


Figure 1. Annual age-adjusted* cancer death rates among females for 
selected cancers (USA, from 1930 to 2004).
*Rates are age-adjusted to the 2000 USA standard population. †“Uterus” includes 
uterine corpus and uterine cervix. Figure drawn from Jemal et al. Cancer Statistics
2008.CA Cancer J Clin. 58:71-96 (2008) (2)
Most patients with endometrial cancer have stage I disease at diagnosis and,
therefore, surgery (usually total abdominal hysterectomy, with bilateral salpingo-
oophorectomy) is the treatment of choice (1). Primary radiotherapy is administered 
for medically inoperable patients and adjuvant radiotherapy is offered for those 
patients at high risk of recurrence.
For metastatic extra-abdominal disease, palliative therapy including radiotherapy, 
hormonal therapy, or chemotherapy is generally used with poor results (4).
1.1.1.
Treatment of Advanced/Metastatic Endometrial Cancer
Surgery (with or without radiotherapy) is recommended for patients with recurrence 
at sites without prior radiotherapy or with previous brachytherapy only. 
Recommended salvage therapy for patients with recurrence at sites previously 
irradiated includes pelvic exenteration with or without intraoperative radiotherapy, 
hormonal therapy or chemotherapy (4). Treatment with systemic agents should be 
considered for those patients with advanced or recurrent disease not amenable to 
radiation or surgery.
Hormonal therapy for metastatic disease involves mainly the use of progestational 
agents, although aromatase inhibitors are also being used (4).
Although phase II/III data is limited, chemotherapy for endometrial cancer includes 
different single agents, such as cisplatin, carboplatin, oxaliplatin, paclitaxel, docetaxel 
and doxorubicin (5, 6). Response rates in first-line chemotherapy with these 
compounds range 20-30% for single-agent regimens and 40-60% for combinations. 
However, despite these relatively high response rates, most patients progress after a 
median of 6-9 months and are candidates for second-line therapy. Results of second-


line chemotherapy are generally poor, and only taxanes (e.g., paclitaxel) have shown 
response rates greater than 20% in this disease setting (Table 2).
Table 2. Antitumor activity of different single-agent therapies administered as 
second-line chemotherapy in recurrent, advanced endometrial carcinoma.
Agent
Reference
No of
patients
Schedule (dose)
Median ORR 
(%)
Cisplatin
Thigpen et al. (7)
25
q3wk (50 mg/m2)
4.0
Docetaxel
García et al. (8)
27
1-hour Day 1, 8 and 15 q4wk (36 
mg/m2)
7.7
Flavopiridol
Grendys et al. (9)
26
i.v. bolus Day 1, 2 and 3 q3wk 
(50 mg/m2/day)
0.0
Ifosfamide
Sutton et al. (10)
52
Daily for 5 days q4wk (1.2 g/m2)
15.0
Irofulven 
Schilder et al. (11)
25
Daily for 4 days (11 mg/m2)
4.0
Ixabepilone
Dizon et al. (12)
NA
NA
12.0
Liposomal 
doxorubicin
Muggia et al. (13)
46
1-hour q4wk (50 mg/m2)
9.5
Oxaliplatin
Fracasso et al. (14)
44
2-hour q3wk (130 mg/m2)
13.5
Lincoln et al. (15)
44
3-hour q3wk (200 mg/m2)
27.3
Paclitaxel
Homesley et al. (16)
16
1-hour weekly (80 mg/m2)
26.7
Pyrazoloacridine 
Plaxe et al.(17)
23*
3-hour q3wk (750 mg/m2) 
4.3
Topotecan
Miller et al.(18)
29
Daily for 5 days  q3wk (0.5-1.5 
mg/m2)
9.0
*11 of 23 patients pretreated.
NA, non available; ORR; overall response rate; q3wk; every three weeks; q4wk, every four weeks.
Two combination regimens of chemotherapy have been tested in phase III clinical 
trials in the first line: doxorubicin/cisplatin/paclitaxel (19)) and cisplatin/doxorubicin 
(19-23)(19-23). The first regimen was the most active, but also the most toxic, in 
particular with respect to neurotoxicity (24). Overall response rate (ORR) ranged 
from 42% (cisplatin/doxorubicin) to 57% (doxorubicin/cisplatin/placlitaxel), but the 
duration of response was relatively short, and the median survival was approximately 
one year (4). The combination of carboplatin plus paclitaxel has also been 
investigated in phase II trials, with response rates of 56% to 63% (25, 26). However, 
all these combinations have not yet proven an improvement in survival or quality of 
life of patients. In fact, combination chemotherapy regimens in endometrial 
carcinoma should be approached with care with respect to toxicity. Many women 
with endometrial cancer are elderly (median age at diagnosis is 60 to 65 years), obese 
and diabetic. All these factors increase the risk of complications with more intensive 
chemotherapy. In addition, many of them have had adjuvant pelvic radiotherapy with 
the consequent limited hematological reserve, and therefore dose-intense regimens 
should be administered with caution.


Biologic and molecular-targeted therapies have no proven role at this time in the 
treatment or relapsed or metastatic endometrial carcinoma. The most tantalizing 
results have been obtained with mTOR inhibitors [temsirolimus (5, 27-29), 
everolimus (30) and deforolimus (31)], with a response rate in chemotherapy-naïve 
patients of up to 26% for temsirolimus. Results in pretreated patients are less 
encouraging, with a clinical benefit rate of 44%, but objective response rate equal or 
lower than 7% (29, 30).
In summary, despite the use of combinations or novel agents and therapies, responses 
in patients with advanced/metastatic endometrial cancer are of short duration. Thus, 
progression-free survival (PFS) of 6-9 months and overall survival (OS) of 12-15 
months have been found with first-line chemotherapy (6). As expected, shorter PFS 
(2 months) and OS (6-8 months) have been found with second-line regimens (8, 13). 
Therefore, treatment of advanced/metastatic endometrial cancer is a clearly unmet 
medical need and investigation of new agents is warranted. Results found in phase I 
studies with PM00104 (Zalypsis®; see Section 1.3.5.4.2) suggest that this novel 
chemotherapeutic agent can be of value as chemotherapy in this disease setting.
1.2.
CERVICAL CANCER
Cervical cancer is a common cancer in women. Squamous cell carcinomas account 
for about 80% of all cervical cancers (32). Other usual histologies are adenosquamous 
carcinoma and adenocarcinoma of the cervix. 
Advanced cervical cancer is a public health problem even in those countries where 
screening and treatment of precursor lesions have had a positive impact on this 
disease. Table 1 shows the incidence and mortality figures for cervical cancer in the 
USA and Europe. In 2008, it was estimated that 11,070 new cases will be found in the 
USA and 3,870 deaths will be caused by cervical cancer (2). Despite the figures for 
new cases of cervical cancer are lower than those of uterine corpus cancer (11,070 vs.
40,100), mortality remains higher in this particular cancer type (35% and 45% of all 
new cases in USA and the European Union will die of their disease, respectively) (2, 
3).
Either surgery or radiation therapy are the mainstay of treatment for most cases of 
cervical carcinoma (32). Surgery is typically reserved for lower-stage disease and 
smaller lesions. However, despite the efforts in screening and early detection, 
carcinoma of the uterine cervix continues to present at a relatively locally advanced 
stage in certain populations, and cisplatin-based concurrent chemoradiation is the 
current standard therapy for locally advanced disease (32). A large population-based 
pattern-of-care study conducted in 4,069 patients confirmed a better survival outcome 
with platinum-based chemoradiotherapy with respect to radiotherapy alone (33). 
As mentioned above, survival in patients with uterine (endometrial or cervical) cancer 
has not improved over the past 25 years despite new treatments. As has been shown 
for endometrial cancer, the 5-year survival rates in patients with cervical cancer are 
drastically reduced in those patients with regional disease at diagnosis (67%), but 
particularly in patients with metastatic disease who have a dismal survival (5-year 
rate of 23%, and median survival of 6-8 months). In those cases, no potentially 
curative therapy exists and the focus of treatment is palliation with chemotherapy.


Therefore, there is an unmet need for new active agents to treat patients with 
advanced/metastatic cervical cancer.
1.2.1.
Treatment of Advanced/Metastatic Cervical Cancer
Patients with a localized recurrence of cervical cancer after surgery should be 
evaluated for radiotherapy for relapse, with salvage rates of 40% in such cases (34). 
For patients with pelvic recurrence with no prior radiotherapy or with relapsed site 
outside the previously irradiated field, therapy for relapse includes definitive pelvic 
radiation and platinum-based chemotherapy with (or without) brachytherapy. Patients 
with advanced, recurrent cervical cancer or with extrapelvic metastases are the most 
difficult to treat, and chemotherapy constitutes the best treatment for these patients
(32, 35). 
Many attempts have been made to identify active agents in advanced, recurrent or 
persistent cervical cancer: these trials have shown cisplatin as the most active agent 
(36, 37). However, cisplatin is still capable of generating an objective response rate in 
only 20-30% of the patients treated, complete responses are rare, and responses are 
usually partial and of short duration (36). Carboplatin, topotecan and paclitaxel have 
also been reported as tolerable and efficacious in recurrent cervical cancer (32) and 
combinations of these agents have been evaluated: the most usual are 
cisplatin/topotecan (38) and cisplatin/paclitaxel (39). Cisplatin-based combination 
regimens have produced higher progression-free survival rates over cisplatin alone,
and one combination (cisplatin/topotecan) has even prolonged survival without 
impairment in the quality of life, making these combinations new standard regimens 
in the setting of advanced, recurrent cervical cancer (38). However, newer agents are 
needed to move from palliation to cure. Other agents listed in the National 
Comprehensive Cancer Network (NCCN) Clinical Guidelines for cervical cancer (32)
as having shown a partial response and that could be useful as second-line therapy 
include ifosfamide (40, 41), irinotecan (42) or vinorelbine (43-45) (Table 3).
However, antitumor activity is limited and generally of short duration (46). The 
median PFS with second-line regimens is 2 months, with a dismal median survival of 
6 months (35).
Table 3. Antitumor activity of different single-agent therapies in recurrent, 
advanced cervical cancer.
Agent
Reference
No of
patients
Chemotherapy 
setting
Histology
Schedule (dose)
Median 
ORR 
(%)
Rose et al.
(47)
25
First-line, n=3
Second-line, 
n=22
Squamous
Single dose, daily 1-21 q4wk 
(50 mg/m2/day)
11.8
Etoposide
Morris et al. 
(48)
44
First-line, n=25
Second-line, 
n=19
Squamous (40)
Non-squamous 
(4)
Single dose, daily 1-21 q4wk 
(37.5 mg/m2/day)
9.1
Gemcitabine
Schilder 
et 
al. (49)
27
First-line, n=13
Second-line, 
n=14
Squamous
30-min 
weekly 
x 
3wks 
+1wke or rest (800 mg/m2)
8.0
Sutton et al. 
(40)
30
First-line, n=1
Second-line, 
n=29
Squamous 
Daily for 5 days q4wk (1.2 
g/m2)
11.1
Ifosfamide
Sutton et al.
(41)
46
NA
Non-squamous 
Daily for 5 days q4wk (1.5 
g/m2)
15.0


Agent
Reference
No of
patients
Chemotherapy 
setting
Histology
Schedule (dose)
Median 
ORR 
(%)
Look et al.
(50)
44
First-line
Squamous
90-min weekly x 4 wks + 
2wks of rest (125 mg/m2)
13.3
Lhommé et 
al. (51)
55
First-line
Squamous
30-min q3wk (350 mg/m2)
15.7
Verschraegen
et al. (42)
42
Second-line
Squamous
90-min q4wk every 6 wks 
(125 mg/m2)
21.0
Irinotecan
Irvin et al.
(52)
16
Second-line
Squamous
q4wk + 2wks of rest (125 
mg/m2)
0.0
McGuire et 
al. (53)
30
First-line
Squamous
24-hour q3wk (170 mg/m2)
17.0
Curtin et al.
(54)
42
First-line, n=37
Second-line, n=5
Non-squamous
24-hour q3wk (170 mg/m2)
31.0
Kudelka 
et 
al. (55)
26
First-line, n=22
Second-line, n=4
Squamous
3-hour q3wk (250 mg/m2)
21.0
Paclitaxel
Homesley et 
al. (16)
28
Second-line
Squamous
1-hour weekly (80 mg/m2)
10.0
Miller et al.
(56)
29
Second-line
Squamous (19)
Non-squamous
(10)
10-min q3wk (900 mg/m2)
15.0
Pemetrexed
Ferrandina et 
al. (57)
18*
Second-line
NA
10-min q3wk (500 mg/m2)
16.7
Muderspach 
et al. (58)
49
First-line
Squamous
30-min daily x 5 consecutive 
days q4wk (1.5 mg/m2)
18.6
Topotecan
Bookman et 
al. (59)
45
First-line, n=11
Second-line, 
n=34
Squamous
30-min daily x 5 consecutive 
days q3wk (1.5 mg/m2)
12.5
Morris et al.
(44)
35
First-line
Squamous 
20-min weekly (30 mg/m2)
18.0
Lhommé et 
al. (60)
46
First-line
Squamous/
adenocarcinoma
20-min weekly (30 mg/m2)
17.8
Muggia et al.
(45)
30
First-line, n=18
Second-line, 
n=12
Non-squamous
Day 1 and 8 q3wk (30 
mg/m2)
7.1
Vinorelbine
Muggia et al.
(43)
44
Second-line
Squamous 
Day 1 and 8 q3wk (30 
mg/m2)
13.7
*Preliminary data after a first stage.
No of patients refers to enrolled patients.
NA, non available; ORR; overall response rate; q3wk; every three weeks; q4wk, every four weeks.
With respect to cisplatin-based combinations, chemotherapy regimens such as 
cisplatin/topotecan or cisplatin/paclitaxel have been extensively investigated in 
clinical studies. Both topotecan and paclitaxel in combination with cisplatin have 
yielded superior response rates and longer PFS without diminishing patient quality of 
life. However, only the combination of cisplatin and topotecan has improved OS and 
has received regulatory approval both in the USA and the European Union in this 
setting (61, 62). A randomized phase III study investigated the combination of 
cisplatin plus topotecan vs. cisplatin alone in recurrent or persistent cervical cancer 
and found the combination regimen superior to single-agent cisplatin with respect to 
ORR (27% vs. 13%), PFS (4.6 vs. 2.9 months) and median OS (9.4 vs. 6.5 months) 
(38). Other randomized phase III study compared cisplatin plus paclitaxel vs. cisplatin 
alone and showed a higher ORR (36% vs. 19%) and longer PFS (4.8 vs. 2.8 months), 
although no improvement was seen in median survival (39).
Despite the therapeutic benefit obtained with the cisplatin/topotecan combination, 
most patients do not respond to treatment and median survival is still less than one 
year (9 months). Therefore, investigation of new agents is clearly necessary to 
incorporate new agents to existing chemotherapy in order to improve the treatment 


results of advanced, persistent or recurrent cervical cancer. Results found in phase I 
studies with PM00104 (Zalypsis®; see Section 1.3.5.4.2) suggest that this novel 
chemotherapeutic agent can be of value as chemotherapy in this disease setting.
1.3.
PM00104 (ZALYPSIS®)
PM00104 (Zalypsis®) is a new synthetic alkaloid, which was selected for clinical 
development as an antineoplastic agent because of its broad in vitro cytotoxic activity 
against human solid and non-solid tumor cell lines, its in vivo activity in human tumor 
xenografts, as well as an acceptable non-clinical toxicology profile. The main bases 
for the preclinical and clinical development of PM00104 are shown here, although 
complete details and references can be found in the Investigator Brochure (IB), 
provided in a separate folder.
1.3.1.
Chemical Structure and Formulation
PM00104 (Figure 2) is currently produced by chemical synthesis.
Molecular formula: C37H38F3N3O8.
Molecular weight: 709.708
Figure 2. Chemical structure of PM00104.
N
N
Me
Me
OMe
HO
Me
OH
O
O
AcO
NH
O
CF3
H H
H
1
5
3
6
7
8
11
12
14
16
2
3
3
1
6
1.3.2.
Mechanism of Action
Preliminary data on mechanism of action suggest that PM00104 exhibits effects on 
the cell cycle, and displays DNA-binding properties as well as transcriptional 
inhibition.
Structure-activity relationship studies have led to the notion that the binding of
PM00104 to DNA is a critical event in its cytotoxic action, but that an additional non-
DNA target may be required to elicit an optimal antitumor response.
PM00104 displayed strong inhibition of the transcriptional response, with a similar
pattern at all the concentrations studied. In addition, PM00104 strongly inhibited the
activation of the transcription of other genes such as MDR1, a gene critically 
involved
in resistance to many chemotherapeutic agents, without affecting 
constitutive transcription.
More details on mechanism of action can be found in Section 1.3.6.1 (Rationale for 
the pharmacogenomic substudy).


1.3.3.
Preclinical Data
In vitro, PM00104 showed strong anti-proliferative activity against most tumor types
at nano-to-picomolar concentrations (Table 4). 
Table 4. In vitro activity of PM00104.
Type 
Tumor
Cell line
IC50 (M)
Bladder
5637
8.6·10-09 – 1.1·10-09
BT-474
6.2·10-07 – 8.2·10-07
Breast
MX-1
4.7·10-06 – 8.5·10-06
Colon
HT-29
1.1·10-08 – 7.7·10-07
Gastric
Hs746T
2.1·10-08 – 5.5·10-11
Kidney
768-O
1.0·10-08 – 2.1·10-09
Liver
SK-HEP-1
2.2·10-07 – 2.3·10-07
Lung
A459
3.0·10-06 – 4.8·10-06
Melanoma
SK-MEL-28
1.7·10-08 – 2.0·10-09
Ovarian
SK-OV-3
1.7·10-06 – 1.5·10-05
Pancreas
PANC-1
7.9·10-08 – 2.3·10-09
DU-145
2.7·10-06 – 4.2·10-06
LNCaP
7.5·10-08 – 1.1·10-08
Prostate
PC-3
4.2·10-08 – 6.8·10-07
A-673
1.6·10-12 – 2.0·10-12
CHSA
1.8·10-08 – 1.0·10-09
OSA-FH
1.5·10-08 – 4.1·10-07
SK-LMS-1
8.7·10-07 – 2.2·10-06
Sarcoma
SW-684
2.7·10-06 – 3.7·10-06
Solid
Thyroid
SW-579
1.1·10-08 – 2.3·10-09
HL-60
5.4·10-08 – 8.6·10-08
Leukemia
K-562
 9.4·10-09 – 1.3·10-08
H9
3.7·10-11 – 2.0·10-9
MC116
3.9·10-08 – 2.5·10-08
Non-solid
Lymphoma
U937
1.4·10-07 – 2.1·10-07
Source: Investigator’s Brochure.
Antitumor activity of PM00104 was confirmed in vivo in most cell lines (Table 5).


Table 5. Antitumor activity of PM00104 in human athymic mouse 
xenografts
Tumor type,
cell line
Route and 
schedule
Dose levels
mg/kg (mg/m2)
Antitumor effect
(optimal day)
Breast, MX-1
i.v., q.d. x 1
0.75 (2.25)
-64% ∆T/∆C (Day 9)*
Colon, HT-29
i.v., q.d. x 1
0.75 (2.25)
47% ∆T/∆C (Day 7)§
Kidney, MRI-H-121
i.v., q.d. x 1
0.75 (2.25)
7% ∆T/∆C (Day 6)*
Ovary, SK-OV-3
i.v., q.d. x 1
0.75 (2.25)
60% ∆T/∆C (Day 6)
Prostate, PC-3
i.v., q.d. x 1
0.75 (2.25)
2% ∆T/∆C (Day 7)*
Gastric, MRI-H-254
i.v., q.d. x 1
0.75 (2.25)
14% ∆T/∆C (Day 15)*
*p < 0.05, statistically significant compared to control cohort. §p < 0.06, trend to significance.
q.d., every day; T/C = % ratio of treated versus control tumor volumes.
Source: Investigator’s Brochure.
PM00104, given by intravenous (i.v.) injection, produced toxicological effects typical 
of cytotoxic antitumor agents. Tissues containing cells with a high turnover rate were 
especially targeted in rats and dogs, i.e., bone marrow, reticuloendothelial system, 
and gastrointestinal tract, as well as the liver, the reproductive system and lesions in 
the injection site. Most toxicities were reversible or in repair at the end of an acute 
toxicity evaluation. Toxicological effects were more severe when the compound was 
given as a multicycle 24-hour infusion in rats and dogs. In the fractionated dose 
studies performed so far, PM00104 was well tolerated when administered to rats and 
dogs at levels based on dividing the maximum tolerated dose (MTD) calculated after 
single administration by a factor of five or three, for five consecutive days or three 
consecutive weeks, respectively. PM00104 displayed less liver toxicity when 
administered using fractionated daily doses compared to single bolus administration. 
In rats receiving PM00104 at MTD levels (single administration), increases in liver 
function markers as well as histology findings related to liver injury were seen. 
However, these findings were not detected in those animals which received an 
equivalent total dose but in a fractionated five consecutive daily schedule of 
PM00104. Regardless of the dosing schedule, toxicity related to hematopoietic and 
thymus systems were observed.
With respect to the safety pharmacology of PM00104, none of the observations 
regarding the alterations triggered by PM00104 on either neurotoxicity, 
cardiovascular or respiratory function, raised any concern. For multicycle studies, 
PM00104 was well tolerated in rats and dogs at the MTD values when administered 
as a bolus. However, the administration of two (on Days 1 and 15) 24-hour infusions 
of PM00104 in rats resulted in deaths occurring at the higher dose levels studied. 
Histology evaluation revealed hemorrhage, necrosis and mineralization of the heart in 
many of the early dead animals, accompanied by degeneration in the animals treated 
at the highest doses. PM00104 appears to be more toxic after multiple 24-h 
administration compared to either single 24-h or single/multiple bolus administration 
in rats and dogs. 


In the human ERG potassium channel (hERG) assay, after a 5 min exposure of 
HEK293 cells stably transfected with hERG cDNA to a concentration of 15µM of 
PM00104, inhibition of the hERG tail current was complete. Increasing 
concentrations of PM00104 (0.01, 0.03, 0.1, 0.3 and 3 M) produced changes which 
were fitted into a sigmoidal function, with a calculated IC50 of 0.4 M (0.28 g/mL), 
well above the Cmax found in animals. 
As a measure of precaution and to ensure the safety of the patients, closer cardiac 
monitoring was performed during the phase I clinical development.
1.3.4.
Metabolism
In the early stages of drug development, several in vitro studies were carried out to 
assess the biotransformation pathways of PM00104 in humans and other animals 
(63). These studies indicated that PM00104 underwent extensive hepatic microsomal-
mediated metabolism in all animal species, including man. Measurement of PM00104 
in urine samples was not possible due to the instability of this drug in this medium.
1.3.5.
Clinical Data
The clinical development program includes four phase I clinical trials aimed to assess 
five different schedules of administration in patients with solid malignancies or 
lymphoma for which no standard therapy would reasonably be expected to result in 
cure or palliation. 
The recommended doses for phase II studies and dose-limiting toxicities (DLTs) 
found in these four phase I studies are summarized in Table 6. The recommended
dose b for phase II studies found in the study PM104-A-004-05 for the schedule 
(PM00104 administered on Day 1, 8 and 15 every four weeks; d1, d8 and d15; q4wk) 
to be used in the current clinical trial (PM104-B-001-09) was 2 mg/m2.
Table 6. Summary of the clinical program of PM00104.
Protocol
(schedule)
Sites
Included
patients
RD
(mg/m2)
Dose intensity 
at the 
recommended 
dose 
(mg/m2/week)
DLTs
Status
27
3.0
(1-hour) 
1.0

Dose level 6 (3.6 mg/m2, 
MTD): grade 3 nausea, grade 3 
vomiting 
despite 
antiemetic 
treatment, grade 3 asthenia, 
grade 
4 
thrombocytopenia, 
grade 4 neutropenia and grade 
3 transaminase increase*.

Cohort 
closed. (64)
PM104-A-
001-04
(1-hour and 
3-hour Day 
1 q3wk)
2 
(Europe)
15
Not 
reached**
(3-hour)
***

Dose level 1 (1.8 mg/m2): grade 
3 hypotension.
Cohort 
ongoing.
                                                
b Doses in phase I trials were expressed in µg/m2, while for phase II development, doses will be 
expressed in mg/m2 for simplification.


Protocol
(schedule)
Sites
Included
patients
RD
(mg/m2)
Dose intensity 
at the 
recommended 
dose 
(mg/m2/week)
DLTs
Status
PM104-A-
002-05
(1-hour 
Day 1-5 
q3wk)
2
 (USA)
12
Not 
reached†
-

No DLTs were found.
Prematurely 
closed****.
PM104-A-
003-05
(24-hour 
Day 1 
q3wk)
2 
(Europe)
37
4.0
1.3 

Dose level 2 (2.6 mg/m2): grade 
3 transaminase increase

Dose level 6 (3.2 mg/m2): grade 
3 tumor and muscle pain and 
stiffness

Dose level 7 (4 mg/m2, RD):
grade 3 asthenia and grade 4 
neutropenia 
and 
thrombocytopenia

Dose level 8 (5 mg/m2, MTD):
grade 
4 
thrombocytopenia, 
grade 4 neutropenia > 5 days of 
duration, grade 3 nausea and 
vomiting.
Closed
PM104-A-
004-05§
(1-hour 
Day 1, 8 
and 15 
q4wk)
2 
(Europe)
49
2.0
1.5

Dose level 7 (2 mg/m2, RD):
grade 4 lipase increase.

Dose level 8 and 9 (2.5 and 3.0 
mg/m2, 
MTD): 
grade 
3/4
asthenia, grade 3 nausea, grade 
1 
neutropenia 
and 
thrombocytopenia leading to 
two missing infusions,  grade 3
febrile neutropenia, grade 3 
anemia, grade 4 neutropenia, 
grade 4 thrombocytopenia and
grade 4 leukopenia.
Closed (65)
* Additionally, grade 4 troponin I increase without cardiac symptoms or ECG alterations was also reported (no 
DLT).
**The highest dose level reached up to December 2008 was 3.5 mg/m2 (three patients enrolled).
***Recommended dose not achieved; dose intensity is expected to be 1.3 mg/m2/week.
****Prematurely closed due to low recruitment and unpractical dosing schedule.
†The highest dose level reached was 0.475 mg/m2/day.
§This schedule is the same than that used in the current phase II study: PM104-B-001-09.
In all studies, escalating dose cohorts are 1 to 3-6 patients per dose level. DLT, dose-limiting toxicities; ECG, 
electrocardiogram; MTD, maximum tolerated dose; RD, recommended dose; q3wk, every 3 weeks; q4wk, every 4 
weeks
.
1.3.5.1. Clinical Safety Data
One hundred and forty patients have been included in phase I trials with PM00104 as 
of December 2008. Safety data collected from these patients registered in these four 
phase I clinical trials show gastrointestinal and general disorders (nausea, asthenia, 
vomiting, anorexia, injection site reactions and diarrhea) as the most frequent 
PM00104-related adverse events (AEs). Most of these AEs were mild to moderate 
(i.e., grade ≤2) and recovered without sequelae. Prophylactic antiemetic therapy with 
dexamethasone plus metoclopramide before the infusions was mandatory, after the 
emetic events and the DLT observed in the clinical trial PM104-A-001-04 (Table 6).


With respect to hematological events, decrease in blood cell counts have been
observed (a toxicity expected according to preclinical toxicology results), especially 
at the highest dose levels. In most cases, these hematological events were mild to 
moderate, transient and not associated with clinical manifestations, such as fever, 
infection or hemorrhages.
With respect to biochemical events, severe increases in liver transaminases were rare 
and no grade 4 cases were reported. The laboratory abnormalities usually recovered 
within few days and no concomitant symptoms were reported. 
As previously mentioned, closer cardiac monitoring was included in the clinical 
phase I program as a measure of precaution due to some findings in preclinical 
studies. Cardiac-related disorders found in these phase I studies have consisted of 
elevations 
of 
cardiac 
troponin 
I 
without 
other 
symptoms 
or 
relevant 
electrocardiogram (ECG)/echocardiography (ECHO) alterations. Four patients treated 
in the study PM104-A-004-05 (1-hour Day 1, 8 and 15 q4wk) had grade 4 troponin I 
increase at the highest dose levels: 2.0 mg/m2 (n=2), 2.5 mg/m2 (n=1) and 3.0 mg/m2
(n=1). None of them had cardiac AEs, abnormal ECG or decrease in left ventricular 
ejection fraction (LVEF) at the same time than troponin I increase, except one patient 
treated with 3.0 mg/m2 who had grade 1 sinus tachycardia and a slight shortening of 
the QT interval in the ECG, which recovered by the next cycle. These events were 
considered not relevant by the investigators and by an external cardiologist who 
evaluated these cases. ECGs performed as per study protocols before and after each 
infusion of PM00104 have been reviewed by an external cardiologist and no evidence 
of cardiotoxicity has been reported. However, close clinical and investigational 
monitoring of cardiac safety will be continued in subsequent studies with PM00104.
No toxic deaths have occurred in the phase I studies with PM00104.
1.3.5.2. Results of PM104-A-004-05 trial
This phase I study evaluated the PM00104 schedule (d1, d8 and d15; q4wk) to be 
used in the current phase II clinical trial (PM104-B-001-09). As of December 2008, 
49 patients with malignant solid tumors have been enrolled and treated at the 
participating institutions (Institut Gustave Roussy, Paris, France and Newcastle 
General Hospital-Northern Centre for Cancer, Newcastle, United Kingdom). The 
starting dose was 0.075 mg/m2. The dose escalation was increasing at a 100% rate 
from levels 1 to 4, and at 50% thereafter. No DLTs were documented until dose level 
9 (3.0 mg/m2), in which two DLTs were reported. Upon agreement with the 
investigators, an intermediate dose between this level and the next lowest (2.0 mg/m2) 
was proposed and subsequent patients were enrolled and treated with a dose of 2.5
mg/m2. Three out of eight patients treated with this dose had DLT; therefore, this 
level and the previously tested next highest were considered maximum tolerated dose 
(MTD) and the dose of 2.0 mg/m2 was defined as the recommended dose (RD). See 
detail of DLTs in Table 6.
1.3.5.3. Clinical Efficacy Data
Out of 140 patients evaluated, no objective response as per the Response Evaluation 
Criteria in Solid Tumors (RECIST) was observed; however, 20 disease stabilizations 
lasting longer than 3 months have been documented, most of them of clinical value
due to being observed in heavily pretreated patients with progressive disease before 


treatment. Indeed, some patients experienced reduction of tumor mass although not 
enough to be qualified as tumor response (i.e., with tumor shrinkage <20%). All 
patients had previously received chemotherapy and many of them had been heavily 
pretreated. The proportion of disease stabilizations was similar in all five schedules 
analyzed; thus, the antitumor activity of PM00104 appears to be independent of the 
administration regimen used. Remarkably, two patients with progressing advanced 
cervix carcinoma had disease stabilization lasting for more than 6 months (see Table 
7 in next section).
1.3.5.4. Evidence for Antitumor Activity against Endometrial Cancer and 
Cervical Cancer in the Phase I Clinical Development of PM00104
Preliminary evidence of antitumor activity was found during the phase I program of 
PM00104 in one patient with endometrial cancer and in three patients with cervical 
cancer (Table 7). All four patients had disease stabilization of their previously 
progressive disease, and treatment was well tolerated, with the exception of injection 
site reactions that nevertheless allowed treatment continuation. Central venous 
catheter was not a requisite for infusion in phase I trials, but it is mandatory in the 
current study protocol (see Section 7.2.1).
Table 7. Characteristics of patients with endometrial and cervical cancer showing 
clinically meaningful disease stabilization with PM00104 in phase I trials.
PM00104 dose
(mg/m²)/schedule
Age ECOG 
PS
Tumor
type
No. of 
prior
regimens 
(including 
CTRT)
TTP/PFS
last
prior
treatment
(months)
Agent
(last treatment)
Best
response
(last 
treatment)
% tumor 
shrinkage
No. of 
cycles
received
TTP**
(months) 
/ best 
response 
with 
PM00104
0.318 / 1-hour 
Day 1-5 q3wk
68
1
Endocervix 
adenocarcinoma 
3
6.9
Cisplatin/topotecan
SD
12.5%
24
10.9 / SD
0.212 / 1-hour 
Day 1-5 q3wk
54
1
Endocervix 
adenocarcinoma 
2***
6.7
Cisplatin/topotecan
SD
1.4%
11
7.9 / SD
0.15 / 1-hour Day 
1, 8 and 15 q4wk
51
1
Squamous 
carcinoma of 
cervix
1
30.4
Cisplatin (as 
chemosensitizing)
Not known
-
4
3.4 / SD
3.2 / 24-hour Day 
1 q3wk
61
0
Endometrium 
adenocarcinoma
3
1.2
Investigational 
drugs
PD
12.5%
4
2.8 / SD
*Not clearly stated if primary tumor was endocervix or endometrium with extension to the endocervix. **Patients ordered by TTP.
***Cetuximab monotherapy (only one cycle) was also administered with non-evaluable response.
ECOG, Eastern Cooperative Oncology group; PD, progressive disease; PFS, progression-free survival; PS, performance status; CTRT, 
chemoradiotherapy; SD, stable disease; TTP, time to progression.
1.3.5.4.1. Endometrial Cancer

Study PM104-A-003-05: In this phase I study, the patients were treated with 
PM00104 administered i.v. over 24-hour every three weeks. 
o
A 61-year-old patient with endometrium adenocarcinoma had two target 
lesions of 45 mm in the peritoneum at study entry. The patient had been 
previously treated with surgery (abdominal hysterectomy plus double 
anexectomy and lymphadenectomy) and systemic therapy with tamoxifen, 


epirubicin and two investigational drugs. Time to progression (TTP) with 
last prior treatment was 1.2 months and best response was disease 
progression. This patient received four cycles of PM00104 3.2 mg/m2 every 
three weeks (1.07 mg/m2/week) and had disease stabilization (tumor
shrinkage of 12.5%), with TTP of 2.8 months.
1.3.5.4.2. Cervical Cancer
Three patients with advanced cervix carcinoma had disease stabilization during the 
phase I program of PM00104: two patients in study PM104-A-002-05 and one patient 
in study PM104-A-004-05.

Study PM104-A-002-05: In this phase I study, the patients were treated with 
PM00104 administered i.v. over 1 hour daily for 5 days, every three weeks.
o
A 54-year-old patient with adenosquamous carcinoma of the endocervix had 
multiple lymph nodes (10-20 mm each) as site of the disease at study entry. 
This patient had had prior treatment with adjuvant cisplatin concomitant with
radiotherapy of pelvis, para-aortic and cervical region previous to surgery 
(fine needle aspiration of the right retroperitoneum and left supraclavicular 
lymph node). The patient had complete response as best response, with 
disease progression after 24 months. Later, two lines of systemic therapy for 
advanced disease (cisplatin with cetuximab, with non-evaluable response; 
cisplatin with topotecan, with stable disease as best response lasting 6.7
months) were administered. This patient received 11 cycles of PM00104 
0.212 mg/m2/day and had disease stabilization (non-significant tumor 
shrinkage), with TTP of 7.9 months. She discontinued the study due to disease 
progression in a left supraclavicular lymph node, which required palliative 
radiotherapy. 
o
A 68-year-old patient with adenosquamous carcinoma of the endocervix had 
multiple lung nodes (10-30 mm each) as site of the disease at study entry, and 
prior treatment with surgery and two systemic lines for advanced disease: 
cisplatin plus radiotherapy of pelvis inguinal region (complete response, with 
disease progression after 28 months), and cisplatin plus topotecan, with stable 
disease lasting 6.9 months. This patient received 24 cycles of PM00104 0.318 
mg/m2/day and had disease stabilization as best response (tumor shrinkage of 
12.5%), with TTP of 10.9 months. 
In these two cases, clear disease progression was documented before treatment 
with PM00104. According to the investigator, it was difficult to determine (at 
least, in the second case) whether the tumor origin was the endocervix or the 
endometrium (with later extension to the endocervix).
Study PM104-A-004-05: In this phase I study, the patients were treated with 
PM00104 administered i.v. over 1 hour on Day 1, 8 and 15 every four weeks (the 
same schedule planned for the current phase II study protocol).
o
A 51-year-old patient with cervical cancer had a left latero-pelvic lesion of 55 
mm at study entry. This patient had had previous treatment with surgery (large 
hysterectomy) followed by adjuvant cisplatin and concomitant pelvic 
radiotherapy (best response was unknown). The patient received four cycles 
of PM00104 0.150 mg/m2/week. This patient had disease stabilization as best 


response, with a TTP of 3.4 months. She discontinued the study due to disease 
progression in non-target lesions (uretheral dilatation).
1.3.5.5. Pharmacokinetic Data
1.3.5.5.1. Renal Function and PM00104 Clearance
In vitro studies indicated that PM00104 underwent extensive hepatic microsomal-
mediated metabolism (see Section 1.3.4). The analysis of pharmacokinetic (PK) data 
obtained during phase I studies has shown no relationship between the renal function 
of the patient (as measured by clearance of baseline creatinine) and PM00104 
clearance (Figure 3). 
Figure 3. Relationship between creatinine clearance and PM00104 clearance from 
patients trated in phase I studies.
0
20
40
60
80
100
120
0
50
100
150
200
250
300
CRCL (ml/min)
CLPM104, clearance of PM00104; CRCL, creatinine clearance.
All these data suggest an unlikely role of the kidney in PM00104 clearance. 
According with this preliminary evidence, calculated creatinine clearance for 
inclusion criteria (see Section 4.1) and for retreatment (see Section 7.2.2, Table 11) 
was established as  30 ml/min (using the Cockcroft and Gault formula, see 
Appendix 3. Cockcroft and Gault Formula).
1.3.5.5.2. PK/PD Analysis of Neutropenia Associated to Treatment with PM00104
Preliminary PK data from the aforementioned phase I clinical trials showed a lack of 
linearity between total dose and maximum PM00104 plasma concentration (Cmax) at 
the higher tested doses (Figure 4). In particular, non-linear PK affecting both Cmax and 
area under the curve (AUC) was found when infused using the 1-hour q3wk schedule 
at doses higher than 3,000 µg/m2 (i.e., 3 mg/m2). Such disproportional, higher Cmax or 
AUC at the highest total doses might result in an increase in the incidence and/or 
severity of toxic events associated to PM00104 treatment, like neutropenia or 
thrombocytopenia.


Figure 4. Total dose vs. maximal plasma concentration (grouped by dose 
level after first cycle of treatment in patients with 1-hour, day 1, q3wk 
PM00104 infusion). 
0
10
20
30
40
50
60
70
80
90
0
1000
2000
3000
4000
5000
6000
7000
8000
Total dose (µg)
225
450
900
1800
3000
3600
Source: Investigator’s Brochure.
To check the effect of PM00104 dose intensity, density and duration on toxic events, 
a preliminary, longitudinal population pharmacokinetic/pharmacodynamic (PK/PD) 
analysis of the relationship between PM00104 exposure and absolute neutrophil 
count (ANC) was conducted with data from 78 patients from four phase I clinical 
trials with PM00104 administered as a single agent. A total of 1,332 plasma samples 
and 1,058 ANC measurements were included in this analysis. 
The pharmacokinetic part of the population model was defined by a 3-compartment 
model with linear elimination from the central compartment and linear 
transfer constants between compartments. The PK/PD model comprised a 
trabectedin-sensitive progenitor cell compartment, linked to the peripheral blood 
compartment, through three transition compartments representing the maturation 
chain in the bone marrow. To capture the rebound effect due to endogenous growth 
factors, the model included a feedback mechanism. The model estimated three 
system-related parameters: ANC at baseline, mean transit time in bone marrow, and a 
feedback parameter. PM00104 plasma concentrations (Cp) were assumed to reduce 
the proliferation rate and/or to increase the killing rate of the progenitor cells 
according to the function αCpβ. The model was qualified and simulations were 
undertaken to evaluate the neutropenia schedule dependency. NONMEM software 
was used to perform the modelling and simulation analyses.
The extent and time-course of neutropenia following the five different dosing 
regimens of PM00104 tested in phase I studies were well predicted by this semi-
physiological PK/PD model. The simulations indicated that PM00104 dose and 
dosing interval, but not infusion duration, are the main determinants of the 
neutropenia severity and duration. The model predicted the time-course of the ANC 
and confirmed that neutropenia is reversible, short-lasting, and non-cumulative. 


The unpublished results of this PK/PD analysis showed a non-linear relationship 
between PM00104 dose intensity and the ANC time-course. Therefore, increases in 
the PM00104 dose for a determined, fixed infusion time could result in decreases in 
the neutrophil nadir higher than those expected for a proportional relationship with 
exposure (Figure 5).
Figure 5. Effect of PM00104 dose intensity on neutropenia.
0
2
4
6
8
10
12
0
2
4
6
8
Dose intensity 
 (1 h inf. every 3 weeks)
Time, weeks
ANC (x10^9 / L)
1500 ug/m2
2000 ug/m2
2500 ug/m2
3000 ug/m2
3500 ug/m2
4000 ug/m2
5000 ug/m2
ANC, absolute neutrophil count; data shown for the PK/PD model with the 1-hour infusion every 3 
weeks schedule. Dose intensity increased from 1500 to 5000 g/m2/week (i.e., 1.5 to 5.0 
mg/m2/week).
This PK/PD analysis also showed that the severity of neutropenia associated with
PM00104 treatment might be reduced by using treatment regimens with a more 
frequent dosing for a given total, cumulative dose (i.e., more dense regimens, such as 
weekly). Thus, large-dose and less frequent dosing regimens (e.g., one single dose 
administered every three weeks) might lead to a more severe neutropenia (Figure 6).
Grade 4 neutropenia


Figure 6. Effect of PM00104 dose density on neutropenia.
0
2
4
6
8
10
12
0
2
4
6
8
1.33 mg/m2 weekly, 3 in 1 out
2 mg/m2 every 2 weeks
3 mg/m2 every 3 weeks
0.6 mg/m2, 5 days every 3 weeks
Dose density 
 (1 h inf. 4 mg/m2 within 4 weeks)
Time, weeks
ANC (x10^9 / L)
ANC, absolute neutrophil count; data shown for the PK/PD model with the 1-hour 
infusion every 4 weeks schedule at a fixed dose of 4 mg/m2. Dose intensity increased 
from 1500 to 5000 g/m2/week (i.e., 1.5 to 5.0 mg/m2/week).
This PK/PD analysis also showed that duration of the PM00014 infusion had a 
negligible effect on the severity of neutropenia (Figure 7).
Figure 7. Effect of PM00104 infusion duration on neutropenia.
0
2
4
6
8
10
12
0
2
4
6
8
Infusion duration 
 (3 mg/m2 every 3 weeks)
Time, weeks
ANC (x10^9 / L)
1 h infusion
3 h infusion
24 h infusion
ANC, absolute neutrophil count; data shown for the PK/PD model with the every three 
weeks schedule at a fixed dose of 3 mg/m2 and varying the infusion time from 1 hour to 
24 hour.
In accordance with the PK/PD modeling discussed above, preliminary analysis of 
data from the phase I study PMA104-004-05 shows that the recommended dose (2 
mg/m2) had a low rate of grade 3/4 neutropenia and a low rate of skipped doses due to 
toxic events and, of note, no skipped doses due to neutropenia (Figure 8). 
Grade 4 neutropenia
Grade 4 neutropenia


Figure 8. Skipped doses due to toxicity in the phase I study 
PMA104-004-05 evaluating the same schedule planned for the 
current phase II study protocol: PM00104 over 1 hour on Day 1, 
8 and 15 every four weeks. 
0%
5%
10%
15%
20%
25%
30%
35%
40%
45%
50%
D8
D15
D8
D15
D8
D15
2025
2025
2500
2500
3037
3037
Fatigue
Neutropenia
Thrombopenia
Nausea
n= 14
n= 8
n= 4
2
2
2
2
1 1
1
1
1
1
1
1.3.6.
Pharmacogenomic Data
During the past 30 years medical oncologists have focused on optimizing the 
outcome of cancer patients, developing new antitumoral agents and defining new
prognostic factors as well as integrating more effective supportive care measures. 
However, clinical anticancer strategies indicate that conceptually active therapies 
benefit just a small proportion of patients; thus, there is a need to expose a large 
cohort of patients to antitumor treatments to obtain benefit in just a fraction of them.
Molecular targeted therapies and personalized cancer therapies are concepts that are 
raising expectations in anticancer drug development as a consequence of the 
genomics technology developed and our improved understanding of cancer at the 
molecular level. 
Pharmacogenomic studies are aimed at identifying prognostic biomarkers that can 
help to define subpopulations of patients who will, or will not, benefit from a 
particular therapy. These molecular markers of response to the drugs are not 
exclusive of the so-called “targeted therapies”, but have also been identified in widely 
used cytotoxic agents. Representative examples include the relation between 
thymilydate synthase mRNA expression and response and survival with antifolates
(66), beta tubulin III mRNA levels and response to tubulin interacting agents (67), 
PTEN methylation and resistance to irinotecan (68), and STAT3 overexpression and 
resistance to epidermal growth factor receptor (EGFR) interacting agents (69).
During the last five years, PharmaMar has implemented a translational research 
program oriented to the identification of molecular markers correlated with the 


response to the anticancer agents that PharmaMar is currently developing. Based on 
the experimental studies that indicate that there is an increased sensitivity to 
trabectedin in tumors with efficient Nucleotide Excision Repair and deficient 
Homologous Recombination Repair DNA repair machinery, the expression of a set of 
DNA repair genes was analyzed in a retrospective cohort of sarcoma patient tumor 
samples (70). The main result obtained was the identification of the levels of 
expression of the gene BRCA1 as a marker that correlates with longer progression-
free survival and overall survival after the treatment with trabectedin. This fact,
which nowadays has been validated in greater patient samples cohort, opens the 
possibility of identifying before to treatment those patients that would benefit from 
the treatment of trabectedin in a prospective fashion.
These very promising results are the founding for a more exhaustive research for 
molecular markers of tumor response to treatment that will in the future allow a real 
personalized antitumoral medicine.
1.3.6.1. Rationale for the Pharmacogenomic Substudy Associated to PM104-B-
001-09
PM00104 is a novel synthetic antineoplastic agent currently in phase I clinical 
development. This agent has strong antitumor activity in a wide variety of tumor lines 
in vitro and in vivo. Preliminary data suggest that PM00104 has DNA binding 
properties, induces cell cycle arrest and inhibits transcription. Although the precise 
mechanism of action of this agent remains mostly unknown, there are increasing 
experimental data describing PM00104 antitumoral activity. Three main molecular 
characteristics describe the antitumoral activity of PM00104:

PM00104 is a DNA binder: PM00104 binds to the minor groove of DNA. This 
binding occurs in preferred GC-rich trinucleotide sequences, preferably to GCG 
trinucleotide (C. Bailey, unpublished PharmaMar internal report). The binding 
of PM00104 to the DNA produces a stabilization of the DNA duplex, with 
notable increase (13-18o C) in the melting temperatures of DNA oligos 
containing either single or tandemly arranged binding sites (71). This 
stabilization 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.

PM00104 produces DNA double strand breaks: treatment of cells with 
PM00104 led to cell cycle delay in S phase, activation of the DNA damage 
checkpoint, and cell death. Additionally, Schizosaccharomyces pombe
containing a RAD51 mutation was found to be extremely sensitive to PM00104, 
thus suggesting that the compound induces double-strand breaks. Since these 
effects are suggestive of stalled transcription and replication forks, the 
dependency of the killing mechanism on an intact NER system was tested by 
studying the cytotoxic effects of the drug on cells deficient in RAD13, which is 
the S. pombe counterpart of human XPG, a protein that has been shown to 
mediate, at least in part, the mechanism of action of other agents in this class in 
human cells. RAD13, haploid deletion mutants were found to be as sensitive to 


PM00104 as wild-type cells, thus indicating the independence of the cytotoxic 
effect of this compound to the lack of a functional nucleotide excision repair 
system. This evidence is in contrast with the pattern noted with other 
antitumoral agents with DNA-binding activity as trabectedin and cisplatin, 
which are highly dependent on the activity of this repair pathway.

PM00104 interferes with DNA repair: experimental data reveal that the DNA 
damage repair machinery is essential to overcome PM00104-induced DNA 
damage and suggest that this damage is mainly due to double strand breaks. The 
sensitivity to PM00104 has been determined in the collection of 5,000 haploid 
deletion mutants of the yeast Saccharomyces cerevisiae as a model. 
Approximately 40 hypersensitive mutants and about 90 mutants resistant to 
PM00104 activity have been identified (72). A set of genes involved in 
sensing/repairing double strand breaks were found among the genes whose 
deletion produced sensitivity to PM00104. These are components of the MRX 
complex; several members of the homologous recombination proteins of the 
Rad52 epistasis group (which are recruited to the sites of DNA damage 
specifically during S-phase and G2); the Swi/Snf complex, a chromatin 
remodeling complex conserved in humans, whose inactivation results in 
inefficient DSB repair and increased DNA damage sensitivity as well as a large 
defect in γ-H2AX phosphorylation strain with a deletion in SUMO ligase Siz1 
was one of the most resistant mutants to PM00104. A role for this protein in the 
inhibition of homologous recombination at replication forks has been described 
recently, indicating again that the main lesions induced by PM00104 are double 
strand breaks. 
This evidence of the lack of effect of NER pathways in PM00104 in vitro cytotoxicity 
is in contrast with the resistance to treatment with platinum-based therapies both in 
vivo and in vitro. The evidence generated at the preclinical and clinical level 
demonstrates that the efficiency of the NER mechanism is associated to a poor 
outcome in patients bearing different tumor types and exposed to a platinum-based 
chemotherapy. Similarly, an increased sensitivity to trabectedin is found in patients 
having increased expression of genes in the NER pathway.
1.4.
RATIONALE FOR THIS PHASE II EXPLORATORY TRIAL OF PM00104 IN 
ENDOMETRIAL AND CERVICAL CANCER

In patients with advanced/metastatic endometrial cancer, despite the use of 
combinations or novel agents and therapies for first-line, responses are of short 
duration, with PFS of 6-9 months and OS of 12-15 months. Results of second-line 
chemotherapy are generally poor, with only taxanes showing response rates 
greater than 20%. Short PFS (2 months) and OS (6-8 months) have been found 
with second-line regimens. Therefore, treatment of advanced/metastatic 
endometrial cancer is a clearly unmet medical need and investigation of new 
agents is warranted.

In patients with cervical cancer, despite the therapeutic benefit obtained with first-
line  cisplatin/topotecan or cisplatin/paclitaxel combinations, most patients do not 


respond to treatment, responses are short and median survival is still less than one 
year. Results with second-line chemotherapy are poor, with median PFS of 2 
months and median survival of 6 months.

Therefore, clinical trials are necessary to incorporate new agents to the existing 
available options in order to improve the treatment outcome in advanced, 
persistent or recurrent endometrial and/or cervical cancer.

Close to the completion of the phase I development program of PM00104 as a 
single-agent, the safety profile of PM00104 indicates a positive risk/benefit ratio, 
which supports the continuation of the program with the beginning of phase II 
studies. 

Minor tumor shrinkage not qualifying as response per RECIST was observed as 
well as clinically meaningful disease stabilization of previously progressive 
disease during the phase I program of PM00104 in one patient with endometrial 
cancer and in three patients with cervical cancer. Therefore, possible indications 
for PM00104 in exploratory phase II studies include endometrium and cervix 
carcinoma. 

PK/PD simulation have indicated that PM00104 dose and dosing interval, but not 
infusion duration, are the main determinants of the neutropenia severity and 
duration. PK/PD model have shown that increasing the PM00104 dose might 
result in a more than proportional decrease in the neutrophil nadir, and that the 
severity and/or incidence of severe neutropenia associated to PM00104 treatment 
might be reduced by using treatment regimens with a more frequent dosing for a 
given total, cumulative dose. Then, dose fractioning increasing dose density could 
result in a safety advantage, while preserving dose intensity. In agreement with 
PK/PD modeling, no skipped doses due to neutropenia occurred in the phase I 
trial at the recommended dose (2 mg/m2) with the schedule to be used in the 
current phase II trial.

The recommended dose for phase II studies found in the phase I study PM104-A-
004-05 for the schedule to be used in the current phase II clinical trial (d1, d8 and 
d15; q4wk) was 2 mg/m2. 

The current exploratory phase II trial will use the PM00104 schedule (d1, d8 and 
d15; q4wk) with the highest dose intensity (1.5 mg/m2/week) of all five schedules 
tested in phase I trials.   
2.
STUDY OBJECTIVES
2.1.
PRIMARY

To evaluate the antitumor activity of PM00104 administered as a 1-hour i.v. 
infusion on Day 1, 8 and 15 every four weeks (d1, d8 and d15; q4wk) to 
patients with advanced and/or metastatic endometrial or cervical cancer 
previously treated with one line of systemic chemotherapy.
2.2.
SECONDARY

To determine the safety profile of this PM00104 regimen in these patients.



To determine the pharmacokinetic (PK) profile of this PM00104 regimen in 
these patients.

To determine the pharmacogenomic (PGx) profile of this PM00104 regimen 
in these patients. Hypothesis-generating exploratory PGx analyses will be 
conducted to correlate the molecular parameters found in the tumor and blood 
samples of the patients with the clinical results achieved with PM00104.
3.
OVERALL STUDY DESIGN
Multicenter, open label, phase II clinical trial with single-agent PM00104 given as a 
1-h i.v. infusion on d1, d8 and d15 q4wk to patients with advanced and/or metastatic 
endometrial or cervical cancer in progression.
The primary endpoint of the study is the overall response rate (ORR), defined as the 
percentage of patients with objective response (OR; complete or partial response) as 
defined by the RECIST.
A comprehensive workup will be performed at baseline and every other cycle (± 1 
week) until evidence of disease progression.
Treatment will be administered in the absence of disease progression and/or 
unacceptable toxicity. In case of obtaining a complete response, two additional cycles 
will be administered and then the treatment will be stopped.
Patients will be evaluated using clinical and laboratory assessments both after and 
before each treatment cycle. Any treatment-related AEs will be followed-up until the 
events or their sequelae resolve or stabilize at a level acceptable to the Investigator 
and the Sponsor. Patients no longer receiving study treatment will be followed up for 
survival (see Section 5.2).
4.
SELECTION OF PATIENTS
4.1.
INCLUSION CRITERIA
In order to be included into the trial, female patients had to fulfill all of the following 
criteria:
1. Voluntary written informed consent, obtained from the patient before the 
beginning of any specific study procedures. 
2. Group 1 (endometrial cancer): histologically confirmed advanced and/or 
metastatic endometrial cancer (any grade, including endometroid, clear cell, 
serous and mixed types) with documented disease progression as per RECIST 
at study entry.
Group 2 (cervical cancer): histologically confirmed advanced and/or 
metastatic cervical cancer with documented disease progression as per 
RECIST at study entry.
3. Group 1 (endometrial cancer): patients must have failed one prior systemic 
chemotherapy 
line 
for 
advanced/metastatic 
disease 
(excluding 
chemosensitizing chemotherapy); prior hormone therapy and biological 
therapy are allowed.                                                                                       


Group 2 (cervical cancer): patients must have failed one prior systemic 
chemotherapy 
line 
for 
advanced/metastatic 
disease 
(excluding 
chemosensitizing chemotherapy); prior hormone therapy and biological 
therapy are allowed.                           
4. Complete recovery from the effects of prior radiotherapy and from any drug-
related AEs derived from previous treatments, excluding alopecia and grade 1 
peripheral neuropathy according to the National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI-CTCAE, v. 3.0).
5. At least one measurable lesion (“target lesion” according to the RECIST), 
located in a non-irradiated area and adequately measured less than four weeks 
before study entry. Tumors within a previously irradiated field will be 
designated as "non-target" lesions unless progression is clearly documented or 
biopsy proven.
6. Age 18 years.
7. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS)  1.
8. Life expectancy  3 months.
9. Appropriate bone marrow reserve, renal and hepatic functions.
a.
Platelet count  100 x 109/l, hemoglobin  9 g/dl and absolute neutrophil 
count (ANC)  1.5 x 109/l.
b. Alkaline phosphatase (AP)  2.5 x upper limit of normality (ULN) (≤ 5 
x ULN in case of extensive bone metastases).
c.
Alanine aminotransferase (ALT), aspartate aminotransferase (AST) ≤ 
2.5 x ULN ( 5 x ULN in case of hepatic metastases). 
d. Total bilirubin  1.5 x ULN, unless due to Gilbert’s syndrome.
e.
Renal function: patients with calculated creatinine clearance (using 
Cockcroft and Gault formula)  30 ml/min. c
f.
Albumin ≥ 2.5 g/dl.
10. Left ventricular ejection fraction (LVEF) within normal limits (LVEF of at 
least 50%).
11. Women of childbearing potential must have a negative serum pregnancy test 
before study entry. In case of childbearing potential, the patients and their 
partners must agree to use a medically acceptable method of contraception 
throughout the treatment period and for three months after discontinuation of 
treatment. Acceptable methods of contraception include complete abstinence, 
intrauterine contraceptive device (IUD), oral contraceptive, subdermal implant 
and double barrier (condom with a contraceptive sponge or contraceptive 
suppository).
                                                
c See details supporting the selection of this level of calculated creatinine clearance ( 30 ml/min) in 
Section 1.3.4 (metabolism of PM00104) and Section 1.3.5.5.1 (renal function and PM00104 
clearance).


4.2.
EXCLUSION CRITERIA
Female patients fulfilling any of the following criteria will not be included into the 
trial:
1. Prior therapy with PM00104.
2. Uterine sarcomas, adenosarcoma and malignant Mullerian tumors.
3. Cervical neuroendocrine or small cell carcinomas, non-epithelial cervical 
neoplasms such as sarcomas. 
4. Patients who have isolated recurrences (vaginal, pelvic or para-aortic) 
potentially curative with radiation therapy or surgery.
5. Pregnant or lactating women, or in case of childbearing potential, women not 
using an appropriate contraceptive method.
6. Less than three weeks from prior radiation therapy, biological therapy or 
chemotherapy. Less than six weeks from prior nitrosourea, mitomycin C, 
high-dose chemotherapy or radiotherapy involving the whole pelvis or over 
50% of the spine, provided that acute effects of radiation treatment have 
resolved. Hormonal therapy and palliative radiation therapy (i.e., for control 
of pain from bone metastases) must be discontinued before study entry.
7. Group 1 (endometrial cancer): more than one line of prior systemic 
chemotherapy for advanced/metastatic disease (excluding chemosensitizing 
chemotherapy).  
Group 2 (cervical cancer): more than one line of prior systemic chemotherapy 
for advanced/metastatic disease (excluding chemosensitizing chemotherapy).  
8. Patients with a prior invasive malignancy (except non-melanoma skin cancer) 
who have had any evidence of disease within the last five years or whose prior 
malignancy treatment contraindicates the current protocol therapy.
9. Patients with serious non-healing wound, ulcer, or bone fracture. This 
includes history of abdominal fistula, gastrointestinal perforation or intra-
abdominal abscess for which an interval of three to six months must pass 
before study entry. In addition, the patient must have undergone correction (or 
spontaneous healing) of the perforation/fistula and/or the underlying process 
causing the fistula/perforation. Patients with granulating incisions healing by 
secondary intention with no evidence of fascial dehiscence or infection are 
eligible but require weekly wound examinations.
10. Evidence of progressive or symptomatic central nervous system (CNS) 
metastases or leptomeningeal metastases.
11. Other diseases or serious conditions:
a.
Increased cardiac risk as defined by:
Unstable angina or myocardial infarction within 12 months before 
inclusion in the study. 
New York Heart Association (NYHA) grade II or greater congestive 
heart failure. 
Symptomatic arrhythmia or any arrhythmia requiring ongoing 
treatment. 


Abnormal electrocardiogram (ECG), i.e., patients with the following 
are excluded: QT prolongation - QTc > 480 msec; signs of cardiac 
enlargement or hypertrophy; bundle branch block; partial blocks; signs 
of ischemia or necrosis, and Wolff Parkinson White patterns.
History or presence of valvular heart disease.
Uncontrolled arterial hypertension despite optimal medical therapy.
Previous mediastinal radiotherapy.
Previous treatment with doxorubicin at cumulative doses exceeding 
400 mg/m2.
b. History of significant neurological or psychiatric disorders.
c.
Active infection requiring systemic treatment.
d. Significant non-neoplastic liver disease (e.g., cirrhosis, active chronic 
hepatitis).
e.
Immunocompromised patients, including those known to be infected with 
the human immunodeficiency virus (HIV).
12. Any other major illness that, in the Investigator’s judgment, will substantially 
increase the risk associated with the patient’s participation in the study. The 
investigator should feel free to consult the Study Coordinator or the Sponsor 
for uncertainty in this regard.
13. Limitation of the patient’s ability to comply with the treatment or to follow-up 
at a participating center. Patients enrolled into this trial must be treated and 
followed at a participating center.
14. Treatment with any investigational product within 30 days prior to inclusion 
in the study.
15. Known hypersensitivity to any component of PM00104.
4.3.
PATIENTS FOR THE PHARMACOGENOMIC SUBSTUDY (ONLY FOR PATIENTS 
INCLUDED IN SITES LOCATED IN THE U.S.)
4.3.1.
Inclusion Criteria 

All patients included in trial PM104-B-001-09 will be eligible.

Only those patients with available tissue samples that voluntarily sign the 
Informed Consent Form for the PGx substudy will participate.
4.3.2.
Exclusion Criteria 

Patients who do not consent to participate in this substudy. Refusal to 
participate in the PGx substudy will not affect the patients’ participation in the 
main trial PM104-B-001-09.
5.
PLAN OF THE STUDY
5.1.
DURATION OF STUDY (WHOLE POPULATION)
The total duration of the study will be approximately 33 months, including about 24
months of active enrolment. 


Planned start date (first patient on study): 3Q09.
Planned enrolment period: 24 months.
Planned study termination (clinical cutoff): six months after the last treatment visit of 
the last evaluable patient included in the study, or nine months after the last patient is 
included, whichever occurs first.
5.2.
DURATION OF STUDY AND TREATMENT (PER PATIENT)
Patients will receive study treatment as long as it is considered to be in their own 
benefit (see Section 7.2.2). Patients will be evaluated at scheduled visits in up to three 
study periods: 
Pre-treatment (PRE TT): from signature of informed consent to the first 
infusion of PM00104.
Treatment (TT): from the first infusion of PM00104 to treatment discontinuation
plus 30 days.
Follow-up (FUP): after treatment discontinuation, patients will be followed until 
all toxicities or their sequelae resolve or stabilize at a level acceptable to the 
Investigator and the Sponsor. Patients who discontinue treatment without 
progression will be followed every three months until:
1. Disease progression;
2. Other antitumor therapy;
3. Death, or 
4. The date of study termination, whichever occurs first. 
After disease progression or after other antitumor therapy, patients will be 
followed every three months until:
1. Death, or 
2. The date of study termination, whichever occurs first. 
Patients may withdraw their consent at any time; no further study activities will be 
conducted on them.
Patients will be considered to be on-study from the signature of the informed consent 
to the end of follow-up period. Patients will be considered to be on-treatment for the 
duration of their treatment and in the first 30 days following the last PM00104
administration. Treatment discontinuation is defined as the day of the last study 
drug dose administration (Figure 9).


Figure 9. Study periods.
FUP, follow-up; ICF, informed consent form; PRE TT, pre-treatment; TT, treatment.
5.2.1.
Discontinuations
5.2.1.1. Treatment Discontinuation
Treatment discontinuation occurs when an enrolled patient ceases to receive the study 
medication, regardless of the circumstances. The primary reason for any 
discontinuation will be recorded on the patient’s Case Report Form (CRF). By 
convention, the date of treatment discontinuation will be the day of the last PM00104
administration.
If a patient discontinues treatment, every effort should be made to complete the 
scheduled assessments.
5.2.1.2. Reasons for Treatment Discontinuation
Administration of the study treatment should be discontinued if this is considered to 
be in the best interest of the patient. More specifically, treatment will be discontinued 
due to any of the following reasons:

Disease progression.

Unacceptable toxicity (including any toxicity leading to the need for a third 
dose reduction or severe hypersensitivity reactions).

Patient refusal. 

Intercurrent serious illness. 

Protocol deviation with an effect on the risk/benefit ratio of the clinical trial.

Treatment delay > two weeks or impossibility to administer both Day 8 and 
Day 15 dose on a given cycle (except in case of clear clinical benefit, with the 
Sponsor’s approval).

Administrative reasons or Sponsor’s decision.
Regardless of the reason, patients who discontinue the treatment must not be re-
treated at any time.


In case of obtaining a complete response, two additional cycles will be administered 
and then the treatment will be discontinued.
Any subsequent therapies for the patients may be provided off-study according to the 
Investigator’s criteria.
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 
follow-up 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/Institutional 
Review Board (IEC/IRB) and Competent Authorities. Therefore, this applies to 
deviations related to patient inclusion and clinical procedures (e.g., assessments to be 
conducted or parameters to be determined), and also to other procedures described in 
the protocol that concern the Good Clinical Practice (GCP) guidelines or ethical 
issues (e.g., issues related to obtaining the patients’ Informed Consent, data reporting, 
the responsibilities of the investigator, etc.).
Deviations with no effects on the risk/benefit ratio of the clinical trial (such as 
minimal delays in assessments or visits) will be distinguished from those that might 
have an effect on this risk/benefit ratio, such as:
Deviations that might affect the clinical trial objectives, such as those involving 
the inclusion/exclusion criteria (which could mean that the patient is not eligible 
for the trial) and those having an effect on patient evaluability.
Deviations that might affect the patient’s well-being and/or safety, such as an 
incorrect dosing of the investigational medicinal product (PM00104) 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.
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 considered particularly relevant, which are related to ethical 
issues, fulfillment of GCP guidelines and trial procedures, will be notified to the 
pertinent IEC/IRB and, if pertinent, to the relevant authorities as established by local 
regulations.


5.3.
REPLACEMENT OF PATIENTS
Patients must be replaced if they are considered not evaluable for efficacy, i.e., if they 
are withdrawn from the study due to significant clinical deterioration of unknown 
reason, hypersensitivity reactions, patient refusal or unrelated AEs without any tumor 
assessment after the start of study treatment.
Patients withdrawn from the study due to toxicity without any tumor assessments 
after the start of study treatment will be considered as “treatment failures” and will 
not be replaced.
The number of patients replaced will be reflected in the overall number of patients 
included into the trial.
5.4.
STUDY TERMINATION (CLINICAL CUTOFF)
The planned study termination (clinical cutoff) will be six months after the last 
treatment visit of the last evaluable patient included in the study, or nine months after 
the last patient is included, whichever occurs first.
All patients on active treatment at the date of study termination will be offered to 
continue to receive PM00104 treatment off-study according to the Investigator 
criteria.
5.5.
SCREENING EVALUATION
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 following assessments (Table 8). 
Additional information on the collection and processing of PGx samples may be 
found 
in 
Appendix
1.
Samples,
Methodology
and
Techniques
of
the
Pharmacogenomic Substudy.
Table 8. Screening assessments.
ASSESSMENT
TIME
Written informed consent.
Prior to any specific study procedures (within 
four weeks prior to Day 1 of Cycle 1). 
Medical history:
o Date of diagnosis of the primary disease.
o Demographic 
information 
(race/ethnicity, 
age).
o Prior 
treatments 
(surgery, 
radiotherapy,
chemotherapy, immunotherapy), specifying
the best response and the date of PD.
Concomitant diseases and treatments.
Weight and height.
Complete physical examination.
Vital signs: heart rate, blood pressure and body 
temperature.
 Performance status (ECOG PS; see Appendix 2.
ECOG Performance Status Assessment Scale).
Within four weeks prior to Day 1 of Cycle 1.
Complete physical examination, ECOG PS and 
vital signs must be repeated on Day 1 of Cycle 
1, prior to administration of the first PM00104 
infusion.
Weight and height: repeat on Day 1 of Cycle 1 
whenever clinically indicated.  
1. History and 
clinical 
examination
 ECG.
 LVEF (ultrasound).
All ECGs and LVEFs will be reviewed by an 
external cardiologist.
Within four weeks prior to Day 1 of Cycle.
Repeat on Day 1 of Cycle 1 whenever 
clinically indicated.  


ASSESSMENT
TIME
2. Laboratory 
tests
Hematology: differential WBC (neutrophils, 
lymphocytes), hemoglobin and platelets.
Biochemistry A: liver function tests (ALT, AP, 
AST, LDH, total and direct bilirubin), creatinine,
CPK, troponin I, glucose and serum electrolytes 
(Na+, Cl-, K+, Ca++, Mg++).
Biochemistry B: total protein, albumin, amylase 
and lipase. CPK-MB fraction to be analyzed if 
CPK and/or troponin I are abnormal. In the case of 
grade  3 increase in serum cardiac troponin I, an 
ECG and cardiac ultrasound will be performed as 
soon as possible. 
Within one week prior to Day 1 of Cycle 1.
Repeat on Day 1 of Cycle 1 prior to treatment 
with PM00104, if the treatment is administered 
more than one week after the screening test. 
Repeat Biochemistry B on Day 1 of Cycle 1
whenever clinically indicated.
3. Calculated 
creatinine 
clearance
Calculated using the Cockcroft and Gault formula
(see Appendix 3. Cockcroft and Gault Formula).
Within one week prior to Day 1 of Cycle 1.
Repeat on Day 1 of Cycle 1 prior to treatment 
with PM00104, if the treatment is administered 
more than one week after the screening test, or 
whenever clinically indicated.
4. Tumor 
assessment
CT-scan or MRI of all measurable/evaluable sites
of disease, as per RECIST (see Appendix 4.
Evaluation of Response. The RECIST).
Within four weeks prior to Day 1 of Cycle 1.
Documentation of PD is mandatory.
5. Pregnancy 
test, if 
applicable
Within two weeks prior to Day 1 of Cycle 1.
Repeat on Day 1 of Cycle 1 whenever 
clinically indicated.
6. PGx samples See details in Appendix 1. Samples, Methodology
and Techniques of the Pharmacogenomic
Substudy.
Tumor tissue samples obtained at disease 
diagnosis.
One blood sample taken prior to the first 
PM00104 infusion of Day1, Cycle 1.
7. Other tests
When indicated by the clinical and laboratory 
context.
Within four weeks prior to Day 1 of Cycle 1.
ALT, alanine aminotransferase; AP, alkaline phosphatase; AST, aspartate aminotransferase; CPK, creatine 
phosphokinase; CPK-MB, creatine phosphokinase-fraction MB; CT, computed tomography, ECG, electrocardiogram; 
ECOG, Eastern Cooperative Oncology Group; LDH, lactate dehydrogenase; LVEF, left ventricular ejection fraction; 
MRI, magnetic resonance imaging; PD, progressive disease; PGx, pharmacogenomics, PS, performance status; 
RECIST, Response Evaluation Criteria In Solid Tumors; WBC, white blood cells.
5.6.
PATIENT REGISTRATION
After ensuring that the patient meets all eligibility criteria and has given written 
informed consent, she will be entered into the trial by contacting the clinical trial 
monitor designated by the Sponsor and faxing the completed Patient Registration 
Form (Fast Fact Sheet). The Sponsor will then check and confirm this Registration 
Form. 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 referred to this patient.
5.7.
EVALUATIONS DURING TREATMENT
The following assessments will be done while the patient is on treatment (Table 9).
A 2-day window is allowed for the different tests and procedures.


Table 9. Evaluations during treatment.
ASSESSMENT
TIME
 Complete physical examination.
 Performance status (ECOG PS; see Appendix 2.
ECOG Performance Status Assessment Scale).
Day 1 of the first cycle prior to the PM00104 
infusion, and then whenever clinically indicated.
 Vital signs: heart rate, blood pressure and body 
temperature.
Before any PM00104 infusion.
Weight and height.
Repeat on Day 1 of each cycle prior to the 
PM00104 infusion, and then whenever clinically 
indicated.
1. Clinical 
examination
Intercurrent events, concomitant disease and 
treatments. 
Throughout the “on treatment” period (i.e., 
treatment plus 30 days following the last 
PM00104 administration).
Hematology: differential WBC (neutrophils, 
lymphocytes), hemoglobin and platelets.
Biochemistry A: liver function tests (AP, ALT, 
AST, LDH, total and direct bilirubin), creatinine,
CPK, troponin I, glucose and serum electrolytes 
(Na+, Cl-, K+, Ca++, Mg++).
Repeat on Day 1 of each cycle prior to the 
PM00104 infusion, and then weekly.
If NCI-CTCAE grade 3 occurs, the appropriate 
test(s) should be repeated at least every 2-3 days 
until recovery.
2. Laboratory 
tests
Biochemistry B: total protein, albumin, amylase 
and lipase. CPK-MB fraction to be analyzed if 
CPK and/or troponin I are abnormal. In the case of 
grade  3 increase in serum cardiac troponin I, an 
ECG and cardiac ultrasound will be performed as 
soon as possible. 
Repeat on Day 1 of each cycle prior to the 
PM00104 infusion, and then whenever clinically 
indicated.
If NCI-CTCAE grade 3 occurs, the appropriate 
test(s) should be repeated at least every 2-3 days 
until recovery.
3. Calculated 
creatinine 
clearance
Calculated using the Cockcroft and Gault formula 
(see Appendix 3. Cockcroft and Gault Formula).
Repeat on Day 1 of each cycle prior to the 
PM00104 infusion, and then whenever clinically 
indicated.
4. ECG
All ECGs will be reviewed by an external 
cardiologist.
Repeat on Day 1 of each cycle prior to the 
PM00104 infusion, and then whenever clinically 
indicated.
In the case of grade  3 increase in serum cardiac 
troponin I, ECG will be performed as soon as 
possible.
5. LVEF
Cardiac ultrasound.
All LVEFs will be reviewed by an external 
cardiologist.
Every other cycle, and then whenever clinically 
indicated.
In the case of grade  3 increase in serum cardiac 
troponin I, cardiac ultrasound will be performed as 
soon as possible.
6. Tumor 
assessment
CT-scan or MRI of all measurable/evaluable sites, 
as per RECIST (see Appendix 4. Evaluation of
Response. The RECIST).
Every other cycle ( ± one week) until PD.
7. Pregnancy 
test, if applicable
Whenever clinically indicated.
8. AEs
As per NCI-CTCAE, version 3.0.
Throughout the “on treatment” period.
9. PK
See Section 6.
Only during the first two PM00104 infusions of 
the first cycle.
10. Other tests
When indicated, according to the clinical and 
laboratory context.
AE, adverse event; ALT, alanine aminotransferase; AP, alkaline phosphatase; AST, aspartate aminotransferase; CPK, 
creatine phosphokinase; CPK-MB, creatine phosphokinase-fraction MB; CT, computed tomography, ECG, 
electrocardiogram; ECOG, Eastern Cooperative Oncology Group; LDH, lactate dehydrogenase; LVEF, left ventricular 
ejection fraction; MRI, magnetic resonance imaging; NCI-CTCAE, National Cancer Institute Common Terminology 


ASSESSMENT
TIME
Criteria for Adverse Events; PD, progressive disease; PK, pharmacokinetics, PS, performance status; RECIST, Response 
Evaluation Criteria In Solid Tumors; WBC, white blood cells.
5.8.
EVALUATION AT END OF TREATMENT
The end-of-treatment visit will be scheduled at 30 days after the last PM00104
infusion (a window of ± 2 days is allowed).
Regardless of the reason for discontinuation, the same complete workup conducted 
before study entry (except for medical history) will have to be done at this end-of-
treatment visit. This will include the following assessments:

Complete physical examination (including weight and height, if clinically 
indicated).

Vital signs.

ECOG PS.

Hematology.

Biochemistry A.

Biochemistry B.

Calculated creatinine clearance (if clinically indicated).

Pregnancy test (if clinically indicated).

ECG and cardiac ultrasound (for LVEF measurement). 

Intercurrent events, concomitant disease and treatments.

Safety assessment (AEs).

Tumor assessment.

Other tests (when indicated, according to the clinical and laboratory context).
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 SAEs 
suspected to be treatment-related will be reported (see Section 9).
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 three months until disease progression, other antitumor therapy or death or until 
the date of study termination, whichever occurs first. After disease progression or 
after other antitumor therapy, patients will be followed every three months until death 
or until the date of study termination, whichever occurs first.
Patients who withdraw consent will not be followed with any study procedures. 


All AEs (including SAEs) suspected to be treatment-related will be followed-up until 
the events or their sequelae resolve or stabilize at a level acceptable to the 
Investigator and the Sponsor.
Additional parameters will be assessed and/or the frequency of observations will be 
increased at the Investigator’s discretion and according to the nature of the observed 
AEs. When available, autopsy data should be provided.
6.
PHARMACOKINETICS
All patients included in this study will be sampled for PK during the first and second 
infusion of PM00104 of the first cycle, following the sampling schedule detailed in 
Table 10.
6.1.
SAMPLE 
COLLECTION,
STORAGE,
AND 
SHIPPING 
OF 
THE 
PHARMACOKINETIC SAMPLES
All sample collection dates and times will be recorded on the CRFs.
In the treatment infusions with plasma sampling for PK, the infusion rate will be 
established so as to ensure that the total dose is infused in 1 hour. The drug will be 
infused at a constant rate throughout the 1-hour period. In order to obtain reliable PK 
information, the infusion rate should not be modified once the infusion has begun. If 
a variation in the infusion time eventually occurs, it is very important to reflect it on 
the CRF, writing clearly the time of the beginning and the end of the infusion. The 
infusion rate should not be changed to maintain the scheduled duration of infusion. It
would be enough with just recording the actual duration on the CRF and on the PK 
sampling sheet for those cycles in which PK sampling is performed.
Blood samples will be obtained through a peripheral vein located in the contralateral 
side to that of infusion. In any case, the sampling vein has to be different to that in which
the study drug is infused. Even the last sample must never be collected from the infusion 
catheter. 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 permeable.
Five-ml blood samples will be collected in sodium heparin tubes. Sample tubes will be 
gently inverted several times to ensure adequate mixing and immediately centrifuged at 
2500 x g for 15 min at +4°C to separate the plasma. If immediate centrifugation is not 
possible, the tubes containing the blood samples must be placed in an ice bath at 0-4°C 
for a maximum of 30 minutes. After centrifugation, the plasma will be transferred to the 
provided polypropylene tubes (one per sample) and stored at -20ºC until shipped to the 
analysis laboratory. The cell pellet should be discarded. Blood and plasma tubes will be 
provided by PharmaMar.
Blood samples will be collected on Day 1 and Day 8 of Cycle 1, at the time points 
shown in Table 10. 


Table 10. Plasma pharmacokinetic sampling schedule.
Sample number
Optimal time point
Adequate time frame
1
Pre SOI
Pre SOI
2
5 min before EOI
1-5 min before EOI
3
1.5 hour after EOI
1-2 h after EOI
4
3 hour after EOI
2-4 hour after EOI
5
7 hour after EOI
6-10 hour after EOI
6
24 hour after EOI
20-28 hour after EOI
7
48 hour after EOI
40-72 hour after EOI
8
168 hour after EOI
120-168 hour after EOI
EOI, end of infusion; SOI, start of infusion.
The accurate recording of actual dosing and sampling times is much more important 
than the strict adherence to the scheduled times.
Once all samples from a patient have been collected, they should be shipped to the 
central laboratory for PK analyses as soon as possible, ideally the next shipping day. 
The time span between the moment when the last PK sample for a patient has been 
collected and the shipment to the central laboratory of all samples from this patient 
should not exceed two months.
Samples will be sent for analysis in the boxes provided for this purpose, filled with dry 
ice, by the study courier service to the following address:
Mrs Sally Hannam
Icon Development Solutions
Manchester Bioanalytical Laboratory
Parkway One
Parkway Business Centre
300 Princess Road
Manchester
M14 7QU, United Kingdom
Samples will be identified with the following data: Study reference, Patient Number, 
sample number, date and time of collection. At all times, the confidentiality of patient’s 
data will be maintained.
7.
TREATMENT
PharmaMar will provide PM00104 (Zalypsis®) with identifying labels that will 
include all the information required by local regulations.
The PM00104 vials will have to be requested to PharmaMar using appropriate forms
provided by the Sponsor.
The study sites will have to ensure drug traceability at all times.


7.1.
DESCRIPTION OF TREATMENT
PM00104 Drug Product (2.5 mg/vial) is provided as a powder for concentrate for 
solution for infusion. There is only one strength: 2.5 mg PM00104. 
For instructions regarding drug inventory, handling, reconstitution, dilution, storage, 
accountability and disposal, please refer to the Preparation Guide for Zalypsis®
(PM00104) and the Zalypsis® Investigator’s Brochure, both provided as separate 
documents.
7.2.
ADMINISTRATION OF STUDY MEDICATION
7.2.1.
Dose Schedule
A treatment cycle consists of the administration of three i.v. 1-hour infusions of 
PM00104 on Day 1, Day 8 and Day 15, and all study evaluations done before the 
next cycle. Treatment cycles will be repeated every four weeks.
The starting dose in each infusion is 2 mg/m2. This is the recommended dose for 
phase II studies found in the phase I study PM104-A-004-05 (see Section 1.3.5). 
The study treatment will be administered to the patients by a central catheter and by 
specialized on-site study personnel. Central catheter is mandatory as some cases of 
infusion site reactions were observed in the phase I trials (see Section 1.3.5.4).
7.2.2.
Criteria for Treatment Continuation
In order to be re-treated on Day 1 of a new cycle, the patients will have to fulfill the 
same criteria as at study entry (Table 11).
If these criteria are not met on Day 1 of a new cycle, treatment administration should 
be delayed up to two weeks and reevaluated weekly. The new cycle will start upon 
recovery of these parameters, according to these same criteria.
A maximum delay of two weeks is allowed for recovery from drug-related AEs. If 
toxicities have not recovered after a maximum delay of two weeks, the patient should 
discontinue the treatment. In the event of obvious clinical benefit, the patient will 
remain on treatment only after having discussed and agreed upon the case with the 
Sponsor, and upon recovery of all parameters according to the aforementioned 
criteria.
In order to be re-treated on Day 8 and Day 15 of each cycle, the patients will have to 
fulfill the criteria also described in Table 11. If these criteria are not met on Day 8 or 
Day 15, the respective infusion will be skipped. If both Day 8 and Day 15 infusions 
cannot be administered for any reason, the patient should discontinue the treatment, 
except in the event of obvious clinical benefit, in which case the patient will be 
allowed to remain on treatment only after having discussed and agreed upon the case 
with the Sponsor, and upon subsequent recovery of all parameters according to the 
aforementioned criteria.


Table 11. Criteria for continuation of treatment.
Parameter
Value on Day 1
Value on Day 8/15
Platelet count
 100 x 109/l
 75 x 109/l
Hb
≥ 9 g/dl
≥ 9 g/dl
ANC
 1.5 x 109/l
 1.0 x 109/l
AP
 2.5 x ULN
(≤ 5 x ULN if bone metastases)
 2.5 x ULN
(≤ 5 x ULN if bone metastases)
ALT, AST
≤ 2.5 x ULN 
(≤ 5 x ULN if hepatic 
metastases)
≤ 2.5 x ULN 
(≤ 5 x ULN if hepatic 
metastases)
Total bilirubin
 1.5 x ULN*
 1.5 x ULN*
Calculated creatinine clearance (using 
Cockcroft and Gault formula)
 30 ml/min**
 30 ml/min**
Other non-hematological related events, 
including renal function (except alopecia 
and/or vomiting in patients not receiving 
optimal antiemetic prophylaxis).
NCI-CTCAE grade ≤ 1 
(≤ grade 2 in case of asthenia).
NCI-CTCAE grade ≤ 1 
(≤ grade 2 in case of asthenia).
*Unless due to Gilbert’s syndrome.
**In vitro data (see Section 1.3.4) and data obtained in phase I trials (see Section 1.3.5.5.1) suggest an unlikely 
role of the kidney in PM00104 clearance. According with this preliminary evidence, calculated creatinine 
clearance for inclusion criteria (see Section 4.1) and for retreatment (see current table) was established as  30 
ml/min (using the Cockcroft and Gault formula, see Appendix 3. Cockcroft and Gault Formula). 
ALT, alanine aminotransferase; ANC, absolute neutrophil count; AP, alkaline phosphatase; AST, aspartate 
aminotransferase; Hb, hemoglobin; NCI-CTCAE, National Cancer Institute Common Terminology Criteria for 
Adverse Events; ULN, upper limit of normal.
Figure 10 summarizes the actions to be done in case of not meeting treatment criteria.
Figure 10. Time schedule of actions when treatment criteria are unmet.


7.2.3.
Dose Reduction
Dose reductions will take place based on the worst drug-related toxicity found since 
the last dose administration. Table 12 shows the dose levels that will be used 
whenever a dose reduction is required.
Table 12. Dose reductions.
PM00104 dose level
% of dose reduction
Level  0
2 mg/m2
-
Level -1
1.6 mg/m2
20%
Level -2
1.3 mg/m2
20%
No more than two dose reductions per patient will be allowed during the trial. 
Patients requiring more than two dose reductions should discontinue the treatment, 
except in the event of obvious clinical benefit, in which case the patient could be 
allowed to remain on treatment after having discussed and agreed upon the case with 
the Sponsor.
A patient who has undergone a dose reduction for whatever reason will not be 
allowed to escalate the dose level in later cycles.
Treatment will continue until disease progression or until discontinuation owing to 
any other reason (see Section 5.2.1).
7.2.3.1. Hematological Toxicity
The PM00104 dose administered to the patients will be reduced based on the nadir 
value of the platelet count and the ANC measured in the preceding cycle. In the event 
of a platelet count < 25 x 109/l or an ANC < 0.5 x 109/l lasting 5 days or associated 
with fever, sepsis or infection in the preceding cycle, the dose administered to the 
patient in following cycles will have to be reduced by one level (Table 13). In 
addition, re-treatment on the next infusion will only be allowed if the patient fulfils 
all pertinent criteria (see Section 7.2.2).
Table 13. Dose adjustments due to hematological toxicity.
Toxicity 
PM00104 dose 
Grade 4 neutropenia (ANC < 0.5 x 109/l) lasting  5 days.
Grade 4 neutropenia with fever (38.5ºC).
Grade 4 neutropenia with sepsis or severe infection. 
Decrease one dose level 
Thrombocytopenia. Platelets < 25 x 109/l 
Decrease one dose level 
Any dose reductions due to treatment-related hematological toxicities other than 
those listed in Table 13 will have to be discussed and agreed with the Sponsor.
7.2.3.2. Non-hematological Toxicity
In the event of non-hematological toxicity, the PM00104 dose administered to the 
patients will have to be reduced in case of:

Any other grade 3/4 drug-related non-hematological AE, excluding alopecia, 
nausea/vomiting not treated with prophylactic medication or hypersensitivity 
reactions (patients with grade 3/4 hypersensitivity reactions should be 
discontinued from the study; see Section 5.2.1.2). 



Any increase in cardiac troponin I ≥ 0.1 ng/ml, together with evidence of 
cardiac damage by ECG or ECHO.

Decrease in the LVEF >20% from the patient baseline value and <50%.
Any dose reductions due to treatment-related non-hematological toxicities other than 
those listed above will have to be discussed and agreed with the Sponsor.
Following the resolution of any of the aforementioned hematological or non-
hematological toxicities, patients may continue treatment at one dose level below. If 
drug-related toxicities reappeared in the following drug administrations, a second 
dose reduction to a level below is allowed. If more than two dose reductions are 
required, the toxicity will be considered unacceptable and the patient must be 
withdrawn from the study. Exceptionally, patients recovering from the toxicity might 
continue treatment if there is objective evidence of antitumor response. This must 
always be discussed with the Sponsor.  
7.2.4.
Dose Escalation
No dose escalations will be allowed in this study.
7.3.
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 must be made to determine all treatments received by 
the patient during administration of the study treatment. This information must be 
documented in the concomitant therapy section of the CRF.
7.3.1.
Prophylactic Antiemetic Treatment
According to the American Society of Clinical Oncology (ASCO) guidelines for 
drugs with moderate emetic risk (73), the patients will receive prophylactic treatment 
for emesis before the infusion of PM00104 consisting of dexamethasone 8 mg i.v. 
and 5-HT3 antagonists (ondansetron 8 mg i.v. or granisetron 1 mg i.v. or tropisetron 5 
mg i.v.).
If necessary, in addition to the above, 10 mg of metoclopramide orally every 8 hours 
may be administered, or the duration of treatment with 5-HT3 antagonists and/or 
dexamethasone can be extended.
7.3.2.
Concomitant Medication Permitted

Therapies for preexisting and treatment-emergent medical conditions.

Prophylactic antiemetic treatment (above described in Section 7.3.1).

Erythropoietin therapy or derivatives (74).

Bisphosphonates.

In case of diarrhea (75) and pruritus, appropriate treatment will be permitted, 
including topical and systemic corticosteroids and antibiotics. 

Palliative local radiation may be applied. The irradiated lesion will then not 
be considered an area of measurable/evaluable disease.


7.3.3.
Concomitant Medication Prohibited

Concomitant administration of any other antineoplastic therapy.

Investigational agents.

Immunosuppressive therapies, including systemic corticosteroids, unless used 
as therapy for preexisting and treatment-emergent medical conditions (e.g., 
emesis, rash, anorexia).

Primary prophylaxis (i.e., before the intended preventable events occurs) with 
colony-stimulating factors such as granulocyte (G-CSF) or granulocyte-
macrophage (GM-CSF) colony-stimulating factors. Their use as secondary 
prophylaxis is permitted according to the ASCO guidelines (76). However, 
dose reduction will be applied if indicated, regardless of the use of secondary 
prophylaxis with colony-stimulating factors.
7.4.
PACKAGING AND LABELING
PM00104 is provided as a sterile lyophilized powder for concentrate for solution for 
infusion. Each vial will contain 2.5 mg of PM00104.
The following information will appear on the labels:

Name and address of the Sponsor.

Study number/Patient number.

Dosage and route of administration.

Quantity or contents of container.

Batch number/packaging number.

Expiration date and storage conditions.

Local legal information, as appropriate.
7.5.
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 
PharmaMar agrees, unused drug supplies may be returned to the drug repository.
7.6.
TREATMENT COMPLIANCE
The Investigator is responsible for supervising compliance with the instructions 
described in this study protocol.
8.
STUDY EVALUATIONS
8.1.
EFFICACY
To be evaluable for efficacy, patients must have:



Received at least four of the six infusions in the first two cycles (i.e., two 
infusions in each cycle, or three infusions in Cycle 1 and one infusion in Cycle 2), 
and

At least one disease measurement recorded not less than six weeks after treatment 
onset. 
In addition, any eligible patient who receives at least two of the three infusions in one 
treatment cycle and experiences disease progression or dies due to progressive 
disease (PD) prior to response evaluation will be considered evaluable for the main 
endpoint (ORR) and will be categorized as an “early progression”.
Patients withdrawn due to toxicity without any tumor assessment after the start of 
study treatment will be considered as “treatment failures” and will not be replaced.
Patients withdrawn due to significant clinical deterioration of unknown reason, 
hypersensitivity reactions, refusal to continue on study for any reason or unrelated 
AEs without any tumor assessment after the start of study treatment will be 
considered not evaluable for efficacy and will have to be replaced.
8.1.1.
Primary Endpoint: Overall Response Rate per RECIST
The primary endpoint of this study is the overall response rate (ORR), defined as the 
percentage of patients with confirmed objective response (OR), either complete (CR) 
or partial (PR) response according to the Response Evaluation Criteria In Solid 
Tumors (RECIST).
Assessment of efficacy will be done using the RECIST and will be essentially based 
on a set of measurable lesions identified at baseline as target lesions and followed 
until disease progression. A comprehensive workup will be performed at baseline and 
every other cycle (± 1 week) until evidence of PD. The same procedure will be used 
to evaluate each identified lesion both at baseline and throughout the treatment 
period.
In case of detection of an objective response (complete or partial response), a 
confirmation assessment has to be performed four weeks after the first documentation 
of the response.
A quick reference to the RECIST may be found in Appendix 4. Evaluation of
Response. The RECIST. The complete criteria may be found in the published RECIST 
document (77).
8.1.2.
Secondary Endpoints of Efficacy
Secondary endpoints of efficacy in this study are:
Progression-free survival rate at four months (PFS4), defined as the percentage of 
patients who are alive and with no evidence of disease progression at four months 
after the first study drug administration.
Progression-free survival rate at six months (PFS6), defined as the percentage of 
patients who are alive and with no evidence of disease progression at six months 
after the first study drug administration.
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.
Overall survival (OS), defined as the time from the first day of treatment to the 
date of death (or the last day when the patient is known to be alive). Survival will 
be followed for up to six months after the treatment discontinuation of the last 
patient.
8.2.
SAFETY
Patients will be evaluable for safety (secondary study endpoint) if they have received 
at least one total or partial infusion of PM00104. 
Safety will be evaluated using clinical examinations, which will comprise vital signs 
analysis, clinical assessment of adverse events (AEs), changes in laboratory 
parameters (hematological and biochemical, including liver function tests) and any 
other analyses that may be considered necessary.
All AEs will be classified according to the NCI-CTCAE, v. 3.0 (78), and will be 
coded using the Medical Dictionary for Regulatory Activities (MedDRA), version 
10.0.
8.3.
CENTRAL CARDIOLOGICAL REVIEW
Due to safety reasons, an independent cardiologist will review all the ECGs and 
ECHOs performed on the patients during the study, so as to improve consistency in 
the application of evaluation criteria.
Originals or copies of all ECGs and ECHOs will be provided by the Investigator to 
the independent reviewer on an ongoing basis. Other clinical or laboratory records
from the patients may be provided by the Investigator, upon request from the 
independent reviewer.
In the event of disagreement between the Investigator’s and the independent 
reviewer’s assessments, discussion will take place between the two parties in order to 
reach a consensus. If no such consensus is reached, the independent reviewer’s 
assessment will be retained in the report of the Expert Review, and in intermediate 
and final reports.  
8.4.
PHARMACOGENOMIC SUBSTUDY (ONLY ON SAMPLES COLLECTED IN THE 
U.S.)
The pharmacogenomic (PGx) profile of PM00104 is a secondary endpoint of this 
study to be evaluated in a PGx substudy. The aim of this PGx substudy is to identify 
and validate molecular markers whose expression may be associated with the clinical 
outcome of patients treated with PM00104. These molecular markers might allow the 
identification of those patients who will benefit from the treatment with PM00104, 
improving the health care by an individualized medicine.
The objectives of this PGx substudy are:


1. To determine the gene and protein expression profiles of selected genes in 
tumor tissue of the patients included in the clinical study PM104-B-001-09.
2. To determine the genotype of the SNP Asp1104His of XPG and other SNPs 
related to the mechanism of action of PM00104.
3. To correlate the gene and protein expression profiles and the SNP genotype 
with the clinical outcome of the patients and the evolution of the disease.
4.
To validate in patient tumor samples selected putative markers of sensitivity 
to PM00104 found during in vitro studies
Appendix 1. Samples, Methodology and Techniques of the Pharmacogenomic
Substudy includes a detailed protocol for sample collection and analysis. Briefly, the 
samples required for the molecular characterization analyses will be blood samples 
taken prior to the first PM00104 infusion and paraffin-embedded tumor tissue slices 
obtained at disease diagnosis from patients included in the trial who accepted to 
participate in the PGx substudy.
9.
ADVERSE EVENTS REPORTING
9.1.
DEFINITIONS
9.1.1.
Adverse Event
An adverse event (AE) is any untoward medical occurrence in a patient or a 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.
Any event involving adverse drug reactions, illnesses with onset during the study or 
exacerbations of pre-existing illnesses should be recorded, including but not limited 
to clinically significant changes in physical examination findings and abnormal 
objective test findings (e.g., x-Ray, ECG). The criteria for determining whether an 
abnormal objective test finding should be reported as an AE are as follows:

the test result is associated with clinically significant symptoms, and/or

the test result leads to a change in the study dosing or discontinuation from the 
clinical trial, significant additional concomitant drug treatment or other 
therapy, and/or

the test result leads to any of the outcomes included in the definition of a 
SAE, and/or

the test result is considered to be an AE by the Investigator.


9.1.2.
Serious Adverse Event (SAE)
A Serious Adverse Event (SAE) is any adverse experience occurring at any dose that:

results in death (is fatal),

is life-threatening,

requires or prolongs inpatient hospitalization,

results in persistent or significant disability or incapacity,

is a congenital anomaly or birth defect, 

is medically significant, or

is any suspected transmission of an infectious agent via a medicinal product. 
Medical and scientific judgment should be exercised in deciding whether expedited 
reporting is appropriate in other situations such an important medical event 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.
9.1.2.1. Death
Death as such is the outcome of a SAE and should not be used as the SAE term itself. 
Instead, the cause of death should be recorded as the SAE term.
9.1.2.2. Life-Threatening Event
Any event in which the patient was at risk of death at the time of the event; it does not 
refer to an event which hypothetically might have caused death if it were more 
severe.
9.1.2.3. Hospitalization or Prolongation of Hospitalization 
Any AE requiring hospitalization (or prolongation of hospitalization) that occurs or 
worsens during the course of a patient’s participation in a clinical trial must be 
reported as a SAE unless exempted from SAE reporting (see Section 9.2.2). 
Prolongation of hospitalization is defined as any extension of an inpatient 
hospitalization beyond the stay anticipated/required for the initial admission, as 
determined by the Investigator or by the 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).
9.1.3.
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 following documents:

The current investigator brochure (IB) for any study drug/IMPs without a 
marketing authorization or used outside the conditions of its marketing 
authorization.

The summary of product characteristics (SPC) or its national equivalent [i.e.,
U.S. package inserts (USPI)] defined in the protocol for non-Pharma Mar 
IMPs used within the conditions of its marketing authorization.
9.1.4.
Adverse Events Related to Study Drug/s (IMP)
An AE is considered related to a study drug/IMP if the Investigator’s assessment of 
causal relationship to the IMP is “1-Yes”. 
The Investigator will assess the causal relationship of each of the IMPs to the SAE.
The Sponsor may also consider related to the study drug/IMP those events for which 
the Investigator assesses the causal relationship with the IMP as “Unk” when it 
cannot rule out a role of the IMP in the event. See below (Section 9.1.6) for causality 
scale.
9.1.5.
Expedited Reporting
The Sponsor is responsible for the appropriate expedited reporting of SAEs to the 
Regulatory Authorities. The Sponsor will also report all SAEs that are unlisted and 
related to the study drug/s (IMP/s), to the Investigators and to the Independent Ethics 
Committees/Institutional Review Board (IECs/IRBs) according to the current 
legislation unless otherwise required and documented by the IECs/IRB.
9.1.6.
Assessment of Causal Relationship to the Study Drug/IMP
The Investigator must provide an assessment of causal relationship of each of the 
clinical trial IMPs (including combination and comparator products) 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.


Unk.
Only to be used in special situations where the Investigator has 
insufficient information (i.e., the patient was not seen at his/her centre) 
if none of the above can be used.
9.2.
PROCEDURES
9.2.1.
Reporting Adverse Events
The Sponsor will collect AEs until 30 days after administration of the last dose of 
study drug/IMP. All AEs suspected to be related to the study drug/IMP must be 
followed 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 using medical terminology in the source document and the 
CRF. Whenever possible, the Investigator will record the main diagnosis instead of 
the signs and symptoms normally included in the diagnoses. 
Investigators must assess severity (grade) of the event following the NCI-CTCAE v.
3.0 and assign relationship to each study drug/IMP; 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 PharmaMar 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 are AEs, but they should be 
collected only in the AE section of the CRF in some cases (please refer to the CRF 
guidelines for comprehensive information).
9.2.2.
Reporting Serious Adverse Events
The Sponsor will collect SAEs from the signing of the Informed Consent Form. 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/IMP. Beyond this period of time, only those SAEs suspected to be related need 
to be reported. 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 treatment group or relationship to the study 
drug/IMP must be reported within 24 hours to the Pharma Mar Pharmacovigilance 
function by fax (+34 91 846 6004) or telephone (+34 91 846 6054). Out of office 
hours (GMT), assistance on SAE reporting can be obtained by calling the 
Pharmacovigilance Service at +34 91 823 4749.  
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.


Death as such, is the outcome of a SAE and should not be used as the SAE term 
itself. Instead the cause of death should be recorded as the SAE term. When available, 
the autopsy report will be provided to the Sponsor.
9.2.3.
Reporting Pregnancy Cases Occurred within the Clinical Trial
National regulations require that clinical trial Sponsors collect information on 
pregnancies occurring during clinical trials, in which exposure to the IMPs 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.
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 
gonadotrophins (βhCGs).
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. If the trial is blinded, the Investigator will open the blind 
whenever the treatment information is needed for the management of the patient.
Any pregnancy, suspected pregnancy, or positive pregnancy test must be reported to 
PharmaMar 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 
PharmaMar 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 PharmaMar 
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/IMP should also 


be reported to PharmaMar Pharmacovigilance by facsimile within 24 hours of the 
Investigators’ knowledge of the event.
10.
STATISTICAL METHODS
The statistical analysis will be done by the Sponsor or under the Sponsor’s authority.
10.1.
SAMPLE SIZE
In this phase II trial, efficacy of PM00104 will be evaluated in two different groups of 
patients with endometrial or cervical cancer. A total of 62 evaluable patients are 
expected to participate in this clinical trial:
30 patients in Group 1(endometrial cancer), and 
32 patients in Group 2 (cervical cancer).
A different ORR is to be expected depending on the type of cancer. Thus, patients 
with endometrial cancer may achieve higher response rates with second-line single-
agent therapies (around 25-30%) (6) than patients with cervical cancer (around 15-
20%) (79, 80). Therefore, the sample size has been calculated in each group using a 
similar design (based on the Simon two-stage design for phase II trials) (81), but 
using different figures for null and alternative hypotheses.
Group 1 (endometrial cancer): patients with endometrial cancer who have received 
one previous systemic chemotherapy line for advanced/metastatic disease (excluding 
chemosensitizing chemotherapy); prior hormone therapy and biological therapy are 
allowed.
A Simon two-stage design will be adopted in this group to test the null hypothesis 
that the ORR by RECIST is ≤10% versus the alternative that ORR ≥ 30% (two-sided 
test; alpha=0.1 and beta=0.1). A maximum of 30 evaluable patients will be included 
in this group. In a first stage, 10 evaluable patients will be recruited. If one or more (≥ 
1) patients achieve an objective response, the accrual in this group will be expanded 
with 20 additional evaluable patients. If the total number of patients with objective 
response is 6 or more (≥ 6) in 30 evaluable patients (i.e., an ORR in the whole study 
of at least 20%), the null hypothesis will be rejected and PM00104 will be considered 
for further clinical development in endometrial cancer.
Group 2 (cervical cancer): patients with cervical cancer who have received one 
previous systemic chemotherapy line for advanced/metastatic disease (excluding 
chemosensitizing chemotherapy); prior hormone therapy and biological therapy are
allowed. 
A Simon two-stage design will be adopted in this group to test the null hypothesis 
that the ORR by RECIST is ≤5% versus the alternative that ORR ≥ 20% (two-sided 
test; alpha=0.1 and beta=0.1). A maximum of 32 evaluable patients will be included 
in this group. In a first stage, 18 evaluable patients will be recruited. If one or more (≥ 
1) patients achieve an objective response, the accrual in this group will be expanded 
with 14 additional evaluable patients. If the total number of patients with objective 
response is 4 or more (≥ 4) in 32 evaluable patients (i.e., an ORR in the whole study 
of at least 12.5%), the null hypothesis will be rejected and PM00104 will be 
considered for further clinical development in cervical cancer.


Early stopping rule
An early stopping rule for excessive toxicity will be evaluated when ten patients in 
each group will be recruited and followed for at least four weeks. A "serious toxicity" 
rate (STR) of 40% or more will be considered inadequate. The following are 
considered serious toxicities: 

Drug-related grade 4 neutropenia lasting for more than seven days.

Grade 4 thrombocytopenia.

Grade 3/4 nausea/vomiting despite adequate prophylaxis.

Grade 3/4 transaminase increase lasting for more than seven days.

Grade 3/4 fatigue.

Any other grade 3/4 drug-related event leading to early study discontinuation.
If 4 patients of the first 10 patients had one of these serious toxicities, the trial will 
be stopped and the recommended dose and/or administration schedule for phase II 
will be re-evaluated.
With this stopping rule, the probability of 4/10 STR in the sample (if the true 
probability of STR is <1/6) is 0.0697. On the other hand, the probability of observing 
3/10 STR in the sample (if the true probability of STR is >40%) would be 0.3822.
10.2.
ENDPOINTS
10.2.1. Primary Endpoint
Overall response rate (ORR) according to the RECIST.
10.2.2. Secondary Endpoints
Efficacy:
Progression-free survival rate at four months (PFS4)
Progression-free survival rate at six months (PFS6)
Duration of response (DR).
Progression-free survival (PFS).
Overall survival (OS).
Safety profile:
Clinical examinations.
Vital signs analysis.
Clinical assessment of AEs and SAEs.
Changes in laboratory parameters (hematological and biochemical, including liver 
function tests).
Reasons for study discontinuations.
Any other analyses that may be considered necessary.


Others:
Pharmacokinetic (PK) profile.
Pharmacogenomic (PGx) profile.
10.3.
STATISTICAL ANALYSIS
Continuous variables will be tabulated and presented with summary statistics (i.e., 
mean, standard deviation, median and range). Categorical variables will be 
summarized in frequency tables by means of counts and percentages.
10.3.1. Efficacy Analysis
All patients who have received at least four of the six infusions in the first two cycles 
(i.e., two infusions in each cycle, or three infusions in Cycle 1 and one infusion in 
Cycle 2), and who have at least one disease measurement recorded not less than six 
weeks after treatment onset, will be considered evaluable for efficacy. In addition, 
any eligible patient who receives at least two of three infusions in one treatment cycle 
and experiences disease progression or dies due to PD prior to response evaluation 
will be considered evaluable for the main endpoint (ORR) and will be categorized as 
an “early progression”. 
Patients withdrawn due to toxicity without any tumor assessment after the start of 
study treatment will be considered as “treatment failures” and will not be replaced.
Patients withdrawn due to significant clinical deterioration of unknown reason, 
hypersensitivity reactions, refusal to continue on study for any reason or unrelated 
AEs without any tumor assessment after the start of study treatment will be 
considered not evaluable for efficacy and will have to be replaced.
Binomial estimates with exact 95% CIs will be calculated for the analysis of the main 
endpoint (ORR) and the secondary endpoints PFS4 and PFS6 rates.
Time-to-event endpoints (DR, PFS and OS) will be analyzed according to the 
Kaplan-Meier method. 
If relevant, efficacy parameters versus baseline covariates will be analyzed and 
appropriate test will be used (i.e., the Fisher exact test for categorical variables, the 
log-rank test or Cox regression for time-to-event variables, etc.).
10.3.2. Safety Analysis
All patients who have received at least one total or partial infusion of PM00104 will 
be included in the safety analysis.
The AEs, SAEs, laboratory evaluations, deaths and the reason for study 
discontinuations will be analyzed. 
All AEs and SAEs will be classified according to the NCI-CTCAE, v. 3.0, and will be 
coded using the MedDRA, v.10.0.
10.3.3. Pharmacokinetic Analysis
Pharmacokinetic parameters will be calculated using population methods, after 
pooling data from this study with data obtained during phase I studies.


10.3.4. Pharmacogenomic Analysis
The results of the PGx analyses conducted on the tumor tissue obtained at disease 
diagnosis and blood samples obtained prior to the first treatment administration will 
help to generate hypotheses for correlating the molecular parameters assessed in these 
samples with the clinical results of the treatment.
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 5. Declaration of Helsinki) and will be consistent with Good Clinical 
Practice (GCP) guidelines and pertinent regulatory requirements.
The study personnel involved in conducting this trial will be qualified by education, 
training and experience to perform their respective task(s).
The study will be conducted in compliance with the protocol. The protocol, any 
amendments 
and 
the 
patient 
informed 
consent 
will 
receive 
IEC/IRB
approval/favorable opinion prior to initiation, according to pertinent regulations.
The decision of the IEC/IRB concerning the conduct of the study will be made in 
writing to the Investigator, and a copy of this decision will be provided to the Sponsor 
before the beginning of the study.
The Investigator and/or the Sponsor is/are responsible for keeping the IEC/IRB 
informed of any significant new information about the study drug.
All protocol amendments will be agreed upon by the Sponsor and the Investigator.
Administrative changes of the protocol are minor corrections and/or clarifications that 
have no impact on the way the study is to be conducted.
11.2.
MONITORING, AUDITING AND INSPECTING
The study will be monitored by regular site visits and telephone calls to the 
Investigator by the PharmaMar clinical trial monitor.
During site visits, the trial monitor should revise original patient records, drug 
accountability records and document retention (study file). Additionally, the trial 
monitor should observe study procedures and will discuss any problems with the 
Investigator.
Adequate time for these visits should be allocated by the Investigator. The 
Investigator should also ensure that the monitor is given direct access [as per 
International Conference on Harmonization (ICH) Topic E6 (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 
PharmaMar 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 health authorities.
11.3.
PATIENT INFORMED CONSENT FORM
The rights, safety and well-being of the trial patients are the most important 
considerations and should prevail over interests of science and society.
The Informed Consent Forms will include all elements required by ICH, GCP and 
applicable regulatory requirements.
Prior to inclusion into the trial, the Investigator or a person designated by the 
Investigator must provide the patient with one copy of the Informed Consent Form
for the clinical trial and one copy of the Informed Consent Form for the PGx 
substudy. Both copies must provide written fully information about the clinical trial
and the PGx substudy in a language that is non-technical and easily understood. The 
Investigator should allow time necessary for the patient or his/her legally acceptable 
representative to inquire about the details of the clinical trial and the PGx substudy;
then, both Informed Consent Forms 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 Informed 
Consent Forms 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 / IDENTIFICATION OF PATIENTS
The collection and processing of personal data from the patients enrolled in this 
clinical trial will be limited to those data that are necessary to investigate the efficacy, 
safety, quality and usefulness of the study drug used in this trial.
It is the Investigator’s responsibility that sufficient information on the identity of the 
patients will be retained.
The trial monitor, the Sponsor’s auditor, the IECs/IRBs and the regulatory 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, and this consent should also address the 
transfer of the data to other entities and countries.


PharmaMar 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. 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 PharmaMar 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 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 PUBLICATIONS
Before the investigators of this study submit a paper or abstract for publication or 
otherwise publicly disclose information concerning the study drug or products, 
PharmaMar 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 PharmaMar determines that patentable patient matter is disclosed in the proposed 
publication or disclosure, the publication or disclosure will be withheld for a period 
of time considered convenient. If the study is part of a multicenter study, the first 
publication of the study shall be made in conjunction with the presentation of a joint, 
multicenter publication of the study results with the investigators and the institutions 
from all appropriate sites that are contributing data, analysis and comments. 
However, if such a multicenter publication is not submitted within 12 months after 
conclusion, abandonment or termination of the study at all sites, the present study 
may be published individually in accordance with the procedure established above.
The order of the coauthors will reflect the relative contribution of each one to study 
development and analysis. In general, the first author will be the investigator who 
recruits the highest number of patients with information finally available for data 


analysis. Relevant PharmaMar personnel who have fully participated in the study 
must be considered for co-authorship of the publication.


12.
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Appendix 1. Samples, Methodology and Techniques of the 
Pharmacogenomic Substudy (Only on Samples Collected in the U.S.)
1. PGx Study Design  
For those patients who consent to participate in the pharmacogenomic study, response 
to therapy will be correlated with RNA/protein expression levels of selected genes. 
Tumor tissue blocks used for the initial diagnosis of the disease and blood samples 
taken prior to the first PM00104 infusion of Cycle 1, Day 1, will be collected.
Provision of samples for such pharmacogenomics analyses will be optional. 
These analyses will include the use of transcriptional profiling technologies and other 
molecular biology techniques to identify and validate pharmacogenomic markers 
from pre-treatment tumor samples. These 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, time to 
disease progression and overall survival.
The gene expression of selected DNA repair related genes and the determination of 
the genotype for the selected SNPs will be determined by qRT-PCR at the laboratory 
of Molecular Oncology of Pangaea Biotech, Barcelona, Spain. The DNA repair 
related protein expression analysis will be determined at the Molecular Pathology 
laboratory of CNIO (Centro Nacional de Investigaciones Oncológicas Madrid, Spain) 
by IHC techniques using the correspondent antibodies. GEP and IHC analysis will be 
determined at basal conditions; that is using the tumor tissue obtained at the diagnosis 
of the disease. SNP analysis will be performed on blood samples obtained before the 
treatment with PM00104.
All patients included in the study PM104-B-001-09 are eligible for the PGx studies. 
However, only those patients that voluntarily sign the Informed Consent for the 
Pharmacogenomic study will participate. The refusal for participation in the 
Pharmacogenomic study will not affect the participation in the associated clinical 
study.
2. Blood and Tumor Tissue Samples
PharmaMar will provide a “Guide for identification, packaging and shipment of 
Pharmacogenomic samples” detailing the procedures to follow for sample collection, 
labeling and shipment.
The ideal sample for gene mRNA expression analysis is paraffin-embedded tumor 
tissue obtained at the diagnosis of the disease because it is frequently conserved in the 
pathology archives and allows the determination of the mRNA expression analysis of 
selected genes by Quantitative RT-PCR.
Depending on the availability of the tissue blocks to be shipped outside the site, the 
investigator can choose between two options:
Option #1 (for sites that will be sending the paraffin-embedded tissue blocks): ship 
only the paraffin block to PharmaMar, at ambient temperature using the labeled zip-
lock bag and the air-bag envelope provided. Fill the biopsy specimen number in the 
PGx Sample Collection Form. PharmaMar will take responsibility for processing the 


tissue block and preparing the slides. The tissue block will be shipped back in 3-4 
weeks after reception.
Option #2 (for sites that will not be sending paraffin blocks): mount the sample slices
into the appropriate microscope slides. A detailed description of the procedure of 
cutting sections is provided in the “Guide for identification, packaging and shipment 
of Pharmacogenomic samples”. Number and characteristics of the paraffin embedded 
tissue samples required.
1.- RNA slices: five tissue slices 5 µm thick mounted in PEN Membrane Slides 
for microdissection of tumoral tissue to extract RNA. 
2.- IHC slices: ten tissue slices 3 µm thick mounted in SuperFrost Slides for 
immunohistochemistry analysis. 
Blood samples: 10 ml of patient’s peripheral blood in a 10 ml purple top tube 
containing EDTA as anticoagulant. Blood samples have to be stored frozen at least at 
–20ºC until shipment.
3. Patient Samples Labeling and Shipment
The blocks or the slides and the tubes containing the samples are labelled with coded 
numbers (PGx code) to ensure the blindness of the study. Samples will be sent to 
PharmaMar stripped of all patient identifiers with the Investigator team holding the 
key that correlates the tumor sample with the response to PM00104 and all patient’s 
clinical data. 
Sample shipments to PharmaMar will be performed every 6 months or 5 patients,
whatever come first. PharmaMar will contact the investigator requesting the 
preparation of the shipment and will obtain the legal authorizations required for 
shipping biological samples (legal authorizations vary between countries of origin of 
the samples). The contact person in PharmaMar is Dr. Juan Carlos Tercero, 
jctercero@pharmamar.com, phone +34 91 846 60 23. 
PharmaMar will cover all the expenses of the shipment and will provide all the 
shipment materials in advance. 
PharmaMar is responsible for long-term storage of the samples and for the shipment 
to the genomics laboratories where the PGx analysis will be performed. Once tissue 
slices have been obtained, the tissue blocks will be returned to the pathology 
departments of origin 3-4 weeks after reception
The labeling and shipment of patient samples is described in more detail in the 
“Guide for identification, packaging and shipment of Pharmacogenomic samples”.
4. Methodology for Analysis
a.
Tumoral tissue microdisection: Those samples having large proportion of non-
tumoral tissue need to be laser microdissected for isolation of the tumoral cells. 
Paraffin-embedded tissue slices need to be mounted on Pen Membrane 
microscope slides provided by PharmaMar. The tumoral tissue is laser captured 
under the microscope and separated for DNA/RNA extraction. If necessary, 
several tissue slices will be microdissected to obtain a minimum of 1 mm2 of 
microdissected tumoral tissue that is required for the analysis. 


b. DNA/RNA isolation: DNA is isolated using a commercial kit (QIAmp® DNA 
blood Mini kit; Qiagen). Total RNA was recovered from formalin-fixed, 
paraffin-embedded surgical specimens using proteinase K digestion and phenol-
chloroform extraction.
c.
Quantitation of mRNA expression will be analyzed by real-time quantitative 
reverse transcriptase PCR using the ABI Prism 7900HT Sequence Detection 
System (Applied Biosystems, Foster City, CA, USA) in a two-step process. In 
the reverse-transcription (RT) step, cDNA synthesized by reverse transcription 
from 1-100 ng of total RNA extracted from the samples using random primers. 
In the PCR step, PCR products are synthesized from cDNA samples using the 
TaqMan Universal PCR Master Mix. The PCR step employs the 5´ nuclease 
assay, which produces a fluorescent signal proportional to the amount of 
amplified DNA produced in each PCR cycle. Finally, the initial relative amount 
of mRNA is determined by the Cycle Threshold method, using as control the 
control gene and the control samples. The mRNA expression levels are 
normalized to the Β-actin expression in the same samples.
d. Genotyping: genotyping of the single nucleotide polymorphisms is performed 
using the 5’ nuclease allelic discrimination assay. The PrimerExpress program 
(Applied Biosystems) was used to design probes and primers for the analysis of 
each single nucleotide polymorphism. To avoid amplification of non-specific 
DNA all oligonucleotide sequences were checked in the BLAST Search 
program (available at http://www.ncbi.nlm.nih.gov/LocusLink/BLAST/). Each 
reaction mixture (25 µL) of polymerase chain reaction contained 50 ng of DNA, 
900 nM of each forward and reverse primer, 300 nM of each allele specific 
probe and 12.5 µL of Taqman Universal PCR Master Mix (Applied 
Biosystems). Fluorescence in each sample well is measured each cycle before 
and after polymerase chain reaction using ABI Prism 7000 Sequence Detection 
System (Applied Biosystems). Data are analyzed using Allelic Discrimination 
Program (Applied Biosystems). To assure the accuracy of genotyping with the 
use of this method, 10 DNA samples will be randomly selected and subjected 
them to polymerase chain reaction and direct DNA sequencing in an ABI Prism 
310 Sequence Detection System (Applied Biosystems).
e.
Generation of tissue-arrays (TMA): for characterization of IHC protein 
expression, we will construct a tissue-array containing the patient samples 
assembled as previously described (1). Briefly, two 1.5-mm-diameter cylinders 
of tissue are taken from representative areas of each archival paraffin block and 
arrayed into a new recipient paraffin block with a custom-built precision 
instrument (Beecher Instruments, Silver Spring, MD) according to the 
previously described method (2). Areas chosen for the cylinder core have high 
tumor cellularity. In order to evaluate the most active part of each primary 
tumor, the invasive border of the tumor in large lesions and all tumor cells in 
smaller samples are selected. In addition, normal tissues and three different cell 
lines with known cell-cycle alterations are placed adjacent to tumoral tissues to 
serve as internal controls and to ensure the quality of staining slides. Initial 


sections are stained for hematoxylin and eosin to verify the histopathological 
findings.
f.
Immunohistochemistry: three-micrometer tissue sections from the TMA blocks 
are sectioned and applied to special immunohistochemistry coated slides 
(Dako). These slides are baked overnight in a 56ºC oven. Sections are 
deparaffinized in xylene for 20 minutes, rehydrated through a graded ethanol 
series and washed with phosphate-buffered saline. Antigen retrieval is achieved 
by a 2-minute heat treatment in a pressure cooker, containing 1 l of 10 mM 
sodium citrate buffer, pH 6.5, that has been previously brought to the boil. 
Before staining, endogenous peroxidase activity is quenched with 1.5 % 
hydrogen peroxide in methanol for 10 min. Immunohistochemical staining is 
performed on these sections using adequate antibodies for detection of the
selected proteins. After incubation, in the case of nuclear markers, 
immunodetection is performed with the LSAB Visualization System (Dako, 
Glostrup, Denmark) using 3,3’-diaminobenzidine chromogen as substrate, 
according to the manufacturer’s instructions. In addition, whenever possible, 
cytoplasmic markers are visualized with the APAAP system (alkaline 
phosphatase anti-alkaline phosphatase, Dako, Glostrup, Denmark), using neo-
fuchsine chromogen as substrate to rule out the possibility of a role of 
endogenous melanin in the observed reactivity. All sections are counterstained 
with hematoxylin. Negative controls are obtained by omitting the primary 
antibody.  
g. Scoring systems: immunostaining intensity is evaluated by two different 
pathologists and scored using uniform and clear cut-off criteria, in order to 
maintain the reproducibility of the method. Discrepancies are resolved by 
simultaneous re-evaluation. Briefly, the result of immunostaining is recorded as 
negative or positive, and low versus high expression, taking into account the 
expression in tumoral cells and the specific cut-off for each marker. As a 
general criterion, the cut-offs are selected in order to facilitate reproducibility, 
and when possible, to translate biological events.
h. Statistics: clinical data and immunohistochemistry scoring are performed blind, 
and data are compiled only after all analyses are completed. Fisher’s exact test 
is used to test whether a specific protein-expression profile is associated with 
the clinical outcome after Zalypsis® treatment. Significance is concluded for 
values of p < 0.05. The prognosis value of markers will be explored for 
objective clinical response, progression free survival and survival. In each case, 
a multivariate model is developed by backwards elimination, starting with all 
markers with a p-value lower than 0.10 in the univariate analysis. Hazard ratios 
will be calculated with the univariate Cox model, and comparison between 
Kaplan-Meier survival and progression free survival curves will be performed 
with the log-rank test. All tests of statistical significance are two-sided, and 
significance is set at 0.05 except in multiple comparisons, where it is set at 
0.017 in accordance with the Bonferroni correction.


References:
1. Kononen, J., Bubendorf, L., Kallioniemi, A., Barlund, M., Schraml, P., Leighton, 
S., Torhorst, J., Mihatsch, M. J., Sauter, G., and Kallioniemi, O. P. (1998). Tissue 
microarrays for high-throughput molecular profiling of tumor specimens. Nat Med 4, 
844-847
2. Schöffski P, Casali PG, Taron M, Van Oosterom AT, Judson IR, Grosso F, et al. 
DNA repair functionality modulates the clinical outcome of patients with advanced 
sarcoma treated with trabectedin (ET-743). Proc Am Soc Clin Oncol. 2006; 2006 
ASCO Annual Meeting Proceedings Part I. Vol 24, No. 18S (June 20 Supplement): 
9522.


Appendix 2. ECOG Performance Status Assessment Scale
Grade
Activity
0
Able to carry on all normal activities without restriction.
1
Restricted in physically strenuous activity but ambulatory and able to 
carry out light 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.


Appendix 3. Cockcroft and Gault Formula
   [(140-age (years)) x weight (Kg)]
Creatinine clearance (ml/min) = 
      72 x serum creatinine (mg/dl)
x G1
1G (Gender) = 0.85 if female; 1 if male.
Reference: Cockcroft, DW, Gault, H. Prediction of creatinine clearance from serum 
creatinine. Nephron 1976;16(1):31-41.


Appendix 4. Evaluation of Response. The RECIST
Measurability of tumor lesions at baseline
Definitions
Measurable disease - the presence of at least one measurable lesion. If the 
measurable disease is restricted to a solitary lesion, its neoplastic nature should be 
pathologically confirmed. 
Measurable lesions - lesions that can be accurately measured in at least one 
dimension with longest diameter  20 mm. With spiral CT scan, lesions must be  10 
mm in at least one dimension.
Non-measurable lesions - all other lesions, including small lesions (longest diameter 
< 20 mm with conventional techniques or < 10 mm with spiral CT scan) and other 
non-measurable lesions. These include: bone lesions, leptomeningeal disease, ascites, 
pleural/pericardial effusion, inflammatory breast disease, cutaneous or pulmonary 
lymphangitis, abdominal masses that are not confirmed and followed by imaging 
techniques, and cystic lesions.
All measurements should be recorded in metric notation using a ruler or calipers. All 
baseline evaluations should be performed as closely as possible to the beginning of 
treatment and never more than four weeks before the beginning of the treatment.
For the present study, lesions in irradiated area are considered as measurable provided 
radiotherapy has ended three months prior to entry, and they have progressed or 
appeared since then. They must satisfy the previous criteria.
Methods of measurements
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.
Clinically detected lesions will only be considered measurable when they are 
superficial (e.g. skin nodules, palpable lymph nodes). For the case of skin lesions, 
documentation by color photography -including a ruler to estimate the size of the 
lesion- is recommended.
Lesions on chest X-ray are acceptable as measurable lesions when they are clearly 
defined and surrounded by aerated lung. However, CT is preferable.
CT and MRI are the best currently available and reproducible methods to measure 
target lesions selected for response assessment. Conventional CT and MRI should be 
performed with contiguous cuts of 10 mm or less in slice thickness. Spiral CT should 
be performed using a 5-mm contiguous reconstruction algorithm; this specification 
applies to the tumors of the chest, abdomen and pelvis, while head and neck tumors 
and those of the extremities usually require specific protocols.
Ultrasound (US) should not be used to measure tumor lesions that are clinically not 
easily accessible. It may be used as a possible alternative to clinical measurements of 
superficial palpable nodes, subcutaneous lesions and thyroid nodules. US might also 
be useful to confirm the complete disappearance of superficial lesions usually 
assessed by clinical examination.


Tumor response evaluation
Baseline documentation of “Target” and “Non-Target” lesions
All measurable lesions up to a maximum of five lesions per organ and 10 lesions in 
total, representative of all involved organs, should be identified as target lesions and 
will be recorded and measured at baseline.
Target lesions should be selected on the basis of their size (those with the longest 
diameter) and their suitability for accurate repetitive measurements (either by 
imaging techniques or clinically).
A sum of the longest diameter (LD) for all target lesions will be calculated and 
reported as the baseline sum LD. The baseline sum LD will be used as reference by 
which to characterize the objective tumor response.
All other lesions (or sites of disease) should be identified as non-target lesions and 
should also be recorded at baseline. Measurements are not required but the presence 
or absence of each should be noted throughout follow-up.
Response Criteria
Evaluation of target lesions
* Complete Response (CR):
Disappearance of all target lesions.
* Partial Response (PR):
At least a 30% decrease in the sum of LD of target 
lesions, taking as reference the baseline sum LD.
* Progression (PD):
At least a 20% increase in the sum of LD of target 
lesions, taking as references the smallest sum LD 
recorded since the treatment started or the appearance 
of one or more new lesions.
* Stable Disease (SD):
Neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD, taking as 
references the smallest sum LD since the treatment 
started.
Evaluation of non target lesions
* Complete Response (CR):
Disappearance of 
all 
non-target 
lesions 
and 
normalization of tumor marker level.
* Incomplete Response / 
Stable Disease
Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal 
limits.
* Progression (PD):
Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions. 


Evaluation of best overall morphological response
The best overall morphological response is the best response recorded from the start 
of the treatment until disease progression/recurrence (taking as reference for 
progressive disease the smallest measurements recorded since the treatment started). 
To be assigned a status of PR or CR, changes in tumor measurements must be 
confirmed by repeat assessments that should be performed not less than four weeks 
after the criteria for response were first met. If PR or CR is found at Week 6, it is 
recommended that response is confirmed using the evaluation scheduled at Week 12.
In the case of SD, follow-up measurements must have met the SD criteria at least 
once after study entry, at a minimum 6-week interval.
Target lesions
Non-target lesions
New lesions
Overall response
CR
CR
No
CR
CR
Incomplete response / SD
No
PR
PR
Non-PD
No
PR
SD
Non-PD
No
SD
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
CR, complete response; PD, progressive disease; PR, partial response; SD, stable 
disease.
Every effort should be made to document objective progression, even after 
discontinuation of treatment.


Appendix 5. Declaration of Helsinki
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI
Ethical Principles for Medical Research Involving Human Subjects
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964, and 
amended by the:
29th WMA General Assembly, Tokyo, Japan, October 1975
35th WMA General Assembly, Venice, Italy, October 1983
41st WMA General Assembly, Hong Kong, September 1989
48th WMA General Assembly, Somerset West, Republic of South Africa, October 
1996
52nd WMA General Assembly, Edinburgh, Scotland, October 2000 
53th WMA General Assembly, Washington 2002 (Note of Clarification on paragraph 
29 added)
55th WMA General Assembly, Tokyo 2004 (Note of Clarification on paragraph 30 
added)
59th WMA General Assembly, Seoul, October 2008
A. INTRODUCTION 
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 not be applied without consideration of all other relevant
paragraphs.
2. Although the Declaration is addressed primarily to physicians, the WMA 
encourages other participants in medical research involving human subjects to 
adopt these principles.
3. It is the duty of the physician to promote and safeguard the health of patients, 
including those who are involved in medical research. The physician's 
knowledge and conscience are dedicated to the fulfilment of this duty.
4. 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."
5. Medical progress is based on research that ultimately must include studies 
involving human subjects. Populations that are underrepresented in medical 
research should be provided appropriate access to participation in research.
6. In medical research involving human subjects, the well-being of the individual 
research subject must take precedence over all other interests.


7. 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 current interventions must be evaluated continually 
through research for their safety, effectiveness, efficiency, accessibility and 
quality.
8. In medical practice and in medical research, most interventions involve risks 
and burdens.
9. Medical research is subject to ethical standards that promote respect for all 
human subjects and protect their health and rights. Some research populations 
are particularly vulnerable and need special protection. These include those 
who cannot give or refuse consent for themselves and those who may be 
vulnerable to coercion or undue influence.
10. Physicians should 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.
B. BASIC PRINCIPLES FOR ALL MEDICAL RESEARCH 
11. It is the duty of physicians who participate in medical research to protect the 
life, health, dignity, integrity, right to self-determination, privacy, and 
confidentiality of personal information of research subjects.
12. 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. 
13. Appropriate caution must be exercised in the conduct of medical research that 
may harm the environment.
14. The design and performance of each research study involving human subjects 
must be clearly described 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, 
other potential conflicts of interest, incentives for subjects and provisions for 
treating and/or compensating subjects who are harmed as a consequence of 
participation in the research study. The protocol should describe arrangements 
for post-study access by study subjects to interventions identified as beneficial 
in the study or access to other appropriate care or benefits.
15. The research protocol must be submitted for consideration, comment, 
guidance and approval to a research ethics committee before the study begins. 
This committee must be independent of the researcher, the sponsor and any 
other undue influence. 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 change to the 
protocol may be made without consideration and approval by the committee.
16. Medical research involving human subjects must be conducted only by 
individuals with the appropriate scientific training and qualifications. 
Research on patients or healthy volunteers requires the supervision of a 
competent and appropriately qualified physician or other health care 
professional. The responsibility for the protection of research subjects must 
always rest with the physician or other health care professional and never the 
research subjects, even though they have given consent.
17. Medical research involving a disadvantaged or vulnerable population or 
community is only justified if the research is responsive to the health needs 
and priorities of this population or community and if there is a reasonable 
likelihood that this population or community stands to benefit from the results 
of the research.
18. Every medical research study involving human subjects must be preceded by 
careful assessment of predictable risks and burdens to the individuals and 
communities involved in the research in comparison with foreseeable benefits 
to them and to other individuals or communities affected by the condition 
under investigation.
19. Every clinical trial must be registered in a publicly accessible database before 
recruitment of the first subject.
20. Physicians may not participate in a research study involving human subjects 
unless they are confident that the risks involved have been adequately 
assessed and can be satisfactorily managed. Physicians must immediately stop 
a study when the risks are found to outweigh the potential benefits or when 
there is conclusive proof of positive and beneficial results.
21. Medical research involving human subjects may only be conducted if the 
importance of the objective outweighs the inherent risks and burdens to the 
research subjects.
22. Participation by competent individuals as subjects in medical research must be 
voluntary. Although it may be appropriate to consult family members or 
community leaders, no competent individual may be enrolled in a research 
study unless he or she freely agrees.
23. Every precaution must be taken to protect the privacy of research subjects and 
the confidentiality of their personal information and to minimize the impact of 
the study on their physical, mental and social integrity.
24. In medical research involving competent human subjects, 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, 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.
25. For medical research using identifiable human material or data, physicians 
must normally seek consent for the collection, analysis, storage and/or reuse. 
There may be situations where consent would be impossible or impractical to 
obtain for such research or would pose a threat to the validity of the research. 
In such situations the research may be done only after consideration and 
approval of a research ethics committee.
26. When seeking informed consent for participation in a research study the 
physician should 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 should be sought by an appropriately 
qualified individual who is completely independent of this relationship.
27. For a potential research subject who is incompetent, the physician must seek 
informed consent from the legally authorized 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 population 
represented by the potential subject, the research cannot instead be performed 
with competent persons, and the research entails only minimal risk and 
minimal burden.
28. When a potential research subject who is deemed incompetent 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 authorized representative. 
The potential subject's dissent should be respected.
29. 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 population. In such circumstances the 
physician should seek informed consent from the legally authorized 
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 should be obtained as soon as possible from the subject 
or a legally authorized representative.


30. Authors, editors and publishers all have ethical obligations with regard to the 
publication of the results of research. Authors 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. They should adhere to 
accepted guidelines for ethical reporting. Negative and inconclusive as well as 
positive results should be published or otherwise made publicly available. 
Sources of funding, institutional affiliations and conflicts of interest should be 
declared in the publication. Reports of research not in accordance with the 
principles of this Declaration should not be accepted for publication.
C. ADDITIONAL PRINCIPLES FOR MEDICAL RESEARCH COMBINED 
WITH MEDICAL CARE
31. The physician may combine medical research with medical care only to the 
extent that the research is justified by its potential preventive, diagnostic or 
therapeutic value and if the physician has good reason to believe that 
participation in the research study will not adversely affect the health of the 
patients who serve as research subjects.
32. The benefits, risks, burdens and effectiveness of a new intervention must be 
tested against those of the best current proven intervention, except in the 
following circumstances:
a. The use of placebo, or no treatment, is acceptable in studies where no 
current proven intervention exists; or 
b. Where for compelling and scientifically sound methodological reasons the 
use of placebo is necessary to determine the efficacy or safety of an 
intervention and the patients who receive placebo or no treatment will not 
be subject to any risk of serious or irreversible harm. Extreme care must be 
taken to avoid abuse of this option.
33. At the conclusion of the study, patients entered into the study are entitled to be 
informed about the outcome of the study and to share any benefits that result 
from it, for example, access to interventions identified as beneficial in the 
study or to other appropriate care or benefits.
34. The physician must fully inform the patient which aspects of the 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 interfere with the 
patient-physician relationship.
35. In the treatment of a patient, where proven interventions do not exist or have 
been ineffective, the physician, after seeking expert advice, with informed 
consent from the patient or a legally authorized representative, may use an 
unproven intervention if in the physician's judgement it offers hope of saving 
life, re-establishing health or alleviating suffering. Where possible, this 
intervention should be made the object of research, designed to evaluate its 
safety and efficacy. In all cases, new information should be recorded and, 
where appropriate, made publicly available.

SAP_001.pdf: 
PM104-B-001-09 
Phase II Clinical and Pharmacokinetic Trial of Zalypsis® in Patients with Advanced 
and/or Metastatic Endometrial or Cervical Cancer Treated with at least One Line of 
Systemic Therapy 
Statistical Analysis Plan 
Author 
Mariano Siguero, Biostatistician 
Version 
1.0 
Date 
28-07-09 
NCT Code
00900562


Table of contents 
1 
INTRODUCTION ................................................................................................................ 5 
1.1 
Study rationale ............................................................................................................. 5 
1.2 
Information on Study Drug ........................................................................................ 5 
2 
OBJECTIVES ...................................................................................................................... 5 
2.1 
Primary......................................................................................................................... 5 
2.2 
Secondary ..................................................................................................................... 5 
3 
STUDY DESIGN .................................................................................................................. 5 
4 
STUDY POPULATIONS .................................................................................................... 6 
4.1 
Analysis populations .................................................................................................... 6 
4.1.1 
Efficacy population ............................................................................................................ 6 
4.1.2 
Safety population ............................................................................................................... 6 
5 
ENDPOINTS ........................................................................................................................ 6 
5.1 
Primary endpoints ....................................................................................................... 6 
5.2 
Secondary endpoints ................................................................................................... 6 
6 
SAMPLE SIZE ..................................................................................................................... 7 
6.1 
Sample size determination .......................................................................................... 7 
6.2 
Interim analyses ........................................................................................................... 8 
7 
STATISTICAL ANALYSIS ................................................................................................ 9 
7.1 
Treatment discontinuation and protocol deviations management .......................... 9 
7.2 
Demographic analysis ................................................................................................. 9 
7.3 
Exposure ..................................................................................................................... 10 
7.4 
Statistical methodology for efficacy ......................................................................... 10 
7.5 
Statistical methodology for safety ............................................................................ 10 
7.6 
Missing values management ..................................................................................... 11 
8 
PHARMACOKINETIC (PK) AND PHARMACOGENOMIC (PGX) EVALUATION11 


9 
STATISTICAL SOFTWARE ........................................................................................... 11 
10 
APPENDIX I. PATIENTS DISPOSITION ..................................................................... 12 
10.1 
General characteristics ............................................................................................. 12 
10.1.1 Patients treated, eligible and evaluable ............................................................................ 12 
10.1.2 Reasons for treatment discontinuation ............................................................................. 13 
10.1.3 Protocol deviations .......................................................................................................... 14 
11 
APPENDIX II. EFFICACY EVALUATION .................................................................. 14 
11.1 
Baseline characteristics ............................................................................................. 14 
11.1.1 Patients characteristics at baseline ................................................................................... 14 
11.1.2 Histology and time from diagnosis .................................................................................. 15 
11.1.3 Prior anticancer therapy ................................................................................................... 16 
11.1.4 Prior history ..................................................................................................................... 18 
11.1.5 Physical examination, vital signs, electrocardiogram and other tests .............................. 18 
11.1.6 Hematological values at baseline ..................................................................................... 19 
11.1.7 Biochemical values at baseline ........................................................................................ 19 
11.1.8 Other metabolic values at baseline .................................................................................. 20 
11.1.9 Signs and symptoms at baseline ...................................................................................... 20 
11.1.10 Concomitant therapy ........................................................................................................ 21 
11.2 
Efficacy ....................................................................................................................... 21 
11.2.1 Response .......................................................................................................................... 21 
11.2.2 Time-to-event variables ................................................................................................... 23 
11.2.3 Patients with clinical benefit ............................................................................................ 24 
11.2.4 Tumor marker evolution/response (group 1) ................................................................... 24 
12 
APPENDIX III. SAFETY EVALUATION ...................................................................... 24 
12.1 
Extent of exposure ..................................................................................................... 24 
12.1.1 Treatment administration ................................................................................................. 24 
12.1.2 Dose delays ...................................................................................................................... 25 
12.1.3 Dose reduction ................................................................................................................. 26 
12.1.4 Skipped doses .................................................................................................................. 27 
12.2 
Toxicity ....................................................................................................................... 28 
12.2.1 Adverse events ................................................................................................................. 28 
12.2.2 Serious toxicity rate ......................................................................................................... 28 
12.2.3 Serious adverse events ..................................................................................................... 28 
12.3 
Laboratory evaluation .............................................................................................. 29 
12.3.1 Hematological abnormalities ........................................................................................... 29 
12.3.2 Biochemistry abnormalities ............................................................................................. 30 
12.3.3 Other metabolic abnormalities ......................................................................................... 32 


12.4 
Vital Signs .................................................................................................................. 33 
12.5 
Concomitant medication during treatment ............................................................. 33 
13 
FIGURES ............................................................................................................................ 34 


 
1 
Introduction 
1.1 
Study rationale 
 
This Statistical Analysis Plan (SAP) explains in detail the statistical analyses that will be carried out 
for Pharmamar in PM104 – B – 001 – 09 study. The analyses described in this SAP are based upon 
and supplement those described in the study protocol (dated 27-Jan-2009). 
 
1.2 
Information on Study Drug 
 
PM00104 is a new synthetic alkaloid that has been selected for clinical development based on its in 
vitro activity against human solid and non-solid tumor cell lines, its in vivo activity in xenografted 
human tumors, as well as an acceptable non-clinical toxicology profile. 
 
2 
Objectives 
 
The study protocol states the following: 
2.1 
Primary 
 
 
To evaluate the antitumor activity of PM00104 administered as a 1-hour intravenous (i.v) 
infusion on Day 1, 8 and 15 every four weeks (d1, d8 and d15; q4wk) to patients with advanced 
and/or metastatic endometrial or cervical cancer previously treated with one line of systemic 
chemotherapy. 
 
2.2 
Secondary 
 
 
To determine the safety profile of this PM00104 regimen in these patients. 
 
 
To determine the pharmacokinetic (PK) profile of this PM00104 regimen in these patients. 
 
 
To determine the pharmacogenomic (PGx) profile of this PM00104 regimen in these patients. 
Hypothesis-generating exploratory PGx analyses will be conducted to correlate the molecular 
parameters found in the tumor samples of the patients with the clinical results achieved with 
PM00104. 
 
3 
Study design 
 
Multicenter, open label, phase II clinical trial with single-agent PM00104 given as a as a 1-hour i.v. 
infusion on d1, d8 and d15 q4wk to patients with advanced and/or metastatic endometrial or 
cervical cancer progressing after at least one line of systemic chemotherapy. 
 
The primary endpoint of the study is the overall response rate (ORR), defined as the percentage of 
patients with objective response (OR; complete or partial response) as defined by the Response 
Evaluation Criteria in Solid Tumors (RECIST). 
 


4 
Study populations 
4.1 
Analysis populations 
 
Female adult patients with endometrial (Group 1) or cervical cancer (Group 2) progressing after at 
least one previous line of systemic chemotherapy are eligible for this trial. To be included in the 
study, patients have to fulfill all inclusion criteria and none of the exclusion criteria. 
4.1.1 
Efficacy population 
 
To be evaluable for efficacy, patients must have received at least four infusions of the six infusions 
in the first two cycles and at least one disease measurement recorded not less than six weeks after 
treatment onset will be evaluable for efficacy.  
 
In addition, any eligible patient who receives at least two of the three infusions in one treatment 
cycle and experience disease progression or die due to progressive disease (PD) prior to response 
evaluation will be considered evaluable for the main endpoint (ORR) and will be categorized as an 
“early progression”.  
 
Patients withdrawn due to toxicity without any tumor assessment after the start of study treatment 
will be considered as “treatment failures” and will not be replaced. 
 
Patients withdrawn due to significant clinical deterioration of unknown reason, hypersensitivity 
reactions, refusal to continue on study for any reason or unrelated AEs without any tumor 
assessment after the start of study treatment will be considered not evaluable for efficacy and will 
be replaced. 
4.1.2 
Safety population 
 
All patients who have received at least one complete or partial infusion of PM00104 infusion will 
be included in the safety analysis. 
 
5 
Endpoints 
5.1 
Primary endpoints 
 
Overall response rate (ORR), defined as the percentage of patients with confirmed objective 
response (OR), either complete (CR) or partial (PR) response according to the RECIST. 
5.2 
Secondary endpoints 
 
 
Progression-free survival at four months (PFS4 rate), defined as the percentage of patients who 
are alive and with no evidence of disease progression at four months after the first study drug 
administration. 
 
 
Progression-free survival rate at six months (PFS6), defined as the percentage of patients who 
are alive and with no evidence of disease progression at six months after the first study drug 
administration. 
 
 
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 tumour evaluation.  
 
 
Overall survival (OS), defined as the time from the first day of treatment to the date of death (or 
the last day when the patient is known to be alive). Survival will be followed for up to six 
months after the treatment discontinuation of the last patient.  
 
 
Safety profile: AEs, SAEs, laboratory evaluations, deaths and the reason for study 
discontinuations, dose delays, modifications or omissions will be analyzed. All AEs and SAEs 
will be classified according to the NCI-CTCAE, version 3.0, and will be coded using the 
Medical Dictionary for Regulatory Activities (MedDRA), version 10.0. 
 
 
Treatment exposure:  
 
- 
Date of treatment start:  Date of treatment dose at cycle 1. 
 
- 
Date of last dose: Date of last treatment dose at last cycle. 
 
- 
Date of treatment discontinuation (for the purpose of exposure calculations): The 
minimum date between the death date and the date of the first infusion of last cycle + 
28 days. 
 
- 
Body Surface Area (BSA): The calculated surface of a human body measured in m². 
 
- 
Treatment duration: The time between the day of the first dose and the day of treatment 
discontinuation (in weeks). 
 
- 
Total cumulative dose: The sum of all the PM00104 doses from the first cycle until last 
cycle including the dose received in last cycle. (Expressed in mg/m²). 
 
- 
Absolute dose intensity: The actual cumulative dose divided by number of weeks of 
treatment. (Expressed in mg/m²/wk). 
 
- 
Intended dose intensity: The planned dose per cycle divided by the planned weeks by 
cycle. (Expressed in mg/m²/wk). 
 
- 
Relative dose intensity: The ratio of absolute dose intensity (x100) divided by the 
intended dose intensity. (Expressed in percentage). 
 
 
Pharmacokinetic/Pharmacodynamic parameters.  
 
 
Pharmacogenomic profile 
 
6 
Sample size  
6.1 
Sample size determination 
 
In this phase II trial, efficacy of PM00104 will be evaluated in two different groups of patients with 
endometrial or cervical cancer.  
 


Group 1 (endometrial cancer): A Simon two-stage design will be adopted in this group to test the 
null hypothesis that the ORR by RECIST is ≤ 10% versus the alternative that ORR ≥ 30% (two-
sided test; alpha=0.1 and beta=0.1).  
 
A maximum of 30 evaluable patients will be included in this group. In a first stage, 10 evaluable 
patients will be recruited. If one or more (≥ 1) patients achieve an objective response, the accrual in 
this group will be expanded with 20 additional evaluable patients. 
 
If the total number of patients with objective response is 6 or more (≥ 6) in 30 evaluable patients 
(i.e., an ORR in the whole study of at least 20%), the null hypothesis will be rejected and PM00104 
will be considered for further clinical development in endometrial cancer.  
 
Group 2 (cervical cancer): Also a Simon two-stage design where the null hypothesis ORR by 
RECIST is ≤ 5% vs. ORR ≥ 20% (two-sided test; alpha=0.1 and beta=0.1).  
 
A maximum of 32 evaluable patients will be included in this group. In a first stage, 18 evaluable 
patients will be recruited. If one or more (≥ 1) patients achieve an objective response, the accrual in 
this group will be expanded with 14 additional evaluable patients. 
 
If the total number of patients with objective response is 4 or more (≥ 4) in 32 evaluable patients 
(i.e., an ORR in the whole study of at least 12.5%), the null hypothesis will be rejected and 
PM00104 will be considered for further clinical development in cervical cancer. 
6.2 
Interim analyses 
 
Interim efficacy analysis will be performed when the 10 first evaluable patients have been recruited 
in the group 1 and 18 patients have been recruited in the group 2. In addition, a safety evaluation 
will be performed when 10 patients in each group will be recruited and followed for at least four 
weeks. The study will be stopped, and the recommended dose re-evaluated if the stopping rule 
described below is met in any of the groups. 
 
Other non-scheduled interim analyses might be performed exclusively for enhancing the safety of 
the patients. 
 
Early stopping rule: 
  
An early stopping rule for excessive toxicity will be evaluated when ten patients in each group will 
be recruited and followed for at least four weeks. A "serious toxicity" rate (STR) of 40% or more 
will be considered inadequate. The following are considered serious toxicities:  
 
 
Drug-related grade 4 neutropenia lasting for more than seven days.  
 
Grade 4 thrombocytopenia.  
 
Grade 3/4 nausea/vomiting despite adequate prophylaxis.  
 
Grade 3/4 transaminase increase lasting for more than seven days.  
 
Grade 3/4 fatigue.  
 
Any other grade 3/4 drug-related event leading to early study discontinuation.  
 
If ≥ 4 patients of the first 10 patients had one of these serious toxicities, the trial will be stopped and 
the recommended dose and/or administration schedule for phase II will be re-evaluated.  
With this stopping rule, the probability of ≥4/10 STR in the sample (if the true probability of STR is 
<1/6) is 0.0697. On the other hand, the probability of observing ≤3/10 STR in the sample (if the 
true probability of STR is >40%) would be 0.3822. 


7 
Statistical analysis 
7.1 
Treatment discontinuation and protocol deviations management 
 
The accrual and study discontinuation details will be presented descriptively. The reasons for 
treatment discontinuation will be described by counts and percentages, overall and by number of 
cycles received. Reasons of treatment discontinuation other than disease progression will be 
detailed. 
 
A study of the protocol deviations deemed relevant according to the Data Management Plan and 
Oncology review will be made following the ICH guidelines. The protocol deviations will be listed 
by type of deviation: 
 
 
Patients entered but not satisfying entry criteria 
 
Patients developing withdrawal criteria but not withdrawn 
 
Patients receiving incorrect dose or schedule 
 
Patients receiving excluded concomitant treatment 
7.2 
Demographic analysis 
 
Demographics and baseline characteristics will be summarized by group for all recruited patients. 
 
Continuous variables will be summarized and presented with summary statistics, i.e., median and 
range, mean, 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. 
 
Age, sex, race, baseline weight, height, body surface area (BSA), PS, pulse, BPS, BPD, 
temperature, LVEF, ECG and X-ray results will be summarized descriptively. Age is calculated 
based on the date of birth at the time date of registration date. 
 
For solid tumors, histology diagnosis, number of organs involved and sites of disease will be 
described following standard tables detailed in section 10 (Appendix I). 
 
A frequency tabulation of the number of patients with the different types of previous cancer 
surgery, radiotherapy and systemic therapy will be given. 
 
A summary of prior relevant history and signs and symptoms will be presented per patient. 
 
Laboratory values at baseline will be tabulated. Median values, ranges and CTC grades will be 
displayed by laboratory parameters. 
 
Concomitant therapies will be categorized per ATC (level 1 and 4) class and coded term. The 
number of patients receiving each type of therapy during the treatment phase will be tabulated in 2 
separate tables: a frequency tabulation of the different therapies that started pre-study, and a 
frequency tabulation of the different therapies that started during the study. Each table will be 


generated once by class, and once by coded term. The accompanying listing will contain all 
concomitant therapies. 
7.3 
Exposure 
 
Cumulative dose, dose intensity and relative dose intensity, cycle delay, and dose modifications or 
omissions will be described following standard tables detailed in section 12 (Appendix III). 
7.4 
Statistical methodology for efficacy 
 
Binomial estimates with exact 95% CIs will be calculated for the analysis of the main endpoint 
(ORR) and the secondary endpoints PFS4 and PFS6 rates. Time-to-event endpoints (DR, PFS and 
OS) will be analyzed according to the Kaplan-Meier method.  
 
If relevant, efficacy parameters versus baseline covariates will be analyzed and appropriate test will 
be used (i.e., the Fisher exact test for categorical variables, the log-rank test or Cox regression for 
time-to-event variables, etc.).  
 
The characteristics of patients with complete response, partial response, or free from progression at 
4 months, will be described.  
 
Statistical tests, if and when they are carried out, will only have an exploratory purpose and have a 
threshold of  = 5%. Exact binomial Confidence Intervals will be calculated with the same 
significance level. 
 
See section 11 (Appendix II) for further details on the efficacy analysis. 
7.5 
Statistical methodology for safety  
 
Descriptive statistics, tabulation and graphic representation will be used for the evaluation of safety 
by tumor type in this phase II study, as described in section 12 (Appendix III).  
 
If the safety profile of PM00104 is similar in both study groups (endometrial and cervical cancer), a 
pooled analysis for all included patients regardless its tumor type could be performed for safety. 
 
Adverse events will be graded according to NCI-CTCAE version 3.0. The incidence and grade of 
adverse events and laboratory abnormalities will be calculated considering the most severe grade 
per patient and cycle. 
 
Descriptive statistics will be used to present the profiles of drug-related adverse events, drug-related 
deaths, SAE and drug-related treatment discontinuation and the observed grade 1-4 toxicities, per 
patient and per cycle. 
 
The shift of severity grades from baseline to the worst occurrence during treatment will be 
tabulated. The time to onset and recovery from neutrophils, platelets and hepatic enzymes 
elevations will be illustrated by means of descriptive statistics. 
 
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, significant consequences 
and actions taken. 
 
PS, weight gain – loss and LVEF measurements evolution during the study will be summarized by 
frequency tabulation. 


 
See section 12 (Appendix III) for further details on the safety analysis. 
7.6 
Missing values management 
 
In case of missing values in the determination of protocol deviations (i.e. time from last anticancer 
treatment to start of treatment with PM00104) the most conservative approach will be taken for the 
evaluation. 
 
If a date is missing, the worst case will be taken into account when calculating the difference 
between two dates. In such a case, this will be specified in the table footnote. 
 
The cycles with missing information regarding laboratory values or adverse events will be 
subtracted from the denominator of the tables. 
 
As regards of the analysis of Time to Progression, in case of more than one missing tumor scan 
between the last evaluation without progression and the documentation of progressive disease, the 
time to progression will be censored at the day of the last tumor evaluation without progression. 
8 
Pharmacokinetic (PK) and pharmacogenomic (PGx) evaluation 
 
These analysis will be described in two different documents not included in this SAP.  
 
9 
Statistical software 
 
Oracle Clinical will be used for double data entry and clinical data management.  
 
SAS v8.2 will be used for all the statistical analysis. 


 
 
 
 
TABLES, LISTINGS AND FIGURE SHELLS 
 
NOTE:  All tables, listings and figures described in this section will be duplicated in two different 
groups. First, patients with endometrial cancer (group 1) and secondly, patients with cervical cancer 
(group 2). 
 
If appropriate, a pooled analysis for all included patients regardless its tumor type (group 1 + group 
2) could be performed for Safety as in Sections 12.2 and 12.3.  
 
Each particular table, listing and figure will have a comprehensive header and/or footnotes, 
identifying the group of treatment and/or relevant specifications. 
 
10 Appendix I. Patients disposition. 
10.1 General characteristics. 
10.1.1 
Patients treated, eligible and evaluable. 
 
Table 10.1.1. 1. Patients accrual by institution. 
 
 
Institution 1 
Institution 2 
Institution  …
Total 
   N 
   % 
    N 
   % 
    N 
  % 
    N 
   % 
N-included 
 
 
 
 
 
 
 
 
N-treated 
 
 
 
 
 
 
 
 
 
Table 10.1.1. 2. Disposition of patients. 
Event 
        Date 
Date first consent 
 
Date first dose of first patient  
Date last consent 
 
Date first dose of last patient  
Date last dose  
 
Last follow up date 
 
 
Table 10.1.1. 3.  Number of patients evaluable for analysis. 
 
 
N. evaluable 
 for efficacy 
N.evaluable 
 for safety 
         Total 
           N 
% 
      N 
        % 
      N        
% 
N-included 
 
 
 
 
 
 
N-treated 
 
 
 
 
 
 
 


 
 
 
 
 
10.1.2 
Reasons for treatment discontinuation. 
 
Table  10.1.2. 1. Reasons for treatment discontinuation. 
 
Total 
N 
% 
   Progressive disease 
 
 
   Patient refusal 
 
 
   Investigator decision 
 
 
   ….. 
 
 
   Other*  
 
 
*See Listing  10.1.2.5 
 
Table  10.1.2. 2. Reasons for treatment discontinuation by number of cycles received. 
 
Last Cycle (or Infusion) 
Cycle 1 
Cycle 2 
Cycle (X) 
Total 
   N 
   %     N 
   % 
    N 
   % 
    N 
   % 
Progressive disease 
 
 
 
 
 
 
 
 
Patient refusal  
 
 
 
 
 
 
 
 
Investigator decision 
 
 
 
 
 
 
 
 
…… 
 
 
 
 
 
 
 
 
Other* 
 
 
 
 
 
 
 
 
* See Listing  10.1.2.5 
 
Table  10.1.2. 3 Reason for end of study. 
 
Total 
N 
% 
   Progressive disease 
 
 
   Toxicity (study drug) 
 
 
   Death 
 
 
    …. 
 
 
    Other  
 
 
* See Listing  10.1.2.6 
 
Table  10.1.2. 4. Time on treatment (months). 
 
N  
Median 
    Min                          Max 
 
 
 
 
 
Listing  10.1.2. 5. Listing of reasons for treatment discontinuation other than progressive disease. 
 
Patient ID  
Reason  
Specify 
 
 
 
 
 
Listing  10.1.2. 6. Listing of reasons for study discontinuation other than progressive disease. 
 
Patient ID  
Reason  
Specify 
 
 
 
 
 
Listing  10.1.2. 7. Listing of treatment discontinuation due to AEs. 
Patient  Cycle 
PT MedDRA 
Code 
AE Literal
Grade
Relation
Action    Significant   
  consequences
 
 
 
 
 
 
 
 
 


 
 
 
 
 
10.1.3 
Protocol deviations. 
 
Listing 10.1.3. 1 Elegibility: Patients who entered the study even though they did not satisfy the 
entry criteria. 
Dose level 
Patient id 
I-E criteria no fulfilled 
Deviation 
 
 
 
 
 
Listing 10.1.3. 2 Protocol deviations: Patients developing withdrawal criteria but were not 
withdrawn. 
Dose level 
Patient id 
Deviation 
 
 
 
 
Listing 10.1.3. 3 Protocol deviations: Patients who received incorrect dose or schedule. 
Dose level 
Patient id 
Deviation 
 
 
 
 
 
Listing 10.1.3. 4 Protocol deviations: Patients who received an excluded concomitant medication. 
Dose level 
Patient id 
Deviation 
 
 
 
 
11 Appendix II. Efficacy evaluation. 
11.1 Baseline characteristics. 
11.1.1 
Patients characteristics at baseline. 
 
Table 11.1.1.  1. Baseline characteristics: Summary statistics. 
 
Total (N=XX) 
N 
% 
Race:  
 
 
Caucasian 
 
 
Black 
 
 
…… 
 
 
Other* 
 
 
Age grouped: 
 
 
18 – XX years 
 
 
XX – YY years 
 
 
     ≥ YY years 
 
 
 
 
 
 
 
* Patient id and race as a footnote. 
** Stands for Not Applicable. Specify details in the footnote. 
 
Table 11.1.1.  2. Summary statistics: baseline characteristics. 
 
N 
Missing 
Median 
Min 
Max 
Mean 
SD 
Age (years) 
 
 
 
 
 
 
 
Weight (Kg) 
 
 
 
 
 
 
 
 


 
 
 
 
 
11.1.2 
Histology and time from diagnosis. 
 
Table 11.1.2.  1.  Cancer diagnosis at baseline. 
 
Total (N=XX) 
N 
% 
Tumor type*:  
 
 
Endometrial 
 
 
        Endometroid 
 
 
        Papillary Serous 
 
 
        Mixed 
 
 
        Clear cell 
 
 
        Other** 
 
 
Cervix 
 
 
        Squamus cells carcinoma 
 
 
        Adenocarcinoma 
        Adenosquamus 
 
 
        Other** 
 
 
Histology Grade:  
 
 
Well differentiated 
 
 
Moderately differentiated 
 
 
Poorly differentiated 
 
 
Undifferentiated 
 
 
Unknown 
 
 
Current Disease 
 
 
Locally advanced 
 
 
Metastatic 
 
 
Number of Sites involved (target-non target):  
 
 
1 
 
 
2 
 
 
3 
 
 
> 3 
 
 
Summary Statistics of Number of Sites involved (target-non 
target):  
 
 
N 
 
 
Median 
 
 
Minimum 
 
 
Maximum 
 
 
Programming Notes: Percentage is based on total patient included. 
* One table for each group. ** See listing 11.1.2.5 


 
 
 
 
 
Table 11.1.2.  2.  Stage at baseline (FIGO criteria). 
 
 
  N 
% 
IA 
 
 
IB 
 
 
… 
 
 
 
 
 
 
Table 11.1.2.  3.  Sites for target and non-target lesions. 
Sites 
Total 
N 
% 
Bone 
 
 
Lung 
 
 
…. 
 
 
 
Listing 11.1.2.  4. Listing of patient histology. 
Patient ID Tumor type   Histology Grade                 ……                         
Stage 
Current stage 
 
 
 
 
Listing 11.1.2. 5. Listing of other tumor types. 
Patient ID 
Histology                              ……… 
Specify 
 
 
 
 
Listing 11.1.2. 6. Listing of target and non target lesions. 
Patient ID 
 Target/non-target               Site/Subsite                                Method 
 
 
 
 
 
Listing 11.1.2.  7. Listing of patients with only one single lesion. 
Patient ID Target/non-target  Site    Biopsy/FNA(Y/N)   
Histology/Cytology 
Previously irradiated(Y/N) 
 
 
 
 
Table 11.1.2.  8.  Summary statistics of cancer diagnosis characteristics: Time from diagnosis and time from last PD. 
 
N    
Median 
Min 
Max 
Mean 
SD  
Time from first diagnosis to first 
infusion (months) 
 
 
 
 
 
 
 
 
 
 
 
 
Time from last progression to fir
infusion (months) 
 
 
 
 
 
 
 
 
 
 
 
 
(*) SD stands for standard deviation 
 
 
11.1.3 
Prior anticancer therapy. 
 
Table 11.1.3. 1  Surgery. 
Surgery 
Total (N=XX) 
N 
% 
 
 
 
 


 
 
 
 
 
Table 11.1.3. 2  Radiotherapy type. 
 
Total (N=XX) 
N 
% 
External 
 
 
Brachytherapy 
 
 
IORT 
 
 
 
Table 11.1.3. 3  Radiotherapy setting 
 
Total (N=XX) 
N 
% 
Radiotherapy 
 
 
Chemoradiotherapy 
 
 
 
Listing 11.1.3. 4  Patients with prior radiotherapy 
Patient ID           Type                  Setting           Site                     First  
date  
Last date 
 
 
 
 
Listing  11.1.3. 5  Patients with prior surgery. 
Patient ID         Intention            Site and Procedures        Residual diseas
Date 
 
 
 
 
Table 11.1.3. 6  Summary statistics of prior systemic anticancer therapy. 
 
N 
Median 
Min 
Max 
     Mean 
SD  
Nº of lines  
 
 
 
 
 
 
Nº of agents 
 
 
 
 
 
 
 
Table 11.1.3. 7  Number of lines and agents of systemic anticancer therapy. 
 
Total (N=XX) 
N 
% 
Number of lines 
 
 
1 
 
 
2 
 
 
3 
 
 
> 3 
 
 
Number agents 
 
 
1 
 
 
2 
 
 
3 
 
 
> 3 
 
 
 
Table 11.1.3. 8  Prior anticancer agents. 
Antineoplastic and Immunomodulating agents  
(ATC-clas. Levels 1-4) 
N  
% 
Antineoplastic Agents (L01) 
 
 
….. 
 
 
Endocrine therapy (L02) 
 
 
….. 
 
 
 


 
 
 
 
 
11.1.4 
Prior history. 
 
Listing 11.1.4. 1. Prior history. 
Patient ID. 
Description 
Onset dat
Resolved date 
 
 
 
 
 
11.1.5 
Physical examination, vital signs, electrocardiogram and other tests. 
 
Table 11.1.5. 1  Physical examination at baseline. 
 
Total (N=XX) 
N 
% 
Physical Examination:  
 
 
Normal 
 
 
Abnormal 
 
 
ECOG-PS: 
 
 
0 
 
 
1 
 
 
ECG:  
 
 
Normal 
 
 
Abnormal 
 
 
LVEF 
 
 
Normal 
 
 
Abnormal 
 
 
Adequate birth control:  
 
 
Yes 
 
 
No 
 
 
NA*  
 
 
Pregnancy test 
 
 
Positive 
 
 
Negative 
 
 
* NA stands for “Not applicable” 
 
Listing 11.1.5. 2  Listing of abnormal ECG. 
Patient ID 
                            ECG result                
 
Specify 
 
 
 
 
Listing 11.1.5. 3  Listing of LVEF. 
Patient ID 
   LVEF(%)              Method        Institutional normal range   
Result 
 
 
 
 


 
 
 
 
 
Table 11.1.5. 4  Vital signs. 
 
N
Missing 
Median 
Min 
  Max 
  Mean    SD 
Heart Rate (beats/min) 
 
 
 
 
 
 
 
BPS (mmHg) 
 
 
 
 
 
 
 
BPD (mmHg) 
 
 
 
 
 
 
 
Temperature (ºC) 
 
 
 
 
 
 
 
 
11.1.6 
Hematological values at baseline. 
 
Table 11.1.6. 1. Hematological abnormalities at baseline. 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Total 
  N
% 
N 
% 
N 
% 
N 
% 
N 
% 
Leukopenia 
 
 
 
 
 
 
 
 
 
 
Neutropenia 
 
 
 
 
 
 
 
 
 
 
Anemia 
 
 
 
 
 
 
 
 
 
 
Thrombocytopenia 
 
 
 
 
 
 
 
 
 
 
Lymphopenia 
 
 
 
 
 
 
 
 
 
 
 
Table 11.1.6. 2. Hematology at baseline. Last value before treatment. 
 
N 
Missing 
Median 
Min 
Max 
Mean 
SD  
Leukocytes 
 
 
 
 
 
 
 
Neutrophils 
 
 
 
 
 
 
 
Hemoglobin 
 
 
 
 
 
 
 
Platelets 
 
 
 
 
 
 
 
Lymphocytes 
 
 
 
 
 
 
 
 
Listing 11.1.6. 3. Hematology at baseline. Patients with hematological parameters missing. 
Patient ID. 
Exam 
 
 
 
 
 
 
 
Listing 11.1.6. 4.  Hematology at baseline. Abnormalities grade >=2. 
Patient ID. 
Parameter 
Value      
Grade 
 
 
 
 
 
11.1.7 
Biochemical values at baseline 
 
Table 11.1.7. 1.  Biochemical abnormalities at baseline. 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Total 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
AST 
 
 
 
 
 
 
 
 
 
 
ALT 
 
 
 
 
 
 
 
 
 
 
Total Bilirubin 
 
 
 
 
 
 
 
 
 
 
Direct Bilirubin 
 
 
 
 
 
 
 
 
 
 
…. 
 
 
 
 
 
 
 
 
 
 
 
Table 11.1.7. 2. Biochemistry at baseline. Last value before treatment.  
 
N 
Missing 
Median 
Min 
Max 
Mean 
Max  
AST 
 
 
 
 
 
 
 
ALT 
 
 
 
 
 
 
 
Total Bilirubin 
 
 
 
 
 
 
 
Direct Bilirubin 
 
 
 
 
 
 
 
…. 
 
 
 
 
 
 
 


 
 
 
 
 
Listing 11.1.7. 3  Biochemistry at baseline. Patients with biochemical parameters missing. 
Patient ID. 
Exam 
 
 
 
 
 
Listing 11.1.7. 4.  Biochemistry at baseline. Abnormalities grade >=2. 
Patient ID. 
Parameter 
Value      
Grade 
 
 
 
 
 
11.1.8 
Other metabolic values at baseline. 
 
Table  11.1.8. 1.  Other metabolic abnormalities at baseline. 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Total 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
Hyperglycemia 
 
 
 
 
 
 
 
 
 
 
…. 
 
 
 
 
 
 
 
 
 
 
* All metabolic parameters susceptible to be graded as per NCI-CTCAE v3.0  
Table  11.1.8. 2.  Other metabolic abnormalities at baseline (Hyper-Hypo). Last value before treatment. 
 
N 
Missing 
Median 
Min 
Max 
   Mean 
SD  
Glucose 
 
 
 
 
 
 
 
 
 
 
*…. 
 
 
 
 
 
 
 
* Glucose (Hyper-Hypo), Albumin, lipase, Total proteins, Troponin I ,LDH, CPK,CPK-MB 
 
Listing  11.1.8. 3. Patients with metabolic parameters missing. 
Patient ID. 
Exam 
 
 
 
 
 
 
 
Listing  11.1.8. 4.  Other metabolic at baseline. Abnormalities grade >=2. 
Patient ID. 
Parameter 
Value      
Grade 
 
 
 
 
 
11.1.9 
Signs and symptoms at baseline. 
 
Table 11.1.9. 1. Summary statistics: Signs and symptoms. 
SOC/MedDRA Preferre
term 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Total 
N
      % 
N 
% 
N 
% 
N 
% 
N 
% 
General  
Disorders 
 
 
Abdominal
Distension 
 
 
 
 
 
 
 
 
 
 
….. 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
Pain 
 
 
 
 
 
 
 
 
 
 
 
Table 11.1.9. 2. Median of signs and symptoms by dose level. 
 
N 
Median 
Min 
Max 
Mean 
SD*  
 
 
 
 
 
 
 
(*) SD stands for standard deviation 
 
Listing 11.1.9. 3. Listing of Baseline characteristics: Signs and symptoms. 
Patient ID 
SOC 
Sign/symptom 
Grade
 
Onset date 
 
 
 
 
 
 
 
 
 


 
 
 
 
11.1.10 Concomitant therapy. 
 
Table  11.1.10. 1.  Agents of Concomitant therapy started at baseline. 
Concomitant medication (ATC1/ATC4) 
 
 
(ATC level 1)             (ATC level 4) 
N  
% 
… 
 
 
 
 
 
 
Table  11.1.10. 2.  Concomitant medication characteristics at baseline. 
 
Total (N=XX) 
N 
% 
Number of Systems (ATC1) 
 
 
1 
 
 
2 
 
 
3 
 
 
> 3 
 
 
Number of agents (ATC4) 
 
 
1 
 
 
2 
 
 
3 
 
 
> 3 
 
 
 
Table  11.1.10. 3.  Concomitant therapy started at baseline. Summary of number of systems involved (ATC1). 
 
N 
Median  
Min 
Max  
     Mean  
SD* 
 
 
 
 
 
 
 
 
Table  11.1.10. 4.  Concomitant therapy started at baseline. Summary of number of agents involved (ATC4). 
 
N 
Median  
Min 
Max  
     Mean  
SD* 
 
 
 
 
 
 
 
 
Listing  11.1.10. 5.  Listing of Baseline characteristics: Concomitant therapy. 
Patient ID 
Start date  
ATC code          Route           ……
Reason for use 
 
 
 
 
 
 
11.2 Efficacy. 
11.2.1 
Response.  
 
Listing 11.2.1. 1. Listing of patients excluded from the efficacy analysis. 
Patient ID 
 
 
Reason 
 
 
 
 
 
 
 
 
 
 
 
Table 11.2.1. 2.  Patients evaluable for efficacy. 
Evaluable 
Total (N=XX) 
N 
% 
Yes 
 
 
No 
 
 
Total 
 
 
Programming Notes: Percentage is based on total patient included (ITT) 


 
 
 
 
 
Table 11.2.1. 3.  Best response in all evaluable patients. 
Response 
N 
% 
CI (95%) 
Complete Response (CR) 
 
 
 
Partial Response (PR) 
Stable Disease ≥ 4 months* 
 
 
 
Stable Disease (SD) 
 
 
 
Progression Disease (PD)** 
 
 
 
Programming Notes: Percentage is based on the total of patient evaluable for efficacy 
(*) Patients who are free from progression in the tumor evaluation at 4 months 
(**)  Patients with Early PD will also be included in this category (provided that they receive at 
least two infusions of PM00104) 
NOTE: An analysis of best response in the 10 and 18 first evaluable patients in the group 1 and 
group 2 respectively will also be performed. Table 11.2.1.3 will be repeated at this interim analysis 
and at the end of the study.  
  
Table 11.2.1. 4.  Best response in all treated patients. 
Response 
N 
% 
CI (95%) 
Complete Response (CR) 
 
 
 
Partial Response (PR) 
Stable Disease ≥ 4 months* 
 
 
 
Stable Disease (SD) 
 
 
 
Progression Disease (PD)** 
 
 
 
Not evaluable 
 
 
 
Programming Notes: Percentage is based on total patient of patients treated 
(*)Patients who are free from progression in the tumor evaluation at 4 months 
(**)  Patients with Early PD will also be included in this category (provided that they receive at 
least two infusions of PM00104) 
 
Table 11.2.1. 5.  Progression Free Survival status at 4 months (PFS4) in all evaluable patients. 
PFS4 
Total (N=XX) 
N 
% (95% CI) 
Yes 
 
 
No 
 
 
Total 
 
 
 
Table 11.2.1. 6 .  Progression Free Survival status at 4 months (PFS4) in all treated patients. 
PFS4 
Total (N=XX) 
N 
% (95% CI) 
Yes 
 
 
No 
 
 
Total 
 
 
 
Table 11.2.1. 7.  Progression Free Survival status at 6 months (PFS6) in all evaluable patients. 
PFS6 
Total (N=XX) 
N 
% (95% CI) 
Yes 
 
 
No 
 
 
Total 
 
 
 


 
 
 
 
 
Table 11.2.1. 8.  Progression Free Survival status at 6 months (PFS6) in all treated patients. 
PFS6 
Total (N=XX) 
N 
% (95% CI) 
Yes 
 
 
No 
 
 
Total 
 
 
 
11.2.2 
Time-to-event variables.  
 
Table 11.2.2. 1. Duration of response. 
Summary 
N=XX 
Events X (XX.X%) 
Censored X (XX.X%) 
Median X.X 95% CI (X.X-X.X) 
DR > 3 months XX.X% 95% CI XX.XX%-XX.X%) 
DR > 6 months XX.X% 95% CI XX.XX%-XX.X%) 
 
Table 11.2.2. 2.  Progression Free Survival (Kaplan-Meier estimates in all evaluable patients). 
Summary 
N=XX 
Events X (XX.X%) 
Censored X (XX.X%) 
Median X.X 95% CI (X.X-X.X) 
PFS rate at 4 months XX.X% 95% CI XX.XX%-XX.X%) 
PFS rate at 6 months XX.X% 95% CI XX.XX%-XX.X%) 
 
Table 11.2.2. 3.  Progression Free Survival (Kaplan-Meier estimates in all treated patients). 
Summary 
N=XX 
Events X (XX.X%) 
Censored X (XX.X%) 
Median X.X 95% CI (X.X-X.X) 
PFS rate at 4 months XX.X% 95% CI XX.XX%-XX.X%) 
PFS rate at 6 months XX.X% 95% CI XX.XX%-XX.X%) 
 
Table 11.2.2. 4.  Overall Survival. Evaluable population. 
Summary 
N=XX 
Events X (XX.X%) 
Censored X (XX.X%) 
Median X.X 95% CI (X.X-X.X) 
OS rate at 6 months XX.X% 95% CI XX.XX%-XX.X%) 
OS rate at 12 months XX.X% 95% CI XX.XX%-XX.X%) 
 


 
 
 
 
 
Table 11.2.2. 5.  Overall Survival. Treated population. 
Summary 
N=XX 
Events X (XX.X%) 
Censored X (XX.X%) 
Median X.X 95% CI (X.X-X.X) 
OS rate at 6 months XX.X% 95% CI XX.XX%-XX.X%) 
OS rate at 12 months XX.X% 95% CI XX.XX%-XX.X%) 
 
Table 11.2.2. 6.  Follow-up period. 
  Parameter 
 Median 
   95% CI Lower bound    95% CI Upper boun
    PFS 
 
 
 
    OS 
 
 
 
 
11.2.3 
Patients with clinical benefit. 
 
Listing 11.2.3. 1. Characteristics of patients with clinical benefit*. 
         Patient characteristics                    Outcome prior treatment                      PM00104 
treatment 
Patient   Sex/Age/PS  Histology  Nº  Prior   Last prior  Cycles       Best    TTP   Cyc    PFS   
OS  ...                                                      
                                                      CT Lines  Treatment  received  Response                              
 
(*) Clinical benefit defined as patients who experience any of the following CR or PR or PFS4. 
 
11.2.4 
Tumor marker evolution/response (group 1). 
 
Table 11.2.4. 1   CA-125 evolution summary. 
 
Baseline
Cyc 1  
Cyc 2 
Cyc 3 
…… 
 
 
N 
 
 
 
 
 
 
 
Median 
 
 
 
 
 
 
 
Max 
 
 
 
 
 
 
 
Min 
 
 
 
 
 
 
 
 
Table 11.2.4. 2   CA-125 evolution during treatment per patient. 
    Patient ID         Baseline        Cycle 1        Cycle 2                      ……..  
 
12 Appendix III. Safety evaluation. 
12.1 Extent of exposure. 
 
12.1.1 
Treatment administration.  
 
Table 12.1.1. 1. Cycles administered. 
Cycles per patient: n (%) 
 
N 
% 
1 
 
 
2 
 
 
3 
 
 
>3 
 
 


 
 
 
 
 
Table 12.1.1. 2. Summary of cycles administered. 
 
N 
Median  
Min 
Max  
Mean  
SD* 
 
 
 
 
 
 
 
(*) SD stands for standard deviation 
 
Table 12.1.1. 3.  Dose intensity. 
 
 
N                 Median        Min                    Max 
Cumulative dose (mg/ m²) 
 
 
 
 
Treatment duration (wk) 
 
Dose intensity (mg/m² wk) 
 
 
 
Relative dose intensity (%) 
 
 
 
 
12.1.2 
Dose delays. 
 
Table 12.1.2. 1.  Dose delay. 
 
N 
% 
Number of patients treated 
 
 
Number of patients with any dose delay 
 
 
Number of cycles administered 
 
 
Number of cycles susceptible to be delayed 
 
 
Patients with 
 
 
No delays 
 
 
1 cycle delayed 
 
 
2 cycles delayed 
 
 
 3 cycles delayed 
 
 
Number of cycles with dose delay*  
 
 
Programming Notes: Percentage is based on number of cycle susceptible to be delayed. 
* Denominator = Number of cycles susceptible to be delayed. 
 
Table 12.1.2. 2.  Dose delay according to their relationship to study drug. 
 
Treatment related** 
Non – Treatment related 
N 
% 
N 
% 
Patients with 
 
 
 
 
No delays 
 
 
 
 
1 cycle delayed 
 
 
 
 
2 cycles delayed 
 
 
 
 
 3 cycles delayed 
 
 
 
 
Number of cycles with dosing delay 
 
 
 
 
Programming Notes: 
*   Denominator = Number of cycles susceptible to be delayed. 
** Hematological reason / Non hematological reason. 


 
 
 
 
 
Table 12.1.2. 3.  Length of dose delay. 
 
Treatment related* Non – Treatment relate
Total 
 
N 
% 
N 
% 
N 
% 
Lenght of delay 
 
 
 
 
 
 
1 – 7 days 
 
 
 
 
 
 
7 – 14 days 
 
 
 
 
 
 
 14 days 
 
 
 
 
 
 
Programming Notes: 
* Denominator = Number of cycles susceptible to be delayed. 
** Hematological reason / Non hematological reason. 
 
Table 12.1.2. 4 .  Dose delay and reason by cycle. 
 
Cycle 2 
Cycle 3 
… 
Total 
N 
% 
N 
% 
N 
% 
N 
% 
Number of delays 
 
 
 
 
 
 
 
 
Treatment related* 
 
 
 
 
 
 
 
 
 Hematological reason  
 
 
 
 
 
 
 
 
 Non hematological reason 
 
 
 
 
 
 
 
 
Non Treatment related* 
 
 
 
 
 
 
 
 
Programming Notes: * Denominator = Number of cycles susceptible to be delayed. 
 
Listing 12.1.2. 5.  Listing of patient with dose delay. 
Patient ID
Cycle  
Reason of delay
Comments 
Delay (days) 
 
 
 
 
 
 
 
12.1.3 
Dose reduction. 
 
Note: All dose reductions will be considered and described, specifying the reason for 
reduction (hematological toxicity, non hematological toxicity or other causes not due to 
study drug). 
 
Table 12.1.3. 1   Dose reduction. 
 
N 
% 
Number of patients treated 
 
 
Number of patients with dose reduced 
 
 
Number of cycles administered 
 
 
Patients with 
 
 
Nº reductions 
 
 
1 cycle reduction 
 
 
2 cycle reductions 
 
 
 3 cycle reductions 
 
 
Number of cycles with dose reduction 
 
 
Programming Notes: Percentage is based on number of cycle susceptible to be reduced. 


 
 
 
 
 
Table 12.1.3. 2   Dose reduction according to their relationship to study drug. 
 
Treatment related** 
Non – Treatment related 
N 
% 
N 
% 
Patients with 
 
 
 
 
  Nº reductions 
 
 
 
 
  1 reduction 
 
 
 
 
  2 reductions 
 
 
 
 
   3 reductions 
 
 
 
 
Number of cycles with dose reduction*  
 
 
 
 
Programming Notes:* Denominator = Number of cycles susceptible to be reduced. 
 ** Hematological reason / Non-hematological reason. 
 
Table 12.1.3. 3   Dose reduction and reason by cycle. 
 
Cycle 2 
Cycle 3 
… 
Total 
N 
% 
N 
% 
N 
% 
N 
% 
Number of patients 
 
 
 
 
 
 
 
 
Number of delays 
 
 
 
 
 
 
 
 
Treatment related* 
 
 
 
 
 
 
 
 
    Hematological reason  
 
 
 
 
 
 
 
 
    Non hematological reason
 
 
 
 
 
 
 
 
Non Treatment related* 
 
 
 
 
 
 
 
 
Programming Notes:* Denominator = Number of cycles susceptible to be reduced. 
 
Listing 12.1.3. 4   Patient with dose reduction. 
Patient ID 
Cycle Reason of reduction
Comments 
Reduction (%) 
 
 
 
 
 
 
 
12.1.4 
Skipped doses. 
 
Table 12.1.4. 1  Skipped doses. 
 
N 
% 
Number of patients treated with at least 2
infusions 
 
 
Number of patients with any skipped dos
 
 
Number of patients with any skipped dos
(drug related) 
 
 
Number of cycles administered 
 
 
Number of cycles susceptible to have any
omission 
 
 
Number of cycles with at least one skippe
dose (drug related) 
 
 
Day 8 
 
 
Day 15 
Day 8+15 
 
 
 
 
 
 
 
 Treatment related** 
          Non – Treatment related 
 
        N 
  %(of all cycles) 
       N 
%(of all cycles) 
Day 8 
 
 
 
 
Day 15 
 
 
 
 
Day 8+15  
 
 
 
 
 
 


 
 
 
 
Listing 12.1.4.3.  Listing of patients with skipped doses. 
Patient ID 
Cycle/infusion  
(skipped dose)  
     Reason (drug related/other) 
Comments 
 
 
 
 
 
 
 
12.2 Toxicity. 
12.2.1 
Adverse events. 
 
Table 12.2. 1  Drug related adverse events. Worst case per patient. 
Table 12.2. 2  Drug related adverse events occurring in > 10% of all patients. Worst case per patient. 
Table 12.2. 3  All adverse events regardless relationship. Worst case per patient. 
Table 12.2. 4  All adverse events regardless relationship occurring in > 10%  of all patients. Worst case per patient. 
Table 12.2. 5  Drug related adverse events. Worst case per cycle. 
Table 12.2. 6  Drug related adverse events occurring in > 10% of all cycles. Worst case per cycle. 
Table 12.2. 7  All adverse events regardless relationship. Worst case per cycle. 
Table 12.2. 8  All adverse events regardless relationship occurring in > 10% of all cycles. Worst case per cycle. 
 
System Organ Class/ 
Preferred Term 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Total 
 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
System Organ Class 1 
 
 
 
 
 
 
 
 
 
 
             Preferred Term 1
 
 
 
 
 
 
 
 
 
 
                     …….. 
 
 
 
 
 
 
 
 
 
 
System Organ Class 2 
 
 
 
 
 
 
 
 
 
 
             Preferred Term 1
 
 
 
 
 
 
 
 
 
 
                     …….. 
 
 
 
 
 
 
 
 
 
 
* Percentages are based on the safety population. Table shows number of distinct patients with 
events. 
 
 
12.2.2 
Serious toxicity rate. 
 
Table 12.2.2. 1   Serious toxicity rate by group. 
 
Group XX 
N 
% (*) 
Yes 
 
 
No 
 
 
 (*) Based on the first 10 consecutive patients by group.  
 
Listing 12.2.2. 1   Listing  of patients with any serious toxicity rate (grades 3-4)  by group. 
Patient ID 
MedDRA 
preferred term Grade 
Relation with  
the study drug          ………  
Onset date   End Date 
 
 
 
 
 
 
 
12.2.3 
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. 
 
Listing 12.2.3. 1. Listing of SAEs 


 
 
 
 
Patient ID 
MedDRA 
preferred term 
Grade 
Relation with  
the study drug      …. 
 Start date 
  End Date 
 
 
 
 
 
 
 
Listing 12.2.3. 2. Listing of deaths related to study drug. 
Patient ID Cause of 
death 
Death 
date  
Time from last infusion    
(days)       
   Autopsy 
    (Y/N)  
      Autopsy report 
      available (Y/N) 
 
 
 
 
 
 
 
 
12.3 Laboratory evaluation. 
 
12.3.1 
Hematological abnormalities. 
 
Table 12.3.1. 1   Hematology worst grade per patient. 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Total 
  N
% 
N 
% 
N 
% 
N 
% 
N 
% 
Leukopenia 
 
 
 
 
 
 
 
 
 
 
Neutropenia 
 
 
 
 
 
 
 
 
 
 
Anemia 
 
 
 
 
 
 
 
 
 
 
Thrombocytopenia 
 
 
 
 
 
 
 
 
 
 
Lymphopenia 
 
 
 
 
 
 
 
 
 
 
Programming Notes: Percentages are based on the safety population. 
 
Table 12.3.1. 2   Hematology worst grade per cycle. 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Total 
  N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
Leukopenia 
 
 
 
 
 
 
 
 
 
 
Neutropenia 
 
 
 
 
 
 
 
 
 
 
Anemia 
 
 
 
 
 
 
 
 
 
 
Thrombocytopenia 
 
 
 
 
 
 
 
 
 
 
Lymphopenia 
 
 
 
 
 
 
 
 
 
 
Programming Notes: Percentages are based on the safety population. 
 
Table 12.3.1. 3  
Supportive listing: Patients with any hematological abnormalities grade 3-4. 
Patient 
Lab. test 
Cycle Examination dat
N 
Std. value
xLLN 
Grade NCI  
CTCAE v3.0 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Listing 12.3.1. 4  Listing of patients with haematology evaluations missing. 
Patient 
       Cycle 
         Lab. test  
 
 
 
 
 
  
 
 
 
  
 


 
 
 
 
 
Table 12.3.1. 5  Time course and recovery from hematological toxicities. 
 
N 
All cycles 
 
Median 
Range 
Neutrophils 
 
 
 
Day of nadir neutrophils count  
 
 
 
Nadir of neutrophils count (/mm3) 
 
 
 
Day of neutropenia G3-4 onset 
 
 
 
Day of recovery to grade 2 
 
 
 
N° of days with grade 3-4 neutropenia   
 
 
 
Day of recovery to grade  1 
 
 
 
Platelets 
 
 
 
Day of nadir platelets count  
 
 
 
Nadir of platelets count (/mm3) 
 
 
 
Day of thrombopenia G3-4 onset 
 
 
 
Day of recovery to grade 2 
 
 
 
N° of days with grade 3-4 thrombopenia   
 
 
 
Day of recovery to grade  1 
 
 
 
Programming notes: (*)Denominator = N of patients with Grade 3-4 
 
Table 12.3.1. 6  Baseline grade and evolution of hematological toxicities. 
 
Worst grade per patient 
 
Grade 0-
Grade 2 
Grade 3 
Grade 4 
 
N
% 
N 
% 
N 
% 
N 
% 
Anemia (Baseline) 
 
 
 
 
 
 
 
 
Grade 0-1 
 
 
 
 
 
 
 
 
Grade 2 
 
 
 
 
 
 
 
 
Grade 3 
 
 
 
 
 
 
 
 
Grade 4 
 
 
 
 
 
 
 
 
Neutropenia (Baseline) 
 
 
 
 
 
 
 
 
Grade 0-1 
 
 
 
 
 
 
 
 
Grade 2 
 
 
 
 
 
 
 
 
Grade 3 
 
 
 
 
 
 
 
 
Grade 4 
 
 
 
 
 
 
 
 
…… 
 
 
 
 
 
 
 
 
Grade 0-1 
 
 
 
 
 
 
 
 
Grade 2 
 
 
 
 
 
 
 
 
Grade 3 
 
 
 
 
 
 
 
 
Grade 4 
 
 
 
 
 
 
 
 
 
12.3.2 
Biochemistry abnormalities. 
 
Table 12.3.2. 1   Biochemistry worst grade per patient. 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Total 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
AST 
 
 
 
 
 
 
 
 
 
 
ALT 
 
 
 
 
 
 
 
 
 
 
Total Bilirubin 
 
 
 
 
 
 
 
 
 
 
Direct  Bilirubin 
 
 
 
 
 
 
 
 
 
 
…. 
 
 
 
 
 
 
 
 
 
 
Programming Notes: Percentages are based on the safety population. 
 


 
 
 
 
Table 12.3.2. 2   Biochemistry worst grade per cycle. 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Total 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
AST 
 
 
 
 
 
 
 
 
 
 
ALT 
 
 
 
 
 
 
 
 
 
 
Total Bilirubin 
 
 
 
 
 
 
 
 
 
 
Direct  Bilirubin 
 
 
 
 
 
 
 
 
 
 
…. 
 
 
 
 
 
 
 
 
 
 
Programming Notes: Percentages are based on the safety population. 
 
Table 12.3.2. 3   Supportive listing: Patients with any Biochemistry abnormalities grades 3-4. 
Patient ID
Lab. test
Cycle 
Examination 
date 
N 
Std. valu
xLLN 
Grade 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Listing 12.3.2. 4 
Listing of patients with biochemistry evaluations missing. 
Patient 
      Cycle 
      Lab. tes
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 12.3.2. 5  Time course and recovery from biochemistry toxicities. 
 
N 
All cycles 
 
Median 
Range 
ALT 
 
 
 
Day of peak ALT count  
 
 
 
Nadir of ALT count (/mm3) 
 
 
 
Day of ALT G3-4 onset 
 
 
 
Day of recovery to grade 2 
 
 
 
N° of days with grade 3-4 ALT increase 
 
 
 
Day of recovery to grade  1 
 
 
 
AST 
 
 
 
Day of peak AST count  
 
 
 
Nadir of AST count (/mm3) 
 
 
 
Day of AST G3-4 onset 
 
 
 
Day of recovery to grade 2 
 
 
 
N° of days with grade 3-4 AST increase 
 
 
 
Day of recovery to grade  1 
 
 
 
 
 
 
 
Programming notes: (*) Denominator= N of patients with Grade 3-4. 


 
 
 
 
 
Table 12.3.2. 6  Baseline grade and evolution of Biochemical toxicities. 
 
Worst grade per patient 
 
   Grade 0-1 
 Grade 2 
Grade 3 
  Grade 4 
 
N 
% 
N 
% 
N 
% 
N 
% 
ALT (Baseline) 
 
 
 
 
 
 
 
 
Grade 0-1 
 
 
 
 
 
 
 
 
Grade 2 
 
 
 
 
 
 
 
 
Grade 3 
 
 
 
 
 
 
 
 
Grade 4 
 
 
 
 
 
 
 
 
AST (Baseline) 
 
 
 
 
 
 
 
 
Grade 0-1 
 
 
 
 
 
 
 
 
Grade 2 
 
 
 
 
 
 
 
 
Grade 3 
 
 
 
 
 
 
 
 
Grade 4 
 
 
 
 
 
 
 
 
…… 
 
 
 
 
 
 
 
 
Grade 0-1 
 
 
 
 
 
 
 
 
Grade 2 
 
 
 
 
 
 
 
 
Grade 3 
 
 
 
 
 
 
 
 
Grade 4 
 
 
 
 
 
 
 
 
 
12.3.3 
Other metabolic abnormalities. 
 
Table 12.3.3. 7   Metabolic abnormalities worst grade per patient. 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Total 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
Hyperglycemia 
 
 
 
 
 
 
 
 
 
 
…. 
 
 
 
 
 
 
 
 
 
 
* All metabolic parameters susceptible to be graded as per NCI-CTCAE v3.0  
 
Table 12.3.3. 8   Metabolic abnormalities grade per cycle. 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Total 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
Hyperglycemia 
 
 
 
 
 
 
 
 
 
 
…. 
 
 
 
 
 
 
 
 
 
 
* All metabolic parameters susceptible to be graded as per NCI-CTCAE v3.0  
 
Table 12.3.3. 9   Supportive listing: Patients with any metabolic abnormalities grades 3-4. 
Patient ID 
Lab. test 
Cycle 
Examination
date 
N 
Std. value 
xLLN 
Grade 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Listing 12.3.3. 10 Listing of patients with metabolic evaluations missing. 
Patient 
Cycle 
Lab. test  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
12.4 Vital Signs. 
 
Table 12.4. 1  Vital signs. 
Vital Signs 
Baseline 
Cycle 1 
Cycle 2 
… 
Cycle (X) 
PS 
 
 
 
 
 
Weigth (Kg) 
 
 
 
 
 
LVEF (%) 
 
 
 
 
 
 
Table 12.4. 2  Listing of abnormal ECG.  
Patient id              Result 
       
   Specify 
 
 
 
 
 
 
 
 
 
 
12.5 Concomitant medication during treatment. 
 
Table  12.5.1. 1.  Agents of Concomitant therapy started during treatment. 
Concomitant medication (ATC1/ATC4) 
 
 
(ATC level 1)             (ATC level 4) 
N  
% 
… 
 
 
 
 
 
 
Table  12.5.1. 2.  Concomitant medication characteristics during treatment. 
 
Total (N=XX) 
N 
% 
Number of Systems (ATC1) 
 
 
1 
 
 
2 
 
 
3 
 
 
> 3 
 
 
Number of agents (ATC4) 
 
 
1 
 
 
2 
 
 
3 
 
 
> 3 
 
 
Programming Notes: Percentage is based on total patient included. 
 
Table  12.5.1. 3.  Concomitant therapy during treatment. Summary of systems involved (ATC1). 
 
N 
Median  
Min 
Max  
Mean  
SD* 
 
 
 
 
 
 
 
(*) SD stands for standard deviation 
 
Table  12.5.1. 4.  Concomitant therapy during treatment. Summary of agents involved (ATC4). 
 
N 
Median  
Min 
Max  
 Mean  
SD 
 
 
 
 
 
 
 
 
Table  12.5.1. 5.  Listing of Baseline characteristics: Concomitant therapy. 
Patient ID 
Start date  
ATC code          Route           ……
Reason for use 
 
 
 
 
 
 
 


 
 
 
 
 
13 Figures. 
 
NOTE:  Figures will be showed for “all evaluable patients” and “all treated patients” by group 
when applicable. Also in case of patients with STR individual figures for the specific toxicity will 
be shown. 
 
Figure 13. 1. Overall survival. 
 
 
 
Figure 13. 2. Progression-free survival. 
 
 


 
 
 
 
 
Figure 13. 3. Duration of response. 
 
 
Kaplan-Meier curve of duration of response (If any response is observed). 
 
 
Figure 13. 4. CA-125 for responders. 
 


 
 
 
 
 
Figure 13. 5. Waterfall plots. 
 
 
Maximum tumor shrinkage in measurable lesions by RECIST will be displayed. Additional graphs 
by tumour type and RECIST/CA-125 response will also be provided when applicable. 
 
Figure 13. 6. Boxplot of LVEF evolution from BL . 
 
 
Boxplot showing the change by cycle in LVEF from baseline.