Phase I Multicenter, Open-label, Clinical and Pharmacokinetic Study of PM060184 in Combination With Gemcitabine in Selected Patients With Advanced Solid Tumors
Phase: PHASE1
Conditions: Solid Tumors
Sponsor: PharmaMar

 
 
 
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 
 
 
PharmaMar USA, Inc. 
205 East 42nd Street, suite 15003 
New York, NY 10017, USA 
Phone: + 1 646 880 4429 
Fax: +1 646 893 5856 
 
 
 
 
CLINICAL TRIAL PROTOCOL 
 
 
Phase I Multicenter, Open-label, Clinical and Pharmacokinetic Study of PM060184 
in Combination with Gemcitabine in Selected Patients with Advanced Solid Tumors 
 
 
INVESTIGATIONAL MEDICINAL PRODUCTS: PM060184 and Gemcitabine 
Protocol No.: PM60184-A-003-14 
EudraCT No.: 2014-002943-16 
NCT Code: 02533674 
 
 
 
Protocol final version 3.0 including amendment #1 dated 14 August 2015, 
nonsubstantial amendment #1 dated 17 Nov 2016, non-substantial amendment #2 
dated 18 Oct 2017 and substantial amendment #2 dated 8 May 2018. 
 

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SPONSORS
Pharma Mar S.A.,
Avda. de los Reyes, 1
Polígono Industrial “La Mina”
28770 Colmenar Viejo (Madrid) Spain
Phone: + 34 91 846 6000 
Fax:+ 34 91 846 6003
Pharma Mar USA, Inc.
205 East 42nd Street, suite 15003
New York, NY 10017, USA
Phone: + 1 646 880 4429
Fax: +1 646 893 5856
CLINICAL TRIAL PROTOCOL
PM60184-A-003-14
Phase I Multicenter, Open-label, Clinical and Pharmacokinetic Study of 
PM060184 in Combination with Gemcitabine in Selected Patients with  
Advanced Solid Tumors
INVESTIGATIONAL MEDICINAL PRODUCTS: PM060184 and Gemcitabine
Protocol Code: PM60184-A-003-14
EudraCT No: 2014-002943-16
Protocol final version 3.0 including amendment #1 dated 14 August 2015, non-
substantial amendment #1 dated 17 Nov 2016, non-substantial amendment #2 
dated 18 Oct 2017 and substantial amendment #2 dated 8 May 2018.    
This study will be conducted in compliance with the protocol, Good Clinical Practice (GCP) 
and the applicable regulatory requirements.
Confidentiality statement
Information and data included in this protocol contain trade secrets and privileged or 
confidential information which is the property of the Sponsor. No person is authorized to make 
it public without written permission of the Sponsor. These restrictions on disclosure will apply 
equally to all future information supplied to you which is indicated as privileged or confidential. 
This material may be disclosed to and used by your staff and associates as it may be necessary 
to conduct the clinical study.

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STUDY CONTACTS
NAME AND ADDRESS
PHONE, FAX NUMBER, 
AND E-MAIL ADDRESS
Sponsors: 
Pharma Mar S.A. 
Pharma Mar USA, Inc.
Avda. de los Reyes, 1
Polígono Industrial “La Mina”
28770 Colmenar Viejo, Madrid, 
Spain.
205 East 42nd Street, suite 15003.
New York, NY 10017, USA.
Phone:
+ 34 91 846 6000
Fax:
+ 34 91 846 6003
Phone:
  + 1 646 880 4429
Fax:
+ 1 646 893 5856
Responsible Physician
Cinthya Coronado, MD
Clinical Oncology.
Clinical Development. 
Pharma Mar S.A.
Phone:
+ 34 91 846 6135
Fax:
+ 34 91 823 4504
E-mail: 
ccoronado@pharmamar.com
Pharmacovigilance Contact
Mirela Cartoafa.
Pharmacovigilance (PhV).
Clinical Development. 
Pharma Mar S.A.
Phone:   + 34 91 846 6143 
Fax:
+ 34 91 846 6004
E-mail: phv@pharmamar.com
Out of office hours (GMT)
PhV service phone:
+34 681-263-592
Clinical Pharmacology 
Contact
Ignacio González García
Clinical Pharmacology. 
Clinical Development.
Pharma Mar S.A.
Phone:
+34 918 23 46 62
Fax:
+ 34 91 823 4504
E-mail: 
iggarcia@pharmamar.com
Central Laboratory for 
Pharmacokinetic Samples
Nicholas King.
DynaKin, S.L.
Parque Tecnológico de Bizkaia. 
Ed.801-B First floor. 
48160 Derio, Vizcaya, Spain.
Phone:
+34 94 404 5504
Fax:
+34 94 655 9463
E-mail: nking@dynakin.com
Central Laboratory for 
Pharmacogenetic Samples
María Luisa Villahermosa.
GENOMICA S.A.U. (Grupo 
PharmaMar).
Parque 
Empresarial 
Alvento, 
Edificio B.
Vía de los Poblados 1, 1ª planta
28033 Madrid, Spain.
Phone:  +34 91 674 8990
Fax:      +34 91 674 8991
E-mail:  
mlvillahermosa@genomica.com

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

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TABLE OF CONTENTS
STUDY CONTACTS .................................................................................................................................2
SYNOPSIS ..................................................................................................................................................7
SCHEDULE OF ASSESSMENTS AND PROCEDURES....................................................................22
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS..........................................................25
1.
INTRODUCTION ...........................................................................................................................28
1.1
BACKGROUND ..........................................................................................................................28
1.2
INFORMATION ON STUDY DRUGS: PM060184........................................................................28
1.2.1
Name and Chemical Information .......................................................................................28
1.2.2
Non-clinical Data ................................................................................................................29
1.2.3
Clinical Data........................................................................................................................30
1.3
INFORMATION ON STUDY DRUGS: GEMCITABINE ..................................................................31
1.4
INFORMATION ON THE COMBINATION OF PM060184 AND GEMCITABINE............................32
1.5
STUDY RATIONALE...................................................................................................................32
2.
STUDY OBJECTIVES ...................................................................................................................33
2.1
PRIMARY ..................................................................................................................................33
2.2
SECONDARY..............................................................................................................................33
3.
OVERALL STUDY DESIGN.........................................................................................................33
3.1
PRIMARY ENDPOINT ................................................................................................................34
3.1.1
Determination of the Maximum Tolerated Dose and the Recommended Dose.................34
3.1.2
Definition of Dose-limiting Toxicities.................................................................................34
3.2
SECONDARY ENDPOINTS..........................................................................................................35
3.2.1
Safety....................................................................................................................................35
3.2.2
Pharmacokinetics ................................................................................................................35
3.2.3
Efficacy ................................................................................................................................35
3.2.4
Pharmacogenetics................................................................................................................35
3.3
DOSE ESCALATION SCHEME....................................................................................................36
3.3.1
Dose Escalation Meetings ...................................................................................................37
4.
SELECTION OF PATIENTS.........................................................................................................38
4.1
INCLUSION CRITERIA...............................................................................................................38
4.2
EXCLUSION CRITERIA..............................................................................................................39
4.3
PATIENTS FOR THE PHARMACOGENETIC EVALUATIONS .......................................................40
5.
PLAN OF THE STUDY..................................................................................................................40
5.1
PLANNED TRIAL PERIODS (FOR THE WHOLE STUDY) ............................................................40
5.2
PLANNED TRIAL PERIODS (INDIVIDUALLY PER PATIENT)......................................................41
5.2.1
Discontinuations..................................................................................................................42
5.2.1.1
End of Treatment........................................................................................................................ 42
5.2.1.2
Reasons for End of Treatment.................................................................................................... 42
5.2.1.3
Study Discontinuation................................................................................................................ 42
5.2.2
Protocol Deviations..............................................................................................................42
5.3
REPLACEMENT OF PATIENTS...................................................................................................43
5.4
PRE-TREATMENT ASSESSMENTS..............................................................................................43
5.5
PATIENT REGISTRATION..........................................................................................................45
5.6
PATIENT RANDOMIZATION......................................................................................................45
5.7
EVALUATIONS DURING TREATMENT.......................................................................................45
5.8
EVALUATIONS AT END OF TREATMENT ..................................................................................47
5.9
FOLLOW-UP AFTER END-OF-TREATMENT VISIT....................................................................48
6.
PHARMACOKINETICS................................................................................................................49
7.
PHARMACOGENETIC EVALUATIONS...................................................................................50
8.
TREATMENT .................................................................................................................................51

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8.1
DESCRIPTION OF TREATMENT.................................................................................................51
8.1.1
Drug Formulation and Supply............................................................................................51
8.1.1.1
Gemcitabine ............................................................................................................................... 51
8.1.1.2
PM060184.................................................................................................................................. 51
8.2
ADMINISTRATION OF THE STUDY MEDICATION .....................................................................51
8.3
CRITERIA FOR TREATMENT CONTINUATION..........................................................................52
8.4
DOSE REDUCTION ....................................................................................................................53
8.5
CONCOMITANT MEDICATION..................................................................................................53
8.5.1
Prophylactic Medication......................................................................................................53
8.5.2
Allowed Medications/Therapies ..........................................................................................53
8.5.3
Prohibited Medications/Therapies ......................................................................................54
8.5.4
Drug-drug Interactions .......................................................................................................54
8.5.5
Drug Accountability.............................................................................................................54
8.6
TREATMENT COMPLIANCE......................................................................................................54
9.
STUDY EVALUATIONS ...............................................................................................................55
9.1
DETERMINATION OF THE MTD AND THE RD .........................................................................55
9.2
SAFETY .....................................................................................................................................55
9.3
ADVERSE EVENTS DEFINITIONS ..............................................................................................55
9.3.1
Adverse Event (AE)..............................................................................................................55
9.3.2
Serious Adverse Event (SAE)..............................................................................................55
9.3.3
Death....................................................................................................................................56
9.3.4
Life-threatening Event.........................................................................................................56
9.3.5
Hospitalization or Prolongation of Hospitalization............................................................56
9.3.6
Unlisted/Unexpected Adverse Event ...................................................................................56
9.3.7
Adverse Reactions................................................................................................................56
9.3.8
Adverse Events Related to the Study Drugs........................................................................57
9.3.9
Expedited Reporting ............................................................................................................57
9.3.10
Assessment of Causal Relationship to the Study Drugs.................................................57
9.4
ADVERSE EVENTS REPORTING PROCEDURES.........................................................................57
9.4.1
Reporting Adverse Events....................................................................................................57
9.4.2
Reporting Serious Adverse Events ......................................................................................58
9.4.3
Reporting Pregnancy Cases Occurred within the Clinical Trial........................................58
9.5
ADVERSE EVENTS MONITORING .............................................................................................59
9.6
EFFICACY .................................................................................................................................60
9.6.1
Progression-free Survival....................................................................................................60
9.6.2
Overall Survival ...................................................................................................................61
9.7
EVALUATION OF PHARMACOKINETICS...................................................................................61
9.8
EVALUATION OF PHARMACOGENETICS ..................................................................................61
10.
STATISTICAL METHODS.......................................................................................................61
10.1
SAMPLE SIZE ............................................................................................................................61
10.2
STATISTICAL ANALYSIS...........................................................................................................61
10.2.1
Safety ...............................................................................................................................61
10.2.2
Efficacy............................................................................................................................61
10.2.3
Pharmacokinetics............................................................................................................62
10.2.4
Pharmacogenetics ...........................................................................................................62
10.3
INTERIM ANALYSIS ..................................................................................................................62
11.
ADMINISTRATIVE SECTION................................................................................................62
11.1
ETHICS......................................................................................................................................62
11.2
MONITORING, AUDITING AND INSPECTING .............................................................................63
11.3
PATIENT INFORMED CONSENT ................................................................................................63
11.4
CONFIDENTIALITY/ PATIENTS IDENTIFICATION.....................................................................64
11.5
CASE REPORT FORMS..............................................................................................................64
11.6
INSURANCE ...............................................................................................................................64
11.7
RETENTION OF RECORDS.........................................................................................................64
11.8
USE OF INFORMATION AND PUBLICATION ..............................................................................65

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12.
REFERENCES............................................................................................................................65
13.
APPENDICES .............................................................................................................................68
APPENDIX 1: ECOG PERFORMANCE STATUS ASSESSMENT SCALE .......................................68
APPENDIX 2: COCKCROFT AND GAULT’S FORMULA.................................................................69
APPENDIX 3: PERCENTAGE OF ACTIVE BONE MARROW AT RISK DUE TO 
RADIOTHERAPY IN VARIOUS SKELETAL SITES..........................................................................70
APPENDIX 4: EVALUATION OF RESPONSE. THE RECIST V.1.1..................................................71
APPENDIX 5: CHOI RESPONSE EVALUATION CRITERIA AND EORTC METABOLIC 
RESPONSE CRITERIA FOR SOLID TUMORS...................................................................................80
APPENDIX 6: CYP1, CYP2 AND CYP3 INHIBITORS, INDUCERS AND SUBSTRATES...............82
APPENDIX 7: GCIG SPECIFIC CRITERIA.........................................................................................85
APPENDIX 8: DECLARATION OF HELSINKI...................................................................................86

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SYNOPSIS
TITLE
Phase 
I 
Multicenter, 
Open-label, 
Clinical 
and 
Pharmacokinetic Study of PM060184 in Combination with 
Gemcitabine in Selected Patients with Advanced Solid 
Tumors.
PROTOCOL CODE
PM60184-A-003-14
INVESTIGATORS
A full list of investigators will be available as a separate 
document.
NUMBER OF SITES/ 
TRIAL LOCATION
Three sites are expected to participate in this study: two in 
Spain and one in the U.S.
STUDY OBJECTIVES 
Primary:

To determine the maximum tolerated dose (MTD) and the 
recommended dose (RD) of PM060184 in combination 
with gemcitabine in selected patients with advanced solid 
tumors. 
Secondary:

To characterize the safety profile and feasibility of this 
combination in this study population.

To characterize the pharmacokinetics (PK) of this 
combination and to detect major drug-drug PK 
interactions.

To obtain preliminary information on the clinical 
antitumor activity of this combination.
STUDY DESIGN
Prospective, open-label, dose-ranging, uncontrolled phase I 
study with escalating doses of PM060184 in combination with 
gemcitabine in selected patients with advanced solid tumors.
Following a classical 3+3 design, successive cohorts of 
patients will receive escalating doses of intravenous (i.v.) 
gemcitabine over 30 minutes
(min), followed by i.v. 
PM060184 over 10 min on Day 1 and Day 8 every three 
weeks (q3wk), until the RD is reached. All evaluable patients 
within a dose level (DL) must be followed for at least one full 
cycle (i.e., three weeks) before dose escalation may proceed 
to the next DL.
The MTD will be the lowest DL explored during dose 
escalation at which more than one third of evaluable patients
experienced a DLT during Cycle 1. The RD will be the 
highest DL explored at which less than one third of evaluable 
patients experienced a DLT during Cycle 1. Dose escalation 
will cease immediately once the MTD is reached. 
Intermediate DLs can be tested, if deemed appropriate upon 
the Sponsor’s and Investigators’ agreement.
At least nine evaluable patients will be treated in an expansion 

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cohort at the RD in order to confirm its tolerability and 
feasibility. Once the RD is confirmed, exploratory cohorts of 
at least 12 patients each will be expanded at RD in selected
tumor type(s) and/or target subpopulations, chosen according 
to the preliminary efficacy observed among patients treated 
during dose escalation, discussed and agreed between the 
Investigators and the Sponsor, as appropriate. 
STUDY POPULATION
Inclusion criteria
1)
Voluntarily signed and dated written informed consent 
prior to any specific study procedure.
2)
Age ≥18 years.
3)
Eastern 
Cooperative 
Oncology 
Group 
(ECOG) 
performance status (PS) of ≤ 1.
4)
Life expectancy ≥3 months.
5)
Patients with a histologically/cytologically confirmed 
diagnosis of advanced disease of any of the following 
tumors that progressed to standard therapy or for whom 
no standard therapy exists (with the exception of 
neuroendocrine, carcinoid, small cell and sarcoma 
histology subtypes, which are not allowed):
a) Breast cancer non-candidate for hormone therapy 
alone.
b) Epithelial
ovarian 
cancer 
(including 
primary 
peritoneal disease and/or fallopian tube carcinomas 
and/or endometrial adenocarcinomas).
c) Locally advanced or metastatic head and neck cancer.
d) Non-small cell lung cancer (NSCLC).
e) Germ cell tumors (GCTs).
f) Biliary tract adenocarcinoma.
g) Adenocarcinoma or carcinoma of unknown primary 
site (UKPS).
h) Cervix carcinoma. 
i)
Gastrointestinal stromal tumor (GIST).
j)
Urothelial cancer. 
6)
Expansion cohort at the RD and tumor-specific 
cohorts:
All patients must have:
a) Measurable disease according to Response Evaluation 
Criteria In Solid Tumors (RECIST) v.1.1 [or Choi 
criteria and/or European Organization for Research 
and Treatment of Cancer (EORTC) metabolic 
response criteria for solid tumors, in the case of 
GIST];  or 
b) Evaluable disease by serum markers in the case of 
ovarian cancer [Gynecologic Cancer Intergroup 
(GCIG) specific criteria]; and
c) Documented
disease 
progression 
during 
or 
immediately after last therapy according to any of the 
aforementioned criteria.

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7)
Wash-out periods: at least three weeks since the last 
administration of an anticancer therapy, including 
radiation therapy (RT) or 
a biological/investigational 
therapy [excluding monoclonal antibodies (MAbs)]; at 
least four weeks since the last MAb-containing therapy;
and at least six weeks since nitrosoureas and mitomycin 
C (systemic). In the case of hormone-sensitive breast 
cancer progressing while on hormone therapy, the latter 
must be either stopped up to one week before or 
continued without changes during the trial.
8)
Adequate bone marrow, renal, hepatic, and metabolic 
function (assessed ≤ 7 days before inclusion in the study):
a) Platelet count ≥ 100 x 109/l, hemoglobin ≥ 9.0 g/dl 
and absolute neutrophil count (ANC) ≥ 1.0 x 109/l.
b) Aspartate 
aminotransferase 
(AST) 
and 
alanine 
aminotransferase (ALT) ≤ 3.0 x upper limit of normal 
(ULN), independently of the presence of liver 
metastases.
c) Alkaline phosphatase (AP) ≤ 2.5 x ULN (≤ 5 x ULN 
if disease-related).
d) Total bilirubin ≤ 1.5 x ULN.
e) International Normalized Ratio (INR) < 1.5 (except if 
patient is on oral anticoagulation therapy).
f) Calculated creatinine clearance (CrCl) ≥ 50 ml/min 
(using Cockcroft and Gault’s formula).
g) Albumin ≥ 2.5 g/dl.
9)
Recovery to grade ≤ 1 from any adverse event (AE) 
derived from previous treatment (excluding alopecia 
and/or cutaneous toxicity and/or asthenia).
10) Left 
ventricular 
ejection 
fraction 
(LVEF) 
by 
echocardiography (ECHO) or multiple-gated acquisition 
(MUGA) within normal range (according to institutional 
standards).
11) Women of childbearing potential must have a negative 
serum or urine pregnancy test before study entry. Both 
women and men must agree to use a medially acceptable 
method of contraception throughout the treatment period 
and for six months after discontinuation of treatment. 
Acceptable methods of contraception include intrauterine 
device (IUD), oral contraceptive, subdermal implant 
and/or double barrier.
Exclusion criteria
1)
Concomitant diseases/conditions:
a) History or presence of unstable angina, myocardial 
infarction, congestive heart failure, or clinically 
significant valvular heart disease within last year.
b) Symptomatic 
arrhythmia 
or 
any 
uncontrolled 
arrhythmia requiring ongoing treatment.
c) Known chronic active hepatitis or cirrhosis.
d) Active 
uncontrolled 
infection
[i.e., 
antibiotic, 

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antifungal or antiviral intervention indicated or 
surgical procedure (i.e., pleural or deep abscess 
drainage) conducted within 15 days prior to 
inclusion].
e) Known 
human 
immunodeficiency 
virus 
(HIV) 
infection.
f) Current or prior history of grade ≥ 2 peripheral 
sensory and/or motor neuropathy.
g) Prior treatment with oxaliplatin.
h) Limitation of the patient’s ability to comply with the 
treatment or follow-up protocol.
i)
Any other major illness that, in the Investigator’s 
judgment, will substantially increase the risk 
associated with the patient’s participation in this 
study.
2)
Symptomatic, progressive or corticosteroids-requiring 
documented brain metastases or leptomeningeal disease 
involvement. 
3)
Men or women of childbearing potential who are not 
using an effective method of contraception as previously 
described; women who are pregnant or breast feeding.
4)
Patients who have had RT in more than 35% of the bone 
marrow.
5)
Prior treatment with PM060184.
6)
Prior treatment with gemcitabine-containing therapy for 
advanced disease (adjuvant therapy is allowed, provided 
not more than six cycles were administered and relapse 
occurred more than six months after the last drug 
administration), and/or:
a) Patients 
who 
have 
previously 
discontinued 
gemcitabine-containing regimens due to gemcitabine-
related toxicity.
7)
Known hypersensitivity to gemcitabine or any component 
of the formulation.
EXPECTED NUMBER 
OF PATIENTS
The number of patients may vary depending both on the 
tolerability of PM060184 combined with gemcitabine and the 
number of dose levels required to identify the MTD. 
Approximately between six and 72 evaluable patients are 
planned to be included in this study.
STUDY DRUGS 
FORMULATION
Gemcitabine:
Commercially available presentations of vials containing 
gemcitabine will be provided as appropriate. Gemcitabine will 
be prepared in accordance with the applicable Summary of 
Product Characteristics
(SmPC). Medication preparation 
records will be kept by the site.
PM060184:
The drug substance PM060184-CD is a mixture of PM060184 

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and 2-hydroxypropyl-β-cyclodextrin.
PM060184 drug product (DP) is provided as a sterile 
lyophilized powder for concentrate for solution for infusion 
with a strength of 15 mg of the active moiety PM060184.
Before use, the vials should be reconstituted with 6 ml of 
water for injection to give a solution containing 2.5 mg/ml of 
PM060184. PM060184 15-mg DP was developed for 
administration by the i.v. route. Prior to administration, the 
reconstituted vials should be further diluted with dextrose 5% 
solution for infusion. Each 15-mg vial of PM060184 is a 
single-use vial. PM060184 reconstitution/dilution records will 
be kept by the site.
The full composition of the reconstituted solution per ml is as 
follows:
Component
Concentratio
n (per ml)
Function
PM060184
2.5 mg/ml
Active moiety
2-Hydroxypropyl-β 
cyclodextrin (DS 4-
5)*
200 mg/ml
Solubilizing 
agent
Water for injection
1 ml
Solvent
* DS = Degree of substitution.
TREATMENT 
SCHEDULE
Gemcitabine will be administered as a 30-min i.v. infusion, 
followed by PM060184 as a 10-min i.v. infusion, both on Day 
1 and Day 8 q3wk.
ADMINISTRATION 
ROUTE AND 
STARTING DOSE
Patients will consecutively receive the following on Day 1 
and Day 8 q3wk (three weeks = one treatment cycle):

Gemcitabine: i.v. infusion over 30 min (± 10 min) at a 
starting dose of 800 mg/m2 via a central or peripheral 
venous catheter through a pump device, followed by:

PM060184: i.v. infusion over 10 min (± 3 min) at a 
starting dose of 6.0 mg/m2 via a central or peripheral 
venous catheter through a pump device.
During PK sampling, PM060184 infusion should start no more 
than 5 min after end of gemcitabine administration.
PROPHYLACTIC 
MEDICATION
Primary antiemetic prophylaxis is compulsory prior to all 
PM060184 infusions. Standard treatment [according to the 
American Society of Clinical Oncology (ASCO) guidelines] 
will be administered: 

5-HT3 antagonists (ondansetron 8 mg i.v. or equivalent).

Steroids (dexamethasone 8 mg i.v. or equivalent).
If necessary, addition of metoclopramide or extension of 
treatment with 5-HT3 antagonists and/or dexamethasone could 
be considered (according to the Investigator’s own criteria).

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ALLOWED 
MEDICATIONS/ 
THERAPIES

Therapies 
for 
pre-existing 
and 
treatment-emergent 
medical conditions, including pain management.

Blood products and transfusions, as clinically indicated.

Bisphosphonates.

In case of nausea or vomiting, secondary prophylaxis
and/or symptomatic treatment for emesis according to 
ASCO guidelines.

Erythropoietin use according to ASCO guidelines.

Hormone-responsive breast cancer patients [i.e., those 
whose tumors express estrogen receptor (ER) and/or 
progesterone receptor (PrR)] may continue receiving their 
same prior hormonal therapy without interruption 
throughout their study participation.

Treatment with granulocyte colony-stimulating factor (G-
CSF) in the event of grade 4 neutropenia lasting > 3 days, 
neutropenic sepsis or febrile neutropenia according to 
ASCO guidelines. Secondary prophylaxis could be 
considered after Cycle 1, if it is in the best interest of the 
patient.

Luteinizing 
hormone-releasing 
hormone 
(LHRH) 
agonists, in women of reproductive age.

Megestrol acetate for appetite stimulation.
PROHIBITED 
MEDICATIONS/ 
THERAPIES

Concomitant administration of any other antineoplastic 
therapy is prohibited, other than the aforementioned 
hormonal therapy for breast cancer. 

Patients who require RT within three weeks after the first 
infusion may remain on the study after being discussed 
and agreed between the Investigator and the Sponsor, but 
will not be evaluable for the analysis of the primary 
endpoint (DLT) and consequently need to be replaced.

Primary prophylaxis with G-CSF in Cycle 1. 

Other investigational agents.

Concomitant RT while on gemcitabine treatment.

Immunosuppressive therapies other than corticosteroids.
EVALUABILITY OF 
PATIENTS
An evaluable patient for the main objective of the study (i.e., 
determination of the MTD and RD) should have received at 
least one complete cycle (including the observation period). 
Patients who are discontinued early or miss/delay doses 
and/or assessments will be evaluable if these events are the 
consequence 
of 
treatment-related 
toxicity
(excluding
hypersensitivity reactions and/or extravasations).
EVALUATION 
CRITERIA
Primary endpoint

Determination of MTD and RD.
o
The MTD will be the lowest DL explored during 
dose escalation at which more than one third of 
evaluable patients experienced a DLT during Cycle 
1. 
o
The RD will be the highest DL explored at which 
less than one third of evaluable patients experienced 

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Protocol PM60184-A-003-14
a DLT during Cycle 1.
Dose-limiting toxicities
DLTs are defined as AEs and laboratory abnormalities related 
to the study treatment that occurred during Cycle 1 and 
fulfilled at least one of the following criteria:

Grade 4 neutropenia (ANC < 0.5 x 109/l) lasting > 3 days.

Grade ≥ 3 febrile neutropenia of any duration or 
neutropenic sepsis.

Grade 4 thrombocytopenia (platelet count < 25 x 109/l) or 
grade 3 with any major bleeding episode requiring a 
platelet transfusion.

Grade 4 ALT and/or AST increase, or grade 3 lasting > 7 
days.

Treatment-related grade ≥ 2 ALT or AST increase 
concomitantly with ≥ 2 x ULN total bilirubin increase and 
normal AP. 

Any other grade 3/4 non-hematological AE that is 
suspected to be related to study drug(s), except 
nausea/vomiting (unless the patient is receiving an 
optimal anti-emetic regimen), hypersensitivity reactions, 
extravasations, grade 3 asthenia lasting less than one 
week, anorexia, and non-clinically relevant isolated 
biochemical abnormalities [e.g., isolated increase in 
gamma-glutamyltransferase (GGT)]. In any case, the 
clinical relevance should be discussed between the 
Investigators and the Sponsor’s representatives.

Delay in the administration of Cycle 2 of the combination 
exceeding seven (+1) days of the treatment due date (i.e., 
Day 22), due to any AEs related to study drug(s).

The following circumstances will be discussed between 
the Principal Investigator and the Sponsor, and the final 
consensus will be documented:
o
DLTs with delayed onset (i.e., that occur after Cycle 
1).
o
Non-compliance with the intended dose intensity 
(DI) in more than half of patients at any dose level 
(i.e., missing infusions on Day 8 or frequent dose 
delays due to treatment-related toxicity despite not 
conforming to a formal DLT definition).
Secondary endpoints

Safety: patients will be evaluable for safety if they have 
received at least one partial or complete infusion of 
PM060184 and one partial or complete infusion of 
gemcitabine. AEs will be graded according to the 
National Cancer Institute Common Terminology Criteria 
for Adverse Events (NCI-CTCAE) v.4. 

Pharmacokinetics: PK analyses will be evaluated in 
plasma by standard non-compartmental analysis (NCA) 
(compartmental 
modeling 
may 
be 
performed 
if 
appropriate).

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Protocol PM60184-A-003-14

Efficacy: although it is not the main objective of this 
study, antitumor activity will be evaluated according to 
RECIST v.1.1 in all patients with measurable disease, 
according to Choi criteria and/or EORTC metabolic 
response criteria for solid tumors, in GIST patients, or by 
evaluation of serum tumor markers if applicable (e.g., 
ovarian cancer), every two cycles (i.e., approximately 
every six weeks) ± one week after treatment initiation 
until Cycle 4. Patients continuing treatment after Cycle 4
will have the assessments performed every three cycles 
(i.e., approximately every nine weeks) ± one week from 
Cycle 4 while on treatment, unless otherwise is clinically 
indicated. Patients included in the expansion cohort at the 
RD and in the tumor-specific cohorts must be evaluable as 
per RECIST v.1.1 (or Choi criteria and/or EORTC 
metabolic response criteria for solid tumors, in GIST 
patients) or by tumor markers.

Pharmacogenetics: a blood sample will be collected to 
evaluate 
the 
presence 
or 
absence 
of 
known 
polymorphisms that may explain individual variability in 
main PK parameters.
REPLACEMENT OF 
PATIENTS
Patients must be replaced if they are not evaluable for the 
assessment of the primary endpoint, i.e. if:

They are withdrawn from the study before receiving at 
least one evaluable cycle for any reason other than 
treatment-related toxicity (excluding hypersensitivity 
and/or extravasations reactions). An evaluable cycle is 
defined as: gemcitabine followed by PM060184 on Day 1 
and Day 8, with the corresponding 2-week observation 
period during the first cycle. 

They require RT or other therapeutic procedure within 
three weeks after the first study drug dose, unless they 
previously had another treatment-related AE included in 
the definition of DLT.

There is a protocol violation resulting in an impossibility 
of concluding anything regarding the safety of the study 
therapy.
All replaced patients will be included in the general safety 
analysis and in the efficacy analysis (if appropriate).
DOSE ESCALATION 
SCHEDULE
The starting dose (DL1) for gemcitabine will be 800 mg/m2. 
This corresponds to a
dose intensity (DI) of 533.33 
mg/m2/week, and is equivalent to 80% of the RD with this 
schedule. This is the minimal gemcitabine dose accepted in 
clinical practice. 
The DL1 for PM060184 will be 6.0 mg/m2. This corresponds 
to a DI of 4.0 mg/m2/week, and is equivalent to 64% of the 
RD determined for PM060184 given as single agent with this 
schedule.

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The dose escalation scheme will follow pre-defined dose 
levels, starting at DL1, as summarized in the following table:
DL
No. of
patient
s
Relative DI 
(%) of
gemcitabine 
/ PM060184
Gemcitabine dose 
(mg/m2) 
on Day 1 and Day 
8  q3wk
PM060184 dose 
(mg/m2) 
on Day 1 and Day 8  
q3wk
DL-1
0-6
80/53
800 
5.0
DL1
3-6
80/64
800 
6.0
DL2
3-6
80/74
800 
7.0
DL3
3-6
100/74
1000
7.0
DL4
and 
beyon
d
3-6
No further dose 
increases beyond 
1000 mg/m2
Further dose 
increases of 0.5 or 
1.0 mg/m2, 
according to 
observed toxicities 
DI, dose intensity; DL, dose level; MTD, maximum tolerated dose.

Cohorts of at least three fully evaluable patients will be 
treated at each cohort.

The second and third patients of a cohort may be included 
simultaneously after the first patient has completed the 
first cycle, except if a DLT is reported in the first patient, 
in which case the third patient of the cohort will be 
included once the second patient has received a complete 
treatment cycle with no reported DLTs. All patients will 
have to be fully evaluable (3-week period) prior to any 
further dose escalation. Patients not fully evaluable will 
be replaced.

Dose escalation will continue if no DLT is observed.

Subsequent dose levels will enroll three patients, and up 
to six fully evaluable patients if one DLT is observed in 
any of the first three fully evaluable patients. 

Once a DLT is observed, further patients will be included 
up to six fully evaluable patients in this dose cohort.
No. of  patients 
evaluable for 
DLT
No. of patients with DLTs 
in Cycle 1
Action
3
0
Escalate DL
1
Add 3 patients
>1
MTD
6
1
Escalate DL
>1
MTD
DL, dose level; DLT, dose-limiting toxicities; MTD, maximum 
tolerated dose.

For gemcitabine: two doses (800 mg/m2 and 1000 
mg/m2) will be initially tested. If the toxicity observed 
during dose escalation is clearly related to gemcitabine 
(i.e. neutropenia and/or thrombocytopenia), intermediate 
gemcitabine doses might be tested after agreement 
between the Investigators and the Sponsor. 

For PM060184: pre-established PM060184 doses have 
been set for the first three DLs. After DL3, dose 
increments of 1.0 mg/m2 will be tested if toxicity at each 
previous DL is acceptable. These dose increments may be 

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Protocol PM60184-A-003-14
of 0.5 mg/m2, according to the toxicity observed. In the 
event of toxicities specifically related with PM060184 
(i.e. peripheral neuropathy, post-infusion abdominal pain 
and/or diarrhea), intermediate PM060184 doses might be 
tested after agreement between the Investigators and the 
Sponsor.
Both the PM060184 and the gemcitabine doses may be 
rounded to the first decimal.
If more than one of three or six evaluable patients at any DL 
experience a DLT during Cycle 1, dose escalation will be 
terminated. The MTD will be the lowest level at which more 
than one third of evaluable patients experienced a DLT in 
Cycle 1. The RD will be the highest DL explored with less 
than one third of evaluable patients experiencing a DLT 
during Cycle 1. 
If two or more evaluable patients (of 3-6 patients) at any DL 
experience a dose delay > 7 (+1) days from the theoretical due 
date (conforming or not to DLT criteria) and/or dose 
omissions exclusively related to PM060184 toxicity during 
Cycle 1, the cohort should be expanded as shown in the table 
below. If more than 50% of evaluable patients in a cohort 
experience dose delays and/or omissions, dose escalation will 
be terminated and this DL will be considered the MTD. An 
alternative schedule could then be explored after discussion 
between the Investigators and with the Sponsor’s agreement. 
The starting dose of the new schedule will be the DL 
immediately below the MTD.
Dose delays  
Dose omissions 
Action
1
-
None
-
1
None
1
1
Add 3 more patients 
≥ 2
-
Add 3 more patients
-
≥ 2
Add 3 more patients
If more than 50% evaluable patients in a cohort 
have dose delays and/or omissions  
MTD
DLT, dose-limiting toxicities; MTD, maximum tolerated dose.
An expansion cohort of a minimum of nine evaluable patients 
will be treated at the RD once it has been determined; this is 
to confirm its feasibility and tolerability. Once the RD is 
confirmed, exploratory cohorts of at least 12 patients each 
will be expanded at RD in selected tumor type(s) and/or target 
subpopulations, chosen according to the preliminary efficacy 
observed among those previously treated during dose 
escalation, discussed and agreed between the Investigators 
and the Sponsor.
Intra-patient dose escalation will not be allowed under any 
circumstances.

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CRITERIA FOR 
TREATMENT 
CONTINUATION
Patients will be treated with additional cycles of PM060184 
combined with gemcitabine as long as no unacceptable 
toxicity and/or progression of the disease and/or withdrawal 
of consent occurs.
The administration of a new cycle should be delayed if the 
criteria in the table below are not met on the corresponding 
Day 1. Parameters will be reevaluated at minimum intervals 
of 48 hours. The new cycle will be started upon recovery of 
these parameters. A maximum delay of 7 (+1) days from 
theoretical due date will be allowed for recovery from 
treatment-related adverse events. If recovery has not occurred 
after that period, the patient should discontinue the treatment, 
except in case of obvious patient benefit at the criteria of the 
Investigator and upon agreement with the Sponsor.
If the re-treatment criteria are not met on Day 8 (±1 day), 
administration of the corresponding drugs should be omitted 
instead of delayed. 
After skipping and/or delaying doses due to treatment-related 
toxicity (except for neutropenia exclusively), or in patients 
who experience a DLT, treatment may only continue after 
appropriate dose reduction. 
Day 1 
Day 8
ANC
1.0 x 109/l
1.0 x 109/l
Platelets
100 x 109/l
75 x 109/l
Hemoglobin
9 g/dl
8 g/dl
Total bilirubin
1.5 x ULN
AST/ALT
Grade 1
Grade ≤ 2
Calculated CrCl (Cockcroft and 
Gault’s formula)
≥ 50 ml/min
30 ml/min
Peripheral sensory / motor 
neuropathy 
Grade ≤ 1
Grade ≤ 2
Other non-hematological drug-
related AEs (except increased GGT, 
alopecia, nausea, anorexia, and/or 
asthenia) a
Grade ≤ 1
Grade ≤ 2
If a patient does not meet the requirements for treatment continuation on Day 
1 of further cycles, the corresponding drug (PM060184 and gemcitabine) 
infusion will be withheld until recovery for a maximum of 7 days after the 
theoretical treatment date. If recovery has not occurred after a delay of > 7 
(+1) days, the patient must be withdrawn from the trial, except in case of 
perceived clinical benefit from the Investigator and upon agreement with the 
Sponsor.
If the above criteria are not met on Day 8 of any cycle, the scheduled infusion 
will be omitted instead of delayed.  
a
Any grade accepted for increased GGT. Up to grade 2 for alopecia, 
nausea, anorexia, and asthenia. Non-symptomatic grade 2-4 metabolic 
abnormalities (e.g.  sodium, magnesium, potassium, calcium) will be 
allowed for treatment continuation.
AE, adverse event; ALT, alanine aminotransferase; ANC, absolute neutrophil 
count; AP: alkaline phosphatase; AST, aspartate aminotransferase; CrCl,
creatinine clearance; GGT, gamma-glutamyltransferase; ULN, upper limit of 
normal.

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DOSE REDUCTION
Treatment after DLT, treatment-related dose delay for > 7 
days from theoretical due date and/or toxicity considered as 
unacceptable by the investigators may continue, after 
appropriate dose reduction, only if there is clear evidence of 
objective patient benefit. This will always be discussed with 
the Sponsor. Under this circumstance, and following recovery 
to pre-specified re-treatment criteria, patients will be re-
treated at the immediately lowest DL. If dose reduction 
beyond DL-1 is required, the PM060184 dose may be reduced 
by an additional 1.0 mg/m2. 
Up to two individual dose reductions will be allowed per 
patient; any patients requiring more than two dose reductions 
will be withdrawn from the study. Once dose has been 
reduced for an individual patient, it will not be re-escalated 
again under any circumstances. 
No individual dose reductions will be allowed during Cycle 1.
Patients requiring dose reduction exclusively due to febrile 
neutropenia or grade 4 neutropenia during the preceding cycle 
may receive secondary prophylaxis with G-CSF instead of a 
dose reduction. If toxicity re-occurs despite G-CSF use, dose 
reduction will then be implemented.
Patients who require limited field RT for pain palliation after
Cycle 1 may continue treatment with PM060184 alone and 
without any dose adjustments if patient benefit is perceived; 
these patients do not need to be replaced. Gemcitabine re-
introduction may be considered in patients without 
progressing disease at least four weeks after the end of RT.
DRUG-DRUG 
INTERACTIONS
In vitro studies using human liver microsomes have pointed to 
CYP2C19 and CYP3A4 as the predominant cytochrome 
(CYP) enzymes responsible for the hepatic metabolism of 
PM060184. Therefore, concomitant drugs which induce or 
inhibit any of these cytochromes in a significant extent should 
be avoided whenever possible.
PHARMACOKINETICS
The plasma PK of PM060184, gemcitabine and gemcitabine 
2,2 -difluorodeoxyuridine (dFdU) will be evaluated during 
Days 1 and 2 of Cycle 1 with a schedule of ten samples in all 
patients (see Table below). Additionally, patients treated in 
the expanded cohort at RD and in the tumor-specific cohorts 
will be sampled for PM060184 analysis on Days 1 and 2 of 
Cycle 2 at the same time points.
The sampling schedule for both compounds will be as 
follows, taking as reference the gemcitabine infusion on Day 
1.

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Pharmacokinetic parameters will be calculated using NCA 
and population methods, after pooling data from this study 
with data obtained during other studies.
Sample
number
Day
Time 
relative to 
gemcitabine 
infusion (h)
Sampling times 
for gemcitabine 
and dFdU
Sampling times 
for PM060184
Sampling 
Windows
#1
1
0
Pre-dose
Pre-dose
-
#2
1
0.5
Just before EOI
--
- 2 min
#3
1
0.67
10 min EOI
Just before EOI
- 2 min
#4
1
0.92
25 min EOI
15 min EOI
± 5 min
#5
1
1.17
40 min EOI
30 min EOI
± 5 min
#6
1
1.67
1 h 10 min EOI
1 h EOI
± 10 min
#7
1
2.67
2 h 10 min EOI
2 h EOI
± 10 min
#8
1
3.67
3 h 10 min EOI
3h EOI
± 10 min
#9
1
5.67
5 h 10 min EOI
5 h EOI
± 30 min
#10
2
24 *
24 h EOI
24 h EOI
± 2 h
dFdU, 2,2-difluorodeoxyuridine; EOI, end of infusion; h, hours; min, 
minutes.
PHARMACOGENETIC
EVALUATIONS
In order to explore factors that may help explain individual 
variability in main PK parameters, the presence or absence of 
germline mutations or polymorphisms will be analyzed in 
leukocyte DNA extracted from a blood sample obtained at 
any time during the study, but ideally before treatment start 
along with PK sample #1 on Day 1 of Cycle 1.
STATISTICAL 
METHODS
The main endpoint of the study is the determination of the 
MTD and the RD of PM060184 in combination with 
gemcitabine in this study population for future trials.   
Descriptive statistics (mean, median, standard deviation and 
95% confidence interval, range of value, frequencies and 
percentages) will be used as appropriate. 
Safety: 
Descriptive statistics will be used to characterize DLTs 
occurring at the RD and/or at DLs above/below it. The 
profiles of AEs, deaths, serious adverse events (SAEs), 
treatment-related delays, dose reductions, dose omissions 
and/or treatment discontinuations will also be displayed as 
appropriate. 
Efficacy:
Response rates as per RECIST v.1.1 (and as per Choi criteria 
and/or EORTC metabolic response criteria, for GIST 
patients) [percentage of patients with any response [partial 
response (PR), complete response (CR) or the sum of both 
being the overall response rate (ORR)], percentage of patients 
with clinical benefit [i.e., patients with any response, or with 
stable disease (SD) ≥ 4 months], will be characterized using 
descriptive statistics (95% exact binomial confidence 
interval) and according to primary tumor type. Time-related 
parameters [e.g., progression-free survival (PFS), overall 
survival (OS)] will also be analyzed according to the Kaplan-
Meier method, if appropriate. If any specific tumor type 

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Protocol PM60184-A-003-14
subset is adequately represented, exploratory subgroup 
analyses will be performed. The characteristics of the patients 
achieving an objective response or SD ≥ 4 months by 
RECIST v.1.1 will be displayed.
Pharmacokinetics:
The PK parameters will be tabulated and selected parameters 
will be graphically displayed per DL. The dose-exposure 
relationships for maximum plasma concentration (Cmax) and 
area under the curve (AUC) will be evaluated, and any 
potential PK interaction between gemcitabine, dFdU and 
PM060184 will also be explored. The potential influence on 
selected PK parameters of selected demographic and clinical 
dichotomous variables (gender, laboratory test results 
above/below selected cutoff values, etc.) will be evaluated by 
Student’s t test or Mann-Whitney’s U test as appropriate. For 
multinomial variables, analysis of variance will be used. For 
selected continuous demographic and clinical variables, 
relationship with selected PK parameters will be graphically 
explored and assessed using correlation and regression 
methods.
Pharmacogenetics:
The influence of known polymorphisms on main PK 
parameters will be assessed by Student’s test or Mann-
Whitney’s U test as appropriate.
PLANNED TRIAL 
PERIODS (individually per 
patient)
Patients will be evaluated at scheduled visits in three study 
periods:

Pre-treatment: from signature of informed consent form
(ICF) to the day of first infusion of study drugs.

Treatment: from first infusion of study drugs to the end 
of treatment (EOT).

Follow-up: after EOT, patients will be followed every 
four weeks until resolution or stabilization of relevant 
(grade > 1) related toxicities, if any. Patients who 
discontinued treatment without disease progression will be 
followed every three months until disease progression, 
other antitumor therapy, death or until the date of study 
termination (clinical cutoff), whichever occurs first. 
Patients will be considered to be on-study from the signature 
of the IC to the end of the follow-up period. Patients will be 
considered to be on-treatment for the duration of their 
treatment and until the EOT. The EOT is defined as 30 days 
(±15 days) after the day of the last study drug dose 
administration. An EOT visit will be performed within 30 
days (± 15 days) after the last study drug dose administration, 
unless the patient starts any subsequent antitumor therapy (in 
which case the EOT visit should be performed before the start 
of the new therapy, whenever possible). If the patient dies
while on treatment, the date of death will be considered the 
EOT date.
Patients will receive the study drugs while it is considered to 

CL_0246 2.0
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Protocol PM60184-A-003-14
be in their best interest. Specifically, treatment will continue 
until:

Disease progression.

Unacceptable toxicity.

Intercurrent illness of sufficient magnitude to preclude 
fulfillment of appropriate re-treatment criteria and/or safe 
continuation of the study.

Patient refusal and/or non-compliance with study 
requirements.

Treatment delay > 7 (+1) days from the theoretical due 
date due to toxicity (except in case of patient’s clear 
clinical benefit, with the Sponsor’s approval).

Requirement of > 2 dose reductions.
PLANNED TRIAL 
PERIODS (for the whole 
study)
The total duration of the study will be approximately 69
months, including approximately a 60-month enrolment 
period. 
Planned start date (first patient on study): 4Q2014.
Planned enrolment period: approximately 60 months.
Planned end-of-study date (clinical cutoff): six months after 
the last patient’s treatment discontinuation (last patient-last 
visit), or nine months after accrual of the last evaluable 
patient, whichever occurs first.

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SCHEDULE OF ASSESSMENTS AND PROCEDURES
Assessments and 
procedures
Screening
Treatment
Follow-up
Cycle 1 
Further cycles
End of 
treatmen
t
D1
D8
D15
D22*
D8
D15**
Written informed 
consent
Before any 
study 
procedures
-
-
-
-
-
-
-
-
Pharmacogenetics 
informed consent 
(optional)
At any time during the study, but always prior 
to pharmacogenetic sample collection
-
Demographic data 
including height
-28  to  0
-
-
-
-
-
-
-
-
Medical and cancer 
history
-28  to  0
-
-
-
-
-
-
-
-
Primary diagnosis
/prior treatment(s) 
-28  to  0
-
-
-
-
-
-
-
-
Assessment of signs 
and symptoms 
-28  to  0
-
-
-
-
-
-
-
-
Gemcitabine 
administration (1)
-


-


-
-
-
PM060184 
administration (1)
-


-


-
-
-
Complete physical 
examination, weight 
and BSA 
-7  to  0
†
-
-
ᴓ
-
-
(2)
-
Performance status 
(ECOG) 
-7  to  0
†





(2)
-
Vital signs (heart rate, 
blood pressure, 
temperature) 
-7  to  0
†





(2)
-
Hematology (3)
-7  to  0
†





(2)
-
Biochemistry-A (3)
-7  to  0
†





(2)
-
Biochemistry-B and 
coagulation. 
-7  to  0
†
-
-

-
-
(2)
-
Pregnancy test (if 
premenopausal 
woman) (4)
-7  to  0
Repeat if clinically indicated
-
ECG (5)
-28  to  0
Repeat if clinically indicated
-
LVEF (6)
-28  to  0
Every other cycle  
(6)
Radiological tumor 
assessment as per 
RECIST v.1.1 (7)
-28  to  0
Every two cycles (every six weeks ± one week) 
until Cycle 4, and then every three cycles (every 
nine weeks ± one week) while on treatment
-
-
(8)
Pharmacokinetics (9) 
One blood 
sample 
collected 
immediately 
before treatment
Cycle 1
Nine blood samples collected from Day 1 
to Day 2 for PK 
-
Pharmacogenetics 
(polymorphisms), if 
consented 
One blood sample collected 
at any time during the study
-
Concomitant therapies 
-14  to  0
Throughout the “on-treatment” period 
Adverse events
- §
Throughout the “on-treatment” period 

(10)
Day 0 = Day 1 of Cycle 1.
*Day 22 = Day 1 of the following cycle. Administration could be delayed up to 7 (+1) days; further delay is only 
acceptable under the Sponsor’s approval of documented clinical benefit.
§ Only information on SAEs that occurred after signature of ICF is required. Grading should be as per NCI-CTCAE 
v.4.
† If performed at screening, the assessment does not need to be repeated on Day 1 of Cycle 1.
ᴓBefore treatment administration of subsequent cycles, BSA will have to be recalculated for patients showing a ≥10 

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Protocol PM60184-A-003-14
% variation in total body weight from baseline or from last dose adjustment; otherwise the same BSA and dose 
calculated for the previous cycle could be used. The same BSA calculation method should be used throughout the 
study.
**From Cycle 5 onwards day 15 visit will not be done unless it is clinically indicated.
Allowed windows for assessments and procedures:

A -24-hour window for clinical assessments (ECOG PS, vital signs, weight, BSA, etc.). Additionally, for 
D15 a +24 hour window will also be allowed.

A -24-hour window for laboratory procedures (a -48-hour window on infusion days, excluding Day 1 of 
Cycle 1). Additionally, for D15 a +24 hour window will also be allowed.

A ±15-day window for the assessments at EOT.

A ±1-week window for radiological procedures.

A ±24-hour window for administration of gemcitabine (but only if at least six days have passed since the 
last infusion) and of PM060184. 
1.
Gemcitabine will be administered as a 30-min (±10 min) i.v. infusion, followed by PM060184 as a 10-min (±3 
min) i.v. infusion. During PK sampling, PM060184 infusion should start no more than 5 min after end of 
gemcitabine administration.
2.
To be repeated only for those parameters for which no measurement is available within 15 (-3) days before the 
end-of-treatment visit, or for those parameters with values that were out of range in the last assessment (grade > 
1 according to NCI-CTCAE v.4).
3.
During the first four cycles, hematology and biochemistry-A analyses will be repeated on Days 1, 8 and 15. If 
any clinically relevant treatment-related NCI-CTCAE grade ≥ 3 toxicity occurs during the first four cycles, the 
abnormal test(s) should be re-assessed at least every 2-3 days until recovery to at least grade 2. In the event of 
febrile neutropenia, grade 4 neutropenia and/or grade 4 thrombocytopenia, re-assessment should be performed 
daily until recovery to at least grade 3 or until fever resolution, if applicable, and then every 2-3 days thereafter 
until recovery to at least grade 2. From Cycle 5 onwards, any treatment-related NCI-CTCAE grade ≥ 3 toxicity 
not considered a major risk for the patient is to be re-evaluated according to Investigator’s criteria.
4.
Beta subunit-human chorionic gonadotropin (ß-hCG) (urine or serum).
5.
It should allow rhythm definition and should include assessment of:

PR interval.

Heart rate.

QT interval (raw).

QRS complex duration.
6.
LVEF assessment: at screening (within 28 days prior to Day 1 of Cycle 1) and then every other cycle. In the 
event of LVEF decrease to grade ≥ 2 by MUGA, an ECHO should be done to confirm this decrease and also to 
rule out any heart injures. Major efforts must be done to find the main cause of this AE (cardiac enzymes, 
troponin I and or T, cardiologist assessment, etc.). LVEF by ECHO should be performed at least every four 
weeks until recovery or stabilization.
7.
Helical contrast-enhanced CT-scan and/or gadolinium-enhanced MRI as appropriate every two cycles ± one 
week until Cycle 4, and then every three cycles ± one week from Cycle 4 while on treatment (the same method 
should be used throughout the study for each individual patient). PET-CT scan might be used, if appropriate, on 
individual cases upon the Sponsor’s agreement. (Patients with GIST should always be assessed with fusion 
or integrated PET-CT scans, and will be assessed according to Choi criteria and/or EORTC metabolic 
response criteria for solid tumors). Anonymized copies of the images showing objective response or 
meaningful tumor shrinkage must be submitted to the Sponsor.
8.
Patients who discontinued treatment without disease progression will be followed every three months until 
disease progression, other antitumor therapy, death or until the date of study termination (clinical cutoff), 
whichever occurs first.
9.
Additionally, patients treated in the expanded cohort at the RD and in the tumor-specific cohorts will be 
sampled for PM060184 PK analysis on Day 1 and Day 2 of Cycle 2 at the same time points.
10. Patients withdrawn from the study with an ongoing relevant (grade > 1) drug-related AE should be followed 
until resolution or stabilization (i.e., to grade 1) or until start of a new therapy. Beyond 30 days (± 15 days) after 
the last administration of study drugs, only those procedures to assess any remaining relevant treatment-related 
AEs need to be performed. 
Hematology: Differential WBC (neutrophils, lymphocytes), hemoglobin and platelets.
Biochemistry A: AST, ALT, total bilirubin, AP, LDH, creatinine, glucose, and serum electrolytes (Na+, K+, Cl–, total 
calcium).
Biochemistry B and coagulation: total proteins, albumin and coagulation tests (PT, aPTT, INR). 
Exploratory serum tumor markers will be measured as appropriate according to primary tumor type only if elevated at 
baseline (≥2 x ULN).
AE, adverse event; ALT, alanine aminotransferase; AP, alkaline phosphatase; aPTT, activated partial thromboplastin 
time; AST, aspartate aminotransferase; BSA, body surface area; CT, computed tomography; ECG, 

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electrocardiogram; ECHO, echocardiography; ECOG, Eastern Cooperative Oncology Group; EORTC, European 
Organization for Research and Treatment of Cancer; EOT, end of treatment; GIST, gastrointestinal stromal tumor; 
ICF, informed consent form; INR, international normalized ratio; LDH, lactic dehydrogenase; LVEF, left ventricular 
ejection fraction; MRI, magnetic resonance imaging; MUGA, multiple gated acquisition scan; NCI-CTCAE, National 
Cancer Institute Common Terminology Criteria for Adverse Events; PET, positron emission tomography; PK, 
pharmacokinetics; PS, performance status; PT, prothrombin time; RD, recommended dose; RECIST, Response 
Evaluation Criteria In Solid Tumors; SAE, serious adverse event; ULN, upper limit of normal; WBC, white blood 
cells.

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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
5-HT3
Serotonin (5-hydroxytryptamine 3)
AE(s)
Adverse Event(s)
ALT
Alanine Aminotransferase
ANC 
Absolute Neutrophil Count
AP
Alkaline Phosphatase
aPTT
Activated Plasma Thromboplastin Time
ASCO
American Society of Clinical Oncology
AST
Aspartate Aminotransferase
AUC
Area Under The Concentration vs. Time Curve
AUKPS
Adenocarcinoma of Unknown Primary Site
β-hCGs
Beta Subunit of Human Chorionic Gonadotropins
BSA
Body Surface Area
CI
Combination Index
CL
Clearance
Cmax
Maximum Plasma Concentration
CR
Complete Response
CRA
Clinical Research Associate
CrCl
Creatinine Clearance
CT-scan
Computed Tomography Scan
CYP
Cytochrome P450
d/D
Day(s)
dFdC
2,2-difluorodeoxycytidine
dFdCDP
dFdC 5’-diphosphate
dFdCTP
dFdC 5’-triphosphate
dFdU
2,2-difluorodeoxyuridine
DI
Dose Intensity
DL
Dose Level
DLT
Dose-limiting Toxicity
DNA
Deoxyribonucleic Acid
DP
Drug Product
DS
Degree of Substitution
ECG
Electrocardiogram
ECHO
Echocardiography
ECOG
Eastern Cooperative Oncology Group
e-CRF
Electronic Case Report Form
EOI
End of Infusion
EORTC
European Organization for Research and Treatment of Cancer

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EOT
End of Treatment
ER
Estrogen Receptor
FUP
Follow-up
G-CSF
Granulocyte Colony-stimulating Factor
GCIG
Gynecologic Cancer Intergroup
GCP
Good Clinical Practice
GCT
Germ Cell Tumor
GGT
Gamma-glutamyltransferase
GI50
50% Growth Inhibition
GIST
Gastrointestinal Stromal Tumor
GMT
Greenwich Meridian Time
hCG
Human Chorionic Gonadotropin
HIV
Human Immunodeficiency Virus
HPβCD
2-hydroxypropyl-β-cyclodextrin
IB
Investigator’s Brochure
ICH
International Conference on Harmonization
ICF
Informed Consent Form
IEC
Independent Ethics Committees
IMP
Investigational Medicinal Product
INR
International Normalized Ratio
IRB
Institutional Review Board
IUD
Intrauterine Device (Contraceptive)
i.v.
Intravenous (intravenously)
LDH
Lactate Dehydrogenase
LHRH
Luteinizing Hormone-releasing Hormone
LVEF
Left Ventricular Ejection Fraction
MAb
Monoclonal Antibody
min
Minute(s)
ml
Milliliter
MRI
Magnetic Resonance Imaging
MTD
Maximum Tolerated Dose
MUGA
Multiple Gated Acquisition Scan
NCA
Non-compartmental Analysis
NCI
National Cancer Institute
NCI-CTCAE
National Cancer Institute-Common Terminology Criteria for Adverse Events
NSCLC
Non-small Cell Lung Cancer
ORR
Overall Response Rate
OS
Overall Survival

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PD
Progressive Disease
PET
Positron Emission Tomography
PFS
Progression-free Survival
PhV
Pharmacovigilance
PK
Pharmacokinetic(s)
PR
Partial Response
PRE TT
Pre-treatment
PrP
Progesterone Receptor
PS
Performance Status
PT
Prothrombin Time
Q
Quarter
q3wk
Every Three Weeks
q4wk
Every Four Weeks
RD
Recommended Dose
RECIST
Response Evaluation Criteria In Solid Tumors
RT
Radiotherapy
SAE(s)
Serious Adverse Event(s)
SD
Stable Disease
SPC
Summary of Product Characteristics
SUSAR/SUA
Suspected Unexpected Serious Adverse Reaction
t1/2
Terminal Elimination Half-life
TGD
Tumor Growth Delay
TT
Treatment
TTP
Time To Progression
Uk
Unknown
UKPS
Adenocarcinoma or Carcinoma of Unknown Primary Site
ULN
Upper Limit of Normal
Vss
Volume of Distribution at Steady State
WBC
White Blood Cells
WHO
World Health Organization
wk/wks
Week/weeks
WMA
World Medical Association

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1.
INTRODUCTION
1.1
BACKGROUND
Despite recent advances in the treatment of cancer, metastatic disease remains mostly 
incurable and there is an urgent need for developing new therapeutic options for these 
patients, particularly including investigational drugs with novel mechanisms of action. 
The introduction of new combination regimens of non-cross-resistant chemotherapy 
agents with acceptable safety profiles is a way to try to improve the outcome of patients 
with advanced solid tumors.
1.2
INFORMATION ON STUDY DRUGS: PM060184
Please refer to the Investigator's Brochure (IB) for full information on PM060184.
1.2.1
Name and Chemical Information
The Drug Substance PM060184-CD is a mixture of PM060184 and 2-hydroxypropyl-β-
cyclodextrin (HPβCD). 
Chemical name
(1Z,4S,6Z)-1-(N-[(2Z,4Z,6E,8S)-8-((2S)-5-methoxy-6-oxo-3,6-
dihydro-2H-pyran-2-yl)-6-methylnona-2,4,6-trienoyl]-3-methyl-L-
valyl}amino)octa-1,6-dien-4-yl carbamate
2-Hydroxypropyl-β-cyclodextrin (DS 4 – 5)
Other name 
PM060184
HPβCD
Molecular formula
PM060184
    C31H45N3O7
HPβCD
    (C6H9O5)7(C3H7O)n n=4-5
Molecular weight
PM060184
    571.7049
HPβCD
    About 1400
Proportion (w/w)
PM060184
    1
HPβCD
    10
The structural and molecular formula of PM060184 and HPβCD are shown in Figure 1: 
Figure 1. Molecular formula of PM060184: C31H45N3O7.

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Figure 2. Molecular formula of 2-Hydroxypropyl-β-cyclodextrin: (C6H9O5)7(C3H7O)n 
n=4-5.
1.2.2
Non-clinical Data
PM060184 is a new chemical entity that depolimerizes tubulin fibers and causes a 
disorganization and fragmentation of the microtubule network leading to multipolar 
mitosis, prometaphase arrest, induction of caspase-dependent apoptosis and/or the 
appearance of cells in a multinucleated interphase-like state. These effects correlate with 
induction of cell death. 
In vitro, PM060184 demonstrated cytotoxicity against a broad panel of solid human 
tumor types, with 50% growth inhibition (GI50) values ranging from 40 pM to 5 nM, 
with the highest activity against representatives of breast (BT-474), colon (HT-29), 
gastric (HGC-27), lung (A549), prostate (22Rv1), renal (RFX-393) and ovarian 
(IGROV-1) tumors. In vivo, intravenous (i.v.) administration of PM060184 induced 
strong antitumor activity in different murine models of xenografted human-derived 
tumor types, such as breast (MAXF401), colon (HCT-116), gastric (HGC-27), non-
small cell lung cancer (NSCLC) (H460), prostate (22RV1), renal (Caki-1 or MRI-H-
121) and ovarian cancer (A2780 or OVXF 899).
After i.v. administration in CD1 mice, Sprague-Dawley rats, Beagle dogs, Cynomolgus
monkeys, New Zealand rabbits and Göttingen mini-pigs, PM060184 pharmacokinetics 
displayed a multi-compartmental distribution, moderate (ranging from ca. 2 to 8 hours) 
terminal elimination half-lives (t1/2) and thus, relatively high plasma clearance (CL). 
Furthermore, volume of distribution at steady state (Vss) and area under the 
concentration vs. time curves (AUCs) were similar in males and females in all species, 
except for rat. 
The in vitro plasma protein binding of PM060184 was higher than 97% in all species 
tested, including humans (98.7%). In vitro, PM060184 underwent extensive turnover by 
microsomes, with a similar metabolic profile from any of the above mentioned species, 
humans included. PM060184 showed a limited potential to inhibit or induce 
cytochrome P450 (CYP) isoforms.
Following
single and repeated (three consecutive weekly doses) intravenous 
administration in rats and dogs, the most toxicologically relevant findings were 
observed 
in 
hematology/bone 
marrow 
(leukopenia, 
thrombocytopenia 
and 

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reticulopenia), clinical chemistry (changes in liver function markers), in the 
gastrointestinal tract (diarrhea and vomiting) and in testes (atrophy). All of them fully 
recovered by the end of the observation period (Day 29), except for the findings in 
testes. The more severe, death-causing toxicities were identified as immunosuppression, 
necrosis, hemorrhages and thrombosis in several organs. As part of the evaluations 
performed in the general toxicology, heart rate and lead II electrocardiogram-derived 
variables monitoring was included. The results showed decreases in heart rate and 
increases in RR and QT intervals that reached a maximal effect at 1 hour post-dose. 
Furthermore, QTc increases were observed at 6 hours (both genders), and they were still 
present at 24 hours in the highly dosed groups. In the repeat-dose study, no variations 
were recorded for any parameter after the third consecutive weekly dose.
No significant gross behavioral or physiological changes were induced by the 
administration of PM060184 at 8 mg/kg in male rats, although slight changes in the 
respiratory function (i.e., decreased inspiration time and enhanced pause; increased peak 
inspiratory flow, respiration rate and minute volume) were observed at one hour post-
dose, followed by increased expiration time and decreased respiration rate and minute 
volume (at 2.5 hours post-dose). 
In vitro studies (1) resulted in the identification of CYP isoenzymes involved in phase I-
mediated PM060184 metabolism. Incubation of PM060184 (1 µM, 37 ºC, 30 min) with 
recombinant microsomes expressing CYP isoforms 1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 
2E1 and 3A4, suggested that CYP2C19 and CYP3A4 are the two major cytochrome 
isoforms involved in PM060184 CYP-mediated metabolism (94% and 85%, 
respectively). CYP2D6 and CYP2C9 also showed involvement to a lesser extent (30% 
of PM060184 was metabolized). No major contribution of CYP2E1, CYP1A2, CYP2B6 
or CYP2A6 isoforms to PM060184 metabolism was seen.
The results gathered from the mechanism of action, in vitro and in vivo experiments 
justify the clinical development of PM060184.
1.2.3
Clinical Data
Based on the promising preclinical results described above, the clinical development 
program of PM060184 was started in January 2011. As of 2014, this clinical 
development program comprised two phase I single-agent studies in patients with 
advanced solid tumors, both of which are still ongoing. As of 30th June 2014, 94
patients had been treated with PM060184 in clinical studies.
The first trial (PM060184-A-001-10) evaluated PM060184 administered as a 10-minute
(min) infusion on Days 1, 8 and 15 every four weeks (q4wk). The recommended dose 
(RD) for this schedule was established at 12.0 mg/m2. The expansion cohort in selected 
tumors is currently ongoing. The second trial (PM60184-A-002-10) first evaluated 
PM060184 as a 10-min infusion on Days 1 and 8 q3wk, and determined its RD to be 9.3 
mg/m2. Preclinical studies suggested a similar antitumor effect when a PM060184 dose 
was split into several daily doses compared to a single administration. Based on these 
findings, trial PM60184-A-002-10 was amended to determine the safety and efficacy of 
a new schedule (PM060184 as 10-min infusions on three consecutive days every two 
weeks in a 28-day cycle. Patient accrual is still ongoing (2, 3).
Similar toxicity profiles were found in all PM060184 schedules evaluated to date. The 
most frequent dose-limiting toxicity (DLT) observed was grade 3 peripheral sensory 
neuropathy, with transient symptoms that involved hands and feet. Most episodes of this 

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adverse event occurred in patients pretreated with oxaliplatin, and some had grade 1 
peripheral neuropathy at baseline. As a result, patients pretreated with oxaliplatin or 
with a previous episode of grade ≥ 2 peripheral neuropathy due to any chemotherapeutic 
or investigational agents are currently excluded from all clinical trials with PM060184.   
A rare but potentially life-threatening heart failure was reported in one patient. Common 
PM060184-related adverse events (AEs) were mild or moderate, and comprised 
alopecia, fatigue, nausea, vomiting, abdominal pain and peripheral sensory neuropathy. 
Owing to the finding of PM060184-related nausea or vomiting in > 60% of patients, 
primary antiemetic prophylaxis with serotonin (5-HT3) antagonists and steroids is 
currently compulsory in clinical trials with PM060184. Most hematological and non-
hematological laboratory abnormalities reported to date were mild or moderate at all 
dose levels. Severe abnormalities were transient and generally did not require dose 
adjustment.
Evidence of objective antitumor activity has been observed in both PM060184 clinical 
trials. This activity consisted of partial response (PR) in three patients: one with cervix 
carcinoma, one with breast cancer and one with non-small cell lung cancer (NSCLC). In 
addition, tumor shrinkage that did not achieve PR criteria was observed in three breast 
cancer patients (shrinkage of 20-28%), and meaningful disease stabilization in 13 
patients with different tumor types (13.8%). One of these disease stabilizations was 
found in a gastrointestinal stromal tumor (GIST) patient with liver metastases, and was 
considered to be a PR as per Choi criteria; the patient had a time to progression (TTP)
of 20.6 months.
1.3
INFORMATION ON STUDY DRUGS: GEMCITABINE
Gemcitabine (2,2-difluorodeoxycytidine, dFdC) is an antimetabolite and the most 
important cytidine analog currently used in solid tumors. Alone or in combinations, 
gemcitabine is commonly used to treat a variety of advanced malignancies, including 
lymphomas (4) and solid tumors such as breast cancer (5), ovarian cancer (6), stromal 
uterine sarcomas (7), non-small cell lung cancer (8), exocrine pancreatic carcinoma (9), 
biliary tract carcinoma (10), relapsed/refractory germ cell tumors (GCTs) (11) and 
adenocarcinoma of unknown primary site (AUKPS) (12).
Gemcitabine inhibits DNA synthesis. It is actively transported through the cell 
membrane, and in the cytoplasm it is phosphorylated to its active form, the dFdC 5’-
triphosphate (dFdCTP), which is incorporated into the DNA and inhibits the DNA 
polymerase (13). This potent DNA polymerase inhibition is explained at least in part by 
the intracellular depletion of deoxyribonucleotide pools through inhibition of the 
ribonucleotide reductase by the dFdC 5’-diphosphate (dFdCDP) (14). Intracellular 
conversion of gemcitabine into 2,2-difluorodeoxyuridine (dFdU) by the enzyme 
cytidine deaminase represents the main catabolic pathway (15). The mechanisms of 
tumor resistance to gemcitabine are not fully understood. Cells deficient in 
deoxycitidine kinase (the rate-limiting enzyme in the activation pathway) are resistant to 
gemcitabine and so are cells overexpressing cytidine deaminase, although 
overexpression of P-glycoprotein (which also confers resistance to many other drugs) 
has not been associated with gemcitabine resistance (16).
The main DLT of gemcitabine is myelosuppression, which is mainly characterized by 
thrombocytopenia and anemia, with a relative sparing of neutrophils (17). Common 
non-hematological toxicities include flu-like symptoms (fever, headache, back pain and 
myalgia) and asthenia in approximately 45% and 42% of the patients, respectively. Mild 

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and transient transaminases elevations [i.e., World Health Organization (WHO) grade 1 
or 2 alanine aminotransferase (ALT) increase] were observed in up to 40% of cycles 
(18). Several rare but potentially life-threatening syndromes have also been described, 
such as a hemolytic-uremic syndrome or an acute respiratory distress syndrome, 
possibly in relation with capillary-leaking toxicity.
Weekly (two, three or seven weeks on - one week off) gemcitabine doses of up to 2200 
mg/m2 as a 30-min infusion have been given to non-heavily pretreated cancer patients 
(19), although due to deoxycitidine kinase saturation (which is the rate-limiting enzyme 
in the process of activation) at infusion rates of approximately 10 mg/m2 per min (20), 
the higher doses resulted in no efficacy improvement. Despite the results of the constant 
dose-rate-infusion presented by Tempero et al. (21), a more practical short i.v. infusion, 
over 30 min of 800-1000 mg/m2 weekly was rapidly extended in the clinical practice 
(18).
For  all  information  related  to  gemcitabine,  please  refer  to  the  Summary  of  
Product Characteristics (SPC).
1.4
INFORMATION ON THE COMBINATION OF PM060184 AND GEMCITABINE
The in vivo antitumor activity of PM060184 administered alone and in combination 
with gemcitabine was investigated in a pancreatic cancer model of mice bearing 
SW1990 xenografted tumors. Treatments administered were:  i) placebo; ii) PM060184 
at four different dose levels, i.e. maximum tolerated dose (MTD) (16 mg/kg), 
0.75•MTD, 0.5•MTD and 0.25•MTD; iii) gemcitabine at four different dose levels, 
MTD (180 mg/kg), 0.75•MTD, 0.5•MTD and 0.25•MTD; and, iv) PM060184 plus 
gemcitabine combination, administered at 0.75+0.75, 0.50+0.50, and 0.25+0.25 of their 
respective MTDs. The highest feasible dose for the PM060184-gemcitabine
combination was 0.75+0.75 of their respective MTDs. PM060184 at the MTD resulted 
in antitumor activity, as reflected by significantly (p < 0.05) smaller tumors than in 
placebo-treated animals. In contrast, gemcitabine at the MTD resulted in marginal 
antitumor activity (p < 0.1) compared to placebo–treated animals. Animals treated with 
the PM060184-gemcitabine combination at (0.75+0.75)•MTD or (0.50+0.50)•MTD 
showed a highly significant (p < 0.01) reduction of tumor volume compared to placebo-
treated animals. In addition, both groups treated with the highest doses [i.e. 
(0.75+0.75)•MTD and (0.50+0.50)•MTD] showed tumor growth delays (TGD) of 123%
and 182%, respectively; these values were longer than those seen with single-agent 
gemcitabine or PM060184 at their respective MTDs. The analysis by the median-effect 
principle of the antitumor effect induced by treatments resulted in a combination index 
(CI) value ≤0.1, which suggested a very strong synergistic effect for the combination of 
both drugs.
1.5
STUDY RATIONALE
Because curative therapy has not been established for many solid tumors, there is a need 
for clinical research to effectively assess new therapeutic proposals including 
investigational drugs. 
PM060184 has been selected for clinical development because in vitro demonstrated 
cytotoxicity against a broad panel of tumor types (breast, colon, renal and ovarian 
tumors) and in vivo induced strong antitumor activity in different murine models of 
xenografted human-derived tumor types, such as breast, colon, gastric, NSCLC, 
prostate, renal and ovarian. In addition, PM060184 in vivo studies showed a good 

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tolerability profiling, with no significant signs of systemic and/or local toxicity when 
given up to 16 mg/kg in a weekly schedule. Evidence of synergistic antitumor activity 
has been observed in vivo when PM060184 was combined with gemcitabine. The 
clinical toxicity of each compound does not seem to overlap completely, according to 
currently available data. Therefore, it is feasible to evaluate the safety and efficacy of a 
combination of PM060184 and gemcitabine in selected patients with advanced solid 
tumors.
Previous phase I data have shown that an administration schedule on Days 1 and 8 
q3wk is feasible for single-agent PM060184, with an RD of 9.3 mg/m2. In this study, no 
DLTs occurred among patients treated at or below this RD. Based on these results, a 
dose of 6.0 mg/m2, which is equivalent to 64% of the RD for this schedule, was chosen 
as a safe starting dose level of PM060184 for its combination with gemcitabine in the 
present study. 
The starting dose for gemcitabine will be 800 mg/m2. This is equivalent to 80% of the 
RD with this schedule, and is also the minimal gemcitabine dose accepted in clinical 
practice.
2.
STUDY OBJECTIVES
2.1
PRIMARY

To determine the MTD and the RD of PM060184 in combination with 
gemcitabine in selected patients with advanced solid tumors.
2.2
SECONDARY

To characterize the safety profile and feasibility of this combination in this study 
population.

To characterize the pharmacokinetics (PK) of this combination and to detect 
major drug-drug PK interactions.

To obtain preliminary information on the clinical antitumor activity of this 
combination.
3.
OVERALL STUDY DESIGN
Prospective, open-label, dose-ranging, uncontrolled phase I study with escalating doses 
of PM060184 in combination with gemcitabine in selected patients with advanced solid 
tumors.
Following a classical 3+3 design, successive cohorts of patients will receive escalating 
doses of i.v. gemcitabine over 30 minutes (min), followed by i.v. PM060184 over 10 
min on Day 1 and Day 8 q3wk, until the RD is reached. All evaluable patients within a 
dose level (DL) must be followed for at least one full cycle (i.e., three weeks) before 
dose escalation may proceed to the next DL.
The MTD will be the lowest DL explored during dose escalation at which more than 
one third of evaluable patients experienced a DLT during Cycle 1. The RD will be the 
highest DL explored at which less than one third of evaluable patients experienced a 
DLT during Cycle 1. Dose escalation will cease immediately once the MTD is reached. 
Intermediate DLs can be tested, if deemed appropriate upon the Sponsor’s and 
Investigators’ agreement.

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At least nine evaluable patients will be treated in an expansion cohort at the RD in order 
to confirm its tolerability and feasibility. Once the RD is confirmed, exploratory cohorts 
of at least 12 patients each will be expanded at RD in selected tumor type(s) and/or 
target subpopulations, chosen according to the preliminary efficacy observed among 
patients treated during dose escalation, discussed and agreed between the Investigators 
and the Sponsor, as appropriate.
Safety will be evaluated continuously during study participation, and AEs will be 
graded according to the National Cancer Institute-Common Terminology Criteria for 
Adverse Events (NCI-CTCAE), v.4. 
Antitumor response will be assessed using the Response Evaluation Criteria In Solid 
Tumors (RECIST) v.1.1 (or Choi criteria and/or EORTC metabolic response criteria for 
solid tumors, for GIST patients).
Patients will be evaluated at scheduled visits on three study periods: Pre-treatment, 
Treatment and Follow-up (see Section 5.2).
3.1
PRIMARY ENDPOINT
3.1.1
Determination of the Maximum Tolerated Dose and the Recommended 
Dose
The MTD will be the lowest DL explored during dose escalation at which more than 
one third of evaluable patients experienced a DLT during Cycle 1.
The RD will be the highest DL explored at which less than one third of evaluable 
patients experience a DLT during Cycle 1. This RD will be confirmed if less than one 
third of the first nine evaluable patients treated during expansion have DLTs during 
their Cycle 1.
A patient evaluable for the primary endpoint should have received at least one complete 
cycle (including the observation period). Patients who are discontinued early or 
miss/delay doses and/or assessments will be evaluable if these events are the 
consequence of treatment-related toxicity (excluding hypersensitivity reactions and/or 
extravasations).
3.1.2
Definition of Dose-limiting Toxicities
DLTs are defined as AEs and laboratory abnormalities related to the study treatment
that occurred in an evaluable patient during Cycle 1 and fulfilled at least one of the
following criteria:

Grade 4 neutropenia [absolute neutrophil count (ANC) < 0.5 x 109/l] lasting > 3
days.

Grade ≥ 3 febrile neutropenia of any duration or neutropenic sepsis.

Grade 4 thrombocytopenia (platelet count < 25 x 109/l) or grade 3 with any major 
bleeding episode requiring a platelet transfusion.

Grade 4 ALT and/or aspartate aminotransferase (AST) increase, or grade 3 lasting 
> 7 days.

Treatment-related grade ≥ 2 ALT or AST increase concomitantly with ≥ 2 x upper 
limit of normal (ULN) total bilirubin increase and normal alkaline phosphatase 
(AP). 

Any other grade ≥ 3 non-hematological AE that is suspected to be related to study 
drug(s), except nausea/vomiting (unless the patient is receiving an optimal anti-
emetic regimen), hypersensitivity reactions, extravasations, grade 3 asthenia 

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lasting less than one week, anorexia, and non-clinically relevant isolated 
biochemical abnormalities [e.g., isolated increase in gamma-glutamyltransferase 
(GGT)]. In any case, the clinical relevance should be discussed between the 
Investigators and the Sponsor’s representatives.

Delay in the administration of Cycle 2 of the combination exceeding seven (+1) 
days of the treatment due date (i.e., Day 22) due to any AEs related to study 
drug(s).

The following circumstances will be discussed between the Principal Investigator 
and the Sponsor, and the final consensus will be documented:
o
DLTs with delayed onset (i.e., that occur after Cycle 1).
o
Non-compliance with the intended dose intensity (DI) in more than half of 
patients at any dose level (i.e., missing infusions on Day 8 or frequent dose 
delays due to treatment-related toxicity despite not conforming to a formal 
DLT definition).
3.2
SECONDARY ENDPOINTS
3.2.1
Safety
Patients will be evaluable for safety if they have received at least one partial or 
complete infusion of PM060184 and one partial or complete infusion of gemcitabine. 
AEs will be graded according to the NCI-CTCAE v.4. For further details on safety 
evaluation see Section 9.2.
3.2.2
Pharmacokinetics
Pharmacokinetic analyses will be evaluated in plasma by standard non-compartmental 
analysis (NCA) (compartmental modeling may be performed if appropriate). Samples 
for PK analysis will be obtained during Cycle 1 (see Section 9.7). 
3.2.3
Efficacy
Although it is not the main objective of this study, antitumor activity will be evaluated 
according to the RECIST v.1.1 in all patients with measurable disease, according to 
Choi criteria and/or EORTC metabolic response criteria for solid tumors in GIST 
patients, or by evaluation of serum tumor markers if applicable (e.g., ovarian cancer)
every two cycles (i.e., approximately every six weeks) ± one week after treatment 
initiation until Cycle 4. Patients continuing treatment after Cycle 4 will have the 
assessments performed every three cycles (i.e., approximately every nine weeks) ± one 
week from Cycle 4 while on treatment, unless otherwise is clinically indicated. Patients 
included in the expansion cohort at the RD and in the tumor-specific cohorts must be 
evaluable as per RECIST v.1.1 (or Choi criteria and/or EORTC metabolic response 
criteria for solid tumors, in the case of GIST), or by tumor markers (see Section 9.6).
3.2.4
Pharmacogenetics 
This analysis will be performed in those patients who signed the ICF for the 
pharmacogenetic substudy. A blood sample will be collected at any time during the 
study, but ideally along with the pre-treatment PK sample on Day 1 of Cycle 1, to 
evaluate the presence or absence of known polymorphisms that may explain individual 
variability in main PK parameters.

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3.3
DOSE ESCALATION SCHEME
The starting dose (DL1) for gemcitabine will be 800 mg/m2. This corresponds to a DI of 
533.33 mg/m2/week, and is equivalent to 80% of the RD with this schedule. This is the 
minimal gemcitabine dose accepted in clinical practice. 
The DL1 for PM060184 will be 6.0 mg/m2. This corresponds to a DI of 4.0
mg/m2/week, and is equivalent to 64% of the RD determined for PM060184 given as 
single agent with this schedule.
The dose escalation scheme will follow pre-defined dose levels, starting at DL1, as 
summarized in Table 1.
Table 1. Dose escalation scheme.
DL
No. of
patients
Relative DI (%) 
of gemcitabine / 
PM060184
Gemcitabine dose (mg/m2) 
on Day 1 and Day 8  
q3wk
PM060184 dose (mg/m2) 
on Day 1 and Day 8  
q3wk
DL-1
0-6
80/53
800 
5.0
DL1
3-6
80/64
800 
6.0
DL2
3-6
80/74
800 
7.0
DL3
3-6
100/74
1000
7.0
DL4 
and 
beyond
3-6
No further dose increases 
beyond 1000 mg/m2
Further dose increases of 
0.5 or 1.0 mg/m2, 
according to observed 
toxicities 
DI, dose intensity; DL, dose level; MTD, maximum tolerated dose.

Cohorts of at least three fully evaluable patients will be treated at each cohort.

The second and third patients of a cohort may be included simultaneously after 
the first patient has completed the first cycle, except if a DLT is reported in the 
first patient, in which case the third patient of the cohort will be included once the 
second patient has received a complete treatment cycle with no reported DLTs. 
All patients will have to be fully evaluable (3-week period) prior to any further 
dose escalation. Patients not fully evaluable will be replaced.

Dose escalation will continue if no DLT is observed.

Subsequent dose levels will enroll three patients, and up to six fully evaluable 
patients if one DLT is observed in any of the first three fully evaluable patients. 

Once a DLT is observed, further patients will be included up to six fully evaluable 
patients in this dose cohort.

For gemcitabine: two doses (800 mg/m2 and 1000 mg/m2) will be initially tested. 
If the toxicity observed during dose escalation is clearly related to gemcitabine 
(i.e. neutropenia and/or thrombocytopenia), intermediate gemcitabine doses might 
be tested after agreement between the Investigators and the Sponsor. 

For PM060184: pre-established PM060184 doses have been set for the first three
DLs. After DL3, dose increments of 1.0 mg/m2 will be tested if toxicity at each 
previous DL is acceptable. These dose increments may be of 0.5 mg/m2, 
according to the toxicity observed. In the event of toxicities specifically related 
with PM060184 (i.e. peripheral neuropathy, post-infusion abdominal pain and/or 
diarrhea), intermediate PM060184 doses might be tested after agreement between 
the Investigators and the Sponsor.

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Both the PM060184 and the gemcitabine doses may be rounded to the first decimal.
If more than one of three or six evaluable patients at any DL experience a DLT during 
Cycle 1, dose escalation will be terminated. The MTD will be the lowest level at 
which more than one third of evaluable patients experienced a DLT in Cycle 1 (Table 
2). The RD will be the highest DL explored with less than one third of evaluable 
patients experiencing a DLT during Cycle 1. 
Table 2. Determination of the maximum tolerated dose.
No. of  patients 
evaluable for DLT
No. of patients with 
DLTs in Cycle 1
Action
3
0
Escalate DL
1
Add 3 patients
>1
MTD
6
1
Escalate DL
>1
MTD
DL, dose level; DLT, dose-limiting toxicities; MTD, maximum tolerated dose.
If two or more evaluable patients (of 3-6 patients) at any DL experience a dose delay 
> 7 (+1) days from the theoretical due date (conforming or not to DLT criteria) and/or 
dose omissions exclusively related to PM060184 toxicity during Cycle 1, the cohort 
should be expanded as shown in the table below. If more than 50% of evaluable 
patients in a cohort experience dose delays and/or omissions, dose escalation will be 
terminated and this DL will be considered the MTD. An alternative schedule could 
then be explored after discussion between the Investigators and with the Sponsor’s 
agreement. The starting dose of the new schedule will be the DL immediately below 
the MTD.
Table 3. Cohort expansion and determination of the maximum tolerated dose in the 
event of dose delays/omissions in Cycle 1.
Dose delays  
Dose omissions 
Action
1
-
None
-
1
None
1
1
Add 3 more patients 
≥ 2
-
Add 3 more patients
-
≥ 2
Add 3 more patients
If more than 50% evaluable patients in a 
cohort have dose delays and/or omissions  
MTD
DLT, dose-limiting toxicities; MTD, maximum tolerated dose.
An expansion cohort of a minimum of nine evaluable patients will be treated at the RD 
once it has been determined; this is to confirm its feasibility and tolerability. Once the 
RD is confirmed, exploratory cohorts of at least 12 patients each will be expanded at 
RD in selected tumor type(s) and/or target subpopulations, chosen according to the 
preliminary efficacy observed among those previously treated during dose escalation, 
discussed and agreed between the Investigators and the Sponsor.
Intra-patient dose escalation will not be allowed under any circumstances.
3.3.1
Dose Escalation Meetings
The Sponsor will organize raw data review and discussion (e.g., a teleconference) with 
the investigators on a regular basis as needed according to study course (e.g., after the 
first patient enrolled at a given DL has completed the first cycle or when a DL cohort 
has been completed). 

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Prior to the meeting, all relevant safety and laboratory non-monitored data must be 
made accessible by the Investigators to the Sponsor’s responsible, preferably using the 
electronic Case Report Form (e-CRF). Investigators must guarantee the accuracy of the 
information provided against the source documents.
At the dose escalation discussions, all available clinical data (safety information, 
including all events that might be considered DLTs, and all grade ≥ 2 toxicity data at 
least during Cycle 1, as well as available PK data) of each treated patient will be 
described and discussed in detail. Updated safety data from prior patients, including 
prior treatment cycles and serious adverse events (SAEs), will also be discussed, if 
appropriate. The Sponsor will document the final agreement or decision adopted, and 
will keep the information and all support documents in the trial master file.
Finally, available slot assignment for the next cohort of patients will also be updated
during these discussions. Whenever possible, the slot assignment will be similarly 
distributed among participating centers and according to the number of identified 
candidates. However, in order not to slow down the recruitment a maximal 2-week 
period is allowed to effectively start treatment after slot assignment. Failure to do so, in 
the presence of waiting candidates in another participating center, will result in 
competitive slot re-allocation. The Investigators will be responsible for informing the 
Sponsor of any potential candidates on screening at that time. The Sponsor will 
immediately update all other investigators on slot availability as soon as a screening 
failure is notified; these slots will be allocated by competitive enrolment.
4.
SELECTION OF PATIENTS
Patients must fulfill all the following inclusion criteria and none of the exclusion criteria 
to be eligible to participate in the study.
4.1
INCLUSION CRITERIA
1) Voluntarily signed and dated written informed consent prior to any specific study 
procedure.
2) Age ≥18 years.
3) Eastern Cooperative Oncology Group (ECOG) performance status (PS) of ≤ 1 (see
APPENDIX 1).
4) Life expectancy ≥ 3 months.
5) Patients with a histologically/cytologically confirmed diagnosis of advanced disease 
of any of the following tumors that progressed to standard therapy or for whom no 
standard therapy exists (with the exception of neuroendocrine, carcinoid, small cell 
and sarcoma histology subtypes, which are not allowed):
a) Breast cancer non-candidate for hormone therapy alone.
b) Epithelial ovarian cancer (including primary peritoneal disease and/or fallopian 
tube carcinomas and/or endometrial adenocarcinomas).
c) Locally advanced or metastatic head and neck cancer.
d) Non-small cell lung cancer (NSCLC).
e) Germ cell tumors (GCTs).
f)
Biliary tract adenocarcinoma.

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g) Adenocarcinoma or carcinoma of unknown primary site (UKPS).
h) Cervix carcinoma. 
i)
Gastrointestinal stromal tumor (GIST).
j)
Urothelial cancer.
6) Expansion cohort at the RD and tumor-specific cohorts:
All patients must have:
a) Measurable disease according to RECIST v.1.1 (or Choi criteria and/or EORTC 
metabolic response criteria for solid tumors, in the case of GIST); or
b) Evaluable disease by serum markers in the case of ovarian cancer [Gynecologic 
Cancer Intergroup (GCIG) specific criteria]; and
c) Documented disease progression during or immediately after last therapy 
according to any of the aforementioned criteria.
7) Wash-out periods: at least three weeks since the last administration of an
anticancer therapy, including radiation therapy (RT) or a biological/investigational 
therapy [excluding monoclonal antibodies (MAbs)]; at least four weeks since the 
last MAb-containing therapy; and at least six weeks since nitrosoureas and 
mitomycin C (systemic). In the case of hormone-sensitive breast cancer 
progressing while on hormone therapy, the latter must be either stopped up to one 
week before or continued without changes during the trial.
8) Adequate bone marrow, renal, hepatic, and metabolic function (assessed ≤ 7 days 
before inclusion in the study):
a) Platelet count ≥ 100 x 109/l, hemoglobin ≥ 9.0 g/dl and ANC ≥ 1.0 x 109/l.
b) AST and ALT ≤ 3.0 x ULN, independently of the presence of liver metastases.
c) AP ≤ 2.5 x ULN (≤ 5 x ULN if disease-related).
d) Total bilirubin ≤ 1.5 x ULN.
e) International Normalized Ratio (INR) < 1.5 (except if patient is on oral 
anticoagulation therapy).
f)
Calculated creatinine clearance (CrCl) ≥ 50 ml/min (using Cockcroft and 
Gault’s formula; see APPENDIX 2).
g) Albumin ≥ 2.5 g/dl.
9) Recovery to grade ≤ 1 from any AE derived from previous treatment (excluding 
alopecia and/or cutaneous toxicity and/or asthenia).
10) Left ventricular ejection fraction (LVEF) by echocardiography (ECHO) or multiple-
gated acquisition (MUGA) within normal range (according to institutional 
standards).
11) Women of childbearing potential must have a negative serum or urine pregnancy 
test before study entry. Both women and men must agree to use a medially 
acceptable method of contraception throughout the treatment period and for six 
months after discontinuation of treatment. Acceptable methods of contraception 
include intrauterine device (IUD), oral contraceptive, subdermal implant and/or 
double barrier.
4.2
EXCLUSION CRITERIA
1) Concomitant diseases/conditions:

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a) History or presence of unstable angina, myocardial infarction, congestive heart 
failure, or clinically significant valvular heart disease within last year.
b) Symptomatic arrhythmia or any uncontrolled arrhythmia requiring ongoing 
treatment.
c) Known chronic active hepatitis or cirrhosis.
d) Active uncontrolled infection [i.e., antibiotic, antifungal or antiviral intervention 
indicated or surgical procedure (i.e., pleural or deep abscess drainage) conducted 
within 15 days prior to inclusion].
e) Known human immunodeficiency virus (HIV) infection.
f)
Current or prior history of grade ≥ 2 peripheral sensory and/or motor 
neuropathy.
g) Prior treatment with oxaliplatin.
h) Limitation of the patient’s ability to comply with the treatment or follow-up 
protocol.
i)
Any other major illness that, in the Investigator’s judgment, will substantially 
increase the risk associated with the patient’s participation in this study.
2) Symptomatic, progressive or corticosteroids-requiring documented brain metastases 
or leptomeningeal disease involvement. 
3) Men or women of childbearing potential who are not using an effective method of 
contraception as previously described; women who are pregnant or breast feeding.
4) Patients who have had RT in more than 35% of the bone marrow (see APPENDIX 
3).
5) Prior treatment with PM060184.
6) Prior treatment with gemcitabine-containing therapy for advanced disease (adjuvant 
therapy is allowed, provided not more than six cycles were administered and relapse 
occurred more than six months after the last drug administration), and/or: 
a) Patients who have previously discontinued gemcitabine-containing regimens due 
to gemcitabine-related toxicity. 
7) Known hypersensitivity to gemcitabine or any component of the formulation.
4.3
PATIENTS FOR THE PHARMACOGENETIC EVALUATIONS
1) Only patients who voluntarily give their consent and sign the ICF for the 
pharmacogenetic substudy will participate. Refusal to participate will not affect 
patient participation in the clinical study PM60184-A-003-14.
5.
PLAN OF THE STUDY
5.1
PLANNED TRIAL PERIODS (FOR THE WHOLE STUDY)
The total duration of the study will be approximately 69 months, including 
approximately a 60-month enrolment period. 
Planned start date (first patient on study): 4Q2014.
Planned enrolment period: approximately 60 months.

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Planned end-of-study date (clinical cutoff): six months after the last patient’s 
treatment discontinuation (last patient-last visit), or nine months after accrual of the last 
evaluable patient, whichever occurs first.
5.2
PLANNED TRIAL PERIODS (INDIVIDUALLY PER PATIENT)
Patients will be evaluated at scheduled visits in three study periods:

Pre-treatment: from signature of IC to the day of first infusion of study drugs.

Treatment: from first infusion of study drugs to the end of treatment (EOT) (see 
Section 5.2.1).

Follow-up: after EOT, patients will be followed every four weeks until resolution 
or stabilization of relevant related (i.e., grade > 1) toxicities if any. Patients who 
discontinued treatment without disease progression will be followed every three 
months until disease progression, other antitumor therapy, death or until the date 
of study termination (clinical cutoff), whichever occurs first. 
Patients will be considered to be on-study from the signature of the IC to the end of the 
follow-up period. Patients will be considered to be on-treatment for the duration of 
their treatment and until the EOT. This EOT is defined as 30 days (±15 days) after the 
day of the last study drug dose administration (see Figure 3). An EOT visit will be 
performed within 30 days (± 15 days) after the last study drug dose administration, 
unless the patient starts any subsequent antitumor therapy (in which case the EOT visit 
should be performed before the start of the new therapy, whenever possible). If the 
patient dies while on treatment, the date of death will be considered the EOT date
Figure 3. Study periods.
d, day; FUP, follow-up; ICF, informed consent form; PRE TT, pre-treatment; TT, treatment; wk, week.
Patients may withdraw their consent at any time; under this circumstance, no further 
study activities will be conducted on them.

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5.2.1
Discontinuations
5.2.1.1 End of Treatment
Treatment discontinuation occurs when an enrolled patient ceases to receive PM060184
and gemcitabine regardless of the circumstances. The primary reason for any treatment 
discontinuation will be recorded on the patient’s e-CRF. 
An end-of-treatment visit (EOT visit) will be performed within 30 days (± 15 days) after 
the last study drug dose administration, unless the patient starts any subsequent new 
antitumor therapy outside this clinical trial (in which case the EOT visit should be 
performed immediately before the start of the new therapy, whenever possible).
If a patient discontinues treatment, every effort should be made to complete the 
scheduled assessments as appropriate, whenever possible.
5.2.1.2 Reasons for End of Treatment
Patients will receive the study drugs while it is considered to be in their best interest. 
Specifically, treatment will continue until:

Disease progression.

Unacceptable toxicity.

Intercurrent illness of sufficient magnitude to preclude fulfillment of appropriate 
re-treatment criteria and/or safe continuation of the study.

Patient refusal and/or non-compliance with study requirements.

Treatment delay > 7 (+1) days from the theoretical due date due to toxicity 
(except in case of patient’s clear clinical benefit, with the Sponsor’s approval).

Requirement of > 2 dose reductions.
Patients who are withdrawn for any reasons must not be re-treated in the context of this 
study at any time. For follow-up activities, please refer to Section 5.9.
5.2.1.3 Study Discontinuation
Study discontinuation occurs when an enrolled patient ceases to participate in the study, 
regardless of the reason (as detailed under “Follow-up” in Section 5.2). Patients have 
the right to withdraw consent at any time; if this is the case, no further study procedures
should be performed, and no further data should be collected from the date of consent 
withdrawal.
The date and reason for study discontinuation will be clearly documented on the 
patient’s e-CRF. 
5.2.2
Protocol Deviations
A protocol deviation is defined as any departure from what is described in the protocol 
of a clinical trial approved by an Independent Ethics Committee (IEC)/Institutional 
Review Board (IRB) and Competent Authorities. Therefore, it applies to deviations 
related to patient inclusion and clinical procedures (e.g., assessments to be conducted or 
parameters to be determined), and also to other procedures described in the protocol that 
concern the Good Clinical Practice (GCP) guidelines or ethical issues (e.g., issues 
related to obtaining the patients’ Informed Consent, data reporting, the responsibilities 
of the Investigator, etc.).

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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 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 IC or not 
following the terms established for reporting SAEs, etc.
As a general rule, NO deviations that may have an effect on the risk/benefit ratio of the 
clinical trial will be authorized. All protocol deviations detected during the study will be 
appropriately documented, and those considered particularly relevant (i.e., those related 
to ethical issues, to fulfillment of GCP guidelines and with an effect on the risk/benefit 
ratio) will be notified to the pertinent IEC/IRB and, if applicable, to the Competent 
Authorities as established by local regulations.
5.3
REPLACEMENT OF PATIENTS
Patients must be replaced if they are not fully evaluable for the assessment of the 
primary endpoint, i.e. if:

They are withdrawn from the study before receiving at least one evaluable cycle 
for any reason other than treatment-related toxicity (excluding hypersensitivity 
and/or extravasations reactions). An evaluable cycle is defined as: gemcitabine 
followed by PM060184 on Day 1 and Day 8, with the corresponding 2-week 
observation period during the first cycle. 

They require RT or other therapeutic procedure within three weeks after the first 
study drug dose, unless they previously had another treatment-related AE 
included in the definition of DLT.

There is a protocol violation resulting in an impossibility of concluding anything 
regarding the safety of the study therapy.
All replaced patients will be included in the general safety analysis and in the efficacy 
analysis (if appropriate).
5.4
PRE-TREATMENT ASSESSMENTS
During the pre-treatment period, following signature of the IC form, the Investigator 
will confirm the patient’s eligibility for the study by conducting the assessments
summarized in Table 4.
Table 4. Screening period: pre-treatment assessments.
ASSESSMENT
TIME
1. Written informed 
consent
Before any study procedures.
2. Pharmacogenetics 
informed consent
(optional)
Before any study procedures.
3. Medical and 
Demographic data (race/ethnicity, age, gender, Within 28 days before the start of 

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ASSESSMENT
TIME
cancer history/ 
clinical examination
height).
Medical and cancer history/baseline condition:
o Date of diagnosis of the primary disease.
o Prior 
treatments 
(surgery, 
radiotherapy, 
chemotherapy, 
biological/targeted 
agents), 
specifying best response and date of PD, when 
available. 
treatment. *
Assessment of signs and symptoms.
Within 28 days before the start of 
treatment. *
Complete physical examination, including weight 
and BSA.
Performance status (ECOG PS; see APPENDIX 1).
Vital signs: heart rate, blood pressure and body 
temperature.
Within seven days before the start of 
treatment. *
Concomitant therapies.
Within 14 days before the start of 
treatment. *
4. Laboratory tests

Hematology:
differential WBC (neutrophils, 
lymphocytes), hemoglobin and platelets.
Biochemistry-A: AST, ALT, total bilirubin, AP, 
LDH, creatinine, glucose and serum electrolytes (Na+, 
K+, Cl–, total calcium).
Biochemistry-B and coagulation:
o Total proteins, albumin. 
o Coagulation tests: PT, aPTT, INR.
o Exploratory serum tumor markers as appropriate, 
according to primary tumor type.
Within seven days before the start of 
treatment. *
5. Pregnancy test (if 
premenopausal 
woman of 
childbearing 
potential)
Assessment of β-hCG (urine or serum).
Within seven days before the start of 
treatment. *
6. Cardiac 
assessment
ECG ** 
Within 28 days before the start of 
treatment. *
LVEF by ECHO or MUGA.
Within 28 days before the start of 
treatment. *
7. Radiological 
tumor assessment
Helical 
contrast-enhanced 
CT-scan 
and/or 
gadolinium-enhanced 
MRI 
of 
all 
measurable/evaluable sites as per RECIST v.1.1,
Choi criteria and/or EORTC metabolic response 
criteria, as applicable (see APPENDIX 4  and 
APPENDIX 5). ***
Within 28 days before the start of 
treatment. *
8. PK 
One blood sample (as in Section 6). 
Immediately before the start of 
treatment.
9. Pharmacogenetics One blood sample. **** 
At any time during the study, but 
ideally immediately before the start 
of treatment (always after the 
specific optional consent has been 
given).
10. Adverse events
Only information on SAEs that occurred after 
signature of the ICF is required before treatment start. 
Grading should be as per the NCI-CTCAE v.4.
-
* A -24-hour window will be allowed for clinical assessments (ECOG PS, vital signs, weight, BSA, etc.), a -24-
hour window for laboratory procedures, and a ±1-week window for radiological procedures. 
** ECG should allow rhythm definition, and should include assessment of PR interval, heart rate, QT interval 
(raw) and QRS complex duration.
*** PET-CT scan might be used, if appropriate additionally, on individual cases upon the Sponsor’s agreement.
Patients with GIST should always be assessed with PET-CT scans, and efficacy will be evaluated according 
to Choi criteria and/or EORTC metabolic response criteria for solid tumors.
**** One blood sample will be collected to evaluate the presence or absence of known polymorphisms. 
ALT, alanine aminotransferase; AP, alkaline phosphatase; aPTT, activated plasma thromboplastin time; AST, 
aspartate aminotransferase; BSA, body surface area; CT-scan, computed tomography scan; ECG, 
electrocardiogram; ECHO, echocardiography; ECOG, Eastern Cooperative Oncology Group; EORTC, European 

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ASSESSMENT
TIME
Organization for Research and Treatment of Cancer; β-hCG, beta subunit of human chorionic gonadotropin; ICF, 
informed consent form; INR, international normalized ratio; LDH, lactate dehydrogenase; LVEF, left ventricular 
ejection fraction; MRI, magnetic resonance imaging; MUGA, multiple gated acquisition scan; NCI-CTCAE, 
National Cancer Institute Common Terminology Criteria for Adverse Events; PD, progressive disease; PET, 
positron emission tomography; PK, pharmacokinetics; PS, performance status; PT, prothrombin time; RECIST, 
Response Evaluation Criteria In Solid Tumors; SAE, serious adverse event; WBC, white blood cells.
5.5
PATIENT REGISTRATION
Once the screening period testing has been done in order to confirm that the consenting 
candidate meets all eligibility criteria, the patient can be registered into the study by 
completing the electronic screening form. This form will be checked and eligibility 
confirmed by the Sponsor. An identification number will be automatically assigned (by 
the system) to the patient during registration; this number should be used on all future 
documentation and correspondence referring this patient. Regardless of circumstances, 
the Investigators will not be allowed to treat any patient before appropriate receipt of the  
Sponsor’s agreement. 
For patients registered but never treated, only baseline and off-study visits modules of 
the e-CRF should be completed.
5.6
PATIENT RANDOMIZATION
Not applicable.
5.7
EVALUATIONS DURING TREATMENT
The following assessments will be done while the patient is on treatment (Table 5).
Table 5. Evaluations during treatment.
ASSESSMENT
TIME
1. Clinical 
examination
Complete physical examination, including 
weight and BSA.
Cycle 1: Day 1 (always prior to treatment 
administration), but only if not done at 
screening.
Cycle 2 and further: Day 1 (always prior 
to treatment administration). *
BSA will have to be recalculated before 
treatment administration in subsequent 
cycles for patients showing a ≥10 % 
variation in total body weight from 
baseline or from last dose adjustment; 
otherwise the BSA and dose calculated for 
the previous cycle could be used. The same 
BSA calculation method should be used 
throughout the study.

Performance status (ECOG PS;
see 
APPENDIX 1).
Vital signs: heart rate, blood pressure and 
body temperature.
Cycle 1: Day 8 (always prior to treatment 
administration) and Day 15.
Also on Day 1 prior to treatment 
administration, but only if not done at 
screening.
Cycle 2, 3 and 4: Days 1 and 8 (always 
prior to treatment administration) and 
Day 15. *
Cycle 5 and further: Days 1 and 8 (always 
prior to treatment administration), unless 
otherwise is clinically indicated. *
Concomitant therapies.
Throughout the “on treatment” period. **
2. Laboratory tests

Hematology:
differential 
WBC 
(neutrophils, lymphocytes), hemoglobin and 
platelets.
Cycle 1: Day 8 (always prior to treatment 
administration) and Day 15. *
Also on Day 1 prior to treatment 

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ASSESSMENT
TIME
administration, but only if not done at 
screening.
Cycles 2, 3 and 4: Days 1 and 8 (always 
prior to treatment administration) and 
Day 15. *
Cycle 5 and further: Days 1 and 8 (always 
prior to treatment administration), unless 
otherwise is clinically indicated. *
During the first four cycles,
if any 
clinically
relevant 
treatment-related 
NCI-CTCAE grade ≥ 3 toxicity occurs, 
the abnormal test(s) should be re-assessed 
at least every 2-3 days until recovery to 
at least grade 2.
In the event of febrile neutropenia, 
grade 4 neutropenia and/or grade 4 
thrombocytopenia, 
re-assessment 
should 
be 
performed 
daily 
until 
recovery to at least grade 3 or until 
fever resolution, if applicable, and then 
every 2-3 days thereafter until recovery to 
at least grade 2. From Cycle 5 onwards, 
any treatment-related NCI-CTCAE grade 
≥ 3 toxicity not considered a major risk 
for the patient is to be re-evaluated 
according to Investigator’s criteria.

Biochemistry-A:
AST, 
ALT, 
total 
bilirubin, AP, LDH, creatinine, glucose and 
serum electrolytes (Na+, K+, Cl–,
total 
calcium).
Cycle 1: Day 8 (always prior to treatment 
administration) and Day 15. *
Also on Day 1 prior to treatment 
administration, but only if not done at 
screening.
Cycles 2, 3 and 4: Days 1 and 8 (always 
prior to treatment administration) and 
Day 15. *
Cycle 5 and further: Days 1 and 8 (always 
prior to treatment administration), unless 
otherwise is clinically indicated. *
During the first four cycles,
if any 
clinically
relevant 
treatment-related 
NCI-CTCAE grade ≥ 3 toxicity occurs, 
the abnormal test(s) should be re-assessed 
at least every 2-3 days until recovery to 
at least grade 2. From Cycle 5 onwards, 
any treatment-related NCI-CTCAE grade 
≥ 3 toxicity not considered a major risk 
for the patient is to be re-evaluated 
according to Investigator’s criteria.
Biochemistry-B and coagulation:
o Total proteins, albumin. 
o Coagulation tests: PT, aPTT, INR.
o Repeat only the same serum tumor 
marker that was abnormally elevated at 
baseline (≥2 x ULN), if applicable.
Cycle 1: Day 1 (always prior to treatment 
administration), but only if not done at 
screening. 
Cycle 2 and further: Day 1 (always prior 
to treatment administration). *
3. Pregnancy test (if 
premenopausal 
woman of 
childbearing 
potential)
Assessment of β-hCG (urine or serum).
Repeat if clinically indicated.
4. Cardiac assessment
ECG. ***
Repeat if clinically indicated (reason 
should be specified in the e-CRF). **
LVEF by ECHO or MUGA. ****
Every other cycle.

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ASSESSMENT
TIME
5. Radiological tumor 
assessment
Helical contrast-enhanced CT-scan and/or 
gadolinium-enhanced 
MRI 
of 
all 
measurable/evaluable sites as per RECIST 
v.1.1, Choi criteria and/or EORTC metabolic 
response criteria for solid tumors, as 
applicable (see APPENDIX 4 and 
APPENDIX 5). *****
Every two cycles ± one week until Cycle 
4, and then every three cycles ± one week 
from Cycle 4 while on treatment, unless 
otherwise is clinically indicated.
The same method should always be used 
for each individual patient throughout the 
study.
6. PK
As in Section 6. 
Nine blood samples collected from Day 1 
to Day 2 of Cycle 1.
Patients treated in the expanded cohort at 
the RD will also be sampled for PK 
analysis on Day 1 and Day 2 of Cycle 2 at 
the same time points.
7. Pharmacogenetics
One blood sample. 
At any time during the study (always after 
the specific optional consent has been 
given).
8. Adverse events
As per NCI-CTCAE v.4.
Throughout the “on treatment” period. **
* A -24-hour window will be allowed for clinical assessments (ECOG PS, vital signs, weight, BSA, etc.), a -24-hour 
window for laboratory procedures (a -48-hour window on infusion days, excluding Day 1 of Cycle 1), and a ±1-week 
window for radiological procedures. Additionally, for D15 a +24 hour window will also be allowed for clinical 
assessments and laboratory procedures.
** “On treatment period” = from first study drug administration to EOT. The EOT visit will be performed within 30 
days (± 15 days) after the last study drug dose administration, unless the patient starts any subsequent antitumor 
therapy (in which case the EOT visit should be performed before the start of the new therapy, whenever possible).
*** ECG should allow rhythm definition, and should include assessment of PR interval, heart rate, QT interval (raw) 
and QRS complex duration.
**** In the event of LVEF decrease to grade ≥ 2 by MUGA, an ECHO should be done to confirm this decrease and 
also to rule out any heart injures. Major efforts must be done to find the main cause of this AE (cardiac enzymes, 
troponin I and or T, cardiologist assessment, etc.). LVEF by ECHO should be performed at least every four weeks 
until recovery or stabilization.
***** PET-CT scan must be used, if appropriate, on individual cases upon Sponsor’s agreement. Patients with 
GIST should always be assessed with fusion or integrated PET-CT scans, and efficacy will be evaluated by 
Choi criteria and/or EORTC metabolic response criteria for solid tumors. Anonymized copies of the images 
showing objective response or meaningful tumor shrinkage must be submitted to the Sponsor.
AE, adverse event; ALT, alanine aminotransferase; AP, alkaline phosphatase; aPTT, activated plasma thromboplastin 
time; AST, aspartate aminotransferase; BSA, body surface area; CT-scan, computed tomography scan; ECG, 
electrocardiogram; ECHO, echocardiography; ECOG, Eastern Cooperative Oncology Group; e-CRF, electronic case 
report form; EORTC, European Organization for Research and Treatment of Cancer; EOT, end of treatment; GIST, 
gastrointestinal stromal tumor; β-hCG, beta subunit of human chorionic gonadotropin; INR, international normalized 
ratio; LDH, lactate dehydrogenase; LVEF, left ventricular ejection fraction; MRI, magnetic resonance imaging; 
MUGA, multiple gated acquisition scan; NCI-CTCAE, National Cancer Institute Common Terminology Criteria for 
Adverse Events; PET, positron emission tomography; PK, pharmacokinetics; PS, performance status; PT, 
prothrombin time; RD, recommended dose; RECIST, Response Evaluation Criteria In Solid Tumors; ULN, upper 
limit of normal; WBC, white blood cells.
5.8
EVALUATIONS AT END OF TREATMENT
The EOT visit will be scheduled within 30 days (± 15 days) after the last study drug 
dose administration, unless the patient starts any subsequent antitumor therapy, in which 
case the EOT visit should be performed immediately before the start of the new therapy, 
whenever possible.
Evaluable patients, regardless of the reason for ending the treatment, will have to 
undergo the following assessments at the EOT visit (with a ± 15-day window to conduct 
them):

Complete physical examination [including weight and body surface area (BSA)].

ECOG PS.

Vital signs (heart rate, blood pressure, body temperature).

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
Hematology.

Biochemistry-A.

Biochemistry-B and coagulation.

LVEF.

Concomitant therapies.

Adverse events.
On individual patients and if clinically indicated according to the Investigator’s 
criteria, it might also include the following:

Pregnancy test.

Electrocardiogram (ECG).

Other tests as appropriate.
All these evaluations will only have to be repeated for those parameters for which no 
measurement is available within 15 (-3) days before the EOT visit, or for those 
parameters with values that were out of range in the last assessment (grade > 1 
according to NCI-CTCAE v.4).
Adverse events must be reported for 30 days after the last study treatment
administration. All SAEs occurring within 30 days of the last study drugs administration
will be reported. Beyond this period of time, only those suspected to be treatment-
related SAEs will be reported (Section 9.4.2).
The Sponsor will evaluate all safety information that is spontaneously reported by an
Investigator beyond the time frame specified in the protocol.
5.9
FOLLOW-UP AFTER END-OF-TREATMENT VISIT
The date and reason of the study discontinuation will be recorded on the patient’s e-
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, death or until the date 
of study termination (clinical cutoff), whichever occurs first.
The end-of-study date (clinical cutoff) is defined as six months after the last patient’s 
treatment discontinuation (last patient-last visit), or nine months after accrual of the last 
evaluable patient, whichever occurs first.
All relevant AEs (grade > 1) suspected to be related to study drugs must be followed 
after the end of treatment until the event resolve or stabilize (i.e., to grade 1), or until 
start of a new therapy. After the end of treatment, patients will be followed every four 
weeks until resolution or stabilization of toxicities, if any, or until onset of new therapy.
Patients who withdraw consent will not be followed with any study procedures, and no 
additional data will be collected after consent withdrawal.
Additional parameters and/or increased frequency of observations should be performed 
at the Investigator’s discretion and according to the nature of the observed AEs. In case 
of death, when available, autopsy data should be provided.

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6.
PHARMACOKINETICS
The plasma PK of PM060184, gemcitabine and 2,2-difluorodeoxyuridine (dFdU) will 
be evaluated during Days 1 and 2 of Cycle 1 with a schedule of ten samples in all 
patients. Additionally, patients treated in the expanded cohort at RD and in the tumor-
specific cohorts will be sampled for PM060184 analysis on Days 1 and 2 of Cycle 2 at 
the same time points.
The sampling schedule for both compounds is described in Table 6, taking as reference 
the gemcitabine infusion on Day 1.
Table 6. Sampling schedule for the determination of gemcitabine, dFdU and 
PM060184.
Sample
number
Day
Time relative to 
gemcitabine infusion 
(h)
Sampling times 
for gemcitabine
and dFdU
Sampling times 
for PM060184
Sampling 
Windows
#1
1
0
Pre-dose
Pre-dose
-
#2
1
0.5
Just before EOI
--
- 2 min
#3
1
0.67
10 min EOI
Just before EOI
- 2 min
#4
1
0.92
25 min EOI
15 min EOI
± 5 min
#5
1
1.17
40 min EOI
30 min EOI
± 5 min
#6
1
1.67
1 h 10 min EOI
1 h EOI
± 10 min
#7
1
2.67
2 h 10 min EOI
2 h EOI
± 10 min
#8
1
3.67
3 h 10 min EOI
3h EOI
± 10 min
#9
1
5.67
5 h 10 min EOI
5 h EOI
± 30 min
#10
2
24
24 h EOI
24 h EOI
± 2 h
dFdU, 2,2-difluorodeoxyuridine; EOI, end of infusion; h, hours; min, minutes.
Drug administration on Day 1 (i.e., on the same day in which most PK samples are to be 
collected) should be as follows: after the pre-dose PK sample, gemcitabine will be 
administered as a 30-min (± 10-min) i.v. infusion. The 10-min (± 3-min) i.v. infusion of 
PM060184 will start immediately (+5 min window) after completion of the gemcitabine 
infusion. Figure 4 summarizes the PK sampling schedule.
Figure 4. Pharmacokinetic sampling schedule.
EOI, end of infusion.
Note: the temporal scale is not uniform, but depends on sample density.
The exact recording of the time of drug administration and sampling times during 
infusions is crucial. The infusion rate will be established to ensure that the whole dose 

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of each compound is infused over the established time, i.e. 30 min (± 10-min) for 
gemcitabine and 10 min (± 3-min) for PM060184. The drugs will be infused at a 
constant rate throughout the corresponding period. In order to obtain reliable PK 
information, the infusion rate should not be modified once the infusion begins.
Blood samples for PK analysis will be obtained through a peripheral vein located in the 
contralateral side to that of the infusion. In any case, the sampling vein has to be 
different to that in which the drugs are infused. Even the last sample must never be 
collected from the catheter used for drug infusion.
If the blood sample is obtained from a catheter, the first milliliter (ml) of blood will be 
discarded to avoid dilution of the sample with the solution used to keep it clean. Heparin 
(10 U/ml in normal saline solution) or a slow drip of normal saline solution (10 ml/h) 
can be used to keep the catheter permeable between extractions.
The Instruction Manual for the Collection, Labeling, Storage and Shipment of 
Pharmacokinetic Samples describes in detail the procedures. Please, read carefully all 
the procedures before PK days. 
In summary, after the collection of each sample (8 ml, whole blood), the sample will be 
centrifuged and the plasma layer transferred into new tubes for the determination of 
gemcitabine, dFdU or PM060184. The plasma tubes will be stored under frozen 
conditions until the shipment to the analysis laboratory. All the PK material will be 
provided by Pharma Mar S.A.
Once all samples from a patient have been collected, they should be shipped to the 
central laboratories for PK analysis as soon as possible, ideally on the next shipping 
day. If the same center has samples from several patients, samples can be sent in the 
same shipment. However, the time span between the moment the last PK sample for a 
patient has been collected and the shipment of all samples from this patient to the 
central laboratory should not exceed one month.
Support PK forms should be sent at the same time, but never in contact with dry ice. 
Samples will be identified with the following data: study reference, IMP, patient 
number, sample number, date and time of collection. The confidentiality of patients’ 
data will be maintained at all times. Samples will be destroyed following the appropriate 
laboratory procedures, after the approval of the final analytical study report by the 
Sponsor.
7.
PHARMACOGENETIC EVALUATIONS
In order to explore factors that may help explain individual variability in main PK 
parameters, the presence or absence of germline mutations or polymorphisms will be 
analyzed in leukocyte DNA extracted from a blood sample obtained at any time during 
the study, but ideally before treatment start along with PK sample #1 on Day 1 of Cycle 
1. 
The collection and management of the polymorphisms samples are quite different than 
those for PK assessment. Please follow carefully the instructions detailed in the 
Instruction Manual for Collection, Labeling, Storage and Shipment of Pharmacogenetic 
Samples. The assessment of polymorphisms is not affected by treatment. Therefore, the 
Sponsor may require the collection of additional polymorphisms samples later on, if the 
sample has not been drawn/processed adequately, thus making the sample not 
analyzable.

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Only patients who voluntarily give their informed consent and sign the ICF for the 
pharmacogenetic substudy will participate in these evaluations. Refusal will not affect 
patient participation in the clinical study PM60184-A-003-14.
8.
TREATMENT
8.1
DESCRIPTION OF TREATMENT
8.1.1 Drug Formulation and Supply
8.1.1.1 Gemcitabine
Commercially available presentations of vials containing gemcitabine will be provided 
as appropriate. Gemcitabine will be prepared in accordance with the applicable 
Summary of Product Characteristics (SmPC). Medication preparation records will be 
kept by the site.
8.1.1.2 PM060184
The drug substance PM060184-CD is a mixture of PM060184 and 2-hydroxypropyl-β-
cyclodextrin.
PM060184 drug product (DP) is provided as a sterile lyophilized powder for 
concentrate for solution for infusion with a strength of 15 mg of the active moiety 
PM060184. 
Before use, the vials should be reconstituted with 6 ml of water for injection to give a 
solution containing 2.5 mg/ml of PM060184. PM060184 15-mg DP was developed for 
administration by the i.v. route. Prior to administration, the reconstituted vials should be 
further diluted with dextrose 5% solution for infusion. Each 15-mg vial of PM060184 is 
a single-use vial. PM060184 reconstitution/dilution records will be kept by the site.
The full composition of the reconstituted solution per ml is shown in Table 7.
Table 7. Composition of PM060184 vials.
Component
Concentration 
(per ml)
Function
PM060184
2.5 mg/ml
Active moiety
2-Hydroxypropyl-β 
cyclodextrin (DS 4-5)*
200 mg/ml
Solubilizing agent
Water for injection
1 ml
Solvent
* DS = Degree of substitution.
For instructions regarding drug inventory, handling, reconstitution, dilution, storage, 
accountability and disposal, please refer to the Preparation Guide for Infusion provided 
as a separate document.
8.2
ADMINISTRATION OF THE STUDY MEDICATION
Patients will consecutively receive the following on Day 1 and Day 8 q3wk (three 
weeks = one treatment cycle):

Gemcitabine: i.v. infusion over 30 min (± 10 min) at a starting dose of 800 
mg/m2 via a central or peripheral venous catheter through a pump device, 
followed by:

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
PM060184: i.v. infusion over 10 min (± 3 min) at a starting dose of 6.0 mg/m2
via a central or peripheral venous catheter through a pump device.
During PK sampling, PM060184 infusion should start no more than 5 min after end of 
gemcitabine administration.
More information on dose escalation may be found in Section 3.3.
8.3
CRITERIA FOR TREATMENT CONTINUATION 
Patients will be treated with additional cycles of PM060184 combined with gemcitabine 
as long as no unacceptable toxicity and/or progression of the disease and/or withdrawal 
of consent occurs.
The administration of a new cycle should be delayed if the criteria in the table below are 
not met on the corresponding Day 1. Parameters will be reevaluated at minimum 
intervals of 48 hours. The new cycle will be started upon recovery of these parameters. 
A maximum delay of 7 (+1) days from theoretical due date will be allowed for recovery 
from treatment-related adverse events. If recovery has not occurred after that period, the 
patient should discontinue the treatment, except in case of obvious patient benefit at the 
criteria of the Investigator and upon agreement with the Sponsor.
If the re-treatment criteria are not met on Day 8 (±1 day), administration of the 
corresponding drugs should be omitted instead of delayed. 
After skipping and/or delaying doses due to treatment-related toxicity (except for 
neutropenia exclusively), or in patients who experience a DLT, treatment may only 
continue after appropriate dose reduction (see Section 8.4).
Table 8. Criteria for treatment continuation.
Day 1 
Day 8
ANC
1.0 x 109/l
1.0 x 109/l
Platelets
100 x 109/l
75 x 109/l
Hemoglobin
9 g/dl
8 g/dl
Total bilirubin
1.5 x ULN
AST/ALT
Grade 1
Grade ≤ 2
Calculated CrCl (Cockcroft and Gault’s formula)
≥ 50 ml/min
30 ml/min
Peripheral sensory / motor neuropathy 
Grade ≤ 1
Grade ≤ 2
Other non-hematological drug-related AEs 
(except increased GGT, alopecia, nausea, anorexia, 
and/or asthenia) a
Grade ≤ 1
Grade ≤ 2
If a patient does not meet the requirements for treatment continuation on Day 1 of further cycles, the 
corresponding drug (PM060184 and gemcitabine) infusion will be withheld until recovery for a 
maximum of 7 days after the theoretical treatment date. If recovery has not occurred after a delay of > 7 
(+1) days, the patient must be withdrawn from the trial, except in case of perceived clinical benefit from 
the Investigator and upon agreement with the Sponsor.
If the above criteria are not met on Day 8 of any cycle, the scheduled infusion will be omitted instead of 
delayed.  
a
Any grade accepted for increased GGT. Up to grade 2 for alopecia, nausea, anorexia, and asthenia. 
Non-symptomatic grade 2-4 metabolic abnormalities (e.g.  sodium, magnesium, potassium, calcium) 
will be allowed for treatment continuation.
AE, adverse event; ALT, alanine aminotransferase; ANC, absolute neutrophil count; AP: alkaline 
phosphatase; AST, aspartate aminotransferase; CrCl, creatinine clearance; GGT, gamma-
glutamyltransferase; ULN, upper limit of normal.

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8.4
DOSE REDUCTION
Treatment after DLT, treatment-related dose delay for > 7 days from theoretical due 
date and/or toxicity considered as unacceptable by the investigators may continue, 
after appropriate dose reduction, only if there is clear evidence of objective patient 
benefit. This will always be discussed with the Sponsor. Under this circumstance, and 
following recovery to pre-specified re-treatment criteria, patients will be re-treated at 
the immediately lowest DL. If dose reduction beyond DL-1 is required, the PM060184 
dose may be reduced by an additional 1.0 mg/m2. 
Up to two individual dose reductions will be allowed per patient; any patients requiring 
more than two dose reductions will be withdrawn from the study. Once dose has been 
reduced for an individual patient, it will not be re-escalated again under any 
circumstances. 
No individual dose reductions will be allowed during Cycle 1.
Patients requiring dose reduction exclusively due to febrile neutropenia or grade 4 
neutropenia during the preceding cycle may receive secondary prophylaxis with 
granulocyte colony-stimulating factor (G-CSF) instead of a dose reduction. If toxicity 
re-occurs despite G-CSF use, dose reduction will then be implemented.
Patients who require limited field RT for pain palliation after Cycle 1 may continue 
treatment with PM060184 alone and without any dose adjustments if patient benefit is 
perceived; these patients do not need to be replaced. Gemcitabine re-introduction may 
be considered in patients without progressing disease at least four weeks after the end 
of RT.
8.5
CONCOMITANT MEDICATION
All treatments received by the patient during the on-treatment period of the trial must be 
documented in the e-CRF.
8.5.1
Prophylactic Medication
Primary antiemetic prophylaxis is compulsory prior to all PM060184 infusions. 
Standard treatment [according to the American Society of Clinical Oncology (ASCO) 
guidelines] will be administered: 

5-HT3 antagonists (ondansetron 8 mg i.v. or equivalent).

Steroids (dexamethasone 8 mg i.v. or equivalent).
If necessary, addition of metoclopramide or extension of treatment with 5-HT3
antagonists and/or dexamethasone could be considered (according to the Investigator’s 
own criteria).
8.5.2
Allowed Medications/Therapies

Therapies for pre-existing and treatment-emergent medical conditions, 
including pain management.

Blood products and transfusions, as clinically indicated.

Bisphosphonates.

In case of nausea or vomiting, secondary prophylaxis and/or symptomatic 
treatment for emesis according to ASCO guidelines.

Erythropoietin use according to ASCO guidelines.

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
Hormone-responsive breast cancer patients [i.e., those whose tumors express 
estrogen receptor (ER) and/or progesterone receptor (PrR)] may continue 
receiving their same prior hormonal therapy without interruption throughout 
their study participation.

Treatment with G-CSF in the event of grade 4 neutropenia lasting > 3 days, 
neutropenic sepsis or febrile neutropenia according to ASCO guidelines. 
Secondary prophylaxis could be considered after Cycle 1, if it is in the best 
interest of the patient.

Luteinizing hormone-releasing hormone (LHRH) agonists, in women of 
reproductive age.

Megestrol acetate for appetite stimulation.
8.5.3
Prohibited Medications/Therapies

Concomitant administration of any other antineoplastic therapy is prohibited, 
other than the aforementioned hormonal therapy for breast cancer. 

Patients who require RT within three weeks after the first infusion may remain 
on the study after being discussed and agreed between the Investigator and the 
Sponsor, but will not be evaluable for the analysis of the primary endpoint 
(DLT) and consequently need to be replaced.

Primary prophylaxis with G-CSF in Cycle 1. 

Other investigational agents.

Concomitant RT while on gemcitabine treatment.

Immunosuppressive therapies other than corticosteroids.
8.5.4
Drug-drug Interactions
In vitro studies using human liver microsomes have pointed to CYP2C19 and CYP3A4 
as the predominant cytochrome (CYP) enzymes responsible for the hepatic metabolism 
of PM060184. Therefore, concomitant drugs which induce or inhibit any of these 
cytochromes in a significant extent should be avoided whenever possible.
A list of commonly prescribed drugs that are inhibitors, inducers and substrates for 
these enzymes is provided in APPENDIX 6.
8.5.5
Drug Accountability
Proper drug accountability of all investigational medicinal products (IMPs) will be done 
by appropriate trained study personnel. Each study site will keep records to allow a 
comparison of quantities of drug received and used at each site for monitoring purposes. 
The Investigator at each study site will be the person ultimately responsible for drug 
accountability at the site.   
All unused drug supplied by the Sponsor will be properly destroyed at the study site. 
Documentation of this procedure must be provided to the clinical trial monitor. If the 
Sponsor agrees, unused drug supplies may be returned to the drug repository.
8.6
TREATMENT COMPLIANCE
The Investigator is ultimately responsible for supervising compliance with the 
instructions described in this study protocol.

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9.
STUDY EVALUATIONS
9.1
DETERMINATION OF THE MTD AND THE RD
The definition of the MTD and the RD may be found in Section 3.1.1.
9.2
SAFETY
Patients will be evaluable for safety if they have received at least one partial or 
complete infusion of PM060184 and one partial or complete infusion of gemcitabine. 
AEs will be graded according to the NCI-CTCAE v.4. 
The evaluation period for individual patients should include observations since start of 
the treatment until 30 days after the last study drug dose administration, death or until 
the start of a new antitumor therapy, whichever occurs first. After end of treatment, any
ongoing relevant (grade > 1) drug-related AEs must be followed until resolution or 
stabilization (i.e., to grade 1), or until start of a new therapy.
9.3
ADVERSE EVENTS DEFINITIONS
9.3.1
Adverse Event (AE)
An AE is any untoward medical occurrence in a patient or clinical investigation patient 
administered a pharmaceutical product which does not necessarily have a causal 
relationship with this treatment. 
An AE can therefore be any unfavorable and unintended sign, (e.g., an abnormal 
laboratory finding), or a disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product.
Illnesses with onset during the study or exacerbations of pre-existing illnesses, including
but not limited to clinically significant changes in physical examination findings and 
abnormal objective test findings (e.g., X-ray, ECG) should be recorded. The criteria for 
determining whether an abnormal objective test finding should be reported as an AE are 
as follows:
The test result is associated with clinically significant symptoms, and/or
The test result leads to a change in the study dosing or discontinuation from the 
clinical trial, significant additional concomitant drug treatment or other therapy, 
and/or
The test result leads to any of the outcomes included in the definition of a SAE
(see definition below), and/or
The test result is considered to be clinically relevant by the Investigator.
9.3.2
Serious Adverse Event (SAE)
A SAE is any adverse experience occurring at any dose that:
Results in death (is fatal),
Is life-threatening,
Requires or prolongs inpatient hospitalization,
Results in persistent or significant disability or incapacity,
Is a congenital anomaly or birth defect, 
Is medically significant, or

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Is any suspected transmission of an infectious agent via a medicinal product. 
Medical and scientific judgment should be exercised in deciding medically significant 
events; these criteria should be applied to AEs that may not be immediately life-
threatening or result in hospitalization but may jeopardize the patient or may require 
intervention to prevent one of the outcomes listed in the above definition.
9.3.3
Death
Death as such is the outcome of a SAE and should not be used as the SAE term itself,
whenever possible. The cause of death should be recorded as the SAE term instead.
When available, the autopsy report will be provided by the Sponsor.
9.3.4
Life-threatening Event
Any event in which the patient was at risk of death at the time of the event is considered 
life-threatening; it does not refer to an event which hypothetically might have caused 
death if it had been more severe.
9.3.5
Hospitalization or Prolongation of Hospitalization
Any AE requiring hospitalization (or prolongation of hospitalization) that occurs or 
worsens during the course of a patient’s participation in a clinical trial must be reported 
as a SAE unless exempted from SAE reporting (see Section 9.4.2). Prolongation of 
hospitalization is defined as any extension of an inpatient hospitalization beyond the 
stay anticipated/required for the initial admission, as determined by the Investigator or 
treating physician.
Hospitalizations that do not meet criteria for SAE reporting are: 
a. Reasons described in protocol (e.g., 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.).
9.3.6
Unlisted/Unexpected Adverse Event
An AE, the nature or severity of which is not consistent with the applicable reference 
safety information.
The Sponsor will use as the reference safety information for the evaluation of 
listedness/expectedness the IB for PM060184 and the SPC for gemcitabine.
9.3.7
Adverse Reactions
All untoward and unintended responses to an investigational medicinal product related 
to any dose administered. This definition covers also medication errors and uses outside 

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what is foreseen in the protocol, including overdose, lack of efficacy, misuse and abuse 
of the product.
9.3.8
Adverse Events Related to the Study Drugs
An AE is considered related to a study drug/investigational medicinal product (IMP) if 
the Investigator’s assessment of causal relationship to the IMP(s) is “Y (yes)” (see 
Section 9.3.10). 
The Investigator will assess the causal relationship of the IMP(s) to the SAE.
The Sponsor may also consider related to the study drug(s)/IMP(s) those events for 
which the Investigator assesses the causal relationship with the IMP(s) as “Uk 
(unknown)” when it cannot rule out a role of the IMP(s) in the event.
9.3.9
Expedited Reporting
The Sponsor is responsible for the appropriate expedited reporting, according to the 
current legislation.
9.3.10
Assessment of Causal Relationship to the Study Drugs
The Investigator must provide an assessment of the causal relationship of each SAE to 
the clinical trial IMP(s) according to the following scale:
Y
There is a reasonable possibility that the IMP(s) caused the SAE.
N
There is no reasonable possibility that the IMP(s) caused the SAE and 
other causes are more probable.
Uk.
(Unknown). Only to be used in special situations where the Investigator 
has insufficient information (i.e., the patient was not seen at his/her 
center) if none of the above can be used.
9.4
ADVERSE EVENTS REPORTING PROCEDURES
9.4.1
Reporting Adverse Events
The Sponsor will collect AEs until 30 days after administration of the last dose of study 
drug(s)/IMP(s) or until the start of a new antitumor therapy, whichever occurs first. All 
relevant (grade > 1) AEs suspected to be related to the study drug/IMP must be 
followed-up after the time of therapy discontinuation until the event resolves or 
stabilizes (i.e., to grade 1), or until start of a new therapy.
All AEs, including misuse, overdose, abuse and medication error, must be recorded in 
English using medical terminology in the source document and the e-CRF. Whenever 
possible, the Investigator will record the main diagnosis instead of the signs and 
symptoms normally included in the diagnoses. 
Investigators must assess severity (grade) of the event following the NCI-CTCAE v.4 
and assign a relationship to each study drug(s)/IMP(s); and pursue and obtain 
information adequate both to determine the outcome and to assess whether it meets the 
criteria for classification as a SAE requiring immediate notification to Pharma Mar S.A. 
or its designated representative. The Investigator must provide any relevant information 
as requested by the Sponsor in addition to that on the e-CRF.
Abnormal laboratory tests occurring during the study should only be recorded in the AE 
section of the e-CRF if the disorder:
Is associated with clinically significant symptoms, and/or

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Leads to a change in study dosing or discontinuation from the study, significant 
additional concomitant drug treatment or other therapy, and/or
Leads to any of the outcomes included in the definition of a SAE.
Leads to a DLT.
The test result is considered to be clinically relevant by the Investigator.
Otherwise, laboratory results should be reported in the corresponding section of the e-
CRF (e.g. biochemistry, hematology).
9.4.2
Reporting Serious Adverse Events
The Sponsor will collect SAEs from the time of signing of the ICF until 30 days after 
administration of the last dose of study drug(s)/IMP(s) or until the start of a new 
antitumor therapy, whichever occurs first. Beyond this period of time, only those SAEs 
suspected to be related to the IMP will be collected. Nonetheless, the Sponsor will 
evaluate any safety information that is spontaneously reported by an Investigator 
beyond the time frame specified in the protocol.
All SAEs (as defined above) that occur after patient registration, regardless of 
relationship to the study drug(s)/IMP(s) must be reported immediately and always 
within 24 hours to the Pharma Mar S.A. Pharmacovigilance Department electronically 
by completing the applicable e-CRF sections. Only in the event of electronic system 
failure, SAEs can be reported using a paper “SAE form” by fax (+34 91 846 6004), e-
mail (phv@pharmamar.com), or telephone (+ 34 91 846 6147). Out of office hours 
[Greenwich Meridian Time (GMT)], assistance on SAE reporting can be obtained by 
calling the Pharmacovigilance Department at +34 91 823 4742. SAEs initially reported 
by alternative (i.e., not electronic) methods must be followed by a completed electronic 
SAE reporting on e-CRF from the investigational staff within one working day.
Those SAEs occurring during the screening phase (from ICF signature to registration) 
and after off-study will be reported using a paper “SAE Form” that must be forwarded 
as mentioned above always within 24 hours to the Pharmacovigilance Department by 
fax or e-mail.
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.
9.4.3
Reporting Pregnancy Cases Occurred within the Clinical Trial
National regulations require that clinical trial Sponsors collect information on 
pregnancies occurring during clinical trials, in which exposure to the IMP(s) at any time 
during pregnancy, via either maternal or paternal exposure, is suspected.
Therefore, pregnancy and suspected pregnancy (including a positive pregnancy test 
regardless of age or disease state) of a female patient or the female partner of a male 
patient occurring while the patient is on study drugs, or within six months 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)].

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All reports of elevated/questionable or indeterminate beta human chorionic 
gonadotropins (β-hCGs).
Immediately after detecting a case of suspected pregnancy in a female clinical trial 
patient, the decision on her continued participation in the clinical trial will be jointly 
taken by the trial patient, the Investigator and the Sponsor, with the patient’s best 
interest in mind. A decision to continue the pregnancy will require immediate 
withdrawal from the trial. 
Any pregnancy, suspected pregnancy, or positive pregnancy test must be reported to 
Pharma Mar S.A. Pharmacovigilance Department immediately using the Pregnancy 
Report form. In the case of pregnancy of the female partner of a trial patient, the 
Investigator will obtain her informed consent to provide the information by using the 
applicable form provided by the Sponsor who will also advise the Investigator in these 
situations.
The Investigator will follow the pregnancy until its outcome, and must notify Pharma 
Mar S.A. Pharmacovigilance Department the outcome of the pregnancy within 24 hours 
of first knowledge as a follow-up to the initial report.
For any event during the pregnancy which meets a seriousness criterion (including fetal 
or neonatal death or congenital anomaly) the Investigator will also follow the 
procedures for reporting SAEs (complete and send the SAE form to Pharma Mar S.A. 
Pharmacovigilance Department within 24 hours of the Investigator’s knowledge of the 
event). 
All neonatal deaths that occur within 30 days of birth should be reported, without regard 
to causality, as SAEs. In addition, any infant death at any time thereafter that the 
Investigator suspects is related to the exposure to the study drug(s)/IMP(s) should also 
be reported to Pharma Mar S.A. Pharmacovigilance Department within 24 hours of the 
Investigators’ knowledge of the event.
9.5
ADVERSE EVENTS MONITORING
Safety review will be performed at Pharma Mar S.A. once SAE forms have been 
received and the e-CRFs electronically completed by the Investigator.
At every monitoring visit performed by the clinical research associate (CRA)/monitor in 
charge of the study, the consistency between the e-CRF/SAE data reported to the 
Pharmacovigilance department and the patient's medical records (source data) will be 
reviewed. Whenever a discrepancy is found during the review, data will be 
amended/updated in the e-CRF and the SAE form/information reported to the 
Pharmacovigilance department (when applicable), according to source data (medical 
history and annexes, such as nurse records, lab reports, image reports, others). An 
update (Follow-up) with changes arisen will be signed by the Principal Investigator (or 
his/her designee) and then reported/provided to the Pharmacovigilance department 
within 24 hours, with the e-CRF updated on the same dates. 
Periodic safety review of clinical data will be performed; however, no formal Data 
Safety Monitoring Board has been appointed for this trial. AEs will be monitored by the 
Investigators and by the study team at Pharma Mar S.A. The personnel in charge of this 
process are defined in the section “Study Contacts” of this protocol. In general, a 
clinical oncologist, together with a member of the Pharma Mar S.A. Pharmacovigilance 
Department will review the safety data of this trial on an ongoing basis.

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SAEs will be collected, assessed and reported as per the applicable Regulations by the 
Pharmacovigilance Department. Periodic safety reviews of SAE reports are to be 
conducted by the clinical oncologist every 3-6 months, depending on recruitment.
Non-serious AEs will be verified during monitoring visits by the monitor, who will 
discuss them with the Investigators, if applicable. 
Any protocol deviation will also be discussed with the Investigator during monitoring 
visits.
9.6
EFFICACY 
Antitumor activity will be evaluated according to the RECIST v.1.1 (see details in 
APPENDIX 4) in all patients with measurable disease, according to Choi criteria and/or 
EORTC metabolic response criteria for solid tumors in GIST patients (APPENDIX 5), 
or by evaluation of tumor markers if applicable (e.g., ovarian cancer), every two cycles 
(i.e., approximately every six weeks) ± one week after treatment initiation until Cycle 4. 
Patients continuing treatment after Cycle 4 will have the assessments performed every
three cycles (i.e., approximately every nine weeks) ± one week from Cycle 4 while on 
treatment, unless otherwise is clinically indicated. Anonymized copies of the images 
showing objective response or meaningful tumor shrinkage must be submitted to the 
Sponsor.
In patients with disease evaluable by serum markers, tumor assessments will also be 
obtained every two cycles ± one week until Cycle 4, and every three cycles ± one week 
from Cycle 4 while on treatment. Tumor response will be evaluated by GCIG specific 
criteria in patients with ovarian cancer (see details in APPENDIX 7).
Analysis of other clinically routinely employed serum markers will be performed for 
individual patients in an exploratory fashion, as clinically indicated. This will include 
baseline measurements of:

CA19-9: for patients diagnosed with non-neuroendocrine pancreatic cancer or 
biliary tract cancer.

CA15-3: for patients diagnosed with breast cancer.

Alpha-fetoprotein: for patients diagnosed with hepatocellular carcinoma and/or 
non-seminoma germ cell tumors.

Beta-hCG: for patients diagnosed with a germ cell tumor.

CA-125: for patients diagnosed with ovarian cancer.
Patients for whom disease diagnostic applies and are found to have elevated baseline 
values, according to the institution reference (which will be also provided), will be 
assessed before treatment at Day 1 of each subsequent cycle.
Since formal response criteria are still pending, the analysis of these markers will be 
only descriptive in nature. Consequently, formal disease evaluation will be performed 
according only to RECIST v.1.1, Choi criteria and/or EORTC metabolic response 
criteria for solid tumors, as stated above, and by GCIG criteria, when applicable.
9.6.1
Progression-free Survival 
Progression-free survival (PFS) is defined as the time from the date of first infusion of 
study treatment to the date of progression or death (due to any cause). If progression or 

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death has not occurred at the time of the analysis, the PFS will be censored on the date 
of last tumor evaluation.
9.6.2
Overall Survival 
Overall survival (OS) is defined as the time from the date of first infusion of study 
treatment to the date of death (due to any cause). Patients with no documented death 
will be censored at the last date they are known to be alive.
9.7
EVALUATION OF PHARMACOKINETICS
PK parameters will be evaluated by standard NCA analysis (compartmental modeling 
may be performed if appropriate).
9.8
EVALUATION OF PHARMACOGENETICS
The presence or absence of known polymorphisms that may explain individual 
variability in main PK parameters will be evaluated using a blood sample collected 
before treatment start along with PK sample #1 on Day 1 of Cycle 1.
10. STATISTICAL METHODS
10.1 SAMPLE SIZE
The number of patients may vary depending both on the tolerability of PM060184 
combined with gemcitabine and the number of dose levels required to identify the 
MTD. Approximately between six and 72 evaluable patients are planned to be included 
in this study.
10.2 STATISTICAL ANALYSIS
Descriptive statistics (mean, median, standard deviation and 95% confidence interval, 
range of value, frequencies and percentages) will be used as appropriate.
10.2.1 Safety 
Descriptive statistics will be used to characterize DLTs occurring at the RD and/or at 
DLs above/below it. The profiles of AEs, deaths, SAEs, treatment-related delays, dose 
reductions, dose omissions and/or treatment discontinuations will also be displayed by 
group as appropriate. All AEs will be graded according to the NCI-CTCAE v.4.
10.2.2 Efficacy
Response rates as per RECIST v.1.1 (and as per Choi criteria and/or EORTC metabolic 
response criteria, for GIST patients) [percentage of patients with any response [PR, CR 
or the sum of both being the overall response rate (ORR)], percentage of patients with 
clinical benefit [i.e., patients with any response, or with stable disease (SD) ≥ 4 
months], will be characterized using descriptive statistics (95% exact binomial 
confidence interval) and according to primary tumor type. Time-related parameters 
(e.g., PFS, OS) will also be analyzed according to the Kaplan-Meier method, if 
appropriate. If any specific tumor type subset is adequately represented, exploratory 
subgroup analyses will be performed. The characteristics of the patients achieving an 
objective response or SD ≥ 4 months by RECIST v.1.1 will be displayed.

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10.2.3 Pharmacokinetics 
The PK parameters will be tabulated and selected parameters will be graphically 
displayed per DL. The dose-exposure relationships for maximum plasma concentration 
(Cmax) and AUC will be evaluated, and any potential PK interaction between
gemcitabine, dFdU and PM060184 will also be explored.
The potential influence on selected PK parameters of selected demographic and clinical 
dichotomous variables (gender, laboratory test results above/below selected cutoff 
values, etc.) will be evaluated by Student’s t test or Mann-Whitney’s U test as 
appropriate. 
For multinomial variables, analysis of variance will be used. For selected continuous 
demographic and clinical variables, relationship with selected PK parameters will be 
graphically explored and assessed using correlation and regression methods.
Other tests may be applied if the results of the above evaluations suggest that they may 
yield additional relevant information.
10.2.4 Pharmacogenetics
The influence of known polymorphisms on main PK parameters will be assessed by 
Student’s test or Mann-Whitney’s U test as appropriate.
10.3 INTERIM ANALYSIS
The patient’s safety will be assessed on a regular basis prior to each dose escalation 
upon completion of a cohort. No formal interim analyses are planned.
11. ADMINISTRATIVE SECTION
11.1 ETHICS
This clinical trial will be conducted in accordance with the ethical principles that have 
their origin in the World Medical Association (WMA) Declaration of Helsinki (see 
APPENDIX 8) and will be consistent with GCP guidelines and pertinent regulatory 
requirements.
The study personnel involved in conducting this trial will be qualified by education, 
training and experience to perform their respective task(s).
The study will be conducted in compliance with the protocol. The protocol, any 
amendments and the patient informed consent will receive IEC/IRB approval/favorable 
opinion prior to initiation, according to pertinent regulations.
The decision of the IEC/IRB concerning the conduct of the study will be made in 
writing to the Investigator, and a copy of this decision will be provided to the Sponsor 
before the beginning of the study.
The Investigator and/or the Sponsor is/are responsible for keeping the IEC/IRB
informed of any significant new information about the study drugs.
All protocol amendments will be agreed upon by the Sponsor and the Investigator.
Administrative changes of the protocol are minor corrections and/or clarifications that 
have no impact on the way the study is to be conducted.

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11.2 MONITORING, AUDITING AND INSPECTING
The study will be monitored by regular site visits and telephone calls to the Investigator 
by the clinical trial monitor designated by Pharma Mar S.A.
During site visits, the trial monitor should revise original patient records, drug records 
and document retention (study file). Additionally, the trial monitor should observe study 
procedures and will discuss any problems with the Investigator.
Adequate time for these visits should be allocated by the Investigator. The Investigator 
should also ensure that the monitor is given direct access [as per International 
Conference on Harmonization (ICH) Topic E6 Guideline for Good Clinical Practice, 
Sections 4.9.7 and 6.10] to source documents (i.e., hospital or private charts, original 
laboratory records, appointment books, etc.) of the patient which support data entered in 
the case report forms, as defined in the ICH Topic E6 Guideline for Good Clinical 
Practice, Sections 1.51 and 1.52.
Systems and procedures will be implemented to ensure the quality of every aspect of the 
trial.
During the course of the trial, the Clinical Quality Assurance Department of Pharma 
Mar S.A. or external auditors contracted by the Sponsor may conduct an onsite audit 
visit (ICH Topic E6 Guideline for GCP, Section 1.6).
Participation in this trial implies acceptance of potential inspection by national or 
foreign Competent Authorities.
11.3 PATIENT INFORMED CONSENT
The rights, safety and well-being of the trial patients are the most important 
considerations and should prevail over interests of science and society.
The Informed Consent Forms (ICFs) will include all elements required by ICH, GCP 
and applicable regulatory requirements.
Prior to inclusion into the trial, the Investigator or a person designated by the 
Investigator, must provide the patient with one copy of the ICF for the clinical trial and 
one copy of the ICF for the pharmacogenetic sub-study, if applicable. Both copies must 
provide written full information about the clinical trial and the sub-study, in a language 
that is non-technical and easily understood. The Investigator should allow the necessary 
time for the patient or his/her legally acceptable representative to inquire about the 
details of the clinical trial and the sub-study; then, both ICFs must be freely signed and 
personally dated by the patient and by the person who conducted the Informed Consent 
discussion before the beginning of the study. In addition, the patient should receive a 
copy of any other written information provided to study patients prior to participation in 
the trial.
During a patient's participation in the trial, any updates to the consent forms and any 
updates to the written information will be provided to him/her.
If there is a need to obtain new consent from the patients, the Investigator or a person 
designated by the Investigator should inform the patients of any new information 
relevant to the patients’ willingness to continue participation in the study, before 
obtaining the written consent.

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11.4 CONFIDENTIALITY/ PATIENTS IDENTIFICATION
The collection and processing of personal data from the patients enrolled in this clinical 
trial will be limited to those data that are necessary to investigate the efficacy, safety, 
quality and usefulness of the study drugs used in this trial.
It is the Investigator’s responsibility that sufficient information on the identity of the 
patients will be retained.
The trial monitor, the Sponsor’s auditor, the IECs/IRBs and the Competent Authorities
should have direct access to all requested trial-related records, and agree to keep the 
identity of study patients confidential.
The data must be collected and processed with adequate precautions to ensure 
confidentiality and compliance with applicable data privacy protection laws and 
regulations.
Explicit consent for the processing of personal data will be obtained from the 
participating patient before data collection, if applicable, and this consent should also 
address the transfer of the data to other entities and countries.
Pharma Mar S.A. shall comply with the Directive 95/46/EEC of the European 
Parliament and of the Council of 24 October 1995 on the protection of individuals with 
regard to the processing of personal data and on the free movement of such data.
11.5 CASE REPORT FORMS
e-CRFs will be used to record all data for each patient. It is the responsibility of the 
Investigator to ensure that the e-CRFs are properly and completely filled in, in English. 
e-CRFs must be completed for all patients who have given their informed consent and 
have been enrolled into the study. For patients who gave their informed consent, 
received an automatic patient number, and for whom registration was not confirmed, the 
screening form will be sufficient.
A patient’s source documentation is the patient’s records (including but not limited to 
physician/hospital notes, nurses notes, IMP preparation records including reconstitution 
and dilution, IMP administration records, etc.) and any original document, and as such 
they should be maintained at the study site.
The data collected in the e-CRF will be entered into Pharma Mar S.A. databases, which 
comply with the Spanish Act implementing the Directive 95/46/EC of the European 
Parliament and of the Council of 24 October 1995 on the protection of individuals with 
regard to the processing of personal data. 
11.6 INSURANCE
The Sponsor will provide insurance or indemnity in accordance with the applicable 
regulatory requirements.
11.7 RETENTION OF RECORDS
The Investigator/Institution should maintain trial documents according to Section 8 of 
the ICH Topic E6 Guideline for Good Clinical Practice and as required by applicable 
regulatory requirements.
Essential documents should be retained as per the aforementioned ICH guideline or for 
a longer period of time, if required by the applicable regulations. 

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11.8 USE OF INFORMATION AND PUBLICATION
Before the investigators of this study submit a paper or abstract for publication or 
otherwise publicly disclose information concerning the study drugs or products, Pharma 
Mar S.A. must be provided with at least 60 days to revise and approve the proposed 
publication or disclosure to ensure that confidential and proprietary data are protected.
If Pharma Mar S.A. determines that patentable patient matter is disclosed in the 
proposed publication or disclosure, the publication or disclosure will be withheld for a 
period of time considered convenient. If the study is part of a multicenter study, the first 
publication of the study shall be made in conjunction with the presentation of a joint, 
multicenter publication of the study results with the investigators and the institutions 
from all appropriate sites that are contributing data, analysis and comments. However, if 
such a multicenter publication is not submitted within 12 months after conclusion, 
abandonment or termination of the study at all sites, the present study may be published 
individually in accordance with the procedure established above.
The order of the coauthors will reflect the relative contribution of each one to study 
development and analysis. In general, the first author will be the investigator who 
recruits the highest number of patients with information finally available for data 
analysis. Relevant Pharma Mar S.A. personnel who have fully participated in the study 
must be considered for co-authorship of the publication.
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escalation study in chemotherapy-naive patients with advanced non-small-cell lung 
cancer. J Clin Oncol. 1997;15(1):310-6.
20.
Grunewald R, Abbruzzese JL, Tarassoff P, Plunkett W. Saturation of 2',2'-
difluorodeoxycytidine 5'-triphosphate accumulation by mononuclear cells during a 
phase I trial of gemcitabine. Cancer Chemother Pharmacol. 1991;27(4):258-62.
21.
Tempero M, Plunkett W, Ruiz Van Haperen V, Hainsworth J, Hochster H, Lenzi 
R, et al. Randomized phase II comparison of dose-intense gemcitabine: thirty-minute 
infusion and fixed dose rate infusion in patients with pancreatic adenocarcinoma. J Clin 
Oncol. 2003;21(18):3402-8.

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

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APPENDIX 2: COCKCROFT AND GAULT’S FORMULA 
For calculating creatinine clearance: 
[(140-age (years)) x weight (Kg)]
Creatinine clearance (ml/min)  =      
x G1
72 x serum creatinine (mg/dl)
[(140-age (years)) x weight (Kg)]
Creatinine clearance (ml/min)  =      
x G1
72 x serum creatinine (mol/l) x 0.0113
1G(Gender)= 0.85 if Female; 1 if Male.
Reference:
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. 
Nephron. 1976;16(1):31-41.

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APPENDIX 3: PERCENTAGE OF ACTIVE BONE MARROW AT RISK DUE TO 
RADIOTHERAPY IN VARIOUS SKELETAL SITES
Skeletal Sites (and Quantities) Used for Spongiosa Volume Estimation
Skeletal site (number of bones)
Percentage of total body active marrow
Cranium (1)
7.6
Mandible (1)
0.8
Humeral heads (2)
2.3
Clavicles (2)
0.8
Scapulae (2)
2.8
Sternum (1)
3.1
Ribs (12)
16.1
Cervical vertebrae (7)
3.9
Thoracic vertebrae (12)
16.1
Lumbar vertebrae (5)
12.3
Sacrum (1)
9.9
Proximal femora (2)
6.7
Ossa coxae (2)
17.5
This table is adapted from Table 9-4 in International Commission on Radiological Protection. Basic 
Anatomical and Physiological Data for Use in Radiological Protection: Reference Values. New York, 
NY: International Commission on Radiological Protection; 2002. ICRP Publication 89. Copyright 
2002, International Commission on Radiological Protection.
Further details can be found in the original article: Brindle JM., Trindade AA., Shah, 
AP., Jokisch DW., Patton PW,. Pichardo JC. and Bolch WE. Linear Regression Model 
for Predicting Patient-Specific Total Skeletal spongiosa volume for use in molecular 
radiotherapy dosimetry. J Nucl Med 2006; 47:1875–1883.

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APPENDIX 4: EVALUATION OF RESPONSE. THE RECIST v.1.1.
This document summarizes the main information contained in RECIST version 1.1. 
Further details can be found in the original article: Eisenhauer EA, Therasse P, 
Bogaerts J, et al.: New response evaluation criteria in solid tumours: revised RECIST 
guideline (version 1.1). Eur J Cancer 2009; 45(2): 228-247.1
LIST OF ABBREVIATIONS
CR
Complete Response
CRF
Case Report Form
CT
Computed Tomography
FDG-PET
Fluorodeoxyglucose-Positron Emission Tomography
MRI
Magnetic Resonance Imaging
NE
Not Evaluable
PD
Progressive Disease
PET
Positron Emission Tomography
PFS
Progression-free Survival
PR
Partial Response
PSA
Prostate-specific Antigen
RECIST
Response Evaluation Criteria in Solid Tumors
SD
Stable Disease
TTP
Time to Progression
LIST OF TABLES
Table 1. Time point response: patients with target (+/–non-target) disease.
Table 2. Time point response: patients with non-target disease only.
Table 3.  Best overall response when confirmation of complete response (CR) and 
partial response (PR) is  required.
1. MEASURABILITY OF TUMOR LESIONS AT BASELINE
1.1 Definitions
At baseline, tumor lesions/lymph nodes will be categorized measurable or non-
measurable as follows:
1.1.1 Measurable
Tumor Lesions:
Must be accurately measured in at least one dimension (longest diameter in the plane of 
measurement is to be recorded) with a minimum size of: 

10 mm by computed tomography (CT) scan (irrespective of scanner type) 
and magnetic resonance imaging (MRI) (no less than double the slice 
thickness and a minimum of 10 mm).

10 mm caliper measurement by clinical exam (when superficial). 
                                                
1 A summary of major changes from RECIST 1.0 to RECIST 1.1 can be found at the beginning of this 
document (Table 1).

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
20 mm by chest X-ray (if clearly defined and surrounded by aerated lung).
Malignant Lymph Nodes:
To be considered pathologically enlarged and measurable, a lymph node must be ≥ 15 
mm in short axis when assessed by CT scan (CT scan slice thickness recommended to 
be no greater than 5 mm). At baseline and in follow-up, only the short axis will be 
measured and followed (see Schwartz et al. Eur J Cancer. 2009; 45(2):261-267). See 
also notes below on ‘Baseline documentation of target and non-target lesions’ for 
information on lymph node measurement. 
1.1.2 Non-measurable
All other lesions, including small lesions (longest diameter < 10 mm or pathological 
lymph nodes with ≥ 10 to < 15 mm short axis) as well as lesions considered truly non-
measurable. Lesions considered truly non-measurable include: leptomeningeal disease, 
ascites, pleural or pericardial effusion, inflammatory breast disease, lymphangitic 
involvement of skin or lung, and abdominal masses/abdominal organomegaly identified 
by physical exam that is not measurable by reproducible imaging techniques. 
1.1.3 Special Considerations Regarding Lesion Measurability
Bone lesions, cystic lesions, and lesions previously treated with local therapy require 
particular comment:
Bone Lesions:

Bone scan, positron emission tomography (PET) scan or plain films are not 
considered adequate imaging techniques to measure bone lesions. However, 
these techniques can be used to confirm the presence or disappearance of bone 
lesions. 

Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, that can be evaluated by cross sectional imaging techniques such as 
CT or MRI can be considered as measurable lesions if the soft tissue component
meets the definition of measurability described above.

Blastic bone lesions are non-measurable.
Cystic Lesions:

Lesions that meet the criteria for radiographically defined simple cysts should 
not be considered as malignant lesions (neither measurable nor non-measurable) 
since they are, by definition, simple cysts.

‘Cystic lesions’ thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the definition of measurability described above. 
However, if non-cystic lesions are present in the same patient, these are 
preferred for selection as target lesions.
Lesions with Prior Local Treatment:

Tumor lesions situated in a previously irradiated area, or in an area subjected to 
other loco-regional therapy, are usually not considered measurable unless there 
has been demonstrated progression in the lesion. Study protocols should detail 
the conditions under which such lesions would be considered measurable.
1.2. Specifications by Methods of Measurement
1.2.1 Measurement of Lesions

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All measurements should be recorded in metric notation, using calipers if clinically 
assessed. All baseline evaluations should be performed as close as possible to the 
treatment start and never more than four weeks before the beginning of the treatment.
1.2.2 Method of Assessment
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. Imaging based 
evaluation should always be done rather than clinical examination unless the lesion(s) 
being followed cannot be imaged but are assessable by clinical exam.
Clinical Lesions: 
Clinical lesions will only be considered measurable when they are superficial and ≥ 10 
mm diameter as assessed using calipers (e.g., skin nodules). For the case of skin lesions, 
documentation by color photography including a ruler to estimate the size of the lesion 
is suggested. As noted above, when lesions can be evaluated by both clinical exam and 
imaging, imaging evaluation should be undertaken since it is more objective and may 
also be reviewed at the end of the study.
Chest X-Ray: 
Chest CT is preferred over chest X-ray, particularly when progression is an important 
endpoint, since CT is more sensitive than X-ray, particularly in identifying new lesions. 
However, lesions on chest X-ray may be considered measurable if they are clearly 
defined and surrounded by aerated lung. See original article, Appendix II, for more 
details.
Computed Tomography (CT), Magnetic Resonance Imaging (MRI):
CT is the best currently available and reproducible method to measure lesions selected 
for response assessment. This guideline has defined measurability of lesions on CT scan 
based on the assumption that CT slice thickness is 5 mm or less. As is described in 
original article (Appendix II), when CT scans have slice thickness greater than 5 mm, 
the minimum size for a measurable lesion should be twice the slice thickness. MRI is 
also acceptable in certain situations (e.g., for body scans). More details concerning the 
use of both CT and MRI for assessment of objective tumor response evaluation are 
provided in the original article, Appendix II.
Ultrasound:
Ultrasound is not useful in assessment of lesion size and should not be used as a method 
of measurement. Ultrasound examinations cannot be reproduced in their entirety for 
independent review at a later date and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken from one 
assessment to the next (described in greater detail in the original article, Appendix II). If 
new lesions are identified by ultrasound in the course of the study, confirmation by CT 
or MRI is advised. If there is concern about radiation exposure at CT, MRI may be used 
instead of CT in selected instances.
Endoscopy, Laparoscopy: 
The use of these techniques for objective tumor evaluation is not advised. However, 
they can be useful to confirm complete pathological response when biopsies are 
obtained or to determine relapse in trials where recurrence following complete response 
or surgical resection is an endpoint.
2. TUMOR RESPONSE EVALUATION

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2.1 Assessment of Overall Tumor Burden and Measurable Disease
To assess objective response or future progression, it is necessary to estimate the overall 
tumor burden at baseline and use this as a comparator for subsequent measurements. 
Only patients with measurable disease at baseline should be included in protocols where 
objective tumor response is the primary endpoint. Measurable disease is defined by the 
presence of at least one measurable lesion (as detailed above in Section 1. Measurability 
of tumor at baseline). In studies where the primary endpoint is tumor progression (either 
time to progression or proportion with progression at a fixed date), the protocol must 
specify if entry is restricted to those with measurable disease or whether patients having 
non-measurable disease only are also eligible.
2.2 Baseline Documentation of “Target” and “Non-target” Lesions
When more than one measurable lesion is present at baseline, all lesions up to a 
maximum of ﬁve lesions total (and a maximum of two lesions per organ) representative 
of all involved organs should be identiﬁed as target lesions and will be recorded and 
measured at baseline (this means in instances where patients have only one or two organ 
sites involved that a maximum of two and four lesions will be recorded, respectively). 
For evidence to support the selection of only ﬁve target lesions, see analyses on a large 
prospective database in the article by Bogaerts et al. Eur J Cancer 2009;45:248–260. 
Target lesions should be selected on the basis of their size (lesions with the longest 
diameter), be representative of all involved organs, but in addition should be those that 
lend themselves to reproducible repeated measurements. It may be the case that, on 
occasion, the largest lesion does not lend itself to reproducible measurement, in which 
circumstance the next largest lesion which can be measured reproducibly should be 
selected. To illustrate this point see the example in the original article, Figure 3 of 
Appendix II. 
Lymph nodes merit special mention since they are normal anatomical structures which 
may be visible by imaging even if not involved by tumor. As noted in the previous 
section, pathological nodes which are defined as measurable and may be identified as 
target lesions must meet the criterion of a short axis of ≥ 15 mm by CT scan. Only the 
short axis of these nodes will contribute to the baseline sum. The short axis of the node 
is the diameter normally used by radiologists to judge if a node is involved by solid 
tumor. Nodal size is normally reported as two dimensions in the plane in which the 
image is obtained (for CT scan this is almost always the axial plane; for MRI the plane 
of acquisition may be axial, saggital or coronal). The smaller of these measures is the 
short axis. For example, an abdominal node which is reported as being 20 mm x 30 mm 
has a short axis of 20 mm and qualifies as a malignant, measurable node. In this 
example, 20 mm should be recorded as the node measurement (see also the example in 
the original article, Figure 4 of Appendix II). All other pathological nodes (those with 
short axis ≥ 10 mm but < 15 mm) should be considered non-target lesions. Nodes that 
have a short axis < 10 mm are considered non-pathological and should not be recorded 
or followed. 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for 
all target lesions will be calculated and reported as the baseline sum diameters. If lymph 
nodes are to be included in the sum, then as noted above, only the short axis is added 
into the sum. The baseline sum diameters will be used as reference to further 
characterize any objective tumor regression in the measurable dimension of the disease.

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All other lesions (or sites of disease) including pathological lymph nodes should be 
identified as non-target lesions and should also be recorded at baseline. Measurements 
are not required and these lesions should be followed as ‘present’, ‘absent’, or in rare 
cases ‘unequivocal progression’ (more details to follow). In addition, it is possible to 
record multiple non-target lesions involving the same organ as a single item on the case 
record form (e.g., ‘multiple enlarged pelvic lymph nodes’ or ‘multiple liver 
metastases’).
2.3 Response Criteria
This section provides the definitions of the criteria used to determine objective tumor 
response for target lesions.
2.3.1 Evaluation of Target Lesions
Complete Response (CR):
Disappearance of all target lesions. Any pathological 
lymph nodes   (whether target or non-target) must have 
reduction in short axis to < 10 mm.
Partial Response (PR):
At least a 30% decrease in the sum of diameters of target 
lesions, taking as reference the baseline sum diameters.
Progressive Disease (PD):
At least a 20% increase in the sum of diameters of target 
lesions, taking as reference the smallest sum on study 
(this includes the baseline sum if that is the smallest on 
study). In addition to the relative increase of 20%, the 
sum must also demonstrate an absolute increase of at least 
5 mm. (Note: the appearance of one or more new lesions 
is also considered progression). 
Stable Disease (SD):
Neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD taking as reference 
the smallest sum diameters while on study.
2.3.2 Special Notes on the Assessment of Target Lesions
Lymph Nodes:
Lymph nodes identified as target lesions should always have the actual short axis 
measurement recorded (measured in the same anatomical plane as the baseline 
examination), even if the nodes regress to below 10 mm on study. This means that when 
lymph nodes are included as target lesions, the ‘sum’ of lesions may not be zero even if 
complete response criteria are met, since a normal lymph node is defined as having a 
short axis of < 10 mm. Case report forms (CRFs) or other data collection methods may 
therefore be designed to have target nodal lesions recorded in a separate section where, 
in order to qualify for CR, each node must achieve a short axis < 10 mm. For PR, SD 
and PD, the actual short axis measurement of the nodes is to be included in the sum of 
target lesions.
Target Lesions that Become ‘Too Small to Measure’:
While on study, all lesions (nodal and non-nodal) recorded at baseline should have their 
actual measurements recorded at each subsequent evaluation, even when very small 
(e.g., 2 mm). However, sometimes lesions or lymph nodes which are recorded as target 
lesions at baseline become so faint on CT scan that the radiologist may not feel 
comfortable assigning an exact measure and may report them as being ‘too small to 
measure’. When this occurs it is important that a value be recorded on the CRF. If it is 
the opinion of the radiologist that the lesion has likely disappeared, the measurement 

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

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

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also 
require 
conﬁrmatory 
measurement 
(see 
Section 
2.6. 
Confirmatory 
Measurement/Duration of Response). Speciﬁcally, in non-randomized trials where 
response is the primary endpoint, conﬁrmation of PR or CR is needed to deem either 
one the ‘best overall response’. This is described further below.
2.4.1 Time Point Response 
It is assumed that at each protocol speciﬁed time point, a response assessment occurs. 
Table 2 provides a summary of the overall response status calculation at each time point 
for patients who have measurable disease at baseline. 
Table 2. Time point response: patients with target (+/–non-target) disease.
Target lesions
Non-target lesions
New
lesions
Overall
response
CR
CR
No
CR
CR
Non-CR/non-PD
No
PR
CR
Not evaluated
No
PR
PR
Non-PD 
or 
not 
all 
evaluated
No
PR
SD
Non-PD 
or 
not 
all 
evaluated
No
SD
Not all evaluated
Non- PD
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
CR, complete response; NE, inevaluable; PD, progressive disease; PR, partial 
response; SD, stable disease. 
When patients have non-measurable (therefore non-target) disease only, Table 3 is to be 
used. 
Table 3. Time point response: patients with non-target disease only.
Non-target lesions
New lesions
Overall response
CR
No
CR
Non-CR/non-PD
No
Non-CR/non-PDa
Not all evaluated
No
NE
Unequivocal PD
Yes or No
PD
Any
Yes
PD
CR, complete response, NE, inevaluable; PD, progressive disease. 
a ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-
target disease since SD is increasingly used as endpoint for 
assessment of efficacy in some trials; so, to assign this category 
when no lesions can be measured is not advised.
2.4.2 Missing Assessments and Inevaluable Designation
When no imaging/measurement is done at all at a particular time point, the patient is not 
evaluable (NE) at that time point. If only a subset of lesion measurements are made at 
an assessment, usually the case is also considered NE at that time point, unless a 
convincing argument can be made that the contribution of the individual missing 
lesion(s) would not change the assigned time point response. This would be most likely 
to happen in the case of PD. For example, if a patient had a baseline sum of 50 mm with 

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

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APPENDIX 5: CHOI RESPONSE EVALUATION CRITERIA AND EORTC 
METABOLIC RESPONSE CRITERIA FOR SOLID TUMORS
Choi Response Evaluation Criteria
Response
Definition
CR
Disappearance of all lesions.
No new lesions.
PR
A decrease in size ≥10% or a decrease in tumor attenuation (HU) ≥15% on CT.
No new lesions.
No obvious progression of non-measurable disease.
SD
Does not meet criteria for CR, PR or PD.
No symptomatic deterioration attributed to tumor progression.
PD
An increase in tumor size ≥10% and does not meet criteria of PR by tumor 
attenuation on CT.
New lesions.
New intratumoral nodules or increase in the size of the existing intratumoral 
nodules.
CR, complete response; CT, computed tomography; HU, Hounsfield unit; PD, progressive disease; 
PR, partial response.
Source: Choi H, Charnsangavej C, Faria SC, Macapinlac HA, Burgess MA, Patel SR, Chen LL, 
Podoloff DA, Benjamin RS. Correlation of computed tomography and positron emission 
tomography in patients with metastatic gastrointestinal stromal tumor treated at a single 
institution with imatinib mesylate: proposal of new computed tomography response criteria. J 
Clin Oncol 2007, 25(13): 1753-9. 
European Organization for Research and Treatment of Cancer (EORTC) 
Metabolic Response Criteria for Solid Tumors
Response
Definition
CMR
Complete resolution of [18F]-FDG uptake within the tumor volume, so that it is 
indistinguishable from surrounding normal tissue.
PMR
Decrease of 15-25% in [18F]-FDG SUV after one cycle of chemotherapy, and 
decrease greater than 25% after more than one cycle of chemotherapy.
Reduction in extent of [18F]-FDG tumor uptake is not required.
SMD
Increase in [18F]-FDG SUV <25%, or decrease <15% and no visible increase in 
extent of [18F]-FDG tumor uptake (i.e., <20% in the longest dimension).
PMD
Increase in [18F]-FDG SUV >25% within the tumor region defined on the 
baseline scan, visible increase in the extent of [18F]-FDG tumor uptake (i.e., 
>20% in the longest dimension), or appearance of new [18F]-FDG uptake in 
metastatic lesions.
CMR, complete metabolic response; FDG, fluorodeoxyglucose; PMD, progressive metabolic disease; 
PMR, partial metabolic response; SMD, stable metabolic disease; SUV, standardized uptake value.

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Source: Young H, Baum R, Cremerius U, Herholz K, Hoekstra O, Lammertsma AA, Pruim J, 
Price P. Measurement of clinical and subclinical tumour response using [18F]-
fluorodeoxyglucose and positron emission tomography: review and 1999 EORTC 
recommendations. European Organization for Research and Treatment of Cancer (EORTC)
PET Study Group. Eur J Cancer 1999, 35(13): 1773-82. 

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APPENDIX 6: CYP1, CYP2 AND CYP3 INHIBITORS, INDUCERS AND 
SUBSTRATES
Table 1. Classification of In Vivo Inhibitors of CYP Enzymes (1).
CYP 
enzymes
Strong Inhibitors (2)  
≥ 5-fold increase in AUC
or > 80% decrease in CL
Moderate inhibitors (3)  
≥ 2 but < 5-fold increase in AUC
or 50-80% decrease in CL
Weak inhibitors (4)  
≥ 1.25 but < 2-fold increase in AUC
or 20-50% decrease in CL
CYP1A2
Ciprofloxacin, enoxacin,
fluvoxamine
Methoxsalen, mexiletine,
oral contraceptives, 
phenylpropanolamine,
thiabendazole, zileuton
Acyclovir, allopurinol, caffeine, 
cimetidine,
Daidzein (5), disulfiram, Echinacea
(5), famotidine, norfloxacin, 
propafenone, propranolol, terbinafine, 
ticlopidine, verapamil
CYP2B6
Clopidogrel, ticlopidine
prasugrel
CYP2C8
Gemfibrozil (6)
Fluvoxamine, ketoconazole, 
trimethoprim
CYP2C9
Amiodarone, fluconazole,
miconazole, oxandrolone
Capecitabine, cotrimoxazole,
etravirine, fluvastatin, fluvoxamine, 
metronidazole, sulfinpyrazone, 
tigecycline,
voriconazole, zafirlukast
CYP2C19
Fluconazole (7),
Fluvoxamine (8),
ticlopidine (9)
Esomeprazole, fluoxetine, 
moclobemide,
omeprazole, voriconazole
Allicin (garlic derivative), 
armodafinil, carbamazepine,
cimetidine,
etravirine,
human growth hormone (rhGH),
felbamate,
ketoconazole,
oral contraceptives (10)
CYP3A
Boceprevir,
clarithromycin, conivaptan,
grapefruit juice (11), 
indinavir, itraconazole, 
ketoconazole,
lopinavir/ritonavir,
mibefradil, (12)
nefazodone, nelfinavir,
posaconazole, ritonavir,
saquinavir,
telaprevir,
telithromycin,
voriconazole
Amprenavir, aprepitant,
atazanavir, ciprofloxacin,
darunavir/ritonavir, diltiazem, 
erythromycin, fluconazole, 
fosamprenavir, grapefruit juice
(11), imatinib, verapamil
Alprazolam, amiodarone, amlodipine, 
atorvastatin, bicalutamide, cilostazol, 
cimetidine,
cyclosporine, fluoxetine, 
fluvoxamine, ginkgo (5), goldenseal
(5), isoniazid, nilotinib,
oral contraceptives, ranitidine, 
ranolazine,
tipranavir/ritonavir, zileuton
CYP2D6
Bupropion, fluoxetine,
paroxetine, quinidine
Cinacalcet, duloxetine,
terbinafine
Amiodarone, celecoxib,
cimetidine, desvenlafaxine, diltiazem, 
diphenhydramine, Echinacea (5), 
escitalopram, febuxostat, gefitinib,
hydralazine, hydroxychloroquine,
imatinib, methadone,
oral contraceptives, propafenone, 
ranitidine,
ritonavir, sertraline,
telithromycin, verapamil
1.
Please note the following: This is not an exhaustive list.
For an updated list, see the following link 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/uc
m093664.htm
2.
A strong inhibitor for a specific CYP is defined as an inhibitor that increases the AUC of a substrate for that 
CYP by equal or more than 5-fold.
3.
A moderate inhibitor for a specific CYP is defined as an inhibitor that increases the AUC of a sensitive substrate 
for that CYP by less than 5-fold but equal to or more than 2-fold.

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4.
A weak inhibitor for a specific CYP is defined as an inhibitor that increases the AUC of a sensitive substrate for 
that CYP by less than 2-fold but equal to or more than 5-fold.
5.
Herbal product.
6.
Gemfibrozil also inhibits OATP1B1.
7.
Fluconazole is listed as a strong CYP2C19 inhibitor based on the AUC ratio of omeprazole, which is also 
metabolized by CYP3A; fluconazole is a moderate CYP3A inhibitor.
8.
Fluvoxamine strongly inhibits CYP1A2 and CYP2C19, but also inhibits CYP2C8/2C9 and CYP3A;
9.
Ticlopidine strongly inhibits CYP2C19, but also inhibits CYP3A, CYP2B6, and CYP1A2.
10. Effect seems to be due to CYP2C19 inhibition by ethinyl estradiol.
11. The effect of grapefruit juice varies widely among brands and is concentration-, dose-, and preparation-
dependent. Studies have shown that it can be classified as a “strong CYP3A inhibitor” when a certain 
preparation was used (e.g., high dose, double strength) or as a “moderate CYP3A inhibitor” when another 
preparation was used (e.g., low dose, single strength).
12. Withdrawn from the United States market because of safety reasons.
Table 2. Classification of In Vivo Inducers of CYP Enzymes (1).
CYP 
enzymes
Strong Inducers
≥ 80% decrease in AUC
Moderate Inducers
50-80% decrease in AUC
Weak Inducers
20-50% decrease in AUC
CYP1A2
Montelukast, phenytoin, 
smokers versus non-smokers (2)
Moricizine, omeprazole, 
phenobarbital,
CYP2B6
Efavirenz, rifampin
Nevirapine
CYP2C8
Rifampin
CYP2C9
Carbamazepine,
rifampin
Aprepitant, bosentan, 
phenobarbital, St. John’s wort
(3,4)
CYP2C19
Rifampin
Artemisinin
CYP3A
Avasimibe, (5) 
carbamazepine, phenytoin, 
rifampin, St. John’s wort
(3)
Bosentan, efavirenz, etravirine, 
modafinil, nafcillin
Amprenavir, aprepitant, 
armodafinil, echinacea,(4)
pioglitazone, prednisone, 
rufinamide
CYP2D6
None known
None known
None known
1.
Please note the following: This is not an exhaustive list. For an updated list, see the following link: 
2.
For a drug that is a substrate of CYP1A2, the evaluation of the effect of induction of CYP1A2 can be 
carried out by comparative PK studies in smokers vs. non-smokers.
3.
The effect of St. John’s wort varies widely and is preparation-dependent.
4.
Herbal product.
5.
Not a marketed drug.
Table 3. Examples (1) of Sensitive In Vivo CYP Substrates and CYP Substrates with Narrow 
Therapeutic Range.
CYP 
enzymes
Sensitive substrates (2)
Substrates with
narrow therapeutic range (3)
CYP1A2
Alosetron, caffeine,
duloxetine, melatonin, ramelteon,
tacrine, tizanidine
Theophylline, tizanidine
CYP2B6 (4)
Bupropion, efavirenz
CYP2C8
Repaglinide (5)
Paclitaxel
CYP2C9
Celecoxib
Warfarin, phenytoin
CYP2C19
Lansoprazole, omeprazole, S-mephenytoin
S-mephenytoin
CYP3A (6)
Alfentanil, aprepitant, budesonide, buspirone, conivaptan, 
darifenacin, darunavir, dasatinib, dronedarone, eletriptan, 
eplerenone, everolimus, felodipine, indinavir, fluticasone, 
lopinavir, lovastatin, lurasidone, maraviroc, midazolam, 
nisoldipine, quetiapine, saquinavir, sildenafil, simvastatin, 
Alfentanil, astemizole (7),
cisapride (7), cyclosporine, 
dihydroergotamine, ergotamine, 
fentanyl, pimozide, quinidine, 
sirolimus, tacrolimus,

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CYP 
enzymes
Sensitive substrates (2)
Substrates with
narrow therapeutic range (3)
sirolimus, tolvaptan, tipranavir, triazolam, vardenafil
terfenadine (7)
CYP2D6
Atomoxetine, desipramine,
dextromethorphan, metoprolol,
nebivolol, perphenazine, tolterodine,
venlafaxine
Thioridazine
1.
Note that this is not an exhaustive list.
For an updated list, see the following link: 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabe
ling/ucm093664.htm
2.
Sensitive CYP substrates refers to drugs whose plasma AUC values have been shown to increase 5-fold 
or higher when co-administered with a known CYP inhibitor.
3.
CYP substrates with narrow therapeutic range refers to drugs whose exposure-response relationship 
indicates that small increases in their exposure levels by the concomitant use of CYP inhibitors may lead 
to serious safety concerns (e.g., Torsades de Pointes).
4.
The AUC of these substrates were not increased by 5-fold or more with a CYP2B6 inhibitor, but they 
represent the most sensitive substrates studied with available inhibitors evaluated to date.
5.
Repaglinide is also a substrate for OATP1B1, and it is only suitable as a CYP2C8 substrate if the 
inhibition of OATP1B1 by the investigational drug has been ruled out.
6.
Because a number of CYP3A substrates (e.g., darunavir, maraviroc) are also substrates of P-gp, the 
observed increase in exposure could be due to inhibition of both CYP3A and P-gp.
7.
Withdrawn from the United States market because of safety reasons.

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APPENDIX 7: GCIG SPECIFIC CRITERIA
GCIC-Rustin-modified Criteria for CA-125 Response1
Patients will be scored as having attained a CA-125 response if they meet the GCIG-
Rustin-modified criteria which require that there is at least a 50% reduction in CA-125 
levels from a pre-treatment sample. The response must be confirmed and maintained for 
at least 28 days. Patients can be evaluated according to CA-125 only if they have a pre-
treatment sample that is at least twice the upper limit of normal and within two weeks 
prior to starting treatment. In addition, CA-125 levels in samples obtained after 
administration of mouse antibodies or within four weeks after surgery or paracentesis 
should not be taken into account. 
Definition of Progression free survival and duration of response by CA-125
PFS based on CA-125 will be defined as the time from first study drug infusion until the 
GCIC-Rustin-modified criteria of progression are met, or until the date of death (with or 
without disease progression).Duration of CA-125 response will be defined as the time 
between when the CA-125 was first documented to have decreased by 50% in a patient 
who meets all the GCIG-Rustin-modified criteria for a CA-125 response, and the time 
the CA-125 is first documented to have risen to the point where the patient meets GCIG 
criteria of disease progression.
GCIC-Rustin-modified definition of progressive disease according to CA-125 criteria
Definition of progression
Date of progression
Patients with elevated CA-125 before
treatment and normalization of CA-125 
during treatment
CA-125 2 X ULN 
documented on 2 occasions*
Date CA-125 is first 
elevated to 2 X ULN
Patients with elevated CA-125 pretreatment 
that never normalizes
CA-125 2 X nadir value on 
2 occasions*
Date CA-125 is first 
elevated to 2 X nadir 
value
Patients with CA-125 in normal range 
pretreatment
CA-125 2 X ULN 
documented on 2 occasions*
Date CA-125 is first 
elevated to 2 X ULN
*Repeat CA-125 anytime but normally not less than one week after the first elevated CA-125 level. CA-
125 levels in samples obtained after administration of mouse antibodies or within four weeks after 
surgery or paracentesis should not be taken into account.
In patients for whom response to treatment is evaluated by both RECIST and CA-125 
criteria, the date of response and progression will be the earliest date of the two 
methods.
1 Rustin GJ, Quinn M, Thigpen T, du Bois A, Pujade-Lauraine E, Jakobsen A, et al. Re: New guidelines to evaluate 
the response to treatment in solid tumors (ovarian cancer). J Natl Cancer Inst 2004;96(6):487-8.

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APPENDIX 8: DECLARATION OF HELSINKI
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI
Ethical Principles for Medical Research Involving Human Subjects
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964
and amended by the:
29th WMA General Assembly, Tokyo, Japan, October 1975
35th WMA General Assembly, Venice, Italy, October 1983
41st WMA General Assembly, Hong Kong, September 1989
48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996
52nd WMA General Assembly, Edinburgh, Scotland, October 2000
53rd WMA General Assembly, Washington DC, USA, October 2002 (Note of 
Clarification added)
55th WMA General Assembly, Tokyo, Japan, October 2004 (Note of Clarification 
added)
59th WMA General Assembly, Seoul, Republic of Korea, October 2008
64th WMA General Assembly, Fortaleza, Brazil, October 2013
Preamble
1.
The World Medical Association (WMA) has developed the Declaration of 
Helsinki as a statement of ethical principles for medical research involving 
human subjects, including research on identifiable human material and data.
The Declaration is intended to be read as a whole and each of its constituent 
paragraphs should be applied with consideration of all other relevant paragraphs.
2.
Consistent with the mandate of the WMA, the Declaration is addressed primarily 
to physicians. The WMA encourages others who are involved in medical 
research involving human subjects to adopt these principles.
General Principles
3.
The Declaration of Geneva of the WMA binds the physician with the words, 
“The health of my patient will be my first consideration,” and the International 
Code of Medical Ethics declares that, “A physician shall act in the patient's best 
interest when providing medical care.”
4.
It is the duty of the physician to promote and safeguard the health, well-being 
and rights of patients, including those who are involved in medical research. The 
physician's knowledge and conscience are dedicated to the fulfilment of this 
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5.
Medical progress is based on research that ultimately must include studies 
involving human subjects.
6.
The primary purpose of medical research involving human subjects is to 
understand the causes, development and effects of diseases and improve 
preventive, diagnostic and therapeutic interventions (methods, procedures and 
treatments). Even the best proven interventions must be evaluated continually 
through research for their safety, effectiveness, efficiency, accessibility and 
quality.
7.
Medical research is subject to ethical standards that promote and ensure respect 
for all human subjects and protect their health and rights.
8.
While the primary purpose of medical research is to generate new knowledge, 
this goal can never take precedence over the rights and interests of individual 
research subjects.
9.
It is the duty of physicians who are involved in medical research to protect the 
life, health, dignity, integrity, right to self-determination, privacy, and 
confidentiality of personal information of research subjects. The responsibility 
for the protection of research subjects must always rest with the physician or 
other health care professionals and never with the research subjects, even though 
they have given consent.
10.
Physicians must consider the ethical, legal and regulatory norms and standards 
for research involving human subjects in their own countries as well as 
applicable international norms and standards. No national or international 
ethical, legal or regulatory requirement should reduce or eliminate any of the 
protections for research subjects set forth in this Declaration.
11.
Medical research should be conducted in a manner that minimises possible harm 
to the environment.
12.
Medical research involving human subjects must be conducted only by 
individuals with the appropriate ethics and scientific education, training and 
qualifications. Research on patients or healthy volunteers requires the 
supervision of a competent and appropriately qualified physician or other health 
care professional.
13.
Groups that are underrepresented in medical research should be provided 
appropriate access to participation in research.
14.
Physicians who combine medical research with medical care should involve 
their patients in research only to the extent that this is justified by its potential 

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

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Scientific Requirements and Research Protocols
21.
Medical research involving human subjects must conform to generally accepted 
scientific principles, be based on a thorough knowledge of the scientific 
literature, other relevant sources of information, and adequate laboratory and, as 
appropriate, animal experimentation. The welfare of animals used for research 
must be respected.
22.
The design and performance of each research study involving human subjects 
must be clearly described and justified in a research protocol.
The protocol should contain a statement of the ethical considerations involved 
and should indicate how the principles in this Declaration have been addressed. 
The protocol should include information regarding funding, sponsors, 
institutional affiliations, potential conflicts of interest, incentives for subjects and 
information regarding provisions for treating and/or compensating subjects who 
are harmed as a consequence of participation in the research study.
In clinical trials, the protocol must also describe appropriate arrangements for 
post-trial provisions.
Research Ethics Committees
23.
The research protocol must be submitted for consideration, comment, guidance 
and approval to the concerned research ethics committee before the study 
begins. This committee must be transparent in its functioning, must be 
independent of the researcher, the sponsor and any other undue influence and 
must be duly qualified. It must take into consideration the laws and regulations 
of the country or countries in which the research is to be performed as well as 
applicable international norms and standards but these must not be allowed to 
reduce or eliminate any of the protections for research subjects set forth in this 
Declaration.
The committee must have the right to monitor ongoing studies. The researcher 
must provide monitoring information to the committee, especially information 
about any serious adverse events. No amendment to the protocol may be made 
without consideration and approval by the committee. After the end of the study, 
the researchers must submit a final report to the committee containing a 
summary of the study’s findings and conclusions.
Privacy and Confidentiality
24.
Every precaution must be taken to protect the privacy of research subjects and 
the confidentiality of their personal information.
Informed Consent

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25.
Participation by individuals capable of giving informed consent as subjects in 
medical research must be voluntary. Although it may be appropriate to consult 
family members or community leaders, no individual capable of giving informed 
consent may be enrolled in a research study unless he or she freely agrees.
26.
In medical research involving human subjects capable of giving informed 
consent, each potential subject must be adequately informed of the aims, 
methods, sources of funding, any possible conflicts of interest, institutional 
affiliations of the researcher, the anticipated benefits and potential risks of the 
study and the discomfort it may entail, post-study provisions and any other 
relevant aspects of the study. The potential subject must be informed of the right 
to refuse to participate in the study or to withdraw consent to participate at any 
time without reprisal. Special attention should be given to the specific 
information needs of individual potential subjects as well as to the methods used 
to deliver the information.
After ensuring that the potential subject has understood the information, the 
physician or another appropriately qualified individual must then seek the 
potential subject’s freely-given informed consent, preferably in writing. If the 
consent cannot be expressed in writing, the non-written consent must be 
formally documented and witnessed.
  
All medical research subjects should be given the option of being informed 
about the general outcome and results of the study.
27.
When seeking informed consent for participation in a research study the 
physician must be particularly cautious if the potential subject is in a dependent 
relationship with the physician or may consent under duress. In such situations 
the informed consent must be sought by an appropriately qualified individual 
who is completely independent of this relationship.
28.
For a potential research subject who is incapable of giving informed consent, the 
physician must seek informed consent from the legally authorised representative. 
These individuals must not be included in a research study that has no likelihood 
of benefit for them unless it is intended to promote the health of the group 
represented by the potential subject, the research cannot instead be performed 
with persons capable of providing informed consent, and the research entails 
only minimal risk and minimal burden.
29.
When a potential research subject who is deemed incapable of giving informed 
consent is able to give assent to decisions about participation in research, the 
physician must seek that assent in addition to the consent of the legally 
authorised representative. The potential subject’s dissent should be respected.
30.
Research involving subjects who are physically or mentally incapable of giving 
consent, for example, unconscious patients, may be done only if the physical or 
mental condition that prevents giving informed consent is a necessary 

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characteristic of the research group. In such circumstances the physician must 
seek informed consent from the legally authorised representative. If no such 
representative is available and if the research cannot be delayed, the study may 
proceed without informed consent provided that the specific reasons for 
involving subjects with a condition that renders them unable to give informed 
consent have been stated in the research protocol and the study has been 
approved by a research ethics committee. Consent to remain in the research must 
be obtained as soon as possible from the subject or a legally authorised 
representative.
31.
The physician must fully inform the patient which aspects of their care are 
related to the research. The refusal of a patient to participate in a study or the 
patient’s decision to withdraw from the study must never adversely affect the 
patient-physician relationship.
32.
For medical research using identifiable human material or data, such as research 
on material or data contained in biobanks or similar repositories, physicians 
must seek informed consent for its collection, storage and/or reuse. There may 
be exceptional situations where consent would be impossible or impracticable to 
obtain for such research. In such situations the research may be done only after 
consideration and approval of a research ethics committee.
Use of Placebo
33.
The benefits, risks, burdens and effectiveness of a new intervention must be 
tested against those of the best proven intervention(s), except in the following 
circumstances:
Where no proven intervention exists, the use of placebo, or no intervention, is 
acceptable; or
Where for compelling and scientifically sound methodological reasons the use of 
any intervention less effective than the best proven one, the use of placebo, or no 
intervention is necessary to determine the efficacy or safety of an intervention
and the patients who receive any intervention less effective than the best proven 
one, placebo, or no intervention will not be subject to additional risks of serious 
or irreversible harm as a result of not receiving the best proven intervention.
Extreme care must be taken to avoid abuse of this option.
Post-Trial Provisions
34.
In advance of a clinical trial, sponsors, researchers and host country 
governments should make provisions for post-trial access for all participants 
who still need an intervention identified as beneficial in the trial. This 
information must also be disclosed to participants during the informed consent 
process.

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Research Registration and Publication and Dissemination of Results
35.
Every research study involving human subjects must be registered in a publicly 
accessible database before recruitment of the first subject.
36.
Researchers, authors, sponsors, editors and publishers all have ethical 
obligations with regard to the publication and dissemination of the results of 
research. Researchers have a duty to make publicly available the results of their 
research on human subjects and are accountable for the completeness and 
accuracy of their reports. All parties should adhere to accepted guidelines for 
ethical reporting. Negative and inconclusive as well as positive results must be 
published or otherwise made publicly available. Sources of funding, institutional 
affiliations and conflicts of interest must be declared in the publication. Reports 
of research not in accordance with the principles of this Declaration should not 
be accepted for publication.
Unproven Interventions in Clinical Practice
37.
In the treatment of an individual patient, where proven interventions do not exist 
or other known interventions have been ineffective, the physician, after seeking 
expert advice, with informed consent from the patient or a legally authorised 
representative, may use an unproven intervention if in the physician's judgement 
it offers hope of saving life, re-establishing health or alleviating suffering. This 
intervention should subsequently be made the object of research, designed to 
evaluate its safety and efficacy. In all cases, new information must be recorded 
and, where appropriate, made publicly available.
Disclaimer: ©2013 World Medical Association, Inc. All Rights Reserved. All intellectual property rights 
in the Declaration of Helsinki are vested in the World Medical Association. Previous permissions granted 
to publish or reproduce otherwise WMA policy don’t apply to this version of the Declaration of Helsinki 
until January 1st, 2014. For further questions, please contact the WMA secretariat at
mailto:secretariat@wma.net.