Clinical trial NCT03427268
Conditions: Advanced Colorectal Cancer
Sponsor: PharmaMar
Start date: 2018-01-16; Completion date: 2019-02-11
Enrollment: 32 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This trial will evaluate the efficacy of PM060184 in terms of progression-free survival at 12 weeks (PFS3) in advanced or metastatic Colorectal Cancer (CRC) patients with any KRAS mutation status (wild- type; mutated; or unknown status) progressing after standard treatments (fluoropyrimidine, irinotecan, and oxaliplatin).

Patients in this trial will receive PM060184 at a dose of 9.3 mg/m2 as a 30-minute intravenous (i.v.) infusion on Days 1 and 8 q3wk.

Detailed description:

Arms: arm 1: PM060184
Interventions: intervention 1: PM060184
Intervention descriptions: intervention 1: PM060184: 9.3 mg/m2 PM060184 i.v. as a 30-minute infusion via a central or peripheral venous catheter.Dose can be rounded to the first decimal point.

PM060184 will be administered on Day 1 and Day 8 q3wk. (Three weeks=one treatment cycle).

Protocol documents:
Prot_000.pdf: 
 
 
 
SPONSOR 
 
Pharma Mar, S.A. 
Avda de los Reyes, 1 
 
Polígono Industrial “La Mina” 
28770 Colmenar Viejo (Madrid), Spain 
Phone: + 34 918 466 000  
Fax:  
+ 34 918 466 003 
 
 
Pharma Mar USA, Inc. 
205 East 42nd Street, suite 15003 
New York, NY 10017, USA 
 
Phone: +1 646 880 4429 
Fax: +1 646 893 5856 
 
 
 
 
CLINICAL TRIAL PROTOCOL 
 
 
A Phase II, Open-label, Multicenter Study of PM060184 in Patients with Advanced 
Colorectal Cancer after Standard Treatment 
 
 
INVESTIGATIONAL MEDICINAL PRODUCTS: PM060184 
Protocol No.: PM60184-B-002-17 
EudraCT No.: 2017-000257-39 
NCT Code: 03427268 
 
 
 
Protocol version 2.0 including substantial amendment #1 dated 27 July 2017 
 


SPONSORS
Pharma Mar, S.A.
Avda de los Reyes, 1
Polígono Industrial “La Mina” 
28770 Colmenar Viejo (Madrid), Spain
Pharma Mar USA, Inc.
205 East 42nd Street, suite 15003
New York, NY 10017, USA
Phone:
+ 34 91 846 6000
Phone:
+1 646 880 4429
Fax:
+ 34 91 846 6003
Fax:
+1 646 893 5856
CLINICAL TRIAL PROTOCOL
PM60184-B-002-17
A Phase II, Open-label, Multicenter Study of PM060184 in Patients with 
Advanced Colorectal Cancer after Standard Treatment
INVESTIGATIONAL MEDICINAL PRODUCT:
PM060184
Protocol Code:
PM60184-B-002-17
EudraCT No:
2017-000257-39
Protocol version 2.0 including substantial amendment #1 dated 27 July 2017
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
Sponsors1: 
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, New York 10017, 
USA.
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
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
Outside office hours: +34 681 263 592
Clinical 
Pharmacology 
(Pharmacokinetics), 
Ignacio González García
Clinical Pharmacology
Pharma Mar, S.A.
Phone:
+ 34 91 823 4662
Fax:
+ 34 91 823 4504
E-mail: iggarcia@pharmamar.com
(Pharmacogenetics, 
Metabolomics)
Rubin Lubomirov, MD, PhD
Clinical Pharmacology
Pharma Mar, S.A.
Phone:
+ 34 91 846 6143
Fax:
+ 34 91 823 4504
E-mail: rlubomirov@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 Metabolomic 
Samples
Cristina Alonso
OWL, One Way Liver, S.L.
Parque Tecnológico de Bizkaia
502 Building, 
48160 Derio, Spain
Phone:
+34 94 431 85 40
Fax:
+34 94 431 71 40
E-mail: 
calonso@owlmetabolomics.com
Pharmacogenomics
Miguel Aracil, PhD
Pharmacogenomics 
Pharma Mar, S.A.
Phone:
+34 91 846 6098
Fax:
+34 91 846 6001
E-mail: maracil@pharmamar.com
Central Laboratory 
for Pharmacogenomic
and Pharmacogenetic
Samples
RNA/DNA analysis:
Maria 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
                                                
1 Abbreviated as PharmaMar or Sponsor in the rest of the protocol.
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STUDY CONTACTS
NAME AND ADDRESS
PHONE, FAX NUMBER, AND E-
MAIL ADDRESS
IHC analysis:
Roger Buchanan
Q Squared Solutions Limited
The Alba Campus (Rosebank)
Livingston
West Lothian EH54 7EG
Scotland, United Kingdom
Phone: +44 1506 814 000
Fax: 
+44 1506 814 199
www.Q2Labsolutions.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
PRINCIPAL INVESTIGATORS..............................................................................................................4
SYNOPSIS ..................................................................................................................................................7
SCHEDULE OF ASSESSMENTS AND PROCEDURES....................................................................20
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS........................................................23
1.
INTRODUCTION ...........................................................................................................................26
1.1
DISEASE BACKGROUND..........................................................................................................26
1.2
INFORMATION ON STUDY DRUG............................................................................................27
1.2.1
Non-clinical Data ...............................................................................................................28
1.2.2
Clinical Data ......................................................................................................................30
1.3
STUDY RATIONALE.................................................................................................................31
2.
OVERALL STUDY DESIGN.........................................................................................................33
3.
STUDY OBJECTIVES ...................................................................................................................33
4.
SELECTION OF PATIENTS.........................................................................................................34
4.1
INCLUSION CRITERIA .............................................................................................................34
4.2
EXCLUSION CRITERIA............................................................................................................35
5.
TREATMENT .................................................................................................................................36
5.1
STUDY DRUG FORMULATION AND SUPPLY............................................................................36
5.2
ADMINISTRATION OF STUDY MEDICATION...........................................................................36
5.3
CRITERIA FOR TREATMENT CONTINUATION........................................................................36
5.4
DOSE REDUCTION...................................................................................................................37
5.5
CONCOMITANT MEDICATION ................................................................................................38
5.5.1
Prophylactic Medication ....................................................................................................38
5.5.2
Allowed Medications/Therapies .........................................................................................39
5.5.3
Prohibited Medications/Therapies .....................................................................................39
5.5.4
Drug-drug Interactions.......................................................................................................39
5.6
DRUG ACCOUNTABILITY........................................................................................................39
5.7
TREATMENT COMPLIANCE ....................................................................................................39
6.
PLAN OF THE STUDY..................................................................................................................40
6.1
DURATION OF THE STUDY (WHOLE POPULATION)..............................................................40
6.2
DURATION OF THE STUDY (PER PATIENT) ...........................................................................40
6.3
DISCONTINUATIONS................................................................................................................40
6.3.1
Treatment Discontinuation.................................................................................................40
6.3.2
Reasons For Treatment Discontinuation............................................................................41
6.3.3
Study Discontinuation.........................................................................................................41
6.3.4
Replacement of Patients .....................................................................................................41
6.4
PROTOCOL DEVIATIONS.........................................................................................................42
7.
STUDY ASSESSMENTS AND PROCEDURES ..........................................................................42
7.1
ELIGIBILITY ASSESSMENTS....................................................................................................42
7.2
PATIENT REGISTRATION........................................................................................................44
7.3
RANDOMIZATION....................................................................................................................44
7.4
EVALUATIONS DURING TREATMENT.....................................................................................44
7.5
EVALUATIONS AT END OF TREATMENT ...............................................................................47
7.6
FOLLOW-UP AFTER THE END OF TREATMENT VISIT...........................................................47
7.7
STUDY TERMINATION (CLINICAL CUTOFF) ..........................................................................48
7.8
PHARMACOKINETICS..............................................................................................................48
7.9
METABOLOMICS.....................................................................................................................49
7.10
PHARMACOGENETICS.............................................................................................................50
7.11
PHARMACOGENOMICS............................................................................................................50
8.
STUDY EVALUATIONS ...............................................................................................................51
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8.1
EFFICACY................................................................................................................................51
8.2
SAFETY....................................................................................................................................51
8.3
PATIENT REPORTED OUTCOMES ...........................................................................................52
8.4
ADVERSE EVENTS...................................................................................................................52
8.4.1
Serious Adverse Event (SAE)..............................................................................................53
8.4.2
Death ..................................................................................................................................53
8.4.3
Life-threatening Event........................................................................................................53
8.4.4
Hospitalization or Prolongation of Hospitalization ...........................................................53
8.4.5
Unlisted/Unexpected Adverse Event...................................................................................54
8.4.6
Adverse Reactions...............................................................................................................54
8.4.7
Adverse Events Related to the Study Drug .........................................................................54
8.4.8
Expedited Reporting ...........................................................................................................54
8.4.9
Assessment of Causal Relationship to the Study Drug .......................................................54
8.5
ADVERSE EVENTS REPORTING PROCEDURES .......................................................................54
8.5.1
Reporting Adverse Events...................................................................................................54
8.5.2
Reporting Serious Adverse Events......................................................................................55
8.5.3
Reporting Pregnancy Cases Occurred within the Clinical Trial........................................55
8.5.4
Adverse Events Monitoring.................................................................................................56
9.
STATISTICAL METHODS ...........................................................................................................57
9.1
PRIMARY ENDPOINT...............................................................................................................57
9.2
SECONDARY ENDPOINTS ........................................................................................................57
9.3
SAMPLE SIZE...........................................................................................................................58
9.4
STATISTICAL ANALYSIS .........................................................................................................58
9.5
EFFICACY ANALYSIS ..............................................................................................................58
9.6
SAFETY ANALYSIS ..................................................................................................................58
9.7
PATIENT REPORTED OUTCOMES ...........................................................................................58
9.8
PHARMACOKINETICS ANALYSIS ............................................................................................59
9.9
METABOLOMICS (BIOMARKERS) ANALYSIS..........................................................................59
9.10
PHARMACOGENETICS ANALYSIS ...........................................................................................60
9.11
PHARMACOGENOMICS ANALYSIS ..........................................................................................60
10.
ADMINISTRATIVE SECTION................................................................................................61
10.1
ETHICS ....................................................................................................................................61
10.2
MONITORING, AUDITING AND INSPECTING...........................................................................61
10.3
PATIENT INFORMED CONSENT...............................................................................................62
10.4
CONFIDENTIALITY/IDENTIFICATION OF PATIENTS...............................................................62
10.5
ELECTRONIC CASE REPORT FORMS......................................................................................62
10.6
INSURANCE..............................................................................................................................63
10.7
RETENTION OF RECORDS.......................................................................................................63
10.8
USE OF INFORMATION AND PUBLICATIONS...........................................................................63
11.
REFERENCES............................................................................................................................64
12.
APPENDICES .............................................................................................................................66
APPENDIX 1. ECOG PERFORMANCE STATUS ASSESSMENT SCALE ....................................66
APPENDIX 2. COCKCROFT-GAULT FORMULA............................................................................67
APPENDIX 3. CONTRACEPTION AND PREGNANCY TESTING ................................................68
APPENDIX 4. CYP1, CYP2 AND CYP3 INHIBITORS, INDUCERS AND SUBSTRATES ...........70
APPENDIX 5. DECLARATION OF HELSINKI .................................................................................73
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SYNOPSIS
TITLE
A Phase II, Open-label, Multicenter Study of PM060184 in 
Patients with Advanced Colorectal Cancer after Standard 
Treatment.
CODE
PM60184-B-002-17
INVESTIGATORS
A full list of Investigators will be available as a separate 
document.
TRIAL SITES/ 
LOCATION
Approximately six sites in the EU, the U.S. and Canada are 
expected to participate.
STUDY OBJECTIVES
Primary:

To evaluate the efficacy of PM060184 in terms of 
progression-free survival at 12 weeks (PFS3) in patients with 
advanced colorectal carcinoma (CRC) after standard therapy.
Secondary:

To evaluate overall survival (OS); progression-free survival 
(PFS); overall response rate (ORR); and duration of response 
(DOR).

To characterize the safety profile and feasibility of PM060184 
in this population.

To describe peripheral neuropathy (PN) and quality of life 
(QoL) profiles in this population using patient-reported 
outcomes (PRO) as measured by the European Organisation 
for Research and Treatment of Cancer (EORTC) quality of 
life 
questionnaires 
(QLQ) 
for 
chemotherapy-induced 
peripheral neuropathy (QLQ-CIPN20) and general QoL 
(QLQ-C30).

To characterize the pharmacokinetics (PK) of PM060184 in 
this population.

To characterize the metabolomics of PM060184, i.e., systemic 
variations in the patient’s pre- and post-treatment metabolic 
profile that allow the identification of potential biomarkers of 
PK, safety and/or efficacy response to PM060184.

To characterize pharmacogenetics (PGt) of PM060184 in this 
population by identifying the presence or absence of germline 
mutations or polymorphisms that may help explain individual 
variability in the main PK parameters and safety outcomes.

To characterize pharmacogenomics (PGx) of PM060184 in 
this population by analyzing the potential predictive factors 
(including BRAF-mutant-like gene expression subtypes) of 
sensitivity/resistance to PM060184 treatment.
STUDY POPULATION
Patients with relapsed, metastatic/locally advanced CRC with any 
KRAS-mutation status (wild-type, mutated, or status unknown),
progressing 
after 
standard 
treatments 
(fluoropyrimidine, 
irinotecan, and oxaliplatin).
STUDY DESIGN
This is a phase II, multicenter, open-label, study of single-agent 
PM060184 to evaluate efficacy in patients with advanced CRC
progressing after standard therapy.
Initially, 24 patients who are evaluable for the primary endpoint
will be included and a futility analysis will be performed (first 
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stage). If at least seven of these patients achieve PFS3, then the 
study will proceed to a second stage and 36 additional patients will 
be recruited.
If at least 25 of 60 evaluable patients are alive and free of 
progression at 12 weeks, PM060184 will be considered active and 
deserving potential development in this setting.
SUBSTUDY DESIGN
An exploratory substudy will address pharmacogenomic and 
pharmacogenetic objectives. All patients who participate in the 
PM60184-B-002-17 clinical trial will be eligible for the substudy
if they voluntarily sign a separate informed consent. Refusal to 
participate in the substudy will not affect a patient’s participation 
in the clinical trial.
INCLUSION 
CRITERIA
1) Voluntarily written informed consent, obtained before the 
beginning of any study-specific procedures.
2) Age ≥ 18 years.
3) Histologically-cytologically documented adenocarcinoma of 
colon or rectum that has progressed to the last prior treatment 
before inclusion.
4) Measurable disease according to Response Evaluation Criteria 
in Solid Tumors (RECIST) v.1.1. If the only tumor lesion is 
situated in a previously irradiated area or in an area subjected 
to other loco-regional therapy, progression in the lesion must 
be demonstrated radiologically.
5) Previous treatment in any setting with fluoropyrimidine, 
oxaliplatin and irinotecan in any combination (unless any is 
contraindicated). 
a)
Adjuvant chemotherapy-based treatments count as prior 
therapy, as long as relapse had occurred during or within 
six months of completion of such therapies.
b) Cumulative dose of prior oxaliplatin (if any) must be 
known.
c)
Prior cetuximab, panitumumab, bevacizumab, aflibercept, 
and regorafenib are allowed.
6) No more than two prior therapies for metastatic disease.
7) Washout periods for prior therapies (defined in relation to 
planned start of study treatment [first dose administration]):
a)
At least three weeks since the last administration of an 
antineoplastic 
treatment 
(chemotherapy, 
biological, 
targeted or investigational therapies).
b) At least three weeks since radiotherapy involving up to 
35% of bone marrow (radiotherapy involving > 35% of 
bone marrow is not allowed) or two weeks since the end 
of palliative radiotherapy including single doses.
c)
At least four weeks since any major surgical procedure, 
open biopsy, or significant traumatic injury.
8) Eastern Cooperative Oncology Group (ECOG) performance 
status (PS) 0 or 1.
9) Life expectancy ≥ 3 months.
10)Adequate bone marrow, liver, and kidney function:
a)
Hemoglobin ≥ 9 g/dL.
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b) Absolute neutrophil count ≥ 1.5 × 109/L.
c)
Platelet count ≥ 100 × 109/L.
d) Serum creatinine ≤ 1.5 mg/dL or calculated creatinine 
clearance ≥ 40 mL/min (Cockcroft-Gault formula). 
e)
Albumin ≥ 2.5 g/dL.
f)
Total serum bilirubin ≤ 1.5 times the upper limit of normal 
(ULN), except in case of Gilbert syndrome. 
g)
Alanine 
aminotransferase 
(ALT) 
and 
aspartate 
aminotransferase (AST) ≤ 3 × ULN (≤ 5.0 × ULN in the 
case of liver metastases).
11)Recovery to grade ≤ 1 from any toxicity due to previous 
therapy (including peripheral sensory/motor neuropathy but 
excluding alopecia).
12)Left ventricular ejection fraction (LVEF) by echocardiography 
(ECHO) or multiple-gated acquisition (MUGA) scan within 
normal range (according to institutional standards).
13)Evidence of non-childbearing status for women of childbearing 
potential (WOCBP). WOCBP must agree to use a highly 
effective contraceptive measure during the trial and up to six 
months after treatment discontinuation, and fertile male 
patients must agree to refrain from fathering a child or 
donating sperm during the trial and up to four months after 
treatment discontinuation.
EXCLUSION 
CRITERIA
1) Prior exposure to PM060184.
2) Known hypersensitivity to the study drug class or study drug 
excipient in the formulation.
3) Patients with locally advanced disease amenable to local 
and/or curative therapy (surgery or radiotherapy) at study 
entry.
4) Other serious and/or relevant diseases or clinical situations 
that, in the opinion of the Investigator, are incompatible with 
the protocol (including any of the following):
a)
History of another neoplastic disease (except for basal cell 
carcinoma of the skin, superficial bladder tumors, or 
properly treated carcinoma in situ of the uterine cervix or 
melanoma in situ) unless in remission for at least five 
years and with no recurrence. 
b) Symptomatic cerebral and/or leptomeningeal metastasis, 
spinal cord compression or carcinomatous meningitis.
c)
Neuropathy of any etiology (other than that caused by 
previous antineoplastic therapy).
d) History of cardiac disease, such as myocardial infarction, 
in the year prior to registration in the clinical trial; 
symptomatic/uncontrolled angina pectoris; congestive 
heart failure or uncontrolled cardiac ischemia; any type of 
uncontrolled arrhythmia, congenital and/or prolonged QT 
interval or abnormal LVEF, or uncontrolled arterial 
hypertension (according to the standards of the World 
Health Organization [WHO]).
e)
History of significant psychiatric disease.
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f)
Active infection requiring antibiotic, antifungal or 
antiviral treatment that, in the opinion of the Investigator, 
could compromise the patient’s capacity to tolerate the 
therapy.
g)
Known active liver (hepatitis B or C or cirrhosis) or renal 
disease.
h) Known human immunodeficiency virus (HIV) infection.
i)
Any other concomitant pathology that could jeopardize 
the patient’s safety or commitment to complete the 
clinical trial.
j)
Inability or refusal to comply with the protocol or with the 
clinical trial procedures.
5) Pregnancy or lactation. 
EXPECTED NUMBER 
OF PATIENTS
The number of evaluable patients for the first stage (until the
futility analysis) is 24, and for the second stage, 36; an expected 
60 patients in total.
STUDY DRUG
Formulation
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, PM060184 15-mg vials should be reconstituted with 6 
mL of water for injection. The total volume of the reconstituted 
vial should be diluted with dextrose (5%) up to a total volume of 
30 mL to give a PM060184 diluted solution containing 0.5 mg/mL 
of PM060184. The diluted solution should be protected from 
exposure to light. 
Each 15-mg vial of PM060184 is a single-use vial. The full 
composition of the reconstituted solution per mL is shown in
Table 1.
Table 1. PM060184 vial composition.
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.
Dose / Route of 
administration
9.3 mg/m2 PM060184 i.v. as a 30-minute infusion via a central or 
peripheral venous catheter.
Dose can be rounded to the first decimal point.
Treatment Schedule
PM060184 will be administered on Day 1 and Day 8 q3wk. (Three 
weeks=one treatment cycle).
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PROPHYLACTIC 
MEDICATION
Primary antiemetic prophylaxis is compulsory before
all 
PM060184 dose administrations. Standard treatment according to 
the American Society of Clinical Oncology (ASCO) guidelines 
will be administered:

5-HT3 antagonists (ondansetron 8 mg or equivalent).

Steroids (dexamethasone 8 mg or equivalent).
Oral or i.v. formulations are allowed according to institutional 
standards.
If necessary, additional antiemetic therapy can be considered in 
accordance with ASCO guidelines.
CRITERIA FOR 
TREATMENT 
CONTINUATION
Patients will be treated with additional cycles of PM060184 until 
disease progression (PD), as long as none of the following occur: 
unacceptable toxicity, and/or patient refusal, and/or Investigators’
decision.
The administration of subsequent cycles (after Cycle 1) should be 
delayed if criteria for treatment continuation (Table 2) are not met 
on the corresponding Day 1. If criteria for treatment continuation
are not met on Day 8 (i.e., seven days after the first dose 
administration of a cycle) (Table 2) of any cycle, administration 
should be omitted instead of delayed. 
Table 2. Criteria for treatment continuation.
A maximum delay of 15 days is allowed for the recovery of 
patients from toxicity. If toxicities have not recovered after this 
period, the patient should discontinue treatment. Exceptionally, in 
case of obvious clinical benefit, the patient can remain on 
Abnormality
Day 1 a
Day 8
ANC
1.5 × 109/L
1.0 × 109/L
Platelets
100 × 109/L
75 × 109/L
Hemoglobin b
9 g/dL
9 g/dL
Total bilirubin
1.5 × ULN (grade 1)
AST/ALT
Grade 1 c
Grade ≤ 2
Calculated CrCL (Cockcroft-Gault 
formula)
≥ 40 mL/min
30 mL/min
Peripheral sensory/motor
neuropathy 
Grade ≤ 2
Grade ≤ 2
Nausea/vomiting, fatigue, anorexia 
Grade ≤ 2
Grade ≤ 2
Other non-hematological drug-
related AEs (except metabolic 
abnormalities d)
Grade ≤ 1
Grade ≤ 2
a Except Day 1 of Cycle 1.
b If hemoglobin levels are not met, the Investigator will have the option of giving 
the patient a transfusion instead of delaying (on Day 1) or omitting (on Day 8) a 
dose.
c Grade ≤ 2, for patients with liver metastases and with AST and/or ALT levels 
≤5.0 x ULN at registration.
d Any grade accepted for increased GGT. Up to grade 4 accepted for non-
symptomatic metabolic abnormalities (e.g., sodium, magnesium, potassium, 
calcium). 
AE, adverse event; ALT, alanine aminotransferase; ANC, absolute neutrophil 
count; AST, aspartate aminotransferase; CrCL, creatinine clearance; GGT,
gamma-glutamyltransferase; ULN, upper limit of normal.
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treatment but only after discussion and mutual agreement with the 
Sponsor, and upon recovery of all parameters according to the 
aforementioned criteria.
A dose is not delayed if it is administered within the permitted 
window (further information may be found in the footnote of the 
Schedule of Assessments and Procedures); delays should be 
calculated from the planned administration day.
DOSE 
MODIFICATIONS
Dose can be reduced on the basis of the worst toxicity (drug-
related AE) occurring since the previous dose (e.g., Day 1 or Day 
8 of any cycle except for Day 1 of Cycle 1). The PM060184 dose 
reduction schedule is described in Table 3, and criteria according 
to toxicity in Table 4 and Table 5.
Table 3. PM060184 dose reduction levels.
Dose level 
PM060184 
–1
7.5 mg/m2
–2
6.0 mg/m2
Table 4. Criteria for PM060184 dose reduction for hematological 
toxicity.
Abnormality
Nadir value
PM060184 
ANC
< 0.5 × 109/L with fever (≥38.5°C)/
infection, or
< 0.5 × 109/L for ≥ 3 days
Reduce one 
dose level
Platelet count
< 50 × 109/L, with significant 
bleeding, or
< 25 × 109/L
Reduce one 
dose level
A second occurrence of the aforementioned toxicities should lead to a further 
dose reduction (i.e., dose level –2). No more than two dose reductions will be 
allowed. 
ANC, absolute neutrophil count.
Table 5. Criteria for PM060184 dose reduction for non-
hematological toxicity.
Abnormality
Worst NCI-
CTCAE grade
PM060184
Peripheral sensory/motor 
neuropathy
≥ 3
Reduce one 
dose level
Prolonged peripheral 
sensory/motor neuropathy a
≥ 2
Reduce one 
dose level
Abdominal pain (if reoccurring 
after the first administration)
≥ 3
Reduce one 
dose level
Nausea/vomiting despite adequate 
antiemetic treatment
≥ 3
Reduce one 
dose level
Fatigue (if reoccurring or 
persistent after Cycle 2)
≥ 3
Reduce one 
dose level
Other treatment-related AEs 
according to the Investigator’s 
criteria
≥ 3
Reduce one 
dose level
A second occurrence of these toxicities should lead to a further dose 
reduction (i.e., reduction to dose level –2). No more than two dose 
reductions will be allowed. 
a Lasting more than two cycles.
AE, adverse event; NCI-CTCAE, National Cancer Institute Common 
Terminology Criteria for the Classification of Adverse Events.
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No more than two dose reductions per patient will be allowed in 
the course of this clinical trial. Patients requiring more dose 
reductions should discontinue treatment, except in the event of 
obvious clinical benefit, in which case, treatment may continue 
after discussion and mutual agreement with the Sponsor.
No dose escalations will be allowed in this clinical trial.
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 that induce or inhibit any of these 
cytochromes to a significant extent should be avoided whenever 
possible. 
ALLOWED 
CONCOMITANT 
MEDICATIONS
Therapies for pre-existing and treatment-emergent medical 
conditions, including pain management.
Blood products and transfusions, as clinically indicated.
Approved therapies for bone metastasis (e.g., bisphosphonates, 
denosumab).
In case of nausea or vomiting, prophylaxis and/or symptomatic 
treatment for emesis according to ASCO guidelines.
Erythropoietin use according to ASCO guidelines.
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 can be considered if it is in the best 
interest of the patient.
Megestrol acetate for appetite stimulation.
Anticoagulant therapy for the treatment or secondary 
prophylaxis of thromboembolic events.
PROHIBITED 
MEDICATIONS
Concomitant administration of any other antineoplastic therapy.  
Any other investigational agents.
Immunosuppressive therapies other than corticosteroids.
Local therapy such as radiation or surgery if the lesion is the 
only target lesion, unless agreed in advance with the Sponsor.
EFFICACY 
EVALUATIONS
Patients will be evaluable for efficacy if they receive at least one 
complete treatment cycle (or two PM060184 dose administrations 
over two cycles) and have, at least, one disease assessment at 
Week 6 and another one at Week 12. 
In addition, any patient who presents disease progression, 
symptomatic deterioration due to the disease or clinical 
progression, dies due to malignant disease, discontinues treatment 
due to unmanageable toxicity, or dies or discontinues treatment 
due to a treatment-related AE before evaluation of the response at 
Week 12 will also be considered evaluable for the primary 
endpoint and classified as a non-responder.
Patients who have no disease assessment at Week 6 but remain on 
treatment and are assessed at Week 12 (or later, and with no 
evidence of disease progression) will be considered evaluable for 
efficacy. 
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Patients who refuse further treatment before Week 12 due to 
reasons other than related AEs not considered unmanageable 
toxicity will be replaced.
A futility analysis will be performed once the first 24 evaluable 
patients complete the Week 12 (± 5 days) tumor assessment; 
progress; die due to PD; or discontinue treatment due to 
unmanageable toxicity (whichever occurs first). If seven patients 
or more achieve PFS3, then 36 additional patients will be recruited
(second stage).
Tumor assessment will be measured using RECIST v.1.1.
SAFETY 
EVALUATIONS
Patients will be evaluable for safety if they receive at least one 
(complete or incomplete) dose of PM060184.
Safety will be evaluated by clinical examinations, analysis of vital 
signs, clinical assessment of AEs, changes in the analytical 
parameters (hematological and biochemical), and any other 
analyses that may be considered necessary.
All treatment-related AEs must be followed-up—even if the 
administration of PM060184 has finalized—until the AE or its 
sequelae have resolved or stabilized at an acceptable level (grade ≤ 
2). AEs will be graded according to the National Cancer Institute 
Common Terminology Criteria for Adverse Events (NCI-CTCAE 
v.4), and will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA).
PATIENT-
REPORTED-
OUTCOMES
EORTC QLQ-CIPN20 and QLQ-C30 will be used to collect 
information on patients’ self-reported QoL and neurotoxicity, 
targeting symptoms, functional limitations, and patient concerns 
specifically associated with treatment-induced PN, and potential 
activity impairment.
Patients will be asked to complete both QLQs at baseline, on Day 
8 of each cycle, at the end-of-treatment visit. 
Patients will be asked to complete the QLQ-CIPN20 (only) during 
the follow-up period (about every three months until start of 
subsequent antitumor therapy). If a patient discontinues treatment 
due to grade ≥ 3 PN, however, the QLQ-CIPN20 should be 
completed more frequently during the follow-up period (every 
month after EOT) until recovery to grade ≤ 2 (or until start of 
subsequent antitumor therapy).
PHARMACO-
KINETICS 
The plasma PK of PM060184 will be evaluated in Cycle 1 and 
Cycle 2 during both stages of the study. In the first stage, PK will 
be evaluated on Days 1 and 2 of Cycle 1 and Cycle 2 with a 
sampling schedule of ten samples; in the second stage, PK will be 
evaluated on Day 1 of Cycle 1 and Cycle 2 only with eight 
samples (Table 6).
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Table 6. Pharmacokinetic sampling schedule for PM060184.
Sample
number
Day
Relative 
times
Sampling times
for PM060184
Sampling 
window
#1
1
0 min
Before start of 
administration
-
#2
1
30 min
Just before EOI
- 2 min
#3
1
45 min
15 min after EOI
± 2 min
#4
1
1 h
30 min after EOI
± 5 min
#5
1
1.5 h
1 h after EOI
± 10 min
#6
1
2.5 h
2 h after EOI
± 10 min
#7
1
4.5 h
4 h after EOI
± 10 min
#8
1
6.5 h
6 h after EOI
± 10 min
#9 a
1 a
12.5 h
12 h after EOI
± 1 h
#10 a
2 a
24.5 h
24 h after EOI
± 4 h
a Samples #9 and #10 are required only in patients included in the first stage 
of the study.
EOI, end of infusion; h, hour; min, minute.
METABOLOMIC 
BIOMARKERS
The metabolomics of PM060184 will be characterized by 
evaluating systemic variations in pre-
and post-treatment 
metabolic profile to identify potential biomarkers of PK, safety 
and/or efficacy response to PM060184.
Patients will have blood samples
collected before drug 
administration on Day 1 and Day 8 of Cycle 1, and also on Day 8 
of Cycle 2, to evaluate the pretreatment profile of endogenous 
metabolite levels and changes after PM060184 treatment.
PHARMACO-
GENETICS
To explore PGt factors that may help to explain individual 
variability in main PK parameters, as well as susceptibility to 
develop treatment-related AEs, the presence or absence of 
germline mutations or polymorphisms that may be involved in the 
metabolism and/or transport of PM060184 will be analyzed in 
leukocyte DNA extracted from blood collected preferably before 
PM060184 treatment start from those patients who have also 
consented to the substudy.
PHARMACO-
GENOMICS
The analysis of potential predictive factors to PM060184 
treatment will be analyzed in paraffin-embedded tumor tissue 
samples from patients participating in the substudy. These factors 
will include, among others, tubulin isotypes and other factors 
related to the mechanism of action of PM060184 and to the tumor 
microenvironment (such as angiogenic factors, and markers of 
lymphocyte subpopulations and tumor associated macrophages), 
and their expression will be analyzed at the protein level and/or 
mRNA level by immunohistochemistry or quantitative PCR, 
respectively; their polymorphisms and mutations might also be 
analyzed, if relevant. 
BRAF-mutant-like gene expression subtypes (and potentially full 
genome expression) will be determined
to show potential 
correlation with response or outcome after treatment with 
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PM060184.
At final study analysis—and if feasible according to overall 
efficacy and to the number of patients with available biopsy—the 
subgroup characteristics will be statistically analyzed for 
correlation with the study efficacy parameters: PFS, ORR, DOR, 
and OS. 
STATISTICAL 
METHODS
Sample size:
Patients will be treated with PM060184 to test the null hypothesis 
(H0) that 30% or less patients are alive and free of progression at 
12 weeks (PFS3) according to RECIST v.1.1 (p ≤ 0.30) versus the 
alternative hypothesis (H1) that 50% or more patients are alive 
and free of progression at twelve weeks according to the 
aforementioned criteria (p ≥ 0.50). The variance of the 
standardized test is based on the null hypothesis. The type I error 
(alpha) associated with this one-sided test is 0.025 and the type II 
error (beta) is 0.1; hence, statistical power is 90%. 
Sixty evaluable patients are necessary to test the hypothesis. A 
futility analysis using O’Brien-Fleming boundaries is planned 
when 24 patients can be evaluated (first stage). If there are seven 
or more patients achieving PFS3 in the first stage then the trial 
will proceed to a second stage and a total of 60 patients will be 
recruited.
If at least 25 of 60 evaluable patients are alive and free of 
progression at 12 weeks then the null hypothesis can be rejected 
and PM060184 considered active and deserving potential 
development in this setting.
Primary endpoint:

PFS3, defined as the percentage of patients remaining alive 
and progression-free at Week 12 (Month 3) after the first 
treatment dose.
Secondary endpoints:

Overall survival (OS), defined as the time from the first day of 
treatment to the date of death or last contact.

Progression-free survival (PFS), defined as the time from the 
first day of study treatment to the day of assessment of 
progression, death or last tumor evaluation. 

Overall response rate (ORR), defined as the percentage of 
patients with either complete response (CR) or partial 
response (PR) according to RECIST v.1.1.

Duration of response (DOR), defined as the time between the 
date when response criteria (PR or CR, the first to be reached) 
are fulfilled and the first date when PD, recurrence or death is 
objectively documented.

Treatment safety, including AEs, SAEs and laboratory 
abnormalities graded according to NCI-CTCAE v.4. Dose 
reductions or delays due to treatment-related AEs, and reasons 
for treatment discontinuations will also be analyzed.

PN and QoL profiles as reported by patients using the EORTC 
QLQ-CIPN20 and QLQ-C30.

PK parameters will be evaluated in plasma by population PK 
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modeling and/or non-compartmental analysis.

Metabolomics of PM060184, i.e., intra- and interpatient 
systemic variations in the patient’s pre- and post-treatment 
metabolic profile.

PGt of PM060184 will be evaluated to identify the presence or 
absence of germline mutations or polymorphisms that may 
help explain individual variability in the main PK parameters 
and safety outcomes.

PGx of PM060184 will be evaluated to determine 
predictive/prognostic markers of response and/or resistance to 
PM060184.
Methods of analysis:
Frequency tables will be prepared for categorical variables and 
summary tables, including median, mean, standard deviation,
minimum, and maximum values for each variable, will be used for 
continuous variables. Exploratory comparisons will be performed 
at a 0.05 level.
The exact binomial estimator and its 95% confidence interval (CI) 
will be used for the primary endpoint (PFS3) and categorical 
variables (i.e., ORR).
Time-to-event variables (DOR, PFS, OS) and their fixed time 
estimates will be analyzed according to the Kaplan-Meier method.
Safety analyses will consider AEs, SAEs, analytical results, deaths 
and the reasons for study discontinuations. All AEs and SAEs will 
be graded according to the NCI-CTCAE v.4, and will be coded 
using MedDRA.
PRO analysis will be performed on summary measures and 
longitudinal modelling of patients’ QLQ responses.
Other analyses will include: number of prior treatment lines, prior 
oxaliplatin exposure, KRAS status, BRAF-like expression, and 
other prognostic/predictive factors.
PLANNED TRIAL 
PERIODS
Patients will be evaluated at scheduled visits in the following 
study periods:

Screening: from signature of informed consent to registration 
(confirmation of eligibility) or screen failure.

Pretreatment: from registration to first dose of study 
treatment.

Treatment: from first administration of study treatment to 
end of treatment (EOT). EOT is standardly defined as 30 days 
(± 15 days) after the day of last administration of study 
treatment, unless the patient starts a new antitumor therapy or 
dies within 30 days of the last dose, in which case the date of 
administration of this new antitumor therapy or the date of 
death will be considered the EOT date.
Patients will receive study drug while considered to be in their 
best interest or until study termination. Specifically, treatment 
will continue until:

Disease progression.

Unacceptable toxicity (including any toxicity leading to 
the need for a third dose reduction or severe hypersensitivity 
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reactions, except in the case of obvious clinical benefit, in 
which event the patient could be allowed to remain on 
treatment once agreed with the Sponsor).

Patient refusal to receive further study treatment and/or 
non-compliance with study requirements.

Intercurrent serious illness.

Pregnancy.

Investigator’s decision.

Protocol deviation with an effect on the risk/benefit ratio 
of the clinical trial.

PM060184 treatment delay > 15 days from the due date 
(except in case of clear clinical benefit and with the Sponsor’s 
approval). Note: this maximum delay of 15 days already 
includes the window of ± 2 days allowed for Day 1 
administration.

Clinical cutoff. Patients who have not progressed at these 
time points could be treated in a compassionate use program 
(according to country regulations). 

Follow-up: after EOT, patients will be followed for both 
safety and efficacy.
1) Safety: every four weeks until resolution or stabilization 
of drug-related AEs (if any).
2) Efficacy: about every three months until death, refusal to 
continue participating in the study, or study termination 
(clinical cutoff), whichever occurs first. 
Subsequent off-study therapies should be provided until 
death, refusal, and/or clinical cutoff (whichever occurs first).
Note: patients without disease progression who discontinue 
treatment due to a drug-related AE must be followed both for the 
AE and for efficacy.
PFS and survival follow-up timelines for the whole population:
If the study ends after the futility analysis at 24 evaluable patients
(first stage):

Patients who are still on study will be followed up to 12 weeks 
after the first PM060184 administration of the last patient 
evaluable for the futility analysis.
If the futility analysis results in continuation of recruitment 
(second stage):

All patients will be followed up to 12 months after the first 
PM060184 administration of the last evaluable patient treated 
in the study, regardless of the stage at which the patients have 
been included.
REPLACEMENT OF 
PATIENTS
Patients must be replaced if they are considered not evaluable for
the primary endpoint (PFS3), i.e., if they are withdrawn from the 
study due to significant clinical deterioration of unknown reason, 
hypersensitivity reactions, unrelated AEs without any tumor 
assessments after the start of study treatment, if they receive less 
than one complete treatment cycle (at least two PM060184 dose 
administrations over two cycles unless treatment discontinuation 
was due to unmanageable toxicity), or do not have the disease 
assessment
at Week 12 (except in the case of treatment 
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discontinuation/death due to a treatment-related AE, symptomatic 
deterioration due to the disease, clinical progression, PD or death
due to malignant disease).
PLANNED TRIAL 
CALENDAR
The total duration of the study will be approximately 36 months. 
Planned start date (first patient first visit): 4Q2017.
Planned enrollment period: approximately 24 months.
Planned study termination (clinical cutoff): 12 months after the 
first PM060184 administration of the last evaluable patient treated
in the study. 
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SCHEDULE OF ASSESSMENTS AND PROCEDURES
Assessments and 
procedures
Days prior to 
registration
Treatment
Follow
-up (2)
Cycle 1
Further cycles  
EOT (1)
Day 1
*
Day 8
Day 22=Day 1
Day 8
Written IC 

-
-
-
-
-
-
Demographic data 
–28 
-
-
-
-
-
-
Medical history (3)
–28
-
-
-
-
-
-
Cancer history (4)
–28
-
-
-
-
-
-
Physical examination
–10

-

-
(5)
-
ECOG PS
–10

-

-
(5)
-
Vital signs 
–10




(5)
-
Hematology (6)
–10




(5)
-
Biochemistry-A (6)
–10




(5)
-
Biochemistry-B 
–10

-

-
(5)
-
Pregnancy (7)
–7
-
-
(7)
-
(7)
-
ECG
–28
Repeat if clinically indicated
-
LVEF
–28
Repeat if clinically indicated

-
PM060184 administration
-




-
-
Pharmacokinetics (8)
-
Cycle 1 and Cycle 2  (8)
-
-
Metabolomics (9)
-


-
-
-
-
Pharmacogenetics (10)
-
(10)
-
-
Pharmacogenomics (11)
Archived 
sample
(11)
-
-
Tumor assessment (12)
–28
-
-
(12)
-
(12)
Concomitant therapies 
–14
Throughout the on-treatment period 
(2)
Adverse events (13)

Throughout the on-treatment period 
(2)
PRO QLQs (14)
–10
-

-


(14)
Registration=confirmation of eligibility and inclusion; Day 1=day of first cycle administration (with infusion start); Day 
8=seven days after the first dose administration of a cycle (± 2 days); Day 22 = Day 1 (± 2 days) of the following cycle.
* Permitted windows for assessments before Day 1 of Cycle 1:
If physical examination, ECOG PS, vital signs, hematology/biochemistry were assessed >10 days before Day 1 of Cycle 
1, the tests must be repeated within 2 days before the first study drug administration.
If pregnancy test was done >7 days before Day 1 of Cycle 1, the test must be repeated within 2 days before the first study 
drug administration. 
If tumor assessments were done >28 days before Day 1 of Cycle 1, the tests must be repeated within 2 days before the 
first study drug administration.
A patient should only be treated if eligibility criteria are still met according to assessments performed closest to treatment 
start.
Permitted windows for assessments after Day 1 of Cycle 1:
- 2 days for physical examination and ECOG PS (on Day 1) and for vital signs (on Days 1 and 8), always before study 
drug administration.
+ 7 days for tumor assessments (except in Week 12 when there is a maximum 5-day window). 
± 2 days for Day 1 study drug administration (from Cycle 2 onwards).
± 2 days for Day 8 study drug administration.
– 2 days for laboratory tests. To confirm criteria for treatment continuation, laboratory assessments must be performed 
within 2 days prior to drug administration. 
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If a drug administration is delayed beyond the permitted protocol window, assessments planned for the original 
administration day must be repeated on the day the dose is finally administered.
1.
EOT assessments should take place approximately 30 days (± 15 days) after the last drug administration or before 
starting new therapy. Loss to follow-up, or failure to attend the EOT visit due to a deteriorated clinical condition or 
due to personal reasons such as returning to their previous hospital, will not be considered protocol deviations.
2.
Patients discontinuing treatment due to a drug-related AE should be followed for safety every four weeks until 
recovery or stabilization. Regardless of the reason for treatment discontinuation, all patients will be followed for 
efficacy about every three months until death, refusal to continue participating in the study, or study termination 
(clinical cutoff), whichever occurs first. Subsequent antitumor therapies should be provided until death, refusal, 
and/or clinical cutoff (whichever occurs first). For the purpose of collecting information on patient’s survival, a 
documented telephone call, email or medical chart review is acceptable; follow-up for survival will be completed 
for all patients only if the study continues to the second stage. Note: patients without disease progression who 
discontinue treatment due to a drug-related AE must be followed both for the AE and for efficacy (see 12.
below).
3.
Medical history includes relevant conditions and syndromes that started before registration and are not ongoing 
(no signs or symptoms) at time of registration or are controlled and do not require evaluation for severity or 
causality. Also includes any event qualifying as serious occurring prior to registration.
4.
Cancer history includes primary diagnosis, response history, date of last confirmed PD, and all prior treatment 
(including cumulative dose of prior oxaliplatin, if any).
5.
The listed assessments are required if no recent data are available (i.e. within the previous 10 days) or if the last 
data available show a grade ≥ 2 treatment-related alteration whenever the medical condition of the patient allows.
6.
If any clinically-relevant, treatment-related grade ≥ 3 AE occurs, the abnormality should be reassessed 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, reassessment 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.
7.
Assessment of β-hCG only if the patient is a WOCBP. During the on-treatment period, testing should be every 
cycle within 2 days before study drug administration (or, at least, every month).
8.
The plasma PK of PM060184 will be evaluated in Cycle 1 and Cycle 2 during both stages of the study. Ten 
plasma PK samples are required from patients included in the first stage: just before start of administration, just 
before EOI, and then 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, and 12.5 h (Day 1) and 24.5 h (Day 2) after EOI in Cycle 
1 and Cycle 2. Only eight plasma samples are required from patients included in the second stage: the samples 
scheduled at 12.5 h and 24.5 h after EOI in Cycle 1 and Cycle 2 are not required. 
9.
One blood sample should be collected prior to each drug administration on Day 1 and Day 8 of Cycle 1, and also 
on Day 8 of Cycle 2.
10. If the patient consents to the substudy, an additional blood sample for PGt analysis should be collected at any 
time during the trial but ideally at the same time as the pretreatment PK sample (sample #1) of Cycle 1.
11. If the patient consents to the substudy, the availability of tumor tissue samples used for the initial diagnosis of the 
disease, or obtained at relapse, should be confirmed and should be prepared and shipped during the trial following 
the instructions detailed in a separate laboratory manual.
12. To be performed every six weeks (+ 7 days, except for Week 12 when a window of ± 5 days applies). The Week-
12 disease evaluation is the primary endpoint of the study and should be performed in all non-PD patients 
(including those who discontinued treatment without progression). The same radiological method should be 
used throughout the study for each individual patient. Anonymized copies of images showing a response (CR or 
PR) must be submitted to the Sponsor. Tumor assessment should be performed about every three months during 
follow-up in patients who discontinue treatment without disease progression. Note: patients without disease 
progression who discontinue treatment due to a drug-related AE must be followed both for the AE AND 
for efficacy (see 2. above).
13. Baseline conditions, signs and symptoms and ongoing toxicities at registration should be reported as screening 
AEs. Clinical assessment of the patient’s signs and symptoms (if any and including nurses’ assessment and 
patient-reported issues) should continue on an ongoing basis throughout the study and be reported at least every 
cycle as AEs graded according to NCI-CTCAE v.4. SAEs will be collected from the time of IC signature
(reported in paper if a patient is not yet registered). During screening and pretreatment periods, AEs are 
considered baseline and non-treatment emergent. If a condition previously reported in Medical History changes 
during treatment, the event should be reported as an AE.
14. Patients will be asked to complete both QLQs at baseline, on Day 8 of each cycle, at the end-of-treatment visit. 
Patients will be asked to complete the QLQ-CIPN20 (only) during the follow-up period (every three months until 
start of subsequent antitumor therapy). If a patient discontinues treatment due to grade ≥ 3 PN, however, the 
QLQ-CIPN20 should be completed more frequently during the follow-up period (every month after EOT) until 
recovery to grade ≤ 2 (or until start of subsequent antitumor therapy).
Assessment details
Biochemistry-A: ALP, AST, ALT, total bilirubin (and direct bilirubin if total is >1.5 x ULN), GGT, creatinine/CrCL
(Cockcroft-Gault formula), glucose, LDH, and serum electrolytes (Na+, K+, Total calcium).
Biochemistry-B: Total proteins and albumin.
ECG: including rhythm definition and PR interval; heart rate; QT interval (raw); QRS complex duration, as well as 
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any ECG anomaly or variation (change in grade) with respect to baseline.
Hematology: Complete blood count, differential WBC (neutrophils, lymphocytes), hemoglobin, and platelets.
Left ventricular ejection fraction: assessed by ECHO or MUGA scan.
Physical examination: Including weight, height (when needed for BSA calculation) and clinical assessment. BSA 
and dosing should be recalculated in the event of weight variation of ±10%.
Tumor assessment: Clinical and radiological disease assessment using RECIST v.1.1. Helical i.v. and oral contrast-
enhanced CT-scan (if appropriate) for chest, abdomen and pelvis and other areas of suspected diseases. If i.v. contrast 
is contraindicated for the CT-scan, chest evaluation should be performed using non-contrasted CT and 
abdomen/pelvis evaluation using gadolinium-enhanced MRI. Tumor markers alone or chest radiography alone are not 
sufficient to assess tumor burden.
Vital signs: Heart rate, arterial blood pressure, and temperature
Abbreviations
AE, adverse event; ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; β-
hCG, beta subunit of human chorionic gonadotropin; BSA, body surface area; CIPN, chemotherapy-induced 
peripheral neuropathy; CR, complete response; CrCL, calculated creatinine clearance; CT, computed tomography;
ECG, electrocardiogram; ECHO, echocardiography; ECOG, Eastern Cooperative Oncology Group; EOI, end of 
infusion; EOT, end of treatment; GGT, gamma-glutamyltransferase; IC, Informed Consent; i.v., intravenous; LDH, 
lactate dehydrogenase; LVEF, left ventricular ejection fraction; MRI, magnetic resonance imaging; MUGA, multiple-
gated acquisition; NCI-CTCAE, National Cancer Institute Common Terminology Criteria for Adverse Events; PD, 
progressive disease; PGt, pharmacogenetics; PK, pharmacokinetics; PN, peripheral neuropathy; PR, partial response; 
PRO, patient reported outcomes; PS, performance status; QLQ, quality of life questionnaire; RECIST, Response 
Evaluation Criteria in Solid Tumors; SAE, serious adverse event; ULN, upper limit of normal; WBC, white blood 
cells; WOCBP, woman of childbearing potential.
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
5-HT3
Serotonin
5-FU
5-fluorouracil
ABP
Arterial Blood Pressure
AE
Adverse Event
ALP
Alkaline Phosphatase
ALT 
Alanine Aminotransferase
ANC
Absolute Neutrophil Count
ANOVA
Analysis of Variance
ASCO
American Society of Clinical Oncology
AST 
Aspartate Aminotransferase
BSA
Body Surface Area
BSC
Best Supportive Care
CI
Confidence Interval
CIPN
Chemotherapy-induced Peripheral Neuropathy
CL
Clearance
CR
Complete Response
CRC
Colorectal Cancer
CrCL
Creatinine Clearance
CT
Computed Tomography
d
Day
DLT
Dose-limiting Toxicity
DNA
Deoxyribonucleic Acid
DP
Drug Product
DOR
Duration of Response
DS
Drug Substance; Degree of Substitution
ECG 
Electrocardiogram
ECHO
Echocardiography
ECOG
Eastern Cooperative Oncology Group
e-CRF
Electronic Case Report Form
EGFR
Epidermal Growth Factor Receptor
EOI
End of Infusion
EORTC
European Organisation for the Research and Treatment of Cancer
EOT
End of Treatment
FP
Fluoropyrimidine
G-CSF
Granulocyte Colony-stimulating Factor
GCP
Good Clinical Practice
GGT
Gamma-glutamyltransferase
GI50
Growth Inhibition at 50%
GMT
Greenwich Meridian Time
HCG
Human Chorionic Gonadotropin
HIV
Human Immunodeficiency Virus
HR
Heart Rate
HSD
Honestly Significant Difference
IB
Investigator’s Brochure
IC
Informed Consent
ICF
Informed Consent Form
ICH
International Conference on Harmonization
IEC
Investigational Ethics Committee
IF
Immunofixation
IHC
Immunohistochemistry
IMP
Investigational Medicinal Product
IRB
Institutional Review Board
i.v.
Intravenous(ly)
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LC-MS/MS
Liquid Chromatography/Mass Spectrometry/Mass Spectrometry
LDH
Lactate Dehydrogenase
LVEF
Left Ventricular Ejection Fraction
mCRC
Metastatic Colorectal Cancer
MedDRA
Medical Dictionary for Regulatory Activities
min
Minute
MRI
Magnetic Resonance Imaging
mRNA
Messenger Ribonucleic Acid
MTD
Maximum Tolerated Dose
MTI
Microtubule Inhibitor
MUGA
Multiple-gated Acquisition Scan
NCI
National Cancer Institute
NCI-CTCAE
National Cancer Institute Common Terminology Criteria for Adverse 
Events
NSCLC
Non-small Cell Lung Cancer
OPLS
Orthogonal Partial Least-squares to Latent Structures
ORR
Overall Response Rate
OS
Overall Survival
PCA
Principal Component Analysis
PCR
Polymerase Chain Reaction
PD
Progressive Disease
PFS
Progression-free Survival
PFS3
Progression-free Survival at 12 weeks (three months)
PGt
Pharmacogenetics
PGx
Pharmacogenomics
PhV
Pharmacovigilance
PIF
Peak Inspiratory Flow
PK
Pharmacokinetics
PN
Peripheral Neuropathy
PR
Partial Response
PRO
Patient Reported Outcomes
PS
Performance Status
PSN
Peripheral Sensory Neuropathy
QoL
Quality of Life
QLQ
Quality of Life Questionnaire 
q28d
Every 28 Days
q3wk
Every Three Weeks
q4wk
Every Four Weeks
RD
Recommended Dose
RECIST
Response Evaluation Criteria in Solid Tumors
RNA
Ribonucleic Acid
RR
Respiratory Rate
Rt-m/z
Retention Time and Mass-to-charge Ratio Pairs
RT-PCR
Reverse Transcription Polymerase Chain Reaction
SAE
Serious Adverse Event
SD
Stable Disease
ULN
Upper Limit of Normal
UPLC
Ultra Performance Liquid Chromatography
U.S.
United States of America
V2
Peripheral Volume
Vss
Volume of Distribution at Steady State
VEGF
Vascular Endothelial Growth Factor
WBC
White Blood Cells
WHO 
World Health Organization
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WMA
World Medical Association
WOCBP
Women of Childbearing Potential
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1.
INTRODUCTION
1.1
DISEASE BACKGROUND
Worldwide, colorectal cancer (CRC) is the third most common cancer (1,360,602 new 
cases in 2012), accounting for 10% of all cancers (not including non-melanoma skin 
cancer) and an estimated 693,933 deaths (8.5% of the total number of cancer deaths; the
fourth most common cause of cancer deaths) (1). Almost 55% of new cases occur in 
more developed regions. In Europe, there were 447,000 new CRC cases and 215,000 
deaths (12% of all cancer deaths) in 2012 (2). The National Cancer Institute (NCI) 
estimates 134,490 new CRC cases and 49,190 deaths (8% of all cancer deaths) in the 
U.S. in 2016 (3).
The median age at diagnosis is 68 years, and 90% of cases are diagnosed in those over 
50 years of age. The lifetime risk for CRC is 6% in average-risk persons living in the 
U.S. The CRC-related 5-year survival rate is 65%. Approximately 20–25% of patients 
present with metastases (metastatic CRC [mCRC]) at initial diagnosis and almost 50% 
of the remainder will subsequently develop metastases, contributing to the high 
mortality rates reported for CRC. The overall prognosis of patients with mCRC is poor, 
with five-year survival in the 5–8% range. However, recent chemotherapeutic regimens 
combined with targeted agents have significantly improved their two-year survival.
For patients with non-curable mCRC, combination chemotherapy including oxaliplatin-
based and irinotecan-based regimens remains standard for first-line and second-line 
therapies. For patients with wild-type KRAS tumors, cetuximab (an epidermal growth 
factor receptor inhibitor) is a common option for third-line therapy, improving median 
survival from 4.8 to 9.5 months when compared with supportive care alone (4). When 
5-fluorouracil (5-FU) was the only active agent, overall survival (OS) was 
approximately one year. There are now eight different classes of drugs with significant 
antitumor activity in mCRC and patients routinely live longer than two years:

Fluoropyrimidines (FP) (including 5-FU, which is usually given with leucovorin, 
capecitabine, S-1, and tegafur plus uracil).

Irinotecan.

Oxaliplatin.

Cetuximab and panitumumab, two monoclonal antibodies directed against the   
epidermal growth factor receptor (EGFR).

Bevacizumab, a monoclonal antibody targeting vascular endothelial growth factor            
(VEGF).

Aflibercept, a recombinant fusion protein consisting of VEGF binding portions from 
the human VEGF receptors 1 and 2 fused to the Fc portion of human 
immunoglobulin G1.

Regorafenib, an orally active inhibitor of angiogenic tyrosine kinases (including the 
VEGF receptors 1 to 3), as well as other membrane and intracellular kinases.

Trifluridine-tipiracil (TAS-102), an oral cytotoxic agent that consists of the 
nucleoside analog trifluridine and tipiracil, which inhibits trifluridine metabolism 
and has antiangiogenic properties.
A median OS of 18.2 months in first-line mCRC patients is now reported with 
combinations of cytotoxic and biological therapies (5). Because OS may be prolonged 
by second- and subsequent-line therapies, exposure to all available treatment options at 
some stage (rather than in a particular order) may be more important so choosing an 
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appropriate treatment approach remains complex with several open questions and the 
need for new drugs as the underlying biology becomes better known and understood (6).  
The best way to combine and sequence these agents is not yet established, and the goals 
of chemotherapy in this setting differ according to clinical scenario: for non-resectable
disease in patients without symptoms, induction of a tumor response is not as important 
as
is delaying tumor progression as long as possible.
Systemic 5FU-based 
chemotherapy produces meaningful improvements in median survival and progression-
free survival (PFS) compared with best supportive care (BSC) alone. These benefits are 
most pronounced with regimens containing irinotecan or oxaliplatin in combination 
with FU, which represent the mainstay of advanced and metastatic CRC chemotherapy. 
Consequently, when patients with advanced or metastatic CRC have received prior  FP, 
irinotecan and oxaliplatin -based regimens (in addition to any ad hoc therapy targeting 
EGFR, and/or VEGF, according to tumor characteristics), new agents within clinical 
trials are warranted.
1.2
INFORMATION ON STUDY DRUG
The drug substance (DS) PM060184-CD is a mixture of PM060184 and 2-
hydroxypropyl- β-cyclodextrin:
Chemical 
Name
(IUPAC)
(1Z,4S,6Z)-1-((3S)-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
The structural and molecular formulas of PM060184 are shown in Figure 1.
Figure 1. Chemical structure of PM060184.
Structural Formula
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
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1.2.1
Non-clinical Data
Pharmacodynamics
PM060184 depolymerizes tubulin fibers and causes disorganization and fragmentation 
of the microtubule network, inducing multipolar mitosis, prometaphase arrest as well as 
an induction of caspase-dependent apoptosis and/or the appearance of cells in a 
multinucleated interphase-like state.
PM060184 demonstrated a potent in vitro cytotoxic activity (average growth inhibition 
at 50% [GI50] of 718 pM) in a broad panel of solid human carcinoma cell lines, the 
strongest activity seen against BT-474 (breast), HT-29 (colon), RXF-393 (renal) and 
Igrov-1 (ovarian) cell lines. In animals bearing xenografted human-derived tumors, 
PM060184 displayed a dose-related, strong antitumor activity (minimal T/C ranging 
from 34.0 to –39.3%), especially against MAXF 401 (breast), HCT-116 (colon), HGC-
27 (gastric), H460 (NSCLC), 22Rv1 (prostate), Caki-1 or MRI-H-121 (renal) and 
A2780 or OVXF 899 (ovarian). 
In male rats, no significant gross behavioral or physiological changes were induced by 
the administration of PM060184 at 8 mg/kg. Also, in male rats administered at 8 mg/kg, 
decreases in inspiration time and enhanced pause, as well as increases in peak 
inspiratory flow (PIF), respiratory rate (RR) and in minute volume were recorded at 1 h 
post-dose; these changes were followed (at 2.5 or 3.5 h post-dose) by increases in 
expiration time and decreases in RR and in minute volume. In dogs, heart rate (HR) and 
lead II electrocardiogram (ECG) derived variables monitoring revealed reductions in 
HR and increases in RR in males at 30 min after a single PM060184 administration (0.8 
mg/kg). In a separate study (3 weekly consecutive doses), following the first 
administration, PM060184 induced decreases in HR and increases in RR and QT 
intervals, the largest variations found at 1 hour post-dose; also, QTc increases (both 
genders) were seen at 6 h, still present at 24 h in the highly dosed groups. No alterations 
in any parameter were seen on Day 15, after the third consecutive weekly 
administration.
Pharmacokinetics and Metabolism
The terminal elimination half-lives, following intravenous administration of PM060184 
in nonclinical species (mice, rats, dogs, rabbits, monkeys and mini-pig) were short and 
ranged from 1.5 to 8.1 h, indicating a relatively high plasma clearance. Similar volume 
of distribution at steady state was found between genders which was much higher than 
the plasma volume for all animal species tested suggesting extensive extravascular 
distribution. The in vitro plasma protein binding of PM060184 was high in all species 
tested, ranging from 97.8 to 99.1 %; in humans, 98.7 % of PM060184 was bound to 
plasma proteins. 
In vitro metabolism studies in subcellular fractions demonstrated that PM060184 
undergoes extensive microsomal-mediated, NADPH-dependent metabolism in animal 
species, including man. The in vitro half-lives of intact PM060184 ranged from 15.5 
(CD-1 male mouse) to 1.6 (Cynomolgus male monkey) min; in human, the half-life was 
calculated as 1.86 min. Preliminary metabolite identification suggests hydroxylation, 
oxidation (either mono- or di-) and N-dealkylation as the major pathways for 
PM060184 metabolism. PM060184 displayed high stability in plasma of all species 
studies, human included.
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Based on in vitro evaluations, PM060184 has a limited potential for cytochrome 
CYP450 either inhibition or induction.
Toxicokinetic evaluations conducted in support of toxicology studies in rats and dogs 
demonstrated similar results, regardless of the administration schedule (single or 
repeated dose). Dose-proportionality and no accumulation of PM060184 plasma 
concentrations were seen in rats and dogs following up to three consecutive weekly 
administrations. Consistency between drug exposures (ca. 2-fold higher) and maximum 
tolerated dose (MTD) (ca. 2-fold lower) values was shown in female rats. 
PM060184 exhibits consistent inter-species pharmacokinetic (PK) parameters with a 
good in vitro-in vivo correlation. Therefore, from a pharmacokinetic viewpoint, the 
evidence so far does not raise any concerns to proceed with the evaluation of this agent 
in cancer patients.
Toxicology
PM060184 has been tested in rats and dogs via the intravenous (i.v.) route either as 
single- or repeat-dose i.v. administration. The most toxicologically relevant findings in 
animals (either in rats and/or dogs) were seen in:

the hematopoietic system, characterized by a moderate to severe reticulopenia, 
leukopenia, and thrombocytopenia, atrophy of the thymus, decrease in bone marrow 
cellularity (mainly in rats), and extramedullary hematopoiesis in the liver and 
spleen;

the gastrointestinal system (mainly in dogs); and,

the testes (azoospermia with severe testicular atrophy) in rats and dogs, at all dose 
levels tested.
Most of the alterations were resolved by the end of the observation period, with 
exception of the testicular lesions, as expected due to the limited observation period.
During repeat-dose toxicity studies, unscheduled mortality was observed in one female 
rat at 3.5 mg/kg (21 mg/m2, on Day 9) and two dogs (after the first drug administration 
at 0.6 and 0.8 m/kg [12 and 16 mg/m2]). In all cases moderate to marked 
immunosuppression (moderate to severe reticulopenia and thrombocytopenia), necrosis, 
hemorrhages in several organs (cervical lymph nodes, and/or spleen, liver, gastro-
intestinal tract, adrenals, thymus, and bone marrow) and thrombosis were considered the 
factors most likely contributory to the deaths of these animals.
Clinical chemistry evaluation in rats and dogs revealed changes in liver and kidney 
related parameters. These changes were of limited magnitude and not dose-related, 
without inter-parameter consistency (e.g., a three-fold increase in alkaline phosphatase 
and alanine aminotransferase, with 75 % decrease in aspartate aminotransferase) and 
lack of concurrent findings on the histopathology examination.
Injection site injury was sporadically noted in dogs and rats; thus, the irritating potential 
of PM060184 cannot be ruled out. The in vitro genotoxicity evaluation indicated 
mutagenic properties attributable to PM060184. No phototoxic potential for PM060184 
is predicted from the in vitro experiment performed.
The MTDs calculated in two animal species either as single or repeated bolus 
administration are summarized in Table 1.
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Table 1. Maximum tolerated dose calculated for PM060184 in different animal species.
Species (Strain)
Gender
MTD mg/kg (mg/m2)
Single-Dose
Repeat-Dose
Rat (Sprague-Dawley)
M
8.0 (48)
5.0 (30)
F
4.0 (24)
2.0 (12)
Dog (Beagle)
M
0.8 (16)
0.4 (8)
F
0.8 (16)
0.4 (8)
F, female; M, male; MTD, maximum tolerated dose.
According to the current data (MTD normalized by body surface area, mg/m2), the dog 
is slightly more sensitive than the rat to PM060184 following single administration; in
the repeated dose studies, closer figures are seen in rats and dogs: MTD was determined 
as 30 and 12 mg/m2 (5 and 2 mg/kg) for male and female rats, respectively, and 8 
mg/m2 (0.4 mg/kg) in dogs. Therefore, starting doses in patients are similarly predicted 
either by taking 1/10th of the lowest rat-derived MTD (1.2 mg/m2) or 1/6th of the dog-
derived MTD (1.3 mg/m2). 
In conclusion, the toxicology properties of PM060184 make the compound suitable for 
further evaluation in cancer patients. The major toxicities observed in animals (rats and 
dogs) are expected for chemotherapeutic agents, and can be adequately monitored by 
hematological, biochemical, and cardiac assessments during clinical development.
1.2.2
Clinical Data
Up to the cutoff date of the 30 September 2016, 113 patients had been treated and 
evaluated with PM060184 as single agent in the clinical development program at 
PharmaMar (Table 2). The phase I program includes two single-agent clinical trials and 
one combination clinical trial (assessing different schedules of administration in patients 
with solid tumors refractory to standard therapy or for which no standard therapy 
exists). Currently, one phase II clinical trial is evaluating the efficacy of PM060184 in 
advanced, hormone receptor positive, HER2 negative, breast carcinoma.
Table 2. Summary of the clinical program of PM060184.
Study
Schedule
Included 
patients a Evaluated 
patients b
Status
Phase I trials
PM60184-A-001-10
PM060184 10-min and 3-h infusions d1,8,15 
q4wk
47
44
Completed
PM60184-A-002a-10
PM060184 10-min infusion d1,8 q3wk
38
38
Completed
PM60184-A-002b-10 PM060184 10-min infusion d1–3,15–17 q4wk
22
22
Ongoing
PM60184-A-003-14
Gemcitabine 30-min infusion/ PM060184 10-
min infusion d1,8 q3wk
23
21
Ongoing
Phase II trials
PM60184-B-001-15
PM060184 5- and 1-min infusions d1,8 q3wk.
The 1-min i.v. administration was validated.
12 c
9
Ongoing
Total
142
134
Cutoff date: 30 September 2016.
a Patients registered in PharmaMar clinical database at cutoff, including patients not finally treated.
b Patients treated and with available data in PharmaMar clinical database at cutoff.
c Three patients were included but data were not available in the PharmaMar clinical database at cutoff.
d, day; min, minute; q3wk, every three weeks; q4wk, every four weeks.
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To date, two phase I clinical trials have treated 104 solid tumor patients with different 
PM060184 schedules administered as single agent and as a 10-minute (min) i.v. 
administration: Days 1, 8 and 15 every four weeks (q4wk), Days 1 and 8 every three 
weeks (q3wk), and Days 1 to 3 and 15 to 17 every 28 days (q28d). The recommended 
dose (RD) has been established at 9.3 mg/m2 for the Days 1 and 8 q3wk schedule. Most 
toxicities reported to date were mild to moderate, with peripheral motor/sensory 
neuropathy as the most frequent dose-limiting-toxicity (DLT), occurring in 6% of 
patients at doses above the RD. 
As expected from a microtubule-binding agent, peripheral sensory neuropathy (PSN) 
was the principal dose-limiting toxicity. Fatigue, nausea/vomiting were also expected 
toxicities (but not dose-limiting). Hematological and biochemical abnormalities 
(regardless of relationship) did not represent a major safety concern.
Preliminary evidence of antitumor activity has been observed, four partial responses 
(PR) were reported in patients with cervix carcinoma, non-small cell lung cancer 
(NSCLC), breast and ovarian cancers, and 21 disease stabilizations (SDs) ≥3 months in 
several tumor types. Thirteen evaluable CRC patients were treated and six (46%) had 
SD lasting three months or longer. Their median number of prior lines of chemotherapy 
for advanced or metastatic disease was three (range, 2–5) and median PFS was 4.7 
months (range, 3.7–12.8 months).
Pharmacokinetics
Preliminary analysis of the integrated data available from clinical trials to date (three 
phase I and one phase II) has shown that the PK of PM060184 is characterized by:

A wide distribution to peripheral tissues (195 L).

Low inter-patient variability in CL and peripheral volume (V2).

A moderate to high total clearance (CL) (62.55 L/h).

Distribution and elimination linearity at the dose levels explored.

Negligible renal elimination.

A clear effect between body surface area (BSA) and CL, weight and V2.
1.3
STUDY RATIONALE
Systemic 5-FU-based chemotherapy produces meaningful improvements in median 
survival and PFS compared with BSC alone (7). These benefits are most pronounced 
with regimens containing irinotecan or oxaliplatin in combination with 5-FU, which 
represent the mainstay of advanced and metastatic CRC chemotherapy. 
Consequently, when patients with advanced or metastatic CRC have received prior FP, 
irinotecan and oxaliplatin-based regimens (in addition to any ad hoc therapy targeting 
EGFR, and/or VEGF, according to tumor characteristics), clinical trials with 
investigational medicinal products (IMPs) are warranted.
PM060184 is a novel microtubule inhibitor (MTI), with a different, specific binding site 
on the β-tubulin, that is distinct from the vinca domain used by vinca alkaloids, as well 
as the taxane domain and binding site. PM060184 induces
microtubule 
depolymerization (8) and caspase-dependent, as well as non-classical apoptosis 
pathways (9). PM060184 has shown in vitro and in vivo antitumor activity at nanomolar 
concentrations in CRC (10). Thirteen evaluable CRC patients were treated with single-
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agent PM060184 to date and six (46%) had SD lasting three months or longer with a 
median PFS of 4.7 months (range, 3.7–12.8 months).
This trial will evaluate the efficacy of PM060184 in terms of progression-free survival 
at 12 weeks (PFS3) in advanced or metastatic CRC patients progressing after standard 
treatments (fluoropyrimidine, irinotecan, and oxaliplatin).
Patients in this trial will receive PM060184 as a 30-minute i.v. infusion on Days 1 and 8 
q3wk. The dose selected (9.3 mg/m2) is the recommended dose for phase II studies that 
was determined for this same schedule, with PM060184 given as a 10-minute i.v. infusion, 
in study PM60184-A-002a-10 (see Section 1.2.2).
Metabolomic (Biomarkers) Study Rationale
Metabolomics (metabonomics/metabolomics), i.e., the determination of endogenous 
low-molecular-weight molecules or metabolites in a body fluid and their changes as a 
consequence of stimuli such as medical interventions, is currently being used to 
evaluate the efficacy and safety of medical interventions in cancer (11), thus allowing 
for the discovery of predictive biomarkers of drug response (12).
The metabolic profile of the patients before and after treatment with PM060184 will be 
compared to search for systematic variations that may serve as biomarkers of PK, safety 
and/or efficacy response to treatment with PM060184. Particular attention will be given 
to specific metabolic patterns observed in patients who develop peripheral neuropathy 
associated with PM060184. For this purpose, a blood sample will be collected prior to 
treatment administration on Day 1 and Day 8 of Cycle 1, and also on Day 8 of Cycle 2. 
Pharmacogenomic/Pharmacogenetic Substudy Rationale
The rationale of the exploratory and optional substudy includes the evaluation of 
potential markers of sensitivity to PM060184 treatment with microtubule-interacting 
agents in a population of advanced CRC patients. These molecular markers would help 
in the future selection of patients who might preferentially benefit from PM060184 
therapy, thus contributing to improved health care through a more individualized 
medicine.
There is growing evidence that the effects of tubulin-targeting drugs in endothelial cells 
are much more subtle than originally thought. In fact, some tubulin-binding drugs have 
been known to have antivascular (antiangiogenesis or vascular-disrupting) activities that 
can target abnormal tumor vessels (13, 14). PM060184 inhibits tubulin polymerization 
inducing alterations of the microtubule mass and dynamics, as well as the appearance of 
multipolar spindles. These effects will induce cell cycle arrest at G2/M. Cells will 
finally die by apoptosis or remain blocked in a multinucleated state. Thus, since 
PM060184 induces cytotoxicity by inhibiting tubulin polymerization, it is possible that 
alterations in -tubulin isotype content and/or MAPs may alter sensitivity to this agent.
BRAF-mutant colon cancers have a characteristic gene expression signature that is also 
found in some tumors lacking this mutation: BRAF-like KRAS mutants and double 
wild-type patients have similarly poor prognosis. This suggests a common biology 
between these tumors and adds prognostic and biologic information that is not captured 
by the mutation classification alone (15). 
These BRAF-like tumors represent 20% of colon cancers and have been shown to 
display far greater sensitivity to the microtubule poison, vinorelbine, and will also be 
explored by the genomic assays in the pharmacogenomic (PGx) substudy (16). 
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PM060184 is a very potent microtubule inhibitor; thus the sensitivity of this subset of 
patients, should sample size allow it, will be explored more specifically for potential 
differences.
Finally, a pharmacogenetic (PGt) analysis will explore factors that may help explain 
individual variability in the main PK parameters and safety outcomes, the presence or 
absence of germline mutations or polymorphisms will be analyzed in leukocyte DNA.
2.
OVERALL STUDY DESIGN
This is a phase II, multicenter, open-label, study of single-agent PM060184 to evaluate 
efficacy in patients with advanced CRC progressing after standard therapy.
Initially, 24 patients who are evaluable for the primary endpoint will be included and a 
futility analysis will be performed (first stage). If at least seven of these patients achieve 
PFS3, then the study will proceed to a second stage and 36 additional patients will be 
recruited.
An exploratory substudy will address pharmacogenomic and pharmacogenetic 
objectives. All patients who participate in the PM60184-B-002-17 clinical trial will be 
eligible for the substudy if they voluntarily sign a separate informed consent (IC). 
Refusal to participate in the substudy will not affect a patient’s participation in the 
clinical trial.
3.
STUDY OBJECTIVES
Primary:

To evaluate the efficacy of PM060184 in terms of progression-free survival at 12 
weeks (PFS3) in patients with advanced CRC after standard therapy.
Secondary:

To evaluate OS; PFS; overall response rate (ORR); and duration of response 
(DOR).

To characterize the safety profile and feasibility of PM060184 in this population.

To describe PN and quality of life (QoL) profiles in this population using patient-
reported outcomes (PRO) as measured by the European Organisation for Research 
and Treatment of Cancer (EORTC) quality of life questionnaires (QLQ) for 
chemotherapy-induced peripheral neuropathy (QLQ-CIPN20) and general QoL 
(QLQ-C30).

To characterize the PK of PM060184 in this population.

To characterize the metabolomics of PM060184, i.e. PM060184, i.e., systemic 
variations in the patient’s pre- and post-treatment metabolic profile that allow the 
identification of potential biomarkers of PK, safety and/or efficacy response to 
PM060184.

To characterize PGt of PM060184 in this population by identifying the presence or 
absence of germline mutations or polymorphisms that may help explain individual 
variability in the main PK parameters and safety outcomes.

To characterize PGx of PM060184 in this population by analyzing the potential 
predictive factors (including BRAF-mutant-like gene expression subtypes) of 
sensitivity/resistance to PM060184 treatment.
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4.
SELECTION OF PATIENTS
Patients with relapsed, metastatic/locally advanced CRC with any KRAS-mutation 
status (wild-type, mutated, or status unknown), progressing after standard treatments 
(fluoropyrimidine, irinotecan, and oxaliplatin).
4.1
INCLUSION CRITERIA
1)
Voluntarily written informed consent, obtained before the beginning of any study-
specific procedures.
2)
Age ≥ 18 years.
3)
Histologically-cytologically documented adenocarcinoma of colon or rectum that 
has progressed to the last prior treatment before inclusion.
4)
Measurable disease according to Response Evaluation Criteria in Solid Tumors 
(RECIST) v.1.1 (17). If the only tumor lesion is situated in a previously irradiated 
area or in an area subjected to other loco-regional therapy, progression in the lesion 
must be demonstrated radiologically.
5)
Previous treatment in any setting with fluoropyrimidine, oxaliplatin and irinotecan 
in any combination (unless any is contraindicated). 
a) Adjuvant chemotherapy-based treatments count as prior therapy, as long as 
relapse had occurred during or within six months of completion of such 
therapies.
b) Cumulative dose of prior oxaliplatin (if any) must be known.
c) Prior cetuximab, panitumumab, bevacizumab, aflibercept, and regorafenib are 
allowed.
6)
No more than two prior therapies for metastatic disease.
7)
Washout periods for prior therapies (defined in relation to planned start of study 
treatment [first dose administration]):
a) At least three weeks since the last administration of an antineoplastic treatment 
(chemotherapy, biological, targeted or investigational therapies). 
b) At least three weeks since radiotherapy involving up to 35% of bone marrow 
(radiotherapy involving > 35% of bone marrow is not allowed) or two weeks 
since the end of palliative radiotherapy including single doses (18).
c) At least four weeks since any major surgical procedure, open biopsy, or 
significant traumatic injury.
8)
Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1
(Appendix 1).
9)
Life expectancy ≥ 3 months.
10) Adequate bone marrow, liver, and kidney function:
a) Hemoglobin ≥ 9 g/dL.
b) Absolute neutrophil count (ANC) ≥ 1.5 × 109/L.
c) Platelet count ≥ 100 × 109/L.
d) Serum creatinine ≤ 1.5 mg/dL or calculated creatinine clearance ≥ 40 mL/min 
(Cockcroft-Gault formula, Appendix 2). 
e) Albumin ≥ 2.5 g/dL.
f) Total serum bilirubin ≤ 1.5 times the upper limit of normal (ULN), except in 
case of Gilbert syndrome. 
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g) Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 ×
ULN (≤ 5.0 × ULN in the case of liver metastases).
11) Recovery to grade ≤ 1 from any toxicity due to previous therapy (including 
peripheral sensory/motor neuropathy but excluding alopecia).
12) Left ventricular ejection fraction (LVEF) by echocardiography (ECHO) or 
multiple-gated acquisition (MUGA) scan within normal range (according to 
institutional standards).
13) Evidence of non-childbearing status for women of childbearing potential 
(WOCBP). WOCBP must agree to use a highly effective contraceptive measure 
during the trial and up to six months after treatment discontinuation, and fertile 
male patients must agree to refrain from fathering a child or donating sperm during 
the trial and up to four months after treatment discontinuation.* 
* Valid methods to determine the childbearing potential, adequate contraception and 
requirements for WOCBP partners are described in Appendix 3.
4.2
EXCLUSION CRITERIA
1)
Prior exposure to PM060184.
2)
Known hypersensitivity to the study drug class or study drug excipient in the 
formulation.
3)
Patients with locally advanced disease amenable to local and/or curative therapy 
(surgery or radiotherapy) at study entry.
4)
Other serious and/or relevant diseases or clinical situations that, in the opinion of 
the Investigator, are incompatible with the protocol (including any of the 
following):
a) History of another neoplastic disease (except for basal cell carcinoma of the 
skin, superficial bladder tumors, or properly treated carcinoma in situ of the 
uterine cervix or melanoma in situ) unless in remission for at least five years and 
with no recurrence. 
b) Symptomatic 
cerebral 
and/or 
leptomeningeal 
metastasis, 
spinal 
cord 
compression or carcinomatous meningitis.
c) Neuropathy of any etiology (other than that caused by previous antineoplastic 
therapy).
d) History of cardiac disease, such as myocardial infarction, in the year prior to 
registration in the clinical trial; symptomatic/uncontrolled angina pectoris; 
congestive heart failure or uncontrolled cardiac ischemia; any type of 
uncontrolled arrhythmia, congenital and/or prolonged QT interval or abnormal 
LVEF, or uncontrolled arterial hypertension (according to the standards of the 
World Health Organization [WHO]).
e) History of significant psychiatric disease.
f) Active infection requiring antibiotic, antifungal or antiviral treatment that, in the 
opinion of the Investigator, could compromise the patient’s capacity to tolerate 
the therapy.
g) Known active liver (hepatitis B or C or cirrhosis) or renal disease. 
h) Known human immunodeficiency virus (HIV) infection.
i) Any other concomitant pathology that could jeopardize the patient’s safety or 
commitment to complete the clinical trial.
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j) Inability or refusal to comply with the protocol or with the clinical trial 
procedures.
5)
Pregnancy or lactation. 
5.
TREATMENT
5.1
STUDY DRUG FORMULATION AND SUPPLY
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, PM060184 15-mg vials should be reconstituted with 6 mL of water for 
injection. The total volume of the reconstituted vial should be diluted with dextrose 
(5%) up to a total volume of 30 mL to give a PM060184 diluted solution containing 0.5 
mg/mL of PM060184. The diluted solution should be protected from exposure to light. 
Each 15-mg vial of PM060184 is a single-use vial. The full composition of the 
reconstituted solution per mL is shown in Table 3.
Table 3. PM060184 vial composition.
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 and 
disposal, please refer to the Preparation Guide for infusion for PM060184 and the 
PM060184 Investigator’s Brochure (IB), both provided as separate documents.
Medication preparation records will be kept by the site.
5.2
ADMINISTRATION OF STUDY MEDICATION
PM060184 at a dose of 9.3 mg/m2 (dose can be rounded to the first decimal point) will 
be administered as a 30-minute i.v. infusion via a central or peripheral venous catheter, 
on Day 1 and Day 8 q3wk (three weeks=one treatment cycle).
5.3
CRITERIA FOR TREATMENT CONTINUATION
Patients will be treated with additional cycles of PM060184 until disease progression 
(PD), as long as none of the following occur: unacceptable toxicity, and/or patient 
refusal to receive further study treatment, and/or Investigators’ decision.
The administration of subsequent cycles (after Cycle 1) should be delayed if criteria for 
treatment continuation (Table 4) are not met on the corresponding Day 1. If criteria for 
treatment continuation are not met on Day 8 (i.e. seven days after the first dose 
administration of a cycle) of any cycle, administration should be omitted instead of 
delayed. 
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Table 4. Criteria for treatment continuation.
A maximum delay of 15 days is allowed for the recovery of patients from toxicity. If 
toxicities have not recovered after this period, the patient should discontinue treatment. 
Exceptionally, in case of obvious clinical benefit, the patient can remain on treatment 
but only after discussion and mutual agreement with the Sponsor, and upon recovery of 
all parameters according to the aforementioned criteria.
5.4
DOSE REDUCTION
Dose can be reduced on the basis of the worst toxicity (drug-related adverse event [AE]) 
occurring since the previous dose (e.g., Day 1 or Day 8 of any cycle except for Day 1 of 
Cycle 1). The PM060184 dose reduction schedule is described in Table 5, and criteria 
according to toxicity in Table 6 and Table 7.
Table 5. PM060184 dose reduction levels.
Dose level 
PM060184 
–1
7.5 mg/m2
–2
6.0 mg/m2
Abnormality
Day 1 a
Day 8
ANC
1.5 × 109/L
1.0 × 109/L
Platelets
100 × 109/L
75 × 109/L
Hemoglobin b
9 g/dL
9 g/dL
Total bilirubin
1.5 × ULN (grade 1)
AST/ALT
Grade 1 c
Grade ≤ 2
Calculated CrCL (Cockcroft-Gault formula)
≥ 40 mL/min
30 mL/min
Peripheral sensory/motor neuropathy 
Grade ≤2
Grade ≤ 2
Nausea/vomiting, fatigue, anorexia
Grade ≤ 2
Grade ≤ 2
Other non-hematological drug-related AEs 
(except metabolic abnormalities d)
Grade ≤ 1
Grade ≤ 2
a Except Day 1 of Cycle 1.
b If hemoglobin levels are not met, the Investigator will have the option of giving the patient a transfusion 
instead of delaying (on Day 1) or omitting (on Day 8) a dose.
c Grade ≤ 2, for patients with liver metastases and with AST and/or ALT levels ≤5.0 x ULN at 
registration.
d Any grade accepted for increased GGT. Up to grade 4 accepted for non-symptomatic metabolic 
abnormalities (e.g., sodium, magnesium, potassium, calcium). 
AE, adverse event; ALT, alanine aminotransferase; ANC, absolute neutrophil count; AST, aspartate 
aminotransferase; CrCL, creatinine clearance; GGT, gamma-glutamyltransferase; ULN, upper limit of 
normal.
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Table 6. Criteria for PM060184 dose reduction for hematological toxicity.
Abnormality
Nadir value
PM060184 
ANC
< 0.5 × 109/L with fever (≥ 38.5°C)/infection, 
or
< 0.5 × 109/L for ≥ 3 days
Reduce one dose level
Platelet count
< 50 × 109/L, with significant bleeding, or
< 25 × 109/L
Reduce one dose level
A second occurrence of the aforementioned toxicities should lead to a further dose reduction (i.e., dose 
level –2). No more than two dose reductions will be allowed. 
ANC, absolute neutrophil count.
Table 7. Criteria for PM060184 dose reduction for non-hematological toxicity.
Abnormality
Worst NCI-CTCAE 
grade
PM060184
Peripheral sensory/motor neuropathy
≥ 3
Reduce one dose level
Prolonged peripheral sensory/motor 
neuropathy a
≥ 2
Reduce one dose level
Abdominal pain (if reoccurring after the 
first administration)
≥ 3
Reduce one dose level
Nausea/vomiting despite adequate 
antiemetic treatment
≥ 3
Reduce one dose level
Fatigue (if reoccurring or persistent after 
Cycle 2)
≥ 3
Reduce one dose level
Other treatment-related AEs according to 
the Investigator’s criteria
≥ 3
Reduce one dose level
A second occurrence of these toxicities should lead to a further dose reduction (i.e., reduction to dose 
level –2). No more than two dose reductions will be allowed.
a Lasting more than two cycles.
AE, adverse event; NCI-CTCAE, National Cancer Institute Common Terminology Criteria for the 
Classification of Adverse Events.
No more than two dose reductions per patient will be allowed in the course of this 
clinical trial. Patients requiring more dose reductions should discontinue treatment, 
except in the event of obvious clinical benefit, in which case, treatment may continue 
after discussion and mutual agreement with the Sponsor.
No dose escalations will be allowed in this clinical trial.
5.5
CONCOMITANT MEDICATION
All medication at study registration, received within the 14 days prior to first drug 
administration and during the on-treatment period must be documented in the electronic 
case report forms (e-CRF). The details to be entered for each type of treatment will 
depend on factors such as relationship to, for example, AEs, underlying disease and 
symptoms, and will be defined in the study’s e-CRF completion guidelines.
5.5.1
Prophylactic Medication
Primary antiemetic prophylaxis is compulsory before all PM060184 dose 
administrations. Standard treatment according to the American Society of Clinical 
Oncology (ASCO) guidelines will be administered:

5-HT3 antagonists (ondansetron 8 mg or equivalent).

Steroids (dexamethasone 8 mg or equivalent).
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Oral or i.v. formulations are allowed according to institutional standards.
If necessary, additional antiemetic therapy can be considered in accordance with ASCO 
guidelines.
5.5.2
Allowed Medications/Therapies

Therapies for pre-existing and treatment-emergent medical conditions, including 
pain management.

Blood products and transfusions, as clinically indicated.

Approved therapies for bone metastasis (e.g., bisphosphonates, denosumab).

In case of nausea or vomiting, prophylaxis and/or symptomatic treatment for emesis 
according to ASCO guidelines.

Erythropoietin use according to ASCO guidelines.

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 can be considered if it is in the best 
interest of the patient.

Megestrol acetate for appetite stimulation.

Anticoagulant therapy for the treatment or secondary prophylaxis
of 
thromboembolic events.
5.5.3
Prohibited Medications/Therapies
Concomitant administration of any other antineoplastic therapy. 
Any other investigational agents.
Immunosuppressive therapies other than corticosteroids.
Local therapy such as radiation or surgery if the lesion is the only target lesion, 
unless agreed in advance with the Sponsor.
5.5.4
Drug-drug Interactions
In vitro studies using human liver microsomes have pointed to CYP2C19 and CYP3A4 
as the predominant cytochrome enzymes responsible for the hepatic metabolism of 
PM060184. Therefore, concomitant drugs that induce or inhibit any of these 
cytochromes to a significant extent should be avoided whenever possible (Appendix 
4).
5.6
DRUG ACCOUNTABILITY
Each study site will keep records to allow a comparison of quantities of drug received 
and used at each site. The Investigators 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.
5.7
TREATMENT COMPLIANCE
The Investigator is responsible for supervising compliance with the instructions 
described in this study protocol.
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6.
PLAN OF THE STUDY
6.1
DURATION OF THE STUDY (WHOLE POPULATION)
The total duration of the study will be approximately 36 months. 
Planned start date (first patient first visit): 4Q2017.
Planned enrollment period: approximately 20 months.
Planned study termination date:
12 months after the first PM060184
administration of the last evaluable patient treated in the study.
6.2
DURATION OF THE STUDY (PER PATIENT)
Patients will be evaluated at scheduled visits in the following study periods:
Screening: from signature of informed consent to registration (confirmation of 
eligibility) or screen failure.
Pretreatment: from registration to first dose of study treatment.
Treatment: from the first administration of the study treatment to end of treatment 
(EOT). EOT is standardly defined as 30 days (± 15 days) after the day of last 
administration of study treatment, unless the patient starts a new antitumor therapy 
or dies within 30 days of the last dose, in which case the date of administration of 
this new antitumor therapy or the date of death will be considered the EOT date.
Follow-up: after EOT, patients will be followed for both safety and efficacy.
1) Safety: every four weeks until resolution or stabilization of drug-related AEs (if 
any).
2) Efficacy: about every three months until death, refusal to continue participating 
in the study, or study termination (clinical cutoff), whichever occurs first.
Subsequent off-study antitumor therapies should be provided until death, refusal 
and/or clinical cutoff (whichever occurs first).
Note: patients without disease progression who discontinue treatment due to a drug-
related AE must be followed both for the AE and for efficacy.
Patients will be considered to be on-study from the signature of the informed consent 
form (ICF) to the end of the follow-up period (or screening failure). Investigators can 
appraise potential study candidates in a pre-screening period but only perform study-
specific screening assessments after the patient formally consents. Patients will be 
considered to be on-treatment from the date of first dose until EOT.
Patients may withdraw their consent at any time; if consent to study participation is 
withdrawn, no further study activities will be conducted on them (Section 6.3.3). If 
consent only to receive the study treatment is withdrawn, treatment will be stopped and 
other study procedures performed as normal (see 7.5 and 7.6 below).
6.3
DISCONTINUATIONS
6.3.1
Treatment Discontinuation
Treatment discontinuation occurs when an enrolled patient ceases to receive the study 
medication, regardless of the circumstances. By convention, the date of end of treatment 
will be 30 days (± 15 days) after the date of the last administration of study drug, unless 
the patient starts a new antitumor therapy or dies within those 30 days, in which case the 
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date of administration of this new therapy or the date of death will be considered the 
date of end of treatment.
The primary reason for any discontinuation will be recorded on the patient’s e-CRF.
If a patient discontinues treatment, every effort should be made to complete the 
scheduled assessments.
6.3.2
Reasons For Treatment Discontinuation
Patients will receive study treatment while it is considered to be in their best interest or 
until study termination. Specifically, treatment will continue until:
Disease progression.
Unacceptable toxicity (including any toxicity leading to the need for a third dose 
reduction or severe hypersensitivity reactions, except in the case of obvious clinical 
benefit, in which event the patient could be allowed to remain on treatment once 
agreed with the Sponsor).
Patient refusal to receive further study treatment and/or non-compliance with study 
requirements.
Intercurrent serious illness. 
Pregnancy.
Investigator’s decision.
Protocol deviation with an effect on the risk/benefit ratio of the clinical trial.
PM060184 treatment delay > 15 days from the due date (except in case of clear 
clinical benefit and with the Sponsor’s approval). 
Clinical cutoff. Patients who have not progressed at these time points could be 
treated in a compassionate use program (according to country regulations). 
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 7.6.
6.3.3
Study Discontinuation
Study discontinuation occurs when an enrolled patient ceases to participate in the study, 
regardless of the reason. Patients have the right to withdraw consent at any time; if this 
is the case, no further study procedures should be performed. The date and reason for 
study discontinuation will be clearly documented on the patient’s e-CRF. 
6.3.4
Replacement of Patients
Patients must be replaced if they are considered not evaluable for efficacy for the 
primary endpoint (PFS3), i.e., if they are withdrawn from the study due to significant 
clinical deterioration of unknown reason, hypersensitivity reactions, unrelated AEs 
without any tumor assessments after the start of study treatment, if they receive less 
than one complete treatment cycle (at least two PM060184 dose administrations over 
two cycles unless treatment discontinuation was due to unmanageable toxicity), or do 
not have the disease assessment at Week 12 (except in the case of treatment 
discontinuation/death due to a treatment-related AE, symptomatic deterioration due to 
the disease, clinical progression, PD or death due to malignant disease).
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6.4
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 the 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 Good Clinical Practice (GCP) guidelines or ethical issues (e.g., issues related to 
obtaining the patients’ Informed Consent, data reporting, Investigator’s responsibilities, 
etc.).
Deviations with no effects on the risk/benefit ratio of the clinical trial (such as minimal 
delays in assessments or visits) will be distinguished from those that might have an 
effect on this risk/benefit ratio, such as:

Deviations that might affect the clinical trial objectives, such as those involving 
inclusion/exclusion criteria (which could mean that the patient is not eligible for the 
trial) and those having an effect on patient’s evaluability.

Deviations that might affect the patient’s well-being and/or safety, such as incorrect 
dosing of the IMP due to not following dose adjustment specifications or an 
incorrect preparation of the medication.

Deviations related to compliance with GCP guidelines as described in the protocol 
and regulations in force, such as deviations when obtaining the Informed Consent or 
not following the terms established for reporting Serious Adverse Events, etc.
As a general rule, NO deviations that may have an effect on the evaluation of the 
risk/benefit ratio of the study treatment 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, fulfillment of GCP guidelines 
and with an effect on the evaluation of the risk/benefit ratio) will be notified to the 
pertinent IEC/IRB and, if applicable, to the Competent Authorities as established by 
local regulations.
Failure to attend the EOT visit exclusively due to a deteriorated clinical condition will 
not be considered a protocol deviation.
Any protocol deviation will also be discussed with the Investigator during monitoring 
visits.
7.
STUDY ASSESSMENTS AND PROCEDURES
7.1
ELIGIBILITY ASSESSMENTS
The patient will be allocated a patient number in the e-CRF after signing the ICF and 
screening for eligibility begins. This patient number should be used on all future 
documentation and correspondence referring to this patient. During the screening 
period, the Investigator will assess the patient’s eligibility for inclusion in the study by 
conducting the assessments summarized below. 
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Table 8. Screening period assessments.
ASSESSMENT
TIME
1.Written informed 
consent
The informed consent process involves an 
explanation and discussion with the patient 
including time for questions and answers and 
culminates in signing and dating the consent form if 
the patient agrees. Document registration in the 
patient’s medical chart as well.
Substudy participation is optional and requires a 
separate signed consent.
Before any study-specific 
procedures. 
2.Medical and 
cancer history/ 
clinical 
examination
Demographic data (race/ethnicity [if permitted], 
age, sex).
Medical history: Includes relevant conditions and 
syndromes that started before registration and are 
not ongoing (no signs or symptoms) at time of 
registration or are controlled and do not require 
evaluation for severity or causality. Also includes 
any event qualifying as serious occurring prior to 
registration.
Cancer history: Primary diagnosis, response 
history, date of last confirmed PD, and all prior 
treatment (including cumulative dose of prior 
oxaliplatin, if any).
Within 28 days prior to 
registration.
Physical examination: Including weight, height (for 
BSA calculation).
Vital signs: HR, ABP, and temperature.
ECOG performance status (Appendix 1).
Within 10 days prior to 
registration.
Concomitant therapies: All Medications taken by 
the patient (including any not prescribed by the 
Investigator) should be documented with indication.
Within 14 days prior to 
registration.
3.Laboratory tests
Hematology: Complete blood count, differential 
WBC (neutrophils, lymphocytes), hemoglobin, and 
platelets.
Biochemistry-A: ALP, AST, ALT, total bilirubin 
(and direct bilirubin if total is >1.5 x ULN), GGT, 
creatinine/CrCL 
(Cockcroft-Gault 
formula,
Appendix 2), glucose, LDH, and serum electrolytes 
(Na+, K+, Total calcium).
Biochemistry-B: Total proteins and albumin.
Within 10 days prior to 
registration.
4.Pregnancy test 
Assessment of β-hCG only if the patient is a 
WOCBP (Appendix 3).
Within 7 days prior to 
registration.
5.Cardiac 
assessment
ECG: Including rhythm definition and PR interval; 
heart rate; QT interval (raw); QRS complex 
duration..
LVEF: ECHO or MUGA scan.
Within 28 days prior to 
registration.
6.Disease 
assessments
Clinical/radiological tumor assessment: Helical
i.v. and oral contrast-enhanced CT-scan (if 
appropriate) for chest, abdomen and pelvis and other 
areas of suspected diseases. If i.v. contrast is 
contraindicated for the CT-scan, chest evaluation 
should be performed using non-contrasted CT and 
abdomen/pelvis evaluation using gadolinium-
enhanced MRI.
Tumor markers alone or chest radiography alone are 
not sufficient to assess tumor burden.
Within 28 days prior to 
registration.
7.Adverse events
Only information on SAEs that occurred after 
signature of the informed consent is required before 
treatment start. Grading should be as per the NCI-
CTCAE v.4.
Within 14 days prior to 
registration.
PRO QLQs: Patients will be asked to complete the 
EORTC QLQ-CIPN20 and QLQ-C30.
Within 10 days prior to 
registration.
Registration=confirmation of eligibility and inclusion.
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ASSESSMENT
TIME
Permitted windows for assessments before Day 1 of Cycle 1:
If physical examination, ECOG PS, vital signs, hematology/biochemistry were assessed >10 days before Day 1 of 
Cycle 1, the tests must be repeated within 2 days before the first study drug administration.
If pregnancy test was done >7 days before Day 1 of Cycle 1, the test must be repeated within 2 days before the first 
study drug administration. 
If tumor assessments were done >28 days before Day 1 of Cycle 1, the tests must be repeated within 2 days before 
the first study drug administration.
A patient should only be treated if eligibility criteria are still met according to assessments performed closest to 
treatment start.
ABP, arterial blood pressure; AE, adverse event; ALP, alkaline phosphatase; ALT, alanine aminotransferase; 
AST, aspartate aminotransferase; β-hCG, beta subunit of human chorionic gonadotropin; BSA, body surface 
area; CrCL, calculated creatinine clearance; CT, computed tomography; ECG, electrocardiogram; ECHO, 
echocardiogram; ECOG, Eastern Cooperative Oncology Group; EORTC, European Organisation for Research 
and Treatment of Cancer; GGT, gamma-glutamyltransferase; HR, heart rate; IC, Informed Consent; IF, 
immunofixation; LDH, lactate dehydrogenase; LVEF, left ventricular ejection fraction; MRI, magnetic resonance 
imaging; MUGA, multiple-gated acquisition; NCI-CTCAE, National Cancer Institute Common Terminology 
Criteria for Adverse Events; PRO, patient reported outcomes; PS, performance status; QLQ, quality of life 
questionnaire; SAE, serious adverse event; ULN, upper limit of normal; WBC, white blood cells; WOCBP, 
woman of childbearing potential..
7.2
PATIENT REGISTRATION
Eligibility will be checked before registration confirmed by the Sponsor. The patient 
will be a screening failure if not all inclusion criteria are met, if any exclusion criterion 
is met, or if the Sponsor does not approve registration. Regardless of circumstances, 
Investigators will not be allowed to treat any patient before appropriate receipt of the 
Sponsor’s agreement to proceed with registration. A patient should only be treated if 
eligibility criteria are still met according to assessments performed closest to first drug 
administration.
A patient who has been treated without the Sponsor’s agreement may not be considered 
evaluable for the primary endpoint of the study and may need to be replaced (although 
can continue in treatment provided this does not pose a risk to the patient until 
discontinuation for any other reason).
For patients included in the study (all registered patients) but never treated, only 
baseline and off-study visit modules of the e-CRF should be completed but serious 
adverse events (SAEs) occurring during screening need to be reported (using paper SAE 
forms).
For screen failures (patients who started screening but were not finally registered), only 
the screening form of the e-CRF should be completed but SAEs occurring during 
screening need to be reported (using paper SAE forms).
7.3
RANDOMIZATION
Not applicable.
7.4
EVALUATIONS DURING TREATMENT
The assessments to be done while the patient is on treatment are shown in Table 9.
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Table 9. Evaluations during treatment.
ASSESSMENT
TIME
1. Clinical 
examination
Physical examination: Including weight and clinical 
assessment. BSA and dosing should be recalculated 
in the event of weight variation of ±10% from 
baseline.
ECOG performance status (Appendix 1).
Day 1 of Cycle 2 and subsequent 
cycles (always prior to drug 
administration). 
Also repeat on Day 1 of Cycle 1 
(prior to drug administration) if more 
than 10 days have passed since the 
screening assessment.
Vital signs: HR, ABP, and temperature.
Day 1 of Cycle 2 and subsequent 
cycles (always prior to drug 
administration). 
Also repeat on Day 1 of Cycle 1 
(prior to drug administration) if more 
than 10 days have passed since the 
screening assessment.
2. Laboratory 
tests
Hematology: Complete blood count, differential 
WBC (neutrophils, lymphocytes), hemoglobin, and 
platelets.
Biochemistry-A: ALP, AST, ALT, total bilirubin
(and direct bilirubin if total is >1.5 x ULN), GGT, 
creatinine/CrCL 
(Cockcroft-Gault 
formula,
Appendix 2), glucose, LDH, and serum electrolytes 
(Na+, K+, Total calcium).
Day 1 of Cycle 2 and subsequent 
cycles (always prior to drug 
administration). 
Also repeat on Day 1 of Cycle 1 
(prior to drug administration) if more 
than 10 days have passed since the 
screening assessment.
If any clinically-relevant, treatment-
related grade ≥ 3 AE occurs, the 
abnormality should be reassessed 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, reassessment 
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
Biochemistry-B: Total proteins and albumin.
Day 1 of Cycle 2 and subsequent 
cycles (always prior to drug 
administration). 
Also repeat on Day 1 of Cycle 1 
(prior to drug administration) if more 
than 10 days have passed since the 
screening assessment.
3. Pregnancy test 
Assessment of β-hCG only if the patient is a WOCBP
(Appendix 3).
Repeat every cycle or (at least) every 
month while on-treatment.
4. Cardiac 
assessment
ECG: Including rhythm definition and PR interval; 
heart rate; QT interval (raw); QRS complex duration, 
as well as any ECG anomaly or variation (change in 
grade) with respect to baseline.
Repeat if clinically indicated.
LVEF: ECHO or MUGA scan
5. Pharmaco-
kinetics
Ten plasma PK samples are required from patients 
included in the first stage of the study: just before 
start of administration, just before EOI, and then 15 
min, 30 min, 1 h, 2 h, 4 h, 6 h, and 12.5 h (Day 1) and 
24.5 h (Day 2) after EOI. 
Only eight plasma PK samples are required from 
patients included in the second stage of the study: the 
samples scheduled at 12.5 h and 24.5 h after EOI are 
not required.
Days 1 and 2 of Cycle 1 and Cycle 2
in all patients included in the first 
stage.
Day 1 of Cycle 1 and Cycle 2 in all 
patients included in the second stage.
See Table 10.
6. Metabolomics
Three blood samples should be collected 
One prior to each dose administration 
on Day 1 and Day 8 of Cycle 1, and 
also on Day 8 of Cycle 2.
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ASSESSMENT
TIME
7. Pharmaco-
genomics
For those patients who consent to participate in the 
substudy, archived paraffin-embedded tumor tissue 
samples should be available.
The availability of tumor tissue 
samples used for the initial diagnosis 
of the disease, or obtained at relapse, 
should be confirmed and should be 
prepared and shipped during the trial 
following the instructions detailed in 
a separate laboratory manual.
8. Pharmaco-
genetics
If the patient consents to the substudy, an additional 
blood sample for PGt analysis should be collected. 
At any time during the trial but 
ideally at the same time as the 
pretreatment PK sample (sample #1)
in Cycle 1.
9. Disease 
assessments
Clinical/radiological tumor assessment: Using 
RECIST v.1.1. Helical i.v. and oral contrast-enhanced 
CT-scan (if appropriate) for chest, abdomen and 
pelvis and other areas of suspected diseases. If i.v.
contrast is contraindicated for the CT-scan, chest 
evaluation should be performed using non-contrasted 
CT and abdomen/pelvis evaluation using gadolinium-
enhanced MRI.
The same radiological method should be used 
throughout the study for each individual patient. 
Anonymized copies of images showing a response 
(CR or PR) must be submitted to the Sponsor. 
Tumor markers alone or chest radiography alone are 
not sufficient to assess tumor burden.
To be performed every six weeks (+ 
7 days, except for Week 12 when a 
window of ± 5 days applies). 
10. Concomitant 
medications
All concomitant therapies taken by the patient 
(including any not prescribed by the Investigator) 
should be documented with indication.
Throughout the on-treatment period.
11. Adverse events 
Grading should be as per the NCI-CTCAE v.4.
Throughout the on-treatment period.
PRO QLQs: Patients will be asked to complete the 
EORTC QLQ-CIPN20 and QLQ-C30.
On Day 8 (day of second dose 
administration) of every treatment 
cycle.
Registration=confirmation of eligibility and inclusion; A patient should only be treated if eligibility criteria are still met 
according to assessments performed closest to first drug administration. Day 1=day of first cycle administration (with 
infusion start); Day 8=seven days after the first dose administration of a cycle (± 2 days ); Day 22 = Day 1 (± 2 days) of 
the following cycle. 
Permitted windows for assessments before Day 1 of Cycle 1:
If physical examination, ECOG PS, vital signs, hematology/biochemistry were assessed >10 days before Day 1 of Cycle 
1, the tests must be repeated within 2 days before the first study drug administration.
If pregnancy test was done >7 days before Day 1 of Cycle 1, the test must be repeated within 2 days before the first study 
drug administration. 
If tumor assessments were done >28 days before Day 1 of Cycle 1, the tests must be repeated within 2 days before the 
first study drug administration.
A patient should only be treated if eligibility criteria are still met according to assessments performed closest to treatment 
start.
Permitted windows for assessments after Day 1 of Cycle 1:
- 2 days for clinical assessments (physical examination, ECOG PS, vital signs), always before study drug administration.
+ 7 days for tumor assessments (except in week 12 when there is a maximum 5-day window). 
± 2 days for Day 1 study drug administration (from Cycle 2 onwards).
± 2 days for Day 8 study drug administration.
– 2 days for laboratory tests. To confirm criteria for treatment continuation, laboratory assessments must be performed 
within 2 days prior to drug administration. 
If a drug administration is delayed beyond the permitted protocol window, assessments planned for the original 
administration day must be repeated on the day the dose is finally administered.
ABP, arterial blood pressure; AE, adverse event; ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, 
aspartate aminotransferase; β-hCG, beta subunit of human chorionic gonadotropin; BSA, body surface area; CrCL, 
calculated creatinine clearance; CR, complete response; CT, computed tomography; ECG, electrocardiogram; ECHO, 
echocardiogram; ECOG, Eastern Cooperative Oncology Group; EOI, end of infusion; EORTC, European 
Organisation for Research and Treatment of Cancer; EOT, end of treatment; GGT, gamma-glutamyltransferase; HR, 
heart rate; IC, Informed Consent; i.v., intravenous; LDH, lactate dehydrogenase; LVEF, left ventricular ejection 
fraction; MRI, magnetic resonance imaging; MUGA, multiple-gated acquisition; NCI-CTCAE, National Cancer 
Institute Common Terminology Criteria for Adverse Events; PGt, pharmacogenetics; PK, pharmacokinetics; PR, 
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ASSESSMENT
TIME
partial response; PRO, patient reported outcomes; PS, performance status; QLQ, quality of life questionnaire; 
RECIST, Response Evaluation Criteria in Solid Tumors; SAE, serious adverse event; ULN, upper limit of normal; 
WBC, white blood cells; WOCBP, woman of childbearing potential.
7.5
EVALUATIONS AT END OF TREATMENT
The EOT visit should take place approximately 30 days (± 15 days) of the last study 
drug 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 
(ideally the day before or the same day). If a patient dies within 30 days from the last 
dose, the date of death will be considered EOT.
The assessments listed below are required if no recent data are available (i.e. within the 
previous 10 days) or if the last data available show a grade ≥ 2 treatment-related 
alteration, whenever the medical condition of the patient allows.

Assessment of disease-related symptoms.

Complete physical examination (including weight).

ECOG PS.

Vital signs (heart rate, blood pressure, body temperature).

Concomitant therapies.

Hematology.

Biochemistry-A.

Biochemistry-B.

Pregnancy test (if patient is a WOCBP).

LVEF.

PRO QLQs (EORTC QLQ-CIPN20 and QLQ-C30)

Adverse events.
For individual patients (and if clinically indicated according to Investigator’s criteria), it 
might also include the following:

ECG.

Other tests as appropriate.
Adverse events must be reported during 30 days after the last study drug administration. 
All SAEs occurring within 30 days of the last study drug administration will be 
reported. Beyond this period of time, only those suspected to be treatment-related SAEs 
will be reported (Section 8.5.2).
The Sponsor will evaluate all safety information that is spontaneously reported by an 
Investigator beyond the time frame specified in the protocol.
Loss to follow-up, or failure to attend the EOT visit due to a deteriorated clinical 
condition or due to personal reasons such as returning to their previous hospital, will not 
be considered protocol deviations.
7.6
FOLLOW-UP AFTER THE END OF TREATMENT VISIT
After EOT, patients will be followed every four weeks until resolution or stabilization 
of toxicities (if any). During follow-up, the QLQ-CIPN20 should be completed every 
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three months until the start of a new antitumor therapy; unless the patient discontinued 
treatment due to grade ≥ 3 PN, in which case, repeat the assessment monthly until 
recovery to grade ≤ 2 (or until start of subsequent antitumor therapy).
The primary endpoint of the study is PFS3, defined as the percentage of patients 
remaining alive and progression-free at Week 12. Therefore, the Week-12 disease 
evaluation should be performed in all non-PD patients. Tumor assessment should be 
performed about every three months during follow-up in patients who discontinue 
treatment without disease progression.
Regardless of the reason for treatment discontinuation, all patients will be followed 
about every three months until death, refusal to continue participating in the study, or 
study termination (clinical cutoff), whichever occurs first. Subsequent antitumor
therapies should be provided until death, refusal, and/or clinical cutoff (whichever 
occurs first).
Patients without disease progression who discontinue treatment due to a drug-related 
AE must be followed both for the AE and for efficacy.
Progression-free Survival and Survival Follow-up Timelines for the Whole 
Population:
If the study ends after the futility analysis at 24 evaluable patients (first stage):

Patients who are still on study will be followed up to 12 weeks after the first 
PM060184 administration of the last patient evaluable for the futility analysis.
If the futility analysis results in continuation of recruitment (second stage):

All patients will be followed up to 12 months after the first PM060184 
administration of the last evaluable patient treated in the study, regardless of the 
stage at which the patients have been included.
For the purpose of collecting information on patient’s survival, a documented telephone 
call, email or medical chart review is acceptable; follow-up for survival will be 
completed for all patients only if the study continues to the second stage.
7.7
STUDY TERMINATION (CLINICAL CUTOFF)
The planned study termination date (clinical cutoff) will be: 12 months after the first 
PM060184 administration of the last evaluable patient treated in the study.
7.8
PHARMACOKINETICS
The plasma PK of PM060184 will be evaluated in Cycle 1 and Cycle 2 during both 
stages of the study. In the first stage, PK will be evaluated on Days 1 and 2 of Cycle 1
and Cycle 2 with a sampling schedule of ten samples; in the second stage, PK will be 
evaluated on Day 1 of Cycle 1 and Cycle 2 only with eight samples (Table 10). 
Concentration data will be pooled with that from other clinical studies with PM060184 
as a single agent and PK parameters will be calculated by means of population PK 
analysis and/or non-compartmental methods.
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Table 10. Pharmacokinetic sampling schedule for PM060184.
Sample
number
Day
Relative 
times
Sampling times
for PM060184
Sampling 
window
#1
1
0 min
Before start of administration
-
#2
1
30 min
Just before EOI
- 2 min
#3
1
45 min
15 min after EOI
± 2 min
#4
1
1 h
30 min after EOI
± 5 min
#5
1
1.5 h
1 h after EOI
± 10 min
#6
1
2.5 h
2 h after EOI
± 10 min
#7
1
4.5 h
4 h after EOI
± 10 min
#8
1
6.5 h
6 h after EOI
± 10 min
#9 a
1 a
12.5 h
12 h after EOI
± 1 h
#10 a
2 a
24.5 h
24 h after EOI
± 4 h
a Samples #9 and #10 are required only in patients included in the first stage of the study.
EOI, end of infusion; h, hour; min, minute.
The accurate recording of actual sampling times is more important than strict adherence 
to the scheduled times. 
Blood samples for PK analysis will be obtained through a peripheral vein located in the 
contralateral side to that of drug administration, whenever possible. In any case, the 
sampling vein has to be different to that in which drugs are administered. Even the last 
sample must never be collected from the catheter used for drug administration. 
A separate manual describes in more detail the required procedures. Please read it 
carefully before PK sampling. In short, after collection, each sample will be centrifuged 
and the resulting plasma layer transferred into a new tube for the determination of 
PM060184 concentration. The plasma-containing tubes will be stored frozen until their 
shipment to the Central Laboratory for further delivery to the Laboratory for PK 
Samples (see Study Contacts). All the material for PK procedures will be provided by 
the Central Laboratory. 
Once all samples from a patient have been collected, they should be shipped for analysis 
to the Central Laboratory as soon as possible, ideally on the next shipping day. If the 
same site has samples from several patients, the samples can be sent in the same 
shipment. However, the time span between the collection time of the last PK sample 
from a patient and the shipment of all the samples from that patient to the Central 
Laboratory should not exceed one week.
7.9
METABOLOMICS
Metabolomics (the determination of endogenous low-molecular-weight molecules or 
metabolites in a body fluid and their changes as a consequence of stimuli such as 
medical interventions), is currently being used to evaluate the efficacy and safety of 
medical interventions in cancer (11), thus allowing for the discovery of predictive 
biomarkers of drug response (12).
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The metabolomics of PM060184 will be characterized by evaluating systemic variations 
in pre- and post-treatment metabolic profile to identify potential biomarkers of PK, 
safety and/or efficacy response to PM060184.
Three blood samples are required for this analysis. Patients will have one blood sample 
collected before each drug administration on Day 1 and Day 8 of Cycle 1, and also on 
Day 8 of Cycle 2, to evaluate the pretreatment profile of endogenous metabolite levels 
and changes after PM060184 treatment.
Blood must be collected without anticoagulant and with a separating gel, allowed to 
clot, and centrifuged. Serum will be collected and stored. The samples should be frozen 
at –80°C within 24 h. If not possible, they can be frozen at –20°C, but only for a 
maximum period of two weeks before shipping in dry ice to the central laboratory.
The required procedures for the collection, processing and storage of the sample for 
metabolomics are described in more detail in the laboratory manual. Please read it 
carefully before sample extraction.
7.10 PHARMACOGENETICS
To explore PGt factors that may help to explain individual variability in main PK 
parameters, as well as susceptibility to develop treatment-related AEs, the presence or 
absence of germline mutations or polymorphisms that may be involved in the 
metabolism and/or transport of PM060184 will be analyzed in leukocyte DNA extracted 
from blood collected at any time during the trial but ideally at the same time as the 
pretreatment PK sample (sample #1) in Cycle 1 from those patients who have also 
consented to the substudy.
The collection and management of this additional sample are quite different from those 
for PK assessment. Please carefully follow the instructions detailed in a separate 
manual. The assessment of polymorphisms is not affected by treatment; hence, the 
Sponsor may require the collection of additional samples later on, if the first assessment 
has not been performed accurately. 
Only patients who voluntarily sign the IC for the PGx/PGt substudy will participate in 
the PGt evaluation. Refusal to participate in the PGx/PGt substudy will not affect 
patient participation in the clinical study PM60184-B-002-17.
7.11 PHARMACOGENOMICS
Provision of samples for PGx analyses will be optional and performed upon patient 
consent by signing the substudy ICF. For those patients who consent to participate in 
the substudy, the availability of tumor tissue samples used for the initial diagnosis of the 
disease, or obtained at relapse, should be confirmed and should be prepared and shipped 
during the trial following the instructions detailed in a separate laboratory manual.
The objective of the PGx substudy is to evaluate the role of potential markers of 
sensitivity to treatment with microtubule-interacting agents in a population of advanced 
CRC patients treated with PM060184. These molecular markers would help in the 
future selection of patients who might preferentially benefit from PM060184 therapy, 
thus contributing to improved health care through a more individualized medicine.
Analyses will be performed at the Central Laboratory for PGx samples (see Study 
Contacts). The analytical methods required for this molecular characterization analysis 
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are described in a separate document detailing the procedures to be followed for sample 
collection, labeling, and shipment.
The following analyses will be performed on paraffin-embedded tumor tissue samples
from patients participating in the substudy if there is evidence of clinical benefit: 

Quantification of protein and/or mRNA expression levels of tubulin isotypes and 
other factors related to the mechanism of action of PM060184 and to the tumor 
microenvironment by immunohistochemistry (IHC) or quantitative polymerase 
chain reaction (PCR) in tumor tissue microarrays constructed from the patients’
samples.

Analysis of polymorphisms and mutations of the above-mentioned selected genes, if 
relevant, by reverse transcription polymerase chain reaction (RT-PCR) and/or DNA 
sequencing.

Analysis of BRAF-mutant-like gene expression subtypes (and potentially full 
genome expression).
If possible, expression levels of the different markers will be correlated with the study 
efficacy parameters.
8.
STUDY EVALUATIONS
8.1
EFFICACY
Patients will be evaluable for efficacy if they receive at least one complete treatment 
cycle (or two PM060184 dose administrations over two cycles) and have, at least, one 
disease assessment at Week 6 and another one at Week 12. 
In addition, any patient who presents disease progression, symptomatic deterioration 
due to the disease or clinical progression, dies due to malignant disease, discontinues 
treatment due to unmanageable toxicity, or dies or discontinues treatment due to a 
treatment-related AE before evaluation of the response at Week 12 will also be 
considered evaluable for the primary endpoint and classified as a non-responder.
Patients who have no disease assessment at Week 6 but remain on treatment and are 
assessed at Week 12 (or later, and with no evidence of disease progression) will be 
considered evaluable for efficacy. 
Patients who refuse further treatment before Week 12 due to reasons other than related 
AEs not considered unmanageable toxicity will be replaced.
A futility analysis will be performed once the first 24 evaluable patients complete the 
Week 12 (± 5 days) tumor assessment; progress; die due to PD; or discontinue treatment 
due to unmanageable toxicity (whichever occurs first). If seven patients or more achieve 
PFS3, then 36 additional patients will be recruited (second stage).
Tumor assessment will be measured using RECIST v.1.1 (17). 
8.2
SAFETY
Patients will be evaluable for safety if they receive at least one (complete or incomplete) 
dose of PM060184.
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Safety will be evaluated by clinical examinations, analysis of vital signs, clinical 
assessment of AEs, changes in the analytical parameters (hematological and 
biochemical), and any other analyses that may be considered necessary.
All treatment-related AEs must be followed-up—even if the administration of 
PM060184 has finalized—until the AE or its sequelae have resolved or stabilized at an 
acceptable level to the Investigator and the Sponsor. AEs will be graded according to 
the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-
CTCAE v.4), and will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA).
8.3
PATIENT REPORTED OUTCOMES
EORTC QLQ-CIPN20 and QLQ-C30 will be used to collect information on patients’ 
self-reported QoL and neurotoxicity, targeting symptoms, functional limitations, and 
patient concerns specifically associated with treatment-induced PN, and potential 
activity impairment.
Patients will be asked to complete both QLQs at baseline, on Day 8 of each cycle, at the 
end-of-treatment visit.
Patients will be asked to complete the QLQ-CIPN20 (only) during the follow-up period 
(about every three months until start of subsequent antitumor therapy). If a patient 
discontinues treatment due to grade ≥ 3 PN, however, the QLQ-CIPN20 should be 
completed more frequently during the follow-up period (every month after EOT) until 
recovery to grade ≤ 2 (or until start of subsequent antitumor therapy).
8.4
ADVERSE EVENTS
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.
For the purposes of this protocol, disease progression, worsening of the underlying 
disease or appearance of new tumor lesions, or any sign or symptom clearly related with 
this circumstance is NOT required to be reported as an AE.
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8.4.1
Serious Adverse Event (SAE)
A SAE is any adverse experience occurring at any dose that:

Results in death (is fatal),

Is life-threatening,

Requires or prolongs inpatient hospitalization,

Results in persistent or significant disability or incapacity,

Is a congenital anomaly or birth defect, 

Is medically significant, or

Is any suspected transmission of an infectious agent via a medicinal product. 
Medical and scientific judgment should be exercised in deciding medically significant 
events; this criterion should be applied to AEs that may not be immediately life-
threatening or result in hospitalization but may jeopardize the patient or may require 
intervention to prevent one of the outcomes listed in the above definition.
8.4.2
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.
8.4.3
Life-threatening Event
Any event in which the patient was at risk of death at the time of the event is considered 
life-threatening; it does not refer to an event which hypothetically might have caused 
death if it were more severe.
8.4.4
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. 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 the criteria for SAE reporting are: 
a. Reasons described in the 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 the absence of an AE.
c. Pre-planned
hospitalizations: any pre-planned hospitalization, surgery or 
procedure must be documented in the source documentation. Only if the pre-
planned hospitalization, surgery or procedure 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.
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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.).
8.4.5
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.
8.4.6
Adverse Reactions
All untoward and unintended responses to an investigational medicinal product related 
to any dose administered. This definition covers also medication errors and uses outside 
what is foreseen in the protocol, including overdose, lack of efficacy, misuse and abuse 
of the product.
8.4.7
Adverse Events Related to the Study Drug
An AE is considered related to a study drug/IMP if the Investigator’s assessment of 
causal relationship to the IMP(s) is “Y (yes)” (see Section 8.4.9). 
The Investigator will assess the causal relationship of the IMP(s) to the AE.
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.
8.4.8
Expedited Reporting
The Sponsor is responsible for the appropriate expedited reporting to the Competent 
Authorities, Investigators, and IECs/IRBs according to the current legislation, unless 
otherwise required and documented by the IECs/IRBs.
8.4.9
Assessment of Causal Relationship to the Study Drug
The Investigator must provide an assessment of the causal relationship of each clinical 
trial IMP(s) to each SAE according to the following scale:
Y
There is a reasonable possibility that the IMP(s) caused the SAE.
N
There is no reasonable possibility that the IMP(s) caused the SAE and 
other causes are more probable.
Uk.
(Unknown). Only to be used in special situations where the Investigator 
has insufficient information (i.e., the patient was not seen at his/her 
center) if none of the above can be used.
8.5
ADVERSE EVENTS REPORTING PROCEDURES
8.5.1
Reporting Adverse Events
The Sponsor will collect AEs until 30 days after administration of the last dose of study 
drug(s)/IMP(s) or until the start of a new antitumor therapy, whichever occurs first. All 
AEs suspected to be related to the study drug/IMP must be followed-up after the time of 
therapy discontinuation until the event or its sequelae resolve or stabilize at an 
acceptable level to the Investigator and the Sponsor.
All AEs, including misuse, overdose, abuse and medication error, must be recorded in 
English using medical terminology in the source document and the e-CRF. Whenever 
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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 the Sponsor 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 must only be recorded in the AE 
section of the e-CRF if the disorder:

is associated with clinically significant symptoms, and/or;

represents a reason for change in study dosing or for discontinuation from the 
study treatment, significant additional concomitant drug treatment or other 
therapy, and/or;

leads to any of the outcomes included in the definition of a SAE.

it is considered clinically relevant by the Investigator.
Otherwise, laboratory results should be reported in the corresponding section of the e-
CRF (e.g., biochemistry, hematology).
8.5.2
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/IMP or until the start of a new antitumor 
therapy, whichever occurs first (or until screening failure, if applicable). Beyond this 
period of time, only those SAEs suspected to be related to the IMP will be collected. 
Nonetheless, the Sponsor will evaluate any safety information that is spontaneously 
reported by an Investigator beyond the time frame specified in the protocol.
All SAEs (as defined above) occurred after patient registration regardless of relationship 
to the study drug(s)/IMP(s) must be reported immediately, and always within 24 hours 
to the Pharma Mar S.A. Pharmacovigilance Department, electronically by completing 
the applicable e-CRF section.
SAEs occurring during the screening phase, SAEs that may occur off-study, or in case 
the electronic system fails or is not available,  will be reported within 24 hours to the 
Pharmacovigilance Department using the paper SAE form by fax (+34 91 846 6004), e-
mail (phv@pharmamar.com) or telephone (+34 91 823 4633). 
Out of office hours [Greenwich Meridian Time (GMT)], assistance on SAE reporting 
can be obtained by calling the Pharmacovigilance Department at +34 681 263 592. 
SAEs initially reported by alternative methods (not electronically), must be followed by 
a completed electronic SAE reporting on e-CRF from the investigational staff within 
one working day.
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.
8.5.3
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.
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Therefore, pregnancy and suspected pregnancy (including a positive pregnancy test 
regardless of age or disease state) of a female patient or the female partner of a male 
patient occurring while the patient is on study drug, or within six months in female 
patients and within four months in male patients after the last study drug administration, 
are considered immediately reportable events.
The Investigator will report the following events immediately and always within 24 
hours from first knowledge:

Any occurrence of a pregnancy where any kind of exposure to the 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 IMPs).

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 
Sponsor Pharmacovigilance immediately by facsimile using the Pregnancy Report form. 
In the case of pregnancy of the female partner of a trial patient, the Investigator will 
obtain her informed consent to provide the information by using the applicable form 
provided by the Sponsor who will also advise the Investigator in these situations.
The Investigator will follow the pregnancy until its outcome, and must notify 
PharmaMar Pharmacovigilance of the outcome of the pregnancy within 24 hours of first 
knowledge as a follow-up to the initial report.
For any event during the pregnancy which meets a seriousness criterion (including fetal 
or neonatal death or congenital anomaly) the Investigator will also follow the 
procedures for reporting SAEs (complete and send the SAE form to PharmaMar 
Pharmacovigilance by facsimile within 24 hours of the Investigator’s knowledge of the 
event). 
All neonatal deaths that occur within 30 days of birth should be reported, without regard 
to causality, as SAEs. In addition, any infant death at any time thereafter that the 
Investigator suspects is related to the exposure to the study drug(s)/IMP(s) should also 
be reported to PharmaMar Pharmacovigilance by facsimile within 24 hours of the 
Investigators’ knowledge of the event.
8.5.4
Adverse Events Monitoring
Safety review will be performed by the Sponsor once SAE forms have been received 
electronically or by fax and the e-CRFs have been electronically completed by the 
Investigator. 
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 Sponsor study team. The personnel in charge of this process are 
listed in the Study Contacts section of this protocol. In general, the clinical oncologist 
medical monitor together with the PharmaMar 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 Pharmacovigilance Department 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. 
At every monitoring visit the consistency between the e-CRF/SAE data reported to the 
Pharmacovigilance Department and the patient's source data will be reviewed. When a 
discrepancy is found, data in the e-CRF and the SAE form/information will be 
amended/updated and reported to the Pharmacovigilance department (when applicable), 
according to source data.
9.
STATISTICAL METHODS
9.1
PRIMARY ENDPOINT
Progression-free survival rate at 12 weeks (PFS3), defined as the rate estimate of the 
percentage of patients who are alive and progression-free at 12 weeks (~3 months) 
after the first treatment administration.
9.2
SECONDARY ENDPOINTS
Overall Survival (OS), defined as the time from the first day of treatment to the date 
of death or last contact.
Progression-free Survival (PFS), defined as the time from the first day of study 
treatment to the day of assessment of progression, death or last tumor evaluation.
Overall Response Rate (ORR), defined as the percentage of patients with objective 
response (OR), either complete response (CR) or partial response (PR) according to 
the RECIST v.1.1.
Duration of Response (DOR), defined as the time between the date when response 
criteria (PR or CR, the first to be reached) are fulfilled and the first date when PD, 
recurrence or death is objectively documented.
Treatment safety, including AEs, SAEs, and laboratory abnormalities graded 
according to NCI-CTCAE v.4. Dose reductions or delays required due to treatment-
related AEs, and reasons for treatment discontinuations will also be analyzed.
Profiles of peripheral neuropathy and quality of life as reported by patients using 
the EORTC QLQ-CIPN20 and QLQ-C30.
Pharmacokinetics (PK) parameters will be evaluated in plasma by population PK 
modeling and/or standard non-compartmental analysis.
Metabolomics of PM060184, i.e., intra- and inter-patient systemic variations in the 
patient’s pretreatment metabolic profile.
Pharmacogenetics (PGt) of PM060184 will be evaluated to identify the presence or 
absence of germline mutations or polymorphisms that may help explain individual 
variability in the main PK parameters and safety outcomes.
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Pharmacogenomics (PGx) of PM060184
will be evaluated to determine 
predictive/prognostic markers of response and/or resistance to PM060184 
(including BRAF-mutant-like gene expression subtypes).
9.3
SAMPLE SIZE
Patients will be treated with PM060184 to test the null hypothesis (H0) that 30% or less 
patients are alive and free of progression at twelve weeks (PFS3) according to RECIST 
v.1.1 (p ≤ 0.30) versus the alternative hypothesis (H1) that 50% or more patients are 
alive and free of progression at 12 weeks according to the aforementioned criteria (p ≥ 
0.50). The variance of the standardized test is based on the null hypothesis. The type I 
error (alpha) associated with this one-sided test is 0.025 and the type II error (beta) is 
0.1; hence, statistical power is 90%. 
Sixty evaluable patients are necessary to test the hypothesis. A futility analysis using 
O’Brien-Fleming boundaries is planned when 24 patients can be evaluated (first stage). 
If there are seven or more patients achieving PFS3 in the first stage then the trial will 
proceed to a second stage and a total of 60 patients will be recruited.
If at least 25 of 60 evaluable patients are alive and free of progression at 12 weeks then 
the null hypothesis can be rejected and PM060184 considered active and deserving 
potential development in this setting.
9.4
STATISTICAL ANALYSIS
Frequency tables will be prepared for categorical variables and summary tables, 
including median, mean, standard deviation, minimum, and maximum values for each 
variable, will be used for continuous variables. Exploratory comparisons will be 
performed at a 0.05 level. Other analyses will include: number of prior treatment lines, 
prior oxaliplatin exposure, KRAS status, BRAF-like expression, and other 
prognostic/predictive factors.
9.5
EFFICACY ANALYSIS
The exact binomial estimator and its 95% confidence interval (CI) will be used for the 
primary endpoint (PFS3) and categorical variables (i.e., ORR). Time-to-event variables 
(DOR, PFS and OS) and their fixed time estimates will be analyzed according to the 
Kaplan-Meier method. For categorical variables, comparisons will be carried out by a 
Fisher exact test and a multivariate analysis by logistic regression. For time-to-event 
variables, comparisons will be carried out by a log-rank test and by a Cox regression 
analysis. No formal conclusions will be expected on these grounds.
9.6
SAFETY ANALYSIS
Safety analyses will consider AEs and SAEs, according to their relationship with study 
treatment, as well as analytical results, deaths and the reasons for treatment 
discontinuations, delays and/or dose reductions. All AEs and SAEs will be graded 
according to NCI-CTCAE v.4., and they will be coded using the MedDRA.
9.7
PATIENT REPORTED OUTCOMES
PRO analysis will be performed on summary measures and longitudinal modelling of 
patients’ QLQ responses. QoL and PN will be evaluated by changes in the EORTC 
QLQ-CIPN20 and QLQ-C30 scores over time and tested for statistical significance by 
means of repeat-measure analyses of variance. The scores will be compared at the pre-
specified time points using a T-test for related samples to establish differences, if any, 
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between pairs of assessments. A p-value of < 0.05 is considered statistically significant
for the exploratory comparisons.
9.8
PHARMACOKINETICS ANALYSIS
Pharmacokinetic data will be listed in the population PK-report for all patients with 
available concentrations of PM060184. Patients will be excluded from the PK analysis 
if their data do not allow for accurate assessment of the PK (e.g. improper handling of 
PK samples, incomplete administration of the study agent, missing time or dosing 
information). All concentrations below the lowest quantifiable concentration or 
missing data will be labeled as such in the concentration data presentation. All patients 
and samples excluded from the analysis will be retained in the data set, but they will be 
flagged out and the criteria for the exclusion documented.
Population PK analysis of plasma concentration-time data of PM060184 will be 
performed using non-linear mixed-effects modeling. Data may be combined with those 
of a selection of phase I and II studies to support a relevant structural model. Available 
patient characteristics (demographics, laboratory variables, genotypes, etc.) will be 
tested as potential covariates affecting PK parameters. Details will be given in a 
population PK analysis plan and the results of the population PK analysis will be 
presented in a separate report.
Pharmacokinetic analysis will be the responsibility of the Sponsor and will be 
performed in accordance with the current guidelines on population pharmacokinetics 
analyses. Clearance and volume of distribution will be the primary parameters of 
interest for the population PK analysis. Additional PK parameters will be calculated, if 
deemed appropriate.
Non-compartmental PK analysis may also be used instead of or in addition to 
population PK analysis.
Plasma samples will be analyzed to determine concentrations of PM060184 using a 
validated, specific, and sensory liquid chromatography/mass spectrometry/mass 
spectrometry (LC-MS/MS) method by or under the supervision of the Sponsor.
9.9
METABOLOMICS (BIOMARKERS) ANALYSIS
Patients’ pretreatment metabolic profile will be evaluated to search for systematic 
variations that may serve as biomarkers of PK, safety and/or efficacy response to 
treatment with PM060184. Systematic variations in the metabolic profile will be 
compared among patients with differences in any of these responses. Particular attention 
will be given to specific metabolic patterns observed in patients who develop PN 
associated with PM060184. 
Metabolite extraction will be accomplished by fractionating the serum sample (19). 
Briefly, an ultra performance liquid chromatography (UPLC)-single quadrupole-MS 
amino acid analysis system will be combined with two separate UPLC-time-of-flight-
MS based platforms analyzing methanol and chloroform/methanol serum extracts. 
Data will be processed using the TargetLynx application manager for MassLynx 4.1 
software (Waters Corp., Milford, USA). A set of predefined retention time and mass-to-
charge ratio pairs (Rt-m/z), corresponding to metabolites included in the analysis will be 
fed into the program. Normalization factors will be calculated for each metabolite (20).
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The metabolomics data analysis will include univariate and multivariate data analysis, 
with pathway mapping tools and visualization capacities to facilitate result 
interpretation.
Principal component analysis (PCA; non-supervised) and orthogonal partial least-
squares to latent structures (OPLS; supervised) multivariate methods will be used to 
reduce the dimensionality of the complex data set to enable easy visualization of any 
metabolic clustering in samples from patients sharing a common outcome.
Among univariate data analysis, a Shapiro-Wilk test (to test the normality of data), a 
Student’s t-test and a Wilcoxon signed-rank test, an analysis of variance (ANOVA) 
and a Tukey’s HSD (Honestly Significant Difference) post hoc test will be used.
9.10 PHARMACOGENETICS ANALYSIS
In order to explore factors that may help explain individual variability in the main PK 
parameters and safety outcomes, the presence or absence of germline mutations or 
polymorphisms will be analyzed in leukocyte DNA extracted from a blood sample 
obtained preferably before treatment start (along with PK sample #1 and the first 
metabolomics sample of Cycle 1). The influence of known polymorphisms on main PK 
parameters or safety outcomes will be assessed by a Student’s test or a Mann-Whitney’s 
U test as appropriate.
9.11 PHARMACOGENOMICS ANALYSIS
The analysis of potential predictive factors to PM060184 treatment will be analyzed in
paraffin-embedded tumor tissue samples from patients participating in the substudy. 
These factors will include, among others, tubulin isotypes and other factors related to 
the mechanism of action of PM060184 and to the tumor microenvironment (such as 
angiogenic factors, and markers of lymphocyte subpopulations and tumor associated 
macrophages), and their expression will be analyzed at the protein level and/or mRNA 
level by IHC or quantitative PCR, respectively; their polymorphisms and mutations 
might also be analyzed, if relevant. 
BRAF-mutant-like gene expression subtypes (and potentially full genome expression) 
will be determined to show potential correlation with response or outcome after 
treatment with PM060184.
At final study analysis—and if feasible according to overall efficacy and to the number 
of patients with available biopsy—the subgroup characteristics will be statistically 
analyzed for correlation with the study efficacy parameters: PFS, ORR, DOR, and OS.
These analyses will include the use of molecular biology techniques to identify and 
validate PGx markers from pretreatment tumor samples. The basal expression levels of 
these markers will be correlated with the patient’s outcome data. In addition, the 
experimental data will be analyzed with respect to duration of response and time to 
disease progression. 
Analysis of RNA/protein expression, polymorphisms and mutations will be performed 
blind, and clinical data compiled only after all analyses are completed. A Fisher’s 
exact test/logistic regression for categorical variables and log rank test/Cox regression 
for time to event variables will be used to test whether a specific profile is associated 
with clinical outcome after treatment with PM060184. The prognosis value of markers 
will be explored for objective clinical response, PFS and OS. In each case, if 
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applicable, a multivariate model will be developed by stepwise selection. All tests of 
statistical significance will be two-sided, and significance will be set at 0.05.
10. ADMINISTRATIVE SECTION
10.1
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 
(Appendix 5) and will be consistent with GCP guidelines and pertinent regulatory 
requirements.
The study personnel involved in conducting this trial will be qualified by education, 
training and experience to perform their respective task(s).
The study will be conducted in compliance with the protocol. The protocol, any 
amendments and the patient informed consent will receive IEC/IRB approval/favorable 
opinion prior to initiation, according to pertinent regulations.
The decision of the IEC/IRB concerning the conduct of the study will be made in 
writing to the Investigators, and a copy of this decision will be provided to the Sponsor 
before the beginning of the study.
The Investigator and/or the Sponsor is/are responsible for keeping the IEC/IRB
informed of any significant new information about the study drug.
All protocol amendments will be agreed upon by the Sponsor and the Investigator.
Administrative changes of the protocol are minor corrections and/or clarifications that 
have no impact on the way the study is to be conducted.
10.2
MONITORING, AUDITING AND INSPECTING
The study will be monitored by regular site visits and telephone calls to the Investigator 
by the clinical trial monitor designated by the Sponsor.
During site visits, the trial monitor should revise original patient records, drug 
accountability records and document retention (study file). Additionally, the trial 
monitor should observe study procedures and will discuss any problems with the 
Investigator.
Adequate time for these visits should be allocated by the Investigator. The Investigator 
should also ensure that the monitor is given direct access (as per International 
Conference on Harmonization [ICH] Topic E6 Guideline for Good Clinical Practice, 
Sections 4.9.7 and 6.10) to source documents (i.e., hospital or private charts, original 
laboratory records, appointment books, etc.) of the patient which support data entered in 
the CRFs, 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 Sponsor’s Clinical Quality Assurance department or 
designee may conduct an onsite audit (ICH Topic E6 Guideline for GCP, Section 1.6).
Participation in this trial implies acceptance of potential inspection by national or 
foreign Competent Authorities.
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10.3
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 process will include all elements required by ICH, GCP and 
applicable regulatory requirements.
Prior to registration in the trial, the Investigator or a person designated by the 
Investigator, must provide the patient with one copy of the ICF. This copy must provide 
written full information about the clinical trial, 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; 
then, the ICF must be freely signed and personally dated by the patient and by the 
person who conducted the informed consent discussion before the beginning of the 
study. The patient should receive a copy of the signed ICF and any other written 
information provided to study patients prior to participation in the trial. Participation in 
the substudy requires separate consent.
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.
10.4
CONFIDENTIALITY/IDENTIFICATION OF PATIENTS
The collection and processing of personal data from the patients enrolled in this clinical 
trial will be limited to those data that are necessary to investigate the efficacy, safety, 
quality and usefulness of the study drug used in this trial.
It is the Investigator’s responsibility that sufficient information on the identity of the 
patients 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.
The Sponsor 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.
10.5
ELECTRONIC CASE REPORT FORMS
Electronic 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 e-CRFs are timely, 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.
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A patient’s source documentation is the patient’s records (included but not limited to 
physician/hospital notes, nurses notes, IMP preparation records including reconstitution 
and dilution, IMP administration records, QLQs, etc.) and as such, they should be 
maintained at the study site.
Data collected in the e-CRF will be entered into the Sponsor’s databases, which comply 
with the Spanish Act implementing the Directive 95/46/EC of the European Parliament 
and of the Council of 24 October 1995 on the protection of individuals with regard to
the processing of personal data. 
Baseline and off-study visit should be completed for patients registered but never 
treated.
10.6
INSURANCE
The Sponsor will provide insurance or indemnity in accordance with applicable 
regulatory requirements.
10.7
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.
10.8
USE OF INFORMATION AND PUBLICATIONS
Before the Investigators of this study submit a paper or abstract for publication or 
otherwise publicly disclose information concerning the study drug or products, the 
Sponsor must be provided with at least 60 days to revise and approve the proposed 
publication or disclosure to ensure that confidential and proprietary data are protected.
If the Sponsor 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 personnel from the Sponsor who have fully participated in the study 
must be considered for co-authorship of the publication.
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11. REFERENCES
1.
CANCER 
FACT 
SHEETS: 
COLORECTAL 
CANCER 
http://gco.iarc.fr/today/home:
International Agency for Research on Cancer (World Health Organization);  [Data Source: GLOBOCAN 
2012]. Available from: http://gco.iarc.fr/today/fact-sheets-cancers?cancer=6&type=0&sex=0.
2.
Ferlay J, Steliarova-Foucher E, Lortet-Tieulent J, Rosso S, Coebergh JW, Comber H, et al. 
Cancer incidence and mortality patterns in Europe: estimates for 40 countries in 2012. Eur J Cancer. 
2013;49(6):1374-403.
3.
Howlader N, Noone A, Krapcho M, Miller D, Bishop K, Altekruse S, et al. SEER Cancer 
Statistics Factsheets: Colon and Rectum Cancer: National Cancer Institute. Bethesda, MD; 2016 
[Available from: http://seer.cancer.gov/statfacts/html/colorect.html.
4.
Karapetis CS, Khambata-Ford S, Jonker DJ, O'Callaghan CJ, Tu D, Tebbutt NC, et al. K-ras 
mutations and benefit from cetuximab in advanced colorectal cancer. The New England journal of 
medicine. 2008;359(17):1757-65.
5.
Shi Q, de Gramont A, Grothey A, Zalcberg J, Chibaudel B, Schmoll HJ, et al. Individual patient 
data analysis of progression-free survival versus overall survival as a first-line end point for metastatic 
colorectal cancer in modern randomized trials: findings from the analysis and research in cancers of the 
digestive system database. Journal of clinical oncology : official journal of the American Society of 
Clinical Oncology. 2015;33(1):22-8.
6.
Stein A, Bokemeyer C. How to select the optimal treatment for first line metastatic colorectal 
cancer. World journal of gastroenterology : WJG. 2014;20(4):899-907.
7.
Van Cutsem E, Nordlinger B, Cervantes A. Advanced colorectal cancer: ESMO Clinical Practice 
Guidelines for treatment. Annals of oncology : official journal of the European Society for Medical 
Oncology / ESMO. 2010;21 Suppl 5:v93-7.
8.
Prota AE, Bargsten K, Diaz JF, Marsh M, Cuevas C, Liniger M, et al. A new tubulin-binding site 
and pharmacophore for microtubule-destabilizing anticancer drugs. Proceedings of the National Academy 
of Sciences of the United States of America. 2014;111(38):13817-21.
9.
Martinez-Diez M, Martinez-Leal JF, Garcia-Fernandez LF, Galmarini CM. Mode of action of 
PM060184, a new interfacial microtubule inhibitor of marine origin. Proc NCI-AACR-EORTC Molecular 
Targets and Cancer Therapeutics, Boston, 2013; A177.
10.
Aviles PM, Guillen MJ, Palomares M, Nuñez P, Martinez-Diez M, Martinez-Leal JF, et al. The 
new marine derived tubulin binding agent PM060184 shows potent antitumor activity in vivo against 
multidrug resistant, Pgp expressing tumors. Proc NCI-AACR-EORTC Molecular Targets and Cancer 
Therapeutics, Boston, 2013; A173.
11.
Spratlin JL, Serkova NJ, Eckhardt SG. Clinical applications of metabolomics in oncology: a 
review. Clinical cancer research : an official journal of the American Association for Cancer Research. 
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12.
Chung YL, Griffiths JR. Using metabolomics to monitor anticancer drugs. Ernst Schering 
Foundation symposium proceedings. 2007(4):55-78.
13.
Rath S, Liebl J, Furst R, Ullrich A, Burkhart JL, Kazmaier U, et al. Anti-angiogenic effects of 
the tubulysin precursor pretubulysin and of simplified pretubulysin derivatives. British journal of 
pharmacology. 2012;167(5):1048-61.
14.
Funahashi Y, Okamoto K, Adachi Y, Semba T, Uesugi M, Ozawa Y, et al. Eribulin mesylate 
reduces tumor microenvironment abnormality by vascular remodeling in preclinical human breast cancer 
models. Cancer science. 2014;105(10):1334-42.
15.
Popovici V, Budinska E, Tejpar S, Weinrich S, Estrella H, Hodgson G, et al. Identification of a 
poor-prognosis BRAF-mutant-like population of patients with colon cancer. Journal of clinical oncology : 
official journal of the American Society of Clinical Oncology. 2012;30(12):1288-95.
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16.
Vecchione L, Gambino V, Raaijmakers J, Schlicker A, Fumagalli A, Russo M, et al. A 
Vulnerability of a Subset of Colon Cancers with Potential Clinical Utility. Cell. 2016;165(2):317-30.
17.
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response 
evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 
2009;45(2):228-47.
18.
Brindle JM, Trindade AA, Shah AP, Jokisch DW, Patton PW, Pichardo JC, et al. Linear 
regression model for predicting patient-specific total skeletal spongiosa volume for use in molecular 
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2006;47(11):1875-83.
19.
Barr J, Caballeria J, Martinez-Arranz I, Dominguez-Diez A, Alonso C, Muntane J, et al. 
Obesity-dependent metabolic signatures associated with nonalcoholic fatty liver disease progression. 
Journal of proteome research. 2012;11(4):2521-32.
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Martinez-Arranz I, Mayo R, Perez-Cormenzana M, Minchole I, Salazar L, Alonso C, et al. 
Enhancing metabolomics research through data mining. Journal of proteomics. 2015.
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12. 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-GAULT FORMULA
For Calculated Creatinine Clearance
CrCL (mL/min) =
(140 −Age) × Weight (kg)
72 × Creatinine !(mg dL
⁄
) × 0.85 if female
Cockcroft D.W., Gault M.H. Prediction of Creatinine Clearance from Serum Creatinine. Nephron 
1976;16:31–41 (DOI:10.1159/000180580)
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Appendix 3. CONTRACEPTION AND PREGNANCY TESTING
This document is based on the Heads of Medicines Agencies’ Recommendations Related 
to Contraception and Pregnancy Testing in Clinical Trials, published by the Clinical 
Trial Facilitation Group (CTFG) on 15 September 2014
and available at 
http://www.hma.eu/ctfg.html (accessed 1 September 2016) 
A woman is considered of childbearing potential (WOCBP) following menarche and 
until becoming post-menopausal unless permanently sterile. Permanent sterilization 
methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. A 
postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal 
range may be used to confirm a post-menopausal state in women not using hormonal 
contraception or hormonal replacement therapy. However, in the absence of 12 months 
of amenorrhea, a single FSH measurement is insufficient. Immediately after detecting a 
case of suspected pregnancy in a patient, the decision on her continued participation in 
the clinical trial will be jointly taken by the patient, the Investigator and the Sponsor, 
with the patient’s best interest in mind. A decision to continue the pregnancy will 
require immediate discontinuation any investigational medicinal product (IMP). 
A man is considered fertile after puberty unless permanently sterile by bilateral 
orchidectomy. Fertile male patients included in this study should refrain from fathering 
a child or donating sperm during the study and for four months following the last IMP 
dose. If they have WOCBP partners the male subject should use condom during 
treatment and for four months following the last IMP dose.
Highly effective birth control methods are:
1.
Combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation 1:
a.
oral
b.
intravaginal 
c.
transdermal 
2.
Progestogen-only hormonal contraception associated with inhibition of ovulation 1: 
a.
oral 
b.
injectable
c.
implantable 2
3.
Intrauterine device (IUD) 2
4.
Intrauterine hormone-releasing system (IUS) 2
5.
Bilateral tubal occlusion 2
6.
Vasectomized partner 2,3
7.
Sexual abstinence 4
8.
A combination of male condom with either cap, diaphragm or sponge with spermicide 
(double barrier methods) are also considered acceptable, but not highly effective, birth 
control methods.
1 Hormonal contraception may be susceptible to interaction with the IMP, which may 
reduce the efficacy of the contraception method (see below).
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2 Contraception methods that are considered to have low user dependency. 
3 Vasectomized partner is a highly effective birth control method provided that partner is the 
sole sexual partner of the WOCBP trial participant and that the vasectomized partner has 
received medical assessment of the surgical success. 
4 Sexual abstinence is considered a highly effective method only if defined as refraining 
from heterosexual intercourse during the entire period of risk associated with the study 
treatments. The reliability of sexual abstinence needs to be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the subject. Periodic 
abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus 
interruptus), spermicides only, and lactational amenorrhea method (LAM) are not 
acceptable methods of contraception. Female condom and male condom should not be used 
together.
Contraception methods with low user dependency should preferably be used, in 
particular when contraception is introduced as a result of participation in this trial. It 
cannot be excluded that the IMP may reduce exposure to substrates of CYP3A 
through enzyme induction; the efficacy of hormonal contraceptives may be reduced 
if co-administered with the IMP.
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Appendix 4. 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.
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.
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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, 
sirolimus, tolvaptan, tipranavir, triazolam, vardenafil
Alfentanil, astemizole, (7) 
cisapride, (7) cyclosporine, 
dihydroergotamine, ergotamine, 
fentanyl, pimozide, quinidine, 
sirolimus, tacrolimus,
terfenadine(7)
CYP2D6
Atomoxetine, desipramine,
dextromethorphan, metoprolol,
nebivolol, perphenazine, tolterodine,
venlafaxine
Thioridazine
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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 5. DECLARATION OF HELSINKI
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964 and amended by the:
29th WMA General Assembly, Tokyo, Japan, October 1975
35th WMA General Assembly, Venice, Italy, October 1983
41st WMA General Assembly, Hong Kong, September 1989
48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996
52nd WMA General Assembly, Edinburgh, Scotland, October 2000
53rd WMA General Assembly, Washington DC, USA, October 2002 (Note of Clarification added)
55th WMA General Assembly, Tokyo, Japan, October 2004 (Note of Clarification added)
59th WMA General Assembly, Seoul, Republic of Korea, October 2008
64th WMA General Assembly, Fortaleza, Brazil, October 2013
Preamble
1.
The World Medical Association (WMA) has developed the Declaration of Helsinki as a 
statement of ethical principles for medical research involving human subjects, including 
research on identifiable human material and data.
The Declaration is intended to be read as a whole and each of its constituent paragraphs 
should be applied with consideration of all other relevant paragraphs.
2.
Consistent with the mandate of the WMA, the Declaration is addressed primarily to 
physicians. The WMA encourages others who are involved in medical research 
involving human subjects to adopt these principles.
General Principles
3.
The Declaration of Geneva of the WMA binds the physician with the words, “The 
health of my patient will be my first consideration,” and the International Code of 
Medical Ethics declares that, “A physician shall act in the patient's best interest when 
providing medical care.”
4.
It is the duty of the physician to promote and safeguard the health, well-being and rights 
of patients, including those who are involved in medical research. The physician's 
knowledge and conscience are dedicated to the fulfilment of this duty.
5.
Medical progress is based on research that ultimately must include studies involving 
human subjects.
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.
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12.
Medical research involving human subjects must be conducted only by individuals with 
the appropriate ethics and scientific education, training and qualifications. Research on 
patients or healthy volunteers requires the supervision of a competent and appropriately 
qualified physician or other health care professional.
13.
Groups that are underrepresented in medical research should be provided appropriate 
access to participation in research.
14.
Physicians who combine medical research with medical care should involve their 
patients in research only to the extent that this is justified by its potential preventive, 
diagnostic or therapeutic value and if the physician has good reason to believe that 
participation in the research study will not adversely affect the health of the patients 
who serve as research subjects.
15.
Appropriate compensation and treatment for subjects who are harmed as a result of 
participating in research must be ensured.
Risks, Burdens and Benefits
16.
In medical practice and in medical research, most interventions involve risks and 
burdens.
Medical research involving human subjects may only be conducted if the importance of 
the objective outweighs the risks and burdens to the research subjects.
17.
All medical research involving human subjects must be preceded by careful assessment 
of predictable risks and burdens to the individuals and groups involved in the research 
in comparison with foreseeable benefits to them and to other individuals or groups 
affected by the condition under investigation.
Measures to minimise the risks must be implemented. The risks must be continuously 
monitored, assessed and documented by the researcher.
18.
Physicians may not be involved in a research study involving human subjects unless 
they are confident that the risks have been adequately assessed and can be satisfactorily 
managed.
When the risks are found to outweigh the potential benefits or when there is conclusive 
proof of definitive outcomes, physicians must assess whether to continue, modify or 
immediately stop the study. 
Vulnerable Groups and Individuals
19.
Some groups and individuals are particularly vulnerable and may have an increased 
likelihood of being wronged or of incurring additional harm.
All vulnerable groups and individuals should receive specifically considered protection.
20.
Medical research with a vulnerable group is only justified if the research is responsive 
to the health needs or priorities of this group and the research cannot be carried out in a 
non-vulnerable group. In addition, this group should stand to benefit from the 
knowledge, practices or interventions that result from the research.
Scientific Requirements and Research Protocols
21.
Medical research involving human subjects must conform to generally accepted 
scientific principles, be based on a thorough knowledge of the scientific literature, other 
relevant sources of information, and adequate laboratory and, as appropriate, animal 
experimentation. The welfare of animals used for research must be respected.
22.
The design and performance of each research study involving human subjects must be 
clearly described and justified in a research protocol.
The protocol should contain a statement of the ethical considerations involved and 
should indicate how the principles in this Declaration have been addressed. The 
protocol should include information regarding funding, sponsors, institutional 
affiliations, potential conflicts of interest, incentives for subjects and information 
regarding provisions for treating and/or compensating subjects who are harmed as a 
consequence of participation in the research study.
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In clinical trials, the protocol must also describe appropriate arrangements for post-trial 
provisions.
Research Ethics Committees
23.
The research protocol must be submitted for consideration, comment, guidance and
approval to the concerned research ethics committee before the study begins. This 
committee must be transparent in its functioning, must be independent of the researcher, 
the sponsor and any other undue influence and must be duly qualified. It must take into 
consideration the laws and regulations of the country or countries in which the research 
is to be performed as well as applicable international norms and standards but these 
must not be allowed to reduce or eliminate any of the protections for research subjects 
set forth in this Declaration.
The committee must have the right to monitor ongoing studies. The researcher must 
provide monitoring information to the committee, especially information about any 
serious adverse events. No amendment to the protocol may be made without 
consideration and approval by the committee. After the end of the study, the researchers 
must submit a final report to the committee containing a summary of the study’s 
findings and conclusions.
Privacy and Confidentiality
24.
Every precaution must be taken to protect the privacy of research subjects and the 
confidentiality of their personal information.
Informed Consent
25.
Participation by individuals capable of giving informed consent as subjects in medical 
research must be voluntary. Although it may be appropriate to consult family members 
or community leaders, no individual capable of giving informed consent may be 
enrolled in a research study unless he or she freely agrees.
26.
In medical research involving human subjects capable of giving informed consent, each 
potential subject must be adequately informed of the aims, methods, sources of funding, 
any possible conflicts of interest, institutional affiliations of the researcher, the 
anticipated benefits and potential risks of the study and the discomfort it may entail, 
post-study provisions and any other relevant aspects of the study. The potential subject 
must be informed of the right to refuse to participate in the study or to withdraw consent 
to participate at any time without reprisal. Special attention should be given to the 
specific information needs of individual potential subjects as well as to the methods 
used to deliver the information.
After ensuring that the potential subject has understood the information, the 
physician or another appropriately qualified individual must then seek the 
potential subject’s freely-given informed consent, preferably in writing. If the 
consent cannot be expressed in writing, the non-written consent must be 
formally documented and witnessed.
  
All medical research subjects should be given the option of being informed 
about the general outcome and results of the study.
27.
When seeking informed consent for participation in a research study the physician must 
be particularly cautious if the potential subject is in a dependent relationship with the 
physician or may consent under duress. In such situations the informed consent must be 
sought by an appropriately qualified individual who is completely independent of this 
relationship.
28.
For a potential research subject who is incapable of giving informed consent, the 
physician must seek informed consent from the legally authorised representative. These 
individuals must not be included in a research study that has no likelihood of benefit for 
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them unless it is intended to promote the health of the group represented by the potential 
subject, the research cannot instead be performed with persons capable of providing 
informed consent, and the research entails only minimal risk and minimal burden.
29.
When a potential research subject who is deemed incapable of giving informed consent 
is able to give assent to decisions about participation in research, the physician must 
seek that assent in addition to the consent of the legally authorised representative. The 
potential subject’s dissent should be respected.
30.
Research involving subjects who are physically or mentally incapable of giving consent, 
for example, unconscious patients, may be done only if the physical or mental condition 
that prevents giving informed consent is a necessary characteristic of the 
research group. In such circumstances the physician must seek informed consent from 
the legally authorised representative. If no such representative is available and if the 
research cannot be delayed, the study may proceed without informed consent provided 
that the specific reasons for involving subjects with a condition that renders them unable 
to give informed consent have been stated in the research protocol and the study has 
been approved by a research ethics committee. Consent to remain in the research must 
be obtained as soon as possible from the subject or a legally authorised representative.
31.
The physician must fully inform the patient which aspects of their care are related to the 
research. The refusal of a patient to participate in a study or the patient’s decision to 
withdraw from the study must never adversely affect the patient-physician relationship.
32.
For medical research using identifiable human material or data, such as research on 
material or data contained in biobanks or similar repositories, physicians must seek 
informed consent for its collection, storage and/or reuse. There may be exceptional 
situations where consent would be impossible or impracticable to obtain for such 
research. In such situations the research may be done only after consideration and 
approval of a research ethics committee.
Use of Placebo
33.
The benefits, risks, burdens and effectiveness of a new intervention must be tested 
against those of the best proven intervention(s), except in the following circumstances:
Where no proven intervention exists, the use of placebo, or no intervention, is 
acceptable; or
Where for compelling and scientifically sound methodological reasons the use of 
any intervention less effective than the best proven one, the use of placebo, or no 
intervention is necessary to determine the efficacy or safety of an intervention
and the patients who receive any intervention less effective than the best proven 
one, placebo, or no intervention will not be subject to additional risks of serious 
or irreversible harm as a result of not receiving the best proven intervention.
Extreme care must be taken to avoid abuse of this option.
Post-Trial Provisions
34.
In advance of a clinical trial, sponsors, researchers and host country governments should 
make provisions for post-trial access for all participants who still need an intervention 
identified as beneficial in the trial. This information must also be disclosed to 
participants during the informed consent process.
Research Registration and Publication and Dissemination of Results
35.
Every research study involving human subjects must be registered in a publicly 
accessible database before recruitment of the first subject.
36.
Researchers, authors, sponsors, editors and publishers all have ethical obligations with 
regard to the publication and dissemination of the results of research. Researchers have 
a duty to make publicly available the results of their research on human subjects and are 
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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.
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SAP_001.pdf: 
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SAP PM60184-B-002-17
PM60184-B-002-17
Phase II, Open-label, Multicenter Study of PM060184 in 
Patients with Advanced Colorectal Cancer after 
Standard Treatment
STATISTICAL ANALYSIS PLAN
Version: 1.0
Date: 20-Feb-2018


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2
TABLE OF CONTENTS
ABBREVIATIONS AND GLOSSARY
5
1.
STUDY RATIONALE
7
2.
STUDY DESIGN
7
3.
OBJECTIVES AND ENDPOINTS
8
3.1.
Primary Objective
8
3.2.
Secondary Objectives
8
3.3.
Endpoints
8
4.
PATIENTS EVALUABILITY CRITERIA
9
4.1.
Included Population
10
4.2.
Efficacy Populations
10
4.3.
Safety Population
10
5.
SAMPLE CONSIDERATIONS
10
5.1.
Sample Size
10
5.2.
Early Stopping Rule for Futility
11
6.
STATISTICAL METHODOLOGY FOR EFFICACY
11
6.1.
Planned Analyses and Definitions
11
6.2.
Efficacy Analysis Methods
11
6.2.1.
Primary Endpoint
11
6.2.2.
Secondary Endpoints
12
6.2.2.1.
QoL Analysis Methods
12
7.
STATISTICAL METHODOLOGY FOR SAFETY
13
7.1.
Toxicity and Adverse Events
13
7.2.
Clinical Laboratory Evaluation
14
7.3.
Vital Signs, Physical Examination, Left Ventricular Ejection Fraction and 
Electrocardiogram Findings
14
7.4.
Deaths and Other Serious Adverse Events
14
8.
OTHER ANALYSES
15
8.1.
Patient Disposition and Treatment/Study Discontinuation
15
8.2.
Protocol Deviations
15
8.3.
Baseline and Demographic Data
15
8.4.
Treatment Administration
16
8.5.
Subsequent Therapy
16
8.6.
Pharmacokinetic Analyses
16
8.7.
Pharmacogenetic Analyses
16
8.8.
Pharmacogenomic Analyses
16
8.9.
Metabolomics (Biomarkers)
17
8.10.
Imputation of Incomplete Dates
17
8.11.
Decimal Places
17
8.12.
Subgroup Analyses
17
8.13.
Methods for Handling Missing Data
18
8.14.
First Stage Analysis
18
8.15.
Identification of Fixed or Random Effects Models
18


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8.16.
Data Analysis Conventions
18
9.
STATISTICAL SOFTWARE
19
I.
APPENDIX: TABLES, LISTINGS AND GRAPHS
20
10.
Study Patients
20
10.1.
Patient Disposition
20
10.2.
Discontinuations
21
10.2.1.
Treatment discontinuations
21
10.2.2.
Study discontinuation
22
10.3.
Protocol Deviations
22
11.
Efficacy Evaluation
23
11.1.
Demographic and Other Baseline Characteristics
23
11.1.1.
Patient Characteristics at Baseline
23
11.1.2.
Disease at diagnosis and current disease
23
11.1.3.
Prior Relevant Medical History
25
11.1.4.
Prior Anticancer Therapy
25
11.1.5.
Physical Examination and performance status
26
11.1.6.
Vital signs, Electrocardiogram, LVEF and other tests
27
11.1.7.
Hematological Values at Baseline
28
11.1.8.
Biochemical Values at Baseline
29
11.1.9.
Signs and Symptoms at Baseline
30
11.1.10.
Peripheral Neuropathy
31
11.1.11.
Concomitant Therapy and Procedures at Baseline
31
11.2.
Measurements of Treatment Compliance
32
11.3.
Efficacy Analysis
32
11.3.1.
Primary Analysis
33
11.3.2.
Secondary Analyses
33
11.3.3.
QoL analyses
36
11.3.3.1.
General QoL (QLQ-C30)
36
11.3.3.2.
Chemotherapy-induced Peripheral Neuropathy (QLQ-CIPN20)
38
11.3.4.
Exploratory Analyses
39
11.3.4.1.
Subgroup Analysis
40
12.
Safety Evaluation
45
12.1.
Extent of Exposure
45
12.1.1.
Treatment Administration
45
12.1.2.
Cycle Delays
45
12.1.3.
Dose Omission
47
12.1.4.
Dose Reductions
47
12.1.5.
Temporarily Interrupted Infusions
49
12.1.6.
Prophylactic Medication Administration
49
12.2.
Adverse Events
49
12.2.1.
Display of Adverse Events
50
12.3.
Serious Adverse Events and Deaths
52
12.3.1.
Serious Adverse Events
52
12.3.2.
Deaths
53
12.4.
Clinical Laboratory Evaluation
53
12.4.1.
Hematological Abnormalities During Treatment
53
12.4.2.
Biochemical Abnormalities During Treatment
55


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12.4.3.
Laboratory abnormalities Over Time
56
12.5.
Physical Findings, ECOG PS, LVEF, ECG and Other Tests
57
12.5.1.
Physical Findings and ECOG PS
57
12.5.2.
LVEF, ECG and Other Related Tests
57
12.6.
Concomitant Therapy / Procedures According to the ATC Classification
58
II.
APPENDIX: DATABASE LISTINGS
60
III.
APPENDIX: ICH LISTINGS
61
13.
REFERENCES
62


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ABBREVIATIONS AND GLOSSARY
5-FU
5-fluorouracil
AE
Adverse Event
ALT
Alanine Aminotransferase 
AP
Alkaline Phosphatase 
AST
Aspartate Aminotransferase 
ATC
Anatomical, Therapeutic, Chemical classification system
BSA
Body Surface Area 
BSC
Best Supportive Care 
CI
Confidence Interval 
CIPN
Chemotherapy-induced Peripheral Neuropathy 
CR
Complete Response 
CRC
Colorectal Cancer 
CRF
Case Report Form
d
Day 
DOR
Duration of Response 
ECG
Electrocardiogram 
ECHO
Echocardiography 
ECOG
Eastern Cooperative Oncology Group 
EGFR
Epidermal Growth Factor Receptor 
EORTC
European Organisation for the Research and Treatment of Cancer 
EOT
End of Treatment 
FP
Fluoropyrimidine 
GGT
Gamma-glutamyltransferase 
IC
Informed Consent 
ICH
International Conference on Harmonization 
IMP
Investigational Medicinal Product 
LDH
Lactate Dehydrogenase 
LVEF
Left Ventricular Ejection Fraction 
MedDRA
Medical Dictionary for Regulatory Activities 
min
Minute 
MTI
Microtubule Inhibitor 
MUGA
Multiple-gated Acquisition Scan 
NCI-CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events 
NOS
Not Otherwise Specified
OR
Objective Response
ORR
Overall Response Rate 
OS
Overall Survival 
PD
Progressive Disease 
PFS
Progression-free Survival 
PFS3
Progression-free Survival at 12 weeks (three months) 


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PGt
Pharmacogenetics 
PGx
Pharmacogenomics 
PK
Pharmacokinetics 
PN
Peripheral Neuropathy 
PR
Partial Response 
PRO
Patient Reported Outcomes 
PS
Performance Status 
QLQ
Quality of Life Questionnaire 
QoL
Quality of Life 
RECIST
Response Evaluation Criteria in Solid Tumors 
SAE
Serious Adverse Event 
SD
Stable Disease 
StD
Standard Deviation
VEGF
Vascular Endothelial Growth Factor 
WBC
White Blood Cells 
WHO
World Health Organization


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1. STUDY RATIONALE
Systemic 5-fluorouracil (5-FU)-based chemotherapy produces meaningful improvements in 
median survival and progression-free survival (PFS) compared with best supportive care 
(BSC) alone. These benefits are most pronounced with regimens containing irinotecan or 
oxaliplatin in combination with 5-FU, which represent the mainstay of advanced and 
metastatic colorectal cancer (CRC) chemotherapy.
Consequently, when patients with advanced or metastatic CRC have received prior FP
(Fluoropyrimidine), irinotecan and oxaliplatin-based regimens (in addition to any ad hoc 
therapy targeting EGFR, and/or Vascular Endothelial Growth Factor (VEGF), according to 
tumor characteristics), clinical trials with investigational medicinal products (IMPs) are 
warranted.
PM060184 is a novel microtubule inhibitor (MTI), with a different, specific binding site on
the β-tubulin, that is distinct from the vinca domain used by vinca alkaloids, as well as the 
taxane domain and binding site. PM060184 induces microtubule depolymerization and 
caspase-dependent, as well as non-classical apoptosis pathways. PM060184 has shown in 
vitro and in vivo antitumor activity at nanomolar concentrations in CRC. Thirteen evaluable 
CRC patients were treated with single-agent PM060184 to date and six (46%) had Stable 
Disease (SD) lasting three months or longer with a median PFS of 4.7 months (range, 3.7–
12.8 months).
This trial will evaluate the efficacy of PM060184 in terms of progression-free survival at 12 
weeks (PFS3) in advanced or metastatic CRC patients progressing after standard treatments 
(fluoropyrimidine, irinotecan, and oxaliplatin).
A full rationale for the study may be found in the appropriate sections of the study Clinical 
Protocol.
2. STUDY DESIGN
This is a phase II, multicenter, open-label, study of single-agent PM060184 to evaluate 
efficacy in patients with advanced CRC progressing after standard therapy.
Initially, 24 patients who are evaluable for the primary endpoint will be included and a 
futility analysis will be performed (first stage). If at least seven of these patients achieve 
PFS3, then the study will proceed to a second stage and 36 additional patients will be 
recruited.
An exploratory substudy will address pharmacogenomic and pharmacogenetic objectives. 
All patients who participate in the PM60184-B-002-17 clinical trial will be eligible for the 
substudy if they voluntarily sign a separate informed consent (IC). Refusal to participate in 
the substudy will not affect a patient’s participation in the clinical trial.


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3. OBJECTIVES AND ENDPOINTS
3.1. Primary Objective

To evaluate the efficacy of PM060184 in terms of PFS3 in patients with advanced 
CRC after standard therapy.
3.2. Secondary Objectives

To evaluate OS; PFS; overall response rate (ORR); and duration of response (DOR).

To characterize the safety profile and feasibility of PM060184 in this population.

To describe Peripheral Neuropathy (PN) and quality of life (QoL) profiles in this 
population using patient-reported outcomes (PRO) as measured by the European 
Organization for Research and Treatment of Cancer (EORTC) quality of life 
questionnaires (QLQ) for chemotherapy-induced peripheral neuropathy (QLQ-
CIPN20) and general QoL (QLQ-C30).

To characterize the Pharmacokinetics (PK) of PM060184 in this population.

To characterize the metabolomics of PM060184, i.e. PM060184, i.e., systemic 
variations in the patient’s pre- and post-treatment metabolic profile that allow the 
identification of potential biomarkers of PK, safety and/or efficacy response to 
PM060184.

To characterize pharmacogenetics (PGt) of PM060184 in this population by 
identifying the presence or absence of germline mutations or polymorphisms that may 
help explain individual variability in the main PK parameters and safety outcomes.

To characterize pharmacogenomics (PGx) of PM060184 in this population by 
analyzing the potential predictive factors (including BRAF-mutant-like gene 
expression subtypes) of sensitivity/resistance to PM060184 treatment.
3.3. Endpoints
Primary endpoint:

Progression-free survival rate at twelve weeks, defined as the rate estimate of the 
percentage of patients who are alive and progression-free at 12 weeks (~3 months) 
after the first treatment administration.
Secondary endpoints:
Overall Survival (OS), defined as the time from the first day of treatment to the date of 
death or last contact.
Progression-free Survival (PFS), defined as the time from the first day of study 
treatment to the day of assessment of progression, death or last tumor evaluation.
Overall Response Rate, defined as the percentage of patients with objective response 
(OR), either complete response (CR) or partial response (PR) according to the 
Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1.
Duration of Response, defined as the time between the date when response criteria (PR 
or CR, the first to be reached) are fulfilled and the first date when PD, recurrence or 
death is objectively documented.


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Treatment safety, including Adverse Events (AEs), Serious Adverse Events (SAEs), 
and laboratory abnormalities graded according to National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI-CTCAE) v.4. Dose reductions or delays 
required due to treatment-related AEs, and reasons for treatment discontinuations will 
also be analyzed.
Profiles of peripheral neuropathy and quality of life as reported by patients using the 
EORTC QLQ-CIPN20 and QLQ-C30.
Pharmacokinetics parameters will be evaluated in plasma by population PK modeling 
and/or standard non-compartmental analysis.
Metabolomics of PM060184, i.e., intra- and inter-patient systemic variations in the 
patient’s pre- and post-treatment metabolic profile.
Pharmacogenetics of PM060184 will be evaluated to identify the presence or absence 
of germline mutations or polymorphisms that may help explain individual variability in 
the main PK parameters and safety outcomes.
Pharmacogenomics of PM060184 will be evaluated to determine predictive/prognostic 
markers of response and/or resistance to PM060184 (including BRAF-mutant-like gene 
expression subtypes).
4. PATIENTS EVALUABILITY CRITERIA
Patients with relapsed, metastatic/locally advanced CRC with any KRAS-mutation status 
(wild-type, mutated, or status unknown), progressing after standard treatments 
(fluoropyrimidine, irinotecan, and oxaliplatin).
Patients must fulfill all the eligibility criteria to be eligible to participate in the study.
The study will include the following analysis population set definitions:

“All Included Patients” analysis set is defined as all patients recorded in the 
database who have been included in the trial (excluding screening failures), 
independently of whether they have received the study drug or not.

“All Treated Patients” analysis set is defined as all included patients who have 
received at least one (complete or incomplete) dose of the study drug.

“All Evaluable Patients for Efficacy” analysis set is defined as all eligible patients 
who have at least one complete treatment cycle (or two PM060184 dose 
administrations over two cycles) and have, at least, one disease assessment at Week 
6 and another one at Week 12. In addition, any patient who presents disease 
progression, symptomatic deterioration due to the disease or clinical progression, 
dies due to malignant disease, discontinues treatment due to unmanageable toxicity, 
or dies or discontinues treatment due to a treatment-related AE before evaluation of 
the response at Week 12 will also be considered evaluable for the primary endpoint 
and classified as a non-responder. Patients who have no disease assessment at Week 
6 but remain on treatment and are assessed at Week 12 (or later, and with no 
evidence of disease progression) will be considered evaluable for efficacy. Patients 
who refuse further treatment before Week 12 due to reasons other than related AEs 
not considered unmanageable toxicity will be replaced. 


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
“All Responder Patients” analysis set is defined as all evaluable patients for efficacy
who have had CR or PR as overall best response according to the RECIST v.1.1.

“All Evaluable Quality of Life (QoL)” analysis set is defined as all patients who 
have fulfilled the EORTC-QLQ-C30 and EORTC-QLQ-CPIN20 questionnaires for 
at least two timepoints, one at baseline and at least one after the start of the therapy.
Patients must be replaced if they are considered not evaluable for efficacy for the primary 
endpoint (PFS3), i.e., if they are withdrawn from the study due to significant clinical 
deterioration of unknown reason, hypersensitivity reactions, unrelated AEs without any 
tumor assessments after the start of study treatment, if they refuse further treatment before 
Week 12 due to reasons other than related AEs not considered unmanageable toxicity, if 
they receive less than one complete treatment cycle (at least two PM060184 dose 
administrations over two cycles unless treatment discontinuation was due to unmanageable 
toxicity), or do not have the disease assessment at Week 12 (except in the cases outlined 
above).
4.1. Included Population
The “All included patients” analysis set will be used to show demographic and other 
baseline characteristics.
4.2. Efficacy Populations
The “All evaluable patients for efficacy” analysis set will be used for the primary endpoint 
analysis of PFS3 and secondary endpoint analyses of OS, PFS and ORR.
The secondary endpoint analysis of DOR will be based on the “All responder patients”.
The “All evaluable QoL” set will be used for the secondary endpoint analysis of changes in 
patients QoL.
4.3. Safety Population
The safety analysis will be based on the “All treated patients” analysis set.
5. SAMPLE CONSIDERATIONS
5.1. Sample Size
The primary endpoint of this phase II study is PFS3. Patients will be treated with 
PM060184 to test the null hypothesis (H0) that 30% or less patients are alive and free of 
progression at twelve weeks according to RECIST v.1.1 (p ≤ 0.30) versus the alternative 
hypothesis (H1) that 50% or more patients are alive and free of progression at 12 weeks 
according to the aforementioned criteria (p ≥ 0.50). The variance of the standardized test is 
based on the null hypothesis. The type I error (alpha) associated with this one-sided test is 
0.025 and the type II error (beta) is 0.1; hence, statistical power is 90%. Sixty evaluable 
patients are necessary to test the hypothesis. If at least 25 of 60 evaluable patients are alive 
and free of progression at 12 weeks then the null hypothesis can be rejected and PM060184 
considered active and deserving potential development in this setting.


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5.2. Early Stopping Rule for Futility
A futility analysis using O’Brien-Fleming boundaries is planned when 24 patients can be 
evaluated (first stage). If there are seven or more patients achieving PFS3 in the first stage 
then the trial will proceed to a second stage and a total of 60 patients will be recruited.
6. STATISTICAL METHODOLOGY FOR EFFICACY
Frequency tables will be performed for categorical variables, whereas continuous variables 
will be described by means of summary tables that will include the mean, standard 
deviation (StD), median, minimum, and maximum values of each variable.
For main efficacy results patients included in the first stage will be summarized together 
with patients included in the second stage.
6.1. Planned Analyses and Definitions
Primary endpoint
Progression-free survival rate at 12 weeks, defined as the rate estimate of the percentage 
of patients who are alive and progression-free at 12 weeks (~3 months) after the first 
treatment administration.
Secondary endpoints
The following time-related parameters will be analyzed according to available follow-up 
data:
Overall Survival, defined as the time from the first day of treatment to the date of death 
or last contact.
Progression-free Survival, defined as the time from the first day of study treatment to 
the day of assessment of progression, death or last tumor evaluation.
Overall Response Rate, defined as the percentage of patients with objective response 
(OR), either complete response or partial response according to the RECIST v.1.1.
Duration of Response, defined as the time between the date when response criteria (PR 
or CR, the first to be reached) are fulfilled and the first date when PD, recurrence or 
death is objectively documented.
Profiles of peripheral neuropathy and quality of life as reported by patients using the 
EORTC QLQ-CIPN20 and QLQ-C30.
6.2. Efficacy Analysis Methods
6.2.1. Primary Endpoint
For the evaluation of the primary endpoint (PFS3), the efficacy population and the exact 
binomial estimator (count and percentage) including its 95% confidence interval will be 
used.


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6.2.2. Secondary Endpoints
Time-to-event variables (DOR, PFS and OS) and their fixed time estimates will be 
analyzed according to the Kaplan-Meier method. Kaplan-Meier curves will be plotted.
For categorical variables, comparisons will be carried out by a Fisher exact test and a 
multivariate analysis by logistic regression. For time-to-event variables, comparisons will 
be carried out by a log-rank test and by a Cox regression analysis. No formal conclusions 
will be expected on these grounds. Exploratory comparisons will be performed at a 0.05 
level.
If appropriate, exploratory multivariate models (main effects or including interaction terms) 
will include all prognostic factors/covariates widely reported and recognized by 
oncologists: age, age at diagnosis, baseline ECOG PS (Eastern Cooperative Oncology Group
Performance Status), stage at diagnosis, Tumor primary location: right vs left side tumors; 
sites of metastasis; visceral vs non visceral, body mass index (BMI), body surface area 
(BSA), time from diagnosis to first infusion, time from diagnostic of metastatic disease to 
first infusion, prior advanced treatment lines, last prior therapy PFS, prior oxaliplatin 
exposure, KRAS status, BRAF-like expression, any relevant concomitant medication at 
baseline; 
EORTC-QLQ-C30 
and 
QLQ-CPN20 
score 
at 
baseline 
and 
other 
prognostic/predictive factors determined by the oncologist. The total number of variables 
included in the final model will always be in accordance with the number of events and the 
sample size, thus, whenever possible, no more than one variable per ten events will be 
included. The parameter estimates, hazard ratios and p-values of the variables retained in 
the model will be presented.
A sensitivity analysis for PFS including all treated patients will be performed. Event will be 
defined as progression or death irrespective of the subsequent therapies received for this 
analysis.
Waterfall plots will be used to describe the best variation of the sum of target lesions during 
treatment. Questionnaires scores over time will be described by time series charts, if 
appropriate.
6.2.2.1.
QoL Analysis Methods
Changes in QoL will be followed using the EORTC-QLQ-C30 and EORTC-QLQ-CPIN20 
questionnaires scores over time.

EORTC-QLQ-C30
General QoL will be evaluated through EORTC QLQ-C30. These include 30 items,
which transformation produces five functional scales, three symptom scales, a global 
health status / QoL scale, and six single items.
All of the scales and single-item measures range in score from 0 to 100, using the 
scoring procedures described in the manual (1). A high scale score represents a higher 
response level. Thus, a high score for a functional scale represents a high / healthy 
level of functioning, a high score for the global health status / QoL represents a high 
QoL but a high score for a symptom scale / item represents a high level of 
symptomatology / problems.


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
EORTC-QLQ-CIPN20
Peripheral neuropathy will be evaluated through EORTC QLQ-CIPN20, a 20-item 
quality of life questionnaire for the patients' self-reported neurotoxicity, targeting 
symptoms and patient concerns specifically associated with treatment-induced PN and 
potential activity impairment.
The EORTC QLQ CIPN20 consists of three subscales: sensory scale, motor scale and 
autonomic scale. For all of them, the individual items and the multi-item scale should 
be scored such that higher scores represent more symptoms/problems (i.e., higher score 
= worse).
If forming a scale appears to be justified, then the same algorithm can be used as is 
applied in the scoring manual for the QLQ-C30 for linearly converting items and/or 
scales to 0-100 scales.
The module items will be reported both individually and in the form of mean scores. If item 
mean scores are being presented, the items should first be linearly converted to a 0 to 100 
scale, whilst it will be reported the percentage of patients endorsing each of the response 
categories for the first case. It could be displayed by dichotomize scores also, if 
appropriate, for example by grouping scores into ‘Not at all’ vs. ‘Any extent’.
Finally, QoL and PN will be evaluated by changes in the EORTC QLQ-CIPN20 and QLQ-
C30 scores over time and tested for statistical significance by means of repeat-measure 
analyses of variance. The scores will be compared at the pre-specified time points using a 
T-test for related samples to establish differences, if any, between pairs of assessments. A 
p-value of < 0.05 is considered statistically significant for the exploratory comparisons.
7. STATISTICAL METHODOLOGY FOR SAFETY
Safety analyses will consider AEs and SAEs, according to their relationship with study 
treatment, as well as analytical results, deaths and the reasons for treatment 
discontinuations, delays and/or dose reductions. All AEs and SAEs will be graded 
according to NCI-CTCAE v.4., and they will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA).
Safety profiles will be described by bar charts. If serious toxicities happen, special follow-
up -with descriptive statistics and graphs (boxplots, line plots) - will be made to find out the 
pattern of the event.
7.1. Toxicity and Adverse Events 
All the AEs will be coded using the MedDRA.
The toxicity evaluation will be coded with the NCI-CTCAE v.4. Toxicities will be 
described according to the worst NCI-CTCAE grade.
Summary of overall AEs will be done by System Organ Class (SOC) and Preferred Term
(PT), by severity (worst toxicity grade) and by relationship to the study drug. Tables will be 
sorted by SOC/PT coded with MedDRA.


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A frequency table will be made for the AEs leading to cycle delay, dose reduction or 
withdrawal of study medication. AEs with outcome of death will also be presented by
relationship to the study drugs.
7.2. Clinical Laboratory Evaluation
Laboratory results will be classified according to the NCI-CTCAE v.4. 
The following hematological values (worst grade per patient and per cycle during 
treatment) will be displayed: white blood cells count (WBC), neutrophil count, lymphocyte 
count, platelet count and hemoglobin.
Overall cross tabulation will be presented for the worst grade during treatment vs. the 
baseline toxicity grading of anaemia, lymphopenia, neutropenia, leukopenia and 
thrombocytopenia.
If a grade 3/4 neutropenia or thrombocytopenia increase occurs during a treatment cycle, 
the first day the onset value is reached (counting from the start of the cycle) will be 
tabulated.
Time to recovery of the abnormality (i.e., grade 3/4 neutropenia or thrombocytopenia) will 
be assessed and defined as the time, in days, from the start of the grade 3/4 abnormality 
until the abnormality is recovered (grade ≤ 2). The analysis will be carried out taking into 
account all events, including those that occur in a same cycle. The information will be 
shown by means of median and range.
Likewise, the following biochemical values (worst grade per patient and per cycle during 
treatment) will be displayed: alanine aminotransferase (ALT), aspartate aminotransferase 
(AST), total bilirubin, direct bilirubin, alkaline phosphatase (AP), creatinine, creatinine 
clearance, calcium (corrected by albumin levels), potassium (K), sodium (NA), glucose and 
albumin.
Time to recovery of the abnormality (grade 3/4 AST or ALT) will be assessed and defined 
as the time, in days, from the start of the grade 3/4 abnormality until recovery to grade ≤ 2. 
The analysis will be carried out taking into account all events, including those that occur in 
a same cycle. The information will be shown by means of median and range.
Overall cross tabulation will be presented for the worst grade during treatment vs. the 
baseline toxicity grading of biochemical abnormalities.
7.3. Vital Signs, Physical Examination, Left Ventricular Ejection Fraction and 
Electrocardiogram Findings
Summary tables will be prepared with the performance status, physical examination, body
weight, left ventricular ejection fraction (LVEF) and electrocardiogram (ECG) 
abnormalities at baseline and during the treatment, if appropriate, for each patient.
7.4. Deaths and Other Serious Adverse Events
Deaths and other SAEs will be tabulated following the same pattern than AEs.


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8. OTHER ANALYSES
Continuous variables will be tabulated and presented with summary statistics (i.e., mean, 
StD, median and range). 
Categorical variables will be summarized in frequency tables by means of counts and 
percentages. Percentages in the summary tables will be rounded and may therefore not 
always add up to exactly 100%.
8.1. Patient Disposition and Treatment/Study Discontinuation
The number of patients included in the study, the number of patients treated and the number 
of patients evaluable for the main endpoint will be shown. Also, accrual by center and 
country and the main dates of the study will be displayed. Reasons for treatment 
discontinuation and for study discontinuation will be tabulated.
8.2. Protocol Deviations
Analysis of deviations regarding patients’ eligibility, retreatment restrictions, concomitant 
medication and clinically relevant discontinuations, among others, will be done as 
described in Appendix I.
8.3. Baseline and Demographic Data
Baseline data such as demographics, cancer history, prior therapy, prior relevant history, 
signs and symptoms, electrocardiogram, LVEF, physical examination, vital signs, 
laboratory values and concomitant medication, coded according to the World Health 
Organization (WHO) Anatomical Therapeutic Chemical (ATC) classification system, will 
be described following standard tables detailed in Appendix I.
Age, baseline weight, height, and BSA values will be summarized descriptively. Age 
categories, race and baseline ECOG PS score will be summarized with frequency counts.
Baseline weight and height are recorded on the Case Report Form (CRF). If BSA value is 
missing, it will be calculated using the Dubois & Dubois formula:
725
.0
425
.0
2
)
(
)
(
007184
.0
)
(
cm
height
kg
weight
m
BSA



For the cancer history, time from initial diagnosis, time from metastatic disease and time 
from last progression before the study entry will be summarized. This time calculations will 
be shown in months and summarized descriptively. Histology and other characteristics of 
the primary and current disease will be described using standard tables detailed in 
Appendix I.
Previous relevant medical history (other than cancer) will be tabulated by SOC and PT.
A frequency tabulation of the number of patients with the different types of previous 
surgery, radiotherapy, or therapy (number of lines) will be given.
Signs and symptoms, defined as AEs reported at baseline, will be displayed by tabulation of 
frequencies according to NCI-CTCAE v.4 toxicity grades. Signs and symptoms will be 
listed.


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In case of pre-treatment characteristics with multiple measurements per subject before the 
start of treatment (laboratory assessments, vital signs), the last value prior to or on the first 
day of treatment will be considered the baseline measurement.
8.4. Treatment Administration
Total cumulative dose, dose intensity and relative dose intensity, administration times, time 
on treatment, cycle delays, dose reductions and omissions will be described using standard 
tables detailed in Appendix I.
Total cumulative dose, expressed in mg, is the sum of all the study drug doses from the first 
cycle until last cycle, including the dose received in the last cycle.
Patients will be considered to be on-treatment for the duration of their treatment and for 30 
days after the last treatment dose. If the patient starts any new antitumor therapy outside 
this clinical trial or dies within 30 days of the last treatment dose, the date of administration 
of this new therapy or the date of death will be considered the date of treatment 
discontinuation.
However, as a convention, the duration of the last cycle is considered to be 21 days (instead 
of 30 days) for dose intensity calculation purposes.
Intended dose intensity is the planned dose per cycle divided by the planned number of 
weeks per cycle. Absolute dose intensity is the actual cumulative dose divided by the
number of weeks of treatment. Relative dose intensity (%) is the ratio of absolute dose 
intensity divided by the intended dose intensity.
The item of the CRF «Infusion delayed: yes/no» will be used to calculate the delayed 
cycles. For those cycles considered as delayed by the Investigator, the delay (days) will be 
calculated as follows:
The infusion of the first cycle will be excluded from all calculations regarding cycle delays
and modifications.
8.5. Subsequent Therapy
A table summarizing the subsequent therapies received after treatment discontinuation will 
be shown.
8.6. Pharmacokinetic Analyses
This analysis will be detailed in a separate document.
8.7. Pharmacogenetic Analyses
This analysis will be detailed in a separate document.
8.8. Pharmacogenomic Analyses
This analysis will be detailed in a separate document.


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8.9. Metabolomics (Biomarkers) 
This analysis will be detailed in a separate document.
8.10.
Imputation of Incomplete Dates
The dates of certain historical or current clinical activities are key component for statistical 
analysis. An incomplete date results from a missing day, month or year; in that case, the 
missing figure can be imputed allowing for the calculation of variables, such as duration 
and time to certain event. However, when all of them, day, month and year are missing no 
imputation will be done. 
Before registration/treatment start
If the day of a month is unknown, then the imputed day will be the 15th of the month; if the 
month is also unknown, then the imputed date will be the 1st of July. This assumption will 
only be valid if the imputed date occurs earlier than the first dose administration date; 
otherwise the imputed date will be the first day of the month in which the first dose was 
administered (i.e. 01/ first dose administration month date/year).
Between treatment start and end of treatment
All date variables during treatment for which information is needed and is not fully 
available, for example AEs or concomitant medications, will be subjected to imputation by 
means of SAS programming. If the day of a date is unknown then the imputed day will be 
the 1st of the month, if the month and/or year are also unknown then the imputed date will 
be the 1st of January. This assumption will be valid if the imputed date is earlier than the 
treatment start date; otherwise, the imputed date will be the treatment start date.
After end of treatment
To ensure the most conservative approach for the time-to-event variables (i.e., DR, PFS and 
OS), which can be affected by missing values, the following rules will be implemented: if 
the day of a date is unknown then the imputed day will be the 1st; if the month is also 
unknown, then the imputed date will be the 1st of July. This assumption will be valid if the 
imputed date occurs later than the last drug administration date; otherwise the imputed date 
will be the date of the last drug administration plus the predefined cycle length (i.e., 21 
days if PM060184), except if the patient dies before, in which case the date of death minus 
1 will be used.
8.11.
Decimal Places
By default, all numeric results will be rounded to one decimal, except when variables are 
integer; in that case, they will be reported without decimals, for example, age in years, 
number of sites, etc. or in the case of p-values and Hazard Ratio values where four decimals 
will be used.
8.12.
Subgroup Analyses
If applicable, specific analyses for different subgroups determined by the following factors
will be developed: prior oxaliplatin exposure, tumor primary location: right vs left side 
tumors, KRAS status, BRAF-like expression, MSI phenotype and other relevant factors 
determined by the oncologist.


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No differentiation by center is planned.
8.13.
Methods for Handling Missing Data
Missing values will not be included in the calculation of outputs.
8.14.
First Stage Analysis
A futility analysis will be performed once the first 24 evaluable patients complete the Week 
12 (± 5 days) tumor assessment; progress; die due to PD; or discontinue treatment due to 
unmanageable toxicity (whichever occurs first). If seven patients or more achieve PFS3, 
then 36 additional patients will be recruited (second stage). 
8.15.
Identification of Fixed or Random Effects Models
Not applicable.
8.16.
Data Analysis Conventions
All data analysis conventions, data calculations and grouping needed to perform the 
statistical analysis will be described in a separate document.


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9. STATISTICAL SOFTWARE
Medidata Rave® EDC will be used for data entry and clinical data management.
EAST v.6 has been used to calculate sample size.
SAS v.9.4 or superior will be used for all statistical analysis outputs.


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I.
APPENDIX: TABLES, LISTINGS AND GRAPHS
Summary tables will have source data footnotes that will refer to the relevant listings. The 
tables' layout may change to adequately accommodate group size as appropriate.
If the number of categories or items does not yield appropriate tabular or graphic 
representations, detailed listings will be shown instead.
10.Study Patients
Main characteristics concerning inclusion in the study, withdrawal from the study and 
protocol deviations will be displayed in this section.
10.1.
Patient Disposition
Patient disposition analysis will be based in the “All included patients” population.
Table 10.1.1 Number of patients included, treated and evaluable for the main endpoint.
N
%
Included patients
Eligible patients*
Treated patients
Evaluable patients for efficacy
(*) Patients meeting all inclusion criteria and not meeting any exclusion criteria.
Listing 10.1.2 Patients who do not meet all inclusion criteria or meet any exclusion criteria.
Patient id.
Criterion number(s) and description
Listing 10.1.3 Screening failures.
Patient 
Inclusion/Exclusion criterion not met
Listing 10.1.4 Non-evaluable patients for efficacy.
Patient id.
Reason
Listing 10.1.5 Non-evaluable patients for safety (Non-treated patients).
Patient id.
Reason
Table 10.1.6 Patients accrual by country/institution.
Country/Institution
No. of patients included
No. of patients treated
N
%
N
%
Institution 1
Institution 2
…


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Table 10.1.7 Relevant study dates.
Total
Date of first patient’s informed consent
Date of first dose of the first patient
Date of last patient’s informed consent
Date of first dose of the last patient
Date of last dose
Date of last follow-up*
(*) Last follow-up, examination or procedure before clinical cut-off or study closure.
10.2.
Discontinuations
Treatment discontinuation tables and listings will be based on “All treated patients”, 
whereas study discontinuation tables and listings will be based on “All included patients”.
10.2.1. Treatment discontinuations
Table 10.2.1 Treatment discontinuation.
Reason
N
%
Progressive disease
Patient refusal to treatment
Death (due to toxicity)*1
Death (non-treatment-related)*2
Investigator’s decision*3
Treatment-related AE
Non treatment-related AE
Other*3
Total
(*1) Cause of death = Study drug related AE; (*2) Cause of death = Malignant disease, Non study drug related AE or 
Other; (*3) See Listing 10.2.2.
Listing 10.2.2 Reasons for treatment discontinuation other than progressive disease.
Patient id.
Reason
Last cycle
Comments 
When the reason for discontinuation is a study treatment-related adverse event or death due 
to toxicity, patients will be identified and described in depth in Listing 10.2.3.
Listing 10.2.3 Treatment discontinuation due to AEs.
Patient id. Last 
cycle
Preferred  
term code
AE
reported 
(verbatim)
Grade 
Relationship 
Onset 
date
Resolved 
date
Seriousness criteria


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10.2.2. Study discontinuation
Table 10.2.4 Study discontinuation.
Reason
N
%
Never treated*1
Withdrawal of consent
Death (due to toxicity)*2
Death (non-treatment-related) *3
Lost to follow-up
Other *4
Total
(*1) See Listing 10.1.5; (*2) Cause of death = Study drug related AE or UK relationship; (*3) Cause of death = Malignant 
disease, Non study drug related AE or Other; (*4) Specified in Listing 10.2.5.
Listing 10.2.5 Study discontinuation due to other reason.
Patient id.
Specify
10.3.
Protocol Deviations
Protocol deviations of “All included patients” population will be shown.
Listing 10.3.1 Protocol deviations.
Patient id.
Deviation type
Description


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11.Efficacy Evaluation
11.1.
Demographic and Other Baseline Characteristics
Demographic and other baseline characteristics of “All Included Patients” population will 
be shown.
11.1.1. Patient Characteristics at Baseline
Table 11.1.1 Baseline characteristics.
N
%
Number of patients
Gender
Female
Male
Age  
Median (range)
Mean (StD)
Age group
18-49
50-69
≥70
Race
American Indian or Alaska Native
Asian 
Black or African American
Native Hawaiian or Other Pacific Islander
White 
Other (specify)*
(*) See Listing 11.1.2.
Listing 11.1.2 Race (other).
Patient
Race
Specify
11.1.2. Disease at diagnosis and current disease
Table 11.1.3 Disease at diagnosis and current disease.
N
%
Time from first diagnosis to first infusion
Median (range)
Mean (StD)
Primary tumor side
Rigth
Left
Primary tumor site
Cecum
Ascending
Transverse
Descending
Sigmoid
Rectum
…
Histology grade
G1. Well differentiated


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N
%
G2. Moderately differentiated
G3. Poorly differentiated
G4. Undifferentiated
GX. Grade cannot be evaluated
KRAS mutational status
Wild type
Not done
UK
Mutated, specify*1
NRAS mutational status
Wild type
Not done
UK
Mutated, specify*2
BRAF mutational status
Wild type
Not done
UK
Mutated, specify*3
MSI status
Done
Not done/UK
MSI phenotype*4
MSI Stable
MSI-H
MSI-L
Stage at diagnosis
I
…
TNM
…
Dukes
A
B
…
MAC
A
B1
…
(*1) See Listing 11.1.4 (*2) See Listing 11.1.5 (*3) See Listing 11.1.6 (*4) Listing 11.1.7.
Listing 11.1.4 KRAS mutational status (mutated).
Patient
Specify
Listing 11.1.5 NRAS mutational status (mutated).
Patient
Specify
Listing 11.1.6 BRAF mutational status (mutated).
Patient
Specify
Listing 11.1.7 MSI phenotype (gene affected).
Patient
MSI phenotype (MSI Stable/MSI-H/MSI-L)
Gen affected


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Table 11.1.8 Current disease.
N
%
Current disease status
Locally recurrent disease
Metastasis
Both
Time from diagnosis of advanced disease to study entry
Median (range)
Mean (StD)
Time from prior last progression before study entry
Median (range)
Mean (StD)
Time from stop date of prior chemotherapy to study entry
Median (range)
Mean (StD)
Site of current disease
Primary tumor site/ Local relapse
Lung
…
Number of sites involved
1
2
…
Median (range)
Mean (StD)
11.1.3. Prior Relevant Medical History
Table 11.1.9 Prior medical history.
SOC
Preferred term
N
%
Patients with any past and/or concomitant disease or past surgeries
Gastrointestinal disorders
Constipation
Diarrhoea
…
…
…
…
Listing 11.1.10 Prior medical history (ongoing events).
Patient id.
Description (Literal)
SOC
PT
Onset date
11.1.4. Prior Anticancer Therapy
Table 11.1.11 Prior surgery (major surgical procedures for study disease only).
N
%
Surgery (Y/N)
Residual disease
Yes
No
UK


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Table 11.1.12 Prior radiotherapy.
N
%
Radiotherapy (Y/N)
Type
External
Brachytherapy
IORT
IMRT
Intention
Curative
Palliative
Concurrent
Table 11.1.13 Prior anticancer medical therapy.
N
%
Number of prior lines (including neo/adjuvant)
1
…
Number of prior lines for advanced disease
1
…
Number of prior agents (including neo/adjuvant)
1
…
Number of prior agents for advanced disease
1
…
Prior agents (ATC coded)
Fluoropyrimidine
Irinotecan
Oxaliplatin
…
Last prior agents (ATC coded)
…
Progression free interval*
Median (range)
Progression free interval to Oxaliplatin
Median (range)
Best response to last prior therapy
Complete Response
Partial Response
Stable Disease
Progressive Disease
NE/UK/NA
(*) Time from last prior therapy to first infusion of PM60184.
11.1.5. Physical Examination and performance status
Table 11.1.14 Baseline ECOG Performance Status.
N
%
ECOG PS
0
1


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Table 11.1.15 Baseline physical examination.
N
%
Physical examination abnormalities (Y/N)
Weight (kg)
Median (range)
Mean (StD)
Height (cm)
Median (range)
Mean (StD)
Body surface area (m2)
Median (range)
Mean (StD)
BMI (kg/m2)
Median (range)
Mean (StD)
20
21-25
26-30
30
11.1.6. Vital signs, Electrocardiogram, LVEF and other tests
Table 11.1.16 Vital signs, Electrocardiogram, LVEF and other tests.
N
%
Vital signs
Heart rate (Beats/minute)
Median (range)
Mean (StD)
Systolic blood pressure (mmHg)
Median (range)
Mean (StD)
Diastolic blood pressure (mmHg)
Median (range)
Mean (StD)
Temperature (ºC)
Median (range)
Mean (StD)
ECG
Normal
Significant abnormalities
Non significant abnormalities
LVEF
Method
ECHO
MUGA
Result
Normal
Non-significant abnormalities
Significant abnormalities
Pregnancy test
Positive
Negative
NA*
(*) See Listing 11.1.17.


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Listing 11.1.17 Patients with not applicable pregnancy test.
Patient
Specify
Listing 11.1.18 Other tests/ procedures.
Patient
Test name
Result
Comments
11.1.7. Hematological Values at Baseline
Table 11.1.19 Hematological abnormalities at baseline*.
Grade 1
Grade 2
Grade 3
Grade 4
Grade 
1/4
Total
N
%
N
%
N
%
N
%
N
%
N
Anaemia
Leukopenia
Neutropenia
Lymphopenia
Thrombocytopenia
(*) Defined as the last value recorded before or on the date of first infusion.
Table 11.1.20 Hematological values at baseline*.
Median (range)
Hemoglobin (g/dL)
WBC (109/L)
Neutrophils (109/L)
Lymphocytes (109/L)
Platelets (109/L)
(*) Defined as the last value recorded before or on the date of first infusion.
Listing 11.1.21 Hematological abnormalities at baseline* (grade >1).
Patient
Test
Grade
(*) Defined as the last value recorded before or on the date of first infusion.
Listing 11.1.22 Hematological tests not assessed at baseline*.
Patient
Test
…
…
(*) Defined as the last value recorded before or on the date of first infusion.


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11.1.8. Biochemical Values at Baseline
Table 11.1.23 Biochemical abnormalities at baseline*.
Grade 
1
Grade 
2
Grade
3
Grade 
4
Grade
1/4
Total
N
%
N
%
N
%
N
%
N
%
N
ALT increased
AP increased
AST increased
Creatinine increased
(*) Defined as the last value recorded before or on the date of first infusion.
Table 11.1.24 Biochemistry values at baseline*.
Median (range)
ALT (IU/L)
AP (IU/L)
AST (IU/L)
Creatinine (mg/dL)
Creatinine Clearance (mg/min)
Direct bilirubin (mg/dL)
GGT (U/L)
Glucose (mmol/L)
K (mmol/L)
LDH (IU/L)
Na (mmol/L)
Total bilirubin (mg/dL)
(*) Defined as the last value recorded before or on the date of first infusion.
Listing 11.1.25 Biochemical abnormalities at baseline* (grade >1).
Patient
Test
Grade
(*) Defined as the last value recorded before or on the date of first infusion.
Listing 11.1.26 Biochemical tests not assessed at baseline*.
Patient
Test
…
…
(*) Defined as the last value recorded before or on the date of first infusion.
Table 11.1.27 Other metabolic abnormalities at baseline*.
Grade 1
Grade 2
Grade 3
Grade 4
Grade 
1/4
Total
N
%
N
%
N
%
N
%
N
%
N
GGT increased
Hypercalcemia*2
Hyperglycemia
Hyperkalaemia
Hypernatremia
Hypoalbuminaemia
Hypocalcemia*2
Hypoglycemia
Hypokalaemia
Hyponatremia
(*) Defined as the last value recorded before or on the date of first infusion.
(*2) Total plasmatic calcium corrected by albumin.


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Listing 11.1.28 Other metabolic abnormalities at baseline* (grade >1).
Patient
Test
Grade
(*) Defined as the last value recorded before or on the date of first infusion.
11.1.9. Signs and Symptoms at Baseline
Table 11.1.29 Signs and symptoms at baseline*.
N
%
No. of signs and symptoms per patient
0
1
2
3
Median (range)
Mean (StD)
No. of disease related signs and symptoms per patient
0
1
2
3
Median (range)
Mean (StD)
(*) AEs with onset day previous to first administration of the study treatment.
Table 11.1.30 Signs and symptoms at baseline.
MedDRA SOC/PT*
N
Grade 
1
Grade 
2
Grade 
3
Grade 
4
Grade 
1/4
N
%
N
%
N
%
N
%
N
%
Constipation
Diarrhoea
Dyspnea
Pain 
…
(*) Sorted by frequency.
Table 11.1.31 Disease related signs and symptoms at baseline.
MedDRA SOC/PT*
N
Grade 
1
Grade 
2
Grade 
3
Grade 
4
Grade 
1/4
N
%
N
%
N
%
N
%
N
%
Constipation
Diarrhoea
Dyspnea 
Pain 
…
(*) Sorted by frequency.
Listing 11.1.32 Signs and symptoms at baseline.
Patient
Sign/symptom
Grade
Onset date Relationship
Treated
(*) Those events with grade ≥ 2 or with relationship=’Prior tumor treatment’ will be highlighted.


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11.1.10. Peripheral Neuropathy
Table 11.1.33 Peripheral neuropathy.
N
%
Peripheral neuropathy (Y/N)
Type of peripheral neuropathy 
Sensory 
Motor
Both
Location
Hands
Feet
Arms
Legs
…
Worst grade observed (NCI-CTCAE v.4)
Grade 1
Grade 2
Grade 3
Grade 4
UK
Outcome of the overall grade
Complete recovery
Recovered with sequelae
Neuropathy due to prior chemotherapies or biological treatments: agents
Oxaliplatin
Other
Neuropathy due to prior chemotherapies or biological treatments: dose modification
/ discontinuation
Yes
No
UK
11.1.11. Concomitant Therapy and Procedures at Baseline
Table 11.1.34 Concomitant medication at baseline (ATC1/ATC2/ATC4/PN).
Concomitant medication at baseline
N
%
Alimentary tract and metabolism
   Antacids
      Magnesium compounds
          Magnesium adipate
…
Blood and blood forming organs
   Antithrombotic agents
      Vitamin K antagonists
          Acenocoumarol
…


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Table 11.1.35 Summary of concomitant medication at baseline.
N
%
No. of systems at BL (ATC1 level)
0
1
2
3
Median (range)
Mean (StD)
No. of indications at BL (ATC2 level)
0
1
2
3
Median (range)
Mean (StD)
No. of agent families at BL (ATC4 level)
0
1
2
3
Median (range)
Mean (StD)
No. of agents at BL (PN level)
0
1
2
3
Median (range)
Mean (StD)
Listing 11.1.36 Concomitant therapy.
Patient
Type
Agent/Procedure Route
Daily 
dose
Units
Start 
date
Reason
Indication
Details
Start date of
study 
drug 
administration
If there is a relevant number of patients receiving the same concomitant medication, a table 
summarizing this information might be added.
11.2.
Measurements of Treatment Compliance
Compliance of individual patients with the treatment regimen under study will be measured 
and tabulated in Appendix I.12.1 and listed in Appendix III (ICH listings).
11.3.
Efficacy Analysis
Efficacy analysis will be carried out on the “All Evaluable Patients” population except 
duration of response analysis which will be carried out on the “All Responding Patients” 
population and QoL analysis, which will be carried out on the “All evaluable QoL”
population.


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11.3.1. Primary Analysis
Patients who are evaluable for efficacy but have not been followed-up for at least 12 weeks 
(+/- 5 days) will be categorized as PFS3=No.
Table 11.3.1 PFS3 rate (binomial exact estimator and 95% confidence interval).
Proportion
Lower 95% limit
Upper 95% limit
PFS3*
(*) Progression-free-survival rate at 12 weeks (+/- 5 days).
Binomial exact estimator and 95% CI.
Listing 11.3.2 Censored patients.
Patient
PFS3 rate
PFS (months)
Reason for censoring
11.3.2. Secondary Analyses
Table 11.3.3 Overall survival.
PM060184
N
Events
Censored
Median OS
OS at 12 months
A Kaplan-Meier plot will also be shown (see Figure 11.3.4).
See Figure 11.3.8 as an example of Kaplan Meier plot.
Table 11.3.5 Progression-free survival.
PM060184
N
Events
Censored
Median PFS
PFS at 3 months
PFS at 6 months
PFS at 12 months
A Kaplan-Meier plot will also be shown (see Figure 11.3.8).
Figure 11.3.6 Kaplan-Meier plot of PFS.


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Table 11.3.7 Sensitive analysis of Progression-free survival.
PM060184
N
Events
Censored
Median PFS
PFS at 3 months
PFS at 6 months
PFS at 12 months
A Kaplan-Meier plot will also be shown (see Figure 11.3.8).
Figure 11.3.8 Kaplan-Meier plot of sensitivity analysis of PFS.
Table 11.3.9 Overall response as per RECIST v1.1.
Response
N
%
Complete response
Partial response
Stable disease
SD < 3 months
SD ≥ 3 months
Progressive disease
Non-evaluable for efficacy*
(*) Treatment failures.
Table 11.3.10 Overall response rate.
Proportion
Lower 95% limit
Upper 95% limit
Response rate*
Response rate or PFS3
(*) CR + PR. Binomial exact estimator and 95% CI


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Figure 11.3.11 Best RECIST efficacy assessment in evaluable patients.
Figure 11.3.12 Waterfall plot of best reduction in sum of diameters of target lesions from baseline
(RECIST v1.1).
50%
50%
 PR
 PD
    Decrease                   Increase (%)
100
90
80
70
60
50
40
30
20
10
0
10
20
30
40
50
60
70
80
90
100
Maximal variation in target lesions according to RECIST(N=16)
'
Table 11.3.13 Duration of response.
PM060184
N
Events
Censored
Median DOR
A Kaplan-Meier plot will also be shown (see Figure 11.3.14).
An example of Kaplan Meier plot could be seen in Figure 11.3.8.
A summary of the main characteristics of responding patients or PFS3 will be performed.


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Listing 11.3.15 Characteristics of patients with response.
Patient
Race
ECOG 
PS
Age
Primary 
tumor side
Primary site
Number of 
prior lines
Last prior treatment
Agent
Best 
response
PFI
Patient
N 
Metastatic 
sites
Cycles 
received
Best 
response
Tumor 
shrinkage
PFS 
(months)
TTP
(months)
PFS3
DOR
OS
Table 11.3.16 Median follow up.
Follow-up*
PM060184
Median
95% CI
PFS
OS
(*) Calculated using the Kaplan-Meier method reversing the censored values and the usual descriptive way.
11.3.3. QoL analyses
11.3.3.1.
General QoL (QLQ-C30)
Table 11.3.17 Raw data for individual items* of EORTC QLQ-C30 over time.
Baseline
N (%)
Cycle 1
N (%)
Cycle X
N (%)
EOT
N (%)
Follow up
N (%)
Item 1
Not at all
A little
Quite a bit
Very much
…
Item 30
Not at all
A little
Quite a bit
Very much
(*) Could also be displayed by dichotomized scores, if appropriate, by for example grouping scores into ‘Not at all’ vs. 
‘Any extent’.


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Table 11.3.18 Over time scores of EORTC QLQ-C30.
Scale / Item
Baseline
Mean (StD)
Cycle 1
Mean (StD)
Cycle X
Mean (StD)
EOT
Mean (StD)
Follow up
Mean (StD)
Global health status / QoL
Functional scales
Physical functioning
Role functioning
Emotional functioning
Cognitive functioning
Social functioning
Symptom scales
Fatigue
Nauseas and vomiting
Pain
Dyspnoea
Insomnia
Appetite loss
Constipation
Diarrhoea
Financial difficulties
A time series chart will also be shown (see Figure 11.3.19).
See Figure 11.3.24 as an example of Time serie chart to describe over time scores of 
EORTC QLQ-C30.
Table 11.3.20 Changes in scores of EORTC QLQ-C30 over time from baseline.
Scale / Item
Cycle 1
Cycle X
EOT
Follow up
Mean 
(StD)
p-value
Mean 
(StD)
p-value
Mean 
(StD)
p-value
Mean 
(StD)
p-value
Global health status / QoL
Functional scales
Physical functioning
Role functioning
Emotional functioning
Cognitive functioning
Social functioning
Symptom scales
Fatigue
Nauseas and vomiting
Pain
Dyspnoea
Insomnia
Appetite loss
Constipation
Diarrhoea
Financial difficulties
Table 11.3.21 Changes in scores of EORTC QLQ-C30 over time (Repeated Measures Analysis of 
Variance).
Source
DF
Mean Square
F value
p-value


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11.3.3.2.
Chemotherapy-induced Peripheral Neuropathy (QLQ-CIPN20)
Table 11.3.22 Raw data for individual items* of EORTC QLQ-CIPN20 over time.
Baseline
N (%)
Cycle 1
N (%)
Cycle X
N (%)
EOT
N (%)
Follow up
N (%)
Item 1
Not at all
A little
Quite a bit
Very much
…
Item 20
Not at all
A little
Quite a bit
Very much
(*) Could also be displayed by dichotomized scores, if appropriate, by for example grouping scores into ‘Not at all’ vs. 
‘Any extent’.
Table 11.3.23 Over time scores of EORTC QLQ-CIPN20.
Scale / Item
Baseline
Mean (StD)
Cycle 1
Mean (StD)
Cycle X
Mean (StD)
EOT
Mean (StD)
Follow up
Mean (StD)
Sensory scale
Motor scale
Autonomic scale
A Time serie chart will also be shown (see Figure 11.3.24).
Figure 11.3.24 Time serie chart of mean and 95% CI for scales of EORTC QLQ-CIPN20.
Table 11.3.25 Changes in scores of EORTC QLQ-CIPN20 from baseline over time.
Scale / Item
Cycle 1
Cycle X
EOT
Follow up
Mean 
(StD)
p-value
Mean 
(StD)
p-value
Mean 
(StD)
p-value
Mean 
(StD)
p-value
Sensory scale
Motor scale
Autonomic scale


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Table 11.3.26 Changes in scores of EORTC QLQ-CIPN20 over time (Repeated Measures Analysis 
of Variance).
Source
DF
Mean Square
F value
p-value
11.3.4. Exploratory Analyses
Table 11.3.27 Multivariate analysis of OS.
Analysis of Maximum Likelihood Estimates
Variable label Variable values DF Parameter
estimate
Standard
error
Chi-square Pr>ChiSq Hazard
ratio
95% Hazard ratio confidence
limits
(See list of covariates in section 6.2.2).
Table 11.3.28 Multivariate analysis of PFS.
Analysis of Maximum Likelihood Estimates
Variable label Variable values DF Parameter
estimate
Standard
error
Chi-square Pr>ChiSq Hazard
ratio
95% Hazard ratio confidence
limits
(See list of covariates in section 6.2.2).
Table 11.3.29 Multivariate analysis of Response Rate.
Analysis of Maximum Likelihood Estimates
Variable 
label
Variable 
values
DF Estimate Standard
error
Wald chi-
square
Pr>ChiSq
Odds ratio 
estimate
95% Wald
confidence 
limits
(See list of covariates in section 6.2.2).
Table 11.3.30 Multivariate analysis of PFS3 (Yes/No).
Analysis of Maximum Likelihood Estimates
Variable 
label
Variable 
values
DF Estimate Standard
error
Wald chi-
square
Pr>ChiSq
Odds ratio 
estimate
95% Wald
confidence 
limits
(See list of covariates in section 6.2.2).


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11.3.4.1.
Subgroup Analysis
Table 11.3.31 Subgroup analysis of PFS3 rate (binomial exact estimator and 95% confidence 
interval).
Proportion (95% CI)
Oxaliplatin exposure
Subgroup
Yes
No
PFS3*
Tumor primary location
Subgroup
Right
Left
PFS3*
KRAS status (mutated)
Subgroup
Yes
No
PFS3*
BRAF-like expression (mutated)
Subgroup
Yes
No
PFS3*
MSI phenotype
Subgroup
MSI Stable
MSI-H
MSI-L
PFS3*
(*) Progression-free-survival rate at 12 weeks (+/- 5 days). Binomial exact estimator and 95% CI.
Table 11.3.32 Subgroup analysis of Overall survival.
Oxaliplatin exposure
Subgroup
Yes
No
N
Events
Censored
Median OS
OS at 12 months
Tumor primary location
Subgroup
Right
Left
N
Events
Censored
Median OS
OS at 12 months
KRAS status (mutated)
Subgroup
Yes
No
N
Events
Censored
Median OS
OS at 12 months
BRAF-like expression (mutated)
Subgroup
Yes
No
N
Events
Censored
Median OS
OS at 12 months
MSI phenotype
Subgroup
MSI Stable
MSI-H
MSI-L
N
Events
Censored
Median OS
OS at 12 months
A Kaplan-Meier plot will also be shown (see Figure 11.3.33).
See Figure 11.3.8 as an example of Kaplan Meier plot.


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Table 11.3.34 Subgroup analysis of progression-free survival.
Oxaliplatin exposure
Subgroup
Yes
No
N
Events
Censored
Median PFS
PFS at 3 months
PFS at 6 months
PFS at 12 months
Tumor primary location
Subgroup
Right
Left
N
Events
Censored
Median PFS
PFS at 3 months
PFS at 6 months
PFS at 12 months
KRAS status (mutated)
Subgroup
Yes
No
N
Events
Censored
Median PFS
PFS at 3 months
PFS at 6 months
PFS at 12 months
BRAF-like expression (mutated)
Subgroup
Yes
No
N
Events
Censored
Median PFS
PFS at 3 months
PFS at 6 months
PFS at 12 months
MSI phenotype
Subgroup
MSI Stable
MSI-H
MSI-L
N
Events
Censored
Median PFS
PFS at 3 months
PFS at 6 months
PFS at 12 months
A Kaplan-Meier plot will also be shown (see  Figure 11.3.8).


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Figure 11.3.35 Kaplan-Meier plot of PFS by subgroups*.
Cumulative probability
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Time (months)
0
3
6
9
12
15
18
21
24
27
30
33
36
39
42
45
48
51
54
57
Overall Survival
(p-value=<0.0001) 
Increase    (N=166 C=40)
No increase (N=153 C=12)
Censored
(*) (A) Oxaliplatin exposure (Yes/No), (B) Tumor primary location (Right/Left), (C) KRAS status (mutated) (Yes/No), 
BRAF-like expression (mutated) (Yes/No) and (D) MSI phenotype (MSI Stable/MSI-H/MSI-L).
Table 11.3.36 Subgroup analysis of overall response as per RECIST v1.1.
N (%)
Oxaliplatin exposure
Subgroup
Yes
No
Response
Complete response
Partial response
Stable disease
SD < 3 months
SD ≥ 3 months
Progressive disease
Non-evaluable for efficacy*
Tumor primary location
Subgroup
Right
Left
Response
Complete response
Partial response
Stable disease
SD < 3 months
SD ≥ 3 months
Progressive disease
Non-evaluable for efficacy*
KRAS status (mutated)
Subgroup
Yes
No
Response
Complete response
Partial response
Stable disease
SD < 3 months
SD ≥ 3 months
Progressive disease
Non-evaluable for efficacy*
BRAF-like expression (mutated)
Subgroup
Yes
No
Response
Complete response
Partial response
Stable disease
SD < 3 months
SD ≥ 3 months


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Progressive disease
Non-evaluable for efficacy*
MSI phenotype
Subgroup
MSI Stable
MSI-H
MSI-L
Response
Complete response
Partial response
Stable disease
SD < 3 months
SD ≥ 3 months
Progressive disease
Non-evaluable for efficacy*
(*) Treatment failures.
Table 11.3.37 Subgroup analysis of overall response rate.
Proportion (95% CI)
Oxaliplatin exposure
Subgroup
Yes
No
Response rate*
Response rate or PFS3
Tumor primary location
Subgroup
Right
Left
Response rate*
Response rate or PFS3
KRAS status (mutated)
Subgroup
Yes
No
Response rate*
Response rate or PFS3
BRAF-like expression (mutated)
Subgroup
Yes
No
Response rate*
Response rate or PFS3
MSI phenotype
Subgroup
MSI Stable
MSI-H
MSI-L
Response rate*
Response rate or PFS3
(*) CR + PR. Binomial exact estimator and 95% CI.
If appropriate, grouping of other similar or clinically related items will be made at the time 
of the analysis.
Figure 11.3.38 Best RECIST efficacy assessment in evaluable patients by subgroups*.
(*) (A) Oxaliplatin exposure (Yes/No), (B) Tumor primary location (Right/Left), (C) KRAS status (mutated) (Yes/No), 
BRAF-like expression (mutated) (Yes/No) and (D) MSI phenotype (MSI Stable/MSI-H/MSI-L).


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Figure 11.3.39 Waterfall plot of best reduction in sum of diameters of target lesions from baseline 
(RECIST v1.1) by subgroups*.
50%
50%
 PR
 PD
    Decrease                   Increase (%)
100
90
80
70
60
50
40
30
20
10
0
10
20
30
40
50
60
70
80
90
100
Maximal variation in target lesions according to RECIST(N=16)
'
(*) (A) Oxaliplatin exposure (Yes/No), (B) Tumor primary location (Right/Left), (C) KRAS status (mutated) (Yes/No), 
BRAF-like expression (mutated) (Yes/No) and (D) MSI phenotype (MSI Stable/MSI-H/MSI-L).
Table 11.3.40 Duration of response.
Oxaliplatin exposure
Subgroup
Yes
No
N
Events
Censored
Median DOR
Tumor primary location
Subgroup
Right
Left
N
Events
Censored
Median DOR
KRAS status (mutated)
Subgroup
Yes
No
N
Events
Censored
Median DOR
BRAF-like expression (mutated)
Subgroup
Yes
No
N
Events
Censored
Median DOR
MSI phenotype
Subgroup
MSI Stable
MSI-H
MSI-L
N
Events
Censored
Median DOR
A Kaplan-Meier plot will also be shown (see Figure 11.3.41).
An example of Kaplan Meier plot could be seen in Figure 11.3.8.


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12.Safety Evaluation
Safety analysis will be carried out on the “All Treated Patients” population.
12.1.
Extent of Exposure
12.1.1. Treatment Administration
Table 12.1.1 Number of cycles administered and dose intensity.
N
%
No. of cycles administered per patient
1
2
3
…
Median (range)
Mean (Std)
Time on treatment* (weeks)
Median (range)
Mean (Std)
Cumulative dose (mg)
Median (range)
Mean (Std)
Dose intensity (mg/wk)
Median (range)
Mean (Std)
Relative dose intensity (%)
Median (range)
Mean (Std)
(*) Time on treatment: defined as last infusion date plus 30 days, or date of death or subsequent therapy (whichever comes 
first) minus first infusion date.
12.1.2. Cycle Delays
Listing 12.1.2 Delays.
Patient id.
Delayed 
cycle
Delayed 
cycle start 
date
Previous cycle
Previous cycle 
start date
Calculated dose 
delay (days)
Reason for 
dose delay
Specify 
reason for 
dose delay
Table 12.1.3 Number of patients and cycles with dose delay, any relationship.
N
%
Patients treated
Patients with any dose delay
Cycles administered
Cycles susceptible to be delayed*1
Cycles with dose delay*2
Patients with
No cycles delayed
1 cycle delayed
2 cycles delayed
3 cycles delayed
(*1) All cycles excluding first cycle. (*2) Denominator= Number of cycles susceptible to be delayed.


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Table 12.1.4 Number of patients and cycles with dose delay according to relationship with study 
treatment.
Treatment-related*2
Non-treatment-related
N
%
N
%
Patients with
No cycles delayed
1 cycle delayed
2 cycles delayed
3 cycles delayed
Cycles with dose delay*1
(*1) Denominator= Number of cycles susceptible to be delayed. (*2) Hematological reason, non-hematological reason or 
both.
Table 12.1.5 Number of patients and cycles with dose delay according to relationship with study 
treatment.
Reasons for treatment-related delays
N
%
Cycles with dose delays*
Hematological
Non-hematological
Both
Patients with dose delays
Hematological
No cycles delayed
1 cycle delayed
2 cycles delayed
3 cycles delayed
Non-hematological
No cycles delayed
1 cycle delayed
2 cycles delayed
3 cycles delayed
Both
No cycles delayed
1 cycle delayed
2 cycles delayed
3 cycles delayed
(*) Denominator= Number of cycles susceptible to have a delay. 
Table 12.1.6 Length of dose delay.
Treatment-related*2
Non-treatment-related
Total
Length of delay 
Median (range)
Length of delay*1
N
%
N
%
N
%
<= 7 days
>7 days and <=14 days
> 14 days
(*1) Denominator= Number of cycles susceptible to be delayed. (*2) Hematological reason, Non-hematological reason or 
both.
The distribution of delays according to the cycle administered will be studied by means of 
counts and percentages. The reasons for cycle delay will be detailed, specifying how many 
were due to treatment or not.


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Listing 12.1.7 Cycle delays due to AEs.
Patient 
id.
Cycle
Preferred  
term code
AE
reported 
(verbatim)
Grade Relationship Onset 
date
Resolved 
date
No. of days 
with delay
Action taken Significant 
consequences
AEs with action = ‘Dose delayed’, ‘Dose delayed/ reduced’, ‘Dose delayed/omitted’ or ‘Dose delayed/ omitted/ reduced’.
12.1.3. Dose Omission
Listing 12.1.8 Dose omission.
Patient id.
Cycle 
Reason for dose omission
Dose omission Spec.
Table 12.1.9 Number of patients and infusions with dose omissions, any relationship.
N
%
Patients treated
Patients with any dose omitted
Infusions susceptible to be omitted
Infusions omitted
Treatment-related
Hematological
Non-hematological
Both
Non-Treatment-related
Patients with
No cycles delayed
1 cycle delayed
2 cycles delayed
3 cycles delayed
(*) Denominator= Number of infusions susceptible to be omitted.
Listing 12.1.10 Dose omissions due to AEs.
Patient 
id.
Cycle
Preferred  
term code
AE reported 
(verbatim)
Grade Relationship
Onset 
date
Resolved 
date
Action taken
Significant 
consequences
AEs with action = ‘Dose omitted’, ‘Dose omitted/ reduced’, ‘Dose delayed/omitted’ or ‘Dose delayed/ omitted/ reduced’.
12.1.4. Dose Reductions
All dose reductions should be considered and described, specifying the reason for 
reduction (hematological toxicity, non-hematological toxicity or other causes). 
Listing 12.1.11 Dose reductions.
Patient id.
Cycle
Day
Cycle start date
Previous dose
Reduced dose
Reason 
for 
dose 
reduction
Dose 
reduction 
Spec.


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Table 12.1.12 Number of patients and infusions with dose reduction, any relationship.
N
%
Patients treated
Patients with any dose reduced
Cycles susceptible to be reduced in dose
Patients with
No dose reductions
1 cycle with dose reduced
2 cycles with dose reduced
3 cycles with dose reduced
Cycles administered
Cycles susceptible to have any dose reduced*1
Cycles with dose reduced *2
Cycles with dose reduced (Treatment-related)*2
(*1) All cycles. (*2) Denominator= Number of cycles susceptible to have a dose reduction.
Table 12.1.13 Number of patients and cycles with dose reduction according to the relationship.
Treatment-related*2
Non-treatment-related
N
%
N
%
Patients with
No dose reductions
1 cycle with dose reduced
2 cycles with dose reduced
3 cycles with dose reduced
Cycles with dose reduction*1
(*1) Denominator= Number of cycles susceptible to be delayed. (*2) Hematological reason, non-hematological reason or 
both.
Table 12.1.14 Number of patients and cycles with dose reduction according to the reason of the 
relationship.
Reasons for treatment-related reduction
N
%
Cycles with dose reduction*
Hematological
Non-hematological
Both
Patients with dose reduction
Hematological
No dose reductions
1 cycle with dose reduced
2 cycles with dose reduced
3 cycles with dose reduced
Non-hematological
No dose reductions
1 cycle with dose reduced
2 cycles with dose reduced
3 cycles with dose reduced
Both
No dose reductions
1 cycle with dose reduced
2 cycles with dose reduced
3 cycles with dose reduced
(*) Denominator= Number of cycles susceptible to have a dose reduction. 


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Listing 12.1.15 Dose reductions due to AEs.
Patient 
id.
Total 
no. of 
cycles
Cycle Preferred  
term code
AE reported 
(verbatim)
Grade Relationship
Onset 
date
Resolved 
date
Action taken
Significant 
consequences
AEs with action = ‘Dose reduced’, ‘Dose omitted/ reduced’, ‘Dose delayed/reduced’ or ‘Dose delayed/ omitted/ reduced’.
12.1.5. Temporarily Interrupted Infusions
A listing of the patients who had temporarily interrupted infusions, with the corresponding 
reasons, will be provided.
Listing 12.1.16 Interrupted infusions.
Patient id.
Cycle
Reason
12.1.6. Prophylactic Medication Administration
A listing of the patients who did not receive, as required per protocol, corticosteroids, 5-HT 
antagonists and other antiemetic prophylaxis (or equivalents), will be reported with the 
corresponding reason.
Listing 12.1.17 Patients and cycles with prophylactic medication not taken per protocol.
Patient id.
Cycle
Prophylactic 
medication 
not 
taken*
Reason
…
(*) Corticosteroids, 5-HT antagonists and other antiemetic prophylaxis
12.2.
Adverse Events
As far as all toxicities are concerned, the NCI-CTCAE v.4 grade will be used wherever an 
NCI-CTCAE grading exists. Otherwise, the severity will be noted. As a convention, the 
term «Grade» will always be used. Toxicities will be described according to the worst NCI-
CTCAE grade or, for toxicities which do not form the subject of NCI-CTCAE 
classification, according to the worst severity, as described in NCI-CTCAE.
AEs will be described in this section; treatment-related events (stated as related to the study 
drug or of unknown relationship) will be tabulated. AEs regardless relationship will be 
tabulated in two different ways as any AE reported or as treatment emergent AEs 
(excluding AEs present before drug administration and without increase in severity grade 
along the treatment).
Type of toxicity and worst grade or severity by cycle and by patient will be summarized 
according to the Preferred Term coded with MedDRA. Tables will be organized per 
category of events using System Organ Class of MedDRA.


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12.2.1. Display of Adverse Events
Table 12.2.1 Summary of AEs.
Category*
N (%)
Any AE
Any drug-related AE
Any grade 3/4 AE
Any grade 3/4 drug-related AE
Any treatment emergent AE*2
Any SAE in clinical database
Any drug-related SAE in clinical database
Any grade 3/4 SAE in clinical database
Any grade 3/4 drug-related SAE in clinical database
Deaths associated with AEs
Deaths associated with drug-related AEs
Treatment discontinuations associated with AEs
Treatment discontinuations associated with drug-related AEs
(*) Drug-related: AEs drug-related and unknown relationship.
(*2) excluding AEs present before drug administration and without increase in severity grade along the treatment.
Table 12.2.2 Treatment-related AEs. Worst grade by patient.
SOC
Preferred Term
Grade 
1
…
Grade 
4
All*
N
%
…
N
%
N
%
Blood 
and 
lymphatic 
system disorders
Anaemia Not Otherwise 
Specified (NOS)
...
…
Cardiac disorders
Neuropathy peripheral
…
(*) Any grade.
Table 12.2.3 Treatment-related AEs. Worst grade by cycle.
SOC
Preferred Term
Grade 
1
…
Grade 
4
All*
N
%
…
N
%
N
%
Blood 
and 
lymphatic 
system disorders
Anaemia NOS
...
…
Cardiac disorders
Neuropathy peripheral
…
(*) Any grade.
Table 12.2.4 Adverse Event regardless of relationship. Worst grade by patient.
SOC
Preferred Term
Grade 
1
…
Grade 
4
All*
N
%
…
N
%
N
%
Blood 
and 
lymphatic 
system disorders
Anaemia NOS
...
…
Cardiac disorders
Neuropathy peripheral
…
(*) Any grade.


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Table 12.2.5 Adverse Event regardless of relationship. Worst grade by cycle.
SOC
Preferred Term
Grade 
1
…
Grade 
4
All*
N
%
…
N
%
N
%
Blood 
and 
lymphatic 
system disorders
Anaemia NOS
...
…
Cardiac disorders
Neuropathy peripheral
…
(*) Any grade.
Table 12.2.6 Treatment emergent AEs. Worst grade by patient.
SOC
Preferred Term
Grade 
1
…
Grade 
4
All*
N
%
…
N
%
N
%
Blood 
and 
lymphatic 
system disorders
Anaemia NOS
...
…
Cardiac disorders
Neuropathy peripheral
…
(*) Any grade.
Table 12.2.7 Treatment emergent AEs. Worst grade by cycle.
SOC
Preferred Term
Grade 
1
…
Grade 
4
All*
N
%
…
N
%
N
%
Blood 
and 
lymphatic 
system disorders
Anaemia NOS
...
…
Cardiac disorders
Neuropathy peripheral
…
(*) Any grade.
Listing 12.2.8 Treatment-related grade 3/4 AEs. Worst grade per patient.
Patient id.
Cycle
SOC Name
Preferred term
Grade
Listing 12.2.9 Treatment-related grade 3/4 AEs. Worst grade by cycle.
Patient id.
Cycle
SOC Name
Preferred term
Grade
Listing 12.2.10 Grade 3/4 adverse events regardless of relationship. Worst grade per patient.
Patient id.
Cycle
SOC Name
Preferred term
Grade
Listing 12.2.11 Grade 3/4 adverse events regardless of relationship. Worst grade by cycle.
Patient id.
Cycle
SOC Name
Preferred term
Grade
Listing 12.2.12 Grade 3/4 treatment emergent AEs. Worst grade per patient.
Patient id.
Cycle
SOC Name
Preferred term
Grade
Listing 12.2.13 Grade 3/4 treatment emergent AEs. Worst grade by cycle.
Patient id.
Cycle
SOC Name
Preferred term
Grade


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If appropriate, grouping of similar or clinically related items will be made at the time of the 
analysis.
Figure 12.2.14 Bar chart of treatment-related AEs. Worst grade per patient.
Grade 4
Grade 3
Grade 2
Grade 1
16(42.1%)
5(13.2%)
1(2.6%)
ALT
15(39.5%)
3(7.9%)
1(2.6%)
AST
3(7.9%)
3(7.9%)
3(7.9%)
Abd. pain
10(26.3%)
15(39.5%)
10(26.3%)
Anaemia
4(10.5%)
5(13.2%)
Anorexia
6(15.8%)
3(7.9%)
Constipation
9(23.7%)
2(5.3%)
Diarrhoea
4(10.5%)
2(5.3%)
Dyspnoea
8(21.1%)
15(39.5%)
3(7.9%)
Fatigue
11(28.9%)
5(13.2%)
Nausea
8(21.1%)
5(13.2%)
1(2.6%)
PSN
4(10.5%)
11(28.9%)
7(18.4%)
1(2.6%)
Neutrop.
2(5.3%)
3(7.9%)
Pyrexia
16(42.1%)
10(26.3%)
3(7.9%)
1(2.6%)
Thromb.
6(15.8%)
2(5.3%)
2(5.3%)
Vomiting
Treated patients (n=38)
0
10
20
30
40
50
60
70
80
90
100
12.3.
Serious Adverse Events and Deaths
12.3.1. Serious Adverse Events
Table 12.3.1 Treatment-related SAEs. Worst grade by patient.
SOC
Preferred Term
Grade 
1
…
Grade 
4
All*
N
%
…
N
%
N
%
Blood 
and 
lymphatic 
system disorders
Anaemia NOS
...
…
Nervous system disorders
Neuropathy peripheral
…
(*) Any grade.
Table 12.3.2 Treatment-related SAEs. Worst grade by cycle.
SOC
Preferred Term
Grade 
1
…
Grade 
4
All*
N
%
…
N
%
N
%
Blood 
and 
lymphatic 
system disorders
Anaemia NOS
...
…
Cardiac disorders
Neuropathy peripheral
…
(*) Any grade.
Table 12.3.3 SAEs regardless of relationship. Worst grade by patient.
SOC
Preferred Term
Grade 
1
…
Grade 
4
All*
N
%
…
N
%
N
%
Blood 
and 
lymphatic 
system disorders
Anaemia NOS
...
…
Cardiac disorders
Neuropathy peripheral
…
(*) Any grade.


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Table 12.3.4 SAEs regardless of relationship. Worst grade by cycle.
SOC
Preferred Term
Grade 
1
…
Grade 
4
All*
N
%
…
N
%
N
%
Blood 
and 
lymphatic 
system disorders
Anaemia NOS
...
…
Cardiac disorders
Neuropathy peripheral
…
(*) Any grade.
Listing 12.3.5 Serious Adverse Events.
Patient 
id.
Preferred  
term code
AE
reported 
(verbatim)
Status
Grade
Relationship
Onset 
date
Resolved 
date
Action
Serious criteria
12.3.2. Deaths
Table 12.3.6 Cause of death.
N
%
Deaths
Reason*
Malignant disease
Study drug related AE
Non-study drug related AE
Other
(*) Denominator=Number of patients who died.
Listing 12.3.7 Death.
Patient 
id.
Date of 
death
Cause
Comments
Autopsy
Number 
of 
cycles 
administered
Date of
last 
infusion
Time 
on 
treatment*1
Time from
last dose*2
(*1) Time on treatment: defined as date of last infusion plus 30 days, or date of death or subsequent therapy (whichever 
comes first) minus date of first infusion. (*2) Time from last dose defined as date of death minus date of last infusion. 
Listing 12.3.8 AEs with an outcome of death.
Patient id. Cycle
Preferred  
term code
AE
reported 
(verbatim)
Grade
Relationship
Onset 
date 
Date of death
Action
12.4.
Clinical Laboratory Evaluation
12.4.1. Hematological Abnormalities During Treatment
Hematological toxicities classified according to the NCI-CTCAE v.4 will be calculated for 
all cycles. The worst grade reached by each patient during treatment will also be calculated.


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Table 12.4.1 Hematological abnormalities during treatment, worst grade per patient.
N
Grade 
1
…
Grade 
4
All*
N
N
%
…
N
%
N
%
Anaemia
Leukopenia
Neutropenia
Lymphopenia
Thrombocytopenia
(*) Any grade
Table 12.4.2 Hematological abnormalities during treatment, worst grade per cycle.
N
Grade 
1
…
Grade 
4
All*
N
N
%
…
N
%
N
%
Anaemia
Leukopenia
Neutropenia
Lymphopenia
Thrombocytopenia
(*) Any grade.
Listing 12.4.3 Grade 3/4 hematological abnormalities. Worst grade per patient.
Patient id.
Test
Grade
Listing 12.4.4 Grade 3/4 hematological abnormalities. Worst grade by cycle.
Patient id.
Cycle
Test
Grade
Listing 12.4.5 Hematological tests not assessed per patient.
Patient id.
Lab. test
Listing 12.4.6 Hematological tests not assessed by cycle.
Patient id.
Cycle
Lab. test


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12.4.2. Biochemical Abnormalities During Treatment
Table 12.4.7 Biochemical abnormalities during treatment, worst grade per patient.
N
Grade 
1
…
Grade 
4
All*1
N
%
…
N
%
N
%
ALT increased
AP increased
AST increased
Creatinine increased
Hyperglycemia
Hypernatremia
Hypercalcemia*2
Hyperkalaemia
Hypoglycemia
Hyponatremia
Hypocalcemia*2
Hypokalaemia
Hypoalbuminaemia
GGT increased
(*1) Any grade. (*2) Total plasmatic calcium corrected by albumin.
Table 12.4.8 Biochemical abnormalities during treatment, worst grade by cycle.
(*1) Any grade. (*2) Total plasmatic calcium corrected by albumin.
Listing 12.4.9 Grade 3/4 biochemical abnormalities. Worst grade per patient.
Patient id.
Test
Grade
Listing 12.4.10 Grade 3/4 biochemical abnormalities. Worst grade by cycle.
Patient id.
Cycle
Test
Grade
Listing 12.4.11 Biochemical tests not assessed per patient.
Patient id.
Lab. test
N
Grade 
1
…
Grade 
4
All*1
N
%
…
N
%
N
%
ALT increased
AP increased
AST increased
Creatinine increased
Hyperglycemia
Hypernatremia
Hypercalcemia*2
Hyperkalaemia
Hypoglycemia
Hyponatremia
Hypocalcemia*2
Hypokalaemia
Hypoalbuminaemia
GGT increased


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Listing 12.4.12 Biochemical tests not assessed by cycle.
Patient id.
Cycle
Lab. test
12.4.3. Laboratory abnormalities Over Time
Table 12.4.13 Evolution of hematological abnormalities from baseline, worst case per patient.
Worst grade per patient
Total
0
1
…
N
%
N
%
N
%
N
%
Baseline*
Neutropenia 
Grade 0
Grade 1
……
….
Grade 0
Grade 1
……
Thrombocytopenia
Grade 0
Grade 1
……
(*) Defined as the last value recorded before or on the date of first infusion.
Table 12.4.14 Evolution of biochemical abnormalities from baseline, worst case per patient.
Worst grade per patient
Total
0
1
…
N
%
N
%
N
%
N
%
Baseline*
AST increased
Grade 0
Grade 1
……
ALT increased
Grade 0
Grade 1
……
….
Grade 0
Grade 1
……
(*) Defined as the last value recorded before or on the date of first infusion.
Table 12.4.15 Platelet count and neutrophil count time course pattern (summary).
Laboratory abnormalities
Onset day
grade 3/4
Days with 
grade 3/4
Time to recovery*
Median (range)
Platelet count
Neutrophil count
(*) Defined as the time, in days, from the start of the grade 3/4 abnormality until the abnormality is recovered (grade ≤ 2).
Table 12.4.16 ALT and AST time course pattern (summary).
Laboratory abnormalities
Onset day
grade 3/4
Days with 
grade 3/4
Time to recovery*
Median (range)
ALT
AST
(*) Defined as the time, in days, from the start of the grade 3/4 abnormality until the abnormality is recovered (grade ≤ 2).


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12.5.
Physical Findings, ECOG PS, LVEF, ECG and Other Tests
12.5.1. Physical Findings and ECOG PS
Table 12.5.1 ECOG performance status during the study.
(*) Worst ECOG PS of the cycle determinations.
Table 12.5.2 Physical examination during the study.
(*) Worst result per cycle.
Table 12.5.3 Weight by patient per cycle.
(*) % of changes compared to baseline.
12.5.2. LVEF, ECG and Other Related Tests
Listing 12.5.4 LVEF evolution during the study.
Patient id.
LVEF (%)
Baseline*
Minimum*
End of treatment*
Median (Range)
(*) LVEF (%) value and method.
Listing 12.5.5 Electrocardiogram results. Evolution during the study.
(*) Worst result of the cycle measurements.
Cycle/PS*
0
1
2
3
4
…
EOT
Patient id.
…
…
Cycle/Physical examination result*
0
1
2
3
4
…
EOT
Patient id.
…
Cycle/Weight
0
(kg)
1*
(%)
2*
(%)
3*
(%)
4*
(%)
…*
(%)
EOT*
(%)
Patient id.
…
Cycle/ECG result*
0
1
2
3
4
…
EOT
Patient id.
…
…


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12.6.
Concomitant Therapy / Procedures According to the ATC Classification
Table 12.6.1 Concomitant medication during treatment (ATC1/ATC2/ATC4/PN).
Concomitant medication during treatment
N
%
Alimentary tract and metabolism
   Antacids
      Magnesium compounds
          Magnesium adipate
…
Blood and blood forming organs
   Antithrombotic agents
      Vitamin K antagonists
          Acenocoumarol
…
Table 12.6.2 Summary of concomitant medication during treatment.
N
%
No. of systems (ATC1 level)
0
1
2
3
Median (range)
No. of indications (ATC2 level)
0
1
2
3
Median (range)
No. of agent families (ATC4 level)
0
1
2
3
Median (range)
No. of agents (PN level)
0
1
2
3
Median (range)
Listing 12.6.3 Patients with any transfusion during treatment.
Patient
Cycle Treatment
Drug dose in 
the previous 
cycle
Platelets 
/ RBC
Date 
of first 
transfusion
Date of last transfusion
No. of units required*
(*) No. of transfusions for platelets or no. of packages for RBC transfusions.


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Table 12.6.4 Subsequent therapy.
N
%
Type
  Chemotherapy
   …
Subsequent chemotherapy agents (ATC)
  …
   …


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II.
APPENDIX: DATABASE LISTINGS
CRF Listings.
-Listing II.1.1.: Cover
-Listing II.1.2.: Screening
-Listing II.1.3.: Demography
-Listing II.1.4.: Pregnancy test and adequate contraception
-Listing II.1.5.: Prior medical history
-Listing II.1.6.: Cancer history: First diagnosis
-Listing II.1.7.: Cancer history: Current disease
-Listing II.1.8.: Prior surgery
-Listing II.1.9.: Prior radiotherapy
-Listing II.1.10.: Prior anticancer medical therapy
-Listing II.1.11.: Peripheral Neuropathy
-Listing II.1.12.: Prophylactic medication
-Listing II.1.13.: Drug administration
-Listing II.1.14.: Hematology laboratory values
-Listing II.1.15.: Biochemistry laboratory values
-Listing II.1.16.: Other metabolic laboratory values
-Listing II.1.17.: Performance status
-Listing II.1.18.: Physical examination
-Listing II.1.19.: Vital signs
-Listing II.1.20.: Electrocardiogram
-Listing II.1.21.: LVEF
-Listing II.1.22.: Other tests/ procedures
-Listing II.1.23.: Tumor assessment
-Listing II.1.24.: Evaluation of response by cycle
-Listing II.1.25.: Best study overall response
-Listing II.1.26.: Concomitant medication/ procedures
-Listing II.1.27.: End of treatment
-Listing II.1.28.: EORTC QLQ C30
-Listing II.1.29.: EORTC QLQ CIPN20
-Listing II.1.30.: Adverse events (including signs and symptoms)
-Listing II.1.31.: Follow up
-Listing II.1.32.: Surgery procedures (after end of treatment)
-Listing II.1.33.: Radiotherapy (after end of treatment)
-Listing II.1.34.: Medical treatment (after end of treatment)
-Listing II.1.35.: Death report form
-Listing II.1.36.: Off study
-Listing II.1.37.: Signature report


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III.
APPENDIX: ICH LISTINGS
In accordance with ICH E-3 guidelines, the patient listings specified as Section 16.2 will be 
prepared.
- 16.2.1 Discontinued Patients
- 16.2.2 Protocol Deviations
- 16.2.3 Patients Not Included in the Efficacy Analysis
- 16.2.4 Demographic Data
- 16.2.5 Compliance and/or Drug Concentration Data
- 16.2.6 Individual Efficacy Response Data
- 16.2.7 Adverse Event Listing (each patient)
- 16.2.8 Listing of Individual Laboratory Measurements by Patient


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13.REFERENCES
1. Fayers, Peter, et al., et al. EORTC QLQ-C30 Scoring Manual (3rd edition). Brussels : 
European Organisation for Research and Treatment of Cancer, 2001. 2-9300-6416-1.