Clinical trial NCT02100657
Conditions: Multiple Myeloma
Keywords: multiple myeloma plitidepsin APLIDIN
Sponsor: PharmaMar
Start date: 2014-06-01; Completion date: 2018-06-01
Enrollment: 39 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Study of Plitidepsin (Aplidin®) to determine the recommended dose (RD) of plitidepsin in Combination with Bortezomib and Dexamethasone in Patients with Relapsed and/or Refractory Multiple Myeloma.

Detailed description:
Phase I Multicenter, Open-label, Dose-escalating Clinical and Pharmacokinetic Trial of Plitidepsin (Aplidin®) to determine the recommended dose (RD) of plitidepsin in combination with bortezomib and dexamethasone in patients with relapsed and/or refractory multiple myeloma (MM), to determine the efficacy of the combination plitidepsin/bortezomib/dexamethasone, to evaluate the safety and tolerability of the combination in patients with relapsing and/or refractory MM and to study the pharmacokinetics (PK) and pharmacodynamics (PDy) of plitidepsin in combination with bortezomib and dexamethasone.

Arms: arm 1: Plitidepsin will be administered as a 3-hour (h) intravenous (i.v.) infusion on Day (D) 1 and 15, every four weeks (q4wk).

Bortezomib will be administered as a subcutaneous (s.c.) injection on D1, 4, 8 and 11, q4wk, for a maximum of eight cycles.

Dexamethasone will be taken orally on D1, 8, 15 and 22, q4wk
Interventions: intervention 1: Plitidepsin intervention 2: Bortezomib intervention 3: Dexamethasone
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None

Protocol documents:
Prot_000.pdf: 
 
SPONSOR: 
 
Pharma Mar, S.A. Sociedad Unipersonal 
Avda de los Reyes, 1 
Polígono Industrial “La Mina” 
28770 Colmenar Viejo (Madrid), Spain 
Phone: + 34 918 466 000  
Fax:  
+ 34 918 466 003 
 
 
CLINICAL TRIAL PROTOCOL 
 
 
 
Phase I Study of Plitidepsin (Aplidin®) in Combination with Bortezomib and 
Dexamethasone in Patients with Relapsed and/or Refractory Multiple Myeloma  
 
 
INVESTIGATIONAL MEDICINAL PRODUCT: plitidepsin (Aplidin®) 
 
bortezomib (Velcade®) 
 
dexamethasone  
Protocol No.: APL-A-012-13 
EudraCT No.: 2013-003835-31 
NCT Code: 02100657 
 
 
 
Version 3.0 (including Amendment #2): 8 October 2015 
 


SPONSOR:
PharmaMar S.A., Sociedad Unipersonal
Avda de los Reyes, 1
Polígono Industrial “La Mina”                                              
28770 Colmenar Viejo (Madrid) Spain
Phone: + 34 91 846 6000 
Fax:
+ 34 91 846 6003
CLINICAL PROTOCOL
APL-A-012-13
Phase I Study of Plitidepsin (Aplidin®) in Combination with Bortezomib and 
Dexamethasone in Patients with Relapsed and/or Refractory Multiple Myeloma
INVESTIGATIONAL MEDICINAL PRODUCTS: plitidepsin (Aplidin®)
                             bortezomib (Velcade®)
                             dexamethasone
Eudra CT : 2013-003835-31
Version 3.0 (including Amendment #2): 8 October 2015
This study will be conducted in compliance with the protocol, GCP and applicable regulatory 
requirements.
CONFIDENTIAL
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 by 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
CONTACT DETAILS
PharmaMar S.A.U.
Avda. de los Reyes, 1
Polígono Industrial “La Mina”
28770 Colmenar Viejo
Madrid
Spain
Phone: +34 91 846 6000
Fax:
+34 91 846 6003
Responsible 
Physician(s)
José Rodríguez Diaz-Pavón, 
MD, PhD
Sara Martínez Gonzalez, MD
Clinical Oncology
Clinical Development Area
Phone: +34 91 846 6157
Fax: +34 91 823 4504 
e-mail: 
jrodriguez@pharmamar.com
Phone: +34 91 823 4647
Fax: +34 91 823 4504 
e-mail: 
smgonzalez@pharmamar.com
Project Manager
Clinical Trial Monitor
Pilar García Paramio, PhD
Clinical Operations
Clinical Development Area
Pharma Mar CRA
Clinical Operations
Clinical Development Area
Phone: +34 91 823 4597
Phone: +34 91 823 4529
E-mail: mpgarcia@pharmamar.com
Phone: +34 91 823 6000
Fax:
+34 91 846 6003
Phamacovigilance
Carmen Martinez Caballero, 
MD
Pharmacovigilance (PhV)
Clinical Development
Pharma Mar S.A.
Phone: +34 91 823 4569
Fax:    +34 91 846 6004
E-mail: phv@pharmamar.com
Out of office hours (GMT)
PhV service phone:
+34 91 823 47 42
Clinical Pharmacology
Salvador Fudio Muñoz. MD
Clinical Pharmacology
Clinical Development
Pharma Mar S.A.
Phone: + 34 91 823 4521
Fax:
+ 34 91 823 4504
E-mail: sfudio@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
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TABLE OF CONTENTS
STUDY CONTACTS.................................................................................................................. 2
TABLE OF CONTENTS............................................................................................................ 3
SYNOPSIS ................................................................................................................................... 6
SCHEDULE OF ASSESSMENTS........................................................................................... 17
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .......................................... 19
1.
BACKGROUND...................................................................................................... 22
1.1
Overview of the Disease........................................................................................... 22
1.2
Current Treatment for Multiple Myeloma............................................................ 22
1.3
Plitidepsin ................................................................................................................. 24
1.3.1
Name and Chemical Information........................................................................... 24
1.3.2
Non-clinical Data...................................................................................................... 24
1.3.2.1
Mechanism of Action in Cell Lines ..................................................................... 24
1.3.2.2
Plitidepsin as Single Agent: In vitro and In vivo Data........................................ 25
1.3.2.3
Plitidepsin in Combination: In vitro and In vivo Data ....................................... 26
1.3.2.4
Toxicology............................................................................................................. 30
1.3.2.5
Safety Pharmacology............................................................................................ 30
1.3.3
Clinical Data............................................................................................................. 31
1.3.3.1
Phase I Trials........................................................................................................ 31
1.3.3.2
Phase II Trials ...................................................................................................... 34
1.3.3.3
Phase III Program................................................................................................ 35
1.3.4
Summary of Pharmacokinetic Results................................................................... 35
1.4
Bortezomib ............................................................................................................... 36
1.4.1
Scientific Background.............................................................................................. 36
1.4.2
Mechanism of Action............................................................................................... 37
1.4.3
Preclinical Experience ............................................................................................. 37
1.4.4
Clinical Pharmacology ............................................................................................ 37
1.4.5
Phase I Clinical Experience .................................................................................... 38
1.4.6
Phase II Clinical Experience................................................................................... 39
1.4.7
Safety Issues ............................................................................................................. 41
1.5
Study Rationale and Drug Selection ...................................................................... 42
2.
OBJECTIVES.......................................................................................................... 43
2.1
Primary Objective.................................................................................................... 43
2.2
Secondary Objectives .............................................................................................. 43
3.
OVERALL STUDY DESIGN................................................................................. 43
3.1
Study Endpoints....................................................................................................... 45
3.1.1
Primary Endpoint.................................................................................................... 45
3.1.2
Secondary Endpoints............................................................................................... 45
3.2
Number of Patients.................................................................................................. 45
3.3
Selection of Patients................................................................................................. 45
3.3.1
Inclusion Criteria..................................................................................................... 46
3.3.2
Exclusion Criteria.................................................................................................... 47
4.
PLAN OF THE STUDY.......................................................................................... 49
4.1
Duration of the Study Individually per Patient .................................................... 49
4.2
Duration of the Study (for the Whole Study) ........................................................ 49
4.3
Subject Participation............................................................................................... 49
4.4
Discontinuations....................................................................................................... 50
4.5
Replacement of Patients .......................................................................................... 50
4.6
Screening and Baseline Assessments...................................................................... 51
4.7
Treatment Period Assessments............................................................................... 52
4.8
Evaluations at the End of Treatment..................................................................... 54
4.8.1
End-of-treatment Visit ............................................................................................ 54
4.8.2
Follow-up Visits ....................................................................................................... 56
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5.
STUDY MEDICATION.......................................................................................... 56
5.1
Plitidepsin ................................................................................................................. 56
5.1.1
Plitidepsin Recommendations for Safe Handling ................................................. 56
5.1.2
Required Prophylactic Medication ........................................................................ 56
5.2
Bortezomib ............................................................................................................... 57
5.2.1
Prophylactic Medication ......................................................................................... 57
5.3
Dexamethasone Drug Formulation ........................................................................ 57
5.4
Treatment Schedule................................................................................................. 57
5.5
Criteria for Treatment Continuation and Re-treatment...................................... 57
5.6
Definition of Dose-limiting Toxicity ....................................................................... 59
5.7
Definition of Recommended Dose........................................................................... 60
5.8
Dose Escalation ........................................................................................................ 60
5.9
Dose Modifications Based on Adverse Events....................................................... 61
5.10
Permitted Treatment and Medication ................................................................... 62
5.10.1
Transfusions......................................................................................................... 62
5.10.1.1
Guidelines for Platelet Transfusions............................................................... 62
5.10.1.2
Guidelines for Red Cell Transfusions ............................................................. 62
5.10.2
Other Therapies................................................................................................... 63
5.11
Prohibited Medication............................................................................................. 63
5.12
Packaging and Labeling .......................................................................................... 63
5.13
Drug Accountability ................................................................................................ 64
6.
STUDY ASSESSMENTS ........................................................................................ 64
6.1
Efficacy ..................................................................................................................... 64
6.1.1
Response Criteria for Multiple Myeloma.............................................................. 64
6.1.1.1
Stringent Complete response (sCR) ..................................................................... 64
6.1.1.2
Complete response (CR)....................................................................................... 64
6.1.1.3
Very good partial response (VGPR)..................................................................... 65
6.1.1.4
Partial response (PR)............................................................................................ 65
6.1.1.5
Minimal response (MR)........................................................................................ 65
6.1.1.6
Stable Disease (SD) .............................................................................................. 65
6.1.1.7
Progressive disease (PD) ...................................................................................... 65
6.1.1.8
Overall Response Rate (ORR).............................................................................. 65
6.1.1.9
Cinical Benefit Rate.............................................................................................. 65
6.1.2
Additional Efficacy Endpoints................................................................................ 66
6.1.3
Efficacy Assessment Determinations...................................................................... 66
6.1.3.1
Myeloma Protein Measurements ......................................................................... 66
6.1.3.2
Bone Marrow........................................................................................................ 67
6.1.3.3
Skeletal Survey and Other Radiographs.............................................................. 67
6.1.3.4
Beta-2-Microglobulin and C-Reactive Protein.................................................... 67
6.2
Safety Assessment .................................................................................................... 67
6.2.1
Adverse Event Definitions....................................................................................... 67
6.2.1.1
Adverse Event ....................................................................................................... 67
6.2.1.2
Serious Adverse Event.......................................................................................... 68
6.2.1.3
Death..................................................................................................................... 68
6.2.1.4
Life Threatening Event ........................................................................................ 68
6.2.1.5
Hospitalization /Prolongation of Hospitalization................................................ 68
6.2.1.6
Unexpected/Unlisted Adverse Event .................................................................... 69
6.2.1.7
Adverse Reaction .................................................................................................. 69
6.2.1.8
Adverse Events Related to the Study Drug .......................................................... 69
6.2.1.9
Expedited Reporting ............................................................................................. 69
6.2.1.10
Causality Assessment ....................................................................................... 69
6.2.2
Adverse Event Reporting Procedures.................................................................... 70
6.2.2.1
Reporting of Adverse Events ................................................................................ 70
6.2.2.2
Reporting Serious Adverse Events....................................................................... 70
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6.2.2.3
Pregnancy ............................................................................................................. 71
6.2.3
Adverse Events Monitoring .................................................................................... 71
6.2.3.1
Discontinuations................................................................................................... 72
7.
PHARMACOKINETIC STUDIES........................................................................ 72
7.1
Pharmacokinetic calculations ................................................................................. 74
8.
STATISTICAL METHODS ................................................................................... 75
8.1
Assessment of the Primary Endpoint..................................................................... 75
8.2
Efficacy ..................................................................................................................... 75
8.3
Toxicity and Adverse Events .................................................................................. 76
8.4
Other Analyses......................................................................................................... 77
8.5
Baseline and Demographic Data ............................................................................ 77
8.6
Treatment Administration...................................................................................... 77
8.7
Protocol Deviations.................................................................................................. 77
8.8
Pharmacokinetics..................................................................................................... 78
8.9
Procedures for Reporting Deviations to Original Statistical Analysis Plan....... 78
9.
ADMINISTRATIVE REQUERIMENTS.............................................................. 78
9.1
Ethics......................................................................................................................... 78
9.2
Monitoring, Auditing and Inspecting..................................................................... 79
9.3
Patient Informed Consent....................................................................................... 79
9.4
Confidentiality/Patients Identification................................................................... 80
9.5
Case Report Forms .................................................................................................. 80
9.6
Insurance .................................................................................................................. 80
9.7
Records Retention.................................................................................................... 80
9.8
Use of Information and Publication....................................................................... 80
10.
REFERENCES......................................................................................................... 82
Appendix 1. Performance Status ........................................................................................... 87
Appendix 2. Cockcroft and Gault’s Formula for Calculating Creatinine Clearance....... 88
Appendix 3.  Multiple Myeloma Diagnosis Criteria ............................................................ 89
Appendix 4. Durie Salmon Staging Criteria......................................................................... 90
Appendix 5. Lists of Drugs that Prolong the Qt Interval and/or Induce Torsades de 
Pointes Ventricular Arrhythmia............................................................................................ 91
Appendix 6. Declaration of Helsinki...................................................................................... 97
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SYNOPSIS
TITLE
Phase I Study of Plitidepsin (Aplidin®) in Combination with 
Bortezomib and Dexamethasone in Patients with Relapsed and/or 
Refractory Multiple Myeloma
PROTOCOL CODE
APL-A-012-13
INVESTIGATORS / 
STUDY LOCATION
A complete list will be provided as a separate document.
STUDY OBJECTIVES 
Primary

To determine the recommended dose (RD) of plitidepsin in 
combination with bortezomib and dexamethasone in patients 
with relapsed and/or refractory multiple myeloma (MM).
Secondary

To determine the efficacy of the combination plitidepsin/ 
bortezomib/dexamethasone.

To evaluate the safety and tolerability of the combination in 
patients with relapsed and/or refractory MM.

To study the pharmacokinetics (PK) and pharmacodynamics
(PDy) of plitidepsin in combination with bortezomib and 
dexamethasone.
STUDY DESIGN
This is a phase I dose finding study in patients with relapsed and/or 
refractory MM. Patients will be enrolled sequentially into three dose 
levels (DLs). The feasibility of administering plitidepsin in 
combination with bortezomib and dexamethasone and the RD of the 
combination will be determined.

Plitidepsin will be administered as a 3-hour (h) intravenous (i.v.)
infusion on Day (D) 1 and 15, every four weeks (q4wk).

Bortezomib will be administered as a subcutaneous (s.c.)
injection on D1, 4, 8 and 11, q4wk, for a maximum of eight 
cycles.

Dexamethasone will be taken orally on D1, 8, 15 and 22, q4wk.
STUDY POPULATION
Patients with relapsed and/or refractory MM.

Refractory myeloma is defined as disease that is non-
responsive while on primary or salvage therapy, or progresses 
within 60 days of the last therapy. There are two categories of 
refractory myeloma:
Primary refractory myeloma is defined as disease that is 
non-responsive in patients who have never achieved a 
minimal response (MR) or better, with any therapy. It 
includes patients who never achieve MR or better in whom 
there is no significant change in monoclonal protein (M-
protein) and no evidence of clinical progression as well as 
primary, refractory disease progression (PD) where patients 
meet criteria for true PD.
Relapsed and refractory myeloma is defined as disease 
that is non-responsive while on salvage therapy, or 
progresses within 60 days of the last therapy in patients 
who have achieved MR or better at some point previously 
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before progressing.

Relapsed myeloma is defined as previously treated myeloma 
that progresses and requires the initiation of salvage therapy but 
does not meet the criteria for either “primary refractory” or 
“relapsed-and-refractory” myeloma categories.
INCLUSION 
CRITERIA
1)
Patients must give written informed consent (IC) in 
accordance with institutional and local guidelines.
2)
Age ≥ 18 years.
3)
Patients must have a confirmed diagnosis of MM according 
to the Durie and Salmon criteria.
4)
Patients must have relapsed and/or refractory disease.
5)
Patients must have measurable disease defined as any of the 
following:
a)
Serum M-protein > 0.5 g/dL or > 0.2 g/24-h urine light 
chain (FLC) excretion. 
a)
In patients who lack measureable M-protein in serum or 
urine, i.e. serum M-protein < 0.5 g/dL and urine M-protein 
< 0.2 g/24 h, serum free light chain (SFLC) levels are most 
informative. SFLC levels can be used only if the baseline 
SFLC ratio is abnormal (<0.26 or >1.65), indicating 
clonality. In addition, the baseline SFLC level must be ≥10 
mg/dl of the appropriate involved light chain isotype.
b)
When applicable, measurable soft tissue plasmacytoma > 2 
cm, by either physical examination and/or applicable 
radiological evaluation (i.e. magnetic resonance imaging 
[MRI], computed tomography [CT]-scan).
6)
Prior autologous and/or allogeneic hematopoietic stem cell 
transplantation (HSCT) patients are allowed. Patients must 
not have acute/chronic graft-versus-host disease (GVHD) or 
be receiving immunosuppressive therapy at least 30 days 
before  the onset of treatment with the study drug(s).
7)
Patients must have received at least one previous treatment 
line, which can consist of:
a)
Induction regimen followed by high dose chemotherapy 
(CT) and peripheral blood stem cell collection.
b)
Induction 
regimen 
alone 
according 
to 
institutional 
guidelines. 
c)
High doses of CT
followed by non-myeloablative 
transplantation.
d)
CT followed by either single or tandem autologous stem 
cell transplantation (ASCT).
e)
CT followed by autologous and (if performed) subsequent 
non-myeloablative allogeneic stem cell transplantation.
f)
Previous line(s) of systemic CT and biological agents
should have been completed at least 30 days and 15 days, 
respectively, prior to starting protocol treatment.
8)
Previous treatment with bortezomib or another proteasome 
inhibitor (PI) is allowed provided patients achieved at least 
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MR lasting a minimum of two months.
9)
Patients must have an Eastern Cooperative Oncology Group 
(ECOG) performance status (PS) ≤ 2.
10)
Recovery to grade ≤ 1 from any non-hematological adverse 
event (AE) derived from previous treatment (excluding 
alopecia).
11)
Laboratory data:
a)
Hemoglobin ≥ 8 g/dL.
b)
Absolute neutrophil count (ANC) ≥ 1,000 cells/mm3 (1.0 x 
109/L) (≥ 0.5 x 109/L if due to extensive bone marrow [BM]
involvement –by ≥ 50% of plasma cells in BM biopsy). 
Screening of ANC should be independent of granulocyte-
and granulocyte/macrophage-colony stimulating factor 
(GCSF and GM-CSF) support for at least one week and of 
pegylated G-CSF for at least two weeks.
c)
Platelet count ≥ 50,000/ mm3 (50.0 x 109/L) for patients in 
whom < 50% of the BM nucleated cells are plasma cells.
d)
Platelet count ≥ 25,000/ mm3 (25.0 x 109/L) for patients in 
whom ≥50% of BM nucleated cells are plasma cells.
e)
Serum total bilirubin < 1.5 x institutional upper limit of 
normal (ULN) (except when Gilbert syndrome is clearly 
documented and other liver function tests are within normal 
levels).
f)
AST (aspartate aminotransferase) and ALT (alanine 
aminotransferase) 3.0 x institutional ULN and AP 
(alkaline phosphatase) 2.5 x institutional ULN.
g)
Creatinine clearance (CrCl) > 30 mL/min, measured or 
calculated according to Cockcroft and Gault’s formula.
h)
Albumin ≥ 2.5 g/dl.
12)
Women of child-bearing potential must have a negative 
serum or urine pregnancy test within seven days prior to 
enrolment. In addition, all sexually active women of child-
bearing potential and fertile male patients must agree to use 
adequate contraceptive methods throughout the study and 
during six months after treatment discontinuation.
13)
Left ventricular ejection fraction (LVEF) above the lower 
limit of normal.
14)
Patients must have a BM assessment within three weeks 
prior to enrolment.
EXCLUSION 
CRITERIA
1)
Previous treatment with plitidepsin.
2)
Active or metastatic primary malignancy other than MM.
3)
Serious concomitant systemic disorders that would 
compromise the safety of the patient or the patient’s ability 
to complete the study, including the following specific 
conditions: 
a)
Uncontrolled psychiatric illness or medical illness that the 
Investigator feels will compromise the patient’s tolerance of 
the study medication.
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b)
Significant non-neoplastic liver disease.
c)
Uncontrolled endocrine diseases (i.e., requiring relevant 
changes in medication within the last month, or hospital 
admission within the last three months).
d)
Uncontrolled systemic infection.
4)
Other relevant cardiac conditions:
a)
Symptomatic arrhythmia (excluding anemia-related grade ≤ 
2 sinusal tachycardia) or any arrhythmia requiring ongoing 
treatment, and/or prolonged grade ≥ 2 QT-QTc; or presence 
of unstable atrial fibrillation (according to the National 
Cancer Institute Common Terminology Criteria for the 
Classification of Adverse Events [NCI-CTCAE] v4.0). 
Patients on treatment for stable atrial fibrillation are 
allowed, provided they do not meet any other cardiac or 
prohibited drug exclusion criterion.
b)
History or presence of unstable angina, myocardial 
infarction, valvular heart disease, cardiac amyloidosis or
congestive heart failure within the last 12 months.
c)
Uncontrolled arterial hypertension (≥150/100 mmHg) 
despite optimal medical therapy.
d)
Previous treatment with doxorubicin at cumulative doses of 
> 400 mg/m².
5)
History of hypersensitivity reactions
to bortezomib, 
polyoxyl 35 castor oil or mannitol.
6)
Myopathy or any clinical situation that causes significant 
and persistent elevation of creatine phosphokinase (CPK) (> 
2.5 ULN) in two different determinations performed within 
one week of each other.
7)
Sequelae of any grade ≥ 1 neuropathy (either bortezomib-
related or not) according to NCI-CTCAE v4.0.
8)
Any other major illness that, in the Investigator’s judgment, 
will substantially increase the risk associated with the 
patients’ participation in this study.
9)
Pregnant and/or lactating women.
10)
Known active human immunodeficiency virus (HIV) 
infection (HIV testing is not required unless infection is 
clinically suspected).
11)
Active hepatitis B or C virus (HBV or HCV) infection.
12)
Treatment with any Investigational Medicinal Product
(IMP) in the 30 days before inclusion in the study.
13)
Concomitant medications that include corticosteroids, CT, 
or other therapy that is or may be active against myeloma. 
Concurrent corticosteroids are allowed as an equivalent to a
prednisone dose of ≤ 10 mg daily, administered as an 
antiemetic or as premedication for blood products.
14)
Wash-out periods after the end of the previous therapy:
a)
Nitrosoureas must be discontinued six weeks prior to Cycle
(C) 1, D1.
b)
Thirty days for other CTs and 15 days for other biological 
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agents prior to C1 D1.
c)
Thirty days after the end of any prior radiation or 
radionuclide therapy (six weeks in the case of prior 
extensive external beam radiation, with more than 25% of 
BM distribution).
15)
Plasma cell leukemia at the time of study entry.
16)
Disease-related symptomatic hypercalcemia despite optimal 
medical therapy.
17)
Limitation of the patient’s ability to comply with the 
treatment or follow-up protocol.
18)
Contraindication for the use of steroids.
EXPECTED NUMBER 
OF PATIENTS
Cohorts of 3-6 patients per dose level (up to three DLs) will be 
treated until the RD is defined. At the RD, at least six patients 
evaluable for determination of dose-limiting toxicities (DLTs) will 
be treated.
A total of 20-30 patients are expected to participate. However, the 
number of patients may vary depending upon the tolerability of the 
combination and the number of DLs required to identify the RD.
EXPECTED NUMBER 
OF CENTERS
Five to 10 centers are expected to participate in the clinical trial. A 
complete list of centers will be provided as a separate document.
STUDY DRUGS  
FORMULATION
Plitidepsin (Aplidin®) is supplied as a lyophilized product in a 
glass vial containing 2 mg. The lyophilized powder is a concentrate 
for solution and contains plitidepsin as the active ingredient and 
mannitol as the inactive ingredient. The reconstitution solvent is 
supplied in ampoules, each containing 4 mL of polyoxyl 35 castor 
oil/ethanol/WFI 
(15/15/70% 
v/v/v).
Plitidepsin 
vials 
and 
reconstitution ampoules should be stored in a locked area with 
limited access at 2 to 8ºC (36ºF to 46ºF) and protected from 
exposure to light.
Bortezomib (Velcade®) is available for i.v. or s.c. injection use. 
Each single dose vial contains 3.5 mg of bortezomib as a sterile 
lyophilized powder. For further information on the drug product, 
please refer to the EU SmPC or the USP.  
Dexamethasone is administered orally as tablets that should be 
stored in well-closed containers.
TREATMENT 
SCHEDULE
A treatment cycle consists of oral dexamethasone administered on 
D1, 8, 15 and 22, q4wk at least one hour before a 3h i.v. infusion of 
plitidepsin on D1 and 15, q4wk, and immediately followed by a 3-5 
second bolus s.c. injection of bortezomib on D1, 4, 8 and 11, q4wk.
Treatment cycles will be repeated q4wk.
Patients will receive a maximum of eight treatment cycles. If the 
patient responds to treatment or achieves stable disease (SD) during 
this time, treatment with plitidepsin and dexamethasone may 
continue in further cycles at the same plitidepsin dose upon 
Investigator’s decision and agreement with the Sponsor.
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CRITERIA FOR 
TREATMENT 
CONTINUATION
Before the administration of each dose (re-treatment), patients must 
fulfill the baseline criteria, as defined in the following table: 
Plitidepsin
Bortezomib
Day 1a and 15b
Day 1a*, 4 b, 8 b and 
11 b
ANC
1.0 x 109/L (≥ 0.5 
x109/L if due to 
extensive BM
involvement)
1.0 x 109/L (≥ 0.5 
x109/L if due to 
extensive BM
involvement)
Platelets
≥ 50.0 x 109/L
(≥ 25.0 x 109/L if ≥
50% of BM 
nucleated cells are 
plasma cells)
≥ 50.0 x 109/L (≥ 
25.0 x 109/L if ≥ 
50% 
of 
BM 
nucleated cells are 
plasma cells)
Hemoglobin
8.0 g/dL
8.0 g/dL
Serum total bilirubin 
1.5 x ULNe
1.5 x ULNe
AST/ALT/AP
2.5 x ULN
2.5 x ULN
Muscular toxicity (myalgia, 
muscular weakness, CPK 
increase)
< Grade 2
< Grade 2
Other non-hematological 
drug-related AEs (except for 
increased GGT, non-optimally 
treated nausea and vomiting, 
hypertension, alopecia)c
< Grade 2
< Grade 2
ECG, ECHO/MUGAd
Baseline values
Baseline values
aIf a patient does not meet the requirements for treatment continuation on D1 of the 
following cycle, the infusion of study drugs will be withheld until recovery or for a 
maximum of 14 days. After this period, if the delay is due to toxicity assessed as related to 
a study drug, a dose reduction by one DL is mandatory; up to a maximum of two 
individual dose reductions are allowed. Patients needing additional dose reductions must 
be withdrawn from the study.
a*From C2 onwards, Hematology and Biochemistry A will only be collected on D1 and 
15, hence only re-treatment criteria other than Hematology/Biochemistry A will apply on 
D4, 8 and 11.
bIf a patient does not meet the requirements for treatment continuation on Day 15
(plitidepsin) or D4, 8 or 11 (bortezomib), the administration of plitidepsin or bortezomib, 
respectively, will be omitted. Patients requiring frequent dose omissions may have a dose 
reduction by one DL upon Investigator and Sponsor’s agreement. Under no circumstances 
will more than two dose reductions be allowed. 
cAny grade accepted for increased GGT.
dTo be performed every three months unless more frequent assessments are clinically 
indicated.
eExcept when Gilbert syndrome is clearly documented and other liver function tests are 
normal.
AEs, adverse event(s); ALT, alanine aminotransferase; ANC, absolute neutrophil count; 
AP, alkaline phosphatase; AST, aspartate aminotransferase; BM, bone marrow; CPK,
creatine phosphokinase; D, day; DL, dose level; ECG, electrocardiogram; ECHO/MUGA,
echocardiogram/multiple-gated acquisition scan; GGT, -glutamyltranspeptidase; L, liter; 
ULN, upper limit of normality.
The 
following 
guidelines 
must 
be 
followed 
before 
the 
administration of each bortezomib dose: 
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Severity of PN
signs and symptoms*
Recommended modification of 
bortezomib dose and regimen
Grade 1 (paresthesia; weakness and/or 
loss of reflexes) without pain or loss 
of function
Reduce current bortezomib dose by 
one DL (1.3 to 1.0 mg/m2) or, for 
patients receiving a twice-weekly 
schedule, change to a once-per-week 
schedule using the same dose.
Grade 1 with pain or grade 2  (with no 
pain but limiting instrumental 
ADLs**)
For patients receiving twice-weekly 
bortezomib, reduce current dose by 
one DL or change to a once-per-week 
schedule using the same dose.
For patients receiving bortezomib on a 
once-per-week schedule, reduce 
current dose by one DL, or consider 
temporary discontinuation; upon 
resolution to grade ≤1, restart once-
per-week dosing at a lower DL in 
cases of favorable benefit/risk ratio.
Grade 2 with pain or grade 3 (limiting 
selfcare and ADL***) or grade 4
Discontinue bortezomib
*Based on posology modifications in phase II and III MM studies and post-marketing 
experience. Grading based on NCI-CTCAE v 4.0.
**Instrumental ADL: refers to preparing meals, shopping for groceries or clothes, using 
telephone, managing money, etc.
***Self care ADL: refers to bathing, dressing and undressing, feeding self, using the 
toilet, taking medicinal products, and not bedridden.
ADL, activities of daily living; DL, dose level; MM, multiple myeloma; NCI-CTCAE, 
National Cancer Institute Common Terminology Criteria for the Classification of Adverse 
Events; PN, peripheral neuropathy.
The criteria for treatment continuation with dexamethasone are to 
be implemented independently from those of plitidepsin and 
bortezomib. Dexamethasone treatment will therefore not be 
delayed in parallel to plitidepsin/bortezomib; if a patient 
experiences grade ≥ 3 muscular toxicity (weakness, myalgia 
and/or CPK elevations), or drug-related grade ≥ 3 fatigue, or 
grade ≥ 2 mood disturbances or agitation or grade ≥ 3 fluid 
retention or grade 4 clinically documented infection, the dose of 
dexamethasone will be reduced by 50%, up to a maximum of two 
consecutive dose reductions (20 mg D1, 8, 15 and 22, and 20 mg 
D1 and 15 of each 28-day cycle). After two dose reductions, 
dexamethasone will be discontinued.
DOSE ESCALATION 
SCHEME
Dose escalation for plitidepsin and bortezomib will follow the rules 
shown in the table:
DL
Number of
Patients
Plitidepsin 
dose 
(mg/m2)
Bortezomib 
dose
(mg/m2)
Dexamethasone
dose
(mg)
-1
0-6
3.0
1.0
40.0
1
3-6
4.0
1.0
40.0
2
3-6
4.0
1.3
40.0
3
3-6
5.0
1.3
40.0
DL, Dose level.
Cohorts of three patients will be treated at each DL (up to three 
DLs):

The first cohort of three patients will start at DL1.

If no DLTs are observed in any of the three patients at a given 
DL, three additional patients will be treated at the next DL.
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
If a DLT is observed in one of three patients treated at a given 
DL, three additional patients will be entered at that same DL.

If DLTs are observed in two of three patients, no additional 
patients will be treated at that DL and the immediately lower DL
will be expanded to at least six patients.

If two out of six patients present DLTs at DL1, the next patients 
enrolled will be treated at DL -1. If two out of six patients 
(≥33%) present DLTs at this DL, the study will be stopped and 
that DL will be considered the maximum tolerated dose (MTD). 

The RD is defined as the DL at which fewer than two out of six
patients (33% of patients) experience DLTs during the first 
cycle.

At the RD, at least six evaluable patients for the determination 
of DLTs will be treated.

At DL1, one patient must have completed the first cycle before 
accrual of the second and third patients. The second and third
patients may be treated simultaneously.

Intermediate dose escalation or de-escalation is allowed. 
Intrapatient dose escalation is not allowed.
DOSE LIMITING 
TOXICITY
Dose limiting toxicities (DLTs) will be defined according to the 
following criteria:
Hematological Toxicity:

Grade 3-4 neutropenia associated with fever or lasting > 7 days, 
considered related to the study drug(s) by the Investigator. 

Grade 3-4
thrombocytopenia accompanied by grade 3/4 
hemorrhage.

For patients with extensive BM infiltration (≥ 50% of BM 
nucleated cells are plasma cells), DLT is defined as grade 4 
thrombocytopenia with grade 3/4 hemorrhage or grade 4 
neutropenia lasting more than seven days or with fever.
Non-hematological Toxicity

Grade 3/4 nausea and vomiting refractory to antiemetic therapy.

Grade ≥3 muscular AEs (myalgia, muscular weakness, muscle 
cramps, myopathy).

Grade ≥3 ALT/AST lasting more than one week.

Grade ≥ 3 bilirubin increase.

Grade ≥ 3 CPK increase.

Cardiac Toxicity:

Symptomatic or treatment-requiring grade ≥ 1 cardiac 
arrhythmia related to plitidepsin.

Grade ≥ 1 left ventricular systolic dysfunction related to 
plitidepsin.

Neuropathic pain and peripheral sensory neuropathy related to 
bortezomib will be considered a DLT if they result in a 
definitive bortezomib discontinuation according to International 
Myeloma Working Group (IMWG) guidelines.
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
Any other grade ≥ 3 toxicity considered related to study 
treatment by the Investigator. 
DEFINITION OF 
RECOMMENDED 
DOSE
The RD will be the highest DL at which fewer than two out of six
(33%) patients experience DLTs during the first 28-day cycle.
PHARMACOKINETICS
Pharmacokinetic (PK) analyses will be evaluated by standard non-
compartmental analysis (population pharmacokinetic modeling may 
be performed if appropriate). Samples for PK analysis will be 
obtained during Cycle 1 exclusively.
EFFICACY 
EVALUATION 
CRITERIA
Patients are evaluable for efficacy if they receive at least one 
complete treatment cycle (two plitidepsin infusions, four 
bortezomib injections, four doses of dexamethasone), or the 
equivalent doses over two cycles and have, at least, one disease 
assessment.
Efficacy will be evaluated according to IMWG criteria:

Overall response rate (ORR), including stringent complete 
response (sCR), complete response (CR), very good partial 
response (VGPR) and partial response (PR).

Minimal response (MR).

Stable disease (SD).

Clinical benefit rate, including ORR plus MR plus SD.

Duration of response (DOR).

Time to progression (TTP).

Progression–free survival (PFS).

Event-free survival (EFS).
SAFETY
EVALUATIONS
Patients are evaluable for safety if they receive at least one 
(complete or incomplete) dose of plitidepsin.
AEs will be graded according to NCI-CTCAE v 4.0.
STATISTICAL 
METHODS

The RD will be descriptively determined according to the 
evaluation of DLTs.

ORR and clinical benefit rate will be calculated with binomial 
exact 95% confidence intervals (CI).

DOR, TTP, PFS and EFS will be calculated by Kaplan-Meier 
estimates with 95% CI.

Safety evaluations will be performed in a descriptive fashion.
DURATION OF 
STUDY 
The total duration of the study will be approximately 24 months.
REPLACEMENT OF 
PATIENTS
Patients must be replaced if:

They are withdrawn from the study due to not being evaluable 
for the primary endpoint, due to hypersensitivity reactions or 
reasons other than drug-related AEs meeting DLT criteria (e.g., 
consent withdrawal, not meeting the eligibility criteria, non-
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compliance with follow-up, early PD, or unrelated AEs).

They require radiation therapy or other anticancer procedure 
within four weeks after the first dose, unless they previously had 
another drug-related AE included in the definition of DLT.

There is a protocol deviation/s precluding conclusions on the 
safety of the study therapy.
PLANNED STUDY
PERIODS (individually 
per patient)
Patients will be evaluated at scheduled visits in three study periods:

Pre-treatment: from signature of the IC to the first study drug 
infusion.

Treatment: from first infusion of study drugs to end of 
treatment (EOT).

Follow-up: after EOT, patients will be followed q4wk until 
resolution of all toxicities, if any. Patients who discontinued 
treatment without disease progression will be followed every 
three months until disease progression, other antitumor therapy, 
death or until the date of study termination (clinical cut-off), 
whichever occurs first. 
Patients will be considered to be on-study from the signature of the 
IC to the end of the follow-up period. Patients will be considered to 
be on-treatment for the duration of their treatment and until the day 
of EOT, immediately before the start of the follow-up period. EOT 
is defined as 30 days after the day of last treatment, unless the 
patient starts a new antitumor therapy or dies (whichever occurs 
first), in which case the date of administration of this new therapy or 
the date of death will be considered the EOT date. An EOT visit 
will be performed within 30 days (± five days) after last treatment, 
unless the patient starts any subsequent new antitumor therapy 
outside this clinical study, in which case the EOT visit should be 
performed immediately before the start of the new therapy, 
whenever possible.
Patients will receive the study drugs while it is considered to be in 
their best interest. Specifically, treatment will continue until:

Confirmed PD.

Life-threatening, unmanageable or unacceptable drug-
related AEs, including the need for more than two dose 
reductions, except in cases of obvious patient benefit in 
continuing the treatment at the Investigator’s criterion.

Intercurrent illness of sufficient magnitude to preclude safe 
continuation of the study.

Patient 
refusal 
and/or 
non-compliance 
with 
study 
requirements.

A major protocol deviation that may affect the balance of 
the risk/benefit ratio for the participating patient.

Treatment delay > 14 days due to toxicity (except in case of 
patient’s clear clinical benefit, with the Sponsor’s 
approval).

Pregnancy.

Investigator’s decision.
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PLANNED STUDY 
PERIODS (for the whole 
study)
Planned start date: First quarter of 2014 (1Q14).
Planned enrolment period: approximately 15 months.
Total duration of the study: approximately 24 months.
Planned end-of-study date (clinical cut-off): six months after the 
patient’s treatment discontinuation (last patient-last visit), or nine 
months after accrual of the last evaluable patient, whichever occurs 
first.
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SCHEDULE OF ASSESSMENTS
PROCEDURE
Pretreatment
(days)
Treatment: 
C14
Treatment: 
further cycles
End of
treatment
visit
Follow-up
D1
D15
D28=1
D15
Written IC
Before any 
procedures
-
-
-
-
-
-
Demographic data
-14  to  0
-
-
-
-
-
-
Medical history
-14  to  0
-
-
-
-
-
-
Primary diagnosis/Prior treatment(s)
-14  to  0
-
-
-
-
-
-
Assessment of signs and symptoms 
-14  to  0

-

-
-
-
Complete physical examination (1) 
and clinical neurological assessment
-14  to  0

-

-

-
ECOG PS (1)
-14  to  0

-

-

-
Concomitant treatments (2)
-14  to  0
Throughout the study
-
Hematology (3,4)
-7  to  0





-
Coagulation panel
-14  to  0
-
-

-

-
Biochemistry-A (3, 4, 5)
-7  to  0





-
Biochemistry-B
-7 to  0
-
-

-

-
Creatinine and measured or 
calculated CrCl
-7 to  0
-
-

-

-
Urinalysis (dipstick, sediment)
-14 to  0
-
-
-
-

-
Viral serology
-14  to  0
Repeat if clinically indicated
-
-
Pregnancy test (if applicable) (6)
-7  to  0
Every 4 weeks

-
ECG (7)
-14  to  0
Before and after each plitidepsin 
infusion

-
LVEF
-14  to  0
Every 12 weeks

-
PK
NA
C1 only
-
-
-
AEs (NCI-CTCAE v4.0) (8)
NA
Throughout the study

Disease Assessments
Serum protein (9)
-14  to  0 

-

-


Urine protein 
-14  to  0

-

-


Serum beta-2 microglobulin
-14  to  0
-
C-Reactive Protein
-14  to  0
Every 8 weeks


Bone Marrow Assessment (10)
-21  to  0
When serology indicates CR
If clinically 
indicated
If clinically 
indicated
Clinical and radiological tumor 
assessment in the presence of soft 
tissue plasmacytoma (11)
-14  to  0
If response is observed (to confirm 
CR) or if clinical symptoms 
suggest new plasmacytomas
If clinically 
indicated
Skeletal evaluation
-28  to  0
If response is observed (to confirm 
CR) or if clinical symptoms 
suggest new bone lytic lesion
If clinically 
indicated
1.
ECOG PS and vital signs must be repeated on D1 prior to drug infusion.
2.
A detailed description of all concomitant treatment (drug name, start and end dates, reason for administration, 
etc.), especially transfusion requirements, should be recorded.
3.
Repeat on C1 D1 prior to first infusion.
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4.
Repeat on D1, 4, 8, 11 and 15 during the first four weeks and on D1 and 15 thereafter. Repeat at least every 
other day if non-febrile neutropenia is present and every day in the presence of febrile neutropenia or grade 4 
thrombocytopenia.      
5.
Repeat at least every other day in the presence of grade 3/4 vomiting or any other drug-related SAE.
6.
For women of child-bearing potential a serum or urine HCG analysis should be done.
7.
It should allow rhythm definition (at least 30 seconds of duration) and include:
- PR interval.
- QT interval (raw and corrected by heart rate using Bazett’s formula).
- QRS complex and the maximum height of QRS complex in leads II.
8.
Serious Adverse Events (SAEs) will be collected from the time of signature of the Informed Consent Form.
9.
Protein electrophoresis, serum Ig determination, M-protein measurement and IF and SFLC determination.
10. BM evaluation is mandatory for all patients at screening, while on treatment if clinically indicated and if there is 
CR. BM evaluation must be repeated eight weeks later in patients with non-secretory MM, to confirm response 
or as clinically indicated. 
11. In patients with non-secretory or oligosecretory MM associated with soft tissue plasmacytoma, assessments may 
be done every two cycles (whenever possible) to confirm response or as clinically indicated.
Complete physical examination: weight, BSA and vital signs including HR, ABP and temperature.
Hematology: Differential WBC count, hematocrit, hemoglobin and platelet count.
Coagulation: PT, INR, APTT.
Biochemistry A: AP, AST, ALT, LDH, bilirubin, electrolytes (Na+, K+, Ca++, Mg++), glucose, CPK, CPK-MB 
fraction.
Biochemistry B: total proteins and albumin.
Viral serology: HBV and HCV; CMV in patients who have undergone allogeneic BM transplantation.
Serum protein: Protein electrophoresis, serum Ig determination and M-protein measurement and IF, SFLC.
Urine protein: 24-h urine protein electrophoresis measurement and IF, UFLC and M-protein measurement.
BM: morphology, cytometry (if available), cytogenetics (if available).
Clinical and radiological tumor assessment: CT-scan or MRI of all involved measurable/evaluable involved sites 
of soft tissue plasmacytoma. For soft tissue plasmacytoma assessment, tumor measurement will be the sum of the 
cross-diameters of the measurable target lesions.
Skeletal evaluation: X-ray of skull, vertebral column, pelvis and proximal long bones or MRI.
ABP, blood pressure; AEs, adverse event(s); ALT, alanine aminotransferase; AP, alkaline phosphatase; APTT, 
activated partial thromboplastin time; AST, aspartate aminotransferase; BM, bone marrow; BSA, body surface area; 
C, cycle; CMV, cytomegalovirus; CPK, creatine phosphokinase; CPK-MB, creatine phosphokinase isoenzymes 
found in cardiac muscle (it will be performed only if CPK is > ULN); CR, complete response; CRP, C-reactive 
protein; CT-scan, computed tomography scan; CR, complete response; CrCl, creatinine clearance; D, day; ECG, 
electrocardiogram; ECOG PS, Eastern Cooperative Oncology Group Performance Status; HBV, hepatitis B virus; 
HCG, human chorionic gonadotropin; HCV, hepatitis C virus; HR, heart rate; IC, informed consent; IF, 
immunofixation; INR, International Normalized Ratio; LDH, lactate dehydrogenase; LVEF, left ventricular ejection 
fraction; MM, multiple myeloma; MRI, Magnet Resonance Imaging; NA, not applicable; NCI-CTCAE, National 
Cancer Institute Common Terminology Criteria for the Classification of AEs; PK, pharmacokinetics; PT, pro-
thrombin time; SAE, serious adverse event; SFLC, serum free light-chain; UFLC, urine free light chain; ULN, upper 
limit of normality; WBC, white blood cell.
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
ABP
Arterial Blood Pressure
ADA
After Drug Administration
ADL
Activities of Daily Living
AE(s)
Adverse Event(s)
ALT
Alanine Aminotransferase
ANC 
Absolute Neutrophil Count
AP
Alkaline Phosphatase
APTT
Activated Partial Thromboplastin Time
ASCO
American Society of Clinical Oncology
ASCT
Autologous Stem Cell Transplantation
ASH/FDA
American Society of Hematology/Food and Drug Administration
AST
Aspartate Aminotransferase
ATC-WHO
Anatomical Therapeutic Chemical Drug Classification by the World Health 
Organization
AUC
Area Under the Curve
BM
Bone Marrow
BSA
Body Surface Area
CBP
CREB-binding Protein
CI
Confidence Interval
c.i.v.i.
Continuous Intravenous Infusion
Cmax
Maximum Plasma Concentration
CMV
Cytomegalovirus
CNS
Central Nervous System
CPK
Creatine Phosphokinase
CPK-MB
Serum CPK Isoenzymes (Found In Cardiac Muscle)
CR
Complete Response
CrCl
Creatinine Clearance
CRF
Case Report Form
e-CRF
Electronic Case Report Form
CRO
Contract Research Organization
CRP
C-Reactive Protein
CT
Chemotherapy
CT-scan
Computed Tomography scan
CTCAE
Common Terminology Criteria for Adverse Events
CV
Cardiovascular
D
Day
DI
Dose Intensity
DL
Dose Level
DLT
Dose Limiting Toxicity
DOR
Duration of Response
DTIC
Dimethyl Triazeno Imidazol Carboxamide
ECG
Electrocardiogram
ECHO
Echocardiogram 
ECOG PS 
Eastern Cooperative Oncology Group Performance Status 
EFS
Event-free Survival
EMA
European Medicines Agency
EOI
End of Infusion
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EOT
End-of-treatment
FLC
Free Light Chains
GCP
Good Clinical Practice
GCs
Glucocorticoids
G-CSF
Granulocyte Colony Stimulating Factor
GGT
Gammaglutamyl Transferase
GM-CSF
Granulocyte/Macrophage Colony Stimulating Factor
GMT
Greenwich Mean Time
h
Hour(s)
Hb
Hemoglobin
HBV
Hepatitis B virus
HCG
Human Chorionic Gonadotropin
HCV
Hepatitis C virus
HDT
High Dose Chemotherapy
HIV
Human Immunodeficiency Virus
HLA
Human Leukocyte Antigen
HSCT
Hematopoietic Stem Cell Transplantation 
IB
Investigator’s Brochure
IC
Informed Consent
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
IF
Immunofixation
IHC
Immunohistochemistry
IL
Interleukin
IMWG
International Myeloma Working Group
IMIDs
Immunomodulatory Drugs
IMP
Investigational Medicinal Product
INR
International Normalized Ratio for blood clotting time
i.p.
Intraperitoneal
IRB
Institutional Review Board
ITT
Intention-to-treat
i.v.
Intravenous
KPS
Karnofsky Performance Status
LDH
Lactate Dehydrogenase
LVEF
Left Ventricular Ejection Fraction
MedDRA AE
Medical Dictionary for Regulatory Activities for Adverse Events
MM
Multiple Myeloma
MOA
Mechanism of Action
MP
Melphalan Prednisone
MPT
Melphalan Prednisone Thalidomide
MR
Minimal Response
MRI
Magnetic Resonance Imaging
MTD
Maximum Tolerated Dose
MTS
Tetrazolium Salt
MUGA scan
Multiple Uptake Gated Acquisition Scan
NCI-CTCAE
National Cancer Institute Common Toxicity Criteria
ORR
Objective Response Rate
OS
Overall Survival
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PD
Progressive Disease
PDy
Pharmacodynamics
PFS 
Progression-free survival
PI
Proteasome Inhibitor
PI3K
Phosphatidylinositol-3 kinase
PK
Pharmacokinetics
PN
Peripheral Neuropathy
PR
Partial Response
PS
Performance Status
PT
Pro-thrombin Time
PVC
Polyvinyl Chloride
qRT-PCR
Real Time Polymerase Chain Reaction
Q3wk
Every Three Weeks
Q4wk
Every Four Weeks
RD
Recommended Dose
RR
Response Rate
SAE(s)
Serious Adverse Event(s)
SAR
Serious Adverse Reaction
s.c.
Subcutaneous
sCR
Stringent Complete Response
SD
Stable Disease
SFLC
Serum Free Light Chains
SPC
Summary of Product Characteristics
SVT
Supra-Ventricular Tachycardia
TBI
Total Body Irradiation
TTP
Time To Progression
T1/2
Half-life
VBAP
Vincristine, Carmustine, Doxorubicin, Prednisone
VEGF
Vascular Endothelial Growth Factor
VEGFR
Vascular Endothelial Growth Factor Receptor
UFLC
Urine Free Light Chains
ULN
Upper Limit of Normal
US
United States
VGPR
VMCP
Very Good Partial Response
Vincristine, Melphalan, Cyclophosphamide, Prednisone
vs.
Versus
Vss
Volume of Distribution at Steady State
WBC
White Blood Cells
WFI
Water For Injection
wk
Week(s)
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1.
BACKGROUND
1.1 Overview of the Disease
Multiple myeloma (MM) is a malignant plasma-cell disorder characterized by the 
production of a monoclonal protein from plasma cells in the bone marrow (BM). 
Information from the National Cancer Institute indicates that in the US, an estimated 
22,350 new cases of MM will be diagnosed in 2013, and 10,710 people will die from 
the disease (1). The incidence of MM in Europe is 4.5-6.0/100,000 a year with a median 
age of diagnosis of between 63 and 70 years and a mortality rate of 4.1/100,000/year 
(2). In the Western hemisphere, about 1% of cancer-related deaths are due to myeloma. 
MM may be staged according to either the Durie-Salmon system (Appendix 4) based on 
the amount of abnormal monoclonal immunoglobulin in the blood or urine, blood 
calcium levels, the amount of bone damage shown by X-ray and blood hemoglobin 
levels (3), or the newer staging system, the International Staging System that relies on 
the levels of albumin and beta-2-microglobulin in the blood (4) (Appendix 4). In both 
systems, all stages are further subclassified by creatinine level either less than 2.0 
mg/dL or greater than or equal to 2.0 mg/dL. Impaired renal function worsens prognosis 
regardless of the stage.
The disease primarily affects individuals later in life with a median age of 63-70 years. 
From the time of diagnosis, survival without treatment is between 6 and 12 months and 
extends to 3 years with chemotherapy (CT). MM is treatable but rarely curable. Most 
patients receive multiple treatments over the course of their disease, and the precise 
sequence of therapy and used regimens can be quite variable. With standard dose CT, 
patients have a median survival of 24–30 months. Twenty five percent of patients 
survive 5 years or longer, and the 10-year survival rate is approximately 3% (1). Failure 
of standard therapy to cure these diseases has led to the study of higher doses of 
chemotherapeutic agents. These conditioning regimens may involve ablative/reduced or 
non-myeloablative intensity and the rescue of the immune system following CT may 
involve autologous or allogeneic stem-cell transplantation.
1.2 Current Treatment for Multiple Myeloma
Patients considered candidates for a CT-based intervention are further divided into those 
who are and those who are not eligible for high-dose CT (HDT) followed by stem cell 
rescue, based on age, performance status (PS), and co-morbid medical conditions. HDT 
for MM was introduced in 1983 (5) and showed for the first time that a substantial 
percentage of complete remissions could be induced. Morbidity and mortality however,
were high, but were strongly reduced later by the application of autologous stem cell 
rescue.
BM was the source of stem cells in the first studies, peripheral blood stem cells (PBSC) 
are now routinely applied as autologous rescue. In 1996, a randomized study was 
published which showed that autologous transplantation was superior to conventional 
treatment regarding response rate (RR), event-free survival (EFS) and overall survival 
(OS) (6). In this study, patients younger than 65 years were randomized at diagnosis to 
receive
vincristine, carmustine, doxorubicin, prednisone/vincristine, melphalan, 
cyclophosphamide, prednisone (VBAP/VMCP) or high dose melphalan 140 mg/m2 and 
total body irradiation (TBI) 8 Gy supported with autologous BM collected after 2 
courses of VBAP/VMCP. 
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In summary, and according to several guidelines, HDT with autologous hematopoietic 
stem cell transplantation (HSCT) should be part of the primary treatment strategy in 
newly diagnosed patients up to the age of 65 years with adequate PS and organ 
function. It may also be considered in patients > 65 years with good PS. Allogeneic 
HSCT with human leukocyte antigen (HLA)-matched sibling donors may also be 
considered in patients up to the age of 50 years who have achieved at least a partial 
remission after initial therapy. Reduced-intensity conditioning allografting may be 
considered in patients up to the age of 70 with a HLA-matched sibling donor.
Until recently, there was general agreement that the standard of care for patients who 
are not eligible for transplantation was the treatment with melphalan and prednisone 
(MP), despite the low overall response rate (approximately 50%), with few complete 
responders, and the modest improvements in 5-year survival (7). Other combination 
chemotherapies have been used in this setting and, although they induced a more rapid 
response and a higher overall response rate, the differences did not translate into a 
survival advantage compared to that achieved with MP. However, new knowledge 
about the pathobiology and pathogenetics of MM, and the introduction of novel agents, 
such as thalidomide, bortezomib, arsenic trioxide, and more recently lenalidomide, with 
novel mechanisms of action (MOA) are defining new standards of care.
Novel agents such as immunomodulatory drugs (IMIDs) (thalidomide, lenalidomide, 
pomalidomide) and proteasome inhibitors (PIs) (bortezomib, carfilzomib, etc…) have 
doubled the duration of survival. However, new active agents are still needed for double 
refractory patients to IMIDs and PIs. With a progression-free survival (PFS) of 6 
months and median survival of a year, treatment in this population is still challenging, 
an optimal combination of chemotherapeutic agents has not been defined and new 
therapies are needed in this setting. In this regard, plitidepsin has shown meaningful 
activity in patients failing treatment with IMIDs and PIs. Moreover, synergism between 
plitidepsin and bortezomib and thalidomide has been shown (unpublished data).
PIs are of particular interest, as they act on the ubiquitin-proteasome system, which is 
responsible for regulation and degradation of the majority of intracellular proteins. 
Proteasome inhibition leads to cell cycle disruption, activation of apoptosis pathways 
and ultimately, cell death. In MM cells, among others, PIs have been shown to target the 
unfolded protein response, a signaling pathway allowing the appropriate folding of 
proteins. A small study showed overall response rates (ORR) (better than minimal 
response) of 50% after re-treatment with bortezomib. Greater responses (56%) were 
seen in patients with a free-interval of at least six months when compared to patients re-
treated within six months (33%). In this study, 75% of patients received bortezomib re-
treatment in combination with dexamethasone. Hence, patients who relapse after 
bortezomib treatment may receive an additional course of bortezomib-based therapy if 
they had an initial response to the drug lasting at least six months and had no 
intervening therapies. The prognosis for patients who relapse after treatment with 
bortezomib plus either lenalidomide or thalidomide is poor, with a median EFS of only 
a few months and OS of six months. 
In summary, therapeutic options are still limited and new active drugs are needed in the 
double-refractory population. Novel agents may give rise to new feasible combinations 
based on their activity and safety profiles and plitidepsin combinations with IMIDs 
and/or PIs are warranted.
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1.3 Plitidepsin
The Sponsor is committed to the development of new drugs in an effort to broaden the 
spectrum of current antitumor therapies. Chemically, plitidepsin is a (now fully 
synthetic) natural occurring depsipeptide originally extracted from the Mediterranean 
Sea tunicate Aplidium albicans. Although the main MOA by which plitidepsin inhibits 
cell growth and/or induces cell death remains to be fully characterized, its major effects 
can be at least partially attributed to a cell cycle block in the G0/G1 phases and the 
induction of apoptosis (8-10) via activation of the JNK pathway; this activation leads to 
a decreased production of intracellular glutathione, an increase in reactive oxygen 
species and an alteration of the mitochondrial membrane potential, ultimately leading to 
both caspase-dependent and independent apoptosis. In addition to the pro-apoptotic 
properties of plitidepsin, the molecule has demonstrated antiangiogenic properties in 
several pre-clinical models via direct activity on vascular endothelial growth factor 
(VEGF)-stimulated angiogenesis. In fact, plitidepsin has been demonstrated to reduce 
the secretion of VEGF and its receptor type 1 (VEGFR-1) from MOLT-4 human 
leukemia cells in vitro (11). It seems that the majority of the pharmacological activity of 
plitidepsin can be attributed to a combination of these cellular effects in vivo.
Antitumor activity has been displayed by plitidepsin in in vitro and in vivo models. In 
addition, this observation has been sustained in early clinical trials as a single agent, 
showing clinical responses in patients with hematological malignancies as well as solid 
tumors. The toxicity of plitidepsin in normal hematopoietic tissue is several folds lower 
than in tumor cells. More importantly, this observation translates into a lack of clinically 
significant hematological toxicity in clinical trials to date, even in leukemia/lymphoma 
patients with limited BM reserve capacity. Consequently, plitidepsin may display a 
positive profile for combination with other agents in CT regimens, avoiding overlapping 
toxicity.
Please refer to the Investigator's Brochure (IB) for full information on plitidepsin.
1.3.1 Name and Chemical Information
Aplidin® is the trade name for plitidepsin [leucine, 1-(1,2-dioxopropyl) prolyl-N-
methyl-leucylthreonyl-4-amino-3-hydroxy-6-methylheptanoyl-4-hydroxy-2,5-dimethyl-
3-oxohexanoyl-N, 0-dimethyltyrosylprolyl, O-lactone)], a cyclic depsipeptide originally 
isolated from a Mediterranean marine tunicate, Aplidium albicans, which is currently 
manufactured by total synthesis. 
1.3.2 Non-clinical Data
1.3.2.1
Mechanism of Action in Cell Lines
The major effects of plitidepsin can be specifically attributed to the induction of 
apoptosis secondary to oxidative stress and activation of JNK activity. Exposure of 
cultured human cervical cancer (HeLa) cells to plitidepsin induced oxidative stress 
resulting in cellular apoptosis (12) and a rapid and sustained activation of JNK, p38 
MAPK and ERK in human breast cancer cells (MDA-MB-231) (13). In fact, genetically 
engineered mouse embryo fibroblast (MEFs) which did not express any JNK isoforms,
were at least an order of magnitude less sensitive to plitidepsin (10). JNK has been 
shown as a critical component in plitidepsin-induced cytotoxicity through a decrease in 
the intracellular reduced glutathione (GSH) levels which, in turn, increases the levels of 
reactive oxygen species (13). The effects of plitidepsin on a pleiotropic regulatory 
protein Rac1, would contribute to the sustained activation of JNK (8, 14). Additionally,
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a cell cycle inhibitor, p27 (kip1), has been shown to determine plitidepsin sensitivity in 
vitro, on a panel of mouse sarcoma cells from resected tumors (15). Data on human 
renal cell carcinoma lines (A-498 and ACHN) confirmed the oxidative operating 
mechanism and recent studies on human melanoma cell lines (SK-MEL-28 and UACC-
257) have again involved a Rac1/JNK pathway in the apoptotic cell arrest induced by 
plitidepsin (13, 14), thus demonstrating a common mechanism in cells of different 
tumor origins. More recent studies have shown plitidepsin to be able to increase levels 
of cell membrane phospholipid oxidation and deoxyribonucleic acid (DNA) oxidation 
in vitro (8).
Apart from its pro-apoptotic properties, plitidepsin has also demonstrated 
antiangiogenic effects. The addition of the drug reduces the active secretion of VEGF 
and the expression of its receptor (VEGFR-1) on human leukemia (MOLT-4) cells in 
vitro (11), suggesting that the block of cell growth might be mediated by dual inhibition 
of the VEGF autocrine loop. Supporting these findings, plitidepsin has been shown to 
be highly cytotoxic on acute myelogenous leukemia cells, both on regular cultures (K-
562, HEL and HL-60) and on blasts obtained from patients (16). Furthermore, 
plitidepsin was able to reduce the secretion of VEGF in a dose-dependent manner, thus 
confirming previous observations. At the functional level, plitidepsin inhibited 
spontaneous and growth factor-induced angiogenesis, prevented proliferation, migration 
and invasiveness, and hampered formation of capillary-like tridimensional structures, in 
in vivo and in vitro models (17).
In summary, it appears that the pharmacological activity of plitidepsin can be attributed, 
at least in part, to a combination of pro-apoptotic and antiangiogenic effects in vivo.
1.3.2.2
Plitidepsin as Single Agent: In vitro and In vivo Data 
In vitro studies demonstrated antiproliferative activity against a broad spectrum of 
tumor types, namely bladder, breast, stomach, prostate thyroid and lung cancer, 
melanoma, neuroblastoma (with IC50 values ranging from 10-7 to 10-9 M), and leukemia, 
myeloma and lymphoma (with IC50 values ranging from 10-8 to 10-9 M) (18). 
In addition, an animal model in MM has been explored (19). At clinically achievable 
concentrations, plitidepsin exhibited potent in vitro activity against primary MM tumor 
cells and a broad spectrum of human MM cell lines, including cells resistant to 
conventional (e.g., dexamethasone, alkylating agents, and anthracyclines) or novel (e.g., 
thalidomide and bortezomib) anti-MM agents. Plitidepsin was active against MM cells 
in the presence of proliferative/antiapoptotic cytokines or BM stromal cells and had 
additive or synergistic effects with some of the established anti-MM agents. The anti-
MM effect of plitidepsin was associated with suppression of a constellation of 
proliferative/antiapoptotic genes and up-regulation of several potential regulators of 
apoptosis. 
In conclusion, plitidepsin showed consistent cytotoxic activity against a broad selection 
of human-derived solid tumor cell lines such as lung, breast, thyroid, prostate, stomach, 
bladder, and kidney, as well as human malignant cell lines of hematological origin.
In the hollow fiber in vivo model, in which athymic rats were treated with i.v. 
plitidepsin, tumors of the bladder, stomach, and prostate were shown to be susceptible 
to the drug. In xenograft models, activity was noted against human renal and pancreatic 
tumors when injected to athymic mice. 
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Additionally, the antitumor and antiangiogenic effects of plitidepsin were evaluated in 
the 5T33MM syngeneic orthotopic model of MM (20). In vitro, plitidepsin inhibited 
DNA synthesis and induced an arrest in transition from G0/G1 to S phase. Furthermore, 
plitidepsin induced apoptosis by lowering the mitochondrial membrane potential. For 
the in vivo experiment, i.p.-injected plitidepsin was well tolerated by the mice and 
reduced serum paraprotein concentration by 42% (p<0.001), while BM invasion with 
myeloma cells was decreased by 35% (p<0.001). Plitidepsin also reduced the myeloma-
associated angiogenesis to basal values. This antiangiogenic effect was confirmed in 
vitro and may be explained by inhibition of endothelial cell proliferation and vessel 
formation. In summary, these data indicate that plitidepsin is well tolerated in vivo and 
its antitumor and antiangiogenic effects support the use of the drug in MM (21).
1.3.2.3
Plitidepsin in Combination: In vitro and In vivo Data 
Clinical experience in the management of MM patients supports the concept that drug 
combinations induce higher RRs than single agents. The ability of plitidepsin to 
increase the activity of other established anticancer agents was assessed in several 
human tumor cell lines. The plitidepsin/dexamethasone combination selected for further 
development in solid tumors and preclinical data are summarized below.
Plitidepsin-Dexamethasone Combination: Non-clinical Data
The plitidepsin/dexamethasone combination was explored with viability analyses in
MM1.S and U266-LR7 cells. The experimental design included both the non-constant 
ratio (for suboptimal drug doses) and the constant ratio. The effects of single and 
combined treatments after 72 hours (h) were evaluated by MTT assays. The results 
clearly showed that plitidepsin increased the anti-MM effect of dexamethasone. The 
combination was additive but tended to be synergistic at higher doses (19) (Figure 1).
Figure 1. MM1.S cell line, 48h incubation.
0.2
0.4
0.6
0.8
1.0
2.0
4.0
6.0
Plitidepsin + Dexamethasone CR
Combination.
Fraction affected
Similar results were obtained in a study by Medina et al. (internal report, March 2008), 
where the plitidepsin/dexamethasone combination (at a fixed ratio of 1/50) was tested in 
four MM cell lines (MM1.S, ARP, RPMI-8226 and the dexamethasone-resistant 
MM1.R). As shown in Figure 2, the plitidepsin/dexamethasone combination resulted in 
a significant increase in cell toxicity in the cell lines MM1.S, ARP and RPMI-8226 
compared to either drug alone (plitidepsin or dexamethasone). In contrast, only 
plitidepsin had an effect on the dexamethasone-resistant cell line, MM1.R. 
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Figure 2. Activity of the combination plitidepsin/dexamethasone in MM cell lines.
The plitidepsin/dexamethasone combination was synergistic in the cell lines MM1.S, 
ARP, and RPMI-8226 at all (nanomolar) tested drug concentrations, while it was 
additive in MM1.R at high concentrations.
Molecular Rationale Based on the MOA of Dexamethasone: Similarities with 
Plitidepsin Activity
The pleiotropic molecular effects elicited by plitidepsin treatment preclude reaching 
conclusions on which pathways are the most important for its antitumor activity; 
however, they offer a potentially unique MOA and a major therapeutic advantage. In 
particular, they may account for the synchronized targeting of different specific 
proliferative/antiapoptotic pathways in MM tumor cells. In fact, gene expression 
profiling data in tumor cells provide a framework for designing a combinatorial therapy 
to potentiate each individual antitumor effect. It is likely that their pleiotropic and 
synergistic effects in vitro over MM cells may neutralize the pathways that enable 
tumors to evade cell death and to become resistant to anticancer treatment.
Glucocorticoids (GCs), such as dexamethasone, induce apoptosis in the hematological 
lineage, while supporting the survival of several non-hematological tissues, such as the 
mammary gland, ovary, liver or fibroblasts (22-24). GCs exert their action through 
interaction with the intracellular GC receptor (GR), a ligand regulated transcription 
factor that positively or negatively alters the expression of specific target genes. In turn, 
GR either induces gene transcription by binding to specific DNA elements in the 
promoter-enhancer regions of responsive genes or reduces gene transcription by 
transrepression (24-27). Thus, dexamethasone acts over genes responsible for the 
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induction of apoptosis in lymphoid cells, in what seems a plitidepsin complementary 
pathway, therefore enhancing plitidepsin cytotoxicity (28-31). 
Like plitidepsin, GCs may induce apoptosis by directly regulating both the extrinsic and 
intrinsic apoptosis pathways. Death receptors (CD95 and TRAIL) and downstream 
effectors have been found deregulated by each of the drugs in the extrinsic pathway. 
Regarding the intrinsic and mitochondria-mediated pathways, which lead to the release 
of pro-apoptotic molecules upon depolarization of the mitochondrial membrane 
potential, the apoptotic response is tightly regulated by the interaction between pro- and 
anti-apoptotic
Bcl-2 
family 
members. 
Additionally, 
both, 
plitidepsin 
and 
dexamethasone, upregulate pro-apoptotic genes (TRAIL-Rl/DR4 and TRAIL-R2/DR5, 
Bax, Bak, Bad, Fas, FasL, TRAIL, Noxa, PIG3, Bim, Bik and Puma, Bcr-Abl [in 
CML], c-Myc, and HDAC3), while they downregulate pro-survival genes (c-FLIP, 
MCl-I, Bel-X, and Bcl-2) (25, 32).
On the other hand, both agents have been found to disrupt the cellular redox state (e.g., 
ROS), and damage mitochondria in cells undergoing apoptosis, as an effect of the 
depolarization of mitochondrial membrane, which will enhance the expression of death 
receptors and ligands resulting again in the activation of the caspase cascade.
Moreover, plitidepsin-induced suppression of caspase inhibitors (FLIP, survivin) may 
contribute to the increased sensitivity of plitidepsin-treated MM cells to caspase-
dependent apoptosis by dexamethasone. Both agents deregulate Hsp90 complexes such 
as receptor FKBP5, HSPs and DNAJs. 
Other molecules and pathways involved in the antiproliferative effect of both 
dexamethasone and plitidepsin, could yet contribute to the synergism of the 
combination. Plitidepsin downregulates genes with a documented role in oncogenic 
transformation in MM: Myb, Myc or Ras families, frequently mutated in MM cells, 
effect also seen after dexamethasone administration (33). Likewise, both had a 
synergistic effect on NF-kappaB (survival transcription factor) and its inhibitor (34, 35).
Besides, a synergistic effect may occur on the cell cycle, where the arrest induced by the 
combination may be mediated by their joint and coordinated regulation of the 
expression of CDKI (p21WAF1/CIP1, p27 KIP), INK4 family of proteins (p15INK4b, 
p18INK4c, p19INK4d), cycA, cycD1 and D2, suppression of CDK4, suppression of 
p107, or hypophosphorylation of Rb (24).
Plitidepsin treatment also reduces Erk (an extracellular signal-regulated kinase, ERK 
1/2) activation but increases activation of p38MAPK (Figure 3), enhancing GC 
sensitivity by the induction of apoptosis. Similarly, MAPK pathway activation by 
plitidepsin may improve the effects of GC.
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Figure 3. Plitidepsin-dexamethasone molecular model of apoptosis.
Combined treatment with plitidepsin and dexamethasone suppresses genes involved in 
cytokine-induced proliferative/antiapoptotic signaling pathways and oncogenic 
transformation triggering MM proliferation: IGF-1R, IL-6R, gp130, CXCR-4 etc.
In addition to the documented effects induced by both drugs at the genomic level, some 
of the effects of dexamethasone seem to be non-specific, i.e., a non-genomic activity, 
with a quick activation of protein kinases, including the MAPK cascade, 
phosphatidylinositol-3 kinase (PI3K) and Akt. These non-specific effects could explain 
the short-term rapid synergism of the combination, since plitidepsin has also shown a 
rapid effect over the same pathways.
GR reduces gene transcription by interaction with proinflammatory transcription factors 
such as AP-1 (Fos-Jun heterodimers) and NF-kB (p65-p50 heterodimers). Both require 
the coactivator CREB binding protein (CBP) for maximal activity. Therefore, these data 
also suggest that alterations in chromatin structure may be important in modulating GC 
actions. 
On this regard, the direct inhibition of CBP-associated histone acetyltransferase (HAT) 
activity and the active recruitment of a histone deacetylase complex 2 (HDAC2) 
induced in cell lines treated with dexamethasone appear crucial (36, 37). Both 
complexes are closely related to chromatin remodeling and consequently, to the 
modulation of gene expression induced by dexamethasone (Figure 4). 
Figure 4. Glucorticoids and the chromatin complex.
Glucocorticoids induce the acetylation of specific lysine residues (K5 and K16) in 
histone H4. The consequences of this epigenetic activity are wide, e.g. preventing other 
transcription factors, such as activator protein 1 (AP-1) and nuclear factor қB (NF-қB), 
from activating their target genes by inhibition of acetylation of specific lysine residues 
in histone H4. This may also have an antiangiogenic potential (reducing VEGF 
expression). 
Plitidepsin
Plitidepsin
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Therefore, histone H4 K5 acetylation can be considered as a marker of dexamethasone 
transactivation. Dexamethasone predominantly targeted acetylation on histone H4 K5 
and K16 in all subjects. However, the GR complex inhibits acetylation of K8 and K12 
by acting both as a direct inhibitor of CBP-associated histone acetylation and by 
recruiting HDAC2 to the p65-CBP HAT complex. Thus, it has been described that both 
HAT and HDAC activities coexist within the same complex in the presence of p65 and 
GR and that they can each act independently. This mechanism for glucocorticoid 
repression is novel and it establishes that inhibition of histone acetylation brings an 
additional level of control of inflammatory/antiproliferative/apoptotic gene expression. 
This further suggests that pharmacological manipulation of specific histone acetylation 
status is a potentially useful approach for the treatment of dexamethasone-sensitive 
diseases. On this regard, the effects of dexamethasone have been shown to improve in 
the presence of trichostatin A (TSA), a classical potent in vitro HDAC inhibitor, and in 
the presence of SAHA, recently approved for in vivo use at the clinical setting. HDACs 
were also pointed out as playing a role in dexamethasone repression. 
Further analysis of the epigenetic activity with dexamethasone revealed an induction of 
phosphorylation of Histone 3 at Ser10 (inhibited in response to TNFα) and histone 3 
methylation at Lysine 4 (H3K4 methylation). These two markers of the histone code are 
targets for rapid hyperacetylation upon treatment with the HDAC inhibitor sodium 
butyrate or with TSA. Moreover, most, if not all, available Lys in the H3 tail becomes
acetylated when they are marked with K4 methylation or S10 phosphorylation. Such 
specificity suggests that the activation of HATs after treatment with dexamethasone 
together with an HDAC inhibitor is not random.  
1.3.2.4
Toxicology
Plitidepsin, given by intravenous (i.v.) injection in daily (d) x1 (dx1), dx5 or 3-cycle 
dx5 regimens, produced toxicological effects typical of cytotoxic antitumor agents. 
Tissues containing cells with a high turnover were especially targeted. In the dx1 and 
dx5 studies, the principal organs affected were the reticuloendothelial system and the 
gastrointestinal tract in all species, testes in the mouse and rat, and pancreas in the dog. 
Additional affected organs were: epididymides, pancreas, heart, mammary gland and 
skeletal muscle in the rat and mouse, and liver, thymus and testes in the dog. In all three 
species, toxic effects were dose-related and generally fully or partially reversible. Most 
toxicities were reversible at the maximum tolerated dose (MTD) level at the end of an 
acute toxicity evaluation.
Of interest is the observation that the toxicity of plitidepsin in normal hematopoietic 
tissue (IC50: 150-2250 nM) was 1-3 orders lower than in tumor cells (IC50: 0.2-27 nM) 
(38). These and other data (39) indicate that plitidepsin might be a potential compound 
in multidrug CT regimens, assuming that it does not increase hematotoxicity 
significantly, which is often the dose-limiting toxicity of these regimens.
1.3.2.5
Safety Pharmacology
Cardiovascular System
The cardiovascular (CV) safety pharmacology evaluation of plitidepsin involved both in
vitro and in vivo studies.
Briefly, no inhibition of the hERG tail current was found after a 15-min exposure of 
HEK293 cells stably transfected with hERG cDNA to a concentration of 1M of 
plitidepsin. Moreover, increasing concentrations of plitidepsin (10, 100 and 1000 nM) 
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did not produce changes in the action potential morphology of isolated cardiac Purkinje 
fibers from dogs.
The effect of plitidepsin on CV parameters [arterial blood pressure (ABP), heart beating 
rate (HBR) and electrocardiogram (ECG) variables - PR interval, QRS duration, RR 
interval, and QT interval] was evaluated in conscious, telemetered dogs. Plitidepsin
infusions at doses up to 0.03 mg/kg (0.6 mg/m2) did not affect ABP. HBR increased 
from 2 to 48 h after administration of 0.03 mg/kg (0.6 mg/m2) of plitidepsin. There were 
no significant effects on corrected QT (QTcF) at the studied plitidepsin doses. No ECG 
abnormalities were observed during or up to 8 h after discontinuation of the plitidepsin 
infusion.
Respiratory System
Intravenous administration of up to 0.50 mg/kg (3 mg/m2) of plitidepsin to male rats did 
not significantly affect either respiratory rate or tidal volume. Significant decreases in 
tidal volume and respiratory rate were detected at 24 h post-dosing with 1.50 mg/kg (9 
mg/m2).
Neurotoxicity
Intravenous administration of up to 0.50 mg/kg (3 mg/m2) of plitidepsin to male rats did 
not produce gross behavioral or physiological state changes at any observation period. 
In rats treated with 1.5 mg/kg (9 mg/m2) occasional cage dispersion, increased 
cutaneous blood flow, diarrhea, and vocalization were observed. 
1.3.3 Clinical Data
1.3.3.1
Phase I Trials
Phase I clinical studies with plitidepsin were started in 1998. These studies were 
conducted according to classical phase I study design standards including 
pharmacokinetic (PK) evaluations. All single-agent phase I studies were conducted in 
the EU and Canada and explored five different infusion times or administration 
schedules of plitidepsin: 3-h infusion on D1 and 15 every four weeks (q4wk), 24-h 
infusion on D1 and 15 q4wk, 1-h infusion on D1, 8 and 15 q4wk, 24-h infusion on D1, 
8 and 15 q4wk and 1-h infusion on D1-5 every three weeks (q3wk). 
Phase I combination studies were conducted in Europe and the US to evaluate 
plitidepsin in combination with other antineoplastic drugs. Three of these studies, which 
evaluated plitidepsin combined with cytarabine, bortezomib or docetaxel, were early 
terminated following a decision by the Sponsor. RDs are currently available for the 
following plitidepsin
combinations:
carboplatin, dacarbazine (DTIC), sorafenib, 
bevacizumab and gemcitabine.
Up to the cut-off date of 31 March 2013, 214 adult patients and 38 pediatric patients 
have been treated with single-agent plitidepsin and 114 adult patients with plitidepsin in 
combination with other drugs in these phase I studies, for a total of 366 patients. Results 
obtained in single-agent phase I trials in adult patients are summarized in Table 1.
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Table 1. Single-agent plitidepsin phase I trials in adult patients.
24 h i.v.
d1,8,15
q4w
3 h i.v.
d1,15
q4w
1 h i.v.
d1,8,15
q4w
24 h c.i.v.i. d1,15 q4w
1 h i.v.
d1-5
q3w
Plitidepsin 
alone
Plitidepsin
+
L-carnitine
No of patients
35
27
48
47
20
37
MTD (mg/m2)
4.50
6
3.60
6
8
1.35
DLTs
MTD
G4 CPK inc. +
muscular 
weakness
G3 trans. inc.
RD
G3 CPK inc. +
renal 
impairment
G3 SVT
MTD
G3 CPK inc.
G4 CPK inc.
+ MOF
RD
G3 CPK 
increase
G3/4 
ALT/AST 
inc.
G3 asthenia
MTD
G3 muscular 
pain + G2 CPK 
elevation
G4 CPK inc.
RD
G3 AP inc.
At 2.7 mg/m2
G3 AST, AP,  
bilirubin inc. +
fatigue
MTD
G4 CPK inc.
G2 CPK inc.
for > 15 days
RD
G4 CPK inc.
MTD
G3 asthenia +
G1 fever
G4 CPK inc.
RD
G4 CPK inc.
and G3 asthenia 
+ myalgia
G4 CPK inc.
At 1.5 
mg/m2
G3 emesis 
+ skin rash
G3 
myalgia
MTD
G3 fatigue 
+ skin rash
G3 fatigue 
and 
diarrhea
RD
none
RD (mg/m2)
3.75
5
3.2
5
7
1.2
DI at the RD 
(mg/m2/week)
2.8
2.5
2.4
2.5
3.5
2.0
c.i.v.i., continuous intravenous infusion; D, day; DI, Dose intensity; DLT, dose-limiting toxicity; inc., increase; i.v., intravenous; 
MOF, multiorgan failure; MTD, maximum tolerated dose; NCI-CTCAE, National Cancer Institute Common Toxicity Criteria for 
the Classification of Adverse Events; RD, recommended dose; SVT, supraventricular tachycardia; trans., transaminase.
Of note, the proposed recommended dose (RD) for further developments as single agent 
after the extensive phase I program consistently delivered a similar dose intensity, 
around 2.5 mg/m2/week and a similar pattern of dose-limiting toxicities (DLTs), without 
unexpected toxicities regardless of the schedule.
Of relevance, a phase I study of plitidepsin in combination with bortezomib and 
dexamethasone in patients with relapsed or refractory MM was started in 2008. This 
study was terminated early, following a Sponsor’s decision. No MTD or RD were 
reached.
Safety Overview in Adult Single-Agent Phase I Trials
The primary DLTs found in the dose-finding phase I studies with single-agent 
plitidepsin were musculoskeletal AEs. The most common were myalgia, muscle 
weakness and increase in serum CPK (non-cardiac fraction) levels. 
In the 77 patients treated at the RD, myalgia occurred in 35 patients (46%) and muscle 
weakness in 12 patients (16%); these events were generally mild and only reached grade 
3 in two (3%) patients each. General symptoms (e.g., fatigue) were also reported during 
treatment with plitidepsin. Grade 1/2 vomiting occurred in about half of the patients 
treated at the RD. Grade 3/4 emesis was far less common, occurring in only two patients 
(3%). Therefore, according to current guidelines, single-agent plitidepsin should be 
considered as a high-emetogenic non-cisplatin agent, and appropriate standard 
prophylaxis is indicated. 
Mild infusion site reactions were found, particularly (although not exclusively) when 
plitidepsin was administered through a peripheral line. As a result, use of a central line 
is suggested to administer plitidepsin although a peripheral line may be used for the 
fortnightly schedule only whenever a central venous line is deemed unsuitable for any 
reason (e.g., coagulation problems, technical difficulties, patient’s refusal, etc.).
Transient and reversible transaminase increases (particularly ALT) were dose-limiting 
in some single-agent phase I studies and in most phase I combination studies. AP 
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increases were far less common, whereas bilirubin increases were extremely rare and 
almost universally were disease-related.
In contrast to many other cytotoxic agents, single-agent plitidepsin did not induce 
clinically significant bone marrow (BM) toxicity, stomatitis or alopecia within the dose 
range explored. Of note, neither grade 3/4 neutropenia nor grade 3/4 thrombocytopenia 
were reported in any phase I trials with single agent plitidepsin.
Overall, clinical data suggest that the safety profile of plitidepsin is acceptable and 
administration is safe for the treatment of cancer patients.
Almost all deaths that occurred during treatment or follow-up were due to progression 
of the underlying malignancy and were unrelated to plitidepsin. One drug-related death 
was reported (0.4%) among the 214 adult patients treated with single-agent plitidepsin 
in phase I clinical trials. This patient had a metastatic renal carcinoma with prior 
nephrectomy and was receiving plitidepsin at 6 mg/m2 as a 3-h infusion on D1,15 q4wk. 
Fatal multiorgan failure with disseminated intravascular coagulation, acute renal failure, 
acute hepatic failure, myositis with CPK elevation and secondary myocardial events 
appeared. The patient did not improve despite intensive supportive measures, such as 
hemodialysis.
A total of 29 (14%) of the 214 adult patients treated with single-agent plitidepsin during 
the phase I program had at least one serious adverse event (SAE) that was possibly, 
probably or definitely drug-related (SAR). 
Safety Overview in Adult Combination Phase I Trials
As of the cut-off date, only one combination (plitidepsin/gemcitabine) was still 
ongoing; patient accrual into this study had been completed, and data verification was 
ongoing at the cut-off. 
The most common DLTs found with the plitidepsin combination schedules were 
transaminase increases, which occurred when plitidepsin was combined with 
carboplatin, sorafenib, bevacizumab, gemcitabine or DTIC. DLTs consisting of 
hematological abnormalities were uncommon and only comprised grade 4 
thrombocytopenia alone or concomitantly with neutropenia for > 5 days (with 
plitidepsin and carboplatin or gemcitabine) and grade 4 febrile neutropenia and 
pancytopenia (with plitidepsin and DTIC). Other DLTs were grade 3 hand-foot 
syndrome (with plitidepsin and sorafenib) and grade 3 fatigue and myalgia (with 
plitidepsin and bevacizumab). 
Efficacy Data in Phase I Trials
Overall, one confirmed PR and three unconfirmed PRs were found in phase I studies of 
plitidepsin as single agent in adult patients. Thirty patients with varied tumor types also 
experienced clinical benefit as SD lasting more than three months. 
Antitumor activity observed with the plitidepsin combinations includes: one complete 
response in a patient with NHL and one confirmed PR and three SD > 3 months with 
tumor reduction in patients with Hodgkin’s lymphoma in patients treated with 
plitidepsin and gemcitabine, one confirmed PR, two unconfirmed PRs and four SD > 3 
months in patients with melanoma treated with plitidepsin and DTIC, one 3-month SD 
in one melanoma patient treated with plitidepsin and carboplatin, and one confirmed PR 
in one patient with MM treated with plitidepsin and bortezomib. These combinations 
only induced SD for > 3 months in other tumor types, the most common being 
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colorectal carcinoma (n=5 patients) and renal cancer (n=4) (with sorafenib, 
bevacizumab or gemcitabine).  
1.3.3.2
Phase II Trials
Two schedules were selected for further evaluation in phase II studies on the basis of 
the findings from phase I studies: a fortnightly schedule with a 3-h i.v. infusion on D1 
and 15, q4wk at the RD of 5 mg/m2 (a 24-h i.v. infusion was also tested at the same RD 
and at 7 mg/m2 if supplemented with L-carnitine) and a weekly schedule (1-h i.v. 
infusion on D1, 8 and 15, q4wk at the RD of 3.2 mg/m2).
The results from completed phase II trials confirm the preliminary safety profile 
described from the subset of patients treated at the proposed RD in phase I trials.
Evidence suggests that the use of shorter infusion times may help reduce the incidence 
of some types of drug-related events, including CPK elevations, gastrointestinal 
(anorexia, nausea and vomiting), constitutional (fatigue) and injection site reactions. In 
addition, shorter infusion times are more convenient for the patient and significantly 
reduce costs and treatment complexity. No significant differences were found in the 
dose intensity and the safety profile of the treatment administration schemes. Therefore, 
the clinical development of 24-h continuous i.v. infusion schedules has been 
discontinued in favor of the 1-h and 3-h infusion schedules.
The cardiac safety of plitidepsin does not seem to be of special concern. The most 
common cardiac adverse event (AE) observed to date in the clinical trials are harmless 
rhythm alterations. No cardiac AEs have resulted in a fatal outcome. In addition, no life-
threatening ventricular arrhythmias have occurred. Relevant predisposing factors are 
mostly related with the patient’s baseline characteristics and disease, but not to drug 
exposure or treatment characteristics. 
Severe hypersensitivity reactions have been found with plitidepsin, even after 
prophylactic premedication with antihistamines and glucocorticoids. These reactions are 
rapidly reversible and to date none has had a fatal outcome. They may be due to the 
Polyoxyl 35 castor oil l present in the formulation, but a direct relationship between 
plitidepsin itself and hypersensitivity may not be excluded yet. 
Phase II Trial of Plitidepsin in Combination with Dexamethasone
The safety and efficacy of plitidepsin in patients with relapsed and/or refractory MM 
have been investigated in a phase II study and final results have been reported (40). This 
was an open-label study of plitidepsin given as a 3-h infusion every two weeks; the 
addition of dexamethasone was allowed in patients with suboptimal response to 
plitidepsin alone (defined as PD after three cycles or SD after four cycles of plitidepsin). 
The primary endpoint was the objective response rate (ORR = CR+ PR + minimum 
response [MR]) according to strict Bladé criteria (41) in the intent-to-treat (ITT) 
population according to Myeloma Response Criteria. Secondary endpoints were time to 
progression (TTP) and safety. 
The safety profile of the plitidepsin/dexamethasone combination was acceptable and did
not significantly change after dexamethasone addition. In particular, the incidence of 
grade 3-4 drug-related hematological toxicity was very low, with only 11% and 21% of 
patients experiencing grade 3-4 neutropenia and thrombocytopenia, respectively 
(similar figures were obtained for plitidepsin alone).
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Response was firstly evaluated using the Myeloma Response Criteria. Two PRs and 
four MRs were found in 47 evaluable patients treated with single-agent plitidepsin 
(ORR = 12.8%). Twenty-four other patients had SD, which lasted for >3 months in four 
patients. Nineteen patients who showed PD or SD after receiving four cycles of single-
agent plitidepsin had dexamethasone added to treatment. Two PRs and two MRs were 
found in 18 evaluable patients in this cohort (ORR = 22.2%), while SD for >3 months 
occurred in eight patients. When response was assessed as per Investigator’s criteria, the 
ORR was 12.8% for single-agent plitidepsin (3 PRs and 3 MRs in 47 evaluable patients) 
and 27.8% for plitidepsin combined with dexamethasone (3 PRs and 2 MRs in 18 
evaluable patients). Overall, these results suggest that plitidepsin administered alone or 
in combination with dexamethasone showed clinical activity in patients with 
relapsed/refractory MM.
1.3.3.3
Phase III Program
An ongoing multicenter, open-label, randomized, Phase III clinical trial started in June 
2010 is comparing the efficacy and safety of plitidepsin combined with dexamethasone 
vs. dexamethasone alone in patients with relapsed/refractory MM previously treated 
with at least three but not more than six therapeutic regimens. This is the first 
plitidepsin pivotal trial and is expected to randomize up to 250 patients worldwide to 
receive either plitidepsin 5 mg/m2 i.v. as a 3-h infusion on D1 and 15 q4wk plus 
dexamethasone 40 mg orally on D1, 8, 15 and 22, q4wk, or dexamethasone alone at the 
same dose and schedule. 
To 31 March 2013, a total of 84 patients have been included into this trial. A total of 
129 SAEs have been reported in 54 patients, regardless of treatment arm. Of these, 44 
SAEs reported in 25 patients have been considered to be related to or with an unknown 
relationship with the treatment. The most common related SAEs were pneumonia (n=7, 
including one case of primary atypical pneumonia), hyperbilirubinemia (n=3), 
transaminase increases, sepsis, myopathy, CPK increase, psychotic disorders and renal 
failure (n=2 each). All three episodes of hyperbilirubinemia were grade 3 and involved 
one patient each; of these, one had tumor lesions in the liver and another one had diffuse 
fatty changes in the liver. No further safety data are available yet. Of note, an interim 
analysis of unblinded data from 79 treated patients conducted by an Independent Data 
Monitoring Committee (IDMC) found no safety reasons to terminate the study. 
On 9 December 2012, the evaluation by the IDMC of efficacy and safety data from the 
60 evaluable patients included in the first stage resulted in a recommendation to 
continue the trial unmodified, as the study met the established efficacy threshold of 30% 
pre-specified in the protocol. No safety issues were reported. Therefore, patient accrual 
was resumed.    
1.3.4 Summary of Pharmacokinetic Results
After non-compartmental analysis, plitidepsin was found to be widely distributed, with 
apparent volumes of distribution in steady state (Vss) of about 500 to 1350 L based on 
plasma, and from about 100 to 225 L based on whole blood, suggesting that blood cells 
are an important distribution compartment. Concentrations were about 3-fold higher in 
whole blood than in plasma. This initial characterization was updated after analyzing 
data from phase II clinical trials, during which samples were collected at later time 
points than in  phase I trials. Furthermore, patients included in phase II trials had 
samples taken for PK evaluation during both the first and third treatment cycle, 
allowing for a more extensive analysis. Population methodology was used, as several 
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phase II studies had sparse sampling. The final model was a three-compartment 
disposition model with linear elimination within the dose ranges clinically explored. In 
this analysis, plitidepsin showed a prolonged terminal half-life of 88 h (almost double 
than initial calculations performed by non-compartmental methods of analysis of phase
I data). Additionally, a population PK/PDy model was developed to evaluate the 
relationship between the pharmacokinetics of plitidepsin and ALT increases, as a 
measure of hepatocyte injury. The main conclusion of this analysis was that the time 
course of the ALT elevation depends on dose and schedule but not on infusion duration. 
1.4 Bortezomib
1.4.1 Scientific Background
Bortezomib (Velcade®; Millennium Pharmaceuticals Inc, Cambridge, MA, USA and 
Johnson & Johnson Pharmaceutical Research and Development LLC, La Jolla, CA, 
USA) is a potent, reversible, and specific inhibitor of the proteasome (PI) and represents 
a first-in-class anti-neoplastic cytotoxic agent that differs from conventional cytotoxic 
agents by a favorable side effect profile, including its lack of significant 
myelosuppression, hair loss and mucositis. 
Bortezomib is a modified dipeptidyl boronic acid derived from leucine and 
phenylalanine; its chemical name is N-pyrazinecarbonyl-L-phenylalanine-L-leucine 
boronic acid and has a molecular weight of 384.25 daltons (42, 43).
Bortezomib was the first clinically-validated boronate-based dipeptide PI approved for 
use in relapsed/refractory MM. It was approved in the USA in 2005 for the treatment of 
patients with MM who have received at least one prior therapy, and in 2008 for front-
line treatment of patients with MM in combination with melphalan and prednisone.
Bortezomib reversibly binds the 20S subunit, inhibiting the ChT-active site and also 
significantly the C-L active site; however, it has minimal effect on T-L activity. 
Bortezomib targets numerous pathways by inhibiting the proteasome and controlling 
key transcription factors. The apoptotic activity of bortezomib results from inhibition of 
NFB activity, disruption of cyclin-dependent kinase activity, stabilization of c-Jun N-
terminal kinases leading to Fas upregulation, stabilization of p53, and a shift of the pro-
apoptotic and antiapoptotic balance in the Bcl-2 family of proteins.
Due to the non-optimal AE profile observed to date with the i.v. administration of 
bortezomib, alternative schemes of administration are currently being investigated. One 
study (44) showed weekly administration of bortezomib to be feasible; more 
importantly, weekly administration, when compared with the standard scheme of 
administration, considerably reduced neuropathic toxicity without interference with 
activity. Furthermore, subcutaneous (s.c.) administration yields the same activity whilst
being much less toxic. Based on this information, we plan to administer weekly 
bortezomib subcutaneously in combination with biweekly plitidepsin along with the 
standard low dose weekly dexamethasone.
Inhibitors of the 26S proteasome act through multiple mechanisms to suppress tumor 
survival pathways, arrest tumor growth, tumor spread and angiogenesis. Unlike 
conventional chemotherapeutics, bortezomib represents a novel class of anti-cancer 
agent because it has the ability to affect a combination of cellular regulatory 
mechanisms. This multiple mechanistic approach potentially represents a more effective 
anti-cancer strategy compared to the anti-tumor activity afforded by conventional CT
(42).
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1.4.2 Mechanism of Action
The mechanisms of anti-tumor activity that have been established for bortezomib 
involve many pathways thought to be integral to cancer treatment strategies (45-48). 
The following mechanisms have been demonstrated in in vitro and in vivo experiments:

Inhibits activation of NF-kB in cells and in tumor microenvironment 

Reduces adherence of myeloma cells to BM stromal cells 

Blocks production and intracellular signaling of IL-6 in myeloma cells 

Blocks production and expression of pro-angiogenic mediators 

Overcomes defects in apoptotic regulators, such as Bcl-2 overexpression and 
alterations in tumor suppressor p53 

Activity is cell-cycle independent 

Stabilizes cell cycle regulatory proteins 

Unaffected by drug efflux pumps
1.4.3 Preclinical Experience
Pre-clinical research with PIs has demonstrated their ability to induce apoptosis and 
inhibit tumor growth, supporting their potential role in the treatment of various tumor 
types, especially hematological malignancies. 
PK and PDy studies have been conducted in the rat and cynomolgus monkey. Upon i.v.
bolus administration, bortezomib displays a rapid distribution phase (t1/2α <10 min) 
followed by a longer elimination phase (t1/2β 5–15 h). Bortezomib has a large volume of 
distribution (range 5–50 L/kg). Its plasma PK profile is well described by a 
two-compartment model. The PDy action of bortezomib is well established and can be 
measured through an ex vivo assay (20S proteasome activity) (49).  This assay was used 
to determine the duration of drug effect in lieu of the PK data in the early preclinical 
toxicology studies as well as to set a guide for dose escalation in humans. Following 
dosing with bortezomib in the rat and cynomolgus monkey, proteasome inhibition in 
peripheral blood had a half-life less than 24 h, with proteasome activity returning to 
pretreatment baseline within 24 h in monkey and within 48 to 72 h in rat after a single 
dose of bortezomib. Further, intermittent but high inhibition (>70%) of proteasome 
activity was better tolerated than sustained inhibition. Thus, a twice-weekly clinical 
dosing regimen was chosen in order to allow return of proteasome activity towards 
baseline between dose administrations (46, 47, 50, 51).
1.4.4 Clinical Pharmacology
The clinical pharmacology program has been designed and partially carried out to 
investigate the disposition characteristics, and the pharmacodynamics of bortezomib
(52, 53). Conclusions from the completed investigations are: 

Upon i.v. bolus administration, bortezomib displays a rapid distribution 
phase (t1/2α< 30 min) followed by a longer elimination phase t1/2β> 10 h) and 
a large volume of distribution, all consistent with a 2-compartment PK 
model. 

The high volume of distribution, rapid distribution phase, prolonged 
biological effect (t1/2~24 h), and high potency (Ki = 0.6 nM with slow off rate), 
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along with in vitro metabolic studies suggest that de-boronation and 
proteolytic cleavage of bortezomib at the cellular level represent the majority 
of the catabolism of this compound. This conclusion is based on extensive 
preclinical evaluation of the disposition characteristics, PK and the PDy of 
bortezomib. Inhibition of 20S proteasome activity occurs in a dose-related 
manner. The maximum pharmacodynamic effect on circulating whole blood 
20S activity occurs within 1 h of dosing. The relationship between 
bortezomib plasma concentrations and proteasome inhibition is well 
described by a simple Emax model.
1.4.5 Phase I Clinical Experience
Data from four phase I studies designed to evaluate the MTD of bortezomib and DLTs 
in a variety of doses and dose schedules have been analyzed. The MTD of bortezomib,
regardless of individual protocol definition, appeared to be dependent on the treatment 
schedule employed and the patient population treated. MTDs and DLTs in these studies 
were as follows: 

The MTD of bortezomib administered twice per week for 2 weeks followed 
by a 10-day rest period to patients with advanced solid tumors was 
determined to be 1.3 mg/m2. DLTs of fatigue, diarrhea and peripheral 
neuropathy (PN) were observed at 1.56 mg/m2/dose (54). 

The MTD of bortezomib administered once per week for 4 weeks followed 
by a 14-day rest period to patients with solid tumors was 1.6 mg/m2. This 
was the least dose-intensive schedule but had the highest individual doses 
administered (55).

The MTD of bortezomib administered twice per week for four weeks in 
eight dose cycles followed by a 14-day rest period to patients with 
hematological malignancies was determined to be 1.04 mg/m2. A DLT 
(hyponatremia) and more frequently grade 3 thrombocytopenia was 
observed at a bortezomib dose of 1.04 mg/m2 and 1.38 mg/m2 (56).
Neurotoxicity was observed in phase I studies, particularly a painful sensory PN, that 
was dose-related, and more prevalent among patients previously treated with neurotoxic 
agents (e.g., platinum, thalidomide, vincristine and taxane-containing regimens) and 
dose-limiting in patients with refractory solid tumors.
A relatively low incidence of significant myelosuppression in Phase I, febrile 
neutropenia, infections and transfusion-dependent thrombocytopenia or anemia, 
mucositis or alopecia was notable; this has also been borne out in the phase II data 
evaluated to date. Effects on the liver, kidney, and heart were rarely found. Decreases in 
platelet count have been observed on treatment during both phase I and II studies and 
appear to be related to dose. Clinically significant thrombocytopenia can occur and 
appears to be influenced by baseline platelet count. Platelet count tends to recover 
during the rest period. Patients should be carefully monitored throughout treatment with 
bortezomib for hematological abnormalities. 
Although demonstration of efficacy was not a primary objective in the phase I clinical 
studies, anti-tumor activity was observed in patients with squamous cell carcinoma of 
the nasopharynx, bronchoalveolar carcinoma of the lung, renal cell carcinoma, prostate 
cancer, lymphoma, Waldenström’s macroglobulinemia and MM.
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1.4.6 Phase II Clinical Experience
The safety and efficacy of bortezomib were evaluated in an open-label, single-arm, 
multicenter phase II study of 202 patients with relapsed and refractory MM who had 
received at least 2 prior lines of treatment and were progressing on most recent therapy 
(SUMMIT) (57). Patients with relapsed and refractory myeloma have an expected 
survival of 6-9 months. 
The 202 patients had multiple poor prognostic factors at study entry including elevated 
beta-2-microglobulin, poor hematopoietic reserve, evidence of organ dysfunction,
abnormal renal function and chromosomal abnormalities. The median number of prior 
lines of therapy was six.
An i.v. bolus injection of bortezomib 1.3 mg/ m2 dose was administered twice weekly 
for 2 weeks without routine pre-medication, followed by a 10-day rest period (21 day 
treatment cycle) for a maximum of eight treatment cycles. Patients who experienced 
benefit from bortezomib treatment were allowed to continue treatment in an extension 
study. Patients who experienced PD after at least 2 cycles, or had SD after at least 4 
cycles with bortezomib were allowed, at their physicians’ discretion, to have high dose 
dexamethasone (40 mg) added to their bortezomib treatment. Response rates to 
bortezomib alone were determined by an independent response committee (IRC) based 
on Bladé’s criteria (58).
Complete remission required 100% reduction in M-protein and included patients with
positive or negative immunofixation (IF+ or IF-, respectively). All 202 patients were 
evaluable for time to event analyses. A total of 193 patients were evaluated for response 
(nine patients with non-measurable disease could not be evaluated for response by the 
IRC). In SUMMIT, bortezomib demonstrated an overall response rate (CR+PR+MR) of 
35% with 59% patients experiencing improved or stable disease (SD). A total of 10% of 
patients experienced a complete remission (4% IF- and 6% IF+). The median time to 
response was 38 days.
The median survival of all patients enrolled in SUMMIT was 16 months. RR was 
independent of the number or type of previous therapies. In addition, the rate of 
response remained consistent regardless of the patients’ gender, race, body surface area, 
performance status, myeloma type or chromosome 13-deletion status. The median time 
to progression for all 202 patients enrolled in SUMMIT was 7 months. Median time to 
progression on their last previous therapy was 3 months and when using patients from 
SUMMIT as their own controls, the median time to progression was twice as long on 
bortezomib relative to the last therapy. Effects on serum and/or urine monoclonal 
paraprotein and plasma cells from BM aspirate and biopsy were also evaluated. Overall,
70% of patients had either reduction or stable serum and/or urine paraprotein levels. A 
total of 69% of patients included in the analysis for BM biopsy results had a 50% 
decrease in plasma cells, thereby demonstrating that treatment with bortezomib reduces 
the number of or clears myeloma cells from the BM. BM aspirate results were 
consistent with those obtained by biopsy. 
Responders (CR+PR) in SUMMIT also had an increase in mean hemoglobin and 
decreased overall transfusion requirements; stable renal function; stable or improved 
Karnofsky 
Performance 
Status 
(KPS) 
and 
increased 
mean 
non-myeloma 
immunoglobulin levels (IgM, IgA and IgG). The mean IgM returned to the normal 
range by the end of treatment; 28% (15/53) of patients had increases of ≥2 fold in one 
of their non-myeloma immunoglobulins. An association between RR and improvement 
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in quality of life was apparent. Patients who responded to treatment experienced an 
improvement in EORTC-C30 Global and Physical parameters, including a decrease in 
disease symptoms, pain and fatigue.
In SUMMIT, 74 patients were administered dexamethasone in combination with 
bortezomib and were assessed for response. Eighteen percent (13/74) achieved an 
improved response (MR or PR) with combination treatment.
The CREST study was a randomized open-label, single-arm, multicenter study which 
enrolled 54 patients with MM that progressed or relapsed on or after front-line therapy 
(CREST) (59). Bortezomib was administered twice weekly for 2 weeks followed by a 
10-day rest period for a maximum of eight treatment cycles as second line therapy.
Patients were prospectively randomized to receive 1.0 or 1.3 mg/m2/dose. A total of 28 
patients received 1.0 mg/m2/dose and 26 patients were administered 1.3 mg/m2/dose. 
Patients who experienced benefit from bortezomib treatment were allowed to continue 
treatment in an extension study. Patients who experienced PD after at least two cycles 
or SD after at least four cycles with bortezomib alone were allowed, at their physician’s 
discretion, to have high dose dexamethasone (40mg) added to their treatment.
Both dose groups were similar with regards to demographic and baseline characteristics. 
The median age for all patients was 63 years; 57% had a KPS score of 90 to 100 with 
only 13% of patients with a score of ≤  70; 19% had a hemoglobin level <100 g/l and no 
patients had a platelet count < 50 x 109/L. The median duration of time between 
diagnosis of MM and the first dose of bortezomib was 2.0 years and patients had 
received a median of one prior treatment line (median of three prior therapies), 
including steroids (98% of patients), alkylating agents (72% of patients), anthracyclines 
(54% of patients), prior stem cell transplant (48% of patients) and thalidomide (30% of 
patients). The median time to progression for all treated patients was 11 months. Eighty 
percent of patients were alive at 1 year. 
In CREST, the combination of bortezomib and dexamethasone was administered to 28 
patients, 16 patients in the 1.0mg/m2 group and 12 patients in the 1.3mg/m2 group. A 
total of 9 patients (32%) had an improved response (CR, PR or MR) with combination 
treatment (4 of the 16 patients receiving 1.0 mg/m2 and 5 of the 12 patients in the 1.3 
mg/ m2 group). Two of these 9 patients achieved a CR while receiving dexamethasone 
in combination with bortezomib therapy. A total of 51 patients entered the extension 
study. 
Initial data indicate that bortezomib can be administered to patients with relapsed and/or 
refractory MM for longer than six months with similar tolerability to that of the first six
months of treatment. Patients were able to maintain their response or had an improved 
response with additional cycles of bortezomib therapy.
The phase III study (M34101-039), also referred to as the APEX study, was designed to 
determine whether bortezomib provided benefit (TTP, RR, and survival) to patients 
with relapsed and/or refractory MM relative to treatment with high-dose dexamethasone
(60). The study was also designed to determine the safety and tolerability of bortezomib 
relative to high-dose dexamethasone, and whether treatment with bortezomib was 
associated with superior clinical benefit and quality of life relative to high-dose 
dexamethasone. A total of 669 patients were enrolled and 663 patients received study 
drug (bortezomib: 331; dexamethasone: 332). Patients randomized to bortezomib 
received 1.3 mg/m2 i.v. push twice weekly on Day 1, 4, 8, and 11 of a 3-week cycle for 
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up to eight treatment cycles as induction therapy, followed by 1.3 mg/m2 bortezomib 
weekly on Day 1, 8, 15, and 22 of a 5-week cycle for three cycles as maintenance 
therapy. Patients randomized to dexamethasone received oral dexamethasone 40 mg 
once daily on Day 1 to 4, 9 to 12, and 17 to 20 of a 5-week cycle for up to four 
treatment cycles as induction therapy, followed by dexamethasone 40 mg once daily on 
days 1 to 4 followed of a 4-week cycle for five cycles as maintenance therapy. The 
EBMT response criteria, as described by Bladé were utilized to determine disease 
response.
There was a 78% increase in TTP for the bortezomib arm. Median TTP was 6.2 months 
for the bortezomib arm and 3.5 months for the dexamethasone arm (p <0.0001). CR + 
PR were 38% with bortezomib vs. 18% with dexamethasone (p < 0.0001). CR was 6% 
with bortezomib vs. <1% with dexamethasone (p < 0.0001). The CR + near CR (nCR) 
rate was 13% with bortezomib vs. 2% with dexamethasone. In patients who had 
received only one prior line of treatment (bortezomib: 132; dexamethasone: 119), CR +
PR were 45% with bortezomib vs. 26% with dexamethasone (p = 0.0035). With a 
median 8.3 months of follow-up, OS was significantly longer (p = 0.0013) for patients 
on the bortezomib arm vs. patients on the dexamethasone arm. 
The probability of survival at one year was 80% for the bortezomib arm vs. 66% for the 
dexamethasone arm, which represented a 41% decreased relative risk of death in the 
first year with bortezomib (p = 0.0005). In patients who had received only one prior line 
of treatment, the probability of survival at one year was 89% for the bortezomib arm vs. 
72% for the dexamethasone arm, which represented a 61% decreased relative risk of 
death in the first year with bortezomib (p = 0.0098) (61).
1.4.7 Safety Issues
The data described below reflect exposure to bortezomib in 256 patients with MM (57)
(58). The median total dose administered across all 256 patients was 46 mg, median 
duration of treatment was 131 days, and median number of doses administered was 22 
(six cycles). The most commonly reported AEs were nausea (62%), fatigue (54%), 
diarrhea (48%), constipation (41%), thrombocytopenia (41%), pyrexia (36%), vomiting 
(34%), and anorexia (30%).
Events reported as PN, peripheral sensory neuropathy and PN aggravated were reported 
in 35% of patients. PN was grade 3 for 13% of patients and grade 4 for < 1% of 
patients. New onset or worsening of existing neuropathy was noted throughout the 
cycles of treatment. Five percent (5%) of patients discontinued bortezomib due to 
neuropathy. Notably, more than 80% of patients had signs or symptoms of PN at 
baseline evaluation. The incidence of grade 3 neuropathy was low (2 of 60 patients, 3%) 
in patients without baseline neuropathy. Symptoms may improve in some patients upon 
discontinuation of bortezomib; complete resolution of PN has been reported.
Transient and uncomplicated thrombocytopenia was reported during treatment with 
bortezomib in 42% of patients. The thrombocytopenia observed was characterized by a 
dose-related decrease in platelet count during the bortezomib dosing period (Days 1 to 
11) with a return to baseline in platelet count during the resting period (Days 12 to 21) 
in each treatment cycle. Thrombocytopenia was assessed as bortezomib-related in 38% 
of patients and grade 3-4 in intensity in 29% of patients. Three percent of patients 
experienced grade 4 thrombocytopenia. All episodes of grade 4 events were 
bortezomib-related. Four percent of patients discontinued bortezomib treatment due to 
thrombocytopenia of any grade.
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Notably, infusion reactions, infusion site reactions, alopecia, mucositis, febrile 
neutropenia and sepsis were rarely reported. Acute development or exacerbation of 
congestive heart failure has been seen in subjects with risk factors for or existing heart 
disease. 
Thirteen percent of patients experienced at least one episode of grade 4 toxicity, with
the most common events being thrombocytopenia (3%) and neutropenia (2%). A total 
of 124 (48%) of the 256 patients experienced SAEs during the studies. The most 
commonly reported SAEs included pyrexia (7%), pneumonia (7%), diarrhea (5%), 
vomiting (5%), dehydration (5%) and nausea (4%).
AEs leading to treatment discontinuation were reported in 28% of patients. The reasons 
for discontinuation were evenly distributed across the most common types of toxicity 
and included PN (5%), thrombocytopenia (4%), PD (3%), diarrhea (2%), and fatigue 
(2%). The majority of patients discontinuing treatment due to AEs were not responding 
to therapy. 
The addition of dexamethasone did not appear to adversely affect the safety profile of 
bortezomib.
1.5 Study Rationale and Drug Selection 
MM is still an incurable disease. As front-line treatment to reduce tumor burden, 
hematopoietic stem cell transplantation as well as emergent drugs used in newly 
diagnosed patients offer the best chance for long-term survival. However, while many 
studies have shown the benefits of this approach, most patients will relapse. Thus, 
additional therapeutic options are needed for these patients.
In 1999, plitidepsin was found to have substantial in vitro anti-tumor activity in cells 
isolated from patients with advanced myeloma, and preliminary clinical data are 
confirmatory of activity against refractory and relapsed MM: a 3-h i.v. plitidepsin 
infusion at a dose of 5 mg/m2, q2w induces objective responses (around 20%) with an 
acceptable toxicity profile,
and with a remarkable lack of neurological and 
hematological toxicity. 
Bortezomib, a novel PI, has been shown to induce clinically significant responses with 
manageable toxic effects in patients with relapsed and/or refractory MM. In the pivotal 
study, the ORR, including complete responses, was 35%. The median duration of 
responses was 12 months, and there was an increase by a factor of 2 to 4 in the TTP
with bortezomib therapy as compared to the last therapy. In the CREST trial patients 
with refractory MM were randomized to receive 1.0 or 1.3 mg/m2 of bortezomib twice 
weekly for 2 weeks, every 3 weeks, for a maximum of eight cycles. Dexamethasone 
was permitted in patients with progressive or SD after 2 or 4 cycles, respectively. 
Patients who received bortezomib at a dose of 1.3 mg/m2 had increased CR+PR rates 
(50% vs. 33%), prolonged median duration of response and median TTP (11 months vs. 
7 months). Thus, the dose of 1.3 mg/m2, twice per week in 3-week cycles, for eight
cycles, seems to be the optimal dose for bortezomib as single agent or in the 
combination with dexamethasone.
The combination of plitidepsin plus bortezomib has been studied in vitro. The degree of 
cytotoxicity was determined by a MTS (tetrazolium salt) assay. Data from the MTS 
assay was expressed as the fraction of cells affected by the dose (Fa) in drug-treated 
cells as compared to single agent treated cells (control). In vitro results of this 
combination showed synergy at the higher dose of the concentration range tested.
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The combination was further tested in a human plasmacytoma (MM-1s) subcutaneously 
implanted in NOD SCID mice. The bortezomib combination showed a trend towards a 
better outcome than the single agents, although differences were not very evident, 
probably due to the low doses of plitidepsin and bortezomib used in the experiment. 
The use of bortezomib is limited by its toxicity, such as PN and thrombocytopenia, 
which restricts the clinical dosing regimen to a biweekly (D1, D4) schedule, allowing 
proteasome activity to recover between doses. In an effort to improve tolerability in 
patients with relapsed and/or refractory MM, a recent analysis evaluated the feasibility 
of a single bortezomib dose in the setting of combination therapy. The majority of 
response parameters, including ORR and PFS, were similar, while the safety profile 
improved (with a PN incidence of 8% vs. 28% in patients receiving twice-weekly 
dosing) (44). A separate phase III study examined the impact of s.c. bortezomib on 
safety and efficacy parameters; in addition to a more convenient administration, s.c.
bortezomib offered similar efficacy but lower toxicity (62). 
Based on the positive results observed with plitidepsin and bortezomib both as single 
agents and in combination with dexamethasone against MM, their different MOA, and 
the potential synergism of the triple combination, the efficacy of plitidepsin plus 
bortezomib and dexamethasone in patients with relapsed and/or refractory MM deserves 
to be addressed in clinical trials.
2.
OBJECTIVES
2.1
Primary Objective
To determine the recommended dose (RD) of plitidepsin in combination with 
bortezomib and dexamethasone in patients with relapsed and/or refractory MM.
2.2
Secondary Objectives

To determine the efficacy of plitidepsin in combination with bortezomib and 
dexamethasone.

To evaluate the safety and tolerability of the combination in patients with 
relapsed and/or refractory MM.

To study the pharmacokinetics (PK) and pharmacodynamics (PDy) of 
plitidepsin in combination with bortezomib and dexamethasone.
3.
OVERALL STUDY DESIGN
This is a multi-center, uncontrolled, single arm, phase I study, designed to establish the 
optimal dose of the combination plitidepsin, bortezomib and dexamethasone in patients 
with refractory and/or relapsed MM. Patients will be enrolled sequentially into three
dose levels. The feasibility of administering plitidepsin with bortezomib in combination 
with dexamethasone and the RD of the combination will be determined. Patients will be 
evaluated at scheduled visits in three study periods: pre-treatment, treatment and follow-
up.
The pre-treatment period includes screening and baseline visits. After providing 
written IC to participate in the study, patients will be screened for study eligibility 
during a screening period of up to 28 days. Baseline assessment consists of a detailed 
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history of pre-existing diseases, a complete physical examination and clinical 
neurological assessment, Eastern Cooperative Oncology Group Performance Status 
(ECOG PS) (Appendix 1), electrocardiogram (ECG), left ventricular ejection fraction 
(LVEF) and laboratory tests (including hematology and biochemistry), urinalysis,
hepatitis B and C virus screening and serum pregnancy tests for women of child bearing 
potential (see Table: Schedule of Assessments).
Disease-specific markers will be analyzed: beta-2-microglobulin, C-reactive protein 
(CRP), IgG, IgA, IgM, immunofixation (IF) from blood and urine, serum free light 
chains (SFLC), a representative BM aspirate and/or BM biopsy, and a skeletal survey: 
X-rays of the skull, vertebral column, pelvis and proximal long bones or MRI. In case 
of extramedullary soft tissue plasmacytoma, CT-scan or MRI of any site involved will 
be performed.
During the treatment period, all patients are to attend study center visits on Day 1, 4, 
8, 11 and 15 on an every four-week basis to assess safety and toxicity. All patients are 
to attend an end-of-treatment visit 30 (±5) days after the last dose of study therapy.
Prior to each administration of study drug, a short medical history focusing on 
plitidepsin-, bortezomib- and dexamethasone-associated side effects will be performed 
as well as cardiac markers, kidney and liver function tests. Complete blood count and 
biochemistry will be carried out before each plitidepsin administration as described in 
Section 4. Other disease-modifying treatments (e.g., alpha interferon) are strictly 
prohibited.
Tests for disease assessment will be performed during the treatment period described in 
Section 4.6.
A cycle is defined as 28 days, plus any additional days required for dosing delays due to 
any reason. All patients will remain in the study until PD, excessive side effects or 
withdrawal of consent (see Section 4.4). Patients who complete eight cycles can 
continue to receive plitidepsin exclusively if they have shown clinical benefit (respond 
to treatment or achieve SD) and upon Investigator’s decision and agreement with the 
Sponsor. Patients who achieve a stringent complete response (sCR), a complete 
response (CR), very good partial response (VGPR), partial response (PR), minimal 
response (MR) or stable disease (SD) as defined by response criteria may be taken off 
the study if eligible to proceed to high dose CT and autologous stem cell transplantation
(ASCT). Treatment may continue in case of obvious patient’s benefit according to the 
Investigator and upon discussion with the Sponsor. Patients who discontinue plitidepsin 
treatment must stop taking bortezomib and dexamethasone in the study setting.
After completion of the treatment period or in case of discontinuation, patients are to 
attend follow-up visits. Patients will be followed for AEs during 30 days after the last 
administration of study drug and until their resolution. In addition, patients will be 
followed every three months to assess disease status. Patients taken off-study due to 
reasons other than PD, will be followed for disease status every three months until PD, 
initiation of another anticancer therapy, study termination or death, whichever comes 
first. 
Detailed visit-by-visit study procedures are contained in Section 4.
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3.1 Study Endpoints
3.1.1
Primary Endpoint
The RD will be the highest dose level (DL) at which fewer than two out of six patients 
(33%) experience DLTs during the first cycle.
3.1.2
Secondary Endpoints

Overall response rate (ORR) (including sCR, CR, VGPR and PR).

Minimal response (MR).

Stable disease (SD).

Clinical benefit rate, (including ORR plus MR and SD).

Duration of response (DOR).

Time to progression (TTP).

Progression-free survival (PFS).

Event-free survival (EFS).

Safety and tolerability.

PK
and PDy of plitidepsin in
combination
with bortezomib and 
dexamethasone.
3.2 Number of Patients
Cohorts of 3-6 patients per DL (in up to three DLs) will be treated until the RD is 
defined. At the RD, at least six patients evaluable for the determination of DLTs will be 
treated. The number of patients may vary depending upon the tolerability to plitidepsin 
administered in combination with bortezomib and the number of DLs required to 
identify the RD, but a total of 20-30 patients are expected.
3.3 Selection of Patients
Patients with relapsed and/or refractory MM will be included.
Refractory myeloma is defined as disease that is non-responsive while on primary 
or salvage therapy, or progresses within 60 days of the last therapy. There are two 
categories of refractory myeloma:
Primary refractory myeloma is defined as disease that is non-responsive in 
patients who have never achieved a MR or better, with any therapy. It includes 
patients who never achieved MR or better in whom there is no significant 
change in monoclonal protein (M-protein) and no evidence of clinical 
progression as well as primary refractory, disease progression (PD) where 
patients meet criteria for true PD.
Relapsed and refractory myeloma is defined as disease that is non-responsive 
while on salvage therapy, or progresses within 60 days of last therapy in patients 
who have achieved MR or better at some point previously before progressing.
Relapsed myeloma is defined as previously treated myeloma that progresses and 
requires the initiation of salvage therapy but does not meet the criteria for either 
“primary refractory” or “relapsed-and-refractory” myeloma categories.
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3.3.1
Inclusion Criteria
A patient is eligible for enrolment if all of the following inclusion criteria are met:
1) Patients must give written IC in accordance with institutional and local 
guidelines.
2) Age ≥ 18 years.
3) Patients must have a confirmed diagnosis of MM according to the Durie & 
Salmon criteria (Appendix 3).
4) Patients must have relapsed and/or refractory disease.
5) Patients must have measurable disease defined as any of the following: 
a) Serum M-protein > 0.5 g/dL or > 0.2 g/24-h urine light chain (UFLC)
excretion.
b) In patients who lack measureable M-protein in serum or urine, i.e. serum M-
protein < 0.5 g/dL and urine M-protein < 0.2 g/24 h,  serum FLC (SFLC)
levels are most informative. SFLC levels can be used only if the baseline 
SFLC ratio is abnormal (<0.26 or >1.65) indicating clonality. In addition, the 
baseline SFLC level must be ≥10 mg/dL of the appropriate involved light 
chain isotype.
c) When applicable, measurable soft tissue plasmacytoma > 2 cm, by either 
physical examination and/or applicable radiological evaluation (i.e. MRI,
CT-scan).
6) Prior autologous and/or allogeneic hematopoietic stem cell transplantation 
(HSCT) patients are allowed. Patients must not have acute/chronic graft-versus-
host disease (GVHD) or be receiving immunosuppressive therapy at least 30 days 
before the onset of treatment with the study drug(s).
7) Patients must have received at least one previous treatment line, which can 
consist of:
a) Induction regimen followed by high dose chemotherapy (CT) and peripheral 
blood stem cell collection.
b) Induction regimen alone according to institutional guidelines. 
c) High doses of CT followed by non-myeloablative transplantation.
d) CT followed by either single or tandem autologous stem cell transplantation
(ASCT).
e) CT followed by autologous and
(if performed)
subsequent non-
myeloablative allogeneic stem cell transplantation.
f)
Previous line(s) of systemic CT and biological agents should have been 
completed at least 30 days and 15 days, respectively, prior to starting 
protocol treatment.
8) Previous treatment with bortezomib or another PI is allowed provided patients 
achieved at least MR lasting a minimum of two months.
9) Patients must have an ECOG PS ≤ 2.
10) Recovery to grade ≤ 1 from any non-hematological AE derived from previous 
treatment (excluding alopecia).
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11) Laboratory data:
a) Hemoglobin ≥ 8 g/dL.
b) Absolute neutrophil count (ANC) ≥ 1,000 cells/mm3 (1.0 x 109/L) (≥ 0.5 x 
109/L if due to extensive BM involvement –by ≥50% of plasma cells in BM
biopsy). Screening of ANC should be independent of granulocyte- and 
granulocyte/macrophage-colony stimulating factor (GCSF and GM-CSF) 
support for at least one week and of pegylated G-CSF for at least two weeks.
c) Platelet count ≥ 50,000/ mm3 (50.0 x 109/L) for patients in whom < 50% of 
the BM nucleated cells are plasma cells.
d) Platelet count ≥ 25,000/ mm3 (25.0 x 109/L) for patients in whom ≥ 50% of 
BM nucleated cells are plasma cells.
e) Serum total bilirubin < 1.5 x institutional upper limit of normal (ULN)
(except when Gilbert syndrome is clearly documented and other liver 
function tests are within normal levels).
f)
AST (aspartate aminotransferase) and ALT (alanine aminotransferase) and 
3.0 x institutional ULN and AP (alkaline phosphatase) 2.5 x institutional 
ULN.
g) Creatinine clearance > 30 mL/min, measured or calculated according to 
Cockcroft and Gault’s formula (Appendix 2).
h) Albumin ≥ 2.5 g/dL.
12) Women of child-bearing potential must have a negative serum or urine pregnancy 
test within seven days prior to enrolment. In addition, all sexually active women 
of child-bearing potential and fertile male patients must agree to use adequate 
contraceptive methods throughout the study and during six months after 
treatment discontinuation.
13) Left ventricular ejection fraction (LVEF) above the lower limit of normal.
14) Patients must have a BM assessment within three weeks prior to enrolment.
3.3.2
Exclusion Criteria
A patient will not be eligible for this study if any of the following exclusion criteria are 
met:
1) Previous treatment with plitidepsin.
2) Active or metastatic primary malignancy other than MM. 
3) Serious concomitant systemic disorders that would compromise the safety of the 
patient or the patient’s ability to complete the study, including the following 
specific conditions: 
a) Uncontrolled psychiatric illness or medical illness that the Investigator feels 
will compromise the patient’s tolerance of the study medication.
b) Significant non-neoplastic liver disease.
c) Uncontrolled endocrine diseases (i.e., requiring relevant changes in 
medication within the last month, or hospital admission within the last three
months).
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d) Uncontrolled systemic infection.
4) Other relevant cardiac conditions:
a) Symptomatic arrhythmia (excluding anemia-related grade ≤ 2 sinusal 
tachycardia) or any arrhythmia requiring ongoing treatment, and/or 
prolonged grade ≥ 2 QT-QTc; or presence of unstable atrial fibrillation
(according to CTCAE v4.0). Patients on treatment for stable atrial 
fibrillation are allowed, provided they do not meet any other cardiac or 
prohibited drug exclusion criterion.
b) History or presence of unstable angina, myocardial infarction, valvular heart
disease, cardiac amyloidosis or congestive heart failure within the last 12 
months.
c) Uncontrolled arterial hypertension (≥ 150/100 mmHg) despite optimal 
medical therapy.
d) Previous 
treatment 
with 
doxorubicin 
at 
cumulative 
doses 
of 
> 400 mg/m².
5) History of hypersensitivity reaction to bortezomib, polyoxyl 35 castor oil or 
mannitol.
6) Myopathy or any clinical situation that causes significant and persistent 
elevation of creatine phosphokinase (CPK) (> 2.5 ULN) in two different 
determinations performed within one week of each other.
7) Sequelae of any grade ≥ 1 neuropathy (either bortezomib-related or not) 
according to CTCAE v4.0.
8) Any other major illness that, in the Investigator’s judgement, will substantially 
increase the risk associated with the patient’s participation in this study.
9) Pregnant and/or lactating women.
10) Known active human immunodeficiency virus (HIV) infection (HIV testing is 
not required unless infection is clinically suspected).
11) Active hepatitis B or C virus (HBV or HCV) infection.
12) Treatment with any Investigational Medicinal Product (IMP) in the 30 days 
before inclusion in the study.
13) Concomitant medications that include corticosteroids, CT, or other therapy that 
is or may be active against myeloma. Concurrent corticosteroids are allowed 
provided as an equivalent of a prednisone dose of ≤ 10 mg daily, administered as
antiemetic or as premedication for blood products.
14) Wash-out periods after the end of previous therapy:
a) Nitrosoureas must be discontinued six weeks prior to Cycle (C)1 Day (D)1.
b) Thirty days for other chemotherapies and 15 days for other biological agents 
prior to C1 D1.
c) Thirty days after the end of any prior radiation or radionuclide therapy (six
weeks in the case of prior extensive external beam radiation, with more than 
25% of BM distribution).
15) Plasma cell leukemia at the time of study entry.
16) Disease-related symptomatic hypercalcemia despite optimal medical therapy.
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17) Limitation of the patient’s ability to comply with the treatment or follow-up 
protocol.
18) Contraindication for the use of steroids.
4.
PLAN OF THE STUDY
4.1 Duration of the Study Individually per Patient
Patients will be evaluated at scheduled visits in three study periods:

Pre-treatment: from signature of the IC to the first study drug infusion.

Treatment: from first infusion of study drugs to end of treatment (EOT).

Follow-up: after EOT, patients will be followed q4wk until resolution of all 
toxicities, if any. Patients who discontinued treatment without disease 
progression will be followed every three months until disease progression, 
other antitumor therapy, death or until the date of study termination (clinical 
cut-off), whichever occurs first. 
Patients will be considered to be on-study from the signature of the IC to the end of the 
follow-up period. Patients will be considered to be on-treatment for the duration of their 
treatment and until the day of EOT, immediately before the start of the follow-up 
period. EOT is defined as 30 days after the day of last treatment, unless the patient starts 
a new antitumor therapy or dies (whichever occurs first), in which case the date of 
administration of this new therapy or the date of death will be considered the EOT date. 
An EOT visit will be performed within 30 days (± five days) after last treatment, unless 
the patient starts any subsequent new antitumor therapy outside this clinical study, in 
which case the EOT visit should be performed immediately before the start of the new 
therapy, whenever possible.
4.2 Duration of the Study (for the Whole Study)

Planned start date: First quarter of 2014 (1Q14).

Planned enrolment period: approximately 15 months.

Total duration of the study: approximately 24 months.

Planned end-of-study date (clinical cut-off): six months after the patient’s 
treatment discontinuation (last patient-last visit), or nine months after accrual 
of the last evaluable patient, wichever occurs first.
4.3 Subject Participation
After ensuring that the patient meets all eligibility criteria and has given IC, patients can 
be enrolled in the study by contacting a designated study monitor at PharmaMar, and 
completing the electronic screening form. Registration will be confirmed and checked 
by PharmaMar. No patient can be included in the study until the electronic screening 
form has been completed and received by Pharma Mar. A patient number will be 
provided to the site of enrollment. This patient number should be used on all future 
documentation and correspondence referring to this patient. Should eligibility criteria 
problems arise, final decisions will be taken between PharmaMar and the Investigator. 
Patients will be evaluated at scheduled visits in up to three study periods: pre-treatment, 
treatment and follow-up. Patients will receive study medication while it is considered to 
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be in their best interest (see Section 4.4 Discontinuations). In responding patients, 
treatment may continue upon Investigators’ discretion.
Patients will be considered to be on-study for the duration of their treatment and during 
the 30 days following treatment discontinuation. Treatment discontinuation is defined as 
the day of the last dose of study drug administration.
4.4 Discontinuations
A discontinuation occurs when an enrolled patient ceases to participate in the study, 
regardless of the circumstances. The primary reason for patient’s discontinuation will be 
recorded on the electronic Case Report Form (e-CRF). The final evaluation required by 
the protocol will be performed thirty days (±5) after the last dose of study therapy.
If the patient is discontinued from the study before completion, every effort should be 
made to complete the assessments scheduled during the post-treatment follow-up 
period. The Investigator is ultimately responsible for the patient’s safety and wellbeing.
Study treatment should be discontinued if this is considered to be in the patient’s best 
interest. Plitidepsin, bortezomib and dexamethasone are to be permanently discontinued 
for patients meeting any of the following criteria:

Confirmed PD.

Life-threatening, unmanageable or unacceptable drug-related AEs, including 
the need for more than two dose reductions, except in cases of obvious 
patient benefit in continuing the treatment at the Investigator’s criterion.

Intercurrent illness of sufficient magnitude to preclude safe continuation of 
the study.

Patient refusal and/or non-compliance with study requirements.

A major protocol deviation that may affect the balance of the risk/benefit 
ratio for the participating patient.

Treatment delay > 14 days due to toxicity (except in case of patient’s clear 
clinical benefit, with the Sponsor’s approval).

Pregnancy.

Investigator’s decision.
Study discontinuation could also occur due to administrative reasons, a Sponsor’s 
decision or unforeseen reasons. Patients withdrawn from the study must not re-enter this 
study at any time.
4.5 Replacement of Patients
Patients must be replaced if:

They are withdrawn from the study due to not being evaluable for the 
primary endpoint, due to hypersensitivity reactions or reasons other than 
drug-related AEs meeting DLT criteria (e.g., withdrawal of consent, not 
meeting the eligibility criteria, non-compliance with follow-up, early PD, or 
unrelated AE).
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
They require radiation therapy or other anti-cancer procedure within four
weeks after the first dose, unless they previously suffered an AE included in 
the definition of DLT.

There is a protocol deviation resulting in the impossibility of evaluating the 
safety of the study therapy.
4.6 Screening and Baseline Assessments
Table 2. Screening and baseline assessments.
Screening and 
baseline
Investigations
Time
General
1. Medical history 
and physical 
examination
Written IC signed by the patient
Demographic data.
Medical history including: 
Date of MM diagnosis, relapse(s) or 
evidence(s) of refractoriness to 
prior treatments.
Documentation of PD prior to 
inclusion.
M-protein determinations.
Previous specific treatments 
(surgery, radiotherapy, CT, 
immunotherapy etc.) with dates, 
best response and TTP.
Concomitant treatments.
Transfusional requirements.
Clinical assessment of signs and 
symptoms (tumor-related or not).
Complete physical examination, 
including weight, height and vital 
signs assessment (HR, ABP and 
temperature). 
Complete clinical neurological 
assessment.
Baseline ECOG PS (Appendix 1).
Prior to any study-specific 
procedure.
Within 14 days prior to inclusion.
To be repeated on C1 D1 prior to 
infusion.
2. Hematology
Differential WBC count.
Hematocrit, hemoglobin.
Platelets.
Within 7 days prior to inclusion.
Repeat prior to the first infusion.
3. Coagulation
PT, INR, APTT.
Within 14 days prior to inclusion.
4. Biochemistry
AP, AST, ALT, LDH, bilirubin, 
electrolytes (Na+, K+, Ca++, Mg++), 
glucose, CPK, CPK-MB fraction, total 
proteins, albumin.
Creatinine and CrCl measured or 
calculated (Appendix 2).
Within 7 days prior to inclusion.
5. Urine 
Dipstick, sediment.
Within 14 days prior to inclusion.
6. Viral serology
HBV and HCV.
CMV in patients who have undergone 
allogeneic BM transplantation.
Within 14 days prior to inclusion.
7. Pregnancy test
Serum or urine in women of child 
bearing potential.
Within 7 days prior to enrolment.
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Screening and 
baseline
Investigations
Time
General
8. Heart function
ECG: It should allow a rhythm 
definition (at least 30 second of 
duration).
PR interval.
QT interval (raw and corrected by 
HR using Bazett’s formula).
QRS complex and the maximum 
height of QRS complex in 
derivation II].
LVEF by ECHO or MUGA scan.
Within 14 days prior to inclusion.
Disease assessment
9. Serum protein
Protein electrophoresis.
Serum Ig determination and M-protein 
measurement and IF
SFLC.
Within 14 days prior to inclusion.
10. Urine protein
24-h urine protein electrophoresis
UFLC.
Urine M-protein measurement and IF.
11. Serum beta-2-
microglobulin and 
CRP
Within 14 days prior to inclusion.
12. Bone marrow
BM morphology.
BM cytometry (if available).
BM cytogenetics (if available).
Within 21 days prior to treatment. 
13. Clinical and 
radiological tumor 
assessment in case of 
soft tissue 
plasmacytoma
CT-scan or MRI of all 
measurable/evaluable involved sites.
Within 14 days prior to inclusion.
14. Skeletal 
evaluation 
X-ray of skull, vertebral column pelvis 
and proximal long bones or MRI.
Within 4 weeks prior to inclusion.
15. Other relevant 
tests
Where indicated, according to the 
clinical context.
Within 14 days prior to inclusion.
ABP, blood pressure; ALT, alanine aminotransferase; AP, alkaline phosphatase; APTT, activated partial thromboplastin time; AST,
aspartate aminotransferase; BM, bone marrow; C, cycle; CMV, cytomegalovirus; CPK, creatine phosphokinase, CPK-MB fraction, 
CPK isoenzymes found in cardiac muscle (it will be performed only if CPK is > ULN); CrCl, creatinine clearance; CRP, C-reactive 
protein; CT, chemotherapy; CT-scan, computed tomography scan; D, day; ECG, electrocardiogram; ECHO, echocardiogram; ECOG 
PS, Eastern Cooperative Oncology Group performance status; FLC, free light chains; HBV, hepatitis B virus; HCV, hepatitis C 
virus; HIV, human immunodeficiency virus; HR, heart rate; IF, immunofixation; INR, international normalized ratio for blood 
clotting time; LDH, lactate dehydrogenase; LVEF, left ventricular ejection fraction; MM, multiple myeloma; MUGA scan, multiple 
uptake gated acquisition scan; MRI, magnetic resonance imaging; PD, disease progression; PT, prothrombin time; SFLC, Serum 
FLC; TTP, time to progression; UFLC, urine FLC; ULN, upper limit of normality; WBC, white blood cell counts.  
4.7 Treatment Period Assessments
Table 3. Treatment period assessments.
Treatment period
Investigations
Time
General
1. Clinical examination
ECOG PS.
D1 of each cycle.
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Treatment period
Investigations
Time
Physical examination, including 
weight, BSA and vital signs (HR, 
ABP, temperature).
Intercurrent adverse events.
Assessment of patient’s signs and 
symptoms (disease related or not).
Complete neurological assessment.
Concomitant treatments (especially 
transfusion requirements)a.
Throughout the study
2.  Hematology
Differential WBC count.
Hematocrit, hemoglobin.
Platelets.
D1, 4, 8, 11 and 15b during the 
first 4 weeks; D1 and 15 
thereafter.
3.  Coagulation 
PT, INR, APTT.
D1 of each cycle from C2 (an 
early 2-day window is allowed).
4.  Biochemistry
Serum chemistry A*.
D1, 4, 8, 11 and 15 during the 
first 4 weeks; D1 and 15 
thereafterc.
Serum chemistry B**.
Day 1 of each cycle from C2 (an 
early 2-day window is allowed).
5.  Creatinine and CrCl
Calculated or measured (Appendix 2).
D1 of each cycle from C2 (an 
early 2-day window is allowed).
6. Viral serology
HBV and HCV.
CMV in patients who have undergone 
allogeneic BM transplantation.
When clinically indicated
7.  Pregnancy test
Serum or urine HCG.
Every 4 weeks (an early 2-day 
window is allowed).
8.  AEs 
Evaluation of AEs (NCI-CTCAE 
v4.0).
Throughout the study
9.  Heart function

ECG: it should allow a rhythm 
definition (at least 30 second of 
duration).
PR interval.
QT interval (raw and corrected by 
heart rate using Bazett’s formula)
QRS complex and the maximum 
height of QRS complex in 
derivation II.

LVEF by ECHO or MUGA scan.
Before and after each plitidepsin 
infusion. 
Every 12 weeks.
10.  PK

As in Section 7.
C1.
Disease assessmentd
11.  Serum Protein

Protein electrophoresis
D1 of each cycle (an early 2-day 
window is allowed).

Serum Ig determination and M-
protein quantitation and IF.

SFLC.
12.  Urine protein

24-h urine protein electrophoresis.
D1 of each cycle (an early 2-day 
window is allowed).

Urine M-protein quantitation and IF.

UFLC.
13.  BMe

BM morphology.

BM cytometry (if available).

BM cytogenetic (if available).
When serology indicates CR. 
When clinically indicated.
14.  Clinical and 
radiological tumor
assessment in the 
presence of soft tissue 
plasmacytomaf

CT-scan or MRI of all 
measurable/evaluable involved sites.
If response is observed (to 
confirm CR) or when clinical 
symptoms suggest new 
plasmacytomas.
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Treatment period
Investigations
Time
15.  Skeletal evaluation

X-ray of skull, vertebral column 
pelvis and proximal long bones or 
MRI (if clinically indicated).
If response is observed (to 
confirm CR) or when clinical 
symptoms suggest new lytic bone 
lesion.
16.  Other relevant 
tests

Where indicated, according to the 
clinical context.
When clinically indicated
a.
Detailed description of the concomitant treatment (drug, start and end date, reason for administration, etc.)
b.
At least every other day if non febrile grade 4 neutropenia is present and every day in the presence of febrile neutropenia or 
grade 4 thrombocytopenia.
c.
At least every other day in the presence of grade 3-4 vomiting or any other drug-related SAE.
d.
Disease assessment is to occur at baseline to document the sites of disease; disease response is to be assessed primarily by 
non-invasive procedures, if possible. If CR is suspected, then invasive procedures required for disease response assessment 
(e.g. BM, skeletal survey, etc) are to be performed.
e.
BM evaluation is mandatory in all patients with CR. In patients with non-secretory MM, it must be repeated eight weeks later 
to confirm response. BM evaluation must be repeated in all cases where there is any clinical indication.
f.
In case of non-secretory or oligosecretory MM associated with soft tissue plasmacytoma assessments may be done every two 
cycles (if possible) to confirm response or as clinically indicated.
* Serum chemistry-A: AST, ALT, bilirubin, AP, LDH, Na+, K+, Ca++, Mg++, glucose and CPK, CPK-MB fraction.
**Serum chemistry-B: total proteins, albumin.
ABP, blood pressure; ALT, alanine aminotransferase; AP, alkaline phosphatase; APTT, activated partial thromboplastin time; AST, 
aspartate aminotransferase; BM, bone marrow; C, cycle; CMV, cytomegalovirus; CPK, creatine phosphokinase, CPK-MB fraction, 
CPK isoenzymes found in cardiac muscle (it will be performed only if CPK is > ULN); CrCl, creatinine clearance; CRP, C-reactive 
protein; CT, chemotherapy; CT-scan, computed tomography scan; D, day; ECG, electrocardiogram; ECHO, echocardiogram; 
ECOG PS, Eastern Cooperative Oncology Group performance status; FLC, free light chains; HBV, hepatitis B virus; HCV, hepatitis 
C virus; HIV, human immunodeficiency virus; HR, heart rate; IF, immunofixation; INR, international normalized ratio for blood 
clotting time; LDH, lactate dehydrogenase; LVEF, left ventricular ejection fraction; MM, multiple myeloma; MUGA scan, multiple 
uptake gated acquisition scan; MRI, magnetic resonance imaging; NCI-CTCAE, National Cancer Institute Common Criteria for the 
Classification of Adverse Events; PD, disease progression; PT, prothrombin time; SFLC, Serum FLC; TTP, time to progression; 
UFLC, urine FLC; ULN, upper limit of normality; WBC, white blood cell counts.  
4.8 Evaluations at the End of Treatment
4.8.1
End-of-treatment Visit
Table 4 lists the procedures that are required during the end-of treatment (EOT) visit. 
EOT is defined as 30 days after the last treatment day unless the patient starts a new 
antitumor therapy or dies (whichever comes first), in which case the date of 
administration of this new therapy or the date of death will be considered the EOT date. 
This visit needs to be performed in all avaluable patients 30 (±5) days after the last dose 
of study therapy.
Please refer to Section 6.2.2 and 6.2.3 for detailed instructions on Adverse Event 
Reporting and Monitoring. 
Table 4. End of treatment visit.
End of treatment visit
Investigations
Time
1.  Clinical examination

ECOG PS.

Complete physical examination, including 
weight and vital signs (HR, ABP, 
temperature)

Concomitant treatments (including 
transfusion requirements).
Thirty (±5) days after the last 
dose of study therapy.
2.  Hematology

Differential WBC count.

Hematocrit, hemoglobin.

Platelets.
Thirty (±5) days after the last 
dose of study therapy.
3.  Coagulation

PT, INR, APTT.
Thirty (±5) days after the last 
dose of study therapy.
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End of treatment visit
Investigations
Time
4.  Biochemistry

AP, AST, ALT, LDH, bilirubin, 
electrolytes (Na+, K+, Mg++, Ca++), glucose, 
CPK CPK-MB fraction, total proteins, 
albumin.
Thirty (±5) days after the last 
dose of study therapy.
5.  Urine 

Dipstick, sediment.
Thirty (±5) days after the last 
dose of study therapy.
6.  Pregnancy test

Serum or urine.
For women of child bearing 
potential, 30 (±5) days after the 
last dose of study therapy.
7. Creatinine and 
creatinine clearance 

Calculated or measured.
Thirty (±5) days after the last 
dose of study therapy.
8.  AEs

Evaluation of AEs (NCI-CTCAE v4).
Thirty (+5) days after the last 
dose of study therapy.
9.  Heart function

ECG: it should allow a rhythm definition 
(at least 30 second of duration).
PR interval.
QT interval (raw and corrected by heart 
rate using Bazett’s formula).
QRS complex and the maximum height 
of QRS complex in derivation II].

LVEF by ECHO or MUGA scan.
Thirty (±5) days after the last 
dose of study therapy.
Disease assessment
10.  Serum Protein

Protein electrophoresis.
Thirty (±5) days after the last 
dose of study therapy.

Serum Ig quantitation and M-protein 
quantitation and IF.

SFLC
11.  Urine Protein

24-h urine protein electrophoresis.
Thirty (±5) days after the last 
dose of study therapy.

Urine M-protein quantitation and IF.

UFLC
12.  C-reactive protein
Thirty (±5) days after the last 
dose of study therapy.
13.  BM

BM morphology.

BM cytometry (if available).

BM cytogenetic (if available).
If indicated, thirty (±5) days 
after the last dose of study 
therapy.
14.  Radiological 
assessment in case of 
soft tissue 
plasmacytoma

CT-scan or MRI of all 
measurable/evaluable sites.
If indicated, thirty (±5) days 
after the last dose of study 
therapy.
15.  Skeletal evaluation 
X-ray of skull, vertebral column pelvis and 
proximal long bones or MRI.
If indicated, thirty (±5) days 
after the last dose of study 
therapy.
16. Other relevant tests 
Where indicated, according to the clinical 
and laboratory context.
Thirty (±5) days after the last 
dose of study therapy.
ABP, blood pressure; ALT, alanine aminotransferase; AP, alkaline phosphatase; APTT, activated partial thromboplastin time; AST,
aspartate aminotransferase; BM, bone marrow; C, cycle; CMV, cytomegalovirus; CPK, creatine phosphokinase, CPK-MB fraction,
serum CPK isoenzymes found in cardiac muscle (it will performed only if CPK is > ULN); CrCl, creatinine clearance; CRP, C-
reactive protein; CT, chemotherapy; CT-scan, computed tomography scan; D, day; ECG, electrocardiogram; ECHO,
echocardiogram; ECOG PS, Eastern Cooperative Oncology Group performance status; FLC, free light chains; HBV, hepatitis B 
virus; HCV, hepatitis C virus; HIV, human immunodeficiency virus; HR, heart rate; IF, immunofixation; INR, international 
normalized ratio for blood clotting time; LDH, lactate dehydrogenase; LVEF, left ventricular ejection fraction; MM, multiple 
myeloma; MUGA scan, multiple uptake gated acquisition scan; MRI, magnetic resonance imaging; NCI-CTCAE, National Cancer 
Institute Common Criteria for the Classification of Adverse Events; PD, disease progression; PT, prothrombin time; SFLC, Serum 
FLC; TTP, time to progression; UFLC, urine FLC; ULN, upper limit of normality; WBC, white blood cell counts.  
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4.8.2
Follow-up Visits
Patients who have not progressed at the end of treatment will have a complete disease 
assessment performed every three months until PD has been documented, a new therapy 
has been started, study termination or death. In this manner, the first follow-up 
assessment should occur at three months after the end-of-treatment visit. All subsequent 
follow-up assessments should be performed in three-month intervals.
Additional parameters and/or increased frequency of observations should be performed 
at the Investigator’s discretion and according to the nature of the AEs observed. In case 
of death, when available, autopsy data should be provided.
The reason and date of removal for all patients will be documented on the e-CRF. The
Investigator will attempt to complete all discharge procedures at the time a patient is 
discontinued from treatment.
5.
STUDY MEDICATION
5.1 Plitidepsin
Plitidepsin is supplied as a lyophilized product in a glass vial containing 2 mg. The 
lyophilized powder is a concentrate for solution. The reconstitution solvent is supplied 
in ampoules, each containing 4 mL of polyoxyl 35 castor oil/ethanol/WFI (15/15/70% 
v/v/v). Plitidepsin vials and reconstitution ampoules should be stored in a locked area 
with limited access at 2 to 8ºC (36ºF to 46ºF) and protected from exposure to light.
Upon reconstitution of the 2 mg plitidepsin vial with 4 mL of reconstitution solvent, the 
reconstituted solution will be clear, colorless, essentially clear from visible particles, 
and contain 0.5 mg/mL of plitidepsin. This solution should be immediately diluted with
sodium chloride (0.9%) solution for infusion or glucose (5%) solution for infusion for 
administration as an intravenous infusion.
The required volume of the reconstituded solution should be determined based on the 
dose established for each individual patient: 
Volume (ml) = [Body Surface Area (BSA) (m2) x xIndividual dosage (mg/m2)]/0.5 
mg/mL
For detailed instructions on the reconstitution and dilution refere to the latest plitidepsin 
IB  and the “Preparation Guide for Infusion” document.
5.1.1 Plitidepsin Recommendations for Safe Handling
Similar to other antineoplastic potentially toxic agents, caution should be exercised 
when handling plitidepsin and when preparing solutions. Personnel should be trained to 
reconstitute the drug. The use of mask, goggles and gloves is recommended. Should
plitidepsin premix solution, or infusion solution come into contact with the skin or 
mucous membranes, the areas should be immediately and thoroughly washed with 
water (mucous membranes) and water and soap (skin).
5.1.2 Required Prophylactic Medication
Patients must receive the following prophylactic medication before the administration 
of plitidepsin (Table 5).
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Table 5. Prophylactic medication for plitidepsin treatment.
Agent
Dose
Route
Day
Ondansetron or equivalent
8.0 mg
intravenous
30 minutes before 
plitidepsin
Diphenhydramine hydrochloride or 
equivalent
25 mg
intravenous
Ranitidine
50 mg
intravenous
In addition to the above, and if necessary, 10 mg metoclopramide every 8 h may be 
administered after the infusion, or the duration of treatment with 5-HT3 antagonists 
and/or dexamethasone will be extended.
5.2 Bortezomib
Bortezomib (Velcade®) is available for use as i.v. infusion and s.c. injection. Each 
single dose vial contains 3.5 mg of bortezomib as a sterile lyophilized powder. For 
further information on bortezomib, please refer to the EU  SmPC and/or USP.
5.2.1 Prophylactic Medication
Prophylactic antiemetic medication for bortezomib will be given according to the 
Investigator’s criteria. Herpes virus infection prophylaxis must be given while patients 
are on bortezomib therapy.
5.3 Dexamethasone Drug Formulation 
Dexamethasone is administered orally as tablets. Dexamethasone tablets should be 
stored in well-closed containers. Dexamethasone will be administered orally at a dose of 
40 mg on D1, 8, 15 and 22 q4wk.
5.4 Treatment Schedule
Oral dexamethasone will be administered at least one hour before the administration of 
plitidepsin infusion. Plitidepsin will be administered as a 3-h i.v. infusion; one minute 
after the end of the plitidepsin infusion, bortezomib should be administered as a 3-5 
second bolus s.c. injection (Table 6).
Treatment cycles will be repeated every 4 weeks.
Patients will receive a maximum of eight treatment cycles. If the patient responds to 
treatment or achieves SD during this time, treatment with plitidepsin and 
dexamethasone may continue in further cycles at the same plitidepsin dose upon 
Investigator’s decision and agreement with the Sponsor.
Table 6. Study drug administration schedule.
Agent
Dose
Route
Day
Dexamethasone
40 mg
Oral
D1, 8, 15 and 22*
Plitidepsin
As assigned by 
PharmaMar
Intravenous
D1 and 15 q4wk*
Bortezomib
Subcutaneous
D1, 4, 8 and 11 q4wk*
* Patients will be allowed a maximum of eight treatment cycles. If the patient responds to treatment or achieves 
stable disease (SD) during this time, treatment with plitidepsin exclusively may continue at the same dose upon 
Investigator’s decision and agreement with the Sponsor.
D, day; q4wk, every four weeks.
5.5 Criteria for Treatment Continuation and Re-treatment
Table 7 lists the minimum requirements needed to re-expose the patient to the study 
drug(s). Other factors might be considered critical by the Investigator, which should be 
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appropriately documented in the patient’s record and on the e-CRF, and discussed with 
the Sponsor. 
Table 7. Criteria for plitidepsin and bortezomib treatment continuation.
Plitidepsin
Bortezomib
Day 1a and 15b
Day 1a*, 4b, 8 b and 11 b
ANC
1.0 x 109/L (≥ 0.5 x109/L
if due to extensive BM
involvement)
1.0 x 109/L (≥ 0.5 
x109/L if due to 
extensive BM
involvement)
Platelets
≥ 50.0 x 109/L (≥ 25.0 
x109/L if due to 
extensive BM 
involvement)
≥ 50.0 x 109/L (≥ 25.0 
x109/L if due to 
extensive BM 
involvement)
Hemoglobin
8.0 g/dl
8.0 g/dl
Serum total bilirubin 
1.5 x ULNe
1.5 x ULNe
AST/ALT/AP
2.5 x ULN
2.5 x ULN
Muscular toxicity (myalgia, muscular 
weakness, CPK increase)
< Grade 2
< Grade 2
Other non-hematological drug-related AEs 
(except for increased GGT, non-optimally 
treated nausea and vomiting or hypertension, 
alopecia)c
< Grade 2
< Grade 2
ECG, ECHO/MUGAd
Baseline
Baseline
aIf a patient does not meet the requirements for treatment continuation on D1 of the following cycle, the infusion of 
study drug(s) will be withheld until recovery or for a maximum of 14 days. After this period, if the delay is due to 
toxicity related to the study drug(s), a dose reduction by one DL is mandatory; up to a maximum of two individual 
dose reductions are allowed. Patients needing additional dose reductions must be withdrawn from the study.
a*From C2 onwards, Hematology and Biochemistry A will only be collected on D1 and 15, hence only re-treatment 
criteria other than Hematology/Biochemistry A will apply on D4, 8 and 11.
bIf a patient does not meet the requirements for treatment continuation on D15 (plitidepsin) or D4, 8 and 11 
(bortezomib), the administration of plitidepsin or bortezomib, respectively, will be omitted. Patients requiring 
frequent dose omissions may have a dose reduction by one DL upon the Investigator and the Sponsor’s agreement. 
No more than two dose reductions are allowed under any circumstances. 
cAny grade accepted for increased GGT.
dTo be performed every three months unless more frequent assessments are clinically indicated.
eExcept when Gilbert syndrome is clearly documented and other liver function tests are normal.AEs,
adverse 
event(s); 
ANC, 
absolute 
neutrophil 
count; 
AP, 
alkaline 
phosphatase; 
AST/ALT,
aspartate 
aminotransferase/alanine 
aminotransferase; 
BM,
bone 
marrow; 
CPK,
creatine 
phosphokinase; 
ECG, 
electrocardiogram; ECHO/MUGA, echocardiogram/multiple-gated acquisition scan; GGT, -glutamyltranspeptidase;
ULN, upper limit of normality.
The following guidelines must be followed before the administration of each 
bortezomib dose (63): 
Table 8. Recommended posology modifications for bortezomib-related neuropathy.
Severity of PN
signs and 
symptoms*
Recommended modification of 
bortezomib dose and regimen
Supportive data
Grade 1 
(paresthesia; 
weakness and/or 
loss of reflexes) 
without pain or 
loss of function
Reduce current bortezomib dose by one 
DL (1.3 to 1.0 mg/m2) or, for patients 
receiving a twice-weekly schedule, 
change to a once-per-week schedule 
using the same dose.
Prior PN was the only risk factor 
associated with bortezomib-related PN in 
newly diagnosed patients treated with 
VMP.
Baseline PN was a risk factor for the 
development of grade ≥3 PN in 
relapsed/refractory MM patients treated 
with single-agent bortezomib.
A VMP regimen using bortezomib 1.3 
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Severity of PN
signs and 
symptoms*
Recommended modification of 
bortezomib dose and regimen
Supportive data
mg/m2 once weekly from the start of 
therapy showed reduced neurotoxicity a 
delivered a similar cumulative dose of 
bortezomib to that in the VISTA trial, and 
resulted in similar efficacy.
Grade 1 with 
pain or grade 2  
(with no pain but 
limiting 
instrumental 
ADLs**)
For patients receiving twice-weekly 
bortezomib, reduce current dose by one 
DL or change to a once-per-week 
schedule using the same dose.
For patients receiving bortezomib on a 
once-per-week schedule, reduce current 
dose by one DL, or consider temporary 
discontinuation; upon resolution to 
grade ≤1, restart once-per-week dosing 
at a lower DL in cases of favorable 
benefit/risk ratio.
Early reduction of bortezomib from 1.3 
mg/m2 twice weekly to once weekly in 
patients receiving VMP showed reduced 
neurotoxicity, delivered similar cumulative 
dose of bortezomib to that of the VISTA 
trial and resulted in similar efficacy.
Dose reduction strategies including dose 
reduction from 1.3 to 1.0 mg/m2 changing 
from twice-weekly to once-weekly dosing, 
and withholding of bortezomib resulted in 
improvement or resolution of PN in most 
patients with bortezomib-related PN.
Grade 2 with 
pain or grade 3 
(limiting selfcare 
and ADL***) or 
grade 4
Discontinue bortezomib
Discontinuation as part of PN management 
strategy resulted in improvement or 
resolution of clinically significant 
neuropathy in 71% of patients in an 
analysis of two phase II bortezomib studies.
*Based on posology modifications in phase II and III MM studies and post-marketing experience. Grading based 
on NCI-CTCAE v 4.0.
**Instrumental ADL: refers to preparing meals, shopping for groceries or clothes, using telephone, managing 
money, etc;
***Self care ADL: refers to bathing, dressing and undressing, feeding self, using the toilet, taking medicinal 
products, and not bedridden.
ADL, activities of daily living; DL, dose level; MM, multiple myeloma; NCI-CTCAE, National Cancer Institute 
Common Terminology Criteria for the Classification of Adverse Events; PN, peripheral neuropathy; VMP, 
Velcade/Melphalan/Prednisone.
The criteria for treatment continuation with dexamethasone are to be implemented 
independently from those of plitidepsin and bortezomib. Dexamethasone treatment will 
therefore not be delayed in parallel to plitidepsin/bortezomib; if a patient experiences 
grade ≥ 3 muscular toxicity (weakness, myalgia and/or CPK elevations), or drug-related 
grade ≥ 3 fatigue, or grade ≥ 2 mood disturbances or agitation or grade ≥ 3 fluid 
retention or grade 4 clinically documented infection, the dose of dexamethasone will be 
reduced by 50%, up to a maximum of two consecutive dose reductions (20 mg D1, 8, 15 
and 22, and 20 mg D1 and 15 of each 28-day cycle). After two dose reductions, 
dexamethasone will be discontinued.
5.6 Definition of Dose-limiting Toxicity
For this protocol DLTs are defined as AEs and laboratory abnormalities related to study 
agent with an attribution of possible, probable, or definite during the first treatment 
cycle and fulfilling one of the following criteria:
Hematological Toxicity:

Grade 3-4 neutropenia associated with fever or lasting > 7 days, considered 
related to the study drug(s) by the Investigator. 

Grade 3-4 thrombocytopenia accompanied by grade 3/4 hemorrhage. 

For patients with extensive BM infiltration (≥ 50% of BM nucleated cells are 
plasma cells), DLT is defined as grade 4 thrombocytopenia with grade 3/4 
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hemorrhage or grade 4 neutropenia lasting more than seven days or with 
fever.
Non-hematological Toxicity:

Grade 3/4 nausea and vomiting refractory to antiemetic therapy.

Grade ≥ 3 muscular AEs (myalgia, muscular weakness, muscle cramps, 
myopathy).

Grade ≥ 3 ALT/AST lasting for more than one week.

Grade ≥ 3 bilirubin increase.

Grade ≥ 3 CPK increase.

Cardiac toxicity:
Symptomatic or treatment-requiring grade ≥ 1 cardiac arrhythmia related 
to plitidepsin.
Left ventricular systolic dysfunction grade ≥ 1 related to plitidepsin.

Neuropathic pain and peripheral sensory neuropathy related to bortezomib 
will be considered as DLT if they result in a definitive bortezomib 
discontinuation according to IMWG guidelines (Table 7).

Any other grade ≥ 3 toxicity considered related to study treatment by the 
Investigator.
5.7 Definition of Recommended Dose
To define the RD for phase II trials, patients will be evaluated for DLTs during the first 
28-day cycle. The RD will be the highest DL at which fewer than two out of six (33%)
of evaluable patients experience a DLT during the first 28-day cycle.
5.8 Dose Escalation
Treatment will start with the 60% of the RD of plitidepsin given as single agent. Dose 
escalation for plitidepsin and bortezomib will follow the rules shown on Table 9.
Table 9. Dose escalation rule for plitidepsin and bortezomib combination.
Dose Level
No. Patients
Plitidepsin dose 
(mg/m2)
Bortezomib dose
(mg/m2)
Dexamethasone
(mg)
-1
0-6
3.0
1.0
40.0
1
3-6
4.0
1.0
40.0
2
3-6
4.0
1.3
40.0
3
3-6
5.0
1.3
40.0
Cohorts of three patients will be treated at each DL (up to three DLs).

The first cohort of three patients will start at DL1.

If no DLTs are observed in any of the three patients at a given DL, three
additional patients will be treated at the next DL.

If a DLT is observed in one of three patients treated at a given DL, three
additional patients will be entered at that same DL.
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
If DLTs are observed in two of three patients, no additional patients will be 
treated at that DL and the immediately lower DL will be expanded to at least 
six patients.

If two out of six patients present a DLT at DL 1, the next patients enrolled 
will be treated at DL-1. If two of six patients (≥33%) present DLTs at this 
DL, the study will be stopped and that DL will be considered the MTD. 

The RD is defined as the DL at which fewer than two out of six patients
(33%) experience DLTs during the first cycle. 

At the RD, at least six evaluable patients for determination of DLTs will be 
treated. 

At DL1, one patient must have completed the first cycle before accrual of the 
second and third patients. The second and third patients may be treated 
simultaneously.

Intermediate dose escalation or de-escalation is allowed. Intrapatient dose 
escalation is not allowed.
5.9 Dose Modifications Based on Adverse Events
Dose modifications will be based on AEs and laboratory abnormalities graded 
according to the National Cancer Institute Common Terminology Criteria for Adverse 
Events (NCI-CTCAE version 4.0). Patients will be assessed for toxicity before each 
plitidepsin infusion or bortezomib injection. If several AEs or laboratory abnormalities 
are seen simultaneously, the dose will be modified according to the greatest reduction 
required for the most severe event observed. Reductions apply to treatment given in the 
preceding cycle and are based on AEs observed since the prior dose. Dose reductions 
levels are the following:

Dose adjustments will initially involve the drug to which an AE is suspected 
to be related to, whenever possible. If causality cannot be attributed to a 
specific drug, the two drugs (bortezomib and plitidepsin) will be reduced one 
DL.

DL reductions for plitidepsin should follow Table 9 (5.0 mg/m2 →4.0 
mg/m2→ 3.0 mg/m2).

For patients receiving twice-weekly bortezomib, reduce current dose by 
one DL (from 1.3 mg/m2 to 1.0 mg/m2) or change to a once-per-week 
schedule (D1, 8, 15 and 22, q4wk) using the same dose. For patients 
receiving bortezomib on a once-per-week schedule (D1, 8, 15 and 22, 
q4wk), reduce current dose by one DL. No additional dose reductions will 
be allowed due to bortezomib-related hematological toxicity. 

Patients for whom bortezomib is discontinued may continue to receive the 
other agents if, in the opinion of the Investigator, the patient may continue to 
benefit from treatment.

Dexamethasone doses are to be reduced by 50%, up to a maximum of two 
consecutive dose reductions (20 mg D1, 8, 15 and 22, and 20 mg D1 and 15 
of each 28-day cycle), if a patient experiences grade ≥ 3 muscular toxicity 
(weakness, myalgia and/or CPK elevations), or drug-related grade ≥ 3 
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fatigue, or grade ≥ 2 mood disturbances or agitation or grade ≥ 3 fluid 
retention or grade 4 clinically documented infection. These dose reductions 
are to be implemented independently from plitidepsin dose reductions, if 
required. After two dose reductions, dexamethasone will be discontinued.

If the patient suffers from vomiting after dexamethasone, it should not be re-
administered and will be considered as omitted.

Patients with toxicities that are manageable with supportive treatment may 
not require dose reductions (e.g., nausea/vomiting may be treated with 
antiemetics, diarrhea may be treated with loperamide rather than by dose 
reductions). 

Patients requiring dose reductions should not have the dose re-escalated with 
subsequent treatments.

Patients will be withdrawn from the study if they fail to recover to baseline 
values from a treatment-related toxicity within 14 days, unless the 
Investigator and the responsible medic at PharmaMar agree that the subject 
should remain in the study because of evidence that the patient may continue 
to benefit from it. The appropriate reduced dose will be determined after 
discussion between the principal Investigator and the responsible medic at 
PharmaMar. 
Patients with bortezomib-related neuropathic pain and/or peripheral sensory neuropathy 
are to be managed according to the guidelines on Table 8 (63).
5.10
Permitted Treatment and Medication
5.10.1 Transfusions
5.10.1.1 Guidelines for Platelet Transfusions
Thrombocytopenia can occur as a consequence of BM infiltration by myeloma cells or 
may be related to study drug administration. The clinical significance of the 
thrombocytopenia should be assessed in light of its etiology (bortezomib treatment, 
underlying disease or both), the state of the myeloma (stable versus worsening disease), 
and whether the patient is bleeding or being prepared for a surgical procedure.
The use of any platelet product should be considered in the following circumstances:

As preparation for an invasive surgical procedure, transfuse in order to 
maintain a platelet count >50.0 x 109/L to prevent bleeding.

If the patient has an active infection, high fever, rapid decrease in platelet 
count to ≤ 20.0 x 109/L and/or coagulopathy, transfuse to maintain a platelet 
count to > 20.0 x 109/L as prophylaxis for spontaneous bleeding.

If the patient is actively bleeding or has a platelet count below 10.0 x 109/L, 
transfuse in order to maintain a platelet count > 10.0 x 109/L.
5.10.1.2 Guidelines for Red Cell Transfusions
The use of any red cell product should be considered in the following circumstances:

If the patient has a hemoglobin < 7.0 g/dL, transfuse to maintain a 
hemoglobin > 8.0 g/dL in order to reduce the risk of inadequate oxygenation. 
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
If the patient is asymptomatic and has a hemoglobin value between 
≥ 7.0 and ≤ 8.0 g/dL, the Investigator may consider transfusion on a per-
patient basis in order to maintain a hemoglobin > 8.0 g/dL.

If the patient is actively bleeding or has symptomatic cardiac or pulmonary 
disease or other extenuating circumstances where oxygenation is impaired, 
the Investigator may elect to transfuse on a per-patient basis. In these 
instances, the trigger hemoglobin value may be > 8.0 g/dL

The use of erythropoietin (e.g. Eprex®/Erypo®) is allowed.
5.10.2 Other Therapies

Therapies for the treatment of preexisting and/or emergent medical 
conditions not specifically forbidden as per protocol elsewhere.

Antiemetics (as in Section 5.1.2 and according to institutional or ASCO 
guidelines) (64).

Use of G-CSF/GM-CSF according to institutional or ASCO guidelines (65)
and after C1.

Palliative local radiation may be applied. The irradiated lesion will then not 
be considered an area of measurable/evaluable disease. 

Systemic and/or local therapies for symptomatic relief, particularly in the 
case of diarrhea or skin toxicity.

Patients who develop grade 2 or greater muscular toxicity may be 
empirically treated with oral L-carnitine at a total daily amount of 3 g, 
divided into 3 doses, until it decreases to grade ≤ 1.

Adequate analgesic medication, including opioids for symptomatic pain 
relief if indicated.

Drugs that prolong QT interval and/or induce Torsades de Pointes may be 
used with caution (Appendix 5).

Patients receiving aminobisphosphonates before study entry may continue to 
receive them during the study according to ASCO guidelines.
5.11
Prohibited Medication

Concomitant administration of any other antineoplastic therapy.

Other investigational agents.

Immunosuppressive therapies, including systemic corticosteroids, unless
given as an equivalent to a prednisone dose of ≤ 10 mg daily administered as 
an antiemetic or as pre-medication for blood prodcuts.

Other disease-modifying treatment (e.g., alpha interferon) is strictly 
prohibited.

Primary prophylaxis with colony-stimulating factors such as G-CSF and 
GM-CSF (i.e., within the first cycle).
5.12
Packaging and Labeling
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The following information will appear on the label:

Name of the Sponsor

Study number and patient number

Dosage and route of administration

Quantity of contents of container

Batch number and packaging number

Expiration date and storage conditions

Local legal requirements as appropriate
5.13
Drug Accountability
Proper drug accountability will be done by the study monitor. The responsible 
institution will keep records to allow a comparison of quantities of drug received and 
used at each site.
All unused drug supplied by PharmaMar will be properly destroyed at the 
investigational site (documentation of this procedure must be provided) or returned to 
the drug repository with the agreement of PharmaMar.
6.
STUDY ASSESSMENTS
6.1 Efficacy
Response or disease progression will be assessed on D1 of each therapy cycle according 
to the International Myeloma Working Group (IMWG) criteria (66) with evaluation of 
serological myeloma specific markers: M-protein, serum FLC and IF from blood and 
urine. When serological markers indicate CR, a BM aspirate or biopsy will be 
performed. Also, a skeletal survey will be performed to confirm no increase in size or 
number of lytic bone lesions (development of a compression fracture does not exclude 
response).
The efficacy analysis will include ORR, clinical benefit rate (ORR + MR + SD), PFS, 
TTP, EFS and DOR. They will be analyzed in all eligible patients who received at least 
one treatment cycle.
Patients are evaluable for efficacy if they receive at least one complete treatment cycle 
(two plitidepsin infusions, four bortezomib injections, four doses of dexamethasone), or 
the equivalent doses over two cycles and have, at least, one disease assessment. 
6.1.1 Response Criteria for Multiple Myeloma
6.1.1.1
Stringent Complete response (sCR)
These patients have a normal FLC ratio and have no clonal cells by BM 
immunohistochemistry (IHC) or immunofluorescence. Clonal cells detected in the BM 
by IHC or immunofluorescence, are considered to be present if there is a kappa/lambda 
ratio of > 4:1 or <1:2 after examination of a minimum of 100 plasma cells. 
6.1.1.2
Complete response (CR)
These patients have absence of M-protein in serum and urine by IF with no current 
evidence of soft tissue plasmacytoma. In addition, BM aspirate and biopsy must 
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demonstrate less than 5% clonal plasma cells. In patients who lack measurable M-
protein in the serum and urine being monitored using the FLC levels, the definition of 
CR requires a normalization of the FLC ratio in addition to the above criteria. 
6.1.1.3
Very good partial response (VGPR)
These patients have serum and urine M-protein detectable by IF but not on 
electrophoresis or at least a 90% reduction in serum M-protein with a urine M-protein 
<100 mg/24 h. In patients who lack measurable M-protein in the serum and urine being 
monitored using the FLC levels, the definition of VGPR requires > 90% decrease in the 
difference between involved and uninvolved FLC levels.
6.1.1.4
Partial response (PR)
These patients have ≥ 50% reduction in serum M-protein and reduction of 24-h urinary 
M-protein by 90% or to < 200 mg/24 h. In patients who lack measurable M-proteins in 
the serum and urine, the definition of PR requires ≥ 50% decrease in the difference 
between involved and uninvolved FLC levels. If the FLC levels were also immeasurable
at baseline, a 50% reduction in BM plasma cells is acceptable as long as the original 
BM contained at least 30% plasma cells. PR also requires a 50% reduction in size of 
any soft tissue plasmacytomas if present at baseline.
6.1.1.5
Minimal response (MR)
These patients have ≥25% but ≤ 49% reduction of serum M-protein and reduction in 
24-h urine M-protein by 50-89%. In addition, if present at baseline, 25-49% reduction 
in the size of soft tissue plasmocytomas is also required. No increase in size or number 
of lytic bone lesions.
6.1.1.6
Stable Disease (SD)
These patients do not meet the criteria for sCR, CR, VGPR, PR, MR or PD.
6.1.1.7
Progressive disease (PD) 
These patients present with a 25% increase from the lowest response value in any of the 
following: serum M-protein (absolute increase must be ≥0.5 g/dL), urine M-protein 
(absolute increase must be ≥200 mg/24h), BM plasma cell percentage (absolute 
increase must be ≥10%), or difference in the kappa and lambda FLC (absolute increase 
must be >10 mg/dL). As discussed earlier, the FLC criteria should only be used for 
patients with immeasurable M-protein in the serum and urine. PD is also diagnosed 
when there is an increase in the size or development of new bone lesions or soft tissue 
plasmacytomas or the development of a serum calcium >11.5 mg/dL with no other 
cause.
6.1.1.8
Overall Response Rate (ORR) 
It includes sCR plus CR plus VGPR plus PR.
6.1.1.9
Cinical Benefit Rate
It includes ORR plus MR plus SD.
Note: clarification to IMWG criteria for coding CR and VGPR in patients in whom the 
only measurable disease is by serum FLC levels: CR in such patients is defined as a 
normal FLC ratio of 0.26–1.65 in addition to the CR criteria listed above. VGPR in such 
patients is defined as a > 90% decrease in the difference between involved and 
uninvolved free light chain (FLC) levels.
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All response categories (CR, sCR, VGPR and PR) require two consecutive assessments 
made at any time before the institution of any new therapy; sCR, CR, VGPR, PR and 
SD categories also require no known evidence of progressive or new bone lesions if 
radiographic studies were performed.
Radiographic studies are not required to satisfy these response requirements. Bone 
marrow assessments need not to be confirmed. 
For PD, serum M-component increases of ≥ 1 g/100 ml are sufficient to define relapse if 
starting M-component is ≥ 5 g/100ml.
6.1.2 Additional Efficacy Endpoints 
According to the American Society of Hematology/Food and Drug Administration 
ASH/FDA clinical endpoints in MM:

DOR is defined as the time from the first observation of response to the time 
of PD, with censoring of deaths due to causes other than PD.

TTP is defined as the duration from treatment start to PD, with censoring of 
deaths due to causes other than PD.

PFS is defined as the duration from treatment start to PD or death (regardless 
of the cause of death), whichever comes first.

EFS is defined as the duration from treatment start to PD or death (regardless 
of the cause of death), whichever comes first. It may include additional 
“events” that are considered to be of importance besides death and PD, 
including serious drug toxicity.
The duration of sCR, CR, VGPR and PR should be reported. Observation curves will be 
estimated using the Kaplan-Meier method. ORR and clinical benefit rate will be 
calculated with binomial exact 95% CI.
6.1.3 Efficacy Assessment Determinations
6.1.3.1
Myeloma Protein Measurements
Serum
Serum quantitation of immunoglobulins and M-protein, and assessment of M-protein by 
IF and FLC must be determined for all patients at screening. The same determinations 
will be performed in patients with secretory MM on D1 of every cycle. For patients 
with “non-secretory myeloma” FLC will be assessed at the same times. If there is 
evidence of PD, these evaluations must be repeated one to three weeks later in order to 
confirm PD.
Urine
Quantitation of M-protein and assessment of M-protein by IF from 24-h urine samples 
must be determined for all patients at screening. For patients with positive results, the 
same determinations will be done from 24-h urine samples collected on D1 of every 
cycle. If there is evidence of PD, this evaluation is to be repeated with a second 
measurement one to four weeks later in order to confirm PD. In patients with IF-
negative non-secretory MM, these tests will not be repeated after screening.
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6.1.3.2
Bone Marrow
A representative BM aspirate or a BM biopsy must be obtained at screening. During the 
treatment period, BM assessment is mandatory in the presence of CR. In patients with 
non-secretory myeloma, collection and evaluation of BM is required eight weeks later 
to confirm CR. BM examination has to be performed in all cases where it is judged as 
clinically necessary. BM studies will include cytogenetics and cell cycle analysis by 
flow cytometry, if available.
6.1.3.3
Skeletal Survey and Other Radiographs
A complete bone survey including examination of the skull, vertebral column, pelvis 
and proximal long bones, should be done at screening. In this period, it is important to 
document sites of myelomatous disease, especially in extramedullary areas. This may 
require clinical examination, CT-scanning or MRI evaluations.
During the treatment phase, a skeletal survey must take place in the presence of CR or if 
clinical symptoms suggest new lytic bone lesions. In the case of non-secretory or 
oligosecretory MM associated with soft tissue plasmacytoma, CT or MRI assessments 
may be performed every two cycles (whenever possible) and to confirm response if 
clinically indicated.
For soft tissue plasmacytomas, tumor assessment will consist of the sum of the cross-
diameters of the measurable lesion
Radiographic examination of any location must be performed when clinical symptoms 
suggest a new bone lytic lesion.
6.1.3.4
Beta-2-Microglobulin and C-Reactive Protein
Beta-2-microglobulin will be measured at screening and C-reactive protein will be 
measured at screening, every eight weeks during the treatment phase and in the last final 
visit (30±5 days) after the last dose of the study therapy.
6.2 Safety Assessment 
Individual patients will be evaluated from treatment start until 30 days after the last IMP 
administration.
Patients will be evaluable for safety if they receive at least one (complete or incomplete) 
dose of plitidepsin.
Safety will be evaluated by the occurrence of clinical and laboratory toxicities and 
changes from baseline in physical examination findings, vital signs, and, if applicable, 
chest X-ray and ECG findings. AEs will be graded according to NCI-CTCAE v 4.0
6.2.1 Adverse Event Definitions
6.2.1.1
Adverse Event
An adverse event (AE) is any untoward medical occurrence in a patient or clinical 
investigation subject which does not necessarily have a causal relationship with the 
study treatment. 
For the purpose of this protocol, PD or worsening of the underlying MM should not be 
reported as AEs.
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6.2.1.2
Serious Adverse Event 
A serious adverse event (SAE) is any adverse experience occurring at any dose that:

results in death (is fatal),

is life-threatening,

requires or prolongs inpatient hospitalization,

results in persistent or significant disability or incapacity,

is a congenital anomaly or birth defect, or

is medically significant.

Any suspected transmission via a medicinal product of an infectious agent.
Medical and scientific judgment should be exercised in deciding whether expedited 
reporting is appropriate in other situations, such as an important medical event that may 
not be immediately life-threatening or result in hospitalization but may jeopardize the 
patient or may require intervention to prevent one of the outcomes listed in the above 
definition.
6.2.1.3
Death
Death as such is the outcome of a SAE and should, whenever possible, not be used as 
the SAE term itself. The cause of death should be recorded as the SAE term instead. 
When available, the autopsy report will be provided by the Sponsor.
Grade 5 should be used for events leading immediately and directly to death, and grade 
4 should be used with outcome death for events leading to death after a longer time 
period, and that may also be linked to additional morbidities.
6.2.1.4
Life Threatening Event
A life threatening event is defined as any event in which the subject is at risk of death at 
the time of the event; it does not refer to an event which hypothetically might have 
caused death if it were more severe.
6.2.1.5
Hospitalization /Prolongation of Hospitalization
Any event requiring hospitalization (or prolongation of hospitalization) that occurs or 
worsens during the course of a patient’s participation in a clinical study must be 
reported as a SAE. Prolongation of hospitalization is defined as any extension of an 
inpatient hospitalization beyond the stay anticipated/required for the initial admission, 
as determined by the Investigator or treating physician.
Hospitalizations that do not meet criteria for SAE reporting are: 

Reasons described in the protocol (e.g., drug administration, protocol-
required investigations). Hospitalization or prolonged hospitalization for a 
complication of therapy administration or procedure will be reported as a 
SAE.

Hospitalization or prolonged hospitalization for technical, practical or social 
reasons, in the absence of an AE. 

Pre-planned hospitalizations (i.e., planned before study entry). Any surgery 
or procedure planned before study entry must be documented on the e-CRF.
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Only if the pre-planned surgery needs to be performed earlier due to a 
worsening of the condition, should this event (worsened condition) be 
reported as a SAE.
Other situations that MUST NOT be considered as hospitalizations are:

An emergency visit due to an accident where the patient is treated and 
discharged.

When the patient is held 24 h for observation and is finally not admitted.

Planned treatments at sites not associated to a hospital and generally 
considered as minor surgical procedures (i.e. laser eye surgery, arthroscopy 
etc…).
6.2.1.6
Unexpected/Unlisted Adverse Event
An AE is considered unexpected when the nature or severity of which is not consistent 
with the applicable product information. The reference safety information for the
evaluation of expectedness will be:

The current IB for the study drug without marketing authorization.

The summary of product characteristics (SPC) for MPs with a marketing 
authorization.
6.2.1.7
Adverse Reaction
All untoward and unintended response to an IMP related to any dose administered. This 
definition also covers medication errors and uses outside what is foreseen in the 
protocol, including overdose, lack of efficacy, misuse and abuse of the product. Any 
event involving adverse drug reactions (ADR), illnesses with onset during the study or 
exacerbations of pre-existing illnesses should be recorded.
6.2.1.8
Adverse Events Related to the Study Drug
An AE is considered associated with the use of the drug if the causality assessment is 
related to the study drug or unknown according to the definitions listed below.
6.2.1.9
Expedited Reporting
The Sponsor will assume responsibility for appropriate expedited reporting of serious 
unlisted/unexpected and related adverse events (SUSAR/SUA), including misuse, 
overdose, abuse, medication error and those considered of special interest to the 
Competent Authorities. The Sponsor will also report all SAEs, including misuse, 
overdose, abuse, medication error, which are unlisted/unexpected and related to the 
study drug(s) [IMP(s)] to the Investigators and to the IEC/IRBs according to current 
legislation unless otherwise required and documented by the IEC/IRB.
6.2.1.10 Causality Assessment
The Investigator must provide an assessment of causality for each of the Investigation
Medicinal Product (IMP) (including combination and comparator products) according 
to the following criteria:

Related to study drug(s).

Not related to study drug(s) but related to:
Disease under study.
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Other illness (must be specified).
Previous/concomitant treatment/therapy.
Unknown but not related to study drug.

Unknown.
If the causality assessment is unknown and the Investigator cannot rule out relationship 
to the study drug, then “unknown” should be chosen. If the causality assessment is 
“unknown but not related to the study drug”, this should be clearly documented on the 
study records.
6.2.2 Adverse Event Reporting Procedures
6.2.2.1
Reporting of Adverse Events
The Sponsor will collect AEs from the onset of the treatment period and until 30 days 
after administration of the last dose of study drug. All AEs suspected to be related to the 
study drug or the combination of the drugs must be followed after the time of therapy 
discontinuation until the event or its sequelae resolve or stabilize to 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 on the source document and the e-CRF. 
Investigators must assess the severity (grade) of the event following NCI-CTCAE v4.0 
and assign a relationship to study therapy, pursue and obtain information adequate to 
determine the outcome and to assess whether it meets the criteria for classification as a 
SAE requiring immediate notification to PharmaMar or its designated representative. 
The Investigator must provide any information as requested by the Sponsor in addition 
to that on the e-CRF.
Abnormal laboratory tests obtained during the study are AEs, but they should only be 
recorded on the AE section of the e-CRF in some cases (please refer to e-CRF 
instructions for comprehensive information).
6.2.2.2
Reporting Serious Adverse Events
All SAEs (as defined above) regardless of treatment group or suspected relationship to 
the study drug must be reported within 24h to Pharmacovigilance by fax (+34 91 846 
6004) or phone (+34 91 823 4569). Out of office hours (Greenwich Mean Time, GMT)
assistance on SAE reporting can be obtained by calling the Pharmacovigilance Service 
phone +34 91 823 47 42.  It is preferable that SAEs be reported by completing the 
electronic AE/SAE summary forms. An initial SAE report by phone must be followed 
by a completed electronic “SAE Form” from the investigational staff within one 
working day.
The Sponsor will collect SAEs from the time of signing of the IC. If the patient is 
definitively included in the study, and the SAE occurs after registration has been 
confirmed, this information will also be recorded on the AE and SAE summary sections
of the e-CRF. The Sponsor will collect SAEs until 30 days after the administration of 
the last dose of study drug. Beyond this period of time, only those SAEs suspected to be 
related will be reported.
The Sponsor will evaluate any safety information that is spontaneously reported by an 
Investigator beyond the time frame specified in the protocol. All SAEs suspected to be 
related to a study drug must be followed after the time of therapy discontinuation until 
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the event or its sequelae resolve or stabilize to an acceptable level to the Investigator
and the clinical monitor or his/her designated representative.
The cause of death of a subject in a clinical study, whether the event is expected or 
associated with the investigational agent, is considered a SAE and should therefore be 
reported using the SAE Form. 
6.2.2.3
Pregnancy
FDA and EMA regulations require that pregnancy be reported as a SAE. Hence, the 
following events will also be handled and reported as SAEs:

Any occurrence of a pregnancy.

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 medication).

All reports of elevated/questionable or indeterminate beta human chorionic 
gonadotrophins (betahCGs).
Pregnancy and suspected pregnancy (including a positive pregnancy test regardless of 
age or disease state) of a female patient or the female partner of a male patient occurring 
while the patient is on study drug, or within 30 days of the patient’s discontinuation 
visit, is considered an immediately reportable event. The study drug must be 
discontinued immediately and the patient instructed to return any unused portion of the 
study drug to the Investigator. The pregnancy, suspected pregnancy, or positive 
pregnancy test must be reported to the Drug Safety Department at PharmaMar 
immediately by facsimile using the SAE Report Form.
The Investigator will follow the pregnancy until completion/termination, and must 
notify the outcome of the pregnancy to the Drug Safety Department at PharmaMar as a 
follow-up to the initial SAE report in patients who receive study medication.
If the outcome of the pregnancy meets the criteria for immediate classification as a SAE 
(i.e., spontaneous or therapeutic abortion [any congenital anomaly detected in an 
aborted fetus is to be documented], stillbirth, neonatal death, or congenital anomaly 
[including that in an aborted fetus]), the Investigator should follow the procedures for 
reporting SAEs (i.e., report the event to the Drug Safety Department at PharmaMar by 
facsimile within 24 h of the Investigator’s knowledge of the event).
All neonatal deaths that occur within 30 days of birth should be reported,  regardless of
causality, as SAEs. In addition, any death of an infant after 30 days of birth that the 
Investigator suspects as related to the in utero exposure to the study drug should also be 
reported to the Drug Safety Department at PharmaMar by facsimile within 24 h of the 
Investigators’ knowledge of the event. If the female is found not to be pregnant, any 
determination regarding the patient’s continued participation in the study will be 
determined by the Investigator and the PharmaMar Clinical Research Physician.
6.2.3 Adverse Events Monitoring
Safety review will be performed at Pharma Mar S.A. once the SAE forms have been 
received electronically or by fax and the CRFs have been completed electronically by 
the Investigator. 
Periodic safety review of clinical data will be performed; however, no formal Data 
Safety Monitoring Board has been appointed for this study. AEs will be monitored by 
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the Investigators and by the study team at Pharma Mar S.A. The personnel in charge of 
this process are defined in the section “Study Contacts” of this protocol. In general, a 
clinical oncologist, together with a member of the Pharma Mar S.A. Pharmacovigilance 
Department will review the safety data of this study on an ongoing basis. 
SAEs will be collected, assessed and reported as per the applicable Regulations by the 
Pharmacovigilance Department. Periodic safety reviews of SAE reports are to be 
conducted by the clinical oncologist every 3-6 months, depending on recruitment.
As per the applicable regulations, Pharma Mar S.A. will report to the IECs/IRBs, 
Investigators and Competent Authorities:

Expeditedly: all serious, related, unlisted/unexpected AEs or critical safety 
finding from this and any other clinical trial with the IMP(s) and, 

Periodically: all relevant safety information generated in all clinical trials 
with the IMP(s) within the Development Safety Update Report.
Non-serious AEs will be assessed during monitoring visits by the monitor, who will 
discuss them with the Investigators. 
Any protocol deviation will also be discussed with the Investigator during monitoring 
visits.
6.2.3.1
Discontinuations
The reason for a patient’s discontinuation from the study will be recorded on the e-CRF. 
A discontinuation occurs when an enrolled patient ceases to participate in the study, 
regardless of the circumstances, prior to completion of the protocol. The Investigator 
must determine the primary reason for discontinuation. Withdrawal due to an AE should 
be distinguished from withdrawal due to insufficient response according to the 
definition of AE noted earlier. A discontinuation must be reported immediately to the
clinical monitor or his/her designated representative if it is due to a SAE. The final 
evaluation required by the protocol will be performed at the time of study 
discontinuation. The Investigator will record the reason for study discontinuation, 
provide or arrange for appropriate follow-up (if required) for such patients, and 
document the course of the subject’s condition.
7.
PHARMACOKINETIC STUDIES
All patients included in the study will be sampled for PK. All sample collection dates 
and times will be recorded on the electronic CRF. 
Samples will be obtained on C1D1 for the PK analysis of plitidepsin and bortezomib. 
Additionally, patients treated in the expanded cohort at the RD will be sampled for 
plitidepsin analysis on C1D15. Time points for blood sample collection for the 
determination of whole blood concentrations of plitidepsin and plasma concentrations 
of bortezomib are detailed on Table 10. Sample volumes will vary according to the drug
being measured: bortezomib, plitidepsin or both. Figure 5 summarizes the PK sampling 
schedule.
Drug administration on the PK sample collection day should be as follows: after 
collection of the pre-dose PK sample, oral dexamethasone will be administered at least 
one hour before the administration of plitidepsin infusion. Plitidepsin should be 
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administered as a 3-h i.v. infusion. One minute after the end of the plitidepsin infusion, 
bortezomib should be administered as a 3-5 second bolus s.c. injection. Those patients 
belonging to the RD expansion cohort will have whole blood samples taken for the 
measurement of plitidepsin on D15 at the same time points as those on D1.
Figure 5. PK sampling schedule on Day 1.
Table 10. Sampling schedule for the determination of bortezomib and plitidepsin.
Sample 
Number
Day
Absolute time 
from the start 
of plitidepsin infusion
(h)
Time points 
for plitidepsin 
samples
Time points 
for bortezomib 
samples
1
1
0
Pre-dose
Pre-dose
2
1
1.5
1.5 ADA
--
3
1
3
Just before EOI
--
4
1
3.08
--
5 min EOI
5
1
3.25
15 min after EOI
15 min EOI
6
1
3.5
30 min after EOI
30 min EOI
7
1
4
1h after EOI
1h EOI
8
1
5
2h after EOI
2h EOI
9
1
6
3h after EOI
3h EOI
10
1
8
5h after EOI
5h EOI
11
1
10
7h after EOI
7h EOI
12
2
27
24h EOI
24h EOI
13
3
51
48h EOI
48h EOI
14#
4
75
72h EOI
72h EOI
15
5
99
96h EOI
--
16##
8
171
168h EOI
--
# This sample has to be taken BEFORE the administration of the second dose of bortezomib.
##This sample has to be taken BEFORE the administration of the second dose of dexamethasone.
ADA, after drug administration; EOI, end of infusion.
Should information obtained during the evaluation allow improvement of the schedule, 
sampling times may be changed while maintaining or decreasing the total sample 
number and volume. Accurate recording of actual dosing and sampling times is much 
more important than the strict adherence to the scheduled times.
Samples intended for the measurement of bortezomib and plitidepsin will have a 
volume of 8 mL. A blood volume of 4 mL will be enough for samples for the 
measurement of only bortezomib or only plitidepsin.
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The exact recording of the time of drug administration and sampling times is crucial on 
those days when sampling for PK testing takes place. The infusion rate of plitidepsin 
will be established so that it ensures that the total dose is infused in 3 h. The drug will 
be infused at a constant rate throughout the 3-h period and the infusion rate should not 
be modified once the infusion begins in order to obtain reliable PK information. If a 
variation in the infusion time does eventually occur, it is very important to reflect this 
modification on the e-CRF, writing clearly the beginning and the end times of the 
infusion. The pre-established infusion rate should not be changed to maintain the 
scheduled duration of infusion; it would just be enough to record the actual duration on 
the e-CRF and in the PK sampling sheet.
Blood samples for PK will be obtained through a peripheral vein located in the 
contralateral side to that of plitidepsin administration. In any case, the sampling vein has 
to be different to that from which drugs are being administered. Even the last sample 
must never be collected from the catheter used for the drug administration. 
If the blood sample is obtained from a catheter, the first milliliter (mL) of blood will be 
discarded to avoid the dilution of the sample with the solution used to keep it clean. 
Heparin (10 U/mL in normal saline solution) or a slow drip of normal saline solution 
(10 mL/h) can be used to keep the catheter permeable between extractions.
Samples should be placed in a sodium heparin tube and gently inverted several times to 
ensure proper mixing. After sampling, test tubes containing the blood samples will 
either be processed immediately or can be placed in an ice bath at 0-4 ºC for a 
maximum of 30 minutes prior to centrifugation. Before centrifugation, a whole blood 
aliquot will be taken from plitidepsin samples for single plitidepsin measurement; 
bortezomib samples will be centrifuged for plasma single bortezomib determination).
Samples for the measurement of both plitidepsin and bortezomib should have an aliquot 
of whole blood (4 mL) taken before centrifugation and the remaining sample should be 
centrifuged at 4ºC at 1200 x g for 10 min; this procedure will yield approximately 2 mL 
of plasma to be used for plasma bortezomib determination.
Once all samples from a patient have been collected, they should be shipped to the 
central PK laboratory for analysis as soon as possible, ideally the next shipping day. 
Samples from several patients can be sent in the same shipment; however, the time span 
between the moment the last PK sample for a patient has been collected and the 
shipment of all samples from this patient to the central laboratory should not exceed 2 
months.
A manual of full instructions for sample extraction, labeling, storage, and shipment will 
be provided as a separate document (Procedure Manual for the Collection, Storage and 
Shipment of Plasma Samples for Pharmacokinetics).
7.1 Pharmacokinetic calculations
PK will be elucidated using standard non-compartmental methods. The following 
parameters will be calculated: maximum drug concentration (Cmax), area under the 
plasma concentration-time curve (AUC), total plasma clearance (Cl), volume of 
distribution at steady state (Vss) and half-life (t1/2). 
Cmax will be derived directly from experimental data. The terminal rate constant (k) will 
be estimated by log-linear regression analysis of the terminal phase of the plasma 
concentration versus time curve. AUCinf will be determined using the log-linear 
trapezoidal method with extrapolation to infinity using the terminal rate constant k 
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(Clast/k, where Clast is the last measured analyte concentration). T1/2 will be calculated 
from the equation 0.693/k; Cl will be determined by dividing the total administered 
dose (mg) by the AUCinf. Vss will be calculated as Vss = Cl x MRTinf, where MRTinf is 
the mean residence time, which is determined as MRTinf = (AUMCinf/AUCinf) - (1⁄2 x 
duration of infusion), where AUMCinf is the area under the first moment curve with 
extrapolation to infinity.
If considered appropriate by PharmaMar, compartmental analysis on the study results 
will also be performed, and population kinetics analysis will be done with pooled results 
of the different studies.
PK parameters will be tabulated and graphically displayed per dose level.
8.
STATISTICAL METHODS
8.1 Assessment of the Primary Endpoint
For the determination of the RD for the combination plitidepsin, bortezomib and 
dexamethasone, eligible patients will be fully evaluable unless: 

They are withdrawn from the study due to not being evaluable for the 
primary endpoint, due to hypersensitivity reactions or for reasons other than 
a drug-related AEs meeting DLT criteria of (e.g., withdrawal of consent, not 
meeting the eligibility criteria, non-compliance with follow up, early PD, or 
unrelated AE).

They require radiation therapy or other anticancer procedure within three 
weeks after the first dose, unless they previously had another drug-related 
AE included in the definition of DLT.

There is a protocol deviation resulting in an impossibility of concluding 
anything regarding the safety of the study therapy.
The RD for the combination plitidepsin, bortezomib and dexamethasone will be 
descriptively determined according to the evaluation of DLTs in the aforementioned 
population. 
8.2 Efficacy 
The efficacy population is defined as all eligible patients without protocol deviations 
with an effect on the risk/benefit ratio of the clinical study, which may jeopardize the 
efficacy evaluation and who have received at least one treatment cycle (two plitidepsin 
infusions, four bortezomib injections, four doses of dexamethasone), or the equivalent
doses over two cycles and have, at least, one disease assessment. Patients from this 
population who have inadequate post-baseline data to assess efficacy according to the 
response criteria in Section 6.1.1 will be considered treatment failures and will be 
included in the ORR and clinical benefit calculations.  For evaluation of ORR and 
clinical benefit, rates will be calculated with binomial exact confidence intervals at 
95%.
Follow-up time will be calculated from the date of the first infusion to the date of the 
last documented exam. The DOR will be analyzed for all patients in whom a response 
has been observed and will be calculated from the date of the first documentation of 
response to the date of PD. Deaths due to causes other than PD will be censored. 
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TTP will be calculated from the date of the first infusion to the date of documented PD 
or death due to PD. PFS will be calculated from the date of the first infusion to the date 
of documented PD or death. EFS will be calculated from the date of the first infusion to 
the date of documented PD or death (may include additional events besides death and 
PD considered of importance). If any patient is lost to follow-up before PD or receives 
another anti-tumor therapy, the TTP, PFS or EFS will be censored on the date of the last 
tumor assessment.  If there were no tumor assessments, the patient will be censored on 
the date of the first drug administration.
Median time to onset and duration of response, time to PD, PFS, EFS and estimated rate 
of patients free of progression will be calculated by Kaplan-Meier estimates with 95% 
confidence intervals.
8.3 Toxicity and Adverse Events
Analysis of safety will be performed on patients who receive at least one or part of one 
plitidepsin infusion.
Safety evaluations will be based on the incidence, intensity, and type of AEs, and 
clinically significant changes in the patient’s physical examination findings, vital signs, 
clinical laboratory results and neurotoxicity score. Safety variables will be tabulated and 
presented for all patients who receive any amount of plitidepsin, bortezomib and
dexamethasone. Exposure to study drugs and reasons for discontinuation of study 
treatment will be tabulated. Analyses will be performed in a descriptive fashion.
AEs will be coded using the MedDRA coding system. All AEs occurring during the
study will be listed in by-patient data listings. Treatment-emergent events will be 
tabulated, where treatment-emergent is defined as any AE
that occurs after 
administration of the first dose of study drug and up to 30 days after the last dose of 
study drug, any event that is considered drug-related regardless of the start date of the 
event, or any event that is present at baseline but worsens in intensity or is subsequently 
considered drug-related by the Investigator. Events that are considered related to 
treatment will also be tabulated.  Deaths, SAEs and events resulting in study 
discontinuation will be tabulated.
Changes from baseline in clinical laboratory parameters will be summarized across time 
throughout the study, and the frequency of clinically significant abnormal laboratory 
values will be tabulated. Shift tables for each cycle will be produced for selected 
laboratory parameters, to include at least hemoglobin, WBC count, neutrophils, 
lymphocytes, platelets, AST, ALT, bilirubin, creatinine, AP, CPK and electrolytes. 
These tables will summarize, by cycle and DL, the number of patients with each 
baseline NCI-CTCAE grade and changes to the maximum NCI-CTCAE grade in the 
cycle.
Changes in vital sign parameters will be summarized over time in a similar fashion to 
laboratory parameters, and any abnormal values will be tabulated.  
In order to most clearly enumerate toxicity rates and to further define the safety profile 
of plitidepsin, bortezomib and dexamethasone, additional safety analyses may be done 
at any time without prejudice.
All toxicities will be graded according to NCI-CTCAE version 4.0, whenever an NCI-
CTCAE grading exists. Otherwise, severity will be noted. As a convention, the term 
“grade” will always be used. Toxicities will be described according to the worst NCI-
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CTCAE grade or, for toxicities which do not form the subject of NCI-CTCAE
classification, according to the worst severity. NCI-CTCAE
grading
will be 
programmed and automatically evaluated versus normal laboratory parameters by each 
center.
Only events reported by the Investigator as ‘not related to plitidepsin +/- bortezomib +/-
dexamethasone’ will be excluded from the study analysis of drug related events. A 
second set of tables including all events will also be presented.
8.4 Other Analyses
Non-continuous variables will be described in frequency tables using counts and 
percentages. Continuous variables will be described by median, minimum and 
maximum values.
8.5 Baseline and Demographic Data
Baseline data such as demographics, serum calcemia, renal function (Cr, CrCl), anemia, 
bone involvement, serum Ig quantitation and M-protein quantitation and IF from the 
beginning of the last CT until inclusion in the current study, prior anticancer therapy, 
biological values, prior relevant history, signs and symptoms, ECG and concomitant 
medication (ATC-WHO coded) will be described.
8.6 Treatment Administration
Cumulative dose, dose intensity and relative dose intensity, cycle delays and dose 
modifications will be described.
8.7 Protocol Deviations
A protocol deviation is defined as any departure from what is described in the protocol 
of a clinical trial approved by an IEC/IRB and Competent Authorities. Therefore, this 
applies to deviations related to patient inclusion and clinical procedures (e.g., 
assessments to be conducted or parameters to be determined), and also to other 
procedures described in the protocol that concern GCP guidelines or ethical issues (e.g., 
issues related to obtaining the patients’ IC, data reporting, Investigator’s responsibilities 
etc.).
Deviations with no effect on the risk/benefit ratio of the clinical study (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 study objectives, such as those 
involving the inclusion/exclusion criteria (which could mean that the patient 
is not eligible for the study) and those having an effect on patient 
evaluability.

Deviations that might affect the patient’s well-being and/or safety, such as 
an incorrect dosing of the IMP(s) due to not following dose adjustment 
specifications or an incorrect preparation of the medication.

Deviations related to the GCP guidelines compliance as described in the 
protocol and regulations in force, such as deviations when obtaining IC or 
not following the terms established for reporting SAEs, etc.
The investigators may suggest the authorization of certain protocol deviations to the 
Sponsor, especially if they are related to inclusion/exclusion criteria or if they may have 
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an effect on the patient’s evaluability. As a general rule, NO deviations that may have 
an effect on the risk/benefit ratio of the clinical study will be authorized. 
All protocol deviations considered particularly relevant (related to ethical issues, 
fulfillment of GCP guidelines and study procedures) will be notified to the pertinent 
IEC/IRB and to the relevant authorities, as established by local regulations.
8.8 Pharmacokinetics
PK parameters will be tabulated and selected parameters will be graphically displayed 
per dose level.
PK interactions between plitidepsin and bortezomib will be evaluated comparing the PK 
parameters obtained in this study with those obtained from single agent plitidepsin 
studies and with literature data for bortezomib.
The potential influence on selected PK parameters of selected demographic and clinical 
dichotomous variables (gender, laboratory test results above/below selected cut-off 
values, etc) will be evaluated by a Student’s t test or a Mann-Whitney’s U test as 
appropriate.
For multinomial variables, analysis of variance will be used. For selected continuous 
demographic and clinical variables (age, laboratory test results…), the relationship with 
selected PK parameters will be graphically explored and assessed using correlation and 
regression methods.
The potential influence on efficacy and safety of the selected PK parameters will be 
graphically explored. For dichotomous outcomes, a Student’s T test or a Mann-
Whitney’s U test, as appropriate, will be used for assessment. For multinomial 
outcomes, analysis of variance will be used. Continuous outcomes will be assessed 
using correlation and regression methods.
Other tests may be applied if the results of the above evaluations suggest that they may 
yield additional relevant information.
8.9 Procedures for Reporting Deviations to Original Statistical Analysis Plan
All deviations from the original statistical analysis plan will be provided in the final 
clinical study report.
9.
ADMINISTRATIVE REQUERIMENTS
9.1 Ethics 
This study will be conducted in accordance with the ethical principles that have their 
origin in the Declaration of Helsinki (Appendix 6) and will be consistent with GCP and 
other applicable regulatory requirements.
Study personnel involved in conducting this study 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 IC will receive IRB/IEC approval/favorable opinion prior 
to initiation. The decision of the IEC/IRB concerning the conduct of the study will be 
made in writing to the Investigator and a copy of this decision will be provided to the 
Sponsor before commencement of the study.
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The Investigator and/or the Sponsor is/are responsible for keeping the IEC/IRB 
informed of significant new information about 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.
9.2 Monitoring, Auditing and Inspecting
The study will be monitored by regular site visits and telephone calls to the Investigator 
by the clinical study monitor and/or the CRO clinical study monitor (if applicable).
During site visits, the study monitor should review original patient records, drug 
accountability records and document retention (study file). Additionally, the monitor 
should observe study procedures and will discuss any problem with the Investigator.
The Investigator should allocate adequate time for these visits. The Investigator should 
also ensure that the monitor is given direct access (as per ICH GCP Guideline, Sections 
4.9.7 and 6.10) to the patient’s source documents (i.e., hospital or private charts, 
original laboratory records, appointment books, etc.), which support data entered in the 
e-CRFs, as defined in the ICH GCP Guideline, Sections 1.51. and 1.52.
The necessary systems and procedures will be implemented to assure the quality of 
every aspect of the study.
At any time during the course or at the end of the study, the Clinical Quality Assurance 
Department of PharmaMar or external auditors contracted by the Sponsor may conduct 
an onsite audit visit to the centers (ICH guideline glossary Section 1.6).
Participation in this study implies acceptance of potential inspections by national or 
foreign Health Authorities.
9.3 Patient Informed Consent
Before agreeing to participate in this study, all patients will be provided with full 
written information about the study in a “Patient Information Sheet” with language that 
is non-technical and easily understood. The Patient Information Sheet will include all 
elements required by ICH, GCP and other applicable regulatory requirements and will 
be submitted for approval to the IEC/IRB along with the protocol. A statement of 
document approval should be provided before commencement of the study.
The Investigator, or designated person, must provide the patient with a copy of the 
Patient Information Sheet and consent form and should allow the necessary time for the
patient to inquire about the details of the study; then, IC must be freely signed and 
personally dated by the patient and by the person who conducted the IC discussion 
before commencement of the study. The patient should receive a copy of the signed IC
and any other written information provided to patients prior to participation in the study.
During a patient's participation in the study, any updates to the IC form and any updates 
to the written information will be provided to the patient.
If there is a need to obtain new consent from the patients, the Investigator, or designated 
person, should inform the patient of any new information relevant to the patient's 
willingness to continue to participate in the study, before obtaining the written consent.
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9.4 Confidentiality/Patients Identification
The collection and processing of personal data from patients enrolled in this study will 
be limited to data that are necessary to investigate the efficacy, safety, quality, and 
utility of the IMP(s) used in this study. It is the Investigator’s responsibility that 
sufficient information pertaining to the patient’s identity be retained. 
The study monitor, auditor at PharmaMar, IRB/IEC, or regulatory authorities should 
have direct access to all requested study related records and agree to keep the identity of 
study patients confidential.
Data must be collected and processed with adequate precautions to ensure 
confidentiality and compliance with applicable data privacy protection laws and 
regulations.
PharmaMar shall comply with Directive 95/46/EEC of the European Parliament and of 
the Council of 24 October 1995, on the protection of individuals with regards to the 
processing of personal data and on the free movement of such data. 
9.5 Case Report Forms
Electronic CRFs will be used to record all data for each patient. It is the responsibility 
of the Investigator to ensure that the e-CRFs are properly and completely filled in. 
Electronic CRFs must be completed for all patients who have given IC and have been 
admitted to the study.
The patient’s source documentation is the physician's patient records, and as such, they 
should be maintained at the study site. 
Data collected in the e-CRF will be entered into a database at PharmaMar which 
complies with the Spanish Act implementing 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.
9.6 Insurance
The Sponsor will provide insurance or indemnity in accordance with the applicable 
regulatory requirements.
9.7 Records Retention 
The Investigator/Institution should maintain study documents according to ICH Topic 
E6, Section 8, and as required by the applicable regulatory requirements.
Essential documents should be retained according to ICH guidelines, or for a longer 
period if required by the applicable regulations. 
9.8 Use of Information and Publication
Before the Investigators of this study submit a paper or abstract for publication or 
otherwise publicly disclose information concerning the study IMP(s), PharmaMar must 
be provided with at least 60 days to review and approve the proposed publication or 
disclosure to assure protection of confidential and proprietary data. If PharmaMar 
determines that patentable subject matter is disclosed in such proposed publication or 
disclosure, the publication or disclosure shall be withheld during the period of time that 
it is considered convenient.
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If the study is part of a multicenter study, the first publication of the study shall be done 
as a multicenter publication, in collaboration with all investigators and institutions 
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 before.
The order of the co-authors will reflect the relative contribution of each one of them to 
the study development and analysis. In general, the first author will be the Clinical 
Investigator who recruits the highest number of patients with information finally 
available for data analysis. Relevant PharmaMar personnel who have fully participated 
in the study must be considered for co-authorship of the publication.
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10. REFERENCES
1.
Information about multiple myeloma and other plasma cell neoplasms: 
treatment, clinical trials, research, and statistics from the National Cancer Institute. 
www.cancer.gov/cancertopics/types/myeloma.
2.
Harousseau JL, Dreyling M. Multiple myeloma: ESMO Clinical Practice 
Guidelines for diagnosis, treatment and follow-up. Annals of oncology : official journal 
of the European Society for Medical Oncology / ESMO. 2010;21 Suppl 5:v155-7. Epub 
2010/06/29.
3.
Durie BG, Salmon SE. A clinical staging system for multiple myeloma. 
Correlation of measured myeloma cell mass with presenting clinical features, response 
to treatment, and survival. Cancer. 1975;36(3):842-54.
4.
Greipp PR, San Miguel J, Durie BG. International staging system for multiple 
myeloma. J Clin Oncol. 2005;23(15):3412-20.
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McElwain TJ, Powles RL. High-dose intravenous melphalan for plasma-cell 
leukaemia and myeloma. Lancet:. 1983;2(822-4).
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Attal M, Harousseau JL, Stoppa AM. A prospective, randomized trial of 
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Engl JMed. 1996;335:91-7.
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Blade J, San Miguel JF, Alcalá A. Alternating combination VCMP/VBAP 
chemotherapy versus melphalan/prednisone in the treatment of multiple myeloma: a 
randomized multicentric study of 487 patients. J Clin Oncol. 1993;11:1165-71.
8.
Gonzalez-Santiago L, Suarez Y, Zarich N, Munoz-Alonso MJ, Cuadrado A, 
Martinez T, et al. Aplidin induces JNK-dependent apoptosis in human breast cancer 
cells via alteration of glutathione homeostasis, Rac1 GTPase activation, and MKP-1 
phosphatase downregulation. Cell Death Differ. 2006;13(11):1968-81.
9.
Erba E, Bassano L, Di Liberti G, Muradore I, Chiorino G, Ubezio P, et al. Cell 
cycle phase perturbations and apoptosis in tumour cells induced by aplidine. Br J 
Cancer. 2002;86(9):1510-7.
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Cuadrado A, Gonzalez L, Suarez Y, Martinez T, Munoz A. JNK activation is 
critical for Aplidin-induced apoptosis. Oncogene. 2004;23(27):4673-80.
11.
Broggini M, Marchini SV, Galliera E, Borsotti P, Taraboletti G, Erba E, et al. 
Aplidine, a new anticancer agent of marine origin, inhibits vascular endothelial growth 
factor (VEGF) secretion and blocks VEGF-VEGFR-1 (flt-1) autocrine loop in human 
leukemia cells MOLT-4. Leukemia. 2003;17(1):52-9.
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Garcia-Fernandez LF, Losada A, Alcaide V, Alvarez AM, Cuadrado A, 
Gonzalez L, et al. Aplidin induces the mitochondrial apoptotic pathway via oxidative 
stress-mediated JNK and p38 activation and protein kinase C delta. Oncogene. 
2002;21(49):7533-44.
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Cuadrado A, Garcia-Fernandez LF, Gonzalez L, Suarez Y, Losada A, Alcaide V, 
et al. Aplidin induces apoptosis in human cancer cells via glutathione depletion and 
sustained activation of the epidermal growth factor receptor, Src, JNK, and p38 MAPK. 
J Biol Chem. 2003;278(1):241-50.
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14.
Munoz-Alonso MJ, Gonzalez-Santiago L, Zarich N, Martinez T, Alvarez E, 
Rojas JM, et al. Plitidepsin Has a Dual Effect Inhibiting Cell Cycle and Inducing 
Apoptosis via Rac1/c-Jun NH2-Terminal Kinase Activation in Human Melanoma Cells 
10.1124/jpet.107.132662. J Pharmacol Exp Ther. 2008;324(3):1093-101.
15.
Moneo V, Serelde BG, Leal JF, Blanco-Aparicio C, Diaz-Uriarte R, Aracil M, et 
al. Levels of p27(kip1) determine Aplidin sensitivity. Mol Cancer Ther. 
2007;6(4):1310-6.
16.
Biscardi M, Caporale R, Balestri F, Gavazzi S, Jimeno J, Grossi A. VEGF 
inhibition and cytotoxic effect of aplidin in leukemia cell lines and cells from acute 
myeloid leukemia. Annals of oncology : official journal of the European Society for 
Medical Oncology / ESMO. 2005;16(10):1667-74. Epub 2005/07/15.
17.
Taraboletti G, Poli M, Dossi R, Manenti L, Borsotti P, Faircloth GT, et al. 
Antiangiogenic activity of aplidine, a new agent of marine origin. Br J Cancer. 
2004;90(12):2418-24.
18.
Sasak H. The cytotoxic effects of Aplidin in a brad spectrum of human tumor 
types using the MTS proliferation assay. Cambridge, MA, USA: PharmaMar Inc, 2004 
PUSA-SR007.
19.
Mitsiades CS, Ocio EM, Pandiella A, Maiso P, Gajate C, Garayoa M, et al. 
Aplidin, a marine organism-derived compound with potent antimyeloma activity in 
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protects primary cultured hepatocytes from death receptor-mediated apoptosis by 
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Adams J. Development of the proteasome inhibitor PS-341. Oncologist. 
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Proteasome inhibition measurements: clinical application. Clinical chemistry. 
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Schwartz R. Pharmacology, Pharmacokinetics, and Practical Applications of 
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Schwartz R, Davidson T. Pharmacology, pharmacokinetics, and practical 
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Aghajanian C, Soignet S, Dizon DS, Pien CS, Adams J, Elliott PJ. A Phase I 
trial of the novel proteasome inhibitor PS341 in advanced solid tumor malignancies. 
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of the proteasome inhibitor bortezomib in patients with advanced solid tumors with 
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Phase I trial of the proteasome inhibitor PS-341 in patients with refractory hematologic 
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Richardson PG, Barlogie B, Berenson J, Singhal S, Jagannath S, Irwin D. A 
Phase II study of bortezomib in relapsed, refractory myeloma. N Engl J Med. 
2003;348(26):2609-17.
58.
Bladé J, Samson D, Reece D, Apperley J, Bjorkstrand B, Gahrton G. Criteria for 
evaluating disease response and progression in patients with multiple myeloma treated 
by high dose of therapy and haemopoietic stem cell transplantation. Br J Haematol. 
1998;102(5):1115-23.
59.
Jagannath S, Barlogie B, Berenson J, Siegel D, Irwin D, Richardson PG. A 
phase II study of two doses of bortezomib in relapsed or refractory myeloma. British 
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Richardson PG, Sonneveld P, Schuster MW. Bortezomib or high-dose 
dexamethasone for relapsed multiple myeloma. N Engl J Med. 2005;352:2487-98.
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Richardson PG, Sonneveld P, Schuster MW. Extended follow-up of a phase 3 
trial in relapsed multiple myeloma: final time-to-event results of the APEX trial. Blood. 
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al. Subcutaneous versus intravenous administration of bortezomib in patients with 
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Richardson PG, Delforge M, Beksac M, Wen P, Jongen JL, Sezer O, et al. 
Management of treatment-emergent peripheral neuropathy in multiple myeloma. 
Leukemia. 2012;26(4):595-608. Epub 2011/12/24.
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2006 update of recommendations for the use of white blood cell growth factors: an 
evidence-based clinical practice guideline. J Clin Oncol. 2006;24(19):3187-205. Epub 
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Rajkumar SV, Harousseau JL, Durie B, Anderson KC, Dimopoulos M, Kyle R, 
et al. Consensus recommendations for the uniform reporting of clinical trials: report of 
the International Myeloma Workshop Consensus Panel 1. Blood. 2011;117(18):4691-5. 
Epub 2011/02/05.
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Appendix 1. Performance Status
Performance Status Criteria
ECOG Performance Status Scale
Karnofsky Performance Scale
Grade
Descriptions
Percent
Description
0
Normal activity.  Fully active, able to 
carry on all pre-disease performance 
without restriction.
100
Normal, no complaints, no 
evidence of disease.
90
Able to carry on normal activity; 
minor signs or symptoms of 
disease.
1
Symptoms, but ambulatory.  Restricted in 
physically strenuous activity, but 
ambulatory and able to carry out work of 
a light or sedentary nature (e.g., light 
housework, office work).
80
Normal activity with effort; some 
signs or symptoms of disease.
70
Cares for self, unable to carry on 
normal activity or to do active 
work.
2
In bed <50% of the time.  Ambulatory 
and capable of all self-care, but unable to 
carry out any work activities.  Up and 
about more than 50% of waking hours.
60
Requires occasional assistance, but 
is able to care for most of his/her 
needs.
50
Requires considerable assistance 
and frequent medical care.
3
In bed >50% of the time.  Capable of only 
limited self-care, confined to bed or chair 
more than 50% of waking hours.
40
Disabled, requires special care and 
assistance.
30
Severely disabled, hospitalization 
indicated.  Death not imminent.
4
100% bedridden.  Completely disabled.  
Cannot carry on any self-care.  Totally 
confined to bed or chair.
20
Very sick, hospitalization 
indicated. Death not imminent.
10
Moribund, fatal processes 
progressing rapidly.
5
Dead.
0
Dead.
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Appendix 2. Cockcroft and Gault’s Formula for Calculating Creatinine Clearance
Creatinine clearance (mL/min)  =      
[(140-age (years)) x weight (Kg)]
72 x serum creatinine (mg/dL)
xG1
Creatinine clearance (mL/min)  =    
[(140-age (years)) x weight (Kg)]
72 x serum creatinine (mol/L)
xG1x0,00113
1G(Gender)= 0.85 if Female; 1 if Male.
DW Cockcroft, H Gault. Prediction of creatinine clearance from serum creatinine. Nephron 1976; 16: 31-41.
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Appendix 3.  Multiple Myeloma Diagnosis Criteria
Durie Salmon Diagnosis Criteria
Standards for diagnosis currently require confirmation of one major and one minor criteria or three minor 
criteria in a patient displaying symptoms of myeloma. 
Major criteria: 

A biopsy-proven plasmacytoma.

A BM sample showing 30% plasma cells.

Elevated monoclonal immunoglobulin levels in the blood or urine.
Minor criteria: 

A BM sample showing 10-30% plasma cells.

Minor monoclonal immunoglobulin levels in blood or urine.

Imaging studies revealing holes in bones due to tumor growth.

Antibody levels (not produced by the cancer cells) in the blood are abnormally low.
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Appendix 4. Durie Salmon Staging Criteria
Stage
Durie-Salmon
Criteria
International Staging 
System
(ISS) Criteria
I
All of the following:

Hemoglobin value >10 g/dL

Serum calcium value normal or ≤12 mg/dL

Bone X-ray, normal bone structure (scale 0) or solitary bone 
plasmacytoma only

Low M-component production rate

IgG value <5 g/dL; IgA value <3 g/dL

Bence Jones protein <4 g/24 h
Beta-2-M<3.5 mg/L
Albumin ≥3.5 g/dL
Median survival: 62 months
II
Neither stage I nor stage III
Neither stage I nor stage III*
Median survival: 44 months
III
One or more of the following:

Hemoglobin value <8.5 g/dL

Serum calcium value >12 mg/dL

Advanced lytic bone lesions (scale 3)

High M-component production rate

IgG value >7 g/dL; IgA value >5 g/dL

Bence Jones protein >12 g/24 h
Beta-2-M > 5.5 mg/L
Median survival: 29 months
Durie-Salmon sub classifications (either A or B)
A: Relatively normal renal function (serum creatinine value <2.0 mg/dL)
B: Abnormal renal function (serum creatinine value ≥2.0 mg/dL)
*There are two categories for stage II: serum ß2-microglobulin < 3.5 mg/L but serum albumin < 3.5 g/dL; or serum 
ß2-microglobulin 3.5 to < 5.5 mg/L irrespective of the serum albumin level.
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Appendix 5. Lists of Drugs that Prolong the Qt Interval and/or Induce Torsades de 
Pointes Ventricular Arrhythmia
List 1: Drugs that prolong the QT interval and/or induce Torsades De Pointes Source: 
www.torsade.org
Drugs that are generally accepted by authorities to have a risk of causing Torsades de Pointes.
Generic Name
(Brand Name)
Drug Class / Clinical Usage
Comments
Amiodarone 
(Pacerone®)
Anti-arrhythmic/abnormal heart rhythm
Females>Males,TdP risk 
regarded as low
Amiodarone 
(Cordarone®)
Anti-arrhythmic/abnormal heart rhythm
Females>Males,TdP risk 
regarded as low
Arsenic 
trioxide 
(Trisenox®)
Anti-cancer/Leukemia
Bepridil (Vascor®)
Anti-anginal/heart pain
Females>Males
Chloroquine (Arelan®)
Anti-malarial/malaria infection
Chlorpromazine 
(Thorazine®)
Anti-psychotic/ Anti-emetic/schizophrenia/ 
nausea
Cisapride (Propulsid®)
GI stimulant/heartburn
Restricted availability; 
Females>Males
Clarithromycin 
(Biaxin®)
Antibiotic/bacterial infection
Disopyramide 
(Norpace®)
Anti-arrhythmic/abnormal heart rhythm
Females>Males
Dofetilide (Tikosyn®)
Anti-arrhythmic/abnormal heart rhythm
Domperidone* 
(Motilium®)
Anti-nausea/nausea
not available in the United 
States.
Droperidol (Inapsine®)
Sedative;Anti-nausea/anesthesia adjunct, 
nausea
Erythromycin 
(Erythrocin®)
Antibiotic;GI stimulant/bacterial infection; 
increase GI motility
Females>Males
Erythromycin (E.E.S. ®) Antibiotic;GI stimulant/bacterial infection; 
increase GI motility
Females>Males
Halofantrine (Halfan®)
Anti-malarial/malaria infection
Females>Males
Haloperidol (Haldol®)
Anti-psychotic/schizophrenia, agitation
Ibutilide (Corvert®)
Anti-arrhythmic/abnormal heart rhythm
Females>Males
Levomethadyl 
(Orlaam®)
Opiate agonist/pain control, narcotic 
dependence
Mesoridazine 
(Serentil®)
Anti-psychotic/schizophrenia.
Methadone 
(Dolophine®)
Opiate agonist/pain control, narcotic 
dependence
Females>Males
Methadone 
(Methadose®)
Opiate agonist/pain control,narcotic
dependence
Females>Males
Pentamidine 
(NebuPent®)
Anti-infective/pneumocystis pneumonia
Females>Males
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Generic Name
(Brand Name)
Drug Class / Clinical Usage
Comments
Pentamidine (Pentam®)
Anti-infective/pneumocystis pneumonia
Females>Males
Pimozide (Orap®)
Anti-psychotic/Tourette's tics
Females>Males
Procainamide 
(Pronestyl®)
Anti-arrhythmic/abnormal heart rhythm
Procainamide (Procan®) Anti-arrhythmic/abnormal heart rhythm
Quinidine 
(Quinaglute®)
Anti-arrhythmic/abnormal heart rhythm
Females>Males
Quinidine 
(Cardioquin®)
Anti-arrhythmic/abnormal heart rhythm
Females>Males
Sotalol (Betapace®)
Anti-arrhythmic/abnormal heart rhythm
Females>Males
Sparfloxacin (Zagam®)
Antibiotic/bacterial infection
Thioridazine 
(Mellaril®)
Anti-psychotic/schizophrenia
List 2: Drugs that in some reports may be associated with Torsades De Pointes but at this time 
lack substantial evidence for causing Torsades De Pointes
Generic Name
(Brand Name)
Drug Class / Clinical Usage
Comments
Alfuzosin (Uroxatral®)
Alpha1-blocker/Benign prostatic 
hyperplasia
Amantadine (Symmetrel®)
Dopaminergic/Anti-viral/Anti-
infective/ Parkinson's Disease
Azithromycin (Zithromax®)
Antibiotic/bacterial infection
Chloral hydrate (Noctec®)
Sedative/sedation/ insomnia
Clozapine (Clozaril®)
Anti-psychotic/schizophrenia
Dolasetron (Anzemet®)
Anti-nausea/nausea, vomiting
Felbamate (Felbatrol®)
Anti-convulsant/seizure
Flecainide (Tambocor®)
Anti-arrhythmic/abnormal 
heart 
rhythm
Foscarnet (Foscavir®)
Anti-viral/HIV infection
Fosphenytoin (Cerebyx®)
Anti-convulsant/seizure
Gatifloxacin (Tequin®)
Antibiotic/bacterial infection
Gemifloxacin (Factive®)
Antibiotic/bacterial infection
Granisetron (Kytril®)
Anti-nausea/nausea and vomiting
Indapamide (Lozol®)
Diuretic/stimulate urine & salt 
loss
Isradipine (Dynacirc®)
Anti-hypertensive/high 
blood 
pressure
Levofloxacin (Levaquin®)
Antibiotic/bacterial infection
Lithium (Eskalith®)
Anti-mania/bipolar disorder
Lithium (Lithobid®)
Anti-mania/bipolar disorder
Moexipril/HCTZ (Uniretic®)
Anti-hypertensive/high 
blood 
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Generic Name
(Brand Name)
Drug Class / Clinical Usage
Comments
pressure
Moxifloxacin (Avelox®)
Antibiotic/bacterial infection
Nicardipine (Cardene®)
Anti-hypertensive/high 
blood 
pressure
Octreotide (Sandostatin®)
Endocrine/acromegaly, carcinoid 
diarrhea
Ofloxacin (Floxin®)
Antibiotic/bacterial infection
Ondansetron (Zofran®)
Anti-emetic/nausea and vomiting
Quetiapine (Seroquel®)
Anti-psychotic/schizophrenia
Ranolazine (Ranexa®)
Anti-anginal/chronic angina
Risperidone (Risperdal®)
Anti-psychotic/schizophrenia
Roxithromycin* (Rulide®)
Antibiotic/bacterial infection
*not available in the 
United States
Tacrolimus (Prograf®)
Immunosuppressant/Immune 
suppression
Tamoxifen (Nolvadex® )
Anti-cancer/breast cancer
Telithromycin (Ketek®)
Antibiotic/bacterial infection
Tizanidine (Zanaflex® )
Muscle relaxant/
Vardenafil (Levitra®)
phosphodiesterase 
inhibitor/vasodilator
Venlafaxine (Effexor®)
Anti-depressant/depression
Voriconazole (VFend®)
Anti-fungal/anti-fungal
Ziprasidone (Geodon®)
Anti-psychotic/schizophrenia
List 3: Drugs to be avoided for use in patients with diagnosed or suspected congenital long QT 
syndrome. (Drugs on Lists 1, 2, and 4 should also be avoided by patients with QT syndrome
Generic Name (Brand Name)
Drug Class / Clinical Usage
Comments
Albuterol (Ventolin®)
Bronchodilator/Asthma
Albuterol (Proventil®)
Bronchodilator/Asthma
Amphetamine/dextroamphetamine 
(Adderall®)
CNS stimulant/ADHD
Atomoxetine (Strattera®)
norepinephrine 
reuptake 
inhibitor /ADHD
Cocaine (Cocaine)
Local anesthetic/
Dexmethylphenidate (Focalin®)
CNS stimulant/ADHD
Dextroamphetamine (Dexadrine®)
CNS stimulant/ADHD
Dobutamine (Dobutrex®)
Catecholamine/heart 
failure 
and shock
Dopamine (Intropine®)
Anti-arrhythmic/abnormal 
heart rhythm
Ephedrine (Broncholate®)
Bronchodilator, 
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Generic Name (Brand Name)
Drug Class / Clinical Usage
Comments
decongestant/Allergies, 
sinusitis, asthma
Ephedrine (Rynatuss®)
Bronchodilator, 
decongestant/Allergies, 
sinusitis, asthma
Epinephrine (Primatene®)
catecholamine, 
vasoconstrictor/anaphylaxis, 
allergic reactions
Epinephrine (Bronkaid®)
catecholamine, 
vasoconstrictor/anaphylaxis, 
allergic reactions
Fenfluramine (Pondimin®)
Appetite suppressant/dieting, 
weight loss
Isoproterenol (Isupres®)
Catecholamine/allergic 
reaction
Isoproterenol (Medihaler-Iso®)
Catecholamine/allergic 
reaction
Levalbuterol (Xopenex®)
Bronchodilator/asthma
Metaproterenol (Alupent®)
Bronchodilator/asthma
Metaproterenol (Metaprel®)
Bronchodilator/asthma
Methylphenidate (Ritalin®)
CNS stimulant/ADHD
Methylphenidate ( Concerta®)
CNS stimulant/ADHD
Midodrine (ProAmatine®)
Vasoconstrictor/low 
blood 
pressure, fainting
Norepinephrine (Levophed®)
Vasconstrictor, 
Inotrope/shock, 
low 
blood 
pressure
Phentermine (Fastin®)
Appetite suppressant/dieting, 
weight loss
Phentermine (Adipex®)
Appetite suppressant/dieting, 
weight loss
Phenylephrine (Neosynephrine®)
Vasoconstrictor, 
decongestant/low 
blood 
pressure, allergies, sinusitis, 
asthma
Phenylpropanolamine (Acutrim®)
Decongestant/allergies, 
sinusitis, asthma
Phenylpropanolamine (Dexatrim®)
Decongestant/allergies, 
sinusitis, asthma
Pseudoephedrine (PediaCare®)
Decongestant/allergies, 
sinusitis, asthma
Pseudoephedrine (Sudafed®)
Decongestant/allergies, 
sinusitis, asthma
Ritodrine (Yutopar®)
Uterine 
relaxant/prevent 
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Generic Name (Brand Name)
Drug Class / Clinical Usage
Comments
premature labor
Salmeterol (Serevent®)
Sympathomimetic/asthma, 
COPD
Sibutramine (Meridia®)
Appetite suppressant/dieting, 
weight loss
Terbutaline (Brethine®)
Bronchodilator/asthma
Tolterodine (Detrol®)
Bladder Antispasmodic/
Tolterodine ( Detrol LA®)
Bladder Antispasmodic/
List 4: Drugs that, in some reports, have been weakly associated with Torsades De Pointes 
and/or QT prolongation but that are unlikely to be a risk for Torsades De Pointes when used at 
the usual recommended dosages and in patients without other risk factors (e.g., concomitant QT 
prolonging drugs, bradycardia, electrolytes disturbances, congenital long QT syndrome, 
concomitant drugs that inhibit metabolism)
Generic 
Name
(Brand Name)
Drug Class / Clinical Usage
Comments
Amitriptyline (Elavil®)
Tricyclic 
Antidepressant/depression
Amoxapine (Asendin®)
Tricyclic 
Antidepressant/depression
Ciprofloxacin (Cipro®)
Antibiotic/bacterial infection
Citalopram (Celexa®)
Anti-depressant/depression
Clomipramine (Anafranil®)
Tricyclic 
Antidepressant/depression
Desipramine (Pertofrane®)
Tricyclic 
Antidepressant/depression
Doxepin (Sinequan®)
Tricyclic 
Antidepressant/depression
Fluconazole (Diflucan®)
Anti-fungal/fungal infection
Fluoxetine (Sarafem®)
Anti-depressant/depression
Fluoxetine (Prozac®)
Anti-depressant/depression
Galantamine (Reminyl®)
Cholinesterase 
inhibitor/ 
Dementia, Alzheimer's
Imipramine (Norfranil®)
Tricyclic 
Antidepressant/depression
Itraconazole (Sporanox®)
Anti-fungal/fungal infection
Ketoconazole (Nizoral®)
Anti-fungal/fungal infection
Mexiletine (Mexitil®)
Anti-arrhythmic/Abnormal 
heart rhythm
Nortriptyline (Pamelor®)
Tricyclic 
Antidepressant/depression
Paroxetine (Paxil®)
Anti-depressant/depression
Protriptyline (Vivactil®)
Tricyclic 
Antidepressant/depression
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Generic 
Name
(Brand Name)
Drug Class / Clinical Usage
Comments
Sertraline (Zoloft®)
Anti-depressant/depression
Solifenacin (VESIcare®)
muscarinic 
receptor 
anatagonist/treatment
of 
overactive bladder
Trimethoprim-Sulfa (Sulfa®)
Antibiotic/bacterial infection
Trimethoprim-Sulfa (Bactrim®)
Antibiotic/bacterial infection
Trimipramine (Surmontil®)
Tricyclic 
Antidepressant/depression
A note about Brand Names: Drugs are listed with up to 2 common brand names. There are 
many more brand names for some of the common drugs, such as pseudoephedrine and 
erythromycin. It is also important to look at the list of active drugs in medicines that contain a 
combination of drugs such as Zyrtec-D®, which contains pseudoephedrine.
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Appendix 6. Declaration of Helsinki
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI
Ethical Principles for Medical Research Involving Human Subjects
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964, and 
amended by the:
29th WMA General Assembly, Tokyo, Japan, October 1975
35th WMA General Assembly, Venice, Italy, October 1983
41st WMA General Assembly, Hong Kong, September 1989
48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996
52nd WMA General Assembly, Edinburgh, Scotland, October 2000 
53th WMA General Assembly, Washington 2002 (Note of Clarification on paragraph 29 
added)
55th WMA General Assembly, Tokyo 2004 (Note of Clarification on paragraph 30 
added)
59th WMA General Assembly, Seoul, October 2008
A. INTRODUCTION 
1. The World Medical Association (WMA) has developed the Declaration of Helsinki 
as a statement of ethical principles for medical research involving human subjects, 
including research on identifiable human material and data. 
The Declaration is intended to be read as a whole and each of its constituent 
paragraphs should not be applied without consideration of all other relevant 
paragraphs.
2. Although the Declaration is addressed primarily to physicians, the WMA 
encourages other participants in medical research involving human subjects to adopt 
these principles.
3. It is the duty of the physician to promote and safeguard the health of patients, 
including those who are involved in medical research. The physician's knowledge 
and conscience are dedicated to the fulfillment of this duty.
4. The Declaration of Geneva of the WMA binds the physician with the words, "The 
health of my patient will be my first consideration," and the International Code of 
Medical Ethics declares that, "A physician shall act in the patient's best interest 
when providing medical care."
5. Medical progress is based on research that ultimately must include studies involving 
human subjects. Populations that are underrepresented in medical research should be 
provided appropriate access to participation in research.
6. In medical research involving human subjects, the well-being of the individual 
research subject must take precedence over all other interests.
7. The primary purpose of medical research involving human subjects is to understand 
the causes, development and effects of diseases and improve preventive, diagnostic 
and therapeutic interventions (methods, procedures and treatments). Even the best 
current interventions must be evaluated continually through research for their safety, 
effectiveness, efficiency, accessibility and quality.
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8. In medical practice and in medical research, most interventions involve risks and 
burdens.
9. Medical research is subject to ethical standards that promote respect for all human 
subjects and protect their health and rights. Some research populations are 
particularly vulnerable and need special protection. These include those who cannot 
give or refuse consent for themselves and those who may be vulnerable to coercion 
or undue influence.
10. Physicians should consider the ethical, legal and regulatory norms and standards for 
research involving human subjects in their own countries as well as applicable 
international norms and standards. No national or international ethical, legal or 
regulatory requirement should reduce or eliminate any of the protections for 
research subjects set forth in this Declaration.
B. BASIC PRINCIPLES FOR ALL MEDICAL RESEARCH 
11. It is the duty of physicians who participate in medical research to protect the life, 
health, dignity, integrity, right to self-determination, privacy, and confidentiality 
of personal information of research subjects.
12. Medical research involving human subjects must conform to generally accepted 
scientific principles, be based on a thorough knowledge of the scientific 
literature, other relevant sources of information, and adequate laboratory and, as 
appropriate, animal experimentation. The welfare of animals used for research 
must be respected. 
13. Appropriate caution must be exercised in the conduct of medical research that 
may harm the environment.
14. The design and performance of each research study involving human subjects 
must be clearly described in a research protocol. The protocol should contain a 
statement of the ethical considerations involved and should indicate how the 
principles in this Declaration have been addressed. The protocol should include 
information regarding funding, sponsors, institutional affiliations, other potential 
conflicts of interest, incentives for subjects and provisions for treating and/or 
compensating subjects who are harmed as a consequence of participation in the 
research study. The protocol should describe arrangements for post-study access 
by study subjects to interventions identified as beneficial in the study or access 
to other appropriate care or benefits.
15. The research protocol must be submitted for consideration, comment, guidance 
and approval to a research ethics committee before the study begins. This 
committee must be independent of the researcher, the sponsor and any other 
undue influence. It must take into consideration the laws and regulations of the 
country or countries in which the research is to be performed as well as 
applicable international norms and standards but these must not be allowed to 
reduce or eliminate any of the protections for research subjects set forth in this 
Declaration. The committee must have the right to monitor ongoing studies. The 
researcher must provide monitoring information to the committee, especially 
information about any serious adverse events. No change to the protocol may be 
made without consideration and approval by the committee.
16. Medical research involving human subjects must be conducted only by 
individuals with the appropriate scientific training and qualifications. Research 
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on patients or healthy volunteers requires the supervision of a competent and 
appropriately qualified physician or other health care professional. The 
responsibility for the protection of research subjects must always rest with the 
physician or other health care professional and never the research subjects, even 
though they have given consent.
17. Medical research involving a disadvantaged or vulnerable population or 
community is only justified if the research is responsive to the health needs and 
priorities of this population or community and if there is a reasonable likelihood 
that this population or community stands to benefit from the results of the 
research.
18. Every medical research study involving human subjects must be preceded by 
careful assessment of predictable risks and burdens to the individuals and 
communities involved in the research in comparison with foreseeable benefits to 
them and to other individuals or communities affected by the condition under 
investigation.
19. Every clinical trial must be registered in a publicly accessible database before 
recruitment of the first subject.
20. Physicians may not participate in a research study involving human subjects 
unless they are confident that the risks involved have been adequately assessed 
and can be satisfactorily managed. Physicians must immediately stop a study 
when the risks are found to outweigh the potential benefits or when there is 
conclusive proof of positive and beneficial results.
21. Medical research involving human subjects may only be conducted if the 
importance of the objective outweighs the inherent risks and burdens to the 
research subjects.
22. Participation by competent individuals as subjects in medical research must be 
voluntary. Although it may be appropriate to consult family members or 
community leaders, no competent individual may be enrolled in a research study 
unless he or she freely agrees.
23. Every precaution must be taken to protect the privacy of research subjects and 
the confidentiality of their personal information and to minimize the impact of 
the study on their physical, mental and social integrity.
24. In medical research involving competent human subjects, each potential subject 
must be adequately informed of the aims, methods, sources of funding, any 
possible conflicts of interest, institutional affiliations of the researcher, the 
anticipated benefits and potential risks of the study and the discomfort it may 
entail, and any other relevant aspects of the study. The potential subject must be 
informed of the right to refuse to participate in the study or to withdraw consent 
to participate at any time without reprisal. Special attention should be given to 
the specific information needs of individual potential subjects as well as to the 
methods used to deliver the information. After ensuring that the potential subject 
has understood the information, the physician or another appropriately qualified 
individual must then seek the potential subject's freely-given informed consent, 
preferably in writing. If the consent cannot be expressed in writing, the non-
written consent must be formally documented and witnessed.
25. For medical research using identifiable human material or data, physicians must 
normally seek consent for the collection, analysis, storage and/or reuse. There 
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may be situations where consent would be impossible or impractical to obtain 
for such research or would pose a threat to the validity of the research. In such 
situations the research may be done only after consideration and approval of a 
research ethics committee.
26. When seeking informed consent for participation in a research study the 
physician should be particularly cautious if the potential subject is in a 
dependent relationship with the physician or may consent under duress. In such 
situations the informed consent should be sought by an appropriately qualified 
individual who is completely independent of this relationship.
27. For a potential research subject who is incompetent, the physician must seek 
informed consent from the legally authorized representative. These individuals 
must not be included in a research study that has no likelihood of benefit for 
them unless it is intended to promote the health of the population represented by 
the potential subject, the research cannot instead be performed with competent 
persons, and the research entails only minimal risk and minimal burden.
28. When a potential research subject who is deemed incompetent is able to give 
assent to decisions about participation in research, the physician must seek that 
assent in addition to the consent of the legally authorized representative. The 
potential subject's dissent should be respected.
29. Research involving subjects who are physically or mentally incapable of giving 
consent, for example, unconscious patients, may be done only if the physical or 
mental condition that prevents giving informed consent is a necessary 
characteristic of the research population. In such circumstances the physician 
should seek informed consent from the legally authorized representative. If no 
such representative is available and if the research cannot be delayed, the study 
may proceed without informed consent provided that the specific reasons for 
involving subjects with a condition that renders them unable to give informed 
consent have been stated in the research protocol and the study has been 
approved by a research ethics committee. Consent to remain in the research 
should be obtained as soon as possible from the subject or a legally authorized 
representative.
30. Authors, editors and publishers all have ethical obligations with regard to the 
publication of the results of research. Authors have a duty to make publicly 
available the results of their research on human subjects and are accountable for 
the completeness and accuracy of their reports. They should adhere to accepted 
guidelines for ethical reporting. Negative and inconclusive as well as positive 
results should be published or otherwise made publicly available. Sources of 
funding, institutional affiliations and conflicts of interest should be declared in 
the publication. Reports of research not in accordance with the principles of this 
Declaration should not be accepted for publication.
C. ADDITIONAL PRINCIPLES FOR MEDICAL RESEARCH COMBINED 
WITH MEDICAL CARE
31. The physician may combine medical research with medical care only to the 
extent that the research is justified by its potential preventive, diagnostic or 
therapeutic value and if the physician has good reason to believe that 
participation in the research study will not adversely affect the health of the 
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patients who serve as research subjects.
32. The benefits, risks, burdens and effectiveness of a new intervention must be 
tested against those of the best current proven intervention, except in the 
following circumstances:
a. The use of placebo, or no treatment, is acceptable in studies where no current 
proven intervention exists; or 
b. Where for compelling and scientifically sound methodological reasons the 
use of placebo is necessary to determine the efficacy or safety of an 
intervention and the patients who receive placebo or no treatment will not be 
subject to any risk of serious or irreversible harm. Extreme care must be 
taken to avoid abuse of this option.
33. At the conclusion of the study, patients entered into the study are entitled to be 
informed about the outcome of the study and to share any benefits that result 
from it, for example, access to interventions identified as beneficial in the study 
or to other appropriate care or benefits.
34. The physician must fully inform the patient which aspects of the care are related 
to the research. The refusal of a patient to participate in a study or the patient's 
decision to withdraw from the study must never interfere with the patient-
physician relationship.
35. In the treatment of a patient, where proven interventions do not exist or have 
been ineffective, the physician, after seeking expert advice, with informed 
consent from the patient or a legally authorized representative, may use an 
unproven intervention if in the physician's judgement it offers hope of saving 
life, re-establishing health or alleviating suffering. Where possible, this 
intervention should be made the object of research, designed to evaluate its 
safety and efficacy. In all cases, new information should be recorded and, where 
appropriate, made publicly available.
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SAP_001.pdf: 
 
 
 
 
 
 
APL-A-012-13 (NTC02100657) 
 
 
A Phase I Study of Plitidepsin (Aplidin®) in combination with Bortezomib 
and Dexamethasone in Patients with Relapsed and/or Refractory Multiple 
Myeloma 
 
STATISTICAL ANALYSIS PLAN 
 
 
 
 
Version: 2.0 
Date: 22APR2016 
-Confidential- 


 
TABLE OF CONTENTS  
 
1. 
STUDY RATIONALE 
8 
2. 
STUDY OBJECTIVES 
9 
2.1. 
Primary Objective 
9 
2.2. 
Secondary Objectives 
9 
3. 
STUDY DESIGN 
9 
4. 
SAMPLE SIZE 
10 
5. 
STUDY ENDPOINTS 
10 
5.1. 
Primary Endpoint: Determination of the RD 
10 
5.2. 
Secondary Endpoints 
10 
6. 
PATIENT EVALUABILITY CRITERIA (POPULATIONS) 
11 
6.1. 
Population Included 
11 
6.2. 
Population Evaluable for RD 
11 
6.3. 
Population Evaluable for Safety 
11 
6.4. 
Population Evaluable for Efficacy 
11 
7. 
GENERAL ANALYSIS METHODS 
12 
7.1. 
Statistical Software 
12 
7.2. 
Data Analysis Conventions 
12 
8. 
STATISTICAL ANALYSIS 
12 
8.1. 
Patient Disposition and Protocol Deviations 
12 
8.2. 
Baseline Characteristics 
13 
8.2.1 
Demographics 
13 
8.3. 
Statistical Analysis for Safety 
14 
8.3.1 
Treatment Administration and Exposure 
14 
8.3.2 
Cycle Delays and Omissions 
15 
8.3.3 
Dose Reductions 
16 
8.3.4 
Dose Interruptions 
16 
8.3.5 
Adverse Events 
16 
8.3.6 
Serious Adverse Events (SAEs) 
17 
8.3.7 
Laboratory Evaluations 
17 
8.3.7.1 
Hematology 
17 
8.3.7.2 
Serum Biochemistry and Coagulation Tests 
18 


 
8.3.7.3 
Physical Examination 
18 
8.3.7.4 
Electrocardiogram (ECG) / Left Ventricular Ejection Fraction (LVEF) 
18 
8.3.4.5 
Vital Signs 
18 
8.3.4.5 
Concomitant Medication 
18 
8.4 
Statistical Analysis for Efficacy 
19 
8.4.1 
Exploratory Analysis of Antitumor Activity 
19 
8.4.2 
Level of Significance 
19 
9 
OTHER STATISTICAL ANALYSIS 
20 
9.1 
Subgroup Analysis 
20 
9.2 
Missing Values Management 
20 
9.3 
Decimals Places 
¡Error! Marcador no definido. 
9.4 
Output Formats 
20 
APPENDIX I 
22 
10 
Appendix I. Patients Disposition 
22 
10.1 
General Characteristics 
22 
10.1.1 
Patient disposition 
¡Error! Marcador no definido. 
10.1.2 
Treatment Discontinuations 
24 
10.1.3 
Protocol Deviations 
25 
10.2 
Patient Characteristics 
27 
10.2.1 
Patient Characteristics at Baseline 
27 
10.2.2 
Multiple Myeloma History 
28 
10.2.3 
Prior Anticancer Therapy: Palliative Radiotherapy 
30 
10.2.4 
Prior Anticancer Medical Therapy 
30 
10.2.5 
Physical Examination, Vital Signs, Electrocardiogram and Other Tests 
32 
10.2.6 
Hematological evaluation at baseline 
36 
10.2.7 
Biochemical evaluation at baseline 
37 
10.2.8 
Signs and Symptoms at Baseline 
41 
   10.3 
Concomitant Medication Starting Pre-Study 
43 
11 
Appendix II. Safety Evaluation 
44 
11.1 
Extent of Exposure 
44 
11.1.1 
Cumulative Dose, Dose Intensity and Relative Dose Intensity 
44 
11.1.2 
Cycle Delays 
47 
11.1.3 
Dose Modification 
50 


 
11.2 
Dose Limiting Toxicities 
51 
11.2.1 
Dose Limiting Toxicities 
51 
11.3 
Adverse Events (AEs) 
52 
11.3.1 
Display of Adverse Events 
52 
11.4 
Deaths and Other Serious Adverse Events 
56 
11.4.1 
Deaths 
56 
11.4.2 
Serious Adverse Events 
57 
11.5 
Clinical Laboratory Evaluation 
63 
11.5.1 
Hematological Abnormalities 
63 
11.5.2 
Biochemical Abnormalities 
68 
11.5.3 
Laboratory Values over Time 
73 
11.6 
Vital Signs 
75 
11.6.1 
Vital Signs, Physical Findings and Other Observations Related to Safety 
75 
11.7 
Concomitant Medication 
80 
11.7.1 
Concomitant Medication During Study 
80 
12 
Appendix III. Efficacy Evaluation 
81 
12.1 
Efficacy Analysis 
81 
12.1.1 
Response 
81 
13 
Figures 
88 
13.1 
Hematological Profile 
88 
13.2 
Transaminase Profile 
89 
13.3 
Time to Event Graphs 
90 
14 
DB Listing 
95 
 


 
ABBREVIATIONS AND GLOSSARY 
AE(s) 
Adverse Event(s) 
ALT 
Alanine Aminotransferase 
AP 
Alkaline Phosphatase 
ASCT 
Autologous Stem Cell Transplantation 
AST 
Aspartate Aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
BL 
Baseline 
BM 
Bone Marrow 
BSA 
Body Surface Area 
CI 
Confidence Interval 
CPK 
Creatine Phosphokinase 
CPK-MB 
Serum CPK Isoenzymes (Found In Cardiac Muscle) 
CR 
Complete Remission 
CRF 
Case Report Form 
CT 
Chemotherapy 
CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
DB 
Data Base 
DF 
Degrees of Freedom 
DL 
Dose Level 
DLT 
Dose Limiting Toxicity 
DOR 
Duration of Response 
DR3 
Durable response rate at 3 months 
DR6 
Durable respone rate at 6 months 
ECG 
Electrocardiogram 
ECHO 
Echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 


 
EFS 
Event-free Survival 
EOT 
End of Treatment 
EPO 
Erythropoietin 
FDA 
Food and Drug Administration 
FU 
Follow-up 
GCP 
Good Clinical Practice 
G-CSF 
Granulocyte Colony Stimulating Factor 
IA 
Investigator Assessment 
ICH 
International Conference on Harmonization 
IEC/IRB 
Independent Ethics Committee/Institutional Review Board 
Ig 
Immunoglobulin 
IPI 
International Prognostic Index 
IR 
Independent Review 
IRC 
Independent Review Committee 
IWC 
International Workshop Criteria 
LDH 
Lactate Dehydrogenase 
LVEF 
Left Ventricular Ejection Fraction 
MedDRA 
Medical Dictionary for Regulatory Activities 
MM 
Multiple Mieloma 
MR 
Major Response 
MUGA 
Multiple-gated Acquisition Scan 
NA 
Not Applicable 
NCI-CTC 
National Cancer Institute Common Toxicity Criteria 
NE 
Not  Evaluable 
NOS 
Not Otherwise Specified 
ORR 
Overall Response Rate 
OS 
Overall Survival 
OS3 
Overall Survival at 3 months 


 
OS6 
Overall Survival at 6 months 
PD 
Progressive Disease 
PDy 
Pharmacodynamics 
PFS 
Progression-free Survival 
PFS3 
Progression-free Survival at 3 months 
PFS6 
Progression-free Survival at 6 months 
PK 
Pharmacokinetics 
PR 
Partial Response 
PS 
Performance Status 
RBC 
Red Blood Cell 
RD 
Recommended Dose 
RR 
Response Rate 
SAE(s) 
Serious Adverse Event(s) 
sCR 
Stringent Complete Response 
SD 
Stable Disease 
SOC 
System Organ Class 
SPD 
Sum of the Product of the Diameters 
StD 
Standard Deviation 
TTP 
Time to Progression 
TTO 
Time to Onset 
ULN 
Upper Limit of Normal 
US 
United States 
v 
Version 
VGPR 
Very Good Partial Response 
WBC 
White Blood Cells 
WHO 
World Health Organization 
wk 
Week 
 
 


 
 
1. 
STUDY RATIONALE 
Multiple myeloma (MM) is a malignant plasma-cell disorder characterized by the 
production of a monoclonal protein from plasma cells in the bone marrow (BM). 
Information from the National Cancer Institute indicates that in the US, an estimated 
22,350 new cases of MM will be diagnosed in 2013, and 10,710 people will die from 
the disease. The incidence of MM in Europe is 4.5-6.0/100,000 a year with a median 
age of diagnosis of between 63 and 70 years and a mortality rate of 4.1/100,000/year. In 
the Western hemisphere, about 1% of cancer-related deaths are due to myeloma. MM 
may be staged according to either the Durie-Salmon system (protocol appendix 4) based 
on the amount of abnormal monoclonal immunoglobulin in the blood or urine, blood 
calcium levels, the amount of bone damage shown by X-ray and blood hemoglobin 
levels, or the newer staging system, the International Staging System that relies on the 
levels of albumin and beta-2-microglobulin in the blood (protocol appendix 4). In both 
systems, all stages are further subclassified by creatinine level either less than 2.0 
mg/dL or greater than or equal to 2.0 mg/dL. Impaired renal function worsens prognosis 
regardless of the stage. 
The disease primarily affects individuals later in life with a median age of 63-70 years. 
From the time of diagnosis, survival without treatment is between 6 and 12 months and 
extends to 3 years with chemotherapy (CT). MM is treatable but rarely curable. Most 
patients receive multiple treatments over the course of their disease, and the precise 
sequence of therapy and used regimens can be quite variable. With standard dose CT, 
patients have a median survival of 24–30 months. Twenty five percent of patients 
survive 5 years or longer, and the 10-year survival rate is approximately 3%. Failure of 
standard therapy to cure these diseases has led to the study of higher doses of 
chemotherapeutic agents. These conditioning regimens may involve ablative/reduced or 
non-myeloablative intensity and the rescue of the immune system following CT may 
involve autologous or allogeneic stem-cell transplantation.  
A full rationale for the study can be found in the appropriate sections of the study’s 
protocol. 
 
 
 
 
 
 
 
 


 
 
2. 
STUDY OBJECTIVES 
2.1.  Primary Objective 
• To determine the recommended dose (RD) of plitidepsin in combination with 
bortezomib and dexamethasone in patients with relapsed and/or refractory MM. 
2.2.  Secondary Objectives 
• 
 To determine the efficacy of plitidepsin in combination with bortezomib and 
dexamethasone. 
• To evaluate the safety and tolerability of the combination in patients with relapsing 
and/or refractory MM. 
• To study the pharmacokinetics (PK) and pharmacodynamics (PDy) of plitidepsin in 
combination with bortezomib and dexamethasone. 
 
3. 
STUDY DESIGN 
This is a multi-center, uncontrolled, single arm, phase I study, designed to establish the 
optimal dose of the combination plitidepsin, bortezomib and dexamethasone in patients 
with refractory and/or relapsed MM. Patients will be enrolled sequentially into three 
dose levels (DLs). The feasibility of administering plitidepsin with bortezomib in 
combination with dexamethasone and the RD of the combination will be determined. 
Patients will be evaluated at scheduled visits in three study periods: pre-treatment, 
treatment and follow-up. 
Cohorts of three patients will be treated at each DL (up to three DLs) according to the 
next table:  
 
DL Number of Patients 
Plitidepsin  
dose (mg/m2) 
Bortezomib dose 
(mg/m2) 
Dexamethasone 
dose 
(mg) 
-1 
0-6 
3.0 
1.0 
40.0 
1 
3-6 
4.0 
1.0 
40.0 
2 
3-6 
4.0 
1.3 
40.0 
3 
3-6 
5.0 
1.3 
40.0 
DL; Dose level. 
 


 
 
 
• The first cohort of three patients will start at DL1.  
• If no DLTs are observed in any of the three patients at a given DL, three 
additional patients will be treated at the next DL.  
• If a DLT is observed in one of three patients treated at a given DL, three 
additional patients will be entered at that same DL.  
• If DLTs are observed in two of three patients, no additional patients will be 
treated at that DL and the immediately lower DL will be expanded to at least six 
patients.  
•  If two out of six patients have DLTs at DL1, the next patients enrolled will be 
treated at DL -1. If two out of six patients (≥33%) have DLTs at this DL, the 
study will be stopped and that DL will be considered the maximum tolerated 
dose (MTD).  
• The RD is defined as the DL at which fewer than two out of six patients (33% of 
patients) experience DLTs during the first cycle.  
• At the RD, at least six evaluable patients for the determination of DLTs will be 
treated.  
• At DL1, one patient must have completed the first cycle before accrual of the 
second and third patients. The second and third patients may be treated 
simultaneously.  
• Intermediate dose escalation or de-escalation is allowed.  
• Intrapatient dose escalation is not allowed. 
4. 
SAMPLE SIZE 
A total of 20-30 patients are expected to participate. However, the number of patients 
may vary depending upon the tolerability of the combination and the number of DLs 
required to identify the RD. 
 
5. 
STUDY ENDPOINTS 
5.1.  Primary Endpoint: Determination of the RD 
• 
 The RD will be the highest DL at which fewer than two out of six patients (33%) 
experience DLTs during the first cycle. 
5.2. Secondary Endpoints 
• Overall response rate (ORR), including sCR, CR, VGPR and PR. 
• Minimal response (MR). 
• Stable disease (SD). 
• Clinical benefit rate, including ORR plus MR and SD.  
• Duration of response (DOR).  
• Time to progression (TTP). 
• Progression-free survival (PFS). 
• Event-free survival (EFS). 


 
• Safety and tolerability.  
• PK and PDy of plitidepsin in combination with bortezomib and dexamethasone. 
 
 
6. 
PATIENT EVALUABILITY CRITERIA (POPULATIONS) 
To be enrolled in this study, the patients must meet all inclusion criteria and no 
exclusion criteria.  
6.1.  Population Included 
Defined as all patients who are enrolled in the study and have been recorded in the 
database, regardless of whether they have received study drugs.  
6.2.  Population Evaluable for RD 
The main objective of the study (determination of the RD) will be assessed in this 
population. 
Patients must be replaced if:  
 
 
•  They are withdrawn from the study due to not being evaluable for the primary 
endpoint, due to hypersensitivity reactions or reasons other than drug-related 
AEs meeting DLT criteria [e.g., consent withdrawal, not meeting the eligibility 
criteria, non-compliance with follow-up, early disease progression (PD), or 
unrelated AEs].  
 
 
• They require radiation therapy or other anticancer procedure within four weeks 
after the first dose, unless they previously had another drug-related AE included 
in the definition of DLT.  
 
• There is a protocol deviation/s precluding conclusions on the safety of the study 
therapy. 
 
All replaced patients will be included in the general safety analysis and in the efficacy 
analysis (if appropriate). 
6.3.  Population Evaluable for Safety 
Defined as all patients who have received at least one (complete or incomplete) dose of 
plitidepsin. 
6.4.  Population Evaluable for Efficacy 
Although it is not the main objective of this study, antitumor activity will be measured 
clinically and/or radiologically according to IMWG. Patients will be evaluable for 
efficacy if they meet all inclusion criteria and no exclusion criteria and receive at least 


 
one complete treatment cycle (two plitidepsin infusions, four bortezomib injections, 
four doses of dexamethasone) and have at least one disease assessment without 
protocol deviations with an effect on the risk/benefit ratio of the clinical trial, which 
may jeopardize the efficacy evaluation. Patients from this population who have 
inadequate post-baseline data to assess efficacy according to the response criteria (see 
section 6.1.1 of the protocol) will be considered treatment failures and will be included 
in the ORR and clinical benefit calculations. 
 
7. 
GENERAL ANALYSIS METHODS 
7.1.  Statistical Software 
Medidata Rave® electronic data capture (EDC) will be used for data entry and clinical 
data management. SAS® Software v9.2 or superior will be used for all statistical 
analyses. 
7.2.  Data Analysis Conventions 
All data analysis conventions, derived data calculations and grouping needed at the time 
to perform the statistical analysis will be detailed in a separate document not included in 
this SAP called “data analysis conventions” (DAC).  
 
8. 
STATISTICAL ANALYSIS 
8.1.  Patient Disposition and Protocol Deviations 
A summary of patients and dose levels will be presented and organized by population 
type: 
• 
 Population included. 
• Population evaluable for safety. 
• Population evaluable for RD (primary endpoint population). 
• Population evaluable for efficacy. 
 
Patients who do not fit into any of these categories will be listed and the reasons for 
each of them will be detailed.  
Accrual and study discontinuation details will be presented in a descriptive manner. 
Reasons for treatment discontinuation will be summarized by counts and percentages 
and will be listed by number of cycles received. Treatment discontinuation for reasons 
other than disease progression will be detailed. 


 
A protocol deviation is defined as any departure from what is described in a clinical trial 
protocol that has been approved by an Independent Ethics Committee/Institutional 
Review Board (IEC/IRB) and a Competent Authority. Therefore, it applies to deviations 
from patient inclusion criteria and clinical procedures (e.g., assessments to be conducted 
or parameters to be determined), and also to any other procedure described in the 
protocol and concerning Good Clinical Practice (GCP) guidelines or ethical issues (e.g., 
issues related to obtaining the patients’ Informed Consent, data reporting, Investigator’s 
responsibilities etc.). 
Protocol deviations will be classified mainly based on the following group categories 
[as defined by International Conference on Harmonization (ICH) E-3]. However, other 
relevant groups could be added. 
- Inclusion/exclusion criteria not met. 
- Withdrawal criteria met, but treatment continued. 
- Incorrect treatment, dose or schedule received. 
- Excluded concomitant medication received. 
- Failure to comply study procedures.  
- Any other relevant subgroup defined at revision. 
8.2. Baseline Characteristics 
8.2.1 
Demographics 
Demographics and baseline characteristics will be summarized for all patients included. 
All patients’ characteristics will be presented by DL or by most adequate dose grouping 
according to the number of finally treated patients. 
Continuous variables will be summarized and presented by means of summary statistics, 
i.e., mean, median, range and standard deviation if appropriate. 
Categorical variables will be summarized in frequency tables, where percentages will be 
rounded to one decimal and may therefore not always add up to exactly 100%. 
When multiple baseline values are available (e.g. laboratory measurements, vital signs), 
the last value prior to or on the first day of treatment will be selected as baseline value. 
Baseline Eastern Cooperative Oncology Group (ECOG) scores will be summarized by 
frequency counts. 
MM history, histology, time from diagnosis, number of baseline lesions and different 
site involvement will be summarized by means of frequency tables or summary 
statistics. Time from initial diagnosis to the start of study treatment and time from the 


 
latest disease progression to the start of study treatment will be shown in months and 
summarized descriptively. Incomplete dates should be recorded following imputation 
rules described in Section 9.2. 
Relevant medical history (other than MM) will be displayed in frequency tables by dose 
level (or the most adequate dose grouping) and by patient. 
Previous surgery, radiotherapy or other anticancer therapy (number of lines and number 
of agents) will be summarized in a frequency table. To ensure the accurate analysis of 
the number of chemotherapy agents and lines, these will be revised and if necessary 
recoded by PharmaMar's physicians. 
Signs and symptoms, hematology and serum biochemistry abnormalities at baseline will 
be displayed in frequency tables according to NCI-CTCAE v4 toxicity grades. Grade ≥2 
signs and symptoms and laboratory abnormalities at baseline will be listed by dose level 
(or the most adequate dose grouping). 
 
8.3. Statistical Analysis for Safety 
Safety variables will be analyzed in a descriptive way. Data retrieved from scheduled 
and unscheduled visits will be tabulated by dose level (or by most adequate dose 
grouping).  
All patients who receive at least part of a plitidepsin infusion will be evaluable for 
safety and will be included in the general safety displays. 
Patients evaluable for RD will be used for the primary analysis. 
For the evaluation of the main endpoint, the total number of patients included, the 
number of patients evaluable for determination of DLTs and the number of patients with 
any DLT (and their categorization) will be summarized by dose level (or the most 
adequate dose grouping). Toxicities meeting the DLT criteria in Cycle 1 and toxicities 
in subsequent cycles, if any, will be listed separately, and the description of laboratory 
abnormalities (hematology / biochemistry) will be supported by graphs depicting the 
evolution in time of laboratory values (including nadir calculation and median time to 
recovery from baseline values). 
 
8.3.1 
Treatment Administration and Exposure 
Patient exposure to plitidepsin, bortezomib and dexamethasone will be summarized by 
dose level for the safety population. 
Total cumulative Plitidepsin dose, expressed in mg/m2, defined as the sum of all the 
Plitidepsin doses from the first to the last dose received. 


 
Total cumulative Bortezomib dose, expressed in mg/m2, defined as the sum of all the 
Bortezomib doses from the first to the last dose received. 
Total cumulative Dexamethasone dose, expressed in mg, defined as the sum of all the 
Dexamethasone doses from the first to the last dose received. 
Intended Plitidepsin dose intensity, is the planned dose for a particular cycle divided by 
the planned duration of a cycle in weeks. Expressed in mg/m2/wk. 
Intended Bortezomib dose intensity, is the planned dose for a particular cycle divided by 
the planned duration of a cycle in weeks. Expressed in mg/m2/wk. 
Intended Dexamethasone dose intensity,  is the planned dose for a particular cycle 
divided by the planned duration of a cycle in weeks. Expressed in mg/week (wk). 
Absolute Plitidepsin dose intensity, is the total cumulative dose divided by the treatment 
duration, expressed in mg/m2/wk. As a convention, the duration of the last cycle is 
considered to be 28 days (planned cycle duration).  
Absolute Bortezomib dose intensity, is the total cumulative dose divided by the 
treatment duration, expressed in mg/m2/wk. As a convention, the duration of the last 
cycle is considered to be 28 days (planned cycle duration).  
Absolute Dexamethasone dose intensity, is the total cumulative dose divided by the 
treatment duration, expressed in mg/wk. As a convention, the duration of the last cycle 
is considered to be 28 days (planned cycle duration).  
Relative Plitidepsin / Bortezomib / Dexamethasone dose intensity (%), is the ratio 
resulting from the absolute dose intensity divided by the intended dose intensity. 
Time on treatment: is the interval, expressed in weeks, between the first infusion date 
and the last infusion date plus 30 days or the start of new treatment or the date of death 
(whichever occurs first). 
Depending on the number of patients cases mean, median, minimum and maximum 
values or standard deviation for the parameters defined above will be tabulated by dose 
level (or the most adequate dose grouping). 
 
8.3.2 
Cycle Delays and Omissions 
Whenever a dose delay for Day 1 has been ticked on the electronic case report form 
(eCRF) field "Infusion delayed: No/Yes" the length of the delay will be calculated as 
follows: 
Cycle delay (days) = [current cycle’s start date] – [previous cycle’s start date] - 28 days 
(planned cycle duration) 


 
A cycle delay is defined as a delay in the administration of the first infusion in one cycle 
(i.e. Day 1 infusion).  
Cycle 1 will be excluded from all calculations of cycle delays. Therefore, the 
denominator used in all cycle delay calculations will exclude Cycle 1 and be equal to 
the number of cycles susceptible to be delayed. 
Dose delays distribution with respect to any given cycle will be studied by means of 
counts and percentages. The reasons for cycle delays will be detailed, specifying how 
many were due to treatment-related toxicity. Other reasons (e.g. administrative reasons) 
will be analyzed separately and additional tables will be prepared. Dose delays 
attributed to study treatment will be detailed, and hematological and/or non-
hematological reasons will be outlined. 
Dose skipping or dose omission is defined as any infusion not administered, including 
the second infusion of the first cycle. The distribution of skipped doses with respect to 
any given cycle will be studied by means of counts and percentages (the denominator 
used for calculations will be equal to the number of patients/cycles susceptible to have 
an omission). A detailed listing of patients with skipped doses and reasons as well as 
reasons for dose omission will be shown. 
8.3.3 
Dose Reductions 
All Plitidepsin/Bortezomib/Dexamethasone dose reductions will be considered and 
described (per cycle and patient), specifying the magnitude and the reason/s for 
treatment-related dose reductions (hematological toxicity, non-hematological toxicity or 
both), or any other causes unrelated to treatment. The denominator used in all dose 
reduced calculations will be equal to the number of cycles susceptible to be reduced, it 
means, the Cycle 1 will be taken into account for dose reduction calculations if more 
infusions than the first infusion of Cycle 1 were taken. 
The distribution of plitidepsin/bortezomib/dexamethasone dose reductions in any given 
cycle will be studied by means of counts and percentages. 
8.3.4 
Dose Interruptions 
All dose interruptions will be listed by patient and compound 
(Plitidepsin/Bortezomib/Dexamethasone). 
8.3.5 
Adverse Events 
All AEs will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). 
Toxicity evaluation will be done in accordance with NCI-CTCAE v.4. Otherwise, 
severity will be noted. As a convention, the term "Grade" will always be used, 
according to the worst NCI-CTCAE grade or, for toxicities which do not form the 
subject of NCI-CTCAE classification, according to the worst severity. 


 
Descriptive statistics will be used for the evaluation of safety. AEs and laboratory 
abnormalities will be displayed in frequency tables using counts and percentages and 
will be graded to the most severe grade per patient and cycle. A separate analysis will 
be done for Cycle 1. The worst grade reached by each patient during Cycle 1 will also 
be shown. 
Shifts in severity grades from baseline to worst occurrence during treatment, deaths,  
serious adverse events (SAEs) and events resulting in study discontinuation will be 
tabulated. 
In order to clearly define the safety profile of Plitidepsin, additional safety analyses, as 
well as additional classifications other than System Organ Class (SOC)/Preferred Term 
(PT) may be added, if necessary. 
8.3.6 
Serious Adverse Events (SAEs) 
Database listings of deaths and SAEs will be provided and will include at least onset 
and resolution dates (if applicable), severity, relationship to study drug, most important 
significant consequence and main action taken. 
If enough number of SAEs are reported, they will be displayed in frequency tables using 
counts and percentages and will be graded to the most severe grade per patient and 
cycle. 
8.3.7 
Laboratory Evaluations 
8.3.7.1 Hematology 
Hematological toxicities will be classified according to NCI-CTCAE v.4, and will be 
presented by cycle and dose level (or the most adequate dose grouping). A separate 
analysis will be done for Cycle 1. The worst grade reached by each patient during Cycle 
1 will also be shown. 
If serious hematological toxicities occur, a special follow-up will be done to determine 
the pattern of thrombocytopenia and neutropenia within and between the different 
cycles. This follow-up will include the calculation of mean, standard deviation, median 
and the range of nadir values and of the time to recovery to baseline values. 
Descriptive tables, and supporting, graphic representations of nadir values for neutrophil 
and platelet counts (by cycle  dose level or the most adequate dose grouping) will be 
used. Also inter-cycle time courses for neutropenia, thrombocytopenia or any other 
significant parameter will be displayed in graphs. If necessary, graphs comparing first 
and second cycle time courses for these parameters will be created. 
Shifts in severity grades from baseline to worst occurrence during treatment will be 
tabulated. 


 
8.3.7.2 Serum Biochemistry and Coagulation Tests 
Non-hematological laboratory abnormalities [e.g. transaminases, creatinine, creatine 
phosphokinase (CPK), bilirubin, AP, etc.] will be classified according to NCI-CTCAE 
v.4 and will also be shown by patient and cycle. A separate analysis will be done for 
Cycle 1. The worst grade reached by each patient during Cycle 1 will also be shown. 
If serious non-hematological toxicities occur, a special follow-up will be done that will 
include the calculation of mean, standard deviation, median and range of peak values, as 
well as the time to recovery to baseline values.  
Descriptive tables will be used to determine toxicity patterns within and between cycles. 
These tables can be complemented with boxplots that help display peak values of 
transaminases, creatinine, CPK, bilirubin, AP, etc. by cycle, dose level or the most 
adequate dose grouping. Also, inter-cycle time course graphs for any significant 
parameter, as well as graphs comparing first and second cycle time courses will be 
created. 
Shifts in severity grades from baseline to worst occurrence during treatment will be 
tabulated. 
8.3.7.3 Physical Examination 
The evaluation of physical examination (i.e., normal/abnormal) will be summarized 
with frequency counts. All data will be listed by dose level. 
8.3.7.4 Electrocardiogram (ECG) / Left Ventricular Ejection Fraction (LVEF) 
Baseline ECG evaluation (normal/abnormal) will be summarized with frequency counts. 
Continuous variables (PR Interval, QT Interval, QRS Complex, Ventricular Rate, LVEF 
and LVEF Normal Range) will be summarized and summary statistics will be provided 
(i.e., median and range). Baseline values and their evolution during treatment will be 
tabulated with summary statistics. 
Corrected QT interval (QTc) will be calculated in the database by using Bazett’s 
formula. 
8.3.4.5 Vital Signs 
Performance status (PS) and weight gain / loss during the study will be summarized by 
frequency tabulation. 
8.3.4.5 Concomitant Medication 
Concomitant therapies will be coded using the World Health Organization Anatomical 
Therapeutic Chemical Classification System (WHO-ATC) dictionary and categorized 
according to ATC class (levels 1, 2 and 4). The number of patients receiving each type 
of therapy will be tabulated in two separated frequency tables: one for therapies that 


 
started pre-study, and another one for those administrated during the study. The 
accompanying listing will include all concomitant therapies. 
Additional listings for patients taking prohibited medications / therapies according to 
protocol will be provided. 
8.4  Statistical Analysis for Efficacy 
8.4.1 
Exploratory Analysis of Antitumor Activity 
The efficacy population is defined as all eligible patients who have received at least one 
treatment cycle and without protocol deviations with an effect on the risk/benefit ratio 
of the clinical trial, which may jeopardize the efficacy evaluation. Patients from this 
population who have inadequate post-baseline data to assess efficacy according to the 
response criteria in Section 6.1.1. of the protocol will be considered treatment failures 
and will be included in the ORR and clinical benefit calculations. 
ORR and clinical benefit rate will be calculated and binomial exact confidence intervals 
at 95% will be presented. 
Follow-up time will be calculated from the date of the first infusion to the date of the 
last documented examination. The DOR will be analyzed for all patients in whom a 
response has been observed and will be calculated from the date of the first 
documentation of response to the date of PD or further therapy or death. 
TTP will be calculated from the date of the first infusion to the date of documented PD 
or death due to PD. PFS will be calculated from the date of the first infusion to the date 
of documented PD or death (regardless of the reason). Likewise, EFS will be 
calculated from the date of first infusion to the date of documented PD or death but may 
include additional events besides death and PD that are considered of importance. If any 
patient is lost to follow-up before PD or receives another antitumor therapy, the TTP, 
PFS or EFS will be censored on the date of the last tumor assessment. If there are no 
tumor assessments, these parameters will be censored on the date of the first drug 
administration. 
Median time to onset and duration of response, time to PD, PFS, EFS and estimated rate 
of patients free of progression will be calculated by Kaplan-Meier estimates with 95% 
confidence intervals. 
8.4.2 
Level of Significance 
Confidence intervals will be constructed using the 95% level. No formal statistical tests 
are defined, but if needed, all will be done at a significance level of 5% (two-sided) and 
will be considered exploratory. 
 


 
9 OTHER STATISTICAL ANALYSIS 
9.1 Subgroup Analysis 
Exploratory subgroup analysis will be done to compare refractary myeloma patients vs. 
relapsed myeloma patients. It is also planned to gather information about the type of 
myeloma, since it can be secretory or non-secretory. According to information given by 
the physician, it is expected to find 97–98% of secretory myelomas and 2–3% of non-
secretory myelomas, evaluating both of them with different methods, according to 
IMWG criteria. 
Non-scheduled analyses could be performed, if considered necessary to 
enhance the patient’s safety/efficacy. 
9.2 Missing Values Management 
Missing laboratory values will be subtracted from the denominator of the tables. 
Imputation of Incomplete Dates 
Dates before registration 
If the day of a month is unknown, the imputed day will be the 15th of that month. If the 
month is also unknown, the imputed date will be the 1st of July. This assumption will 
only be valid if the imputed date is earlier than the date of the patient’s informed 
consent; otherwise, the imputed date will be the first day of the month in which the 
informed consent was signed (i.e., 01/ date of signing of the informed consent/year). 
Dates after the end of treatment 
To ensure the most conservative approach for the efficacy time-to-event variables (e.g., 
PFS), which can be affected by missing values, the following rules will be followed: if 
the day of a month 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 one. 
9.3  Decimals 
By default, all numeric results will be rounded to one decimal point, except when 
variables are integer; in which case, they will be reported without decimals; e.g. age in 
years, number of sites, tumor size in mm for target lesions etc. 
9.4 Output Formats 
Tables, listings and graphs could be performed by MM type. Dose levels or any variable 
susceptible to be grouped (e.g. toxicity grades) may be joined to add clarity to the 
reported tables. Table formats could also be modified to clarify the reported information 
(e.g. if dose level sample sizes ≤3 then the only percentage shown will be the total 


 
column percentage, for the others, only the number of patients will be shown), if 
appropriate. Table categories will usually be ordered by descending frequency. If 
appropriate, continuous variables could be complemented with mean, standard deviation 
or 95% CIs. Likewise, the range of continuous variables with only one observation 
might be deleted to avoid duplicated information. The structure of the tables and the 
graphs is given as an example. Changes may be done in order to improve interpretation 
of the results. 


 
APPENDIX I 
10 Appendix I. Patients Disposition 
The general characteristics analysis will be presented on the included population. 
10.1 General Characteristics 
10.1.1  Patient Disposition 
Main characteristics concerning inclusion in the study, withdrawal from the study and 
protocol deviations will be displayed in this section. 
Table 10.1.1.1 
Included and evaluable patients by dose level. 
Included  and  evaluable 
patients 
Dose level 
I 
(N = XX) 
II 
(N = XX) 
III 
(N = XX) 
Total 
(N = XX) 
N (%) 
N (%) 
N (%) 
N (%) 
Included 
 
 
 
 
 
 
 
Evaluable  for RD 
Evaluable for Safety 
Evaluable for Efficacy 
 
 
 
 
 
 
 
Table 10.1.1.2 
Patients not Evaluable for RD. 
Patient No 
Criteria number /s and description 
 
 
 
 
 
 
 
 
 
 
 
  
 
Table 10.1.1.3 
Patients not evaluable for Safety. 
Patient No 
Criteria number /s and description 
 
 
 
 
 
 
 
 
 
 
 
  
 
Table 10.1.1.4 
Patients not evaluable for Efficacy. 
Patient No 
Criteria number /s and description 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
Table 10.1.1.5 
Patient Accrual by Institution and Dose Level 
 
Dose level* 


 
I 
(N = XX) 
II 
(N = XX) 
III 
(N = XX) 
Total 
(N = XX) 
N (%) 
N (%) 
N (%) 
N (%) 
Institution Institution 1 
 
 
 
 
 
 
 
Institution 2 
 
 
 
 
 
 
 
…. 
 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
Notes: Percentage is based on number of patients by dose level. 
(*) The actual dose level in mg/m2 will be shown in all headings for all tables in sections 10, 11 and 12. 
 
 
Table 10.1.1.6 
Patient Accrual by Country and Dose Level 
 
Dose level* 
I 
(N = XX) 
II 
(N = XX) 
III 
(N = XX) 
Total 
(N = XX) 
N (%) 
N (%) 
N (%) 
N (%) 
Country Country 1 
 
 
 
 
 
 
 
Country 2 
 
 
 
 
 
 
 
…. 
 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
Notes: Percentage is based on number of patients by Dose Level 
(*) The actual dose level in mg/m2 will be shown in all headings for all tables in sections 10, 11 and 12. 
 
Table 10.1.1.7 
Study dates 
Dates information 
Date of  first consent 
 
Date of  first dose 
 
Date of  last consent 
 
Date of  first dose of last  patient 
 
Date of  last dose 
 
Date of  last  follow  up* 
 
(*) Last follow up, examination or procedure before study closure. 
 
Table 10.1.1.8 
Time on Treatment (Weeks) by Dose Level 
Median and Range of 
Time on treatment (days) 
Dose level 
I 
(N = XX) 
II 
(N = XX) 
III 
(N = XX) 
Total 
(N = XX) 
N 
 
 
 
 
Median 
 
 
 
 
Min 
 
 
 
 
Max 
 
 
 
 
 
 
 
 


 
10.1.2 Treatment Discontinuations 
Table 10.1.2.1 
Treatment Discontinuation by Dose Level 
Treatment 
discontinuation 
Dose level 
I 
(N = XX) 
II 
(N = XX) 
III 
(N = XX) 
Total 
(N = XX) 
N (%) 
N (%) 
N (%) 
N (%) 
Progressive disease 
 
 
 
 
 
 
 
Treatment related AE 
Non-treatment related AE  
 
 
 
 
 
Patient refusal 
 
 
 
 
 
 
Death 
 
 
 
 
 
 
Investigator's decision 
 
 
 
 
 
 
Other  
 
 
 
 
 
 
Total 
 
 
 
 
 
 
Notes: Percentage is based on number of patients by Dose Level 
 
Table 10.1.2.2 
Treatment Discontinuation Details 
Patient No 
Last cycle infused 
Treatment 
discontinuation reason Details 
 
 
 
 
 
 
 
 
 
 
 
  
 
Table 10.1.2.3 
Reasons for Treatment Discontinuation by Cycle and Dose Level (all Treated Patients) 
Treatment discontinuation 
Dose level 
I 
(N = XX) 
II 
(N = XX) 
III 
(N = XX) 
Total 
(N = XX) 
N (%) 
N (%) 
N (%) 
N (%) 
Progressive disease 1 cycle  
 
 
 
 
 
 
 
2-3 cycles 
 
 
 
 
 
 
>=4 cycles 
 
 
 
 
 
 
Patient refusal to 
treatment 
1 cycle  
 
 
 
 
 
 
 
2-3 cycles 
 
 
 
 
 
 
>=4 cycles 
 
 
 
 
 
 
Investigator's 
decision 
1 cycle  
 
 
 
 
 
 
 
2-3 cycles 
 
 
 
 
 
 
>=4 cycles 
 
 
 
 
 
 
Toxicity 
1 cycle  
 
 
 
 
 
 
 
2-3 cycles 
 
 
 
 
 
 
>=4 cycles 
 
 
 
 
 
 
Death 
1 cycle  
 
 
 
 
 
 
 
2-3 cycles 
 
 
 
 
 
 
>=4 cycles 
 
 
 
 
 
 
Other 
1 cycle  
 
 
 
 
 
 
 
2-3 cycles 
 
 
 
 
 
 
>=4 cycles 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 


 
Notes: Percentage is based on number of patients by Dose Level 
 
Table 10.1.2.4 
Treatment Discontinuation Due to Adverse Events 
Dose level  
Patient id. 
SOC 
MedDra PT 
Relationship 
…. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 10.1.2.5  
Reasons for Treatment Discontinuation Other Than Progressive Disease 
Dose Level Patient No 
Last cycle infused 
End of study reason 
Specify 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
Table 10.1.2.6 
Study Discontinuation. Specify 
Dose Level      Patient No 
Study discontinuation date 
   Study discontinuation reason 
Off-Study reason 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
Table 10.1.2.7 
Reasons for Study Discontinuation by Dose Level 
Study discontinuation 
Dose level 
I 
(N = XX) 
II 
(N = XX) 
III 
(N = XX) 
Total 
(N = XX) 
N (%) 
N (%) 
N (%) 
N (%) 
End of Study 
 
 
 
 
 
 
 
 
Patient refusal  
 
 
 
 
 
 
 
Investigator's decision 
 
 
 
 
 
 
 
Lost to follow up 
 
 
 
 
 
 
 
Death 
 
 
 
 
 
 
 
Other 
 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
10.1.3 Protocol Deviations 
Table 10.1.3.1 
Protocol Deviations. Ineligible Patients as Per Protocol by Dose Level 
Ineligible 
patients as per 
protocol 
Dose level 
I 
(N = XX) 
II 
(N = XX) 
III 
(N = XX) 
Total 
(N = XX) 
N (%) 
N (%) 
N (%) 
N (%) 
Protocol 
deviation  
 
 
 
 
 
 
 


 
Ineligible 
patients as per 
protocol 
Dose level 
I 
(N = XX) 
II 
(N = XX) 
III 
(N = XX) 
Total 
(N = XX) 
N (%) 
N (%) 
N (%) 
N (%) 
Without 
deviation  
 
 
 
 
 
 
Total 
 
 
 
 
 
 
Notes: Percentage is based on number of patients by Dose Level 
 
Table 10.1.3.2 
Protocol Deviations. Patients Not Withdrawn as Per Protocol by Dose Level 
Patients not 
withdrawn 
Dose level 
I 
(N = XX) 
II 
(N = XX) 
III 
(N = XX) 
Total 
(N = XX) 
N (%) 
N (%) 
N (%) 
N (%) 
Protocol 
deviation  
 
 
 
 
 
 
 
Without 
deviation  
 
 
 
 
 
 
Total 
 
 
 
 
 
 
Notes: Percentage is based on number of patients by Dose Level 
 
 
Table 10.1.3.3 
Protocol Deviations. Incorrect Dose or Schedule by Dose Level* 
Incorrect dose 
or schedule 
Dose level 
I 
(N = XX) 
II 
(N = XX) 
III 
(N = XX) 
Total 
(N = XX) 
N (%) 
N (%) 
N (%) 
N (%) 
Protocol 
deviation  
 
 
 
 
 
 
 
Without 
deviation  
 
 
 
 
 
 
Total 
 
 
 
 
 
 
Notes: Percentage is based on number of patients by Dose Level 
* Including patients not meeting criteria for re-treatment. 
 
Table 10.1.3.4 
Protocol Deviations. Patients Receiving Prohibited Concomitant Medication by Dose 
Level 
Excluded 
Concomitant 
Medication 
Dose level 
I 
(N = XX) 
II 
(N = XX) 
III 
(N = XX) 
Total 
(N = XX) 
N (%) 
N (%) 
N (%) 
N (%) 
Protocol deviation   
 
 
 
 
 
 
Without deviation   
 
 
 
 
 
Total 
 
 
 
 
 
 
Notes: Percentage is based on number of patients by Dose Level 
 
Table 10.1.3.5 
Supportive Listing Protocol Deviations. 
Dose level  Patient No 
Protocol deviation type 
Specify 
 
 
 
 
 
 
 
 
 
 
 
 


 
Dose level  Patient No 
Protocol deviation type 
Specify 
 
 
 
 
 
10.2 Patient Characteristics 
10.2.1 Patient Characteristics at Baseline 
Table 10.2.1.1 
Age at Entry by Dose Level 
Age at entry 
Dose level 
I 
(N = XX) 
II 
(N = XX) 
III 
(N = XX) 
Total 
(N = XX) 
N (%) 
N (%) 
N (%) 
N (%) 
18 - XX years 
 
 
 
 
 
 
 
XX-YY years  
 
 
 
 
 
 
· · ·  
 
 
 
 
 
 
>= ZZ years  
 
 
 
 
 
 
Total 
 
 
 
 
 
 
Notes: Percentage is based on number of patients by Dose Level 
 
Table 10.2.1.2 
Age Mean, Median, Std and Range by Dose Level 
Age median and 
range 
Dose level 
I 
(N = XX) 
II 
(N = XX) 
III 
(N = XX) 
Total 
(N = XX) 
N 
Mean 
 
 
 
 
Median 
Std 
 
 
 
Min 
 
 
 
Max 
 
 
 
 
 
Table 10.2.1.3 
Race by Dose Level 
Race 
Dose level 
I 
(N = XX) 
II 
(N = XX) 
III 
(N = XX) 
Total 
(N = XX) 
N (%) 
N (%) 
N (%) 
N (%) 
Caucasian  
 
 
 
 
 
 
 
Black 
 
 
 
 
 
 
Asian 
 
 
 
 
 
 
· · ·  
 
 
 
 
 
 
Total 
 
 
 
 
 
 
Notes: Percentage is based on number of patients by Dose Level 
 
Table 10.2.1.4 
Gender by Dose Level 
Gender 
Dose level 
I 
(N = XX) 
II 
(N = XX) 
III 
(N = XX) 
Total 
(N = XX) 
N (%) 
N (%) 
N (%) 
N (%) 
Male  
 
 
 
 
 
 
 


 
Gender 
Dose level 
I 
(N = XX) 
II 
(N = XX) 
III 
(N = XX) 
Total 
(N = XX) 
N (%) 
N (%) 
N (%) 
N (%) 
Female 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
Notes: Percentage is based on number of patients by Dose Level 
 
 
Table 10.2.1.5 
RelapseRelapsed / Refractory Disease by Dose Level 
Type 
Dose level 
I 
(N = XX) 
II 
(N = XX) 
III 
(N = XX) 
Total 
(N = XX) 
N (%) 
N (%) 
N (%) 
N (%) 
Primary refractory myeloma 
 
 
 
 
 
 
 
Relapsed and refractory myeloma   
 
 
 
 
 
Relapsed myeloma 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
Notes: Percentage is based on number of patients by Dose Level 
 
 
10.2.2 Multiple Myeloma History 
Table 10.2.2.1 
Time from Diagnosis to First Infusion (months) by Dose Level 
Time from Diagnosis to 
First Infusion 
Dose level 
I 
(N = XX) 
II 
(N = XX) 
III 
(N = XX) 
Total 
(N = XX) 
N (%) 
N (%) 
N (%) 
N (%) 
N 
Mean 
 
 
 
 
 
 
 
Median 
Std 
 
 
 
 
 
 
Min 
 
 
 
 
 
 
Max 
 
 
 
 
 
 
 
 
Table 10.2.2.2 
Time from last PD (months) by Dose Level 
Time from  last PD 
Dose level 
I 
(N = XX) 
II 
(N = XX) 
III 
(N = XX) 
Total 
(N = XX) 
N (%) 
N (%) 
N (%) 
N (%) 
N 
Mean 
 
 
 
 
 
 
 
Median 
Std 
 
 
 
 
 
 
Min 
 
 
 
 
 
 
Max 
 
 
 
 
 
 
 
 


 
Table 10.2.2.3 
Multiple Myeloma Type by Dose Level 
Multiple Myeloma  Type 
Dose level 
I 
(N = XX) 
II 
(N = XX) 
III 
(N = XX) 
Total 
(N = XX) 
N (%) 
N (%) 
N (%) 
N (%) 
IgG 
 
 
 
 
 
 
 
IgA 
 
 
 
 
 
 
Light Chain Disease 
 
 
 
 
 
 
IgD 
 
 
 
 
 
 
IgE 
 
 
 
 
 
 
IgM 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
Notes: Percentage is based on number of patients by Dose Level 
 
 
Table 10.2.2.4 
Durie-Salmon stage at First Diagnosis by Dose Level 
Durie-Salmon Stage 
Dose level 
I 
(N = XX) 
II 
(N = XX) 
III 
(N = XX) 
Total 
(N = XX) 
N (%) 
N (%) 
N (%) 
N (%) 
I 
II 
 
 
 
 
 
 
 
III 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
Notes: Percentage is based on number of patients by Dose Level 
 
 
Table 10.2.2. 5 
Durie-Salmon Sub-classification at First Diagnosis by Dose Level 
Durie-Salmon  Sub-
classification 
Dose level 
I 
(N = XX) 
II 
(N = XX) 
III 
(N = XX) 
Total 
(N = XX) 
N (%) 
N (%) 
N (%) 
N (%) 
A 
B 
 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
Notes: Percentage is based on number of patients by Dose Level 
 
 
Table 10.2.2.6 
ISS stage at First Diagnosis by Dose Level 
ISS Stage 
Dose level 
I 
(N = XX) 
II 
(N = XX) 
III 
(N = XX) 
Total 
(N = XX) 
N (%) 
N (%) 
N (%) 
N (%) 
I 
II 
 
 
 
 
 
 
 
III 
 
 
 
 
 
 
Not Done 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
Notes: Percentage is based on number of patients by Dose Level 
 
 
 


 
10.2.3 Prior Anticancer Therapy: Palliative Radiotherapy 
Table 10.2.3.1 Previous Treatment Summary by Dose Level 
Previous Palliative 
Radiotherapy 
Dose level 
I 
(N = XX) 
II 
(N = XX) 
III 
(N = XX) 
Total 
(N = XX) 
N (%) 
N (%) 
N (%) 
N (%) 
Yes 
No 
 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
Notes: Percentage is based on number of patients by Dose Level 
 
 
10.2.4 Prior Anticancer Medical Therapy 
Table 10.2.4.1  Autologous and/or allogeneic hematopoietic stem cell transplantation (HSCT) 
by Dose Level 
 
HSCT 
 
Dose level 
I 
(N = XX) 
II 
(N = XX) 
III 
(N = XX) 
Total 
(N = XX) 
N (%) 
N (%) 
N (%) 
N (%) 
Autologous HSCT 
 
 
 
 
 
 
 
Allogenic HSCT 
 
 
 
 
 
 
Both  
Total  
 
 
 
 
 
 
 
Table 10.2.4.2  
Previous Anticancer Therapy by Dose Level 
Therapy Type 
Dose level 
I 
(N = XX) 
II 
(N = XX) 
III 
(N = XX) 
Total 
(N = XX) 
N (%) 
N (%) 
N (%) 
N (%) 
Induction 
 
 
 
 
 
 
 
Consolidation 
 
 
 
 
 
 
Maintenance Therapy  
 
 
 
 
 
Rescue Therapy 
Total  
 
 
 
 
 
 
Notes: Production of this table will need a clinical review to classify all therapies in the aforementioned categories (not recorded 
in the CRF). 
 
 
 
 
 
 
Table 10.2.4.3 
Agents of Previous Chemotherapy (ATC level 1 & 4) by Dose Level 
Medication 
Dose level 
I 
(N = XX) 
II 
(N = XX) 
III 
(N = XX) 
Total 
(N = XX) 
N (%) 
N (%) 
N (%) 
N (%) 
ATC level 1 
 
 
 
 
 
 
 


 
Medication 
Dose level 
I 
(N = XX) 
II 
(N = XX) 
III 
(N = XX) 
Total 
(N = XX) 
N (%) 
N (%) 
N (%) 
N (%) 
ATC level 4 
 
 
 
 
 
 
· · ·  
 
 
 
 
 
 
· · ·  
 
 
 
 
 
 
· · ·  
 
 
 
 
 
 
· · ·  
 
 
 
 
 
 
ATC level 4 
 
 
 
 
 
 
Notes: Percentage is based on number of patients by Dose Level 
 
Table 10.2.4.4 
No of Lines of Prior Chemotherapy by Dose Level 
No of lines 
Dose level 
I 
(N = XX) 
II 
(N = XX) 
III 
(N = XX) 
Total 
(N = XX) 
N (%) 
N (%) 
N (%) 
N (%) 
01 lines 
 
 
 
 
 
 
 
02 lines 
 
 
 
 
 
 
· · ·  
 
 
 
 
 
 
N lines 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
Notes: Percentage is based on number of patients by Dose Level 
 
Table 10.2.4.5 
Summary Statistics. No of Lines of Prior Chemotherapy by Dose Level 
Median and range 
for No of lines 
Dose level 
I 
(N = XX) 
II 
(N = XX) 
III 
(N = XX) 
Total 
(N = XX) 
N 
 
 
 
 
Median 
Mean 
Std 
 
 
 
Min 
 
 
 
Max 
 
 
 
 
Table 10.2.4.6 
No of Agents of Prior Chemotherapy by Dose Level 
No of agents* 
Dose level 
I 
(N = XX) 
II 
(N = XX) 
III 
(N = XX) 
Total 
(N = XX) 
N (%) 
N (%) 
N (%) 
N (%) 
01 agent 
 
 
 
 
 
 
 
02 agents 
 
 
 
 
 
 
· · ·  
 
 
 
 
 
 
· · ·  
 
 
 
 
 
 
· · ·  
 
 
 
 
 
 
· · ·  
 
 
 
 
 
 
N agents 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
Notes: Percentage is based on number of patients by Dose Level. An agent used more than one will count 1once will count as 
1. 
 


 
Table 10.2.4.7 
Summary Statistics. No of Agents of Prior Chemotherapy by Dose Level 
Median and range 
for No of agents 
Dose level 
I 
(N = XX)  
II 
(N = XX) 
III 
(N = XX) 
Total 
(N = XX) 
N 
Mean 
 
 
 
 
Median 
Std 
 
 
 
Min 
 
 
 
Max 
 
 
 
 
Table 10.2.4.8 
Supportive Listing: Previous Anticancer Therapy 
Patient 
 No 
Not  
done Type Literal Start 
 date 
End 
 date 
Best  
response 
PD  
applicable 
PD  
date  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Notes: Production of this table will need a clinical review to classify all therapies in the aforementioned categories (not recorded 
in the CRF). 
 
 
Table 10.2.4.8 Best Response to last Prior Anticancer Medical Therapy 
Best Response 
Dose level 
I 
(N = XX) 
II 
(N = XX) 
III 
(N = XX) 
Total 
(N = XX) 
N (%) 
N (%) 
N (%) 
N (%) 
Response Criteria for 
Multiple Myeloma 
 
 
 
 
 
 
 
 
sCR 
CR 
VGPR 
 
 
 
 
 
 
 
PR 
MR 
 
 
 
 
 
 
 
SD  
 
 
 
 
 
 
 
PD 
NE/NA 
Total 
 
 
 
 
 
 
 
 
 
10.2.5 Physical Examination, Vital Signs, Electrocardiogram and Other Tests 
Table 10.2.5.1 
Physical Examination at baseline by Dose Level 
Physical 
Examination 
Dose level 
I 
(N = XX) 
II 
(N = XX) 
III 
(N = XX) 
Total 
(N = XX) 
N (%) 
N (%) 
N (%) 
N (%) 
Normal  
 
 
 
 
 
 
 
Abnormal 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
Notes: Percentage is based on number of patients by Dose Level 


 
 
Table 10.2.5.2 
Weight at baseline by Dose Level 
Weight (Kg) 
Dose level 
I 
(N = XX) 
II 
(N = XX) 
III 
(N = XX) 
Total 
(N = XX) 
N 
 
 
 
 
Median 
Mean 
Std 
 
 
 
Min 
 
 
 
Max 
 
 
 
 
 
 
 
Table 10.2.5.3 
Height at baseline by Dose Level 
Height (cm) 
Dose level 
I 
(N = XX) 
II 
(N = XX) 
III 
(N = XX) 
Total 
(N = XX) 
N 
 
 
 
 
Median 
Mean 
Std 
 
 
 
Min 
 
 
 
Max 
 
 
 
 
Table 10.2.5.4 
Body Surface Area (BSA) at baseline by Dose Level 
BSA (m2) 
Dose level 
I 
(N = XX) 
II 
(N = XX) 
III 
(N = XX) 
Total 
(N = XX) 
N 
 
 
 
 
 
Median 
Mean 
Std 
 
 
 
 
Min 
 
 
 
 
Max 
 
 
 
 
 
 
 
Table 10.2.5.5 
Supportive Listing: Physical Examination Abnormal 
Patient No 
Date of physical exam 
Weight 
Height 
Body surface area 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 10.2.5.6 
ECOG PS at baseline by Dose Level 
ECOG PS 
Dose level 


 
I 
(N = XX) 
II 
(N = XX) 
III 
(N = XX) 
Total 
(N = XX) 
N (%) 
N (%) 
N (%) 
N (%) 
0 
 
 
 
 
 
 
 
1 
 
 
 
 
 
 
· · ·  
 
 
 
 
 
 
Total 
 
 
 
 
 
 
Notes: Percentage is based on number of patients by Dose Level 
 
 
Table 10.2.5.7 
Supportive Listing: Patients with PS  1 at baseline 
Dose level 
Patient No 
Performance status 
 
 
 
 
 
 
 
 
 
 
 
Table 10.2.5.8  
Electrocardiogram Measures at baseline.  
Dose level 
Patient 
Cycle 
PR interval 
RR interval 
… 
Max height of QRS 
complex 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 10.2.5.9  
Electrocardiogram Results at baseline by Dose Level (After Plitidepsin Administration).  
 
Electrocardiogram Results 
Dose level 
I 
(N = XX) 
II 
(N = XX) 
III 
(N = XX) 
· · ·  
(N = XX) 
· · ·  
(N = XX) 
N 
(N = XX) 
Total 
(N = XX) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
Normal 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Significant Abnormalities 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Non-significant Abnormalities 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 10.2.5.10 Supportive Listing: Electrocardiogram Abnormalities at baseline 
Dose level 
Patient No 
Abnormality Specification 
 
 
 
 
 
 
 
 
 
 
 
Table 10.2.5.11 Left Ventricular Ejection Fraction (LVEF) at baseline 
LVEF 
Dose level 
I 
(N = XX) 
II 
(N = XX) 
III 
(N = XX) 
Total 
(N = XX) 
N (%) 
N (%) 
N (%) 
N (%) 
Normal 
 
 
 
 
 
 
 
Significant Abnormalities 
 
 
 
 
 
 
Non-significant Abnormalities 
 
 
 
 
 
 
Total 
 
 
 
 
 
 


 
Notes: Percentage is based on number of patients by Dose Level 
 
Table 10.2.5.12 Mean, Median, Std and Range values of Left Ventricular Ejection Fraction (LVEF) at 
baseline (MUGA) 
MUGA 
Dose level 
I 
(N = XX) 
II 
(N = XX) 
III 
(N = XX) 
Total 
(N = XX) 
N (%) 
N (%) 
N (%) 
N (%) 
Mean 
Median 
Std 
Minimum 
Maximum 
 
 
 
 
 
 
 
Notes: Percentage is based on number of patients by Dose Level 
 
 
Table 10.2.5.13 Mean, Median, Std and Range values of Left Ventricular Ejection Fraction (LVEF) at 
baseline (ECHO) 
ECHO 
Dose level 
I 
(N = XX) 
II 
(N = XX) 
III 
(N = XX) 
Total 
(N = XX) 
N (%) 
N (%) 
N (%) 
N (%) 
Mean 
Median 
Std 
Minimum 
Maximum 
 
 
 
 
 
 
 
Notes: Percentage is based on number of patients by Dose Level 
 
 
Table 10.2.5.14 Baseline Characteristics: Pregnancy Test by Dose Level 
Pregnancy 
Test 
Dose level 
I 
(N = XX) 
II 
(N = XX) 
III 
(N = XX) 
Total 
(N = XX) 
N (%) 
N (%) 
N (%) 
N (%) 
Positive 
 
 
 
 
 
 
 
Negative 
 
 
 
 
 
 
NA* 
Total 
 
 
 
 
 
 
Notes: Percentage is based on number of patients by Dose Level 
(*) Specify  reasons 
 
 
Table 10.2.5.15 Supportive Listing: Pregnancy Test by Dose Level 
Dose level 
Patient No 
Reason 
 
 
 
 
 
 
 
 
 
 
 


 
10.2.6 Hematological evaluation at baseline 
Table 10.2.6.1 
Hematology Abnormalities at Baseline by Dose Level 
Abnormality 
Dose Level 
I 
(N = XX) 
II 
(N = XX) 
III 
(N = XX) 
Total 
(N = XX) 
Anemia 
 
 
 
 
Grade 1 - 4, N(%) 
 
 
 
Grade 1 
 
 
 
Grade 2 
 
 
 
Grade 3 
 
 
 
Grade 4 
 
 
 
Leukopenia 
 
 
 
 
Grade 1 - 4, N(%) 
 
 
 
Grade 1 
 
 
 
Grade 2 
 
 
 
Grade 3 
 
 
 
Grade 4 
 
 
 
… 
 
 
 
 
Grade 1 - 4, N(%) 
 
 
 
Grade 1 
 
 
 
Grade 2 
 
 
 
Grade 3 
 
 
 
Grade 4 
 
 
 
XXXXXXX 
 
 
 
 
Grade 1 - 4, N(%) 
 
 
 
Grade 1 
 
 
 
Grade 2 
 
 
 
Grade 3 
 
 
 
Grade 4 
 
 
 
Notes: Percentage is based on number of patients by Dose Level 
 
 
 
Table 10.2.6.2 
Summary for Hematology Parameters at Baseline by Dose Level. 
 Mean, Median, Std 
and  Range by 
abnormality 
Dose Level 
I 
(N = XX) 
II 
(N = XX) 
III 
(N = XX) 
Total 
(N = XX) 
Hemoglobin 
 
 
 
 
N 
Mean 
 
 
 
Median 
Std 
 
 
 
Min 
 
 
 
Max 
 
 
 
WBC 
 
 
 
 
N 
Mean 
 
 
 
Median 
Std 
 
 
 
Min 
 
 
 
Max 
 
 
 
 
 
 
 


 
 Mean, Median, Std 
and  Range by 
abnormality 
Dose Level 
I 
(N = XX) 
II 
(N = XX) 
III 
(N = XX) 
Total 
(N = XX) 
Lymphocytes 
 
 
 
 
N 
Mean 
 
 
 
Median 
Std 
 
 
 
Min 
 
 
 
Max 
 
 
 
… 
 
 
 
 
N 
Mean 
 
 
 
Median 
Std 
 
 
 
Min 
 
 
 
Max 
 
 
 
 
 
 
 
XXXXXXX 
 
 
 
 
N 
Mean 
 
 
 
Median 
Std 
 
 
 
Min 
 
 
 
Max 
 
 
 
Notes: Percentage is based on number of patients by Dose Level 
 
 
 
 
 
 
 
 
 
Table 10.2.6.3 
Supportive Listing: Patients with grade >=2 Hematology Abnormalities at Baseline 
Dose 
level 
(mg /m²) 
Patient 
Lab. test 
Examination date 
N 
Std. 
value 
xLLN 
Grade 
CTC 
v4.0 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
10.2.7 Biochemical evaluation at baseline 
Table 10.2.7.1 
Biochemical Abnormalities at Baseline by Dose Level 
Abnormality 
Dose Level 
I 
(N = XX) 
II 
(N = XX) 
III 
(N = XX) 
Total 
(N = XX) 
ALT increase 
 
 
 
 
Grade 1 - 4, N(%) 
 
 
 


 
Abnormality 
Dose Level 
I 
(N = XX) 
II 
(N = XX) 
III 
(N = XX) 
Total 
(N = XX) 
Grade 1 
 
 
 
Grade 2 
 
 
 
Grade 3 
 
 
 
Grade 4 
 
 
 
AST increase 
 
 
 
 
Grade 1 - 4, N(%) 
 
 
 
Grade 1 
 
 
 
Grade 2 
 
 
 
Grade 3 
 
 
 
Grade 4 
 
 
 
… 
 
 
 
 
Grade 1 - 4, N(%) 
 
 
 
Grade 1 
 
 
 
Grade 2 
 
 
 
Grade 3 
 
 
 
Grade 4 
 
 
 
XXXXXXX 
 
 
 
 
Grade 1 - 4, N(%) 
 
 
 
Grade 1 
 
 
 
Grade 2 
 
 
 
Grade 3 
 
 
 
Grade 4 
 
 
 
Notes: Percentage is based on number of patients by Dose Level 
 
 
 
 
 
 
 
Table 10.2.7.2 
Biochemical Abnormalities at Baseline by Dose Level for patients with creatinine 
<2mg/dl 
Abnormality 
Dose Level 
I 
(N = XX) 
II 
(N = XX) 
III 
(N = XX) 
Total 
(N = XX) 
ALT increase 
 
 
 
 
Grade 1 - 4, N(%) 
 
 
 
Grade 1 
 
 
 
Grade 2 
 
 
 
Grade 3 
 
 
 
Grade 4 
 
 
 
AST increase 
 
 
 
 
Grade 1 - 4, N(%) 
 
 
 
Grade 1 
 
 
 
Grade 2 
 
 
 
Grade 3 
 
 
 
Grade 4 
 
 
 
… 
 
 
 
 
Grade 1 - 4, N(%) 
 
 
 
Grade 1 
 
 
 
Grade 2 
 
 
 


 
Abnormality 
Dose Level 
I 
(N = XX) 
II 
(N = XX) 
III 
(N = XX) 
Total 
(N = XX) 
Grade 3 
 
 
 
Grade 4 
 
 
 
XXXXXXX 
 
 
 
 
Grade 1 - 4, N(%) 
 
 
 
Grade 1 
 
 
 
Grade 2 
 
 
 
Grade 3 
 
 
 
Grade 4 
 
 
 
Notes: Percentage is based on number of patients by Dose Level 
 
 
 
Table 10.2.7.3 
Biochemical Abnormalities at Baseline by Dose Level for patients with creatinine 
≥2mg/dl 
Abnormality 
Dose Level 
I 
(N = XX) 
II 
(N = XX) 
III 
(N = XX) 
Total 
(N = XX) 
ALT increase 
 
 
 
 
Grade 1 - 4, N(%) 
 
 
 
Grade 1 
 
 
 
Grade 2 
 
 
 
Grade 3 
 
 
 
Grade 4 
 
 
 
AST increase 
 
 
 
 
Grade 1 - 4, N(%) 
 
 
 
Grade 1 
 
 
 
Grade 2 
 
 
 
Grade 3 
 
 
 
Grade 4 
 
 
 
… 
 
 
 
 
Grade 1 - 4, N(%) 
 
 
 
Grade 1 
 
 
 
Grade 2 
 
 
 
Grade 3 
 
 
 
Grade 4 
 
 
 
XXXXXXX 
 
 
 
 
Grade 1 - 4, N(%) 
 
 
 
Grade 1 
 
 
 
Grade 2 
 
 
 
Grade 3 
 
 
 
Grade 4 
 
 
 
Notes: Percentage is based on number of patients by Dose Level 
 
 
 
 
 
 
Table 10.2.7.4 
Summary for Biochemical Parameters at Baseline by Dose Level 
Median and Range 
Dose Level 


 
by abnormality 
I 
(N = XX) 
II 
(N = XX) 
III 
(N = XX) 
Total 
(N = XX) 
ALT  
 
 
 
 
N 
Mean 
 
 
 
Median 
Std 
 
 
 
Min 
 
 
 
Max 
 
 
 
AST  
 
 
 
 
N 
Mean 
 
 
 
Median 
Std 
 
 
 
Min 
 
 
 
Max 
 
 
 
… 
 
 
 
 
N 
Mean 
 
 
 
Median 
Std 
 
 
 
Min 
 
 
 
Max 
 
 
 
XXXXXXX 
 
 
 
 
N 
Mean 
 
 
 
Median 
Std 
 
 
 
Min 
 
 
 
Max 
 
 
 
 
Table 10.2.7.5 
Supportive Listing: Patients with grade >=2 Biochemistry Abnormalities at Baseline 
Dose 
level 
(mg /m²) 
Patient 
Lab. test 
Examination 
date 
N 
Std. 
value 
xULN 
Grade 
CTC 
v4.0 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
10.2.8 Signs and Symptoms at Baseline 
11 Table 10.2.8.1 
Incidence of Signs and Symptoms by Dose Level Worst Per Patient 
MedDRA System 
Organ Class 
Preferred Term 
 
 
I 
(N = XX) 
 
II 
(N = XX) 
… 
 
Total 
(N = XX) 
 
Grade 
 
Grade 
 
Grade 
1-4 
1 
2 
3 
4 
1-4 
1 
2 
3 
4 
1-4 
1 
2 
3 
4 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12 Notes: Percentage is based on number of patients by Dose Level 
 
Table 10.2.8.2 
Listing of Signs and Symptoms 
Dose 
Level 
Patient 
No 
Not 
done 
N 
Literal 
MedDRA 
Preferred Term 
CTC 
v4.0 
grade 
Start date 
Disease 
Related 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
Table 10.2.8.3 
Summary of Signs and Symptoms by Dose Level 
  
  
I 
(N = XX) 
II 
(N = XX) 
III 
(N = XX) 
Total 
(N = XX) 
No. signs 
1 
 
 
 
 
 
2 
 
 
 
 
· · ·  
 
 
 
 
· · ·  
 
 
 
 
· · ·  
 
 
 
 
N 
 
 
 
 
Total 
 
 
 
 
No. signs 
 
 
 
 
  
N 
Mean 
Median 
Std 
 
 
 
  
Range 
 
 
 
Notes: Percentage is based on number of patients by Dose Level 
 
 
 
 
 
 
 
 
 


 
10.3 Concomitant Medication Starting Pre-Study 
Table 10.3.1  
Concomitant Medication Starting Pre-Study (ATC Level 1, 2 and 4) by Dose Level 
Medication Term 
(ATC level 1) 
 
Medication Term 
(ATC level 4) 
Dose level 
Medication Term 
(ATC level 2) 
I 
(N = XX) 
II 
(N = XX) 
III 
(N = XX) 
Total 
(N = XX) 
 
N (%) 
N (%) 
N (%) 
N (%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Notes: Percentage is based on number of patients by Dose Level 
 
Table 10.3.2  
Concomitant Medication Starting Pre-Study (Patients with transfusions and ATC Level 1, 2 and 4) by Dose Level 
Medication Term 
(ATC level 1) 
 
Medication Term 
(ATC level 4) 
Dose level 
Medication Term 
(ATC level 2) 
I 
(N = XX) 
II 
(N = XX) 
III 
(N = XX) 
Total 
(N = XX) 
 
N (%) 
N (%) 
N (%) 
N (%) 
Platelet transfusion 
 
 
 
 
 
 
 
 
 
RBC transfusion 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
Notes: Percentage is based on number of patients by Dose Level 
 
Table 10.3.3  
Supportive Listing: Patients with transfusions (Pre-Study) 
Patient 
No 
Not 
done 
Type 
Literal 
Route 
Specify of 
route 
Dose 
Unit 
Start 
date 
(text) 
Start date 
ongoing 
End 
date 
(text) 
End date 
ongoing 
Reason 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 


 
11 
Appendix II. Safety Evaluation 
This analysis will be presented on the evaluable for safety population. 
11.1 Extent of Exposure 
11.1.1 Cumulative Dose, Dose Intensity and Relative Dose Intensity 
Table 11.1.1.1 
No of cycles administered 
  
Patients 
Dose 
level 
Max cycle infused 
No of patients  
I  
Cycle 1 
 
 
  
Cycle 2 
 
 
II 
Cycle 1 
 
 
  
Cycle 2 
 
 
III 
Cycle 1 
 
 
  
Cycle 2 
 
 
· · ·  
Cycle 1 
 
 
  
Cycle 2 
 
 
N 
Cycle 1 
 
 
  
Cycle 2 
 
 
Total  
Cycle 1 
 
 
  
Cycle 2 
 
 
  
Cycle 3 
 
 
  
· · ·  
 
 
  
Cycle N 
 
 
 
 
 
Table 11.1.1.2 
Supportive Listing: No of Patients by Dose Level 
Dose level Patient Id 
Evaluable for safety (Y/N) 
Evaluable for DLT (Y/N) 
I 
 
 
 
II 
 
 
 
III 
 
 
 
· · ·  
 
 
 
· · ·  
 
 
 
N 
 
 
 
 
Table 11.1.1.3 
Number of Cycles Administered by Dose Level 
No cycles 
administered per 
patient 
Dose level 
I 
(N = XX) 
II 
(N = XX) 
III 
(N = XX) 
Total 
(N = XX) 
N (%) 
N (%) 
N (%) 
N (%) 
1 Cycle 
 
 
 
 
 
 
 
2 Cycles 
 
 
 
 
 
 
3 Cycles 
 
 
 
 
 
 
· · ·  
 
 
 
 
 
 
· · ·  
 
 
 
 
 
 
N Cycles 
 
 
 
 
 
 


 
Notes: Percentage is based on number of patients by Dose Level 
Table 11.1.1.4  
Mean, Median, Std and Range of Cycles Administered by Dose Level 
Mean, Median , Std 
and  range of cycles 
administered 
Dose level 
I 
(N = XX) 
II 
(N = XX) 
III 
(N = XX) 
Total 
(N = XX) 
N 
Mean 
 
 
 
 
Median 
Std 
 
 
 
Min 
 
 
 
Max 
 
 
 
 
 
Table 11.1.1.5  
Plitidepsin Cumulative Dose by Dose Level 
Plitidepsin 
Cumulative dose 
(mg/m²) 
Dose level 
I 
(N = XX) 
II 
(N = XX) 
III 
(N = XX) 
Total 
(N = XX) 
N 
Mean 
 
 
 
 
Median 
Std 
 
 
 
Min 
 
 
 
Max 
 
 
 
 
Table 11.1.1.6  
Bortezomib Cumulative Dose by Dose Level 
Bortezomib 
Cumulative dose 
(mg/m²) 
Dose level 
I 
(N = XX) 
II 
(N = XX) 
III 
(N = XX) 
Total 
(N = XX) 
N 
Mean 
 
 
 
 
Median 
Std 
 
 
 
Min 
 
 
 
Max 
 
 
 
 
Table 11.1.1.7  
Dexamethasone Cumulative Dose by Dose Level 
Dexamethasone 
Cumulative dose 
(mg) 
Dose level 
I 
(N = XX) 
II 
(N = XX) 
III 
(N = XX) 
Total 
(N = XX) 
N 
Mean 
 
 
 
 
Median 
Std 
 
 
 
Min 
 
 
 
Max 
 
 
 
 
 
 


 
Table 11.1.1.8  
Plitidepsin Intended Dose by Dose Level 
Plitidepsin 
Intended dose 
(mg/m²/week) 
Dose level 
I 
(N = XX) 
II 
(N = XX) 
III 
(N = XX) 
Total 
(N = XX) 
N 
Mean 
 
 
 
 
Median 
Std 
 
 
 
Min 
 
 
 
Max 
 
 
 
 
Table 11.1.1.9  
Bortezomib Intended Dose by Dose Level 
Bortezomib 
Intended dose 
(mg/m²/week) 
Dose level 
I 
(N = XX) 
II 
(N = XX) 
III 
(N = XX) 
Total 
(N = XX) 
N 
Mean 
 
 
 
 
Median 
Std 
 
 
 
Min 
 
 
 
Max 
 
 
 
 
Table 11.1.1.10  Dexamethasone Intended Dose by Dose Level 
Dexamethasone 
Intended dose 
(mg/week) 
Dose level 
I 
(N = XX) 
II 
(N = XX) 
III 
(N = XX) 
Total 
(N = XX) 
N 
Mean 
 
 
 
 
Median 
Std 
 
 
 
Min 
 
 
 
Max 
 
 
 
 
 
 
 
 
 
 
 
Table 11.1.1.11  Plitidepsin Relative Dose Intensity by Dose Level 
Plitidepsin 
Absolute Dose 
Intensity 
(mg/m²/week) 
Dose level 
I 
(N = XX) 
II 
(N = XX) 
III 
(N = XX) 
Total 
(N = XX) 
N 
Mean 
 
 
 
 
Median 
Std 
 
 
 
Min 
 
 
 


 
Plitidepsin 
Absolute Dose 
Intensity 
(mg/m²/week) 
Dose level 
I 
(N = XX) 
II 
(N = XX) 
III 
(N = XX) 
Total 
(N = XX) 
Max 
 
 
 
 
 
 
Table 11.1.1.12  Bortezomib Relative Dose Intensity by Dose Level 
Bortezomib 
Absolute Dose 
Intensity 
(mg/m²/week) 
Dose level 
I 
(N = XX) 
II 
(N = XX) 
III 
(N = XX) 
Total 
(N = XX) 
N 
Mean 
 
 
 
 
Median 
Std 
 
 
 
Min 
 
 
 
Max 
 
 
 
 
Table 11.1.1.13  Dexamethasone Relative Dose Intensity Dose Level 
Dexamethasone 
Absolute Dose 
Intensity 
(mg/week) 
Dose level 
I 
(N = XX) 
II 
(N = XX) 
III 
(N = XX) 
Total 
(N = XX) 
N 
Mean 
 
 
 
 
Median 
Std 
 
 
 
Min 
 
 
 
Max 
 
 
 
 
 
Table 11.1.1.14  Supportive Listing: Drug Administration: Patients with Less Than 60% of Dose 
Intensity 
Dose level 
Patient No 
 
Agent Cycle 
Date 
Intended dose  
(mg /m²) 
Total 
dose  
(mg /m²) 
Delay 
Delay 
specify 
Dose 
modification 
Dose  
modification 
specify 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
11.1.2 Cycle Delays 
Table 11.1.2.1  
No of Patients with Dosing Delayed by Dose Level 
No. of patients 
Dose level 


 
with dosing 
delayed 
I 
(N = XX) 
II 
(N = XX) 
III 
(N = XX) 
Total 
(N = XX) 
N (%) 
N (%) 
N (%) 
N (%) 
No  
 
 
 
 
 
 
 
Yes 
 
 
 
 
 
 
    Any DR* 
 
 
 
 
 
 
    All NDR** 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
* Drug related ** Non drug related. 
 
Table 11.1.2.2  
No of Cycles with Dosing Delayed by Dose Level 
No of cycles with 
dosing delayed 
Dose level 
I 
(N=XX) 
II 
(N = XX) 
III 
(N = XX) 
Total 
(N = XX) 
N (%) 
N (%) 
N (%) 
N (%) 
No  
 
 
 
 
 
 
 
Yes 
 
 
 
 
 
 
Drug Related 
 
 
 
 
 
 
 
Hematological 
 
 
 
 
 
 
Non 
Hematological 
 
 
 
 
 
 
Both 
 
 
 
 
 
 
Non Drug 
Related 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
Table 11.1.2.3  
No of Cycles Delayed Per Patient by Dose Level 
No patients with : 
Dose level 
I 
(N = XX) 
II 
(N = XX) 
III 
(N = XX) 
Total 
(N = XX) 
N (%) 
N (%) 
N (%) 
N (%) 
No cycle delayed 
 
 
 
 
 
 
 
01 cycle delayed 
 
 
 
 
 
 
02 cycles delayed 
 
 
 
 
 
 
· · ·  
 
 
 
 
 
 
· · ·  
 
 
 
 
 
 
Total 
Mean 
 
 
 
 
 
 
 
Median 
Std 
 
 
 
 
 
 
Min 
 
 
 
 
 
 
Max 
 
 
 
 
 
 
 
 
Table 11.1.2.4  
Number of Cycles with Drug Related Delay per patient by Dose Level 
No patients  with : 
Dose level 
I 
(N = XX) 
II 
(N = XX) 
III 
(N = XX) 
Total 
(N = XX) 
N (%) 
N (%) 
N (%) 
N (%) 
No cycle delayed 
 
 
 
 
 
 
 


 
No patients  with : 
Dose level 
I 
(N = XX) 
II 
(N = XX) 
III 
(N = XX) 
Total 
(N = XX) 
N (%) 
N (%) 
N (%) 
N (%) 
01 cycle delayed 
 
 
 
 
 
 
02 cycles delayed 
 
 
 
 
 
 
· · ·  
 
 
 
 
 
 
· · ·  
 
 
 
 
 
 
Total 
Mean 
 
 
 
 
 
 
 
Median 
Std 
 
 
 
 
 
 
Min 
 
 
 
 
 
 
Max 
 
 
 
 
 
 
 
Table 11.1.2.5  
Length of Delay by Dose Level 
Length of delay 
Dose level 
I 
(N = XX) 
II 
(N = XX) 
III 
(N = XX) 
Total 
(N = XX) 
N 
Mean 
 
 
 
 
Median 
Std 
 
 
 
Min 
 
 
 
Max 
 
 
 
 
Table 11.1.2.6  
Length of Delay for Drug Related Events by Dose Level 
Length  of  delay 
Dose level 
I 
(N = XX) 
II 
(N = XX) 
III 
(N = XX) 
Total 
(N = XX) 
Hematological 
 
 
 
 
N 
 
 
 
Median 
 
 
 
Min 
 
 
 
Max 
 
 
 
Non Hematological  
 
 
 
N 
 
 
 
Median 
 
 
 
Min 
 
 
 
Max 
 
 
 
Both 
 
 
 
 
N 
 
 
 
Median 
 
 
 
Min 
 
 
 
Max 
 
 
 
Total 
 
 
 
 
N 
 
 
 
Median 
 
 
 
Min 
 
 
 


 
Length  of  delay 
Dose level 
I 
(N = XX) 
II 
(N = XX) 
III 
(N = XX) 
Total 
(N = XX) 
Max 
 
 
 
 
Table 11.1.2.7  
Supportive Listing: Drug Administration: Dose Delays 
Dose 
level 
Patient 
No 
 
Agent 
Cycle 
Date 
Intended 
dose  
(mg /m²) 
Total 
dose  
(mg 
/m²) 
Length 
of 
Delay 
Delay 
Reason Delay specify 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
11.1.3 Dose Modification 
Table 11.1.3.1  
No of Patients with Dosing Modifications by Dose Level 
No of patients with 
dosing reduced 
Dose level 
I 
(N = XX) 
II 
(N = XX) 
III 
(N = XX) 
Total 
(N = XX) 
N (%) 
N (%) 
N (%) 
N (%) 
No  
 
 
 
 
 
 
 
Yes 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
Table 11.1.3.2  
No of Patients with Cycles Reduced by Dose Level 
No of patients 
with cycles 
reduced 
Dose level 
I 
(N = XX) 
II 
(N = XX) 
III 
(N = XX) 
Total 
(N = XX) 
N (%) 
N (%) 
N (%) 
N (%) 
No reduction 
 
 
 
 
 
 
 
1 cycle 
 
 
 
 
 
 
2 cycles 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 11.1.3.3  
Reasons for Dose Reduction by Dose Level 
No of patients with 
Dose level 


 
cycles reduced 
I 
(N = XX) 
II 
(N = XX) 
III 
(N = XX) 
Total 
(N = XX) 
N (%) 
N (%) 
N (%) 
N (%) 
No dose reduction 
 
 
 
 
 
 
 
Hematological 
 
 
 
 
 
 
Non-hematological 
 
 
 
 
 
 
Both 
Non-drug related 
Other 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
Table 11.1.3.4  
Listing of Dose Reductions 
Dose level 
Patient No 
Cycle 
DA Start 
Date 
DA Is infusion 
reduced? 
DA Reduce 
reason 
Specify 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
11.2 Dose Limiting Toxicities 
This analysis will be carried out on the evaluable for RD population. 
11.2.1 Dose Limiting Toxicities 
Table 11.2.1.1  
Summary of Patients with DLT by Dose Level 
Dose level (mg /m²) 
Escalation factor 
N 
DLT 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: Each row shows the number of patients N of that Dose Level, the number of cases with defined DLT. 
 
Table 11.2.1.2  
Details of DLT 
Dose level (mg /m²) 
Patient Id 
DLT Description 
Comments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
11.3 Adverse Events (AEs) 
This analysis will be carried out on the evaluable for safety population. 
11.3.1 Display of Adverse Events 
Table 11.3.1.1  
Drug-Related Adverse Events. Worst Grade by Patient and Dose Level 
 
 
 
 
 
Dose level 
 
I 
(N = XX) 
… 
(N=XX) 
 
III 
(N = XX) 
 
Total 
(N = XX) 
 
 
 
 
Grade 
1-4 
1 
2 
3 
4 
… 
1-4 
1 
2 
3 
4 
1-4 
1 
2 
3 
4 
MedDRA System Organ Class 
Preferred Term 
N 
(%) 
N 
(%) 
N 
(%) 
N 
(%) 
N 
(%) 
… 
N 
(%) 
N 
(%) 
N 
(%) 
N 
(%) 
N 
(%) 
N 
(%) 
N 
(%) 
N 
(%) 
N 
(%) 
N  
(%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Unknown  terms  included 
Table 11.3.1.2  
Drug-Related Adverse Events in the First Cycle by Patient and Dose Level 
 
 
 
 
Dose level 
 
I 
(N = XX) 
II 
(N = XX) 
 
III 
(N = XX) 
 
Total 
(N = XX) 
 
 
 
Grade 
1-4 
1 
2 
3 
4 
   … 
1-4 
1 
2 
3 
4 
1-4 
1 
2 
3 
4 
MedDRA System 
Organ Class 
Preferred Term 
 
N(%) 
N (%) 
N (%) 
N (%) 
N (%) 
… 
 
N(%) 
N (%) 
N (%) 
N (%) 
N (%) 
 
N(%) 
N (%) 
N (%) 
N (%) 
N (%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Unknown  terms  included 


 
Table 11.3.1.3  
Drug-Related Adverse Events. Worst Grade Per Cycle by Dose Level 
 
 
 
 
Dose level 
 
I 
(N = XX) 
II 
(N = XX) 
 
III 
(N = XX) 
 
Total 
(N = XX) 
 
 
 
Grade 
1-4 
1 
2 
3 
4 
 
1-4 
1 
2 
3 
4 
1-4 
1 
2 
3 
4 
MedDRA System 
Organ Class 
Preferred Term 
 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
… 
 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
 
 
 
 
 
 
 
 
 
 
       …  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Unknown  terms  included 
 
 
 
Table 11.3.1.4  
Adverse Events Regardless of Relationship. Worst Grade by Patient by Dose Level 
 
 
 
 
Dose level 
 
I 
(N = XX) 
II 
(N = XX) 
 
III 
(N = XX) 
 
Total 
(N = XX) 
 
 
 
Grade 
1-4 
1 
2 
3 
4 
… 
1-4 
1 
2 
3 
4 
1-4 
1 
2 
3 
4 
MedDRA System Organ Class 
Preferred Term 
 
N (%) 
 
N (%) 
N (%) 
N (%) 
N (%) 
… 
 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Notes: Percentage is based on number of patients by Dose Level 
 
 
 


 
Table 11.3.1.5  
Adverse Events Regardless of Relationship in the First Cycle by Patient and Dose Level 
 
 
 
 
Dose level 
 
I 
(N = XX) 
II 
(N = XX) 
 
III 
(N = XX) 
 
Total 
(N = XX) 
 
 
 
Grade 
1-4 
1 
2 
3 
4 
… 
1-4 
1 
2 
3 
4 
1-4 
1 
2 
3 
4 
MedDRA System Organ Class 
Preferred Term 
 
N (%) 
 
N (%) 
N (%) 
N (%) 
N (%) 
… 
 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Notes: Percentage is based on number of patients by Dose Level 
Table 11.3.1.6  
Adverse Events Regardless of Relationship. Worst Grade per Cycle by Dose Level 
 
 
 
 
Dose level 
 
I 
(N = XX) 
II 
(N = XX) 
 
III 
(N = XX) 
 
Total 
(N = XX) 
 
 
 
Grade 
1-4 
1 
2 
3 
4 
… 
1-4 
1 
2 
3 
4 
1-4 
1 
2 
3 
4 
MedDRA System Organ Class 
Preferred Term 
 
N (%) 
 
N (%) 
N (%) 
N (%) 
N (%) 
… 
 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Notes: Percentage is based  on  number of patients by Dose Level 
 
 
 
 


 
Table 11.3.1.7  
Adverse Events Observed in ≥10% of Patients regardless of relationship. Worst Grade per Patient by Dose Level 
 
 
 
 
Dose level 
 
I 
(N = XX) 
II 
(N = XX) 
 
III 
(N = XX) 
 
Total 
(N = XX) 
 
 
 
Grade 
1-4 
1 
2 
3 
4 
… 
1-4 
1 
2 
3 
4 
1-4 
1 
2 
3 
4 
MedDRA System Organ Class 
Preferred Term 
 
N (%) 
 
N (%) 
N (%) 
N (%) 
N (%) 
… 
 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Notes: Percentage is based on number of patients by Dose Level 
 
 
 
Table 11.3.1.8  
Adverse Events Observed in ≥10% of Patients regardless of relationship. Worst Grade per Cycle by Dose Level 
 
 
 
 
Dose level 
 
I 
(N = XX) 
II 
(N = XX) 
 
III 
(N = XX) 
 
Total 
(N = XX) 
 
 
 
Grade 
1-4 
1 
2 
3 
4 
… 
1-4 
1 
2 
3 
4 
1-4 
1 
2 
3 
4 
MedDRA System Organ Class 
Preferred Term 
 
N (%) 
 
N (%) 
N (%) 
N (%) 
N (%) 
… 
 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Notes: Percentage is based on number of patients by Dose Level 
 
 


 
Table 11.3.1.9 
Supportive Listing: Patients with grade >=2 AEs at Baseline 
Dose 
level 
(mg /m²) 
Patient 
Lab. test 
Examination 
date 
N 
Std. 
value 
xULN 
Grade 
CTC 
v4.0 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
11.4 Deaths and Other Serious Adverse Events 
11.4.1 Deaths 
Table 11.4.1.1  
Patients who Died While on Treatment 
Dose 
level 
Patient No 
Last cycle received 
Last infusion date 
Death date 
Time from last 
infusion date (days) 
Cause 
Comments 
Time on study (weeks) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: Patient with Death reported as End of Study Reason. 
 
Table 11.4.1.2  
Patients Who Died Within 30 Days of Last Drug Administration 
Dose 
level 
Patient No 
Last cycle received 
Last infusion date 
Death date 
Time from last 
infusion date (days) 
Cause 
Comments 
Time on study (weeks) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
Table 11.4.1.3  
Listing of All Deaths 
Dose 
level 
Patient 
No 
Last cycle 
received 
Last infusion 
date 
Death date 
Cause 
Comments 
Autopsy 
Time on study 
(weeks) 
Time from last infusion 
date (days) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 11.4.1.4  
Summary of All Deaths by Dose Level 
Deaths 
Dose level 
I 
(N = XX) 
II 
(N = XX) 
III 
(N = XX) 
Total 
(N = XX) 
N (%) 
N (%) 
N (%) 
N (%) 
Deaths 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
11.4.2 Serious Adverse Events 
Table 11.4.2.1  
All SAEs 
Dose 
(mg 
/m²) 
Patient 
MedDRA System 
Organ Class 
Preferred Term 
Grade 
AE Status 
AE relationship 
AE consequences 
SAE 
Onset date 
Resolved date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 11.4.2.2  
Drug-Related SAEs. Worst Grade by Patient and Dose Level 
 
Dose level 


 
I 
(N = XX) 
· · ·  
(N = XX) 
N 
(N = XX) 
Total 
(N = XX) 
Grade 
1 
2 
3 
4 
1 
2 
3 
4 
1 
2 
3 
4 
1 
2 
3 
4 
MedDRA System Organ Class 
Preferred Term 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N  
(%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Unknown  terms  included 
 
 
 
 
 
 
 
Table 11.4.2.3  
Drug-Related SAEs in the First Cycle by Patient and Dose Level 
 
Dose level 
I 
(N = XX) 
· · ·  
(N = XX) 
N 
(N = XX) 
Total 
(N = XX) 
Grade 
1 
2 
3 
4 
1 
2 
3 
4 
1 
2 
3 
4 
1 
2 
3 
4 
MedDRA System 
Organ Class 
Preferred Term 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Unknown  terms  included 
 
 


 
Table 11.4.2.4  
Drug-Related SAEs. Worst Grade Per Cycle by Dose Level 
 
Dose level 
I 
(N = XX) 
II 
(N = XX) 
III 
(N = XX) 
Total 
(N = XX) 
Grade 
1 
2 
3 
4 
1 
2 
3 
4 
1 
2 
3 
4 
1 
2 
3 
4 
MedDRA System 
Organ Class 
Preferred Term 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Unknown  terms  included 
 
 
 
 
Table 11.4.2.5  
SAEs Regardless of Relationship. Worst Grade by Patient by Dose Level 
 
Dose level 
I 
(N = XX) 
II 
(N = XX) 
III 
(N = XX) 
Total 
(N = XX) 
Grade 
1 
2 
3 
4 
1 
2 
3 
4 
1 
2 
3 
4 
1 
2 
3 
4 
MedDRA System Organ Class 
Preferred Term 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N  
(%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Notes: Percentage is based on number of patients by Dose Level 
 
Table 11.4.2.6  
SAEs Regardless of Relationship in the First Cycle by Patient and Dose Level 
 
Dose level 


 
I 
(N = XX) 
II 
(N = XX) 
III 
(N = XX) 
Total 
(N = XX) 
Grade 
1 
2 
3 
4 
1 
2 
3 
4 
1 
2 
3 
4 
1 
2 
3 
4 
MedDRA System Organ Class 
Preferred Term 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N 
 (%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Notes: Percentage is based on number of patients by Dose Level 
 
 
 
 
 
 
 
Table 11.4.2.7  
SAEs Regardless of Relationship. Worst Grade per Cycle by Dose Level 
 
Dose level 
I 
(N = XX) 
II 
(N = XX) 
III 
(N = XX) 
Total 
(N = XX) 
Grade 
1 
2 
3 
4 
1 
2 
3 
4 
1 
2 
3 
4 
1 
2 
3 
4 
MedDRA System Organ Class 
Preferred Term 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N  
(%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Notes: Percentage is based  on  number of patients by Dose Level 
 
Table 11.4.2.8  
SAEs Observed in ≥10% of Patients regardless of relationship. Worst Grade per Patient by Dose Level 
 
Dose level 


 
I 
(N = XX) 
II 
(N = XX) 
III 
(N = XX) 
Total 
(N = XX) 
Grade 
1 
2 
3 
4 
1 
2 
3 
4 
1 
2 
3 
4 
1 
2 
3 
4 
MedDRA System Organ Class 
Preferred Term 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N  
(%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Notes: Percentage is based on number of patients by Dose Level 
 
 
 
 
 
 
 
Table 11.4.2.9  
SAEs Observed in ≥10% of Patients regardless of relationship. Worst Grade per Cycle by Dose Level 
 
Dose level 
I 
(N = XX) 
II 
(N = XX) 
III 
(N = XX) 
Total 
(N = XX) 
Grade 
1 
2 
3 
4 
1 
2 
3 
4 
1 
2 
3 
4 
1 
2 
3 
4 
MedDRA System Organ Class 
Preferred Term 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N  
(%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Notes: Percentage is based on number of patients by Dose Level 
 
 


 
 
 
 
 
 
 
 
 


 
11.5 Clinical Laboratory Evaluation 
11.5.1 Hematological Abnormalities 
Table 11.5.1.1  
Hematological Abnormalities: Worst Grade Per Patient by Dose Level in Cycle 1 
Toxicity 
I 
(N = XX) 
II 
(N = XX) 
III 
(N = XX) 
Total 
(N = XX) 
Anemia 
 
 
 
 
Grade 1 - 4, N (%) 
 
 
 
Grade 1 
 
 
 
Grade 2 
 
 
 
Grade 3 
 
 
 
Grade 4 
 
 
 
Leukopenia 
 
 
 
 
Grade 1 - 4, N (%) 
 
 
 
Grade 1 
 
 
 
Grade 2 
 
 
 
Grade 3 
 
 
 
Grade 4 
 
 
 
Lymphopenia 
 
 
 
 
Grade 1 - 4, N (%) 
 
 
 
Grade 1 
 
 
 
Grade 2 
 
 
 
Grade 3 
 
 
 
Grade 4 
 
 
 
Neutropenia 
 
 
 
 
Grade 1 - 4, N (%) 
 
 
 
Grade 1 
 
 
 
Grade 2 
 
 
 
Grade 3 
 
 
 
Grade 4 
 
 
 
XXXXXXX 
 
 
 
 
Grade 1 - 4, N (%) 
 
 
 


 
Toxicity 
I 
(N = XX) 
II 
(N = XX) 
III 
(N = XX) 
Total 
(N = XX) 
Grade 1 
 
 
 
Grade 2 
 
 
 
Grade 3 
 
 
 
Grade 4 
 
 
 
Notes: Percentage is based on number of patients by Dose Level 
 
Table 11.5.1.2  
Hematological Abnormalities: Worst Grade Per Cycle by Dose Level in Cycle 1 
Toxicity 
I 
(N = XX) 
II 
(N = XX) 
III 
(N = XX) 
Total 
(N = XX) 
Anemia 
 
 
 
 
Grade 1 - 4, N (%) 
 
 
 
Grade 1 
 
 
 
Grade 2 
 
 
 
Grade 3 
 
 
 
Grade 4 
 
 
 
Leukopenia 
 
 
 
 
Grade 1 - 4, N (%) 
 
 
 
Grade 1 
 
 
 
Grade 2 
 
 
 
Grade 3 
 
 
 
Grade 4 
 
 
 
Lymphopenia 
 
 
 
 
Grade 1 - 4, N (%) 
 
 
 
Grade 1 
 
 
 
Grade 2 
 
 
 
Grade 3 
 
 
 
Grade 4 
 
 
 
Neutropenia 
 
 
 
 
Grade 1 - 4, N (%) 
 
 
 
Grade 1 
 
 
 
Grade 2 
 
 
 
Grade 3 
 
 
 


 
Toxicity 
I 
(N = XX) 
II 
(N = XX) 
III 
(N = XX) 
Total 
(N = XX) 
Grade 4 
 
 
 
XXXXXXX 
 
 
 
 
Grade 1 - 4, N (%) 
 
 
 
Grade 1 
 
 
 
Grade 2 
 
 
 
Grade 3 
 
 
 
Grade 4 
 
 
 
Notes: Percentage is based on number of patients by Dose Level 
 
 
Table 11.5.1.3  
Hematological Abnormalities: Worst Grade Per Patient by Dose Level 
Toxicity 
I 
(N = XX) 
II 
(N = XX) 
III 
(N = XX) 
Total 
(N = XX) 
Anemia 
 
 
 
 
Grade 1 - 4, N (%) 
 
 
 
Grade 1 
 
 
 
Grade 2 
 
 
 
Grade 3 
 
 
 
Grade 4 
 
 
 
Leukopenia 
 
 
 
 
Grade 1 - 4, N (%) 
 
 
 
Grade 1 
 
 
 
Grade 2 
 
 
 
Grade 3 
 
 
 
Grade 4 
 
 
 
Lymphopenia 
 
 
 
 
Grade 1 - 4, N (%) 
 
 
 
Grade 1 
 
 
 
Grade 2 
 
 
 
Grade 3 
 
 
 
Grade 4 
 
 
 


 
Toxicity 
I 
(N = XX) 
II 
(N = XX) 
III 
(N = XX) 
Total 
(N = XX) 
Neutropenia 
 
 
 
 
Grade 1 - 4, N (%) 
 
 
 
Grade 1 
 
 
 
Grade 2 
 
 
 
Grade 3 
 
 
 
Grade 4 
 
 
 
XXXXXXX 
 
 
 
 
Grade 1 - 4, N (%) 
 
 
 
Grade 1 
 
 
 
Grade 2 
 
 
 
Grade 3 
 
 
 
Grade 4 
 
 
 
Notes: Percentage is based on number of patients by Dose Level 
 
 
 
 
 
 
 
 
 
 
Table 11.5.1.4  
Hematological Abnormalities: Worst Grade Per Cycle by Dose Level 
Toxicity 
I 
(N = XX) 
II 
(N = XX) 
III 
(N = XX) 
Total 
(N = XX) 
Anemia 
 
 
 
 
Grade 1 - 4, N (%) 
 
 
 
Grade 1 
 
 
 
Grade 2 
 
 
 
Grade 3 
 
 
 
Grade 4 
 
 
 


 
Toxicity 
I 
(N = XX) 
II 
(N = XX) 
III 
(N = XX) 
Total 
(N = XX) 
Leukopenia 
 
 
 
 
Grade 1 - 4, N (%) 
 
 
 
Grade 1 
 
 
 
Grade 2 
 
 
 
Grade 3 
 
 
 
Grade 4 
 
 
 
Lymphopenia 
 
 
 
 
Grade 1 - 4, N (%) 
 
 
 
Grade 1 
 
 
 
Grade 2 
 
 
 
Grade 3 
 
 
 
Grade 4 
 
 
 
Neutropenia 
 
 
 
 
Grade 1 - 4, N (%) 
 
 
 
Grade 1 
 
 
 
Grade 2 
 
 
 
Grade 3 
 
 
 
Grade 4 
 
 
 
XXXXXXX 
 
 
 
 
Grade 1 - 4, N (%) 
 
 
 
Grade 1 
 
 
 
Grade 2 
 
 
 
Grade 3 
 
 
 
Grade 4 
 
 
 
Notes: Percentage is based on number of patients by Dose Level 
 
Table 11.5.1.5  
Supportive Listing: Patients with Grade ≥3 Hematological Abnormalities. 
Dose level 
(mg /m²) 
Patient Lab. test 
Cycle 
Examination date 
N 
Std. 
value 
Normal 
Range 
Grade 
CTC 
v4.0 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
Dose level 
(mg /m²) 
Patient Lab. test 
Cycle 
Examination date 
N 
Std. 
value 
Normal 
Range 
Grade 
CTC 
v4.0 
 
 
 
 
 
 
 
 
 
 
 
Table 11.5.1.6 
Supportive Listing: Patients with grade >=2 Hematological Abnormalities at Baseline 
Dose 
level 
(mg /m²) 
Patient 
Lab. test 
Examination 
date 
N 
Std. 
value 
xULN 
Grade 
CTC 
v4.0 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
11.5.2 Biochemical Abnormalities 
Table 11.5.2.1  
Biochemical Abnormalities: Worst Grade Per Patient by Dose Level in Cycle 1 
Toxicity 
I 
(N = XX) 
II 
(N = XX) 
III 
(N = XX) 
Total 
(N = XX) 
AP increase 
 
 
 
 
Grade 1 - 4, N (%) 
 
 
 
 
Grade 1 
 
 
 
 
Grade 2 
 
 
 
 
Grade 3 
 
 
 
 
Grade 4 
 
 
 
 
ALT increase 
 
 
 
 
Grade 1 - 4, N (%) 
 
 
 
 
Grade 1 
 
 
 
 
Grade 2 
 
 
 
 
Grade 3 
 
 
 
 


 
Toxicity 
I 
(N = XX) 
II 
(N = XX) 
III 
(N = XX) 
Total 
(N = XX) 
Grade 4 
 
 
 
 
AST increase 
 
 
 
 
Grade 1 - 4, N (%) 
 
 
 
 
Grade 1 
 
 
 
 
Grade 2 
 
 
 
 
Grade 3 
 
 
 
 
Grade 4 
 
 
 
 
Amylase increased 
 
 
 
 
Grade 1 - 4, N (%) 
 
 
 
 
Grade 1 
 
 
 
 
Grade 2 
 
 
 
 
Grade 3 
 
 
 
 
Grade 4 
 
 
 
 
XXXXXXX 
 
 
 
 
Grade 1 - 4, N (%) 
 
 
 
 
Grade 1 
 
 
 
 
Grade 2 
 
 
 
 
Grade 3 
 
 
 
 
Grade 4 
 
 
 
 
Notes: Percentage is based on number of patients by Dose Level 
 
 
Table 11.5.2.2  
Biochemical Abnormalities: Worst Grade Per Cycle by Dose Level in Cycle 1 
Toxicity 
I 
(N = XX) 
II 
(N = XX) 
III 
(N = XX) 
Total 
(N = XX) 
AP increase 
 
 
 
 
Grade 1 - 4, N (%) 
 
 
 
 
Grade 1 
 
 
 
 
Grade 2 
 
 
 
 
Grade 3 
 
 
 
 
Grade 4 
 
 
 
 


 
Toxicity 
I 
(N = XX) 
II 
(N = XX) 
III 
(N = XX) 
Total 
(N = XX) 
ALT increase 
 
 
 
 
Grade 1 - 4, N (%) 
 
 
 
 
Grade 1 
 
 
 
 
Grade 2 
 
 
 
 
Grade 3 
 
 
 
 
Grade 4 
 
 
 
 
AST increase 
 
 
 
 
Grade 1 - 4, N (%) 
 
 
 
 
Grade 1 
 
 
 
 
Grade 2 
 
 
 
 
Grade 3 
 
 
 
 
Grade 4 
 
 
 
 
Amylase increased 
 
 
 
 
Grade 1 - 4, N (%) 
 
 
 
 
Grade 1 
 
 
 
 
Grade 2 
 
 
 
 
Grade 3 
 
 
 
 
Grade 4 
 
 
 
 
XXXXXXX 
 
 
 
 
Grade 1 - 4, N (%) 
 
 
 
 
Grade 1 
 
 
 
 
Grade 2 
 
 
 
 
Grade 3 
 
 
 
 
Grade 4 
 
 
 
 
Notes: Percentage is based on number of patients by Dose Level 
 
Table 11.5.2.3  
Biochemical Abnormalities: Worst Grade Per Patient by Dose Level 
Toxicity 
I 
(N = XX) 
II 
(N = XX) 
III 
(N = XX) 
Total 
(N = XX) 
AP increase 
 
 
 
 
Grade 1 - 4, N (%) 
 
 
 
 


 
Toxicity 
I 
(N = XX) 
II 
(N = XX) 
III 
(N = XX) 
Total 
(N = XX) 
Grade 1 
 
 
 
 
Grade 2 
 
 
 
 
Grade 3 
 
 
 
 
Grade 4 
 
 
 
 
ALT increase 
 
 
 
 
Grade 1 - 4, N (%) 
 
 
 
 
Grade 1 
 
 
 
 
Grade 2 
 
 
 
 
Grade 3 
 
 
 
 
Grade 4 
 
 
 
 
AST increase 
 
 
 
 
Grade 1 - 4, N (%) 
 
 
 
 
Grade 1 
 
 
 
 
Grade 2 
 
 
 
 
Grade 3 
 
 
 
 
Grade 4 
 
 
 
 
Amylase increased 
 
 
 
 
Grade 1 - 4, N (%) 
 
 
 
 
Grade 1 
 
 
 
 
Grade 2 
 
 
 
 
Grade 3 
 
 
 
 
Grade 4 
 
 
 
 
XXXXXXX 
 
 
 
 
Grade 1 - 4, N (%) 
 
 
 
 
Grade 1 
 
 
 
 
Grade 2 
 
 
 
 
Grade 3 
 
 
 
 
Grade 4 
 
 
 
 
Notes: Percentage is based on number of patients by Dose Level 
 


 
Table 11.5.2.4  
Biochemical Abnormalities: Worst Grade Per Cycle by Dose Level 
Toxicity 
I 
(N = XX) 
II 
(N = XX) 
III 
(N = XX) 
Total 
(N = XX) 
AP increase 
 
 
 
 
Grade 1 - 4, N (%) 
 
 
 
 
Grade 1 
 
 
 
 
Grade 2 
 
 
 
 
Grade 3 
 
 
 
 
Grade 4 
 
 
 
 
ALT increase 
 
 
 
 
Grade 1 - 4, N (%) 
 
 
 
 
Grade 1 
 
 
 
 
Grade 2 
 
 
 
 
Grade 3 
 
 
 
 
Grade 4 
 
 
 
 
AST increase 
 
 
 
 
Grade 1 - 4, N (%) 
 
 
 
 
Grade 1 
 
 
 
 
Grade 2 
 
 
 
 
Grade 3 
 
 
 
 
Grade 4 
 
 
 
 
Amylase increased 
 
 
 
 
Grade 1 - 4, N (%) 
 
 
 
 
Grade 1 
 
 
 
 
Grade 2 
 
 
 
 
Grade 3 
 
 
 
 
Grade 4 
 
 
 
 
XXXXXXX 
 
 
 
 
Grade 1 - 4, N (%) 
 
 
 
 
Grade 1 
 
 
 
 
Grade 2 
 
 
 
 
Grade 3 
 
 
 
 
Grade 4 
 
 
 
 
Notes: Percentage is based on number of patients by Dose Level 


 
 
Table 11.5.2.5 
Supportive Listing: Patients with Some  Grade ≥3 Biochemical Abnormalities. 
Dose level (mg /m²) 
Patient 
Lab. test 
Cycle 
Examination date 
N 
Std. value 
Value 
(xULN) 
Grade CTC v4.0 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 11.5.2.6 
Supportive Listing: Patients with grade >=2 Biochemical Abnormalities at Baseline 
Dose 
level 
(mg /m²) 
Patient 
Lab. test 
Examination 
date 
N 
Std. 
value 
xULN 
Grade 
CTC 
v4.0 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
11.5.3 Laboratory Values over Time 
Table 11.5.3.1  
Worst Severity of Hematological Abnormalities During the First and Later Cycles by Dose Level 
Over time 
Toxicity 
I 
(N = XX) 
II 
(N = XX) 
III 
(N = XX) 
Total 
(N = XX) 
Cycle 1 
Anemia / . . . 
 
 
 
 
  
Grade 1 - 4, N (%)  
 
 
 
  
Grade 1 
 
 
 
 
  
Grade 2 
 
 
 
 
  
Grade 3 
 
 
 
 
  
Grade 4 
 
 
 
 


 
Over time 
Toxicity 
I 
(N = XX) 
II 
(N = XX) 
III 
(N = XX) 
Total 
(N = XX) 
Cycle >1 
Anemia / . . . 
 
 
 
 
  
Grade 1 - 4, N (%)  
 
 
 
  
Grade 1 
 
 
 
 
  
Grade 2 
 
 
 
 
  
Grade 3 
 
 
 
 
  
Grade 4 
 
 
 
 
Notes: Percentage is based on number of patients by Dose Level 
 
Table 11.5.3.2 
Worst Severity of Biochemical Abnormalities During the First and Later Cycles by Dose Level 
Over time 
Toxicity 
I 
(N = 
XX) 
II 
(N = XX) 
III 
(N = XX) 
Total 
(N = XX) 
Cycle 1 
AP increase / . . . 
 
 
 
 
  
Grade 1 - 4, N(%)  
 
 
  
Grade 1 
 
 
 
  
Grade 2 
 
 
 
  
Grade 3 
 
 
 
  
Grade 4 
 
 
 
Cycle >1 
AP increase / . . . 
 
 
 
 
  
Grade 1 - 4, N(%)  
 
 
  
Grade 1 
 
 
 
  
Grade 2 
 
 
 
  
Grade 3 
 
 
 
  
Grade 4 
 
 
 
Notes: Percentage is based on number of patients by Dose Level 
 
 
 
 
 
 


 
 
 
 
11.6 Vital Signs 
11.6.1 Vital Signs, Physical Findings and Other Observations Related to Safety 
Table 11.6.1.1 
Physical Examination during treatment by Dose Level 
Physical 
Examination 
Dose level 
I 
(N = XX) 
II 
(N = XX) 
III 
(N = XX) 
Total 
(N = XX) 
N (%) 
N (%) 
N (%) 
N (%) 
Normal  
 
 
 
 
 
 
 
Abnormal 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
Notes: Percentage is based on number of patients by Dose Level 
 
 
Table 11.6.1.2 
Supportive Listing: Physical Examination Abnormal 
Patient No 
Date of physical exam 
Weight 
 
Body surface area 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 11.6.1.3  
Electrocardiogram Measures during treatment.  
Dose level 
Patient 
Cycle 
PR interval 
RR interval 
… 
Max height of QRS complex 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
Table 11.6.1.4  
Electrocardiogram Results during treatment by Dose Level .  
 
Electrocardiogram Results 
Dose level 
I 
(N = XX) 
II 
(N = XX) 
III 
(N = XX) 
· · ·  
(N = XX) 
· · ·  
(N = XX) 
N 
(N = XX) 
Total 
(N = XX) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
Normal 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Significant Abnormalities 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Non-significant Abnormalities 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 11.6.1.5 
Supportive Listing: Electrocardiogram Abnormalities during treatment 
Dose level 
Patient No 
Abnormality Specification 
 
 
 
 
 
 
 
 
 
 
 
Table 11.6.1.6 
Left Ventricular Ejection Fraction (LVEF) during treatment 
LVEF 
Dose level 
I 
(N = XX) 
II 
(N = XX) 
III 
(N = XX) 
Total 
(N = XX) 
N (%) 
N (%) 
N (%) 
N (%) 
Normal 
 
 
 
 
 
 
 
Significant Abnormalities 
 
 
 
 
 
 
Non-significant Abnormalities 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
Notes: Percentage is based on number of patients by Dose Level 
 
Table 11.6.1.7 
Mean, Median, Std and Range values of Left Ventricular Ejection Fraction (LVEF) during treatment (MUGA) 
MUGA 
Dose level 


 
I 
(N = XX) 
II 
(N = XX) 
III 
(N = XX) 
Total 
(N = XX) 
N (%) 
N (%) 
N (%) 
N (%) 
Mean 
Median 
Std 
Minimum 
Maximum 
 
 
 
 
 
 
 
Notes: Percentage is based on number of patients by Dose Level 
 
 
 
Table 11.6.1.8 
Mean, Median, Std and Range values of Left Ventricular Ejection Fraction (LVEF) during treatment (ECHO) 
ECHO 
Dose level 
I 
(N = XX) 
II 
(N = XX) 
III 
(N = XX) 
Total 
(N = XX) 
N (%) 
N (%) 
N (%) 
N (%) 
Mean 
Median 
Std 
Minimum 
Maximum 
 
 
 
 
 
 
 
Notes: Percentage is based on number of patients by Dose Level 
 
 
 
 
Table 11.6.1.9  
Performance Status During the Study by Cycle and Dose Level 
 
Cycle 


 
Baseline 
Cycle 1 
Cycle 2 
Total 
Dose 
level 
Patient 
No 
Performance 
status 
Performance 
status 
Performance  
status 
Performance 
status 
I 
(N = XX) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
II 
(N = XX) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
III 
 
 
 
 
 
(N=XX) 
 
 
 
 
 
 
 
 
 
Total 
(N = XX) 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
If  more  than  one  measurement,  only worst will be presented 
 
Table 11.6.1.10  Weight Gain-Loss During the Study by Dose Level 
 
Cycle 
Baseline 
Cycle 1 
Cycle 2 
Total 
Dose 
level 
Patient 
No 
Weight at 
baseline (kg) 
% 
change 
% 
change 
% 
change 
% 
change 
I 
(N = XX) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
II 
(N = XX) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
Cycle 
Baseline 
Cycle 1 
Cycle 2 
Total 
Dose 
level 
Patient 
No 
Weight at 
baseline (kg) 
% 
change 
% 
change 
% 
change 
% 
change 
III 
 
 
 
 
 
 
(N=XX) 
 
 
 
 
 
 
 
 
 
 
 
Total 
(N = XX) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
If  more  than  one  measurement,  only worst will be presented 
 
 
Table 11.6.1.2  
Troponin Values. Evolution During Study 
Dose level 
Patient 
Cycle 
Troponin I Value 
Troponin T Value 
ULN 
 
… 
 
 
 
 
 
… 
 
 
 
 
 
… 
 
 
 
 
 
 


 
11.7 
Concomitant Medication 
11.7.1 Concomitant Medication During Study 
Table 11.7.1.1  
Concomitant Medication During Study (ATC Level 1, 2 and 4) by Dose Level 
Medication Term 
(ATC level 1) 
 
Medication Term 
(ATC level 4) 
Dose level 
Medication Term 
(ATC level 2) 
I 
(N = XX) 
II 
(N = XX) 
III 
(N = XX) 
Total 
(N = XX) 
 
N (%) 
N (%) 
N (%) 
N (%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Notes: Percentage is based on number of patients by Dose Level 
 
Table 11.7.1.2  
Transfusions 
 
Type 
Dose level 
I 
(N = XX) 
II 
(N = XX) 
III 
(N = XX) 
Total 
(N = XX) 
N (%) 
N (%) 
N (%) 
N (%) 
Platelet transfusion 
 
 
 
 
 
 
 
 
RBC transfusion 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
Notes: Percentage is based on number of patients by Dose Level 
 
 
 


 
12 Appendix III. Efficacy Evaluation 
This analysis will be carried out on the evaluable for efficacy population. 
12.1 Efficacy Analysis 
12.1.1 Response  
Table 12.1.1.1 
Overall Response Rate 
Summary 
Estimate proportion 
95% Confidence Interval (XX – XX)* 
(*) Calculated  using  exact binomial distribution. 
 
 
Table 12.1.1.2 
Overall response by Dose Level. Treated Patients 
Overall response 
Dose level 
I 
(N = XX) 
II 
(N = XX) 
III 
(N = XX) 
Total 
(N = XX) 
N (%) 
N (%) 
N (%) 
N (%) 
Response Criteria for 
Multiple Myeloma 
 
 
 
 
 
 
 
sCR 
CR 
VGPR 
 
 
 
 
 
 
PR 
MR 
 
 
 
 
 
 
SD < 4 months  
 
 
 
 
 
 
SD ≥ 4 months  
 
 
 
 
 
 
PD 
 
 
 
 
 
 


 
Overall response 
Dose level 
I 
(N = XX) 
II 
(N = XX) 
III 
(N = XX) 
Total 
(N = XX) 
N (%) 
N (%) 
N (%) 
N (%) 
NE 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
Notes: Percentage is based on number of patients by Dose Level 
 
 
Table 12.1.1.3   SD ≥ 4 months by Dose Level. Treated Patients 
SD ≥ 4 months 
Dose level 
I 
(N = XX) 
II 
(N = XX) 
III 
(N = XX) 
Total 
(N = XX) 
N (%) 
N (%) 
N (%) 
N (%) 
No  
 
 
 
 
 
 
 
Yes 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
Notes: Percentage is based on number of patients by Dose Level 
 
 
 
 
Table 12.1.1.4 
Overall response by Dose Level. Evaluable Population 
Overall response 
Dose level 
I 
(N = XX) 
II 
(N = XX) 
III 
(N = XX) 
Total 
(N = XX) 
N (%) 
N (%) 
N (%) 
N (%) 
Response Criteria for 
Multiple Myeloma 
 
 
 
 
 
 
 
sCR 
CR 
VGPR 
 
 
 
 
 
 


 
Overall response 
Dose level 
I 
(N = XX) 
II 
(N = XX) 
III 
(N = XX) 
Total 
(N = XX) 
N (%) 
N (%) 
N (%) 
N (%) 
PR 
MR 
 
 
 
 
 
 
SD < 4 months  
 
 
 
 
 
 
SD ≥ 4 months  
 
 
 
 
 
 
PD 
Total 
 
 
 
 
 
 
Notes: Percentage is based on number of patients by Dose Level 
 
 
Table 12.1.1.5 
SD ≥ 4 months by Dose Level. Evaluable population 
SD ≥ 4 months 
Dose level 
I 
(N = XX) 
II 
(N = XX) 
III 
(N = XX) 
Total 
(N = XX) 
N (%) 
N (%) 
N (%) 
N (%) 
No  
 
 
 
 
 
 
 
Yes 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
Notes: Percentage is based on number of patients by Dose Level 
 
 
 
 
Table 12.1.1.6 
Clinical Benefit Rate* 
Summary 
Estimate proportion* 
95% Confidence Interval (XX – XX)** 
(*)Let define 'Evidence of Clinical Benefit' when response is sCR, CR, VGPR, PR, MR or SD  
(**) Calculated using exact binomial distribution. 
 


 
Table 12.1.1.6B Clinical Benefit Rate* 
Summary 
Estimate proportion* 
95% Confidence Interval (XX – XX)** 
(*)(*)Let define 'Evidence of Clinical Benefit' when response is sCR, CR, VGPR, PR, MR 
(**) Calculated using exact binomial distribution. 
 
 
 
 


 
Table 12.1.1.7 
Characteristics of Patients with Evidence of Clinical Benefit* 
Patient No 
Dose 
Level 
Sex Age PS MM  type 
Relapse / 
Refractory-Relapse / 
Refractory 
Number of 
lines of 
previous 
treatment 
 
 
ASCT** 
Agents 
(previous 
treatment) 
Best 
Response last 
Previous CT 
TTP 
Previous 
last CT 
Cycles 
Received 
Overall 
Response 
PFS 
(months) 
Overall 
Survival 
(months) 
Treatment 
Discontinuation 
Reason 
Cause of 
death 
 
(*) Let define "Evidence of Clinical Benefit" when response is sCR, CR, VGPR, PR, MR or SD   
(**) Autologous Stem Cell Transplantation 
 
 
 
Table 12.1.1.8 
Supportive Listing Efficacy Dataset Analyzed 
Dose level 
Patient 
Evaluable 
Evaluation criteria 
Best Response 
Progression 
Progression Date 
Death 
Death Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
Table 12.1.1.9 
Progression-Free Survival Treated Population 
Summary 
N=XX 
Events  X (XX.X%) 
Censored  X (XX.X%) 
Median X.X  95% CI (XX-XX) 
PFS at 3 months XX.X% 95% CI  (XX-XX) 
PFS at 6 months XX.X% 95% CI (.XX-XX) 
 
 
 
 
 
Table 12.1.1.10 Progression-Free Survival Evaluable Population 
Summary 
N=XX 
Events X (XX.X%) 
Censored X (XX.X%) 
Median X.X  95% CI (XX-XX) 
PFS at 3 months XX.X% 95% CI  (XX-XX) 
PFS at 6 months XX.X% 95% CI (.XX-XX) 
 
 
 
Table 12.1.1.11 Overall Survival. Treated Population 
Summary 
N=XX 
Events X (XX%) 
Censored X (XX%) 
Median X.X 95% CI (X.X-X.X) 
OS at 6 months XX.X% 95% CI (XX.-XX) 
OS at 12  months XX.X% 95% CI (XX-XX) 
 
 
Table 12.1.1.12 Overall Survival. Evaluable Population 
Summary 
N=XX 
Events X (XX%) 
Censored X (XX%) 
Median X.X 95% CI (X.X-X.X) 
OS at 6 months XX.X% 95% CI (XX.-XX) 
OS at 12  months XX.X% 95% CI (XX-XX) 
 
 
 
Table 12.1.1.13 Duration of Response. Treated Population 
Summary 
N=XX 


 
Summary 
Events X (XX%) 
Censored X (XX%) 
Median X.X 95% CI (X.X-X.X) 
Duration of Response at 3 months XX.X% 95% CI (XX.-XX) 
Duration of Response at 6 months XX.X% 95% CI (XX-XX) 
 
Table 12.1.1.14 Duration of Response. Evaluable Population 
Summary 
N=XX 
Events X (XX%) 
Censored X (XX%) 
Median X.X 95% CI (X.X-X.X) 
Duration of Response at 3 months XX.X% 95% CI (XX.-XX) 
Duration of Response at 6 months XX.X% 95% CI (XX-XX) 
 
 
Table 12.1.1.15 Time-To-Progression. Treated Population 
Summary 
N=XX 
Events X (XX%) 
Censored X (XX%) 
Median X.X  95% CI (XX-XX) 
PFS at 3 months XX.X% 95% CI  (XX-XX) 
PFS at 6 months XX.X% 95% CI (.XX-XX) 
 
 
 
Table 12.1.1.16 Time-To-Progression. Evaluable Population 
Summary 
N=XX 
Events X (XX%) 
Censored X (XX%) 
Median X.X  95% CI (XX-XX) 
PFS at 3 months XX.X% 95% CI  (XX-XX) 
PFS at 6 months XX.X% 95% CI (.XX-XX) 
 
 
 
Table 12.1.1.17 Event-Free Survival. Treated Population 
Summary 
N=XX 
Events X (XX%) 
Censored X (XX%) 
Median X.X  95% CI (XX-XX) 
PFS at 3 months XX.X% 95% CI  (XX-XX) 
PFS at 6 months XX.X% 95% CI (.XX-XX) 
 


 
Table 12.1.1.18 Event-Free Survival. Evaluable Population 
Summary 
N=XX 
Events X (XX%) 
Censored X (XX%) 
Median X.X  95% CI (XX-XX) 
PFS at 3 months XX.X% 95% CI  (XX-XX) 
PFS at 6 months XX.X% 95% CI (.XX-XX) 
 
 
13 Figures 
13.1 Hematological Profile 
Figure 13.1.1  
Pattern of hematological/non hematological DLTs in individual patients 
 
 


 
13.2 Transaminase Profile 
Figure 13.2.1  
Transaminase series. Patient XX 
 
This profile will be done to patients with DLTs related to Transaminase 
Figure 13.2.2  
Bar charts of hematological/biochemical laboratory abnormalities by dose level 
 
 
 


 
Figure 13.2.3  
Hematology / Transaminase Worst Severity by Cycle 
 
 
13.3 Time to Event Graphs 
Figure 13.3.1  
Progression-Free Survival (PFS) 
 
 
Figure 13.3.2  
Overall Survival (OS) 
 


 
 
Figure 13.3.3  
Duration of response (DOR) 
 
 
 
 
Figure 13.3.4  
Time to Progression (TTP) 
 


 
 
Figure 13.3.5  
Event Free Survival (EFS) 
 
 
 
 
Figure 13.3.6  
Time to Onset (TTO) 
 


 
 
 
 
 
 
Figure 13.3.7  
Example of plot of individual m-protein values of responder patients. 
 
 


 
Figure 13.3.8  
Waterfall plot. (Maximum reduction of m-protein in serum) 
 
Figure 13.3.9  
Waterfall plot. (Maximum reduction of m-protein in urine) 
 
 
 


 
14 DB Listing 
 
-Listing 14.1.1: Study registration  
-Listing 14.1.2: Demography 
-Listing 14.1.3: Medical history 
-Listing 14.1.4: Pregnancy test  
-Listing 14.1.5: MM history 
-Listing 14.1.6: End of Treatment 
-Listing 14.1.7: Adverse Events 
-Listing 14.1.8: SAE Summary 
-Listing 14.1.9: Concomitant Therapy/Procedures  
-Listing 14.1.10: Blood products use 
-Listing 14.1.11: Prior AntiCancer Therapy: Palliative RadioTherapy 
-Listing 14.1.12: Prior AntiCancer Medical Therapy for Study Disease 
-Listing 14.1.13: Unscheduled 
-Listing 14.1.14: Hematology 
-Listing 14.1.15: Coagulation Test 
-Listing 14.1.16: Biochemistry A 
-Listing 14.1.17: Biochemistry B 
-Listing 14.1.18: Physical Examination 
-Listing 14.1.19: Clinical Neurological Assessment 
-Listing 14.1.20: Performance Status 
-Listing 14.1.21: Vital Signs 
-Listing 14.1.22: Electrocardiogram (also after Plitidepsin admin.) 
-Listing 14.1.23: Left Ventricular Ejection Fraction (LVEF) 
-Listing 14.1.24: Viral Serology 
-Listing 14.1.25: Follow Up 
-Listing 14.1.26: Surgery Procedures for Study Disease (after End of Treatment) 
-Listing 14.1.27: Radiotherapy (after End of Treatment) 
-Listing 14.1.28: Medical Treatment (after End of Treatment) 
-Listing 14.1.29: MM Serum Protein Measurements 
-Listing 14.1.30: MM Urine Protein Measurements 
- Listing 14.1.31: C-Reactive Protein 
-Listing 14.1.32: Beta-2-microglobulin 
-Listing 14.1.33: Tumor Evaluation 
-Listing 14.1.34: Skeletal Evaluation 
-Listing 14.1.35: Bone Marrow Evaluation 
-Listing 14.1.36: Evaluation of Response 
-Listing 14.1.37: Prophylactic Mediation (Per Protocol) 
-Listing 14.1.38: Oral Dexamethasone Administration 
-Listing 14.1.39: Plitidepsin Administration 
-Listing 14.1.40: Plitidepsion Readministration 


 
-Listing 14.1.41: Bortezomib Administration 
-Listing 14.1.42: Urinalysis 
-Listing 14.1.43: Other test/Procedures 
-Listing 14.1.44: Best Overall Response / Off Study 
-Listing 14.1.45: Death Resport Form 
 
15 SAP Version History 
 
Two substancial protocol amendments (Number 1 on 23SEP2015 and number 2 on 
08OCT2015) have been implemented after the first version of the statistical analysis 
plan (SAP) was approved. The SAP has been updated accordingly.  
The most relevant changes to the SAP are: 
-Patient evaluability criteria for the efficacy analysis have been updated to 
include the need for patients to have undergone at least one disease assessment 
in order to be considered evaluable. 
-Clinical Benefit Rate defined as sCR, CR, VGPR, PR and MR has been added 
to the previous one defined in the protocol as sCR, CR, VGPR, PR, MR and SD. 
-Some tables have been renumbered 
-Some tables have been deleted because after physician consultation they are not 
enough informative to be shown. 
-Other minor corrections have also been made, e.g. a reference has been 
added to the protocol. 
Summary of proposed changes 
Changes are highlighted in Italic bold. Text removed has been crossed out (crossed out). 
 
 
Section 6.4 Population Evaluable for Efficacy 
 
Original text: 
Although it is not the main objective of this study, antitumor activity will be measured 
clinically and/or radiologically according to IMWG.  Patients will be evaluable for 


 
efficacy if they meet all inclusion criteria and no exclusion criteria and receive at least 
one complete treatment cycle (two plitidepsin infusions, four bortezomib injections, 
four doses of dexamethasone) without protocol deviations with an effect on the 
risk/benefit ratio of the clinical trial, which may jeopardize the efficacy evaluation. 
Patients from this population who have inadequate post-baseline data to assess efficacy 
according to the response criteria (see section 6.1.1 of the protocol) will be considered 
treatment failures and will be included in the ORR and clinical benefit calculations. 
Changes to: 
Although it is not the main objective of this study, antitumor activity will be measured 
clinically and/or radiologically according to IMWG. Patients will be evaluable for 
efficacy if they meet all inclusion criteria and no exclusion criteria and receive at least 
one treatment cycle (two plitidepsin infusions, four bortezomib injections, four doses of 
dexamethasone) and have at least one disease assessment without protocol deviations 
with an effect on the risk/benefit ratio of the clinical trial, which may jeopardize the 
efficacy evaluation. Patients from this population who have inadequate post-baseline 
data to assess efficacy according to the response criteria (see section 6.1.1 of the 
protocol) will be considered treatment failures and will be included in the ORR and 
clinical benefit calculations. 
Section 8.4.1 Exploratory Analysis of Antitumor Activity  
Original text: 
Patients from this population who have inadequate post-baseline data to assess efficacy 
according to the response criteria in Section ¡Error! No se encuentra el origen de la 
referencia. of the protocol will be considered treatment failures and will be included in 
the ORR and clinical benefit calculations 
 
Changes to: 
Patients from this population who have inadequate post-baseline data to assess efficacy 
according to the response criteria in Section ¡Error! No se encuentra el origen de la 
referencia 6.1.1 of the protocol will be considered treatment failures and will be 
included in the ORR and clinical benefit calculations 
 
Section 10.2.2  Multiple Myeloma History 
Some tables have been renamed because of typing mistakes: 


 
Table 10.2.2.2 Multiple Myeloma Type by Dose Level renamed to Table 10.2.2.3 
Multiple Myeloma Type by Dose Level 
Table 10.2.2.3 Durie-Salmon stage at First Diagnosis by Dose Level renamed to Table 
10.2.2.4 Durie-Salmon Stage at First Diagnosis by Dose Level 
Table 10.2.2.4 Durie-Salmon Sub-classification at First Diagnosis by Dose Level 
renamed to Table 10.2.2.5 
Durie-Salmon Sub-classification at First Diagnosis by 
Dose Level 
Table 10.2.2.5 ISS stage at First Diagnosis by Dose Level renamed to Table 10.2.2.6 
 
ISS stage at First Diagnosis by Dose Level 
 
Table 10.2.2.6 ISS stage at First Diagnosis by Dose Level renamed to Table 10.2.2.7 
 
ISS stage at First Diagnosis by Dose Level 
 
Section 11.1.1 Cumulative Dose, Dose Intensity and Relative Dose Intensity 
 
In Table 11.1.1.1:  the column  ‘No of patients (Accumulated)’ has been deleted: 
Table 11.1.1.2 
No of cycles administered 
  
Patients 
Dose 
level 
Max cycle infused 
No of patients No of patients (Accumulated) 
I  
Cycle 1 
 
 
  
Cycle 2 
 
 
II 
Cycle 1 
 
 
  
Cycle 2 
 
 
III 
Cycle 1 
 
 
  
Cycle 2 
 
 
· · ·  
Cycle 1 
 
 
  
Cycle 2 
 
 
N 
Cycle 1 
 
 
  
Cycle 2 
 
 
Total  
Cycle 1 
 
 
  
Cycle 2 
 
 
  
Cycle 3 
 
 
  
· · ·  
 
 
  
Cycle N 
 
 
 


 
 
In Table 11.1.2.3 the cell named ‘Nº cycles with’ has been corrected. 
 
Original table: 
Table 11.1.2.4  
Number of Cycles with Drug Related Delay per patient by Dose Level 
No cycles with : 
Dose level 
I 
(N = XX) 
II 
(N = XX) 
III 
(N = XX) 
Total 
(N = XX) 
N (%) 
N (%) 
N (%) 
N (%) 
No cycle delayed 
 
 
 
 
 
 
 
01 cycle delayed 
 
 
 
 
 
 
02 cycles delayed 
 
 
 
 
 
 
· · ·  
 
 
 
 
 
 
· · ·  
 
 
 
 
 
 
Total 
Mean 
 
 
 
 
 
 
 
Median 
Std 
 
 
 
 
 
 
Min 
 
 
 
 
 
 
Max 
 
 
 
 
 
 
 
Changes to: 
Table 11.1.2.5  
Number of Cycles with Drug Related Delay per patient by Dose Level 
No. of patients with: 
Dose level 
I 
(N = XX) 
II 
(N = XX) 
III 
(N = XX) 
Total 
(N = XX) 
N (%) 
N (%) 
N (%) 
N (%) 
No cycle delayed 
 
 
 
 
 
 
 
01 cycle delayed 
 
 
 
 
 
 
02 cycles delayed 
 
 
 
 
 
 
· · ·  
 
 
 
 
 
 
· · ·  
 
 
 
 
 
 
Total 
Mean 
 
 
 
 
 
 
 
Median 
Std 
 
 
 
 
 
 
Min 
 
 
 
 
 
 
Max 
 
 
 
 
 
 
 


 
 
Section 11.6.1  Vital Signs, Physical Findings and Other Observations Related to 
Safety 
 
Three tables have been deleted because it is meaningless to analyze the weight, height 
and BSA during the treatment (as these tables were displayed). And the following tables 
have been renamed according with this change. 
 
 
 
Deleted: 
 
Table 11.6.1.1 
Weight during treatment by Dose Level 
Weight (Kg) 
Dose level 
I 
(N = XX) 
II 
(N = XX) 
III 
(N = XX) 
Total 
(N = XX) 
N 
 
 
 
 
Median 
Mean  
Std 
 
 
 
Min 
 
 
 
Max 
 
 
 
 
 
Table 11.6.1.2 
Height during treatment by Dose Level 
Height (cm) 
Dose level 
I 
(N = XX) 
II 
(N = XX) 
III 
(N = XX) 
Total 
(N = XX) 
N 
 
 
 
 
Median 
Mean 
Std 
 
 
 
Min 
 
 
 
Max 
 
 
 
 
Table 11.6.1.3 
Body Surface Area (BSA) during treatment by Dose Level 
BSA (m2) 
Dose level 
I 
(N = XX) 
II 
(N = XX) 
III 
(N = XX) 
Total 
(N = XX) 
N 
 
 
 
 
 


 
BSA (m2) 
Dose level 
I 
(N = XX) 
II 
(N = XX) 
III 
(N = XX) 
Total 
(N = XX) 
Median 
Mean 
Std 
 
 
 
 
Min 
 
 
 
 
Max 
 
 
 
 
 
Renamed: 
Table 11.6.1.4 Supportive Listing: Physical Examination Abnormal renamed to Table 
11.6.1.2 Supportive Listing: Physical Examination Abnormal 
 
Table 11.6.1.5 Electrocardiogram Measures during treatment renamed to Table 11.6.1.3 
Electrocardiogram Measures during treatment 
Table 11.6.1.6 Electrocardiogram Results during treatment by Dose Level renamed to  
Table 11.6.1.4 Electrocardiogram Results during treatment by Dose Level 
 
Table 11.6.1.7 Supportive Listing: Electrocardiogram Abnormalities during treatment  
renamed to Table 11.6.1.5 Supportive Listing: Electrocardiogram Abnormalities  
during treatment 
 
Table 11.6.1.8 Left Ventricular Ejection Fraction (LVEF) during treatment renamed to  
Table 11.6.1.6 Supportive Listing: Electrocardiogram Abnormalities during  
Treatment 
 
Table 11.6.1.9 Mean, Median, Std and Range values of Left Ventricular Ejection  
Fraction (LVEF)  during treatment (MUGA) renamed to Table 11.6.1.7 Mean,  
Median, Std and Range values of Left Ventricular Ejection Fraction (LVEF) during  
treatment (MUGA) 
 
Table 11.6.1.10 Mean, Median, Std and Range values of Left Ventricular Ejection  
Fraction (LVEF)  during treatment (ECHO) renamed to Table 11.6.1.8 
Mean,  
Median, Std and Range values of Left Ventricular Ejection Fraction (LVEF) during  
treatment (ECHO) 
 


 
Table 11.6.1.11 Performance Status During the Study by Cycle and Dose Level  
renamed to Table 11.6.1.9  Performance Status During the Study by Cycle and Dose  
Level 
 
Table 11.6.1.12 Weight Gain-Loss During the Study by Dose Level renamed to Table  
11.6.1.13  Weight Gain-Loss During the Study by Dose Level 
 
In Table 11.6.1.5: the column ‘Height’ has been deleted because this parameter is 
not recorded in the physical examination during treatment  
Original table: 
Table 11.6.1.5 
Supportive Listing: Physical Examination Abnormal 
Patient No 
Date of physical exam 
Weight 
Height 
Body surface area 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Changes to: 
Table 11.6.1.2 
Supportive Listing: Physical Examination Abnormal 
Patient No 
Date of physical exam 
Weight 
 
Body surface area 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section 11.7.1. Concomitant Medication During Study 
Original table: 
 
Table 11.7.1.1  
Transfusions 
Medication Term 
(ATC level 1) 
Medication Term 
(ATC level 4) 
Dose level 
I 
(N = XX) 
II 
(N = XX) 
III 
(N = XX) 
Total 
(N = XX) 
N (%) 
N (%) 
N (%) 
N (%) 
Platelet transfusion 
 
 
 
 
 
 
 
 
RBC transfusion 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
Notes: Percentage is based on number of patients by Dose Level 


 
 
Changes to: 
Table 11.7.1.2  
Transfusions 
Type 
 
Dose level 
I 
(N = XX) 
II 
(N = XX) 
III 
(N = XX) 
Total 
(N = XX) 
N (%) 
N (%) 
N (%) 
N (%) 
Platelet transfusion 
 
 
 
 
 
 
 
 
RBC transfusion 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
Notes: Percentage is based on number of patients by Dose Level 
 
Section 12.1.1 Response 
Added: 
Table 12.1.1.6B Clinical Benefit Rate* 
Summary 
Estimate proportion* 
95% Confidence Interval (XX – XX)** 
(*)Let define 'Evidence of Clinical Benefit' when response is sCR, CR, VGPR, PR, MR 
(**) Calculated using exact binomial distribution. 
 
SECTION 13. 
In Figure 13.3.3 the legend has been deleted and the new word ‘serum’ has been added 
to the title: 
Figure 13.3.4  
Waterfall plot. (Maximum reduction of m-protein) renamed  to Figure 13.3.5   
Waterfall plot. (Maximum reduction of m-protein in serum)  
 
 


 
 
Figure added: 
Figure 13.3.9 Waterfall plot. (Maximum reduction of m-protein in urine) 
 
 
As the company has changed its logo, the SAP has been updated accordingly: 


 
Original logo: 
 
 
Changes to: