Conditions: Lymphoma
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 14
Healthy volunteers: no

Brief summary:
Prospective, multicenter, phase II clinical trial to determine the efficacy of plitidepsin in patients with relapsed/refractory (R/R) angioimmunoblastic Tcell lymphoma (AITL).This is an international, multicenter study (with approximately 17 investigative sites).

Detailed description:
Prospective, multicenter, phase II clinical trial to determine the efficacy of plitidepsin in patients with relapsed/refractory (R/R) AITL. The primary endpoint will be overall response rate (ORR) according to the Lugano classification response criteria per independent review.

Medical specialists (radiologists and hematologists) who are directly involved in the care of patients with AITL (but are not participating in this trial as investigators) will review all efficacy data (including radiological assessments, bone marrow biopsies) and will assign the best response and the date of objective response or progression/censoring according to their independent evaluation.

Central pathological review of each patient's original diagnosis report(s) will be required before inclusion.

Two futility analyses of the primary endpoint (ORR according to the Lugano classification criteria and per Independent Review Committee (IRC)) are planned around six months after approximately 25% and 50% of eligible patients (i.e., 15 and 30 patients respectively with AITL confirmed by central pathological review) have been treated. Two or less responders out of 15 patients or seven or less responders out of 30 patients, according to boundaries and sample size assumptions, will mean that the alternative hypothesis could be rejected, and thus recruitment might be stopped at the time of the first or second futility analysis, respectively. Otherwise, accrual will continue to 60 patients with AITL confirmed by central pathological review. This decision will be taken at the time by an Independent Data Monitoring Committee (IDMC). The IDMC, which will include specialists in peripheral T-cell lymphomas (PTCL) supported by a medical statistician, will review data provided by the Investigators, the IRC efficacy assessments and safety information and will advise whether the study should continue. Recruitment can continue during the review period.

If there are 19 or more responders of 60 patients, the efficacy of plitidepsin will be considered as clinically relevant in AITL patients.

Central pathological review will be conducted by experienced pathologists appointed by the Sponsor and available to the investigative sites for consultation about AITL diagnosis confirmation. Central pathological review is required for (a) local histopathology reports prior to patient treatment, and (b) tumor samples before each futility analysis and at the end of the study.

The central laboratory pathologists will be responsible for (a) approving patient inclusion on the basis of investigative site pathology reports provided during screening, (b) analyzing tumor biopsies (initial diagnosis and/or relapses) to confirm the AITL diagnosis, and (c) analyzing blood samples to identify plasma biomarkers and extract DNA.

Tumor samples (initial diagnosis and relapses) are required for central review to confirm AITL diagnosis but not to approve inclusion. Archived tissue samples of representative tumors must be sent for central review and biomarker analysis. If the diagnosis biopsy is not available (because the patient was diagnosed at another site, for example), the most recent representative biopsy (relapse and/or progression) will be used. Submitting both, however, is strongly recommended. Tumor blocks will be returned to the centers.

Arms:
arm 1: None

Interventions: intervention 1: plitidepsin
Intervention descriptions: intervention 1: None

Protocol document:
Prot_000.pdf: 
 
 
 
 
 
 
SPONSORS 
 
Pharma Mar, S.A., 
Avda de los Reyes, 1 
Polígono Industrial “La Mina” 
28770 Colmenar Viejo (Madrid), Spain 
Phone: + 34 91 846 6000 
Fax: + 34 91 846 6003 
Pharma Mar USA, Inc. 
205 East 42nd Street, suite 15003 
New York, NY 10017, USA 
Phone: +1 646 880 4429 
Fax: +1 646 893 5856 
 
 
 
 
 
CLINICAL TRIAL PROTOCOL 
 
 
APL-B-021-13 
 
A Phase II Study of Plitidepsin in Patients with Relapsed or 
Refractory Angioimmunoblastic T-cell Lymphoma 
 
 
INVESTIGATIONAL MEDICINAL PRODUCT: Plitidepsin (Aplidin®) 
Protocol Code: APL-B-021-13 
EudraCT No: 2015-001909-14 
NCT Code: 03070964 
 
 
Protocol version 4.0 (including amendments #1 dated 6 July 2016, #2 dated 9 June  
2017 and #3 dated 07 May 2018) 
 


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SPONSORS
Pharma Mar, S.A., 
Avda de los Reyes, 1
Polígono Industrial “La Mina” 
28770 Colmenar Viejo (Madrid), Spain
Phone: + 34 91 846 6000 
Fax:       + 34 91 846 6003
Pharma Mar USA, Inc.
205 East 42nd Street, suite 15003
New York, NY 10017, USA
Phone:    +1 646 880 4429
Fax:
  +1 646 893 5856
CLINICAL TRIAL PROTOCOL
APL-B-021-13
A Phase II Study of Plitidepsin in Patients with Relapsed or 
Refractory Angioimmunoblastic T-cell Lymphoma
INVESTIGATIONAL MEDICINAL PRODUCT: Plitidepsin (Aplidin®)
Protocol Code: APL-B-021-13
EudraCT No: 2015-001909-14
Protocol version 4.0 (including amendments #1 dated 6 July 2016, #2 dated 9 June 
2017 and #3 dated 07 May 2018)   
This study will be conducted in compliance with the protocol, Good Clinical Practice (GCP),
and the applicable regulatory requirements.
Confidentiality statement
Information and data included in this protocol contain trade secrets and privileged or 
confidential information which is the property of the Sponsor. No person is authorized to make 
it public without written permission of the Sponsor. These restrictions on disclosure will apply 
equally to all future information supplied to you which is indicated as privileged or confidential. 
This material may be disclosed to and used by your staff and associates as it may be necessary 
to conduct the clinical study.


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STUDY CONTACTS
NAME AND ADDRESS
PHONE, FAX NUMBER, AND E-
MAIL ADDRESS
Sponsors1: 
Pharma Mar, S.A. 
Avda. de los Reyes, 1
Polígono Industrial “La Mina”
28770 Colmenar Viejo, 
Madrid, Spain.
Phone:
+ 34 91 846 6000
Fax:
+ 34 91 846 6003
Pharma Mar USA, 
Inc.
205 East 42nd Street, suite 15003
New York, New York 10017, 
USA.
Phone:     +1 646 880 4429
Fax:
  +1 646 893 5856
Responsible 
Physicians
José Rodríguez Díaz-Pavón, M.D.
Clinical Oncology
Pharma Mar, S.A.
Phone:
+ 34 91 846 6157
Fax:
+ 34 91 823 4504
E-mail: jrodriguez@pharmamar.com
Sara Martínez González, M.D.
Clinical Oncology
Pharma Mar, S.A.
Phone:
+ 34 91 823 4647
Fax:
+ 34 91 823 4504
E-mail: smgonzalez@pharmamar.com 
Project Manager
Pilar García Paramio
Clinical Operations
Pharma Mar S.A.
Phone:
+34 91 823 4597
Fax:
+34 91 846 6003
E-mail: mpgarcia@pharmamar.com
Pharmacovigilance 
Contact
Hervé Dhellot, M.D., M.Sc.
Pharmacovigilance Physician
Pharma Mar, S.A
Phone:
+ 34 91 823 4633
Fax:
+ 34 91 846 6004
E-mail: phv@pharmamar.com
Outside office hours (GMT)
phone:   + 34 91 823 4742
Clinical 
Pharmacology 
Contact
Ignacio González García
Clinical Pharmacology
Pharma Mar S.A.
Phone:
+ 34 91 823 4662
Fax:
+ 34 91 823 4504
E-mail: iggarcia@pharmamar.com
Central Pathology and 
Biomarker Analysis 
Laboratory
Juan Fernando García, M.D.
Anatomopathology Department, 
MD Anderson Cancer Center,
C/ Arturo Soria 270,
28033 Madrid, Spain.
Phone:
+ 34 91 787 86 00, Ext. 2731
Fax:
+ 34 91 787 8633
E-mail: jfgarcia@mdanderson.es
Collaborating 
Pathology Laboratory
Pier Paolo Piccaluga, M.D.
Istituto Euro-Mediterraneo di 
Scienza e Tecnologia,
Via Michele Miraglia 20, 
90139 Palermo, Italy.
Phone: +39 091 333 913
Fax:     +39 091 662 2514
E-mail: pierpaolopiccaluga@iemest.eu
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
                                                
1 Abbreviated as PharmaMar or Sponsor in the rest of the protocol.


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


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TABLE OF CONTENTS
STUDY CONTACTS .................................................................................................................................2
PRINCIPAL INVESTIGATORS..............................................................................................................3
SYNOPSIS ..................................................................................................................................................7
SCHEDULE OF ASSESSMENTS AND PROCEDURES....................................................................18
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS..........................................................21
1.
INTRODUCTION ...........................................................................................................................24
1.1
DISEASE BACKGROUND: ANGIOIMMUNOBLASTIC T-CELL LYMPHOMA................................24
1.1.1
Clinical Features of Angioimmunoblastic T-cell Lymphoma............................................24
1.1.2
Pathogenesis of Angioimmunoblastic T-cell Lymphoma...................................................25
1.1.3
Natural History of Angioimmunoblastic T-cell Lymphoma and Prognostic Factors .......25
1.1.4
Definition and Pathological Diagnosis of Angioimmunoblastic T-cell Lymphoma .........25
1.1.5
Treatment for Angioimmunoblastic T-cell Lymphoma......................................................26
1.2
INFORMATION ON THE STUDY DRUG: PLITIDEPSIN...............................................................27
1.2.1
Name and Chemical Information .......................................................................................27
1.2.2
Non-clinical Data ................................................................................................................28
1.2.2.1
Mechanism of Action................................................................................................................. 28
1.2.2.2
In Vitro and In Vivo Activity..................................................................................................... 28
1.2.3
Clinical Data........................................................................................................................28
1.2.3.1
Phase I Trial in Multiple Myeloma............................................................................................. 29
1.2.3.2
Phase II Trials in Hematological Malignancies.......................................................................... 29
1.2.3.2.1
Phase II Trials in Non-Hodgkin Lymphoma ......................................................................... 30
1.2.3.2.2
Phase II Trials in Multiple Myeloma..................................................................................... 30
1.2.3.2.3
Phase II Trials in Myelofibrosis ............................................................................................ 30
1.2.3.2.4
Phase II Trials in Acute Lymphoblastic Leukemia................................................................ 31
1.2.3.3
Phase III Trials in Multiple Myeloma (ADMYRE trial) ............................................................ 31
1.3
STUDY RATIONALE...................................................................................................................31
2.
STUDY OBJECTIVES ...................................................................................................................34
2.1
PRIMARY ..................................................................................................................................34
2.2
SECONDARY..............................................................................................................................34
3.
OVERALL STUDY DESIGN.........................................................................................................34
3.1
PRIMARY ENDPOINT ................................................................................................................36
3.2
SECONDARY ENDPOINTS..........................................................................................................36
4.
SELECTION OF PATIENTS.........................................................................................................37
4.1
INCLUSION CRITERIA...............................................................................................................37
4.2
EXCLUSION CRITERIA..............................................................................................................38
5.
PLAN OF THE STUDY..................................................................................................................39
5.1
PLANNED TRIAL PERIODS (FOR THE WHOLE STUDY) ............................................................39
5.2
PLANNED TRIAL PERIODS (INDIVIDUALLY PER PATIENT)......................................................39
5.2.1
Discontinuations..................................................................................................................41
5.2.1.1
Treatment Discontinuation......................................................................................................... 41
5.2.1.2
Reasons for Treatment Discontinuation ..................................................................................... 41
5.2.1.3
Study Discontinuation................................................................................................................ 42
5.2.2
Protocol Deviations..............................................................................................................42
5.3
ADDITION OF PATIENTS ...........................................................................................................42
5.4
PRETREATMENT ASSESSMENTS...............................................................................................43
5.5
PATIENT REGISTRATION..........................................................................................................44
5.6
CENTRAL PATHOLOGICAL REVIEW........................................................................................45
5.7
PATIENT RANDOMIZATION......................................................................................................46
5.8
EVALUATIONS DURING TREATMENT.......................................................................................46
5.9
EVALUATIONS AT END OF CYCLE 6.........................................................................................48
5.10
EVALUATIONS AT END OF TREATMENT ..................................................................................48


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5.11
FOLLOW-UP AFTER END-OF-TREATMENT VISIT....................................................................49
5.12
INDEPENDENT REVIEW COMMITTEE ......................................................................................50
5.13
INDEPENDENT DATA MONITORING COMMITTEE ...................................................................50
6.
PHARMACOKINETICS................................................................................................................51
7.
TREATMENT .................................................................................................................................52
7.1
DESCRIPTION OF TREATMENT.................................................................................................52
7.1.1
Drug Formulation and Supply............................................................................................52
7.2
ADMINISTRATION OF STUDY MEDICATION.............................................................................53
7.3
PROPHYLACTIC MEDICATION .................................................................................................53
7.4
CRITERIA FOR TREATMENT CONTINUATION..........................................................................53
7.5
DOSE REDUCTION ....................................................................................................................54
7.6
CONCOMITANT MEDICATION..................................................................................................54
7.6.1
Allowed Medications/Therapies ..........................................................................................54
7.6.1.1
Transfusions............................................................................................................................... 55
7.6.2
Prohibited Medications/Therapies ......................................................................................55
7.7
DRUG ACCOUNTABILITY..........................................................................................................55
7.8
TREATMENT COMPLIANCE......................................................................................................55
8.
STUDY EVALUATIONS ...............................................................................................................55
8.1
EFFICACY .................................................................................................................................55
8.2
SAFETY .....................................................................................................................................57
8.3
PHARMACOKINETICS ...............................................................................................................57
8.4
BIOMARKERS AND EXPLORATORY EVALUATIONS .................................................................57
8.5
ADVERSE EVENTS DEFINITIONS ..............................................................................................58
8.5.1
Adverse Event (AE)..............................................................................................................58
8.5.2
Serious Adverse Event (SAE)..............................................................................................58
8.5.3
Death....................................................................................................................................59
8.5.4
Life-threatening Event.........................................................................................................59
8.5.5
Hospitalization or Prolongation of Hospitalization............................................................59
8.5.6
Unlisted/Unexpected Adverse Event ...................................................................................60
8.5.7
Adverse Reactions................................................................................................................60
8.5.8
Adverse Events Related to the Study Drug..........................................................................60
8.5.9
Expedited Reporting ............................................................................................................60
8.5.10
Assessment of Causal Relationship to the Study Drug ..................................................60
8.6
ADVERSE EVENTS REPORTING PROCEDURES.........................................................................60
8.6.1
Reporting Adverse Events....................................................................................................60
8.6.2
Reporting Serious Adverse Events ......................................................................................61
8.6.3
Reporting Pregnancy Cases Occurred within the Clinical Trial........................................62
8.7
ADVERSE EVENTS MONITORING .............................................................................................62
9.
STATISTICAL METHODS...........................................................................................................63
9.1
SAMPLE SIZE ............................................................................................................................63
9.2
STATISTICAL ANALYSIS...........................................................................................................64
9.2.1
Efficacy ................................................................................................................................64
9.2.2
Safety....................................................................................................................................64
9.2.3
Pharmacokinetics ................................................................................................................64
9.2.4
Biomarkers Analysis............................................................................................................64
9.3
INTERIM ANALYSIS ..................................................................................................................64
10.
ADMINISTRATIVE SECTION................................................................................................65
10.1
ETHICS......................................................................................................................................65
10.2
MONITORING, AUDITING AND INSPECTING .............................................................................65
10.3
PATIENT INFORMED CONSENT ................................................................................................66
10.4
CONFIDENTIALITY/ PATIENTS IDENTIFICATION.....................................................................66
10.5
CASE REPORT FORMS..............................................................................................................67
10.6
INSURANCE ...............................................................................................................................67
10.7
RETENTION OF RECORDS.........................................................................................................67
10.8
USE OF INFORMATION AND PUBLICATION ..............................................................................67


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11.
REFERENCES............................................................................................................................69
12.
APPENDICES .............................................................................................................................75
APPENDIX 1: WHO CLASSIFICATION OF TUMORS OF HEMATOPOIETIC AND LYMPHOID 
TISSUES....................................................................................................................................................75
APPENDIX 2: THE LUGANO CLASSIFICATION: REVISED CRITERIA FOR RESPONSE 
ASSESSMENT..........................................................................................................................................78
APPENDIX 3: PROGNOSTIC INDEX FOR PERIPHERAL T-CELL LYMPHOMA (PIT)..............81
APPENDIX 4: PROGNOSTIC INDEX FOR ANGIOIMMUNOBLASTIC T-CELL LYMPHOMA 
(PIAI).........................................................................................................................................................82
APPENDIX 5: ANN ARBOR STAGING SYSTEM................................................................................83
APPENDIX 6: CONTRACEPTION AND PREGNANCY TESTING...................................................84
APPENDIX 7: DECLARATION OF HELSINKI...................................................................................86
APPENDIX 8: LISTS DRUGS THAT PROLONG THE QT INTERVAL AND/OR INDUCE 
TORSADES DE POINTES VENTRICULAR ARRHYTHMIA............................................................92


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SYNOPSIS
TITLE
A Phase II Study of Plitidepsin in Patients with Relapsed or Refractory 
Angioimmunoblastic T-cell Lymphoma
PROTOCOL 
CODE
APL-B-021-13
INVESTIGATORS
A full list of Investigators will be available as a separate document. 
NUMBER OF 
SITES/TRIAL 
LOCATION
This is an international, multicenter study (with approximately 25
investigative sites).
STUDY
OBJECTIVES 
Primary:
To evaluate the efficacy of plitidepsin on the basis of overall response 
rate (ORR) in patients with relapsing/refractory angioimmunoblastic T-
cell lymphoma (AITL).
Secondary:
To evaluate other efficacy endpoints (time-to-event parameters: 
duration of response [DoR], progression-free survival [PFS], PFS at 
6/12 months [PFS6/PFS12], intrapatient PFS/TTP, overall survival 
[OS] and OS at 6/12 months [OS6/OS12]).
To evaluate the safety profile of plitidepsin in this patient 
population.
To characterize the pharmacokinetics (PK) of plitidepsin.
To identify biomarkers that may be clinical endpoint surrogates for 
future plitidepsin studies or that may be predictive of plitidepsin 
activity.
STUDY DESIGN
Prospective, multicenter, phase II clinical trial to determine the efficacy
of plitidepsin in patients with relapsed/refractory (R/R) AITL. The 
primary endpoint will be ORR according to the Lugano classification
response criteria per independent review.
An Independent Review Committee (IRC) consisting of medical 
specialists (radiologists and hematologists) who are directly involved in 
the care of patients with AITL (but are not participating in this trial as 
investigators) will review all efficacy data (including radiological 
assessments, bone marrow biopsies) and will assign the best response 
and the date of objective response or progression/censoring according 
to their independent evaluation. 
Central pathological review of each patient’s original diagnosis
report(s) will be required before inclusion. 
Two futility analyses of the primary endpoint (ORR according to the 
Lugano classification criteria and per IRC) are planned around six 
months after approximately 25% and 50% of eligible patients (i.e., 15
and 30
patients
respectively with AITL confirmed by central 
pathological review) have been treated. Two or less responders out of 
15 patients or seven or less responders out of 30 patients, according to 


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boundaries and sample size assumptions, will mean that the alternative 
hypothesis could be rejected, and thus recruitment might be stopped at
the time of the first or second futility analysis, respectively. Otherwise, 
accrual will continue to 60 patients with AITL confirmed by central 
pathological review. This decision will be taken at the time by an 
Independent Data Monitoring Committee (IDMC). The IDMC, which 
will include specialists in peripheral T-cell lymphomas (PTCL)
supported by a medical statistician, will review data provided by the 
Investigators, the IRC efficacy assessments and safety information and 
will advise whether the study should continue. Recruitment can 
continue during the review period.
If there are 19 or more responders of 60 patients, the efficacy of 
plitidepsin will be considered as clinically relevant in AITL patients.
Operational details for the IRC and IDMC will be detailed in 
corresponding charters.
CENTRAL 
PATHOLOGICAL 
REVIEW
Central pathological review
will be conducted by experienced 
pathologists appointed by the Sponsor and available to the investigative 
sites for consultation about AITL diagnosis confirmation. Central 
pathological review is required for (a) local histopathology reports prior 
to patient treatment, and (b) tumor samples before each futility analysis 
and at the end of the study. 
The central laboratory pathologists will be responsible for (a) 
approving patient inclusion on the basis of investigative site pathology 
reports provided during screening, (b) analyzing tumor biopsies (initial 
diagnosis and/or relapses) to confirm the AITL diagnosis, and (c) 
analyzing blood samples to identify plasma biomarkers and extract 
DNA. 
Tumor samples (initial diagnosis and relapses) are required for central 
review to confirm AITL diagnosis but not to approve inclusion. 
Archived tissue samples of representative tumors must be sent for 
central review and biomarker analysis. If the diagnosis biopsy is not 
available (because the patient was diagnosed at another site, for 
example), the most recent representative biopsy (relapse and/or 
progression) will be used. Submitting both, however, is strongly 
recommended. Tumor blocks will be returned to the centers. 
STUDY 
POPULATION
Adult patients with a diagnosis of AITL and with R/R disease. Patients 
must have measurable disease according to the Lugano classification
criteria.
PATIENT 
ELIGIBILITY
INCLUSION 
CRITERIA
1)
Voluntary written informed consent of the patient (both to 
participate in the study and to provide biopsy samples) obtained 
before any study-specific procedure.
2)
Age ≥ 18 years.
3)
Eastern Cooperative Oncology Group (ECOG) performance 
status (PS) ≤ 2.
4)
Life expectancy ≥ 3 months.
5)
Histologically confirmed diagnosis of R/R AITL (eligibility 


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needs to be confirmed by central pathological review.*)
6)
At least a two-week washout period since the end of the last 
therapy (six weeks for a prior nitrosourea-containing regimen), 
recovery to grade ≤ 1 from any non-hematological adverse event 
(AE) derived from previous treatment (excluding alopecia). 
7)
Adequate bone marrow (BM), renal, hepatic, and metabolic 
function (assessed ≤ 14 days before inclusion in the study):
a)
Absolute neutrophil count (ANC) ≥ 1.0 × 109/L.
Screening of ANC should be independent of granulocyte-
colony stimulating factor (G-CSF) support for at least one 
week and of pegylated G-CSF for at least two weeks.
b)
Platelet count ≥ 75 × 109/L.
c)
Hemoglobin ≥ 9 g/dL. 
Patients may receive red blood cells (RBC) and/or 
erythropoietin 
(EPO) 
and/or 
platelet 
transfusions 
in 
accordance with institutional guidelines.
d)
Aspartate 
aminotransferase 
(AST) 
and 
alanine 
aminotransferase (ALT) ≤ 3.0 × the upper limit of normal 
(ULN).
e)
Total bilirubin ≤ 1.5 × ULN. 
f)
Alkaline phosphatase (ALP) ≤ 3.0 × ULN (< 5 × ULN if 
isolated ALP increase, i.e., without ALT/AST or bilirubin 
increase).
g)
Calculated creatinine clearance (CrCL) ≥ 30 mL/minute 
(Cockcroft-Gault formula).
h)
Creatine phosphokinase (CPK) ≤ 2.5 × ULN.
i)
Albumin ≥ 2.5 g/dL.
j)
Normal value of electrolytes, including potassium, magnesium 
and calcium.
8)
Left ventricular ejection fraction (LVEF) by echocardiogram 
(ECHO) or multiple-gated acquisition (MUGA) scan within 
normal range (according to institutional standards).
* Patient inclusion can be approved based on local histopathological report(s). 
Eligibility will be confirmed using diagnosis and/or relapse biopsy specimens 
submitted for central pathological review prior to each futility analysis/end of the 
study.
PATIENT 
ELIGIBILITY
EXCLUSION 
CRITERIA
1)
Prior treatment with plitidepsin.
2)
Concomitant diseases/conditions:
a)
History or presence of angina, myocardial infarction, clinically 
relevant valvular heart disease, uncontrolled hypertension, or 
congestive heart failure within the previous 12 months.
b)
Symptomatic arrhythmia (excluding grade ≤ 2 anemia-related 
sinusal tachycardia) or any arrhythmia requiring ongoing 
treatment, and/or prolonged grade ≥ 2 QT-QTc, or presence of 
unstable atrial fibrillation. Patients with stable atrial fibrillation 
on treatment are allowed provided they do not meet any other 
cardiac or prohibited drug exclusion criterion.


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c)
History (or family history) of long QT syndrome.
d)
Corrected QT interval (QTcF, Fridericia correction) ≥ grade 2 
on screening electrocardiogram (ECG).
e)
Clinically significant resting bradychardia, or history of 
syncope.
f)
History or presence of ventricular arrhythmias, including 
ventricular tachycardia or Torsades de Pointes.
g)
Patients receiving treatment with any medication with known 
risk of producing Torsade de Pointes (see Appendix 8).
h)
Active uncontrolled infection. Active hepatitis B or C virus 
(HBV or HCV), or human immunodeficiency virus (HIV) 
infection.
i)
Morphological or cytological features of myelodysplasia and/or 
post-chemotherapy aplasia on BM assessment.
j)
Myopathy > grade 2 or any clinical situation that causes 
significant and persistent elevation of CPK (> 2.5 × ULN in 
two different determinations performed one week apart).
k)
Limitation of the patient’s ability to comply with the treatment 
or follow-up requirements.
l)
Diagnosis of another invasive malignancy unless free of 
disease for at least three years following therapy with curative 
intent. Patients with early-stage basal cell or squamous cell 
skin cancer, cervical intraepithelial neoplasia, cervical 
carcinoma in situ, or superficial bladder cancer, may be eligible 
to participate at the Investigator’s discretion.
m) Any other major illness that, in the Investigator’s judgment, 
will substantially increase the risk associated with the patient’s 
participation in this study.
3)
Central nervous system (CNS) involvement.
4)
Women who are pregnant or breast feeding. Fertile patients 
(men and women) who are not using an effective method of 
contraception. All patients (men and women) must agree to use 
an effective contraceptive measure (if applicable) up to six
months after treatment discontinuation.
5)
Concomitant 
medications 
that 
include 
corticosteroids, 
chemotherapy, or other therapy that is or may be active against 
AITL, within the two weeks prior to treatment start. Concurrent 
corticosteroids are allowed, provided they are administered at an 
equivalent prednisone dose of ≤ 10 mg daily, as premedication 
for blood products and/or for the relief of the symptoms derived 
from the disease.
6)
Major upper gastrointestinal bleeding episode occurring during 
the previous year before screening.
7)
Known hypersensitivity to any of plitidepsin’s formulation 
components (see Study Drug Formulation).
EXPECTED 
NUMBER OF 
PATIENTS
A total of 60 patients with AITL confirmed by central pathological 
review are to be included in this study (unless one of the two planned
futility analyses stops recruitment after the inclusion of approximately 


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15 and 30 patients).
STUDY DRUG 
Formulation
Plitidepsin will be supplied as a powder and solvent for concentrate for 
solution for infusion. The 2-mg vial should be reconstituted with a 4-
mL ampoule of reconstitution solution. The list of excipients is: D-
mannitol, nitrogen, polyoxyl 35 castor oil (Macrogolglycerol 
Ricinoleate Ph.Eur.), absolute ethanol, and water for injections. The 
composition of the reconstitution solution is: polyoxyl 35 castor 
oil/ethanol/water for injection (15/15/70% v/v/v).
Administration
route 
One-hour intravenous infusion (fixed rate) via central or peripheral 
venous catheter.
Starting dose and 
schedule
A cycle is defined as a four-week period. Patients will receive 3.2 
mg/m2 plitidepsin on Day 1, 8 and 15 every four weeks (q4wk). A 1-
day window is allowed for plitidepsin administration.
PROPHYLACTIC 
MEDICATION
All patients must receive the following prophylactic medication 
30–60 min before infusion of plitidepsin:
1)
Dexamethasone (8 mg i.v. or equivalent)
2)
5-HT3 receptor antagonist: palonosetron 0.25 mg i.v. or tropisetron 
5 mg i.v. or granisetron 3 mg i.v. (avoid ondansetron as this drug is 
categorized within a known risk of producing Torsade de Pointes)
(see Appendix 8). Alternatively, metoclopramide or other 
antiemetic drugs may be used instead as per Investigator’s 
criteria/institutional guidelines, and
3)
Diphenhydramine hydrochloride (25 mg i.v.) or equivalent, and
4)
Ranitidine (50 mg i.v.) or equivalent.
Oral metoclopramide and/or extended oral 5-HT3 receptor antagonist
may be used as per Investigator’s criteria/institutional guidelines.
Additional dexamethasone can only be used as an antiemetic in the 
event alternative antiemetics cannot be used; and only if the 
Investigator considers the options above as insufficient.
CRITERIA FOR  
TREATMENT 
CONTINUATION
Patients can continue to receive plitidepsin infusions (Day 1, 8, 15 of 
each cycle) for a maximum of six cycles (unless with PR or SD after 
Cycle 6) if they fulfill the following requirements:

ANC ≥ 1.0 × 109/L (or baseline values in the case of 
extensive bone marrow infiltration).

Platelet count ≥ 75 × 109/L. 

Hemoglobin ≥ 9.0 g/dL.

Calculated CrCL ≥ 30 mL/min (Cockcroft-Gault formula).

Total bilirubin ≤ 1.5 × ULN (grade 1).

AST, ALT ≤3.0 × ULN (grade 1).

Normal 
value 
of 
electrolytes, 
including 
potassium, 
magnesium and calcium.

Muscular toxicity (myalgia, muscular weakness, CPK 


CL_0254 4.0
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Protocol APL-B-021-13
increase) < grade 2.

Other non-hematological drug-related AEs [except for 
increased gamma glutamyltransferase (GGT), not optimally-
treated nausea and vomiting, hypertension or alopecia] 
grade 1.

No clinically relevant ECG changes compared with grade at 
baseline.

QTc must be ≤ grade 1 before receiving the study treatment. 
In case of grade 1 QTc prolongation during treatment, and 
after discussion with the Sponsor, treatment must be 
continued with a normal value of electrolytes, including 
potassium, magnesium and calcium, being mandatory before 
the re-administration of plitidepsin. 

In case of QTc ≥ grade 2, the study treatment must be 
discontinued, and the patient must be followed until 
recovery.
If these criteria are not met on Day 1 of any cycle after Cycle 1, the 
new cycle is to be delayed for up to two weeks until recovery. If these 
toxicities do not recover after a 2-week delay, the patient is to 
discontinue treatment and start the follow-up period unless there is 
obvious clinical benefit, in which case the patient might restart 
treatment at the Investigator’s discretion and after obtaining approval
from the Sponsor.
If these criteria are not met on Day 8 and 15 of any cycle (including 
Cycle 1), the scheduled infusion is to be omitted. Omitted doses for a 
given cycle are not to be recovered. 
“Cycle delay”, therefore, is only applicable to the first infusion of a 
new cycle (i.e., Day 1) and not when an infusion takes place within the 
protocol-permitted window (one day) and not when treatment resumes 
after radiological assessment.
DOSE 
REDUCTION
Dose adjustments are to be based on the worst toxicity occurring during 
the previous cycle. The following table shows the plitidepsin dose 
levels used in this study. 
Dose level
Plitidepsin dose (mg/m2)
0
3.2 
–1
2.7 
–2
2.3 
Once the dose given to a patient is reduced, it cannot be re-escalated. 
Patients requiring dose reduction below dose level –2 should 
discontinue treatment and enter follow-up (except in cases of obvious 
clinical benefit when further dosing changes must be agreed with the 
Sponsor).
The plitidepsin dose should be reduced if the patient meets any of the 
following criteria:

Less than 50% compliance with the treatment schedule.

Febrile neutropenia.

Grade 4 neutropenia and infection, or grade 4 neutropenia lasting > 
7 days.

Grade 4 thrombocytopenia.


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Protocol APL-B-021-13

Grade ≥2 muscular toxicity (weakness, myalgia and/or CPK 
elevations). 

Grade ≥ 3 AST/ALT increase.

Any grade ≥ 3 clinically relevant, non-hematological toxicity 
(except non-optimally treated nausea and vomiting, diarrhea lasting 
< 48 h and/or grade ≥ 3 fatigue lasting < 5 days).
ALLOWED 
MEDICATIONS/ 
THERAPIES
1)
Erythropoietin.
2)
Therapies for the treatment of pre-existing and/or emergent 
medical conditions not specifically forbidden as per protocol 
elsewhere.
3)
Antiemetics according to institutional or American Society of 
Clinical Oncology (ASCO) guidelines.
4)
G-CSFs according to institutional or ASCO guidelines (except for 
primary prophylaxis and when screening for eligibility).
5)
Systemic and/or local therapies for symptomatic relief, 
particularly in the case of diarrhea or skin toxicity.
6)
Adequate 
analgesic 
medication, 
including 
opioids 
for 
symptomatic pain relief if indicated.
7)
Platelet and red cell transfusions are allowed within one week 
prior to the infusion and during the study.
PROHIBITED 
MEDICATIONS/
THERAPIES
1)
Concomitant administration of any other antineoplastic therapy.
2)
Other investigational agents.
3)
Immunosuppressive therapies, except hydrocortisone used on 
isolated occasions as treatment for hypersensitivity reactions, or 
for the relief of the symptoms derived from the disease, if 
required.
4)
Primary prophylaxis with colony-stimulating factors such as G-
CSF.
5)
Any medication with known risk of producing Torsade de 
Pointes, including ondansetron (see Appendix 8).
EFFICACY 
EVALUATIONS
Main efficacy analyses will be assessed in all eligible and treated 
patients with AITL diagnosis confirmed after central pathological 
review. 
Supportive efficacy analyses will be assessed in all treated patients 
and in all evaluable patients—defined as eligible patients who 
receive at least two plitidepsin cycles in which at least two complete 
infusions have been administered and had at least one disease 
assessment—as well as in patients who discontinue treatment 
without Cycle 3 tumor assessment after at least two plitidepsin 
infusions due to disease progression (PD) (or death due to PD) or 
toxicity (or death due to toxicity), defined as “early PD” and 
“treatment failures” respectively.
SAFETY 
EVALUATIONS
Patients will be evaluable for safety if they have received any partial 
or complete treatment cycle. All AEs will be graded according to the 
National Cancer Institute Common Terminology
Criteria for 


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Protocol APL-B-021-13
Adverse Events (NCI-CTCAE) v.4. Cycle delays, skipped doses, 
dose 
reduction 
requirements, 
and 
reasons 
for 
treatment 
discontinuation will be monitored throughout the study.
The safety profile of patients will be monitored throughout the 
treatment and up to 30 days after the last treatment dose (end of
treatment, EOT), or until the patient starts a new antitumor therapy 
or until the date of death, whichever occurs first.
Any treatment-related AEs will be followed until recovery to at least 
grade 1 or stabilization of symptoms, whenever possible.
PHARMACO-
KINETICS
All patients included in the study will be sampled for 
pharmacokinetics (PK). Twelve PK samples will be obtained on 
Days 1, 8 and 15 of Cycle 1 and will be evaluated by standard non-
compartmental analysis (population pharmacokinetic modeling may 
be performed if appropriate).  
BIOMARKER 
ANALYSIS
The assessment of potential predictive factors to plitidepsin treatment 
will be analyzed on available paraffin-embedded tumor tissue samples 
(obtained at diagnosis and relapse) and on blood samples. These factors 
will include molecular markers related to the mechanism of action of 
plitidepsin or to the pathogenesis of the disease. The following analysis 
will be carried out, whenever relevant: 
a) alterations in DNA and RNA, including DNA mutational status, 
RNA expression levels and miRNA expression, for common 
genetic lesions affecting the AITL clone; 
b) alteration in tumor tissue biomarkers including (but not limited to) 
assessment of pathways and mechanisms of action of plitidepsin, 
mainly status at the protein expression level; and
c) peripheral blood analyses, to identify plasma biomarkers including 
(but not limited to) cancer-related mutations and to extract DNA. 
STATISTICAL 
METHODS
Primary Endpoint

Overall response rate (ORR), defined as the percentage of 
patients with remission, either complete (CR) or partial 
remission (PR), according to the Lugano classification
response criteria per independent review.
An external IRC will assign the objective response and a 
progression or censoring date for each patient according to a 
predefined algorithm provided in a separate charter.
Secondary Endpoints

ORR per Investigator assessment (IA).

CR rate, defined as the percentage of patients with complete 
remission according to the Lugano classification per IRC and
per IA.

Duration of response (DoR), defined as the time from the 
date when the remission criteria (PR or CR, whichever is 
first achieved) are fulfilled to the first date when PD, 
recurrence or death (due to any cause) is documented. 
Response will be assessed according to Lugano classification


CL_0254 4.0
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Protocol APL-B-021-13
and per IRC and IA.

Progression-free survival (PFS), defined as the time from the 
date of first drug administration to the date of PD, death (of 
any cause), or last tumor evaluation per IRC and IA.

Progression-free survival at 6/12 months (PFS6/PFS12), 
defined as the Kaplan-Meier estimate of the percentage of 
patients who are progression-free at six/twelve months after 
the first drug administration per IRC and IA.

Intrapatient PFS/TTP, defined as the ratio of PFS achieved 
with the experimental treatment versus prior last TTP in the 
R/R setting. 

Overall survival (OS), defined as the time from the date of 
the first dose to the date of death (of any cause) or last 
patient contact.

Overall survival at 6/12 months (OS6/OS12), defined as the 
Kaplan-Meier estimate of the percentage of patients who are 
alive at six/twelve months after first drug administration.

Treatment safety [AEs, serious adverse events (SAEs) and 
laboratory abnormalities] graded according to the NCI-
CTCAE, v.4. Dose reductions, omitted doses or cycle delays 
due to treatment-related AEs, and reasons for treatment 
discontinuations will be analyzed.

Pharmacokinetics (PK), samples for PK analysis will be 
obtained during Cycle 1 exclusively.

Exploratory Biomarker Analysis, biopsy samples (initial and 
relapse) and blood samples will be analyzed in order to 
examine any correlation of efficacy with molecular markers 
related to the mechanism of action of plitidepsin or to the 
pathogenesis of the disease.
A total of 60 patients with AITL confirmed by central pathological 
review will be treated, 19 or more responders will be needed to get 
an overall estimate for response rate higher than 30% and its lower 
limit for the 95% confidence interval (CI) greater than 20% (31.7% 
CI95% 20.3–45.0% following the binomial distribution). 
Two futility analyses of the primary endpoint (ORR according to the 
Lugano classification response criteria per independent review) are 
planned to reject the alternative hypothesis around six months after 
approximately 25% and 50% of eligible patients have been treated 
(15 and 30 patients, respectively).  
ADDITION OF 
PATIENTS
All eligible and treated patients with AITL diagnosis confirmed after 
central pathological review will be included in the main efficacy 
analyses (primary and secondary endpoints). If a patient is treated but 
AITL diagnosis is not finally confirmed after central pathological 
review of the biopsy (even if inclusion was approved on the basis of 
the local histopathological report) then an additional patient will be 
included. Specifically, cases with features of follicular-PTCL and 
PTCL-NOS with TFH phenotype or with features of progression/
transformation from AITL to Diffuse Large B-cell Lymphoma need to 
be excluded from the main efficacy analysis so additions are permitted 


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Protocol APL-B-021-13
in the event such patients are included before (or in spite of) central 
pathological exclusion. All patients without central confirmation will 
be excluded from the main efficacy analyses but included in safety 
analyses and, as supportive analyses, efficacy assessments will be 
done including all treated patients.
PLANNED TRIAL 
PERIODS
(individually per 
patient)
Patients will be evaluated at scheduled visits in three study periods:

Pretreatment: from signature of informed consent to first dose of 
study treatment.

Treatment: from first dose of study treatment to End of 
treatment (EOT). EOT is standardly defined as 30 days (± one 
week) after the day of last administration of study treatment or as 
soon as possible after the End of Cycle 6 radiological and clinical 
assessments (if the patient discontinues), unless the patient starts a 
new antitumor therapy or dies within 30 days from the last dose, 
in which case the date of administration of this new antitumor 
therapy or the date of death will be considered the EOT date.

Follow-up: after EOT, patients will be followed every four weeks 
until resolution or stabilization of toxicities (if any). Patients who 
discontinue treatment without disease progression will be 
followed every four months (+ two weeks) for the first two years
of follow-up, and every six months (+ two weeks) thereafter,
unless clinically indicated, until PD, start of other antitumor 
therapy, death or the date of study termination (clinical cutoff), 
whichever occurs first. After documented progression or start of a 
new antitumor therapy, patients will be followed for survival 
approximately every four months during the first two years, and 
then approximately every six months until death or the date of 
study termination, whichever occurs first. For the purpose of 
collecting information on the patient’s survival exclusively, a 
documented telephone call is acceptable; follow-up for survival 
will be completed for all patients only if results of the primary 
endpoint confirm the trial as positive.  
Patients will be considered to be on-study from the signature of the 
informed consent form (ICF) to the end of the follow-up period (or 
screening failure).
Investigators can appraise potential study 
candidates in a pre-screening period but only perform study-specific 
screening assessments after the patient formally consents. Patients will 
be considered to be on-treatment from the date of first dose until 
EOT. 
Patients will receive study treatment until: 

Disease progression (PD).

Maximum of six cycles unless the patient is in:
PR 4–8 weeks after last dose of Cycle 6: in accordance 
with Investigator decision, the patient may then 
continue in treatment until CR or progression.
SD 4–8 weeks after last dose of Cycle 6: in 
accordance with Investigator decision, the patient 
may continue in treatment until CR or progression. 

If patient is in CR after six treatment cycles, treatment 


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Protocol APL-B-021-13
should be stopped. 

The patient achieves PR or CR at any time during the 
planned six cycles and is eligible for consolidation with 
autologous or allogeneic stem cell transplant (SCT) as per 
Investigator criteria. 

There is unacceptable toxicity.

There is intercurrent illness of sufficient magnitude to 
preclude safety continuation of the study.

There is patient refusal and/or non-compliance with study 
requirements.

Investigator’s decision.

There is a protocol deviation with an effect on the 
risk/benefit ratio management of the patient.

There is a treatment delay > 15 days from the treatment due 
date (except in case of clear clinical benefit, with the 
Sponsor’s approval).

There is a requirement of > 2 dose reductions (except in 
case of clear clinical benefit and with the Sponsor’s 
approval).
PLANNED TRIAL 
PERIODS (for the 
whole study)
The total duration of the study will be approximately 42 months. 
Planned start date (first patient on study): 2Q2016.
Planned enrollment period: 36 months.
Planned end-of-study date (clinical cutoff): 12 months after the last 
patient’s inclusion. If there are patients still being treated at the 
planned cutoff date, the actual cutoff date will be the date when those 
patients have completed the ongoing treatment cycle and the 
corresponding EOT visit.
The study will be closed earlier if fewer than 15 patients are recruited 
in the first year after most of the sites are in active enrollment. 
Recruitment reviews will continue annually to assess the feasibility of 
meeting the study objectives and study continuation. 


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Protocol APL-B-021-13
SCHEDULE OF ASSESSMENTS AND PROCEDURES
Study day
Screening/
Baseline
Cycle 1
Further cycles
End of 
Cycle 6
EOT (1)
Follow-
up (5,6)
1
8
15
22
29=1
8
15
22
Written IC (before any 
study procedures)

-
-
-
-
-
-
-
-
-
-
-
Plitidepsin 
administration
-



-



-
-
-
-
Demographic data
–28 to 0
-
-
-
-
-
-
-
-
-
-
-
Medical history/baseline 
conditions
–28 to 0
-
-
-
-
-
-
-
-
-
-
-
Cancer history (2)
–28 to 0
-
-
-
-
-
-
-
-
-
-
-
Complete physical 
examination (weight, 
BSA) 
–14 to 0

-
-
-

-
-
-


-
Basic neurological 
examination 
–14 to 0

-
-
-

-
-
-


-
Performance status 
(ECOG)
–14 to 0

-
-
-

-
-
-


-
Vital signs (HR, ABP, 
temp)
–14 to 0

-
-
-

-
-
-


-
Hematology (3)
–14 to 0







-


-
Biochemistry-A (3, 4)
–14 to 0







-


-
Biochemistry-B (4)
–14 to 0

-
-
-

-
-
-
-

-
Coagulation tests 
–14 to 0

-
-
-

-
-
-
-

-
Serum beta-2 
microglobulin
–14 to 0
-
-
-
-
-
-
-
-
-
-
-
ECG (7)
–14 to 0



-



-
-
-
-
Pregnancy test (8)
–14 to 0
-
-
-
-

-
-
-
-

-
Urine elemental dipstick 
and sediment
–14 to 0
Repeat if clinically indicated
-
-
Complete serology (viral 
load tests if indicated)
–14 to 0
Repeat if clinically indicated
-
-
Coombs test
–14 to 0
Repeat if clinically indicated
-
-
Serum immunoglobulin 
quantification 
(immunoelectrophoresis)
–14 to 0
Repeat if clinically indicated

-
Serum protein 
electrophoresis
–14 to 0
Repeat if clinically indicated

-
LVEF (ECHO or 
MUGA)
–28 to 0
Repeat if clinically indicated
-
-
Chest X-ray (if needed)
–28 to 0
Repeat if clinically indicated

-
Tumor assessment 
(PET/CT + CT) (9)
–28 to 0
1–2 wks after last dose of Cycle 3 and 4–8 wks after last 
dose of Cycle 6 (or at suspected clinical progression) (9)
-
-
Tumor assessment (CT) 
(10)
-
-
-
(10)
Bone marrow 
biopsy/aspirate
–14 to 0
Repeat if clinically indicated
If involved 
at  
diagnosis
-
Biopsy/blood sample
(11)
(11)
-
-
-
Concomitant therapies
–14 to 0
Throughout the on-treatment period 
-
Pharmacokinetics
-



-
-
-
-
-
-
-
-
Adverse events (12)
–14 to 0
Throughout the on-treatment period 
(5,6)


CL_0254 4.0
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Protocol APL-B-021-13
Day 0 = registration, confirmation of eligibility; Day 1 = day of first cycle administration (with infusion start); Day 29 = Day 1 of the 
next cycle. Note that registration may or may not be the calendar day prior to Day 1 but Day 0 implies that there should be no gap in the 
collection of relevant patient data; in either case, the total screening duration must be no longer than the 28-day period prior to Day 1.
If an infusion is delayed beyond the permitted protocol window, assessments planned for the original infusion day must be repeated on 
the day infusion finally takes place. Assessments for a particular visit do not need to all take place on the same day but should all be 
within the planned time window. Physical examination and laboratory assessments, for example, can be performed more frequently 
during the study if clinically required.
Permitted windows for assessments
±1 day for study treatment administration and clinical assessments (ECOG PS, vital signs, weight, BSA, neurological assessment—
always prior to infusion).
–2 days for hematology, biochemistry-A, serum β-2 microglobulin, biochemistry-B and coagulation tests. Note: windows for laboratory 
assessments only apply prior to the scheduled infusion, that is within 48 hours before the next scheduled infusion (except C1D1). 
(1)
EOT assessments should take place approximately 30 days (± one week) after discontinuation of study treatment or as soon as 
possible after the End of Cycle 6 radiological and clinical assessments (if the patient discontinues). Failure to attend the EOT visit 
exclusively due to a deteriorated clinical condition will not be considered a protocol deviation. The listed assessments are 
required if no recent data are available (i.e. within the previous 10 days) or if the last data available show a grade ≥ 2 
treatment-related alteration whenever the medical condition of the patient allows.
(2)
The patient’s anonymized local histopathology report must be provided as early as possible in the screening process for central 
pathological review. Cancer history includes: primary diagnosis; prognostic factors at first diagnosis (PIT, IPI, PIAI); prior 
treatment(s) with best response and TTP; documented relapse or refractory disease. Prognostic Index for Peripheral T-cell 
lymphoma (PIT) uses four variables as predictive for survival: age, PS, LDH level, and BM involvement (see Appendix 3). The 
standard International Prognostic Index (IPI) comprises the following variables: age ≥ 60 years, disease stages III to IV, LDH > 
normal, extranodal sites (ENSs) > one and PS ≥ 2. The alternative Prognostic Index for AITL (PIAI) comprises the following 
factors: age ≥ 60 years, PS ≥ 2, ENSs > one, B symptoms and platelet count < 150 × 109/L (see Appendix 4). Ann-Arbor staging is 
also required (see Appendix 5).
(3)
Not necessary on C1D1 if performed within the seven previous days and there is no change in the patient’s clinical status and 
medications. To be performed at least every other day in the presence of grade 4 non-febrile neutropenia or febrile neutropenia, 
and every day in the presence of grade 4 thrombocytopenia until recovery.
(4)
Not necessary on C1D1 if performed within the seven previous days and there is no change in the patient’s clinical status and
medications. Biochemistry-A to be performed at least every other day in the presence of grade 3/4 vomiting or any other drug-
related SAE.
(5)
Patients discontinuing treatment due to a drug-related AE should be followed until recovery/stabilization. Beyond 30 days after the 
last administration of the study drug, only those procedures that are relevant to response assessment or any remaining toxicity need 
to be performed. 
(6)
Patients who discontinue treatment without progression will be followed until PD, start of other antitumor therapy, death or the 
date of study termination (clinical cutoff), whichever occurs first: see schedule in point (10). After documented progression or 
start of a new antitumor therapy, patients will be followed for survival approximately every four months during the first two
years, and then approximately every six months until death or the date of study termination, whichever occurs first. For the 
purpose of collecting information on patient’s survival, a documented telephone call is acceptable; follow-up for survival will 
be completed for all patients only if results of the primary endpoint confirm the trial as positive.
(7)
First cycle, Day 1: Prior to the first infusion (unless performed as part of screening within the previous 14 days), at the end of the 
first infusion, at 30 min post-infusion and at 1-hour post-infusion. First cycle, Day 8 and Day 15: Prior to the infusion, and at 1-
hour post-infusion (see Table 6). Further cycles: Prior to each infusion.
Rhythm, frequency and QT interval should be specifically described, as well as any ECG anomaly or variation with respect to 
baseline.
(8)
Assessment of β-hCG only if the patient is a WOCBP. During the on-treatment period, testing should be every cycle (or, at 
least, every month).
(9)
Clinical and radiological assessment. When PET-CT is performed it must be in combination with diagnostic quality CT with 
intravenous contrast (except medically contraindicated). Two alternatives are allowed: Hybrid PET CT scanners may be used 
to acquire diagnostic quality CT which includes intravenous contrast OR PET CT without intravenous contrast and diagnostic 
quality CT images with intravenous contrast using a standalone CT scanner must be performed.
A PET-CT scan for radiological tumor assessment is required at baseline, one to two weeks after last dose of Cycle 3 and at least 
four weeks (but no more than 8 weeks) after last dose of Cycle 6 (or earlier in the event of treatment discontinuation for whatever 
reason; no radiological assessment is necessary in the event of withdrawal due to any reason other than PD during or after Cycle 4 
if the Cycle 3 radiological assessment has been performed correctly) or at suspected clinical progression while on treatment. Cycle 
4 can be started without waiting for the results of the Cycle 3 tumor assessment. The End of Cycle 6 visit should take place 4–8 
weeks after last dose of Cycle 6 (when the PET-CT results are available). If a patient is shown to have SD or PR at this 
assessment, treatment can resume (Cycle 7), and tumor assessment may be evaluated by CT scans every four months (+ 2 weeks)
for the first two years and every six months (+ 2 weeks) thereafter, but any subsequent improvement in response should be 
confirmed by PET-CT. If a patient is shown to have CR or PD, the patient should be discontinued and the EOT visit performed as 
soon as possible. Disease progression at any time during the study should be confirmed by imaging (if the physical condition of 
the patient permits).
(10) Clinical and radiological assessment. A CT scan may be used for radiological tumor assessment of patients who showed clinical 
benefit (SD, PR, CR) every four months (+2 weeks) for the first two years of follow-up, and every six months (+2 weeks)
thereafter, unless clinically indicated. In the case a patient continues in treatment beyond Cycle 6 (see section 5.2.1.2), CT may be 
used but any subsequent improvement in response should be confirmed by PET-CT.
(11) Diagnosis and/or re-biopsy specimens are required for central pathological review and prior to each futility analysis. An incisional 
or excisional biopsy is preferred but a core-needle biopsy can be considered when excisional biopsy is not possible. Archived 
tissue samples of representative tumors: a formalin-fixed paraffin-embedded (FFPE) tissue block (preferred) or freshly-cut 
unstained tumor slides. Collect 10 mL blood at the same time as the first PK sample on Day 1: one whole blood sample for 
germline DNA extraction (6 mL) and another blood sample (4 mL) to obtain plasma. A separate instruction manual for sites will 
be provided.


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(12) Clinical assessment of the patient’s signs and symptoms (if any and including nurses’ assessment and patient-reported issues) 
should continue on an ongoing basis throughout the study and be reported at least every cycle as AEs graded according to 
NCI-CTCAE v.4: between IC and Day 0, AEs are considered baseline and non-treatment emergent.
Hematology: Differential white blood cells (WBC), hemoglobin, hematocrit and platelets.
Biochemistry-A: AST, ALT, total bilirubin (direct bilirubin if total bilirubin > 1.5 × ULN), ALP, creatinine, calculated creatinine 
clearance (Cockcroft-Gault formula), glucose, serum electrolytes (Na+, K+, Mg++, Ca++) and CPK (CPK-MB fraction should be 
measured if CPK is abnormally high).  
Biochemistry-B: Uric acid, LDH, total proteins, albumin and C-reactive protein.
Coagulation tests: PT, PTT and INR.
ABP, arterial blood pressure; AE, adverse event; ALT, alanine aminotransferase; ALP, alkaline phosphatase; AST, aspartate 
aminotransferase; BM, bone marrow; CPK, creatine phosphokinase; CPK-MB, creatine phosphokinase-isoenzyme MB; ECG, 
electrocardiogram; ECHO, echocardiogram; ECOG, Eastern Cooperative Oncology Group; EOT, end of treatment; HR, heart rate; 
IC, Informed Consent; INR, international normalized ratio; LDH, lactic dehydrogenase; LVEF, left ventricular ejection fraction; 
MUGA, multiple-gated acquisition scan; NCI-CTCAE, National Cancer Institute Common Terminology Criteria for Adverse 
Events; PD, progressive disease; PS, performance status; PT, prothrombin time; PTT, partial thromboplastin time; SAE, serious 
adverse event; TTP, time to progression; ULN, upper limit of normality; WBC, white blood cells; wk, week; WOCBP, woman of 
childbearing potential.


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
ACVBP
Doxorubicin, Cyclophosphamide, Vindesine, Bleomycin and Prednisone
AE(s)
Adverse Event(s)
AITL
Angioimmunoblastic T-cell Lymphoma
ALP
Alkaline Phosphatase
ALT
Alanine Aminotransferase
ANC 
Absolute Neutrophil Count
ASCO
American Society of Clinical Oncology
ASCT
Autologous Stem Cell Transplantation
AST
Aspartate Aminotransferase
BM
Bone Marrow
BSA
Body Surface Area
CHOP
Cyclophosphamide, Doxorubicin, Vincristine and Prednisone
CI
Confidence Interval
CLL
Chronic Lymphocytic Leukemia
CNS
Central Nervous System
CPK
Creatine Phosphokinase
CPK-MB
Creatine Phosphokinase-isoenzyme MB
CR
Complete Remission/Complete Response
CrCL
Creatinine Clearance
CRF
Case Report Form
d/D
Day(s)
DoR
Duration of Response
EBV
Epstein-Barr Virus
ECG
Electrocardiogram
ECHO
Echocardiogram
ECOG
Eastern Cooperative Oncology Group
EDTA
Ethylenediaminetetraacetic Acid
EOI
End of Infusion
EOT
End of Treatment
EPO
Erythropoietin
FDA
Food and Drug Administration (United States)
FDC
Follicular Dendritic Cells
FFPE
Formalin-fixed Paraffin-Embedded
FFS
Failure-free Survival
FUP
Follow-up
GCP
Good Clinical Practice
G-CSF
Granulocyte Colony-stimulating Factor


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GELA
Groupe d'Etude des Lymphomes de l'Adulte
GGT
Gamma-glutamyltransferase
GMT
Greenwich Meridian Time
H
Hour
HBV
Hepatitis B Virus
hCG
Human Chorionic Gonadotropin
HCV
Hepatitis C Virus
HIV
Human Immunodeficiency Virus
i.v.
Intravenous (Intravenously)
IA
Investigator’s Assessment
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Conference on Harmonization
ICOS
Inducible T-cell Co-stimulator
IDMC
Independent Data Monitoring Committee
IEC
Independent Ethics Committees
IHC
Immunohistochemistry
IMP
Investigational Medicinal Product
INR
International Normalized Ratio
IPI
International Prognostic Index
IRB
Institutional Review Board
IRC
Independent Review Committee
ISH
In Situ Hybridization
IWG
International Working Group 
LDH
Lactate Dehydrogenase
LLN
Lower Limit of Normal
LVEF
Left Ventricular Ejection Fraction
MR 
Minimal Response
MUGA
Multiple-gated Acquisition Scan
MVD
Microvessel Density
NCI
National Cancer Institute
NCI-CTCAE
National Cancer Institute-Common Terminology Criteria for Adverse Events
NE
Not Evaluable
NGS
Next-generation Sequencing
NHL
Non-Hodgkin Lymphoma
ORR
Overall Response Rate
OS
Overall Survival
OS12
Overall Survival at 12 Months
OS6
Overall Survival at 6 Months
p.o.
Per os (orally)


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PD
Progressive Disease
PET
Positron Emission Tomography
PFS
Progression-Free Survival
PFS12
Progression-Free Survival at 12 Months
PFS6
Progression-Free Survival at 6 Months
PhV
Pharmacovigilance
PIAI
Prognostic Index for AITL
PIT
Prognostic Index for Peripheral T-cell Lymphoma
PK
Pharmacokinetic
PR
Partial Remission/Partial Response
PRE TT
Pretreatment
PS
Performance Status
PT
Prothrombin Time
PTCL
Peripheral T-Cell Lymphoma
PTCL-NOS
Peripheral T-Cell Lymphoma - Not Otherwise Specified
PTT
Partial Thromboplastin Time
q4wk
Every Four Weeks
R/R
Relapsed/Refractory
RBC(s)
Red Blood Cell(s)
SAE(s)
Serious Adverse Event(s)
SCT
Stem Cell Transplantation
SD
Stable Disease
SPEP
Serum Protein Electrophoresis
SUSAR/SUA
Suspected Unexpected Serious Adverse Reaction
TFH
T Follicular Helper
TT
Treatment
TTP
Time to Progression
ULN
Upper Limit of Normal
VEGF
Vascular Endothelial Growth Factor
VEGF-R
Vascular Endothelial Growth Factor Receptor
WBC
White Blood Cells
WMA
World Medical Association
WOCBP
Woman/Women of Childbearing Potential
β-hCGs
Beta Subunit of Human Chorionic Gonadotropins


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1.
INTRODUCTION
1.1
DISEASE BACKGROUND: ANGIOIMMUNOBLASTIC T-CELL LYMPHOMA
Angioimmunoblastic T-cell lymphoma (AITL) is the second most common form of 
peripheral T-cell lymphoma (PTCL), accounting for approximately 20% of PTCLs and 
2% of non-Hodgkin lymphomas (NHL) (1). In the United States, the incidence is 
approximately 0.05 cases per 100,000 person years (2). The disease is more common in 
Europe (29% of PTCL cases) than in the United States or Asia (3).
1.1.1
Clinical Features of Angioimmunoblastic T-cell Lymphoma
AITL characteristically affects elderly people, particularly those aged 60 to 80 years, 
with male predominance. Interestingly, some cases present as a subacute or acute 
systemic illness, which may manifest after the administration of drugs, especially 
antibiotics, or after a viral infection. 
Immune dysregulation is an important characteristic of this disease. Generalized 
lymphadenopathy is almost constant, as well as the presence of constitutional symptoms 
such as fever and weight loss (4). Extranodal disease is common, with 
hepatosplenomegaly and bone marrow (BM) involvement in up to 70% of cases. The 
presence of circulating tumor cells is frequent and approximately 50% of cases show a 
maculopapular rash (5).
Other variable manifestations of AITL include arthralgias, pleural effusions, ascites, 
lung involvement with irregular infiltrates, neurological manifestations and 
gastrointestinal involvement. Stage III or IV is observed in more than 80% of AITL 
cases (6, 7).
Some laboratory abnormalities are frequently observed: anemia (often hemolytic and 
Coombs positive), hypereosinophilia, polyclonal hypergammaglobulinemia as well as 
lactate dehydrogenase (LDH) elevation are characteristic aspects of the disease. Other 
less common laboratory abnormalities include lymphopenia, thrombocytopenia and the 
presence of various autoantibodies (rheumatoid factor, antinuclear factor, anti-smooth 
muscle, cryoglobulins or cold agglutinins) (8).
Distinguishing pathological features include the presence of diffuse polymorphous 
infiltrate consisting of typical tumor cells admixed to small lymphocytes, histiocytes, 
immunoblasts, eosinophils and plasma cells. Prominent branching high endothelial cells 
and irregular proliferation of follicular dendritic cells are frequently observed and 
represent unique histological features among the PTCL subtypes. B immunoblasts may 
be numerous in areas between follicular dendritic cells (FDC) and they often harbor 
Epstein-Barr virus (EBV). Occasionally in the course of the disease, this immunoblast 
EBV-expressed population gives rise to secondary large B-cell lymphomas (9, 10).
The malignant T-cell has been characterized as an unusual subset of CD4 positive 
follicular T helper (TFH) cells, and typical markers may help in the diagnosis of the 
disease, such as CD10, CXCL13, PD-1 and bcl-6 as well as the expression of ICOS (11-
14). CD10 positivity is observed in up to 30% of cases of AITL in contrast to other 
PTCL subtypes. These markers are distinctive enough to help in the diagnosis of the 
disease in contrast with other PTCL subtypes (15).
AITL has been associated with some viruses, specifically EBV and herpes virus 6 
(HPV6) genomes (16). Although there is not a single characteristic genetic alteration in 
the disease, trisomy 3, trisomy 5 and an additional X chromosome may be observed 
(17).


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Recently, critical insights into AITL have been gained from molecular analysis. A 
global molecular signature of AITL has been described which defines characteristically 
the disease and contrasts with the molecular signature of other PTCL subtypes (18, 19). 
The contribution of tumor and microenvironment has been highlighted by these studies. 
Indeed, characteristic overexpression of B-cell related genes, chemokines and 
chemokine receptors as well as genes related to the extracellular matrix and 
angiogenesis have been clearly delineated (19, 20). This signature is unique among the 
PTCL setting and offers the opportunity to target these events as therapeutic strategies.
1.1.2
Pathogenesis of Angioimmunoblastic T-cell Lymphoma
AITL is a tumor of TFH cells (14, 21). In this context, the expression of the CXCL13 
chemokine is a key pathogenic factor. Throughout this chemokine, recruitment of B-cell 
lymphocytes into the germinal centers takes place. Furthermore, the expression of this 
chemokine by tumor cells activates this B-cell component and expands and facilitates 
plasmacytic differentiation, which in turn results in hyperglobulinemia and secretion of 
Il 21 (22).
The tumor microenvironment displays characteristic functional alterations. For instance, 
quantitative and qualitative abnormalities of T-cell subsets lead to paraneoplastic 
immunological dysfunction. Aside from the expanded B-cell component and T-cell 
alterations, other stroma alterations are important in the pathogenesis of AITL. Indeed, 
vascular endothelial growth factor (VEGF) and its receptors, as well as angiopoietin 1 
are typically expressed and secreted by both tumor cells and FDC, then stimulating 
tumor angiogenesis (19, 20). Thus, angiogenesis might be a therapeutic target of AITL.
1.1.3
Natural History of Angioimmunoblastic T-cell Lymphoma and Prognostic 
Factors
The clinical course of AITL varies, with occasional spontaneous remissions. 
Nevertheless, the prognosis of the disease is dismal, with median survival < 3 years, and 
with 20–30% of long-term survivors (3, 23). Different clinical risk factors as well as 
biological parameters have been described as prognostic factors. In a retrospective study 
of 157 cases of AITL, a multivariate analysis showed the following covariates as 
adversely associated with prognosis: male gender, anemia and the presence of 
mediastinal lymphadenopathy (7).
Other systems such as the International Prognostic Index (IPI) (24) or the prognostic 
index for peripheral T-cell lymphoma (PIT) (Appendix 3) were of limited value in this 
disease (25). Recently, a risk model for AITL (prognostic index for AITL, PIAI) was 
designed based on the following adverse covariates: age > 60 years, performance status
≥2, extranodal sites > 1, B-symptoms, and platelet count < 150,000/mL (23). The 
simplified PIAI had a low-risk group (zero to one factors) with a 5-year survival of 
44%, and a high-risk group (two to five factors) with a 5-year survival of 24%
(Appendix 4).
1.1.4
Definition and Pathological Diagnosis of Angioimmunoblastic T-cell 
Lymphoma
Definition and diagnosis of AITL will be based on current standard criteria (Appendix 
1).
Systemic clinical manifestations are a hallmark of AITL and include: generalized 
lymphadenopathy, hepatosplenomegaly, skin rash (often with pruritus), bone marrow 


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involvement, advanced clinical stage, and polyclonal hypergammaglobulinemia. In the 
absence of systemic clinical syndrome, an AITL diagnosis is doubtful.
Pathologically, AITL is a morphologically heterogeneous T-cell lymphoma 
characterized by a polymorphous infiltrate of the lymph nodes by small to medium-size 
lymphocytes, with clear to pale cytoplasm, and with expression of TFH markers (PD1, 
BCL6, CXCL13, CD10, ICOS), associated with a prominent proliferation of high 
endothelial venules and follicular dendritic cells (26). Several morphologic variants 
have been described, including classic (diffuse +/- epithelioid cells), rich in large cells, 
and hyperplastic germinal centers.
1.1.5
Treatment for Angioimmunoblastic T-cell Lymphoma
Conventional chemotherapy regimens with cyclophosphamide, doxorubicin, vincristine 
and prednisone (CHOP) or CHOP-like fail to increase the long-term survival rate to 
more than 30% (7). Different single agents (cyclosporine, thalidomide, lenalidomide or 
gemcitabine) have been associated with responses, including complete durable 
responses. Activity has also been observed with nucleoside analogs, such as fludarabine, 
2-chlorodeoxyadenosine, interferon-alfa corticosteroids and others (27).
In the 
International Peripheral T-cell lymphoma project, the 5-year overall survival (OS) and 
failure-free survival (FFS) were 33% and 18%, respectively (3).
Due to the poor prognosis of the disease, more intensive conventional chemotherapeutic 
regimens have been tested in AITL, such as adding etoposide to CHOP or the Groupe 
d'Etude des Lymphomes de l'Adulte (GELA) regimen of ACVBP (doxorubicin, 
cyclophosphamide, vindesine, bleomycin and prednisone) (7). However, no substantial 
improvement has been observed. In retrospective analyses, consolidation of response 
with autologous stem cell transplantation (ASCT) yielded superior results than 
conventional chemotherapeutic regimens (28, 29). However, the role of ASCT as 
consolidation in the first-line therapy of AITL has not been proven to date.
Data on allogeneic transplantation are encouraging but population size is limited. Other 
available agents, such as alemtuzumab or Ontak®, or therapies targeting VEGF (e.g., 
bevacizumab) have shown anecdotal activity in PTCL (7, 30-33). More robust data 
evaluating the efficacy and safety of bendamustine as single agent in refractory or 
relapsed PTCL were reported from the BENTLY trial (34). In this study, 60 patients 
were included with 27 of them (45%) being refractory to their last prior chemotherapy. 
The median number of previous lines of chemotherapy was one and 33% of patients 
received fewer than three cycles of bendamustine, mostly because of progression. In an
intention-to-treat analysis, the overall response rate (ORR) was 50%, with 28% of 
patients showing complete remissions (CRs). The duration of response (DoR), 
progression-free survival (PFS) and OS were 3.5, 3.6 and 6.2 months, respectively. The 
response rate of AITL patients in this population was not significantly different from the 
overall PTCL group. To date, three single agents, pralatrexate, romidepsin and 
bendamustine, are considered active drugs in PTCL, with higher activity for the AITL 
subtype with romidepsin and bendamustine. 
Since the tumor microenvironment has a key role in the pathogenesis of AITL, several 
therapeutic maneuvers have been tested in this regard. For instance, the GELA group 
tested the regimen of CHOP-rituximab targeting the B-cell component of the disease, 
which may have importance in the maintenance of the tumor cell. However, the results 
of this study do not demonstrate any improvement over the results obtained with CHOP 
alone. Few case reports in the literature have shown complete remissions with


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immunomodulators such as thalidomide or lenalidomide (35). Other drugs target the 
epigenetic alterations typically observed in AITL, with some responses with histone 
deacetylase inhibitors such as SAHA (suberoylanilide hydroxamic acid), depsispeptide 
or bellinostat. Furthermore, mutations in genes involved in the control of chromatin 
structures, such as IDH 1, 2 and TET2 have been recently described (36, 37); this opens 
the door to testing hypomethylating agents in this disease. Other compounds like aurora 
kinase inhibitors are currently the subject of intensive investigation. 
In any case, due to the poor prognosis of the disease, new specific active agents are 
needed. Since PTCL represents a heterogeneous group of lymphomas, with several 
subtypes biologically different, the search of specific agents for the different subtypes 
must continue. Research challenges include the fact that these are very rare diseases 
with low frequency and, therefore, many logistic difficulties are encountered in these 
trials. Nevertheless, if we want to make progress in therapeutics, we need specific 
agents to treat these neoplastic diseases.
Two drugs (pralatrexate and romidepsin) have been approved by the FDA for the wide 
group of PTCL, in the particular case of refractory or relapsing patients after 
conventional or high-dose chemotherapy supported with stem cell transplantation, on 
the basis of modest activity in this group of Non-Hodgkin, poor prognosis lymphomas. 
However, the activity of these two drugs in the small number of treated patients with 
AITL, which were included in the more general group of PTCL, was variable. Indeed, 
only one of 13 patients with AITL (8%) who received pralatrexate responded to 
treatment, whereas eight of 27 patients (30%) treated with romidepsin responded, being 
included 5 CRs (19%) (38, 39). 
In the search for new active drugs, promising activity has been observed with plitidepsin 
in AITL. A phase II study evaluating plitidepsin in non-cutaneous PTCL (study APL-B-
013-02), showed a response rate of 20.7% in the whole group of treated patients. The 
response rate increased to 33.3% in the nine patients with AITL treated in this clinical 
trial (including CR in 22.2% of patients). Interestingly, one complete remission was 
obtained in a patient who had previously received ASCT; this remission was durable 
after more than 29 months since he was treated.
On the basis of the promising activity observed in this small cohort of AITL patients, 
this phase II clinical trial will evaluate plitidepsin as a treatment for patients with R/R
AITL.
1.2
INFORMATION ON THE STUDY DRUG: PLITIDEPSIN
Please refer to the Investigator’s Brochure (IB) for more detailed information on 
plitidepsin.
1.2.1
Name and Chemical Information
Plitidepsin (Aplidin®) is a cyclic depsipeptide originally isolated from a Mediterranean 
marine tunicate, Aplidium albicans. The molecular formula is C57H87N7O15 with a 
molecular weight of 1,110.341. Plitidepsin is manufactured by total synthesis.


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Figure 1. Molecular formula of plitidepsin.
N
O
NH
O
O
O
O
O
NH
OH
O
O
N
H
O
N
OMe
Me
O
N
Me
O
N
O
O
NMe-L-Tyr6
L-Pro5
L-Leu4
(2S,4S)-Hip3
Isostatine2
NMe-D-Leu7
L-Pro8
Pyr9 (Pyruvyl)
L-Thr1
1.2.2
Non-clinical Data
1.2.2.1
Mechanism of Action
Plitidepsin interacts and forms different complexes with eEF1A in two subcellular 
regions, first bound to the inner side of the plasma membrane and then free in the 
cytoplasm of tumor cells. This interaction leads to a decrease in production of 
intracellular glutathione, an increase in reactive oxygen species and ultimately to 
activation of the Rac1/JNK pathway and caspase-dependent apoptosis (40-42). In 
addition to the pro-apoptotic properties of plitidepsin, the molecule has demonstrated 
anti-angiogenic properties in several preclinical models via direct activity on VEGF-
stimulated angiogenesis. In fact, plitidepsin has been shown in vitro to reduce the 
secretion of VEGF and its receptor type 1 (VEGFR-1) from MOLT-4 human leukemia 
cells (43). It seems that the majority of the pharmacologic activity of plitidepsin can be 
attributed to a combination of these cellular effects in vivo.
1.2.2.2
In Vitro and In Vivo Activity
Plitidepsin showed antitumor activity with in vitro and in vivo models. In vitro studies 
showed cytotoxic effects of plitidepsin against a broad panel of cell lines with values of 
IC50 ≤ 1 nM. Plitidepsin was particularly active against multiple myeloma cell lines, 
human leukemia and lymphoma (48), as well as against pancreas, non-small cell lung, 
breast, melanoma, sarcoma, bladder, gastric, ovarian, and colon tumor cell lines. In vivo
studies showed an antitumor effect of plitidepsin in xenograft models of multiple 
myeloma (as a single agent or in combination with dexamethasone) and T-cell 
lymphoma (48). 
1.2.3
Clinical Data
As of 31 March 2015 (cutoff date for the Investigator’s Brochure version 15.0), 1103 
cancer patients had been included in the clinical development program of plitidepsin: 
381 in phase I studies, 474 in phase II studies (24 in one investigator-initiated phase II 
trial), and 248 in a phase III study. 
Two clinical trials in patients with relapsed/refractory multiple myeloma are ongoing at 
the time of the last analysis: a pivotal randomized phase III trial (APL-C-001-09–
ADMYRE) comparing plitidepsin in combination with dexamethasone against 


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dexamethasone alone that started in 2010; and a phase I trial (APL-A-012-13) of 
plitidepsin in combination with bortezomib and dexamethasone that started in 2014.
1.2.3.1
Phase I Trial in Multiple Myeloma
A phase I clinical trial (APL-A-012-13) of plitidepsin in combination with bortezomib 
and dexamethasone in patients with relapsed/refractory multiple myeloma started in 
April 2014. The primary objective is to determine the recommended dose of the 
combination. Fourteen patients had been included up to July 2015.
1.2.3.2
Phase II Trials in Hematological Malignancies
Table 1 summarizes the completed phase II clinical trials conducted with plitidepsin in 
patients with hematological malignancies.
Table 1. Completed phase II trials evaluating plitidepsin in hematological malignancies.
Study
Study design and objectives
Dose
(infusion)
Treated
patients
Efficacy
(objective response or TTP > 3 
months)
Fortnightly schedule (d1,15 q4wk)
APL-B-014-03
(49, 50)
Phase II multicenter, open-label, 
clinical and PK study of plitidepsin 
as a 3-hour infusion every 2 weeks 
alone or in combination with 
dexamethasone, in pre- treated 
patients with relapsing or 
refractory multiple myeloma
Plitidepsin
5 mg/m2
(3-h i.v.)
51
(n=47): 2 PR and 4 MR as per the 
Myeloma 
Response 
Criteria 
(ORR: 
12.8%). 
Plitidepsin
5 mg/m2
(3-h iv)
+
dexamethasone
20 mg p.o. d1-
4 q4wk
19*
(n=18): 2 PR and 2 MR as per the 
Myeloma 
Response 
Criteria 
(ORR: 
22.2%). 
Median TTP = 4.2 months; median PFS = 
3.8 months.
APL-B-020-10
(51)
Open-label, phase II clinical trial of 
plitidepsin in patients with primary 
myelofibrosis and post 
polycythemia vera/essential 
thrombocythemia myelofibrosis
Plitidepsin
5 mg/m2
(3-h i.v.)
12
(n=11): 1 clinical improvement as per the 
IWG-MRT consensus criteria (ORR: 
9.1%).
Median PFS = 4.6 months.
Weekly schedule (d1,8,15 q4wk)
APL-B-012-02
(52)
A Phase II multicenter, open-label, 
clinical and PK study of plitidepsin 
as a 1-hour weekly iv infusion, in 
patients with relapsed or refractory 
indolent non-Hodgkin lymphoid 
neoplasms
Plitidepsin 
3.2 mg/m2
(1-h i.v.)
8
(n=6): No objective responses as per the 
NCI-sponsored 
Working 
Group 
guidelines for NHL and CLL. 
SD in 5 patients. Median TTP = 4.0 mo; 
median PFS = 4.7 months; median OS = 
12.4 months.
APL-B-013-02
(53, 54)
A Phase II multicenter, open-label, 
clinical and PK study of plitidepsin 
as a 1-hour weekly iv infusion, in 
patients with relapsed or refractory 
aggressive non-Hodgkin 
lymphoma
Plitidepsin 
3.2 mg/m2
(1-h i.v.)
64
Non-cutaneous PTCL (n=29): 2 CR and 4 
PR as per the IWG criteria for NHL 
(ORR: 20.7%). 
Median TTP/PFS = 1.6 months; median 
OS = 10.2 months.
AITL (subgroup included in PTCL 
cohort; n=9): 2 CR and 1 PR as per the 
IWG criteria for NHL (ORR: 33.3%).
Duration of response of 121, 12 and 4 
weeks.
Other lymphomas (n=30): No objective 
responses as per the IWG criteria for 
NHL. 
Median TTP/PFS = 1.3 months; median 
OS = 4.5 months.


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Study
Study design and objectives
Dose
(infusion)
Treated
patients
Efficacy
(objective response or TTP > 3 
months)
APL-B-015-04
(55)
A Phase II multicenter, open-label, 
clinical and PK study of plitidepsin 
as a 1-hour weekly iv infusion, in 
patients with relapsed or refractory 
acute lymphoblastic leukemia 
Plitidepsin 
3.2 mg/m2
(1-h i.v.)
17
(n=13):
No 
complete 
or 
partial 
remissions. 
Median PFS = 0.6 months, median OS = 
2.1 months.
*All 19 patients were first given plitidepsin alone in this study, and after showing suboptimal response their treatment was 
supplemented with dexamethasone.   
The underlined n value shown in the efficacy column refers to patients evaluable for efficacy. 
CLL, chronic lymphocytic leukemia; CR, complete remission/complete response; i.v., intravenous; IWG, International Working 
Group; IWG-MRT, International Working Group for Myelofibrosis Research and Treatment; MR, minimal response; NCI, National 
Cancer Institute; NHL, non-Hodgkin lymphoma; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; 
PK, pharmacokinetic; p.o., orally; PR, partial remission/partial response; PTCL, peripheral T-cell lymphoma; q4wk, every four 
weeks; SD, stable disease; TTP, time to progression. 
1.2.3.2.1 Phase II Trials in Non-Hodgkin Lymphoma
Two phase II clinical trials evaluated the efficacy of the weekly (D1, 8 and 15 q4wk) 
schedule in patients with NHL. In one of these two studies (APL-B-012-02), no 
remissions were found. Evidence of antitumor activity was found in trial APL-B-013-
02, in which the D1, 8 and 15 q4wk schedule was administered to 64 patients with 
relapsed/refractory aggressive NHL: 32 with non-cutaneous PTCL and 32 with other 
lymphomas. In the PTCL cohort, two CRs and four PRs as per the International 
Working Group (IWG) criteria for NHL occurred in 29 evaluable patients 
(ORR=20.7%), and two patients had SD for >3 months. Within the PTCL cohort, two 
CRs and one PR were reported in nine patients with AITL (ORR=33.3%). No treatment 
responses were found in the cohort of patients with other lymphomas. Research efforts, 
including pharmacogenomic studies, are currently ongoing to elucidate the potential 
mechanism responsible for the observed clinical activity in patients with non-cutaneous 
mature PTCL.
1.2.3.2.2 Phase II Trials in Multiple Myeloma
A phase II trial (APL-B-014-03) evaluated the fortnightly schedule [plitidepsin on day 1 
and 15 every four weeks (q4wk)] in 51 patients with R/R multiple myeloma. Antitumor 
response was evaluated according to the Myeloma Response Criteria. Two partial 
responses (PRs) and four minimal responses (MRs) were found in 47 evaluable patients 
treated with plitidepsin (ORR=12.8%). Twenty-four other patients had stable disease 
(SD), which lasted for >3 months in four patients. Nineteen patients who showed 
disease progression (PD) or SD after receiving four cycles of 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 plitidepsin and 27.8% for plitidepsin combined with dexamethasone. Overall, these 
results suggest that plitidepsin administered alone or in combination with 
dexamethasone have clinical activity in patients with R/R multiple myeloma.
1.2.3.2.3 Phase II Trials in Myelofibrosis
The D1, 15 q4wk plitidepsin schedule was evaluated in 12 patients with myelofibrosis 
in other phase II trial (APL-B-020-10). Response was evaluated according to the 
International Working Group for Myelofibrosis Research and Treatment criteria. 
Clinical improvement was found in one of 11 evaluable patients (ORR=9.1%). In 


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addition, one patient had SD for >3 months. This antitumor activity was considered too 
modest to warrant further evaluation of plitidepsin in patients with myelofibrosis.
1.2.3.2.4 Phase II Trials in Acute Lymphoblastic Leukemia
A phase II clinical trial (APL-B-015-04) evaluated the efficacy of the weekly (D1, 8 and 
15 q4wk) schedule in patients with R/R acute lymphoblastic leukemia. No responses or 
remissions were found. 
1.2.3.3
Phase III Trials in Multiple Myeloma (ADMYRE trial)
An ongoing multicenter, open-label, randomized, phase III clinical trial (APL-C-001-
09, ADMYRE) started in June 2010 and is currently comparing the efficacy and safety 
of plitidepsin combined with dexamethasone vs. dexamethasone alone in patients with 
relapsed/refractory multiple myeloma previously treated with at least three but no 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-
hour infusion on D1 and 15 q4wk plus dexamethasone 40 mg orally on D1, 8, 15 and 22 
q4wk (Arm A), or dexamethasone alone at the same dose and schedule (Arm B). On 9 
December 2012, the evaluation by an Independent Data Monitoring Committee (IDMC) 
of efficacy and safety data from 60 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. 
At the last cutoff date (31 March 2015), recruitment was almost complete with a total of 
248 patients included into this trial. Of 243 patients treated so far, 162 were in Arm A 
and 81 in Arm B; of those 81, 29 subsequently crossed over to Arm A.
1.3
STUDY RATIONALE
In phase I studies conducted with plitidepsin, the schedule consisting of 1-hour i.v. 
infusion given weekly on D1, 8 and 15 q4wk was found to be the most convenient for 
patients with NHL. An exploratory phase II clinical trial (APL-B-013-02) was 
conducted to evaluate the efficacy, tolerability and pharmacokinetics of this weekly 
plitidepsin schedule at a starting dose of 3.2 mg/m2 in patients with R/R aggressive 
NHL. This phase II trial included two cohorts: patients with non-cutaneous PTCL and 
patients with other aggressive lymphomas (53, 54). No remissions were found in the 
cohort of 33 patients with other aggressive lymphomas. However, interesting antitumor 
activity was observed in 29 evaluable patients from the non-cutaneous PTCL cohort: 
ORR was 20.7% (95% CI, 8.0–39.7%) and SD rate was 20.7% (Table 2). 


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Table 2. Objective tumor response according to IWG criteria in evaluable patients with 
relapsed/refractory non-Hodgkin lymphoma treated with plitidepsin (study APL-B-013-
02).
Patient response
Non-cutaneous PTCL
(n=29)*
Other lymphomas
(n=30)*
n
%
n
%
CR 
2
6.9
-
-
PR 
4
13.8
-
-
SD 
6
20.7
6
20.0
PD 
17
58.6
24
80.0
ORR (95% CI)
20.7% (8.0–39.7%)
.
* There were 5 non-evaluable patients in the Non-cutaneous PTCL group and 3 in the Other lymphomas 
group.
PTCL, peripheral T-cell lymphoma; CR, complete remission; PR, partial remission; SD, stable disease; 
PD, progressive disease; NE, not evaluable; ORR; overall response rate; CI, confidence interval.
Plitidepsin was well tolerated in this trial. The most common adverse events (AEs) in 
the non-cutaneous PTCL cohort were nausea, fatigue, vomiting, myalgia, muscle 
weakness and pyrexia. The most common grade 3/4 hematological abnormalities were 
lymphopenia, neutropenia, anemia and thrombocytopenia found in 28%, 12%, 10% and 
10% of the cases, respectively (Figure 2).
Figure 2. Most common AEs (related to plitidepsin or with unknown relationship) in 
the cohort of patients with PTCL treated in study APL-B-013-02.
Nine patients with AITL were included in the cohort of 34 non-cutaneous PTCL 
patients. Of note, ORR in these nine patients was 33.3%, with CR in two patients 
(22.2%) and PR in one patient (11.1%). Furthermore, SD was reported in other two 
patients. Table 3 shows the clinical and treatment characteristics of these nine patients. 
The median number of previous lines was 2 and the DoR of the three responders was 
121, 12 and 4 weeks, respectively. It should be highlighted that the two patients with 
CR had bone marrow involvement at diagnosis and had previously failed high dose 
chemotherapy with stem cell transplantation (SCT) support.
48
4
31
10
3
35
48
21
10
22
9
6
6
6
35
43
7
19
25
19
6
3
9
13
9
3
10
21
3
6
3
26
16
3
3
3
7
7
6
6
10
3
0
10
20
30
40
50
60
70
80
90
100
Anemia
Lymphopenia
Thrombopenia
Neutropenia
Leukopenia
ALT Increased
AST Increased
T bilirubin
increased
CPK Increased
Nausea
Fatigue
Vomiting
Muscule
weakness
Myalgia
Percentage of p atients
Grade 1
Grade 2
Grade 3
Grade 4


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Table 3. Characteristics of the nine patients with angioimmunoblastic T-cell lymphoma 
included in the APL-B-013-02 clinical trial.
Lymphoma 
history
Prior 
therapy
Baseline
Plitidepsin 
treatment
Efficacy
Gender/Age 
(years)
Bulky 
disease
IPI 
risk
Ann-
Arbor
CT 
lines SCT PS LDH B2-
m
BM
No. 
of 
cycles
End of 
treatment
Best 
response
Response 
duration 
(weeks)
PFS 
(months)
OS 
(months)
Male/56
Yes
H
IV
3
Yes
1
H
NA Involved
8
Treatment 
complete
CR
121.0
29.6
41.7+
Male/35
No
I/H
IV
2
Yes
0
N
3 Involved
4
Toxicity 
(rash 
maculo-
papular)
CR
12.0
4.4
31.6
Male/69
No
I/H
IV
2
No
0
N
>3
Normal
3
PD
PR
4.4
2.7
3.3+
Female/71
No
H
IV
2
No
2
N
>3 Involved
5
PD
SD
.
4.5
5.7
Male/36
No
L/I
IV
2
Yes
1
H
>3
Normal
2
Toxicity  
(CPK 
increase)
SD
.
2.4+
7.9+
Male/69
No
I/H
IV
1
No
1
H
NA Involved
2
PD
PD
.
1.7
1.7+
Male/80
No
I/H
IV
2
No
1
H
>3 Involved
1
PD
PD
.
0.9
6.5
Male/61
No
NA
III
2
No
0
H
>3
Normal
1
PD
PD
.
0.8
0.9
Male/75
No
I/H
IV
2
No
2
N
>3
Normal
1
Death
PD
.
0.4
0.4
Patients with remission (CR or PR) to plitidepsin treatment are indicated in shaded columns.
B2-m, beta-2 microglobulin; BM, bone marrow; CPK, creatine phosphokinase; CR, complete remission; CT, chemotherapy; H, high 
risk/high; I, intermediate risk; IPI, International Prognostic Index; L, low risk; LDH, lactate dehydrogenase; N, normal; NA, not 
available; OS, overall survival; PD, progressive disease; PFS, progression-free survival; PR, partial remission; PS, performance 
status; SCT, stem cell transplantation; SD, stable disease.
In summary, the interesting antitumor activity observed with plitidepsin in non-
cutaneous PTCL was mainly found in patients with AITL. Bearing in mind the small 
number of agents with meaningful activity in non-cutaneous PTCL and, in particular, 
the lack of specific agents with reliable and specific activity in AITL, and considering 
the important signs of activity of plitidepsin in this disease, this phase II clinical trial 
was designed to evaluate plitidepsin as single-agent treatment for patients with R/R
AITL.
The rationale of the exploratory biomarker objectives is related to recent studies 
exploring the genetic basis of the disease: a study by Odejide and colleagues showed 
high incidences of gene mutations of TET2, for example, in 85 AITL tissue samples, as 
well as in DNMT3A, and IDH2: common and frequent mutations that make AITL more 
comparable to myeloid disorders than other PTCLs and suggest the need to re-evaluate 
therapeutic strategies (56, 57).
Several studies have shown that plitidepsin induces apoptosis in a cell type- and dose-
dependent manner, and these effects are related to the induction of early oxidative 
stress, the activation of Rac1 GTPase and the inhibition of protein phosphatases, which 
in conjunction cause the sustained activation of JNK and p38 MAPK. The final 
consequence is the triggering of the mitochondrial apoptotic pathway with caspase 9 
and caspase 3 activation (44). Additional effects may be mediated by indirect effects on 
the cell microenvironment, mainly mediated by antiangiogenic properties (43, 52, 58)
and indirect effects on monocyte-derived cells, including follicular dendritic cells (59). 


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2.
STUDY OBJECTIVES
2.1
PRIMARY
To evaluate the efficacy of plitidepsin on the basis of overall response rate (ORR) in 
patients with relapsing/refractory (R/R) angioimmunoblastic T-cell lymphoma (AITL). 
2.2
SECONDARY

To evaluate other efficacy endpoints (time-to-event parameters: duration of 
response [DoR], progression-free survival [PFS], PFS at 6/12 months 
[PFS6/PFS12], intrapatient PFS/TTP, overall survival [OS] and OS at 6/12 
months [OS6/OS12]).

To evaluate the safety profile of plitidepsin in this patient population.

To characterize the pharmacokinetics (PK) of plitidepsin.

To identify biomarkers that may be clinical endpoint surrogates for future 
plitidepsin studies or that may be predictive of plitidepsin activity.
3.
OVERALL STUDY DESIGN
This is a prospective, multicenter, phase II clinical trial to determine the efficacy of 
plitidepsin in patients with R/R AITL. The primary endpoint will be the ORR according 
to the Lugano classification response criteria (see Appendix 2) per independent review
(60, 61).
Tumor radiological assessments will be by PET-CT in combination with diagnostic 
quality CT2 one to two weeks after last dose of Cycle 3 and at least four weeks after last 
dose of Cycle 6 (but no more than eight weeks), and by CT-scan every four months (+ 
two weeks) for the first two years, and every six months (+ two weeks) thereafter, at 
suspected clinical progression, unless otherwise clinically indicated. Patients who 
discontinue treatment without disease progression will be followed every four months
(+ two weeks) for the first two years, and then every six months (+ two weeks) until 
progressive disease (PD), start of other antitumor therapy, death or the date of study 
termination (clinical cutoff), whichever occurs first. After documented progression or 
the start of a new antitumor therapy, patients will be followed for survival 
approximately every four months during the first two years, and then approximately
every six months until death or the date of study termination, whichever occurs first. 
An Independent Review Committee (IRC) consisting of medical specialists (radiologists 
and hematologists) who are directly involved in the care of patients with AITL (but are 
not participating in this trial as investigators) will review all efficacy data (including 
radiological assessments, bone marrow biopsy) and will assign the best response and the 
date of objective response or progression/censoring according to their independent 
evaluation. 
                                                
2 When PET-CT is performed it must be in combination with diagnostic quality CT with intravenous 
contrast (except medically contraindicated). Two alternatives are allowed: Hybrid PET CT scanners may 
be used to acquire diagnostic quality CT which includes intravenous contrast OR PET CT without 
intravenous contrast and diagnostic quality CT images with intravenous contrast using a standalone CT 
scanner must be performed.


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The diagnostic pathological criteria of AITL are still quite arbitrary and the availability 
of extensive immunophenotype panels and molecular testing for proper classification 
are limited in most institutions. Also, several reports have described low rates of 
agreement in the diagnosis of AITL, with around 30% of discordant diagnosis when 
comparing the initial (referring) and the final pathology reports in academic centers 
(62). Central pathological review of each patient’s original diagnosis report(s) will be 
required before inclusion. Molecular diagnosis by miRNA will be used to confirm the 
investigative centers’ AITL diagnosis and will include: 

Differential diagnosis with other entities can be difficult (Hodgkin lymphoma, 
rare B-cell neoplasms, reactive processes, etc.). Extensive phenotype studies and 
molecular testing are needed in many instances.

The differential diagnosis between PTCL NOS and AITL needs the 
integration of clinical data including histomorphological features of tumors, 
phenotype markers of TFH cells (PD1, CD10, BCL6, CXCL13, ICOS), EBV 
detection.

The boundaries between follicular-PTCL and
PTCL-NOS with TFH 
phenotype are still unknown. For consistency of the analyses, diagnosis of 
AITL will be based on standard criteria (Appendix 1), and these controversial 
cases will be excluded from the trial.
For all patients, immunophenotyping studies must consist of a minimum panel of T-cell 
markers, including markers of TFH cells and follicular dendritic cells. The presence of 
EBV 
must 
be 
identified 
by 
in 
situ
hybridization 
(ISH), 
since 
LMP-1 
immunohistochemistry is not sufficient in AITL. 
Major immunophenotyping criteria for diagnosis: 

Markers of TFH cells in the neoplastic population: CD4+/CD8-, BCL6, CD10, 
PD1, CXCL13, ICOS (at least three markers must be positive) (63, 64).

Hyperplasia of follicular dendritic cells: CD23+, CD21+

Variable presence of CD30 + EBV + B-cell blasts (in most cases). 
The differential diagnosis between AITL and PTCL/NOS with TFH phenotype will be 
integrated with miRNA analysis as recently described by Laginestra and colleagues 
(65). Cases with features of follicular-PTCL and PTCL-NOS with TFH phenotype or 
with features of progression/transformation from AITL to Diffuse Large B-cell 
Lymphoma will not be included in the trial.
Two futility analyses of the primary endpoint (ORR according to Lugano classification
response criteria and per IRC) are planned around six months after approximately 25%
and 50% of eligible patients (i.e., 15 and 30 patients respectively with AITL confirmed
by central pathological review) have been treated. Two or less responders out of 15 
patients or seven or less responders out of 30 patients, according to boundaries and 
sample size assumptions, will mean that the alternative hypothesis could be rejected, 
and thus recruitment might be stopped at the time of the first or second futility analysis, 
respectively. Otherwise, accrual will continue to a total of 60 patients with AITL 
confirmed by central pathological review. This decision will be taken at the time by an 
Independent Data Monitoring Committee (IDMC). The IDMC, which will include 
specialists in PTCL supported by a medical statistician, will review data provided by the 
Investigators, the IRC efficacy assessments and safety information and will advise 
whether the study should continue. Recruitment can continue during the review period.


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If there are 19 or more responders over the total of 60 patients, the efficacy of
plitidepsin will be considered as clinically relevant in AITL patients.
Operational details for the IRC and IDMC will be detailed in the corresponding 
charters.
3.1
PRIMARY ENDPOINT
The primary endpoint is ORR—defined as the percentage of patients with either 
complete (CR) or partial (PR) remission—according to the Lugano classification
response criteria per Independent Review Committee (IRC). An IRC will assign the 
objective response and progression or censoring dates for each patient according to a 
predefined algorithm provided in a separate charter.
3.2
SECONDARY ENDPOINTS

ORR per Investigator assessment (IA).

CR rate, defined as the percentage of patients with complete remission according to 
Lugano classification response criteria per IRC and IA.

Duration of response (DoR), defined as the time from the date when the remission
criteria (PR or CR, whichever is achieved first) are fulfilled to the first date when 
PD, recurrence or death (due to any cause) is documented. Response will be 
assessed according to Lugano classification per IRC and IA.

Progression-free survival (PFS), defined as the time from the date of first drug 
administration to the date of PD, death (of any cause), or last tumor evaluation; both 
IRC and IA will be used.

Progression-free survival at 6/12 months (PFS6/PFS12), defined as the Kaplan-
Meier estimate of the percentage of patients who are progression-free at six/twelve 
months after the first drug administration; both IRC and IA will be used.

Intrapatient PFS/TTP, defined as the ratio of PFS achieved with the experimental 
treatment versus prior last TTP in the R/R setting.

Overall survival (OS), defined as the time from the date of the first dose to the date 
of death (of any cause) or last patient’s contact.

Overall survival at 6/12 months (OS6/OS12), defined as the Kaplan-Meier estimate 
of the percentage of patients who are alive at six/twelve months after first drug 
administration.

Treatment safety [AEs, serious adverse events (SAEs) and laboratory abnormalities] 
graded according to the NCI-CTCAE, v.4. Dose reductions, omitted doses or cycle
delays due to treatment-related AEs, and reasons for treatment discontinuations will 
be analyzed.

Pharmacokinetics (PK), samples for PK analysis will be obtained during Cycle 1 
exclusively (see Section 6). 

Exploratory biomarker analysis, correlation of efficacy with molecular markers 
(targets/pathways) related to the mechanism of action of plitidepsin or to the disease
(see Section 8.4). 


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4.
SELECTION OF PATIENTS
4.1
INCLUSION CRITERIA
1) Voluntary written informed consent of the patient (both to participate in the study 
and to provide biopsy samples) obtained before any study-specific procedure.
2) Age ≥ 18 years.
3) ECOG PS ≤ 2.
4) Life expectancy ≥ 3 months.
5) Histologically confirmed diagnosis of R/R AITL (eligibility needs to be confirmed
by central pathological review.*)
6) At least a two-week washout period since the end of the last therapy (six weeks for 
a prior nitrosourea-containing regimen), recovery to grade ≤ 1 from any non-
hematological AE derived from previous treatment (excluding alopecia). 
7) Adequate BM, renal, hepatic, and metabolic function (assessed ≤ 14 days before 
inclusion in the study):
a)
Absolute neutrophil count (ANC) ≥ 1.0 × 109/L.
Screening of ANC should be independent of granulocyte-colony stimulating 
factor (G-CSF) support for at least one week and of pegylated G-CSF for at least 
two weeks.
b)
Platelet count ≥ 75 × 109/L.
c)
Hemoglobin ≥ 9 g/dL. 
Patients may receive red blood cells (RBC) and/or erythropoietin (EPO), and/or 
platelet transfusions in accordance with institutional guidelines.
d)
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3.0 ×
the upper limit of normal (ULN).
e)
Total bilirubin ≤ 1.5 × ULN. 
f)
Alkaline phosphatase (ALP) ≤ 3.0 × ULN (< 5 × ULN, if isolated ALP increase, 
i.e., without ALT/AST or bilirubin increase).
g)
Calculated creatinine clearance (CrCL) ≥ 30 mL/minute (Cockcroft-Gault 
formula).
h)
Creatine phosphokinase (CPK) ≤ 2.5 × ULN.
i)
Albumin ≥ 2.5 g/dL.
j)
Normal value of electrolytes, including potassium, magnesium and calcium.
8) Left ventricular ejection fraction (LVEF) by echocardiogram (ECHO) or multiple-
gated acquisition (MUGA) scan within normal range (according to institutional 
standards).
* Patient inclusion can be approved based on local histopathological report(s). Eligibility will be 
confirmed using diagnosis and/or relapse biopsy specimens submitted for central pathological review 
prior to each futility analysis/end of study.


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4.2
EXCLUSION CRITERIA
1) Prior treatment with plitidepsin.
2) Concomitant diseases/conditions:
a) History or presence of angina, myocardial infarction, clinically relevant valvular 
heart disease, uncontrolled hypertension, or congestive heart failure within the 
previous 12 months.
b) Symptomatic arrhythmia (excluding grade ≤ 2 anemia-related sinusal 
tachycardia) or any arrhythmia requiring ongoing treatment, and/or prolonged 
grade ≥ 2 QT-QTc, or presence of unstable atrial fibrillation. Patients with stable 
atrial fibrillation on treatment are allowed provided they do not meet any other 
cardiac or prohibited drug exclusion criterion.
c) History (or family history) of long QT syndrome.
d) Corrected QT interval (QTcF, Fridericia correction) ≥ grade 2 on screening 
electrocardiogram (ECG).
e) Clinically significant resting bradychardia, or history of syncope.
f)
History or presence of ventricular arrhythmias, including ventricular tachycardia 
or Torsades de Pointes.
g) Patients receiving treatment with any medication with known risk of producing 
Torsade de Pointes (see Appendix 8).
h) Active uncontrolled infection. Active hepatitis B or C virus (HBV or HCV), or 
human immunodeficiency virus (HIV) infection.
i)
Morphological or cytological features of myelodysplasia and/or post-
chemotherapy aplasia on BM assessment.
j)
Myopathy > grade 2 or any clinical situation that causes significant and 
persistent elevation of CPK (> 2.5 × ULN in two different determinations 
performed one week apart).
k) Limitation of the patient’s ability to comply with the treatment or follow-up 
requirements.
l)
Diagnosis of another invasive malignancy unless free of disease for at least three 
years following therapy with curative intent. Patients with early-stage basal cell 
or squamous cell skin cancer, cervical intraepithelial neoplasia, cervical 
carcinoma in situ, or superficial bladder cancer, may be eligible to participate at 
the Investigator’s discretion.
m) Any other major illness that, in the Investigator’s judgment, will substantially 
increase the risk associated with the patient’s participation in this study.
3) Central nervous system (CNS) involvement.
4) Women who are pregnant or breast feeding. Fertile patients (men and women) who 
are not using an effective method of contraception. All patients (men and women)
must agree to use an effective contraceptive measure (if applicable) up to six 
months
after treatment discontinuation. Valid methods to determine the 
childbearing potential, adequate contraception and requirements for women of 
childbearing potential (WOCBP) and their partners are described in Appendix 6.
5) Concomitant medications that include corticosteroids, chemotherapy, or other 
therapy that is or may be active against AITL, within the two weeks prior to 
treatment start. Concurrent corticosteroids are allowed, provided they are 


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administered at an equivalent prednisone dose of ≤ 10 mg daily, as premedication 
for blood products and/or for the relief of the symptoms derived from the disease.
6) Major upper gastrointestinal bleeding episode occurring during the previous year 
before screening.
7) Known hypersensitivity to any of plitidepsin’s formulation components (See 
Section 7.1.1, Study Drug Formulation).
5.
PLAN OF THE STUDY
5.1
PLANNED TRIAL PERIODS (FOR THE WHOLE STUDY)
The total duration of the study will be approximately 42 months. 
Planned start date (first patient on study): 2Q2016.
Planned enrollment period: 36 months.
Planned end-of-study date (clinical cutoff): 12 months after the last patient’s 
inclusion. If there are patients still being treated at the planned cutoff date, the actual 
cutoff date will be the date when those patients have completed the ongoing treatment 
cycle and the corresponding EOT visit.
The study will be closed earlier than planned if less than 15 patients are recruited in the 
first year after most of the sites are in active enrollment. Recruitment reviews will 
continue annually to assess the feasibility of meeting the study objectives and study 
continuation.
5.2
PLANNED TRIAL PERIODS (INDIVIDUALLY PER PATIENT)
Patients will be evaluated at scheduled visits in three study periods:

Pretreatment: from signature of the informed consent to the first dose of study 
treatment. 

Treatment: from first dose of study treatment to EOT (see Section 5.2.1.1). EOT is 
defined as 30 days (± one week) after the day of last administration of study 
treatment or as soon as possible after End of Cycle 6 radiological and clinical 
assessments (if the patient discontinues: see Figure 3 below), unless the patient 
starts a new antitumor therapy or dies within 30 days from the last dose, in which 
case the date of administration of this new antitumor therapy or the date of death 
will be considered the EOT date.

Follow-up: after EOT, patients will be followed every four weeks until resolution 
of all toxicities (if any). Patients who discontinue treatment without progression will 
be followed every four months (+ two weeks) for the first two years of follow-up, 
and every six months (+ two weeks) thereafter, unless clinically indicated, until PD, 
start of other antitumor therapy, death or the date of study termination (clinical 
cutoff), whichever occurs first. After documented progression or start of a new 
antitumor therapy, patients will be followed for survival approximately every four
months during the first two years, and then approximately every six months until 
death or the date of study termination, whichever occurs first. For the purpose of 
collecting information on patient’s survival exclusively, a documented telephone 
call is acceptable; follow-up for survival will be completed for all patients only if 
results of the primary endpoint confirm the trial as positive.


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Patients will be considered to be on-study from the signature of the informed consent
form (ICF) to the end of the follow-up period (or screening failure). Investigators can 
appraise potential study candidates in a pre-screening period but only perform study-
specific screening assessments after the patient formally consents. Patients will be 
considered to be on-treatment from the date of first dose until EOT. 
Figure 3. Study design.
CR, complete response; D, day; EOT, end of treatment; ICF, informed consent form; PD, progressive 
disease; PR, partial response; SD, stable disease; wk, week.


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Patients may withdraw their consent at any time; if consent to study participation is 
withdrawn, no further study activities will be conducted on them (5.2.1.3 Study 
Discontinuation). If consent only to the study treatment is withdrawn, treatment will be 
stopped and other study procedures performed as normal (see 5.2.1.1 below).
5.2.1
Discontinuations
5.2.1.1
Treatment Discontinuation
Treatment discontinuation occurs when an enrolled patient ceases to receive plitidepsin
regardless of the circumstances. By convention, the date of the end of treatment is 
defined as 30 days after the day of the last dose of plitidepsin (treatment 
discontinuation), the start of a new antitumor therapy or death, whichever occurs first, in 
which case the date of administration of this new therapy or the date of death will be 
considered the date of EOT. In this study, however, EOT will also be conditioned by an 
End of Cycle 6 visit in which a radiological assessment 4–8 weeks after the last dose of 
Cycle 6 will determine whether treatment can continue to Cycle 7.
The primary reason for any treatment discontinuation will be recorded on the patient’s 
Case Report Form (CRF).
If a patient discontinues treatment, every effort should be made to complete the 
scheduled assessments as appropriate, whenever possible.
5.2.1.2
Reasons for Treatment Discontinuation
Patients will receive study treatment until:

Disease progression (PD).

Maximum of six cycles unless the patient is in:

PR 4–8 weeks after last dose of Cycle 6: in accordance with Investigator 
decision, the patient may then continue in treatment until CR or progression.

SD 4–8 weeks after last dose Cycle 6: in accordance with Investigator decision, 
the patient may then continue until CR or progression. 

If patient is in CR after six treatment cycles, treatment should be stopped. 

The patient achieves PR or CR at any time during the planned six cycles and is 
eligible for consolidation with autologous or allogeneic stem cell transplant (SCT) 
as per Investigator criteria. 

There is unacceptable toxicity.

There is intercurrent illness of sufficient magnitude to preclude safety continuation 
of the study.

There is patient refusal and/or non-compliance with study requirements.

Investigator’s decision.

There is a protocol deviation with an effect on the risk/benefit ratio management of 
the patient.

There is a treatment delay > 15 days from the treatment due date (except in case of 
clear clinical benefit and with the Sponsor’s approval).

There is a requirement of > 2 dose reductions (except in case of clear clinical benefit 
and with the Sponsor’s approval).
Patients who are withdrawn for any reasons must not be re-treated in the context of this 
study at any time. For follow-up activities, please refer to Section 5.11.


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5.2.1.3
Study Discontinuation
Study discontinuation occurs when an enrolled patient ceases to participate in the study, 
regardless of the reason (as detailed under “Follow-up” in Section 5.2). Patients have 
the right to withdraw consent at any time; if this is the case, no further study procedures
should be performed.
The date and reason for study discontinuation will be clearly documented on the 
patient’s CRF. 
5.2.2
Protocol Deviations
A protocol deviation is defined as any departure from what is described in the protocol 
of a clinical trial approved by an Independent Ethics Committee (IEC)/Institutional 
Review Board (IRB) and the Competent Authorities. Therefore, it applies to deviations 
related to patient inclusion and clinical procedures (e.g., assessments to be conducted or 
parameters to be determined), and also to other procedures described in the protocol that 
concern Good Clinical Practice (GCP) guidelines or ethical issues (e.g., issues related to 
obtaining the patients’ Informed Consent, data reporting, Investigator’s responsibilities, 
etc.).
Deviations with no effects on the risk/benefit ratio of the clinical trial (such as minimal 
delays in assessments or visits) will be distinguished from those that might have an 
effect on this risk/benefit ratio, such as:

Deviations that might affect the clinical trial objectives, such as those involving 
inclusion/exclusion criteria (which could mean that the patient is not eligible for the 
trial) and those having an effect on patient’s evaluability.

Deviations that might affect the patient’s well-being and/or safety, such as incorrect 
dosing of the investigational medicinal product (plitidepsin) due to not following 
dose adjustment specifications or an incorrect preparation of the medication.

Deviations related to the following of GCP guidelines as described in the protocol 
and regulations in force, such as deviations when obtaining the Informed Consent or 
not following the terms established for reporting Serious Adverse Events, etc.
As a general rule, NO deviations that may have an effect on the risk/benefit ratio of the 
clinical trial will be authorized. All protocol deviations detected during the study will be 
appropriately documented, and those considered particularly relevant (i.e., those related 
to ethical issues, fulfillment of GCP guidelines and with an effect on the risk/benefit 
ratio) will be notified to the pertinent IEC/IRB and, if applicable, to the Competent 
Authorities as established by local regulations.
Failure to attend the EOT visit exclusively due to a deteriorated clinical condition will 
not be considered a protocol deviation.
Furthermore, non-availability or non-evaluability of a diagnosis or re-biopsy specimen 
for central pathological review will not be considered a deviation (given that, in some 
instances, re-biopsy may not be feasible because of disease location) but eligibility must 
first be confirmed with the sponsor prior to inclusion.
5.3
ADDITION OF PATIENTS
All eligible and treated patients with AITL diagnosis confirmed after central 
pathological review will be included in the main efficacy analyses (primary and 
secondary endpoints). 


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If a patient is treated but AITL diagnosis is not finally confirmed after central 
pathological review of the biopsy (even if inclusion was approved on the basis of the 
local histopathological report) then an additional patient will be included. Specifically, 
cases with features of follicular-PTCL and PTCL-NOS with TFH phenotype or with 
features of progression/transformation from AITL to Diffuse Large B-cell Lymphoma 
need to be excluded from the main efficacy analysis so additions are permitted in the 
event such patients are included before (or in spite of) central pathological exclusion. 
All patients without central confirmation will be excluded from the main efficacy 
analyses but included in safety analyses and, as supportive analyses, efficacy 
assessments will be done including all treated patients.
5.4
PRETREATMENT ASSESSMENTS
During the pretreatment (or screening) period, following signature of the Informed 
Consent Form, the Investigator will assess the patient’s eligibility for inclusion in the 
study by conducting the assessments summarized below. The Sponsor must confirm 
eligibility before the patient starts treatment: see also Figure 3. Study design.
Table 4. Screening period: pretreatment assessments.
ASSESSMENT
TIME
1. Written 
informed consent
The 
informed 
consent 
process 
involves 
an 
explanation and discussion with the patient including 
time for questions and answers and culminates in 
signing and dating the consent form if the patient 
agrees. Document participation in the patient’s 
medical chart as well.
Before
any 
study-specific
procedures.
2. Medical and 
cancer history/ 
clinical 
examination
Demographic data (race/ethnicity [if permitted], 
age, sex, height).
Medical and cancer history/baseline condition:
o Primary diagnosis.
o Prognostic factors at first diagnosis.*
o Prior treatments (with best response and TTP, 
when available).
o Documented date of relapse or refractory 
disease.
o Ann-Arbor staging (see Appendix 5)
Within 28 days prior to Day 0.
Complete physical examination, including weight 
and BSA. 
Basic neurological examination.
Performance status (ECOG PS).
Vital signs: heart rate, blood pressure and body 
temperature.
Concomitant therapies.
Within 14 days prior to Day 0.
3. Laboratory 
tests

Hematology:
differential WBC, hemoglobin, 
hematocrit and platelets.
Biochemistry-A: AST, ALT, total bilirubin (direct
bilirubin if total bilirubin > 1.5 × ULN), ALP, 
creatinine, calculated creatinine clearance (Cockcroft-
Gault formula), glucose, serum electrolytes (Na+, K+, 
Mg++, Ca++) and CPK (CPK-MB fraction should be 
measured if CPK is abnormally high).
Biochemistry-B: Uric acid, LDH, total proteins, 
albumin and C-reactive protein.
Coagulation tests: PT, PTT and INR.
Serum beta-2 microglobulin.

Complete serology:
including viral load (if 
indicated).
Coombs test.
Serum immunoglobulin quantification.
Serum protein electrophoresis.
Within 14 days prior to Day 0. **


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ASSESSMENT
TIME
Urine elemental dipstick and sediment.
4. Central 
pathological 
review
To confirm patient eligibility, the original diagnosis 
histopathology report must be provided for central 
pathological review.
Within 
28 
days 
and 
with 
sufficient 
time 
to 
allow 
confirmation of eligibility prior 
to Day 0.
Archived tissue samples of representative tumors [a 
formalin-fixed paraffin-embedded (FFPE) tissue 
block (preferred) or freshly-cut unstained tumor 
slides] must be available. An incisional or excisional 
biopsy is preferred but a core-needle biopsy can be 
considered when excisional biopsy is not possible.
Other sample specifications (number and thickness) 
must be confirmed in advance with the central 
laboratory: see separate instruction manual.
Although 
availability 
of 
the 
diagnosis and/or relapse sample 
is 
required 
for 
central 
pathological 
review, 
the 
specimens need not be sent or 
evaluated until later in the study
(before each futility analysis or 
when instructed).
5. Biomarker 
analysis
Available archived paraffin-embedded tumor tissue 
samples obtained at diagnosis or/and relapse.
See point 4 above.
6. Pregnancy test
Only if the patient is a WOCBP. Assessment of β-
hCG.
Within 14 days prior to Day 0, if 
applicable.
7. Cardiac 
assessment
ECG: Rhythm, frequency and QT interval should 
be specifically described.
Within 14 days prior to Day 0.
LVEF by ECHO or MUGA
Within 
28 
days 
prior 
to 
registration.
8. Bone marrow 
biopsy/aspirate
Within 14 days prior to Day 0.
9. Chest X-ray
If needed.
Within 28 days prior to Day 0.
10. Tumor 
assessment
Radiological (PET-CT + CT***) and clinical tumor 
assessment.
Within 28 days prior to Day 0.
11. Adverse 
events
Clinical assessment of the patient’s signs and 
symptoms (if any and including nurses’ assessment 
and patient-reported issues) should continue on an 
ongoing basis throughout the study and be reported at 
least every cycle as AEs: between IC and Day 0, AEs 
are considered baseline and non-treatment emergent.
Grading should be as per the NCI-CTCAE v.4.
Within 14 days prior to Day 0.
* Prognostic Index for Peripheral T-cell lymphoma (PIT) uses four variables as predictive for survival: age, PS, LDH level and BM 
involvement (Appendix 3). The standard International Prognostic Index (IPI) comprises the following variables: age ≥ 60 years, 
disease stages III to IV, LDH > normal, ENSs > one and PS ≥ 2. The alternative Prognostic Index for AITL (PIAI) comprises the 
following factors: age ≥ 60 years, PS ≥ 2, ENSs > one, B symptoms and platelet count <150 × 109/L (Appendix 4).
** Hematology and Biochemistry-A, -B not to be repeated prior to C1D1 if performed within the seven previous days and there are 
no changes in the patient’s clinical status and medications.
*** When PET-CT is performed it must be in combination with diagnostic quality CT with intravenous contrast (except 
medically contraindicated). Two alternatives are allowed: Hybrid PET CT scanners may be used to acquire diagnostic quality 
CT which includes intravenous contrast OR PET CT without intravenous contrast and diagnostic quality CT images with 
intravenous contrast using a standalone CT scanner must be performed.
ALT, alanine aminotransferase; ALP, alkaline phosphatase; AST, aspartate aminotransferase; BSA, body surface area; CPK, 
creatine phosphokinase; CPK-MB, creatine phosphokinase-isoenzyme MB; ECG, electrocardiogram; ECOG, Eastern 
Cooperative Oncology Group; β-hCG, beta subunit of human chorionic gonadotropin; INR, international normalized ratio; 
LDH, lactate dehydrogenase; NCI-CTCAE, National Cancer Institute Common Terminology Criteria for Adverse Events; PS, 
performance status; PT, prothrombin time; PTT, partial thromboplastin time; SAE, serious adverse event; TTP, time to 
progression; WBC, white blood cells; WOCBP, woman of childbearing potential.
5.5
PATIENT REGISTRATION
The patient will be allocated a patient number in the e-CRF after signing the ICF and 
screening begins. This patient number should be used on all future documentation and 
correspondence referring this patient. Eligibility will be checked before inclusion and 
registration (approval from the central pathological review of the local histopathology
report) confirmed by the Sponsor. The patient will be a screening failure if not all 
inclusion criteria are met, if any exclusion criterion is met, if central pathological review 
of the local histopathology report does not confirm the AITL diagnosis, or if the 
Sponsor does not approve inclusion. Regardless of circumstances, Investigators will not 


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be allowed to treat any patient before appropriate receipt of the Sponsor’s agreement to 
proceed with inclusion: see also Figure 3. Study design.
A patient who has been treated without the Sponsor’s agreement will not be considered 
evaluable for the study and will need to be replaced (although can continue in treatment 
until discontinuation for any other reason).
For patients included in the study (all registered patients) but never treated, only 
baseline and off-study visit modules of the e-CRF should be completed.
For screen failures (patients who started screening but were not finally included), only 
the screening form of the e-CRF should be completed but SAEs occurring during 
screening need to be reported.
5.6
CENTRAL PATHOLOGICAL REVIEW
Central pathological review will be conducted by experienced pathologists appointed by 
the Sponsor and available to the investigative sites for consultation about AITL 
diagnosis confirmation. Central pathological review is required for (a) local 
histopathology reports prior to patient treatment, and (b) tumor samples before each 
futility analysis and at the end of the study: see also Figure 3. Study design.
The central laboratory pathologists will be responsible for (a) approving patient 
inclusion on the basis of investigative site pathology reports provided during screening, 
(b) analyzing tumor biopsies (initial diagnosis and/or relapses) to confirm the AITL 
diagnosis, and (c) analyzing blood samples to identify plasma biomarkers and extract 
DNA.
Tumor samples (initial diagnosis and relapses) are required for central review to 
confirm AITL diagnosis but not to approve inclusion. Archived tissue samples of 
representative tumors must be sent for central review and biomarker analysis. If the 
diagnosis biopsy is not available (because the patient was diagnosed at another site, for 
example), the most recent representative biopsy (relapse and/or progression) will be 
used. Submitting both, however, is strongly recommended. Tumor blocks will be 
returned to the centers. 
Samples requirements are as follows:

Archived tissue samples of representative tumors:  
o
A formalin-fixed paraffin-embedded (FFPE) tissue block (preferred), 
usually from lymph node excisional biopsy. 
or
o
Freshly-cut unstained tumor slides. 

One whole blood sample for germline DNA extraction (6 mL) and another 
blood sample (4 mL) to obtain plasma are required for biomarker analyses: 10 
mL will be collected in EDTA tubes will be collected at the same time as the 
first PK sample (prior to infusion) on Day 1 of Cycle 1.
Central pathological confirmation of AITL diagnosis for the 15 and 30 patients in the 
futility analyses is mandatory and for all patients at the end of the study; the central 
review pathologists will also be available when required for consultation in 
controversial cases and at the investigators’ discretion. 
Tissue sample specifications (number and thickness) must be confirmed in advance with 
the central laboratory. Procedures for collection, handling, and shipping of the samples 
will be provided in a separate instruction manual for sites. 


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5.7
PATIENT RANDOMIZATION
Not applicable.
5.8
EVALUATIONS DURING TREATMENT
The assessments listed in Table 5 below will be made while the patient is on treatment: 
see also Figure 3. Study design.
Table 5. Evaluations during treatment.
ASSESSMENT
TIME
1. Clinical examination
Complete physical examination, including 
weight and BSA. 
Basic neurological examination.
Performance status (ECOG PS).
Vital signs: heart rate, blood pressure and 
body temperature.
By Day 1 of each cycle (always prior 
to plitidepsin administration).
Concomitant therapies.
Throughout the on-treatment period.
2. Laboratory tests

Hematology:
differential 
WBC, 
hemoglobin, hematocrit and platelets.
Cycle 1: Day 1, 8, 15 and 22 (always 
prior to plitidepsin administration). 
Not necessary on C1D1 if performed 
within the seven previous days and 
there is no change in the patient’s 
clinical status and medications. To be 
performed at least every other day in 
the presence of grade 4 non-febrile 
neutropenia or febrile neutropenia, and 
every day in the presence of grade 4 
thrombocytopenia until recovery.
Cycle 2 and beyond: Day 1, 8 and 15 
of each cycle (always prior to 
plitidepsin administration). 
Biochemistry-A: AST, ALT, total bilirubin 
(direct bilirubin if total bilirubin > 1.5 × 
ULN), ALP, creatinine, calculated creatinine 
clearance (Cockcroft-Gault formula), glucose, 
serum electrolytes (Na+, K+, Mg++, Ca++) and 
CPK (CPK-MB fraction should be measured 
if CPK is abnormally high).
Cycle 1: Day 1, 8, 15 and 22 (always 
prior to plitidepsin administration).
Not necessary on C1D1 if performed 
within the seven previous days and 
there is no change in the patient’s 
clinical status and medications. To be 
performed at least every other day in 
the presence of grade 3/4 vomiting or 
any other drug-related SAE. 
Cycle 2 and beyond: Day 1, 8 and 15 
of each cycle (always prior to 
plitidepsin administration). 
Biochemistry-B: Uric acid, LDH, total 
proteins, albumin and C-reactive protein.
Day 1 of each cycle (always prior to 
plitidepsin 
administration). 
Not 
necessary on C1D1 if performed within 
the seven previous days and there is no 
change in the patient’s clinical status 
and medications. 
Coagulation tests: PT, PTT and INR.
Day 1 of each cycle (always prior to 
plitidepsin administration).
Urine elemental dipstick and sediment.
Repeat if clinically indicated.
Complete serology
Coombs test 
Serum immunoglobulin quantification.
Serum protein electrophoresis.
Repeat if clinically indicated.
3. Central pathological 
review
Tumor tissue sample.
Ship prior to futility analysis (or as 
instructed).


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ASSESSMENT
TIME
4. Pharmacokinetics
See Table 6 Sampling schedule for the 
determination of plitidepsin.
Day 1, 8 and 15 of Cycle 1. 
5. Biomarker analysis 
Tumor tissue sample.
Collect 10 mL blood: one whole blood sample
for germline DNA extraction (6 mL) and 
another blood sample (4 mL) to obtain
plasma. A separate instruction manual for 
sites will be provided.  
Tumor biopsy obtained at diagnosis or 
relapse. (See point 3 above.)
Blood draw C1D1: with the first PK 
sample (before plitidepsin infusion).
6. Pregnancy test 
Only if the patient is a WOCBP. Assessment 
of β-hCG.
Repeat every cycle (or, at least, every 
month).
7. Cardiac assessment
ECG: Rhythm, frequency and QT interval 
should be specifically described, besides any 
ECG anomaly or variation respect to baseline.
First cycle, Day 1: Prior to the first 
infusion (unless performed as part of 
screening within the previous 14 
days), at the end of the first infusion, 
at 30 min post-infusion and at 1-hour 
post-infusion (see Table 6). 
First cycle, Day 8 and Day 15: Prior 
to the infusion, and at 1-hour post-
infusion (see Table 6). 
Further cycles: prior to each infusion.
LVEF by ECHO or MUGA.
Repeat if clinically indicated.
8. Bone marrow 
biopsy/aspirate
Repeat if clinically indicated.
9. Chest X-ray
Repeat if clinically indicated.
10. Tumor assessment
Radiological (PET-CT + CT*) and clinical 
tumor assessment.
In the case a patient continues in treatment 
beyond Cycle 6, CT scans may be used every 
four months (+ 2 weeks) for the first  two 
years and every six months (+ 2 weeks)
thereafter, but any subsequent improvement 
in response should be confirmed by PET-
CT*.
Disease progression at any time during the 
study should be confirmed by imaging (if the 
physical condition of the patient permits).
One to two weeks after last dose of
Cycle 3 and at least 4 weeks (but no 
more than 8 weeks) after last dose of
Cycle 6 (or earlier in the event of 
treatment
discontinuation
for 
whatever reason). Cycle 4 can be 
started without waiting for the results 
of the Cycle 3 tumor assessment. No 
radiological assessment is necessary 
in the event of discontinuation due to 
any reason other than PD during or 
after Cycle 4 if the Cycle 3 
radiological assessment has been 
performed correctly.
11. Concomitant 
medications
All concomitant therapies taken by the patient 
(including 
any 
not 
prescribed 
by 
the 
Investigator) should be documented with 
indication from two weeks prior to starting 
study treatment.
Throughout the on-treatment period.
12. Adverse events **
As per NCI-CTCAE v.4.
Throughout the on-treatment period.
* When PET-CT is performed it must be in combination with diagnostic quality CT with intravenous contrast (except medically 
contraindicated). Two alternatives are allowed: Hybrid PET CT scanners may be used to acquire diagnostic quality CT which 
includes intravenous contrast OR PET CT without intravenous contrast and diagnostic quality CT images with intravenous contrast 
using a standalone CT scanner must be performed.
** Clinical assessment of the patient’s signs and symptoms (if any and including nurses’ assessment and patient-reported issues) 
should continue on an ongoing basis throughout the study and be reported at least every cycle (unless relevant enough to program 
an unscheduled visit or the criteria for seriousness are reached and an SAE report is required). Assessments for a particular visit do 
not need to all take place on the same day but should all be within the planned time window. Physical examination and laboratory 
assessments, for example, can be performed more frequently during the study if clinically required.
Permitted windows for assessments
±1 day for study treatment administration and clinical assessments (ECOG PS, vital signs, weight, BSA, neurological assessment—
always prior to infusion).
–2 days for hematology, biochemistry-A, serum β-2 microglobulin, biochemistry-B and coagulation tests. Note: windows for 
laboratory assessments only apply prior to the scheduled infusion, that is within 48 hours before the next scheduled infusion (except 
C1D1).
ALT, alanine aminotransferase; ALP, alkaline phosphatase; AST, aspartate aminotransferase; BSA, body surface area; CPK, 
creatine phosphokinase; CPK-MB, creatine phosphokinase-isoenzyme MB; ECG, electrocardiogram; ECOG, Eastern Cooperative 
Oncology Group; β-hCG, beta subunit of human chorionic gonadotropin; INR, international normalized ratio; LDH, lactate 
dehydrogenase; NCI-CTCAE, National Cancer Institute Common Terminology Criteria for Adverse Events; PS, performance 


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ASSESSMENT
TIME
status; PT, prothrombin time; PTT, partial thromboplastin time; SAE, serious adverse event; WBC, white blood cells; WOCBP, 
woman of childbearing potential.
5.9
EVALUATIONS AT END OF CYCLE 6
A PET-CT + CT3 scan for radiological tumor assessment is required at least four weeks 
(but no more than 8 weeks) after last dose of Cycle 6 (or earlier in the event of treatment 
discontinuation for whatever reason; no radiological assessment is necessary in the event 
of withdrawal due to any reason other than PD during or after Cycle 4 if the Cycle 3 
radiological assessment has been performed correctly) or at suspected clinical progression 
while on treatment. 
The End of Cycle 6 visit should take place 4–8 weeks after last dose of Cycle 6 (when the 
PET-CT results are available). If a patient is shown to have SD or PR at this assessment, 
treatment can resume (Cycle 7) and evaluations will continue as described in Section 5.8. 
If a patient is shown to have CR or PD, the patient should be discontinued and the EOT 
visit performed as soon as possible: see also Figure 3. Study design.
The following assessment should be performed/evaluated: 

Assessment of disease-related symptoms.

Complete physical examination (including weight and BSA).

Basic neurological examination.

ECOG PS.

Vital signs (heart rate, blood pressure, body temperature).

Concomitant therapies.

Hematology.

Biochemistry-A.

Tumor assessment (clinical and radiological using PET-CT + CT).

Adverse events.

Bone marrow biopsy/aspirate assessment (if involved at diagnosis).
If the patient does not resume treatment in Cycle 7, adverse events must be reported 
during 30 days after the last study drug administration. All serious adverse events 
(SAEs) occurring within 30 days of the last study drug administration will be reported. 
Beyond this period of time, only those suspected to be treatment-related SAEs will be 
reported (Section 8.6.2).
5.10 EVALUATIONS AT END OF TREATMENT
The end-of-treatment visit (EOT) should take place approximately 30 days (± one week) 
of the last plitidepsin administration or as soon as possible after the End of Cycle 6 
radiological and clinical assessments (if the patient discontinues), unless the patient 
                                                
3 When PET-CT is performed it must be in combination with diagnostic quality CT with intravenous 
contrast (except medically contraindicated). Two alternatives are allowed: Hybrid PET CT scanners may 
be used to acquire diagnostic quality CT which includes intravenous contrast OR PET CT without 
intravenous contrast and diagnostic quality CT images with intravenous contrast using a standalone CT 
scanner must be performed.


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starts any subsequent antitumor therapy, in which case the EOT visit should be 
performed immediately before the start of the new therapy (ideally the day before or the 
same day): see also Figure 3. Study design.
Treated patients, regardless of the reason for ending the treatment, will undergo the 
following EOT assessments:

Assessment of disease-related symptoms.

Complete physical examination (including weight and BSA).

Basic neurological examination.

ECOG PS.

Vital signs (heart rate, blood pressure, body temperature).

Concomitant therapies.

Hematology.

Biochemistry-A.

Biochemistry-B.

Pregnancy test.

Coagulation tests.

Serum immunoglobulin quantification.

Serum protein electrophoresis.

Adverse events. 
For individual patients (and if clinically indicated according to Investigator’s criteria), it 
might also include the following:

Chest X-ray (if needed).

Bone marrow biopsy/aspirate (if involved at diagnosis).

Other tests as appropriate.
All these evaluations will only have to be repeated for those parameters for which no 
measurement is available within ten days before the EOT visit, or for those parameters 
with values that were out of range in the last assessment (grade ≥ 2 according to NCI-
CTCAE v.4).
Adverse events must be reported during 30 days after the last study drug administration. 
All serious adverse events (SAEs) occurring within 30 days of the last study drug 
administration will be reported. Beyond this period of time, only those suspected to be 
treatment-related SAEs will be reported (Section 8.6.2).
The Sponsor will evaluate all safety information that is spontaneously reported by an
Investigator beyond the time frame specified in the protocol.
Failure to attend the EOT visit exclusively due to a deteriorated clinical condition will 
not be considered a protocol deviation.
5.11 FOLLOW-UP AFTER END-OF-TREATMENT VISIT
The date and reason of the study discontinuation will be recorded on the patient’s e-
CRF (see Section 5.2.1.1).
Patients who discontinue treatment without disease progression will be followed every 
four months (+ two weeks) for the first two years of follow-up, and every six months (+


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two weeks) thereafter, unless clinically indicated, until PD, start of other antitumor 
therapy, death or the date of study termination (clinical cutoff), whichever occurs first. 
Tumor assessment (clinical and radiological using CT-scan) is required only for patients
who showed clinical benefit, every four months (+ two weeks) for the first two years,
and approximately every six months (+ two weeks) thereafter (unless clinically 
indicated).
After documented progression or start of a new antitumor therapy, patients will be 
followed for survival approximately every four months during the first two years, and 
then approximately every six months until death or the date of study termination, 
whichever occurs first. For the purpose of collecting information on the patient’s 
survival exclusively, a documented telephone call would be acceptable; follow-up for 
survival will be completed for all patients only if results of the primary endpoint 
confirm the trial as positive. 
The end-of-study date (clinical cutoff) is defined as 12 months after the last patient’s
inclusion. If there are patients still being treated at the planned cutoff date, the actual 
cutoff date will be the date when those patients have completed the ongoing treatment 
cycle and the corresponding EOT visit. The study will be closed earlier than planned if 
fewer than 15 patients are recruited in the first year after most sites are in active 
enrollment.
All AEs suspected to be related to the study treatment must be followed every four 
weeks after the end of treatment until the event or its sequelae resolve or stabilize at a 
level acceptable to the Investigator and the clinical monitor or his/her designated 
representative.
Patients who withdraw consent will not be followed with any study procedures (unless 
only consent to treatment was withdrawn). 
Additional parameters and/or increased frequency of observations should be performed 
at the Investigator’s discretion and according to the nature of the observed AEs. When 
available, autopsy data should be provided in case of death possibly related to treatment.
5.12 INDEPENDENT REVIEW COMMITTEE
Radiological tumor assessment and all efficacy data will be reviewed and evaluated by 
an Independent Review Committee (IRC) made up of radiologists and hematologists. 
Operational details and instructions to centers on the data entry and transfer will be 
given in a separate charter. 
5.13 INDEPENDENT DATA MONITORING COMMITTEE
An independent expert advisory group commissioned by the Sponsor will evaluate 
efficacy and safety data in enrolled patients. The primary objectives of this Independent 
Data Monitoring Committee (IDMC) are as follows:

To maintain the integrity of the trial conduct, to evaluate risk/benefit where 
possible of the APL-B-021-13 patients by monitoring the efficacy and safety 
data and making recommendations regarding treatment continuation and options 
for those on active treatment.

To inform the Sponsor’s Executive Committee regarding the outcome of the 
planned futility analyses as specified in the trial’s Statistical Analysis Plan 
(SAP) and to make recommendations. 


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The IDMC’s procedures will be detailed in a separate charter: investigators may be 
expected to provide complete and timely patient data for committee meetings in 
addition to normal CRF data entry.
6.
PHARMACOKINETICS
All patients included in the study will be sampled for PK.
All sample collection dates and times will be recorded on the CRF. Samples will be 
obtained on infusion days, i.e., Days 1, 8 and 15 of the Cycle 1 for the PK analysis of 
plitidepsin.
Twelve blood samples will be collected at the time points detailed in Table 6 for the 
determination of whole blood concentrations of plitidepsin.
Table 6. Sampling schedule for the determination of plitidepsin, including concomitant 
ECG measurements.
Sample 
Number
Day
Absolute time (h) 
from the start of 
plitidepsin 
infusion
Time-points for 
plitidepsin samples
ECG measurement
1#
1
0
Just before first infusion
Just before first infusion
2
1
1
Just before EOI
At EOI
3
1
1.5
30 min after EOI
30 min after EOI
4
1
2
1h after EOI
1h after EOI
5
1
4
3h after EOI
-
6
1
6
5h after EOI
-
7
8
168
Just before Day 8 infusion 
start
Just before Day 8 infusion 
start
8
8
1
Just before EOI
-
9
8
2
1h after EOI
1h after EOI
10
15
168
Just before Day 15 
infusion start
Just before Day 15 infusion 
start
11
15
1
Just before EOI
-
12
15
2
1h after EOI
1h after EOI
EOI, End of infusion; h, hour.
# Apart from the first PK sample (2 mL), a second sample (10 mL in total: 6 mL whole blood sample and 4 mL to 
obtain plasma) for biomarker analysis review should be drawn at this time-point.
Figure 4. PK sampling schedule during Cycle 1


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The sampling times may be changed while maintaining or decreasing the total number 
and volume of samples if information obtained during the evaluation allows 
improvement of the schedule. Samples for the measurement of plitidepsin will have a 
volume of 2 mL. 
The accurate recording of actual dosing and sampling times is much more important 
than the strict adherence to the scheduled times. The exact recording of the time of drug 
administration and sampling times is crucial on treatment days with PK sampling (and 
should be noted accurately even if not according to the planned time schedule). The 
infusion rate of plitidepsin will be established in order to ensure that the total dose is 
infused in 1 h. The drug will be infused at a constant rate throughout the 1-hour period. 
In order to obtain reliable PK information, the infusion rate should not be modified once 
the infusion begins. If a variation in the infusion time does occur, it is very important to 
reflect this in the e-CRF, writing clearly the time of the beginning and the end of the 
infusion. The infusion rate should not be changed to maintain the scheduled duration of 
infusion. It would be enough just to record the actual duration in the CRF and on the PK
sampling sheet.
Blood samples for PK will be obtained through a peripheral vein located in the 
contralateral side to that of administration of plitidepsin. In any case, the sampling vein 
has to be different to that in which drugs are administered. Even the last sample must 
never be collected from the catheter used for 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 collected in a sodium heparin tube and gently inverted several times 
to ensure proper mixing. After sampling, the test tubes containing the blood samples 
will be immediately frozen until analysis.
All material for PK procedures will be provided by the Sponsor. A separate instruction 
manual for sites describing sample extraction, labeling, storage, and shipment will be 
provided as a separate document.
7.
TREATMENT
7.1
DESCRIPTION OF TREATMENT
7.1.1 Drug Formulation and Supply
Plitidepsin will be supplied as a powder and solvent for concentrate for solution for 
infusion. The 2-mg vial should be reconstituted with a 4-mL ampoule of reconstitution 
solution. The list of excipients is: D-mannitol, nitrogen, polyoxyl 35 castor oil 
(Macrogolglycerol Ricinoleate Ph.Eur.), absolute ethanol, and water for injections. The 
composition of the reconstitution solution is: polyoxyl 35 castor oil/ethanol/water for 
injection (15/15/70% v/v/v).
For instructions regarding drug inventory, handling, reconstitution, dilution, storage, 
accountability and disposal, please refer to the Preparation Guide for plitidepsin and the 
Aplidin® IB, both provided as separate documents.


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7.2
ADMINISTRATION OF STUDY MEDICATION
Plitidepsin will be administered intravenously as a 1-hour infusion (fixed rate) via 
central or peripheral venous catheter. 
Patients will receive plitidepsin at a starting dose of 3.2 mg/m2 on Day 1, 8 and 15 every 
four weeks (q4wk). A 1-day window is allowed for plitidepsin administration.
A cycle is defined as a four-week period.
7.3
PROPHYLACTIC MEDICATION
All 
patients 
must 
receive 
the 
following 
prophylactic 
medication 
30–60 min before infusion of plitidepsin:
1) Dexamethasone (8 mg i.v. or equivalent)
2) 5-HT3 receptor antagonist: palonosetron 0.25 mg i.v. or tropisetron 5 mg i.v. or 
granisetron 3 mg i.v. (avoid ondansetron as this drug is categorized within a known 
risk of producing Torsade de Pointes)
(see Appendix 8). Alternatively, 
metoclopramide or other antiemetic drugs may be used instead as per Investigator’s 
criteria/institutional guidelines, and
3) Diphenhydramine hydrochloride 25 mg i.v. or equivalent, and
4) Ranitidine 50 mg i.v. or equivalent.
Oral metoclopramide and/or extended oral 5-HT3 receptor antagonist may be used as 
per Investigator’s criteria/institutional guidelines. Additional dexamethasone can only 
be used as an antiemetic in the event alternative antiemetics cannot be used; and only if 
the Investigator considers the options above as insufficient.
7.4
CRITERIA FOR TREATMENT CONTINUATION 
Patients can receive plitidepsin infusions (Day 1, 8, 15 of each cycle) for a maximum of 
six cycles (unless with PR or SD after Cycle 6: see Section 5.2.1.2) if they fulfill the 
following requirements:

ANC ≥ 1.0 × 109/L.

Platelet count ≥ 75 × 109/L. 

Hemoglobin ≥ 9.0 g/dL.

Calculated CrCL ≥ 30 mL/min (Cockcroft-Gault formula).

Total bilirubin ≤ 1.5 × ULN (grade 1).

AST, ALT ≤3.0 × ULN (grade 1).

Normal value of electrolytes, including potassium, magnesium and calcium.

Muscular toxicity (myalgia, muscular weakness, CPK increase) < grade 2.

Other non-hematological drug-related AEs [except for increased gamma 
glutamyltransferase (GGT), not optimally treated nausea and vomiting, 
hypertension or alopecia] grade 1.

No clinically relevant ECG changes compared with grade at baseline. 

QTc must be ≤ grade 1 before receiving the study treatment. In case of grade 1 QTc 
prolongation during treatment, and after discussion with the Sponsor, treatment 
must be continued with a normal value of electrolytes, including potassium, 
magnesium and calcium, being mandatory before the re-administration of 
plitidepsin. 


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
In case of QTc ≥ grade 2, the study treatment must be discontinued, and the patient 
must be followed until recovery.
If these criteria are not met on Day 1 of any cycle after Cycle 1, the new cycle is to be 
delayed for up to two weeks until recovery. If these toxicities do not recover after a 2-
week delay, the patient is to discontinue treatment and start the follow-up period unless 
there is obvious clinical benefit, in which case the patient might restart treatment at the 
Investigator’s discretion and after obtaining the approval of the Sponsor.
If these criteria are not met on Day 8 and 15 of any cycle (including Cycle 1), the 
scheduled infusion is to be omitted. Omitted doses for a given cycle are not to be 
recovered. 
“Cycle delay”, therefore, is only applicable to the first infusion of a new cycle (i.e., Day 
1) and not when an infusion takes place within the protocol-permitted window (one day)
and not when treatment resumes after radiological assessment (see Section 5.10).
7.5
DOSE REDUCTION
Dose adjustments are to be based on the worst toxicity occurring during the previous 
cycle. Table 7 shows the plitidepsin dose levels used in this study. 
Table 7. Dose levels.
Dose level
Plitidepsin dose (mg/m2)
0
3.2 
–1
2.7 
–2
2.3 
Once the dose given to a patient is reduced, it cannot be re-escalated. Patients requiring 
dose reduction below dose level –2 are to discontinue treatment and start the follow-up 
period (except in cases of obvious clinical benefit when further dosing changes must be 
agreed with the Sponsor). 
The plitidepsin dose should be reduced if the patient meets any of the following criteria:

Less than 50% compliance with the treatment schedule.

Febrile neutropenia.

Grade 4 neutropenia and infection, or grade 4 neutropenia lasting > 7 days.

Grade 4 thrombocytopenia. 

Grade ≥2 muscular toxicity (weakness, myalgia and/or CPK elevations). 

Grade ≥ 3 AST/ALT increase.

Any grade ≥ 3 clinically relevant, non-hematological toxicity (except non-optimally 
treated nausea and vomiting, diarrhea lasting < 48 h and/or grade ≥ 3 fatigue lasting 
< 5 days).
7.6
CONCOMITANT MEDICATION
All treatments received by the patient during the on-treatment period of the trial must be 
documented in the e-CRF. The details to be entered for each type of treatment will 
depend on factors such as relationship to, for example, AEs, underlying disease and 
symptoms, and will be defined in the study’s Monitoring Plan.
7.6.1
Allowed Medications/Therapies
1) Erythropoietin.


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2) Therapies for the treatment of pre-existing and/or emergent medical conditions not 
specifically forbidden as per protocol elsewhere.
3) Anti-emetics according to institutional or ASCO guidelines.
4) G-CSFs according to institutional or ASCO guidelines (except for primary 
prophylaxis and when screening for eligibility).
5) Systemic and/or local therapies for symptomatic relief, particularly in the case of 
diarrhea or skin toxicity.
6) Adequate analgesic medication, including opioids for symptomatic pain relief if 
indicated.
7.6.1.1
Transfusions
Platelet and red cells transfusions are allowed within one week prior to the infusion and 
during the study. 
7.6.2
Prohibited Medications/Therapies
1) Concomitant administration of any other antineoplastic therapy.
2) Other investigational agents.
3) Immunosuppressive therapies, except hydrocortisone used on isolated occasions as 
treatment for hypersensitivity reactions, or for the relief of the symptoms derived 
from the disease, if required.
4) Primary prophylaxis with colony-stimulating factors such as G-CSF.
5) Any medication with known risk of producing Torsade de Pointes, including 
ondansetron (see Appendix 8).
7.7
DRUG ACCOUNTABILITY
Proper drug accountability will be done by the pharmacist and/or appropriately trained 
study personnel. Each study site will keep records to allow a comparison of quantities of 
drug received and used at each site for monitoring purposes. The Investigator at each 
study site will be the person ultimately responsible for drug accountability at the site. 
All unused drug supplied by the Sponsor will be properly destroyed at the study site. 
Documentation of this procedure must be provided to the clinical trial monitor. If the 
Sponsor agrees, unused drug supplies may be returned to the drug repository.
7.8
TREATMENT COMPLIANCE
The Investigator is ultimately responsible for supervising compliance with the 
instructions described in this study protocol.
8.
STUDY EVALUATIONS
8.1
EFFICACY
The aim of this clinical trial is to determine the antitumor activity of plitidepsin in 
patients with AITL. The primary endpoint will be the ORR according to the Lugano 
classification response criteria per independent central review (see Section 3.1 and 
Appendix 2 for more details). Secondary endpoints of efficacy include ORR per 
investigator assessment (IA), CR, DoR, PFS, PFS6/12, OS and OS6/12 (see Section 3.2
for more details).


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All eligible and treated patients with AITL diagnosis confirmed after central 
pathological review will be included in the main efficacy analyses (primary and 
secondary endpoints). If a patient is treated but AITL diagnosis is not finally confirmed 
after central pathological review of the biopsy (even if inclusion was approved on the 
basis of the local histopathological report) then an additional patient will be included. 
Specifically, cases with features of follicular-PTCL and PTCL-NOS with TFH
phenotype or with features of progression/transformation from AITL to Diffuse Large
B-cell Lymphoma need to be excluded from the main efficacy analysis so additions are 
permitted in the event such patients are included before (or in spite of) central 
pathological exclusion. 
Supportive efficacy analyses will be assessed in all treated patients and in all evaluable 
patients—defined as eligible patients who receive at least two plitidepsin cycles in 
which at least two complete infusions have been administered and had at least one 
disease assessment—as well as in patients who discontinue treatment without Cycle 3 
tumor assessment after at least two plitidepsin infusions due to disease progression (PD) 
(or death due to PD) or toxicity (or death due to toxicity) defined as “early PD” and 
“treatment failures” respectively.
Patients without confirmation of AITL by central pathological review be excluded from 
the main efficacy analyses but, as supportive analyses, efficacy assessment will be done 
including all treated patients.
Radiological tumor assessment will be performed by PET-CT in combination with 
diagnostic quality CT4 one to two weeks after last dose of Cycle 3 and at least four 
weeks after last dose of Cycle 6 (but no more than eight weeks), and by CT-scan every 
four months (+ two weeks) for the first two years, and every six months (+ two weeks) 
thereafter or at suspected clinical progression, unless otherwise clinically indicated. An 
IRC consisting of medical specialists (radiologists and hematologists) who are directly 
involved in the care of patients with AITL—but not investigators in this trial—will 
review all efficacy data (including radiological assessments, bone marrow biopsies) and 
will assign the best response and the date of objective response or progression/censoring 
according to their independent evaluation.
Two futility analyses of the primary endpoint (ORR according to the Lugano 
classification criteria and per IRC) are planned for the time six months after 25% and 
50% of eligible patients have been treated (i.e., 15 and 30 patients, respectively). For 
example, if there are two or less responders out of 15 patients or seven or less 
responders out of 30 patients, according to boundaries and sample size assumptions, the 
alternative hypothesis could be rejected, and thus recruitment might be stopped at the
time of the first or second futility analysis, respectively. Otherwise, accrual will 
continue to a total of 60 patients with AITL confirmed by central pathological review.  
This decision will be taken at the time by an IDMC. The IDMC, which will include 
specialists in PTCL supported by a medical statistician, will review data provided by the 
                                                
4 When PET-CT is performed it must be in combination with diagnostic quality CT with intravenous 
contrast (except medically contraindicated). Two alternatives are allowed: Hybrid PET CT scanners may 
be used to acquire diagnostic quality CT which includes intravenous contrast OR PET CT without 
intravenous contrast and diagnostic quality CT images with intravenous contrast using a standalone CT 
scanner must be performed.


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Investigators, the IRC efficacy assessments and safety information and will provide 
advice on whether the study should continue.
Operational details (including procedures for review data submission) for the IRC and 
IDMC will be detailed in the corresponding charters.
8.2
SAFETY
Patients will be evaluable for safety if they have received any partial or complete 
treatment cycle. All AEs will be graded according to the NCI-CTCAE, v.4 and will be 
coded using the Medical Dictionary for Regulatory Activities (MedDRA). Cycle delays,
skipped doses, dose reduction requirements, and reasons for treatment discontinuation 
will be monitored throughout the study.
The safety profile of patients will be monitored throughout the treatment and up to 30 
days after the last treatment dose (EOT), or until the patient starts a new antitumor 
therapy or until the date of death, whichever occurs first.
Any treatment-related AEs will be followed until recovery to at least grade 1 or 
stabilization of symptoms, whenever possible.
8.3
PHARMACOKINETICS
All patients included in the study will be sampled for pharmacokinetics (PK). Twelve 
PK samples will be obtained on Day 1, 8 and 15 of Cycle 1 and will be evaluated by 
standard non-compartmental analysis (population pharmacokinetic modeling may be 
performed if appropriate).  
The following parameters will be calculated: AUC, Cmax, CL, and half-life (t1/2). 
The area under the blood concentration-time curve (AUC) will be determined using the 
log-linear trapezoidal method with extrapolation to infinity using the terminal rate 
constant k (Clast/k, where Clast is the last measured analyte concentration). The Cmax will 
be derived directly from the experimental data. The terminal rate constant (k) will be 
estimated by log linear regression analysis of the terminal phase of the blood
concentration vs. time curve. The t1/2 will be calculated from the equation 0.693/k; total 
blood CL will be determined by dividing the total administered dose by the AUC.
If considered appropriate by the Sponsor, compartmental analysis on the study results 
will also be performed, and population PK analysis will be made in pooled results of the 
different studies. If applicable, PK/PD parameters will be correlated.
8.4
BIOMARKERS AND EXPLORATORY EVALUATIONS
Biomarker analyses will look for a correlation of efficacy with molecular markers 
related to the mechanism of action of plitidepsin or to the pathogenesis of the disease, 
such as a) alterations in DNA and RNA, including DNA mutational status, RNA 
expression levels and miRNA expression for common genetic lesions affecting the 
AITL clone, b) alteration in tumor factors including (but not limited to) assessment of 
pathways and mechanisms of action of plitidepsin, at the RNA and/or protein 
expression level, and c) peripheral blood analyses, to identify plasma biomarkers 
including (but not limited to) cancer-related mutations and to extract DNA. Examples of 
exploratory evaluations and analyses, whenever relevant and depending on sample 
availability, include:

Common genetic lesions affecting the AITL clone: for example, TET2, IDH2, 
DNMT3A, RHOA, ITK or SYK.

Transcriptional profile of AITL.


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
Microenvironment factors: for example, markers of B cells (CD40, ICOS),
endothelial cells (VEGF, Angiopoietin), follicular dendritic cells (CXCL13), and 
other T-cell subpopulations (IL10, IL21, TGF-β). 

Factors associated with the mechanism of action of plitidepsin: for example, 
eEF1A2, Rac1 GTPase, JNK/phospo-JNK.

Predictive and prognostic tissue or plasma biomarkers associated with response 
to treatment: to identify possible mechanisms of resistance to plitidepsin through 
the comparative analysis of potential biomarkers in the pretreatment samples, 
and comparison with the post-progression biopsy tissue samples (when 
available), and in peripheral blood. For this objective, new representative 
biopsies in relapsed patients would be optimal.
8.5
ADVERSE EVENTS DEFINITIONS
8.5.1
Adverse Event (AE)
An AE is any untoward medical occurrence in a patient or clinical investigation patient 
administered a pharmaceutical product which does not necessarily have a causal 
relationship with this treatment. 
An AE can therefore be any unfavorable and unintended sign, (e.g., an abnormal 
laboratory finding), or a disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product.
Illnesses with onset during the study or exacerbations of pre-existing illnesses, including
but not limited to clinically significant changes in physical examination findings and 
abnormal objective test findings (e.g., X-ray, ECG) should be recorded. The criteria for 
determining whether an abnormal objective test finding should be reported as an AE are 
as follows:

The test result is associated with clinically significant symptoms, and/or

The test result leads to a change in the study dosing or discontinuation from the 
clinical trial, significant additional concomitant drug treatment or other therapy, 
and/or

The test result leads to any of the outcomes included in the definition of a SAE (see 
definition below), and/or

The test result is considered to be clinically relevant by the Investigator.
For the purposes of this protocol, disease progression, worsening of the underlying 
disease or appearance of new tumor lesions, or any sign or symptom clearly related with 
this circumstance is NOT an AE.
8.5.2
Serious Adverse Event (SAE)
A SAE is any adverse experience occurring at any dose that:

Results in death (is fatal),

Is life-threatening,

Requires or prolongs inpatient hospitalization,

Results in persistent or significant disability or incapacity,

Is a congenital anomaly or birth defect, 

Is medically significant, or

Is any suspected transmission of an infectious agent via a medicinal product. 


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Medical and scientific judgment should be exercised in deciding whether expedited 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in hospitalization but may jeopardize the 
patient or may require intervention to prevent one of the outcomes listed in the above 
definition.
8.5.3
Death
Death as such is the outcome of a SAE and should not be used as the SAE term itself,
whenever possible. The cause of death should be recorded as the SAE term instead.
When available, the autopsy report will be provided by the Sponsor.
Grade 5 should be used only for events for which there is a causal relationship with the 
patient’s death (e.g. the event was the direct cause of the death). Grade 4 should be used 
for the events with the outcome of death but there is no causal relationship between 
them (e.g. the death was not directly caused by the reported event but related to other 
comorbidities or complications).
8.5.4
Life-threatening Event
Any event in which the patient was at risk of death at the time of the event is considered 
life-threatening; it does not refer to an event which hypothetically might have caused 
death if it were more severe.
8.5.5
Hospitalization or Prolongation of Hospitalization
Any AE requiring hospitalization (or prolongation of hospitalization) that occurs or 
worsens during the course of a patient’s participation in a clinical trial must be reported 
as a SAE unless exempted from SAE reporting. Prolongation of hospitalization is 
defined as any extension of an inpatient hospitalization beyond the stay 
anticipated/required for the initial admission, as determined by the Investigator or 
treating physician.
Hospitalizations that do not meet the criteria for SAE reporting are: 
a. Reasons described in the protocol [e.g., investigational medicinal product (IMP) 
administration, protocol-required intervention/investigations, etc.]. However, 
events requiring hospitalizations or prolongation of hospitalization as a result of a 
complication of therapy administration or clinical trial procedures will be reported 
as SAEs.
b. Hospitalization or prolonged hospitalization for technical, practical or social 
reasons, in the absence of an AE.
c. Pre-planned hospitalizations: any pre-planned surgery or procedure must be 
documented in the source documentation. Only if the pre-planned surgery needs to 
be performed earlier due to a worsening of the condition, should this event 
(worsened condition) be reported as a SAE. 
Other situations that MUST NOT be considered as hospitalizations are the following:
d. An emergency visit due to an accident where the patient is treated and discharged.
e. When the patient is held 24 hours for observation and finally is not admitted.
f. Planned treatments at sites not associated to a hospital and generally considered as 
minor surgical procedures (i.e., laser eye surgery, arthroscopy, etc.).


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8.5.6
Unlisted/Unexpected Adverse Event
An AE, the nature or severity of which is not consistent with the applicable reference 
safety information.
The Sponsor will use as the reference safety information for the evaluation of 
listedness/expectedness the most updated IB for plitidepsin.
8.5.7
Adverse Reactions
All untoward and unintended responses to an investigational medicinal product related 
to any dose administered. This definition covers also medication errors and uses outside 
what is foreseen in the protocol, including overdose, lack of efficacy, misuse and abuse 
of the product.
8.5.8
Adverse Events Related to the Study Drug
An AE is considered related to a study drug/IMP if the Investigator’s assessment of 
causal relationship to the IMP(s) is “Y (yes)” (see Section 8.5.10). 
The Investigator will assess the causal relationship of the IMP(s) to the SAE.
The Sponsor may also consider related to the study drug(s)/IMP(s) those events for 
which the Investigator assesses the causal relationship with the IMP(s) as “Uk 
(unknown)” when it cannot rule out a role of the IMP(s) in the event.
8.5.9
Expedited Reporting
The Sponsor is responsible for the appropriate expedited reporting of serious 
unlisted/unexpected and related adverse events (SUSAR/SUA), including misuse, 
overuse and abuse, to the Competent Authorities. The Sponsor will also report all SAEs, 
including misuse, overuse and abuse, which are unlisted/unexpected and related to the 
study drug(s) [IMP(s)] to the Investigators and to the IECs/IRBs according to the 
current legislation, unless otherwise required and documented by the IECs/IRBs.
8.5.10 Assessment of Causal Relationship to the Study Drug
The Investigator must provide an assessment of the causal relationship of the clinical 
trial IMP(s) to each SAE according to the following scale:
Y
There is a reasonable possibility that the IMP(s) caused the SAE.
N
There is no reasonable possibility that the IMP(s) caused the SAE and 
other causes are more probable.
Uk.
(Unknown). Only to be used in special situations where the Investigator 
has insufficient information (i.e., the patient was not seen at his/her 
center) if none of the above can be used.
8.6
ADVERSE EVENTS REPORTING PROCEDURES
8.6.1
Reporting Adverse Events
The Sponsor will collect AEs until 30 days after administration of the last dose of study 
drug(s)/IMP(s) or until the start of a new antitumor therapy, whichever occurs first. All 
AEs suspected to be related to the study drug/IMP must be followed-up after the time of 
therapy discontinuation until the event or its sequelae resolve or stabilize at an 
acceptable level to the Investigator and the Sponsor.
All AEs, including misuse, overdose, abuse and medication error, must be recorded in 
English using medical terminology in the source document and the e-CRF. Whenever 


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possible, the Investigator will record the main diagnosis instead of the signs and 
symptoms normally included in the diagnoses. 
Investigators must assess severity (grade) of the event following the NCI-CTCAE v.4
and assign a relationship to each study drug(s)/IMP(s); and pursue and obtain 
information adequate both to determine the outcome and to assess whether it meets the 
criteria for classification as a SAE requiring immediate notification to the Sponsor or its 
designated representative. The Investigator must provide any relevant information as 
requested by the Sponsor in addition to that on the e-CRF.
Abnormal laboratory tests occurring during the study should only be recorded in the AE 
section of the e-CRF if the disorder:
is associated with clinically significant symptoms, and/or
leads to a change in study dosing or discontinuation from study treatment, 
significant additional concomitant drug treatment or other therapy, and/or
leads to any of the outcomes included in the definition of a SAE.
Otherwise, laboratory results should be reported in the corresponding section of the e-
CRF (e.g. biochemistry, hematology).
Disease progression or appearance of new tumor lesions, or any sign or symptom 
clearly related with this circumstance is NOT an AE.
8.6.2
Reporting Serious Adverse Events
The Sponsor will collect SAEs from the time of signing of the ICF until 30 days after 
administration of the last dose of study drug(s)/IMP(s) or until the start of a new 
antitumor therapy, whichever occurs first (or until screening failure, if applicable). 
Beyond this period of time, only those SAEs suspected to be related to the IMP will be 
collected. Nonetheless, the Sponsor will evaluate any safety information that is 
spontaneously reported by an Investigator beyond the time frame specified in the 
protocol.
All SAEs (as defined above) that occur after patient registration, regardless of 
relationship to the study drug(s)/IMP(s) must be reported immediately and always 
within 24 hours to the PharmaMar Pharmacovigilance Department electronically by 
completing the applicable e-CRF sections. Only in the event of electronic system failure
can SAEs be reported using a paper “SAE form” by fax (+34 91 846 6004), e-mail 
(phv@pharmamar.com), or by telephone (+ 34 91 823 4633). Out of office hours 
[Greenwich Meridian Time (GMT)], assistance on SAE reporting can be obtained by 
calling the Pharmacovigilance Department at +34 91 823 4742. SAEs initially reported 
by alternative (i.e., not electronic) methods must be followed by a completed electronic 
SAE reporting on e-CRF from the investigational staff within one working day.
Those SAEs occurring during the screening phase (from ICF signature to registration) 
and after off-study will be reported using a paper “SAE Form” that must be forwarded 
as mentioned above always within 24 hours to the Pharmacovigilance Department by 
fax or e-mail.
All SAEs suspected to be related to the IMP(s) must be followed until the event or its 
sequelae resolves or stabilizes at an acceptable level by the Investigator and the clinical 
monitor or his/her designated representative.
Disease progression or appearance of new tumor lesions, or any sign or symptom 
clearly related with this circumstance should NOT be reported as an SAE.


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8.6.3
Reporting Pregnancy Cases Occurred within the Clinical Trial
National regulations require that clinical trial Sponsors collect information on 
pregnancies occurring during clinical trials, in which exposure to the IMP(s) at any time 
during pregnancy, via either maternal or paternal exposure, is suspected.
Therefore, pregnancy and suspected pregnancy (including a positive pregnancy test 
regardless of age or disease state) of a female patient or the female partner of a male 
patient occurring while the patient is on study drug, or within 30 days of the patient’s 
discontinuation visit, are considered immediately reportable events.
The Investigator will report the following events immediately and always within 24 
hours from first knowledge:

Any occurrence of a pregnancy where any kind of exposure to the IMP(s) is 
suspected.

Possible exposure of a pregnant woman [this could involve a partner of a male 
patient or a pregnant female who came in contact with the clinical trial IMP(s)].

All reports of elevated/questionable or indeterminate beta human chorionic 
gonadotropins (β-hCGs).
Immediately after detecting a case of suspected pregnancy in a female clinical trial 
patient, the decision on her continued participation in the clinical trial will be jointly 
taken by the trial patient, the Investigator and the Sponsor, with the patient’s best 
interest in mind. A decision to continue the pregnancy will require immediate 
withdrawal from the trial. 
Any pregnancy, suspected pregnancy, or positive pregnancy test must be reported to 
Sponsor Pharmacovigilance immediately by facsimile using the Pregnancy Report form. 
In the case of pregnancy of the female partner of a trial patient, the Investigator will 
obtain her informed consent to provide the information by using the applicable form 
provided by the Sponsor who will also advise the Investigator in these situations.
The Investigator will follow the pregnancy until its outcome, and must notify 
PharmaMar Pharmacovigilance of the outcome of the pregnancy within 24 hours of first 
knowledge as a follow-up to the initial report.
For any event during the pregnancy which meets a seriousness criterion (including fetal 
or neonatal death or congenital anomaly) the Investigator will also follow the 
procedures for reporting SAEs (complete and send the SAE form to PharmaMar 
Pharmacovigilance by facsimile within 24 hours of the Investigator’s knowledge of the 
event). 
All neonatal deaths that occur within 30 days of birth should be reported, without regard 
to causality, as SAEs. In addition, any infant death at any time thereafter that the 
Investigator suspects is related to the exposure to the study drug(s)/IMP(s) should also 
be reported to PharmaMar Pharmacovigilance by facsimile within 24 hours of the 
Investigators’ knowledge of the event.
8.7
ADVERSE EVENTS MONITORING
Safety review will be performed by the Sponsor once SAE forms have been received 
electronically or by fax and the CRFs have been electronically completed by the 
Investigator.
Periodic safety review of clinical data will be performed; however, no formal Data 
Safety Monitoring Board has been appointed for this trial. AEs will be monitored by the 


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Investigators and by the Sponsor study team. The personnel in charge of this process are 
defined in the Study Contacts section of this protocol. In general, a clinical oncologist
medical monitor, together with a member of the PharmaMar Pharmacovigilance 
Department will review the safety data of this trial 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, the Sponsor will report to the IECs/IRBs, 
Investigators and Competent Authorities:

expeditedly: all serious, related, unlisted/unexpected AEs or critical safety findings 
from this and any other clinical trial with plitidepsin 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 verified during monitoring visits by the monitor, who will 
discuss them with the Investigators. 
Any protocol deviation will also be discussed with the Investigator during monitoring 
visits.
9.
STATISTICAL METHODS
9.1
SAMPLE SIZE
The primary endpoint for this study is ORR according to the Lugano classification
criteria per independent review.
A total of 60 patients with AITL confirmed by central pathological review will be 
treated, 19 or more responders will be needed to get an overall estimate for response 
rate higher than 30% and its lower limit for the 95% confidence interval greater than 
20% (31.7% CI95% 20.3%–45.0% following the binomial distribution). 
The type I error (alpha) associated with this one-sided test is 0.025 and the type II error 
(beta) is 0.1; hence, statistical power is 90%. The null hypothesis (H0) is set at ORR ≤
20% (P0=0.208) versus the alternative hypothesis (H1) at ≥40% patients (Pa=0.41)
having an objective response, the variance of the standardized test is under the null 
hypothesis. 
Two futility analyses of the primary endpoint (ORR according to Lugano classification 
and per IRC) are planned to reject the alternative hypothesis six months after 25% and 
50% of eligible patients have been treated (15 and 30 patients, respectively). Pocock 
boundary and the actual number of patients confirmed by central pathological review
will be used to control type II error for both analyses. For example, if there are two or 
less responders out of 15 patients or seven or less responders out of 30 patients, 
according to boundaries and sample size assumptions, the alternative hypothesis could 
be rejected, and thus recruitment might be stopped at the time of the first or second 
futility analysis, respectively. Otherwise, accrual will continue to a total of 60 patients
AITL confirmed by central pathological review. Active recruitment will not be halted 
while the analysis is being carried out.
Therefore, if there are 19 or more responders of 60 patients, the null hypothesis can be 
rejected, allowing consideration of the observed activity plitidepsin as clinically 
relevant in the setting of patients with AITL.


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9.2
STATISTICAL ANALYSIS
9.2.1
Efficacy
For ORR and CR rate, the exact binomial estimator and its 95% confidence interval (CI) 
will be used. The test statistic for stopping boundaries and final analysis will be 
calculated using observed results and normal distribution.
Time-to-event variables (DoR, PFS and OS) will be analyzed according to the Kaplan-
Meier method. Time to event endpoints will be used as exploratory endpoints.
Intra-patient PFS/TTP ratio will be categorized and analyzed as a dichotomous variable. 
Clinical benefit will be defined in the event of > 33% longer PFS with the experimental 
treatment vs. TTP with the immediate prior chemotherapy in R/R setting (ratio >1.33)
(66, 67).
Frequency tables will be prepared for categorical variables, whereas continuous 
variables will be described by means of summary tables that will include the median,
mean, standard deviation, minimum, and maximum of each variable.
9.2.2
Safety 
Safety analyses will consider AEs and SAEs, according to their relationship with the 
study treatment, as well as analytical results, deaths and the reasons for cycle delays, 
omitted doses and/or dose reductions. All AEs and SAEs will be graded according to
NCI-CTCAE, v.4.
9.2.3
Pharmacokinetics 
PK parameters will be tabulated and selected parameters will be graphically displayed. 
The dose-exposure relationship will be evaluated.
The potential influence on selected PK parameters of selected demographic and clinical 
dichotomous variables (gender, laboratory test results above/below selected cutoff 
values, etc.) will be evaluated by 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, etc.), relationship with 
selected PK parameters will be graphically explored and assessed using correlation and 
regression methods.
Other tests may be applied if the results of the above evaluations suggest that they may 
yield additional relevant information.
9.2.4
Biomarkers Analysis
Biomarkers will be analyzed from pharmacodynamic parameters tabulated and selected 
parameters will be graphically displayed describing specimen analysis, gene mutations,
gene/protein expression profiles, microenvironment analysis and any potential AITL 
biomarkers identified.
Other tests may be applied if the results of the above evaluations suggest that they may 
yield additional relevant information regarding plitidepsin’s mechanism of action.
9.3
INTERIM ANALYSIS
Two futility analyses of the primary endpoint (ORR according to the Lugano 
classification criteria and per IRC) are planned to reject the alternative hypothesis six 
months after approximately 25% and 50% of eligible patients have been treated (15 and 


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30 patients, respectively). Pocock boundary and the actual number of patients confirmed 
by central pathological review will be used to control type II error for both analyses. An 
IDMC, which will include specialists in PTCL supported by a medical statistician, will 
review data provided by the Investigators, the IRC efficacy assessments and safety 
information and will provide advice on whether the study should continue. For example, 
if there are two or less responders out of 15 patients or seven or less responders out of 
30 patients, according to boundaries and sample size assumptions, the alternative 
hypothesis could be rejected, and thus recruitment might be stopped at the time of the 
first or second futility analysis, respectively. Otherwise, accrual will continue to a total 
of 60 patients with AITL confirmed by central pathological review. Active recruitment 
will not be halted while the analysis is being carried out.
10. ADMINISTRATIVE SECTION
10.1 ETHICS
This clinical trial will be conducted in accordance with the ethical principles that have 
their origin in the World Medical Association (WMA) Declaration of Helsinki (see
Appendix 7) and will be consistent with GCP guidelines and pertinent regulatory 
requirements.
The study personnel involved in conducting this trial will be qualified by education, 
training and experience to perform their respective task(s).
The study will be conducted in compliance with the protocol. The protocol, any 
amendments and the patient informed consent will receive Competent Authorities 
authorization and IEC/IRB approval/favorable opinion prior to initiation, according to 
pertinent regulations.
The Competent Authorities authorization and 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 
these authorizations will be provided to the Sponsor before the beginning of the study.
The Investigator and/or the Sponsor is/are responsible for keeping the Competent 
Authorities and the IEC/IRB informed of any significant new information about the 
study drug.
All protocol amendments will be agreed upon by the Sponsor and the Investigator.
Administrative changes of the protocol are minor corrections and/or clarifications that 
have no impact on the way the study is to be conducted.
10.2 MONITORING, AUDITING AND INSPECTING
The study will be monitored by regular site visits and telephone calls to the Investigator 
by the clinical trial monitor designated by the Sponsor.
During site visits, the trial monitor should revise original patient records, drug 
accountability records and document retention (study file). Additionally, the trial 
monitor should observe study procedures and will discuss any problems with the 
Investigator.
Adequate time for these visits should be allocated by the Investigator. The Investigator 
should also ensure that the monitor is given direct access [as per International 
Conference on Harmonization (ICH) Topic E6 Guideline for Good Clinical Practice, 
Sections 4.9.7 and 6.10] to source documents (i.e., hospital or private charts, original 
laboratory records, appointment books, etc.) of the patient which support data entered in 


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the case report forms, as defined in the ICH Topic E6 Guideline for Good Clinical 
Practice, Sections 1.51 and 1.52.
Systems and procedures will be implemented to ensure the quality of every aspect of the 
trial.
During the course of the trial, the Sponsor’s Clinical Quality Assurance department or 
external auditors contracted by the Sponsor may conduct an onsite audit visit (ICH 
Topic E6 Guideline for GCP, Section 1.6).
Participation in this trial implies acceptance of potential inspection by national or 
foreign Competent Authorities.
10.3 PATIENT INFORMED CONSENT
The rights, safety and well-being of the trial patients are the most important 
considerations and should prevail over interests of science and society.
The informed consent process will include all elements required by ICH, GCP and 
applicable regulatory requirements (such as the biobanks 1716/2011 decree and 
biomedical research 14/2007 legislation).
Prior to inclusion into the trial, the Investigator or a person designated by the 
Investigator, must provide the patient with one copy of the Informed Consent Form 
(ICF). This copy must provide written full information about the clinical trial, in a 
language that is non-technical and easily understood. The Investigator should allow the 
necessary time for the patient or his/her legally acceptable representative to inquire 
about the details of the clinical trial; then, the ICF must be freely signed and personally 
dated by the patient and by the person who conducted the informed consent discussion 
before the beginning of the study. The patient should receive a copy of the signed ICF 
and any other written information provided to study patients prior to participation in the 
trial.
During a patient’s participation in the trial, any updates to the consent forms and any 
updates to the written information will be provided to him/her.
If there is a need to obtain new consent from the patients, the Investigator or a person 
designated by the Investigator should inform the patients of any new information 
relevant to the patients’ willingness to continue participation in the study, before 
obtaining the written consent.
10.4 CONFIDENTIALITY/ PATIENTS IDENTIFICATION
The collection and processing of personal data from the patients enrolled in this clinical 
trial will be limited to those data that are necessary to investigate the efficacy, safety, 
quality and usefulness of the study drug used in this trial.
It is the Investigator’s responsibility that sufficient information on the identity of the 
patients will be retained.
The trial monitor, the Sponsor’s auditor, the IECs/IRBs and the Competent Authorities
should have direct access to all requested trial-related records, and agree to keep the 
identity of study patients confidential.
The data must be collected and processed with adequate precautions to ensure 
confidentiality and compliance with applicable data privacy protection laws and 
regulations.


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Explicit consent for the processing of personal data will be obtained from the 
participating patient before data collection, if applicable, and this consent should also 
address the transfer of the data to other entities and countries.
The Sponsor shall comply with the Directive 95/46/EEC of the European Parliament 
and of the Council of 24 October 1995 on the protection of individuals with regard to 
the processing of personal data and on the free movement of such data.
10.5 CASE REPORT FORMS
CRFs will be used to record all data for each patient. It is the responsibility of the 
Investigator to ensure that CRFs are properly and completely filled in, in English. CRFs 
must be completed for all patients who have given their informed consent and have been 
enrolled into the study.
A patient’s source documentation is the physician’s patient records and original 
documents, and as such they should be maintained at the study site.
The data collected in the CRF will be entered into the Sponsor’s databases, which 
comply with the Spanish Act implementing the Directive 95/46/EC of the European 
Parliament and of the Council of 24 October 1995 on the protection of individuals with 
regard to the processing of personal data. 
10.6 INSURANCE
The Sponsor will provide insurance or indemnity in accordance with the applicable 
regulatory requirements.
10.7 RETENTION OF RECORDS
The Investigator/Institution should maintain trial documents according to Section 8 of 
the ICH Topic E6 Guideline for Good Clinical Practice and as required by applicable 
regulatory requirements.
Essential documents should be retained as per the aforementioned ICH guideline or for 
a longer period of time, if required by the applicable regulations. 
10.8 USE OF INFORMATION AND PUBLICATION
Before the investigators of this study submit a paper or abstract for publication or 
otherwise publicly disclose information concerning the study drug or products, the 
Sponsor must be provided with at least 60 days to revise and approve the proposed 
publication or disclosure to ensure that confidential and proprietary data are protected.
If the Sponsor determines that patentable patient matter is disclosed in the proposed 
publication or disclosure, the publication or disclosure will be withheld for a period of 
time considered convenient. If the study is part of a multicenter study, the first 
publication of the study shall be made in conjunction with the presentation of a joint, 
multicenter publication of the study results with the investigators and the institutions 
from all appropriate sites that are contributing data, analysis and comments. However, if 
such a multicenter publication is not submitted within 12 months after conclusion, 
abandonment or termination of the study at all sites, the present study may be published 
individually in accordance with the procedure established above.
The order of the co-authors will reflect the relative contribution of each one to study 
development and analysis. In general, the first author will be the investigator who 
recruits the highest number of patients with information finally available for data 


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


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36.
Cairns RA, Iqbal J, Lemonnier F, Kucuk C, de Leval L, Jais JP, et al. IDH2 
mutations 
are 
frequent 
in 
angioimmunoblastic 
T-cell 
lymphoma. 
Blood. 
2012;119(8):1901-3. Epub 2012/01/05.
37.
Lemonnier F, Couronne L, Parrens M, Jais JP, Travert M, Lamant L, et al. 
Recurrent TET2 mutations in peripheral T-cell lymphomas correlate with TFH-like 
features and adverse clinical parameters. Blood. 2012;120(7):1466-9. Epub 2012/07/05.
38.
O'Connor OA, Pro B, Pinter-Brown L, Bartlett N, Popplewell L, Coiffier B, et 
al. Pralatrexate in patients with relapsed or refractory peripheral T-cell lymphoma: 
results from the pivotal PROPEL study. J Clin Oncol. 2011;29(9):1182-9. Epub 
2011/01/20.
39.
Coiffier B, Pro B, Prince HM, Foss F, Sokol L, Greenwood M, et al. Results 
from a pivotal, open-label, phase II study of romidepsin in relapsed or refractory 
peripheral T-cell lymphoma after prior systemic therapy. J Clin Oncol. 2012;30(6):631-
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40.
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. Epub 2002/05/03.
41.
Cuadrado A, Gonzalez L, Suarez Y, Martinez T, Munoz A. JNK activation is 
critical for Aplidin-induced apoptosis. Oncogene. 2004;23(27):4673-80. Epub 
2004/05/04.
42.
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 and differentiation. 2006;13(11):1968-81. Epub 
2006/03/18.
43.
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. Epub 2003/01/17.
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Munoz-Alonso MJ, Gonzalez-Santiago L, Martinez T, Losada A, Galmarini 
CM, Munoz A. The mechanism of action of plitidepsin. Curr Opin Investig Drugs. 
2009;10(6):536-42. Epub 2009/06/11.
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Suarez Y, Gonzalez-Santiago L, Zarich N, Davalos A, Aranda JF, Alonso MA, 
et al. Plitidepsin cellular binding and Rac1/JNK pathway activation depend on 
membrane cholesterol content. Molecular pharmacology. 2006;70(5):1654-63. Epub 
2006/08/25.
46.
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. Epub 2002/10/19.
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Galmarini CM, D'Incalci M, Allavena P. Trabectedin and plitidepsin: drugs 
from the sea that strike the tumor microenvironment. Marine drugs. 2014;12(2):719-33. 
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Maghazachi AA. In Vitro and in Vivo Evaluation of Aplidin® Alone and in 
Combination with Rituxan in Human T Cell Lymphoma. 22-0977-PMM-IA , B, C and 
D. 2007;BioQuant, San Diego, CA, USA.
49.
Mateos MV, Cibeira MT, Richardson PG, Prosper F, Oriol A, de la Rubia J, et 
al. Phase II clinical and pharmacokinetic study of plitidepsin 3-hour infusion every two 
weeks alone or with dexamethasone in relapsed and refractory multiple myeloma. Clin 
Cancer Res. 2010;16(12):3260-9. Epub 2010/06/10.
50.
Hiddemann W, Cheson BD. How we manage follicular lymphoma. Leukemia. 
2014;28(7):1388-95. Epub 2014/03/01.
51.
Pharma Mar S.A. Final Study Report on "APL-B-020-10 Ooen-label, Phase II 
Clinical Trial of Aplidin® (Plitidepsin) in Patients with Primary Myelofibrosis (PMF) 
and Post Polycythemia Vera/Essential Thormbocythemia (post-PV/ET) Myelofibrosis". 
7 February 2012.
52.
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.
53.
Pharma Mar S.A. Final Study Report on "APL-B-013-02 A Phase II 
Multicenter, Open-label, Clinical and Pharmacokinetic Study of Aplidin® as a 1-hour 
Weekly iv Infusion, in Patients with Relapsed or Refractory Aggressive non-Hodgkin’s 
Lymphoma". 30 November 2010.
54.
Ribrag V, Caballero D, Ferme C, Zucca E, Arranz R, Briones J, et al. 
Multicenter phase II study of plitidepsin in patients with relapsed/refractory non-
Hodgkin's lymphoma. Haematologica. 2013;98(3):357-63. Epub 2012/10/16.
55.
Gendrel D, Biscardi S, Marc E, Moulin F, Iniguez JL, Raymond J. [Mycoplasma 
pneumoniae, community-acquired pneumonia and asthma]. Archives de pediatrie : 
organe officiel de la Societe francaise de pediatrie. 2005;12 Suppl 1:S7-11. Epub 
2005/05/17. Mycoplasma pneumoniae, pneumonies et asthme.
56.
Odejide O, Weigert O, Lane AA, Toscano D, Lunning MA, Kopp N, et al. A 
targeted mutational landscape of angioimmunoblastic T-cell lymphoma. Blood. 
2014;123(9):1293-6. Epub 2013/12/19.
57.
Muto H, Sakata-Yanagimoto M, Nagae G, Shiozawa Y, Miyake Y, Yoshida K, 
et al. Reduced TET2 function leads to T-cell lymphoma with follicular helper T-cell-
like features in mice. Blood cancer journal. 2014;4:e264. Epub 2014/12/17.
58.
Taraboletti G, Poli M, Dossi R, Manenti L, Borsotti P, Faircloth GT, et al. 
Antiangiogenic activity of aplidine, a new agent of marine origin. British journal of 
cancer. 2004;90(12):2418-24. Epub 2004/06/03.
59.
Morande PE, Zanetti SR, Borge M, Nannini P, Jancic C, Bezares RF, et al. The 
cytotoxic activity of Aplidin in chronic lymphocytic leukemia (CLL) is mediated by a 
direct effect on leukemic cells and an indirect effect on monocyte-derived cells. 
Investigational new drugs. 2012;30(5):1830-40. Epub 2011/09/03.
60.
Cheson BD, Pfistner B, Juweid ME, Gascoyne RD, Specht L, Horning SJ, et al. 
Revised response criteria for malignant lymphoma. J Clin Oncol. 2007;25(5):579-86. 
Epub 2007/01/24.


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61.
Cheson BD, Fisher RI, Barrington SF, Cavalli F, Schwartz LH, Zucca E, et al. 
Recommendations for initial evaluation, staging, and response assessment of Hodgkin 
and non-Hodgkin lymphoma: the Lugano classification. Journal of clinical oncology : 
official journal of the American Society of Clinical Oncology. 2014;32(27):3059-68. 
Epub 2014/08/13.
62.
Herrera AF, Crosby-Thompson A, Friedberg JW, Abel GA, Czuczman MS, 
Gordon LI, et al. Comparison of referring and final pathology for patients with T-cell 
lymphoma 
in 
the 
National 
Comprehensive 
Cancer 
Network. 
Cancer. 
2014;120(13):1993-9. Epub 2014/04/08.
63.
Dupuis J, Boye K, Martin N, Copie-Bergman C, Plonquet A, Fabiani B, et al. 
Expression of CXCL13 by neoplastic cells in angioimmunoblastic T-cell lymphoma 
(AITL): a new diagnostic marker providing evidence that AITL derives from follicular 
helper T cells. The American journal of surgical pathology. 2006;30(4):490-4. Epub 
2006/04/21.
64.
Grogg KL, Attygalle AD, Macon WR, Remstein ED, Kurtin PJ, Dogan A. 
Expression of CXCL13, a chemokine highly upregulated in germinal center T-helper 
cells, distinguishes angioimmunoblastic T-cell lymphoma from peripheral T-cell 
lymphoma, unspecified. Modern pathology : an official journal of the United States and 
Canadian Academy of Pathology, Inc. 2006;19(8):1101-7. Epub 2006/05/09.
65.
Laginestra MA, Piccaluga PP, Fuligni F, Rossi M, Agostinelli C, Righi S, et al. 
Pathogenetic and diagnostic significance of microRNA deregulation in peripheral T-cell 
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66.
Mick R, Crowley JJ, Carroll RJ. Phase II clinical trial design for noncytotoxic 
anticancer agents for which time to disease progression is the primary endpoint. Control 
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designs--twenty-first Richard and Hinda Rosenthal Foundation Award Lecture. Clin 
Cancer Res. 1998;4(5):1079-86. Epub 1998/06/02.


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12. APPENDICES
APPENDIX 1: WHO Classification of Tumors of Hematopoietic and Lymphoid 
Tissues 
Extract from WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, 
Fourth Edition, WHO Classification of Tumours, Volume 2, Swerdlow, S.H., Campo, 
E., Harris, N.L., Jaffe, E.S., Pileri, S.A., Stein, H., Thiele, J., Vardiman, J.W. (IARC, 
Lyon, 2008), pp309–11.
Definition
Angioimmunoblastic T-cell lymphoma (AITL) is a peripheral T-cell lymphoma 
characterized by systemic disease, a polymorphous infiltrate involving lymph nodes, 
with a prominent proliferation of high endothelial venules and follicular dendritic cells.
ICD-O code
9705/3
Synonyms and historical annotation
AITL was previously felt to be an atypical reactive process, angioimmunoblastic 
lymphadenopathy, with an increased risk of progression of lymphoma. Currently, 
overwhelming evidence suggests that AITL rises de novo as a peripheral T-cell 
lymphoma.
Epidemiology
AITL occurs in the middle-aged and elderly, with an equal incidence in males and 
females. It is one of the more common specific subtypes of peripheral T-cell lymphoma, 
accounting for approximately 15–20% of cases, or 1–2% of all non-Hodgkin 
lymphomas.
Etiology
The nearly constant association with Epstein Barr virus (EBV) has suggested a possible 
role for the virus in the etiology, possibly through antigen-drive. However, the 
neoplastic T cells are EBV negative.
Sites of involvement
The primary site of disease is the lymph node and virtually all patients present with 
generalized lymphadenopathy. In addition, spleen, liver, skin and bone marrow (BM) 
are frequently involved.
Clinical features
AITL typically presents with advanced stage disease, generalized lymphadenopathy, 
hepatosplenomegaly, systemic symptoms, and polyclonal hypergammaglobulinemia. 
Skin rash, often with pruritus, is frequently present. Other common findings are pleural 
effusion, arthritis and ascites. Laboratory findings include circulating immune 
complexes, cold agglutinins with hemolytic anemia, positive rheumatoid factor and anti-
smooth muscle antibodies.


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Patients exhibit immunodeficiency secondary to the neoplastic process. In the majority 
of cases (75%), expansion of B-cells positive for EBV is seen, thought to be a 
consequence of underlying immune dysfunction.
Morphology
AITL is characterized by partial effacement of the lymph node architecture, often with 
perinodal infiltration but sparing of the peripheral cortical sinuses. There is marked 
proliferation of arborizing high endothelial venules (HEV). There is predominantly 
paracortical polymorphic infiltrate composed of small to medium-sized lymphocytes, 
with clear to pale cytoplasm and distinct cell membranes and minimal cytological 
atypia. The neoplastic cells often form small clusters around the follicles and HEV and 
are admixed with variable numbers of small reactive lymphocytes, eosinophils, plasma 
cells and histiocytes. The polymorphic infiltrate is frequently associated with increased 
follicular dendritic cell meshworks. Early cases may contain hyperplastic follicles with 
ill-defined borders and the characteristic histology may be limited to the perifollicular 
areas with predominance of clear cells. The relationship between AITL showing limited 
paracortical involvement and the follicular variant of peripheral T-cell lymphoma, NOS 
remains to be clarified. An expansion of B immunoblasts is usually present in the 
paracortex. The expansion of normal B-cells and follicular dendritic cells in the lesions 
has been linked to the functional properties of the neoplastic cells as follicular helper T-
cells (TFH) of the normal follicle. The expression of CXCL13 mediates expansion of 
follicular dendritic cells, and, adhesion of B-cells to HEV with subsequent entry to the 
lymph nodes. EBV-positive B-cells are nearly always present. They range in cell size 
and expansion of B immunoblasts may be prominent. The EBV-positive B 
immunoblastic proliferation may progress, either composite with AITL, or at relapse to 
EBV-positive diffuse large B-cell lymphoma. EBV-positive Reed-Sternberg-like cells 
of B-cell lineage may be present and may simulate classical Hodgkin lymphoma. In 
advanced cases, the inflammatory component is diminished, and the proportion of clear 
cells and large cells is increased.
Immunophenotype
The neoplastic T-cells express most pan T-cell antigens such as CD3, CD2 and CD5 
and, in vast majority of the cases, CD4 although numerous reactive CD8+ T-cells are 
often present. Characteristically, the tumor cells show the phenotype of normal TFH 
expressing CD10, CXCL13 and PD-1 in 60–100% of the cases. This phenotype is 
helpful in distinguishing AITL from atypical paracortical hyperplasia and other 
peripheral T-cell lymphomas as well as diagnosing extranodal dissemination. B 
immunoblasts and plasma cells are polytypic; however, secondary EBV-positive B-cell 
proliferations including diffuse large B-cell lymphoma, classical Hodgkin lymphoma or 
plasmacytoma may be seen. Follicular dendritic cell meshworks expressing CD21, 
CD23, CD35 and CNA42 are expanded, usually surrounding the high HEV.
Postulated normal counterpart
CD4+ follicular helper T-cell.
Genetics
T-cell receptor genes show clonal rearrangements in 75–90% of cases. Clonal 
immunoglobulin gene rearrangements may be found in around 25–30% of cases, and 
correlate with expanded EBV+ B-cells. The most frequent cytogenetic abnormalities are 
trisomy 3, trisomy 5 and an additional X chromosome and comparative genetic 


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hybridization has shown gains of 22q, 19 and 11q13 and losses of 13q in subset of 
cases. Gene expression profiling studies have shown that the neoplastic cells show 
features of CD4+ TFH.
Prognosis and predictive factors
The clinical course is aggressive with a median survival of less than three years. 
Patients often succumb to infectious complications, which makes delivery of aggressive 
chemotherapy difficult. Supervening large B-cell lymphoma (often but not invariably 
EBV-positive) can occur.


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APPENDIX 2: THE LUGANO CLASSIFICATION: REVISED CRITERIA FOR
RESPONSE ASSESSMENT
Response and 
Site
PET-CT-Based Response
CT-Based Response
Complete
Complete metabolic response
Complete radiologic response 
(all of the following)
Lymph nodes 
and extra-
lymphatic sites  
Score 1, 2, or 3* with or without a residual mass on 5PS†
Target nodes/nodal masses must regress 
to ≤ 1.5 cm in LDi
It is recognized that in Waldeyer’s ring or extranodal sites with 
high physiologic uptake or with activation within spleen or marrow 
(eg, with chemotherapy or myeloid colony-stimulating factors), 
uptake may be greater than normal mediastinum and/or liver. In 
this circumstance, complete metabolic response may be inferred if 
uptake at sites of initial involvement is no greater than surrounding 
normal tissue even if the tissue has high physiologic uptake
No extralymphatic sites of disease
Nonmeasured 
lesion
Not applicable
Absent
Organ 
enlargement
Not applicable
Regress to normal
New lesions
None
None
Bone marrow
No evidence of FDG-avid disease in marrow
Normal by morphology; if indeterminate, 
IHC negative
Partial
Partial metabolic response
Partial remission (all of the following)
Lymph nodes 
and extra-
lymphatic sites
Score 4 or 5† with reduced uptake compared with baseline and 
residual mass(es) of any size
≥ 50% decrease in SPD of up to 6 target
measurable nodes and extranodal sites
At interim, these findings suggest responding disease
When a lesion is too small to measure on 
CT, assign 5 mm × 5 mm as the default 
value
At end of treatment, these findings indicate residual disease
When no longer visible, 0 × 0 mm
For a node > 5 mm × 5 mm, but smaller 
than normal, use actual measurement for 
calculation
Nonmeasured 
lesions
Not applicable
Absent/normal, regressed, but no increase
Organ 
enlargement
Not applicable
Spleen must have regressed by > 50% in 
length beyond normal
New lesions
None
None
Bone marrow
Residual uptake higher than uptake in normal marrow but reduced 
compared with baseline (diffuse uptake compatible with reactive 
changes from chemotherapy allowed). If there are persistent focal 
changes in the marrow in the context of a nodal response, 
consideration should be given to further evaluation with MRI or 
biopsy or an interval scan
Not applicable
No response or 
stable disease
No metabolic response
Stable disease


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Response and 
Site
PET-CT-Based Response
CT-Based Response
Target 
nodes/nodal 
masses, 
extranodal 
lesions
Score 4 or 5 with no significant change in FDG uptake from 
baseline at interim or end of treatment
< 50% decrease from baseline in SPD of 
up to 6 dominant, measurable nodes and 
extranodal sites; no criteria for 
progressive disease are met
Nonmeasured 
lesions
Not applicable
No increase consistent with progression
Organ 
enlargement
Not applicable
No increase consistent with progression
New lesions
None
None
Bone marrow
No change from baseline
Not applicable
Progressive 
disease
Progressive metabolic disease
Progressive disease requires at least 1 of 
the following
Individual 
target 
nodes/nodal 
masses
Score 4 or 5 with an increase in intensity of uptake from baseline 
and/or
PPD progression:
Extranodal 
lesions
New FDG-avid foci consistent with lymphoma at interim or end-
of-treatment assessment
An individual node/lesion must be 
abnormal with:
LDi > 1.5 cm and
Increase by ≥ 50% from PPD nadir and
An increase in LDi or SDi from nadir
0.5 cm for lesions ≤ 2 cm
1.0 cm for lesions > 2 cm
In the setting of splenomegaly, the splenic 
length must increase by > 50% of the 
extent of its prior increase beyond 
baseline (eg, a 15-cm spleen must 
increase to > 16 cm). If no prior 
splenomegaly, must increase by at least 2 
cm from baseline
New or recurrent splenomegaly
Nonmeasured 
lesions
None
New or clear progression of preexisting 
nonmeasured lesions
New lesions
New FDG-avid foci consistent with lymphoma rather than another 
etiology (eg, infection, inflammation). If uncertain regarding 
etiology of new lesions, biopsy or interval scan may be considered
Regrowth of previously resolved lesions
A new node > 1.5 cm in any axis
A new extranodal site > 1.0 cm in any 
axis; if < 1.0 cm in any axis, its presence 
must be unequivocal and must be 
attributable to lymphoma
Assessable disease of any size 
unequivocally attributable to lymphoma
Bone marrow
New or recurrent FDG-avid foci
New or recurrent involvement
Footnotes on following page


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Footnotes refer to table on previous pages
Abbreviations: 5PS, 5-point scale; CT, computed tomography; FDG, fluorodeoxyglucose; IHC, immunohistochemistry; LDi, 
longest transverse diameter of a lesion; MRI, magnetic resonance imaging; PET, positron emission tomography; PPD, cross 
product of the LDi and perpendicular diameter; SDi, shortest axis perpendicular to the LDi; SPD, sum of the product of the 
perpendicular diameters for multiple lesions.
* A score of 3 in many patients indicates a good prognosis with standard treatment, especially if at the time of an interim scan. 
However, in trials involving PET where de-escalation is investigated, it may be preferable to consider a score of 3 as inadequate 
response (to avoid undertreatment). Measured dominant lesions: Up to six of the largest dominant nodes, nodal masses, and 
extranodal lesions selected to be clearly measurable in two diameters. Nodes should preferably be from disparate regions of the 
body and should include, where applicable, mediastinal and retroperitoneal areas. Non-nodal lesions include those in solid organs 
(eg, liver, spleen, kidneys, lungs), GI involvement, cutaneous lesions, or those noted on palpation. Nonmeasured lesions: Any 
disease not selected as measured, dominant disease and truly assessable disease should be considered not measured. These sites 
include any nodes, nodal masses, and extranodal sites not selected as dominant or measurable or that do not meet the 
requirements for measurability but are still considered abnormal, as well as truly assessable disease, which is any site of suspected 
disease that would be difficult to follow quantitatively with measurement, including pleural effusions, ascites, bone lesions, 
leptomeningeal disease, abdominal masses, and other lesions that cannot be confirmed and followed by imaging. In Waldeyer’s 
ring or in extranodal sites (eg, GI tract, liver, bone marrow), FDG uptake may be greater than in the mediastinum with complete 
metabolic response, but should be no higher than surrounding normal physiologic uptake (eg, with marrow activation as a result 
of chemotherapy or myeloid growth factors).
† PET 5PS: 1, no uptake above background; 2, uptake ≤ mediastinum; 3, uptake > mediastinum but ≤ liver; 4, uptake moderately 
> liver; 5, uptake markedly higher than liver and/or new lesions; X, new areas of uptake unlikely to be related to lymphoma.
Source: Recommendations for Initial Evaluation, Staging, and Response Assessment of 
Hodgkin and Non-Hodgkin Lymphoma: The Lugano Classification
Bruce D. Cheson, Richard I. Fisher, Sally F. Barrington, Franco Cavalli, Lawrence H. 
Schwartz, Emanuele Zucca and T. Andrew Lister.
JCO September 20, 2014 vol. 32 no. 27 3059-3067
Available at http://jco.ascopubs.org/content/32/27/3059.long (accessed 30 July 2015).


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APPENDIX 
3: 
PROGNOSTIC 
INDEX 
FOR 
PERIPHERAL 
T-CELL 
LYMPHOMA (PIT)
Source: Gallamini A, Stelitano C, Calvi R, Bellei M, Mattei D, Vitolo U, et al. 
Peripheral T-cell lymphoma unspecified (PTCL-U): a new prognostic model from a 
retrospective multicentric clinical study. Blood. 2004;103(7):2474-9. 
Available 
at
http://www.bloodjournal.org/content/bloodjournal/103/7/2474.full.pdf
(accessed 30 July 2015). 
To assess the prognosis of peripheral T-cell lymphoma unspecified, 385 cases were 
retrospectively analyzed fulfilling the criteria defined by the World Health Organization 
classification. Multivariate analysis showed that age (relative risk, 1.732; 95% CI, 
1.300–2.309; P < .0001), PS (relative risk, 1.719; 95% CI, 1.269–2.327, P < .0001), 
lactate dehydrogenase (LDH) level (relative risk, 1.905; 95% CI, 1.415–2.564; P 
< .0001), and bone marrow involvement (relative risk, 1.454; 95% CI, 1.045–2.023; P 
= .026) were factors independently predictive for survival (Table 1). 
Table 1. Clinical parameters influencing survival in PTCL (multivariate analysis)
Parameter
Significance, P
Relative risk
95% CI, low 95% CI, high
Age 
< .0001
1.732
1.300
2.309
PS 
< .0001
1.719
1.269
2.327
LDH level 
< .0001
1.905
1.415
2.564
BM involvement 
.026
1.454
1.405
2.023
BM, bone marrow; CI, confidence interval; PS, performance status; LDH, lactate dehydrogenase.
Using these four variables a new prognostic model (PIT, Prognostic Index for PTCL) 
that singled out four groups of patients at different risk was constructed (P ≤ .0001; log-
rank, 66.79): 
Group 1: no adverse factors, with 5-year and 10-year OS of 62.3% and 54.9%, 
respectively.
Group 2: one factor, with a 5-year and 10-year OS of 52.9% and 38.8%, 
respectively.
Group 3: two factors, with 5-year and 10-year OS of 32.9% and 18.0%, 
respectively.
Group 4: Three or four factors, with a 5-year and 10-year OS of 18.3 and 12.6%, 
respectively.


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APPENDIX 4: PROGNOSTIC INDEX FOR ANGIOIMMUNOBLASTIC T-CELL 
LYMPHOMA (PIAI)
Source: Federico M, Rudiger T, Bellei M, Nathwani BN, Luminari S, Coiffier B, et al. 
Clinicopathologic characteristics of angioimmunoblastic T-cell lymphoma: analysis of 
the international peripheral T-cell lymphoma project. J Clin Oncol. 2013;31(2):240-6. 
Available at http://jco.ascopubs.org/content/31/2/240.long (accessed 30 July 2015).
The International Peripheral T-Cell Lymphoma Project was undertaken to better 
understand 
the 
subtypes 
of 
T-cell 
and 
natural 
killer-cell 
lymphomas. 
Angioimmunoblastic T-cell lymphoma (AITL) was diagnosed according to the 2001 
WHO criteria by a central review process consisting of panels of expert 
hematopathologists. Clinical, pathologic, immunophenotyping, treatment, and survival 
data were correlated. Of 1,314 patients, 243 (18.5%) were diagnosed with AITL. At 
presentation, generalized lymphadenopathy was noted in 76% of patients, and 89% had 
stages III to IV disease. Skin rash was observed in 21% of patients. Hemolytic anemia 
and hypergammaglobulinemia occurred in 13% and 30% of patients, respectively. Five-
year overall and failure-free survivals were 33% and 18%, respectively. 
At presentation, prognostic models were evaluated, including the standard International 
Prognostic Index, which comprised the following factors: age ≥ 60 years, stages III to 
IV disease, lactic dehydrogenase (LDH) > normal, extranodal sites (ENSs) > one, and 
performance status (PS) ≥ 2 (see Appendix 3).
The Prognostic Index for Peripheral T-Cell Lymphoma comprised: age ≥ 60 years, PS ≥ 
2, LDH > normal, and bone marrow involvement; and the alternative Prognostic Index 
for AITL (PIAI) proposed by the authors, comprised: age > 60 years, PS ≥ 2, ENSs > 
one, B symptoms, and platelet count < 150 × 109/l. The simplified PIAI had a low-risk 
group (zero to one factors), with 5-year survival of 44%, and a high-risk group (two to 
five factors), with 5-year survival of 24% (P = .0065) (Table 1).
Table 1. Survival of patients with AITL by prognostic model
No. of Risk Factors
Patients (%)
5-year OS (%)
5-year FFS (%)
IPI
0/1
14
56
34
2
28
38
21
3
30
20
12
4/5
28
25
16
PIT
0/1
36
46
22
2
37
19
12
3/4
27
30
22
PIAI
0/1 (low-risk group)
30
44
28
2-5 (high-risk group)
70
24
15
AITL, angioimmunoblastic T-cell lymphoma; FFS, failure-free survival; IPI, International Prognostic 
Index; OS, overall survival; PIAI, Prognostic Index for AITL; PIT, Prognostic Index for Peripheral T-
Cell Lymphoma, Unspecified. 


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APPENDIX 5: ANN ARBOR STAGING SYSTEM
Source: Lister TA, Crowther D, Sutcliffe SB, et al. (November 1989). "Report of a 
committee convened to discuss the evaluation and staging of patients with Hodgkin's 
disease: Cotswolds meeting". J. Clin. Oncol. 7 (11): 1630–6.
Cotswold Modification 
Stage
Area of Involvement
I
Single lymph node group
II
Multiple lymph node groups on same side of diaphragm
II
Multiple lymph node groups on both sides of diaphragm
IV
Multiple extranodal sites or lymph nodes and extranodal disease
X
Bulk > 10 cm
E
Extranodal extension or single, isolated site of extranodal disease


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APPENDIX 6: CONTRACEPTION AND PREGNANCY TESTING
This document is based on the Heads of Medicines Agencies’ Recommendations Related 
to Contraception and Pregnancy Testing in Clinical Trials, published by the Clinical 
Trial Facilitation Group (CTFG) on 15 September 2014
and available at 
http://www.hma.eu/ctfg.html (accessed 30 July 2015) 
A woman is considered of childbearing potential (WOCBP) following menarche and 
until becoming post-menopausal unless permanently sterile. Permanent sterilization 
methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. A 
postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal 
range may be used to confirm a post-menopausal state in women not using hormonal 
contraception or hormonal replacement therapy. However, in the absence of 12 months 
of amenorrhea, a single FSH measurement is insufficient. Immediately after detecting a 
case of suspected pregnancy in a patient, the decision on her continued participation in 
the clinical trial will be jointly taken by the patient, the Investigator and the Sponsor, 
with the patient’s best interest in mind. A decision to continue the pregnancy will 
require immediate discontinuation any investigational medicinal product (IMP). 
A man is considered fertile after puberty unless permanently sterile by bilateral 
orchidectomy. Fertile male patients included in this study should refrain from fathering 
a child or donating sperm during the study and for four months following the last IMP 
dose. If they have WOCBP partners the male subject should use condom during 
treatment and for four months following the last IMP dose.
Highly effective birth control methods are:
1. Combined (estrogen and progestogen containing) hormonal contraception 
associated with inhibition of ovulation 1:
a.
oral
b. intravaginal 
c.
transdermal 
2. Progestogen-only hormonal contraception associated with inhibition of 
ovulation 1: 
a.
oral 
b. injectable
c.
implantable 2
3. Intrauterine device (IUD) 2
4. Intrauterine hormone-releasing system (IUS) 2
5. Bilateral tubal occlusion 2
6. Vasectomized partner 2,3
7. Sexual abstinence 4
8. A combination of male condom with either cap, diaphragm or sponge with 
spermicide (double barrier methods) are also considered acceptable, but not 
highly effective, birth control methods.


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1 Hormonal contraception may be susceptible to interaction with the IMP, which may 
reduce the efficacy of the contraception method (see below).
2 Contraception methods that are considered to have low user dependency. 
3 Vasectomized partner is a highly effective birth control method provided that partner is the 
sole sexual partner of the WOCBP trial participant and that the vasectomized partner has 
received medical assessment of the surgical success. 
4 Sexual abstinence is considered a highly effective method only if defined as refraining 
from heterosexual intercourse during the entire period of risk associated with the study 
treatments. The reliability of sexual abstinence needs to be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the subject. Periodic 
abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus 
interruptus), spermicides only, and lactational amenorrhea method (LAM) are not 
acceptable methods of contraception. Female condom and male condom should not be used 
together.
Contraception methods with low user dependency should preferably be used, in 
particular when contraception is introduced as a result of participation in this trial. It 
cannot be excluded that the IMP may reduce exposure to substrates of CYP3A 
through enzyme induction; the efficacy of hormonal contraceptives may be reduced 
if co-administered with the IMP.


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APPENDIX 7: DECLARATION OF HELSINKI
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964
and amended by the:
29th WMA General Assembly, Tokyo, Japan, October 1975
35th WMA General Assembly, Venice, Italy, October 1983
41st WMA General Assembly, Hong Kong, September 1989
48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996
52nd WMA General Assembly, Edinburgh, Scotland, October 2000
53rd WMA General Assembly, Washington DC, USA, October 2002 (Note of Clarification added)
55th WMA General Assembly, Tokyo, Japan, October 2004 (Note of Clarification added)
59th WMA General Assembly, Seoul, Republic of Korea, October 2008
64th WMA General Assembly, Fortaleza, Brazil, October 2013
Preamble
1.
The World Medical Association (WMA) has developed the Declaration of 
Helsinki as a statement of ethical principles for medical research involving 
human subjects, including research on identifiable human material and data.
The Declaration is intended to be read as a whole and each of its constituent 
paragraphs should be applied with consideration of all other relevant paragraphs.
2.
Consistent with the mandate of the WMA, the Declaration is addressed primarily 
to physicians. The WMA encourages others who are involved in medical 
research involving human subjects to adopt these principles.
General Principles
3.
The Declaration of Geneva of the WMA binds the physician with the words, 
“The health of my patient will be my first consideration,” and the International 
Code of Medical Ethics declares that, “A physician shall act in the patient's best 
interest when providing medical care.”
4.
It is the duty of the physician to promote and safeguard the health, well-being 
and rights of patients, including those who are involved in medical research. The 
physician's knowledge and conscience are dedicated to the fulfilment of this 
duty.
5.
Medical progress is based on research that ultimately must include studies 
involving human subjects.
6.
The primary purpose of medical research involving human subjects is to 
understand the causes, development and effects of diseases and improve 
preventive, diagnostic and therapeutic interventions (methods, procedures and 
treatments). Even the best proven interventions must be evaluated continually 
through research for their safety, effectiveness, efficiency, accessibility and 
quality.
7.
Medical research is subject to ethical standards that promote and ensure respect 
for all human subjects and protect their health and rights.
8.
While the primary purpose of medical research is to generate new knowledge, 
this goal can never take precedence over the rights and interests of individual 
research subjects.
9.
It is the duty of physicians who are involved in medical research to protect the 
life, health, dignity, integrity, right to self-determination, privacy, and 
confidentiality of personal information of research subjects. The responsibility 
for the protection of research subjects must always rest with the physician or 


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other health care professionals and never with the research subjects, even though 
they have given consent.
10.
Physicians must consider the ethical, legal and regulatory norms and standards 
for research involving human subjects in their own countries as well as 
applicable international norms and standards. No national or international 
ethical, legal or regulatory requirement should reduce or eliminate any of the 
protections for research subjects set forth in this Declaration.
11.
Medical research should be conducted in a manner that minimises possible harm 
to the environment.
12.
Medical research involving human subjects must be conducted only by 
individuals with the appropriate ethics and scientific education, training and 
qualifications. Research on patients or healthy volunteers requires the 
supervision of a competent and appropriately qualified physician or other health 
care professional.
13.
Groups that are underrepresented in medical research should be provided 
appropriate access to participation in research.
14.
Physicians who combine medical research with medical care should involve 
their patients in research only to the extent that this is justified by its potential 
preventive, diagnostic or therapeutic value and if the physician has good reason 
to believe that participation in the research study will not adversely affect the 
health of the patients who serve as research subjects.
15.
Appropriate compensation and treatment for subjects who are harmed as a result 
of participating in research must be ensured.
Risks, Burdens and Benefits
16.
In medical practice and in medical research, most interventions involve risks and 
burdens.
Medical research involving human subjects may only be conducted if the 
importance of the objective outweighs the risks and burdens to the research 
subjects.
17.
All medical research involving human subjects must be preceded by careful 
assessment of predictable risks and burdens to the individuals and groups 
involved in the research in comparison with foreseeable benefits to them and to 
other individuals or groups affected by the condition under investigation.
Measures to minimise the risks must be implemented. The risks must be 
continuously monitored, assessed and documented by the researcher.
18.
Physicians may not be involved in a research study involving human subjects 
unless they are confident that the risks have been adequately assessed and can be 
satisfactorily managed.
When the risks are found to outweigh the potential benefits or when there is 
conclusive proof of definitive outcomes, physicians must assess whether to 
continue, modify or immediately stop the study.
Vulnerable Groups and Individuals
19.
Some groups and individuals are particularly vulnerable and may have an 
increased likelihood of being wronged or of incurring additional harm.


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All vulnerable groups and individuals should receive specifically considered 
protection.
20.
Medical research with a vulnerable group is only justified if the research is 
responsive to the health needs or priorities of this group and the research cannot 
be carried out in a non-vulnerable group. In addition, this group should stand to 
benefit from the knowledge, practices or interventions that result from the 
research.
Scientific Requirements and Research Protocols
21.
Medical research involving human subjects must conform to generally accepted 
scientific principles, be based on a thorough knowledge of the scientific 
literature, other relevant sources of information, and adequate laboratory and, as 
appropriate, animal experimentation. The welfare of animals used for research 
must be respected.
22.
The design and performance of each research study involving human subjects 
must be clearly described and justified in a research protocol.
The protocol should contain a statement of the ethical considerations involved 
and should indicate how the principles in this Declaration have been addressed. 
The protocol should include information regarding funding, sponsors, 
institutional affiliations, potential conflicts of interest, incentives for subjects and 
information regarding provisions for treating and/or compensating subjects who 
are harmed as a consequence of participation in the research study.
In clinical trials, the protocol must also describe appropriate arrangements for 
post-trial provisions.
Research Ethics Committees
23.
The research protocol must be submitted for consideration, comment, guidance 
and approval to the concerned research ethics committee before the study 
begins. This committee must be transparent in its functioning, must be 
independent of the researcher, the sponsor and any other undue influence and 
must be duly qualified. It must take into consideration the laws and regulations 
of the country or countries in which the research is to be performed as well as 
applicable international norms and standards but these must not be allowed to 
reduce or eliminate any of the protections for research subjects set forth in this 
Declaration.
The committee must have the right to monitor ongoing studies. The researcher 
must provide monitoring information to the committee, especially information 
about any serious adverse events. No amendment to the protocol may be made 
without consideration and approval by the committee. After the end of the study, 
the researchers must submit a final report to the committee containing a 
summary of the study’s findings and conclusions.
Privacy and Confidentiality
24.
Every precaution must be taken to protect the privacy of research subjects and 
the confidentiality of their personal information.


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


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be obtained as soon as possible from the subject or a legally authorised 
representative.
31.
The physician must fully inform the patient which aspects of their care are 
related to the research. The refusal of a patient to participate in a study or the 
patient’s decision to withdraw from the study must never adversely affect the 
patient-physician relationship.
32.
For medical research using identifiable human material or data, such as research 
on material or data contained in biobanks or similar repositories, physicians 
must seek informed consent for its collection, storage and/or reuse. There may 
be exceptional situations where consent would be impossible or impracticable to 
obtain for such research. In such situations the research may be done only after 
consideration and approval of a research ethics committee.
Use of Placebo
33.
The benefits, risks, burdens and effectiveness of a new intervention must be 
tested against those of the best proven intervention(s), except in the following 
circumstances:
Where no proven intervention exists, the use of placebo, or no intervention, is 
acceptable; or
Where for compelling and scientifically sound methodological reasons the use of 
any intervention less effective than the best proven one, the use of placebo, or no 
intervention is necessary to determine the efficacy or safety of an intervention
and the patients who receive any intervention less effective than the best proven 
one, placebo, or no intervention will not be subject to additional risks of serious 
or irreversible harm as a result of not receiving the best proven intervention.
Extreme care must be taken to avoid abuse of this option.
Post-Trial Provisions
34.
In advance of a clinical trial, sponsors, researchers and host country 
governments should make provisions for post-trial access for all participants 
who still need an intervention identified as beneficial in the trial. This 
information must also be disclosed to participants during the informed consent 
process.
Research Registration and Publication and Dissemination of Results
35.
Every research study involving human subjects must be registered in a publicly 
accessible database before recruitment of the first subject.
36.
Researchers, authors, sponsors, editors and publishers all have ethical 
obligations with regard to the publication and dissemination of the results of 
research. Researchers have a duty to make publicly available the results of their 
research on human subjects and are accountable for the completeness and 
accuracy of their reports. All parties should adhere to accepted guidelines for 
ethical reporting. Negative and inconclusive as well as positive results must be 
published or otherwise made publicly available. Sources of funding, institutional 
affiliations and conflicts of interest must be declared in the publication. Reports 


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of research not in accordance with the principles of this Declaration should not 
be accepted for publication.
Unproven Interventions in Clinical Practice
In the treatment of an individual patient, where proven interventions do not exist or 
other known interventions have been ineffective, the physician, after seeking 
expert advice, with informed consent from the patient or a legally authorised 
representative, may use an unproven intervention if in the physician's judgement it 
offers hope of saving life, re-establishing health or alleviating suffering. This 
intervention should subsequently be made the object of research, designed to 
evaluate its safety and efficacy. In all cases, new information must be recorded 
and, where appropriate, made publicly available.


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APPENDIX 8: LISTS DRUGS THAT PROLONG THE QT INTERVAL AND/OR 
INDUCE TORSADES DE POINTES VENTRICULAR ARRHYTHMIA
Source:  www.azcert.org
Because the evidence for risk of Torsade de Pointes (TdP) is often imperfect, AZCERT, 
inc. has divided the drugs into four groups based on their analysis of the evidence:
1.
Known Risk of TdP: Substantial evidence supports the conclusion that these 
drugs prolong the QT interval AND are clearly associated with a risk of TdP, 
even when taken as directed in official labeling. In bold at the listing below.
Generic Name (Brand Name)
Drug Class / Clinical Usage
Risk List
Amiodarone (Cordarone®)
Anti-arrhythmic/abnormal heart rhythm
1
Anagrelide (Agrylin®, Xagrid®)
Phosphodiesterase inhibitor/thrombocythemia
1
Arsenic trioxide (Trisenox®)
Anti-cancer/leukemia
1
Astemizole (Hismanal®)
Antihistamine/allergic rhinitis
1
Azithromycin (Zithromax®)
Antibiotic/bacterial infection
1
Bepridil (Vascor®)
Anti-anginal/heart pain
1
Chloroquine (Aralen®)
Anti-malarial/malaria infection
1
Chlorpromazine (Thorazine®)
Anti-psychotic/anti-
emetic/schizophrenia/nausea
1
Cilostazol (Pletal®)
Phosphodiesterase 
inhibitor/intermittent 
claudication
1
Cisapride (Propulsid®)
GI stimulant/heartburn
1
Citalopram (Celexa®)
Anti-depressant/depression
1
Clarithromycin (Biaxin®)
Antibiotic/bacterial infection
1
Cocaine
Local anesthetic
1
Disopyramide (Norpace®)
Anti-arrhythmic/abnormal heart rhythm
1
Dofetilide (Tikosyn®)
Anti-arrhythmic/abnormal heart rhythm
1
Domperidone (Motilium®)
Anti-nausea/nausea
1
Donepezil (Aricept®)
Cholinesterase inhibitor/Dementia
1
Dronedarone (Multaq®)
Anti-arrhythmic/atrial fibrillation
1
Droperidol (Inapsine®)
Sedative;anti-nausea/anesthesia adjunct, nausea
1
Erythromycin (E.E.S.® )
Antibiotic;GI 
stimulant/bacterial 
infection; 
increase GI motility
1
Escitalopram (Cipralex®)
Anti-depressant/depression/ anxiety disorders
1
Flecainide (Tambocor®)
Anti-arrhythmic/abnormal heart rhythm
1
Halofantrine (Halfan®)
Anti-malarial/malaria infection
1
Haloperidol (Haldol®)
Anti-psychotic/schizophrenia, agitation
1
Ibutilide (Corvert®)
Anti-arrhythmic/abnormal heart rhythm
1
Levomethadyl (Orlaam®)
Opiate 
agonist/pain 
control, 
narcotic 
dependence
1
Mesoridazine (Serentil®)
Anti-psychotic/schizophrenia
1
Methadone (Methadose®)
Opiate 
agonist/pain 
control, 
narcotic 
dependence
1
Moxifloxacin (Avelox®)
Antibiotic/bacterial infection
1
Ondansetron (Zofran®)
Anti-emetic/nausea and vomiting
1
Pentamidine (Pentam®)
Anti-infective/pneumocystis pneumonia
1
Pimozide (Orap®)
Anti-psychotic/Tourette's tics
1
Probucol (Lorelco®)
Antilipemic/hypercholesterolemia
1
Procainamide (Procan®)
Anti-arrhythmic/abnormal heart rhythm
1
Quinidine (Quinaglute®)
Anti-arrhythmic/abnormal heart rhythm
1
Sevoflurane (Ulane®)
Anesthetic, general/anesthesia
1
Sotalol (Betapace®)
Anti-arrhythmic/abnormal heart rhythm
1
Sparfloxacin (Zagam®)
Antibiotic/bacterial infection
1
Sulpiride (Dogmatil®, Dolmatil®)
Anti-psychotic, atypical/schizophrenia
1


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Generic Name (Brand Name)
Drug Class / Clinical Usage
Risk List
Terfenadine (Seldane®)
Antihistamine/allergic rhinitis
1
Thioridazine (Mellaril®)
Anti-psychotic/schizophrenia
1
Vandetanib (Caprelsa®)
Anti-cancer/thyroid cancer
1
2.
Possible risk of TdP: Substantial evidence supports the conclusion that these 
drugs can cause QT prolongation BUT there is insufficient evidence at this time 
that these drugs, when used as directed in official labeling, are associated with a 
risk of causing TdP.
3.
Conditional risk of TdP: Substantial evidence supports the conclusion that these 
drugs are associated with a risk of TdP BUT only under certain conditions (e.g. 
excessive dose, hypokalemia, congenital long QT or by causing a drug-drug 
interaction that results in excessive QT interval prolongation).
1 to 4. Drugs to Avoid in Congenital Long QT: Substantial evidence supports the 
conclusion that these drugs pose a risk of TdP for patients with congenital long 
QT. Drugs on this list include those in the above three risk cathegories 1, 2 and 
3, and other drugs, 4, that do not prolong the QT interval per se but they have a 
theoretical risk of causing arrhythmia that is based on their known stimulant 
actions on the heart.
Generic Name (Brand Name)
Drug Class / Clinical Usage
Risk List
Albuterol/salbutamol (Proventil®, Ventolin)
Bronchodilator/Asthma
4
Alfuzosin (Uroxatral®)
Alpha1-blocker/benign prostatic hyperplasia
2
Amantadine (Symmetrel®)
anti-viral/anti-infective/Parkinson's disease
3
Amphetamine (Adderal-XR®, Dexedrine®)
CNS stimulant/ADHD
4
Amiodarone (Cordarone®)
Anti-arrhythmic/abnormal heart rhythm
1
Amisulpride (Solian® and others)
Antipsychotic, atypical/psychosis
3
Amitriptyline (Elavil®)
Tricyclic antidepressant/depression
3
Amoxapine (Asendin®, Amokisan®)
Tetracyclic anti-depressant/depression
3
Anagrelide (Agrylin®, Xagrid®)
Phosphodiesterase inhibitor/thrombocythemia
1
Apomorphine (Apokyn®, Ixense®)
Dopamine agonist/Parkinson's disease
2
Aripiprazole (Abilify®, Aripiprex®)
Antipsychotic/psychosis, adjunct for 
depression
2
Arsenic trioxide (Trisenox®)
Anti-cancer/leukemia
1
Arformoterol (Brovana®)
Bronchodilator/Chronic obs. lung disease
4
Astemizole (Hismanal®)
Antihistamine/allergic rhinitis
1
Atazanavir (Reyataz®)
Protease inhibitor/HIV
2
Atomoxetine (Strattera®)
Norepinephrine reuptake inhibitor/ADHD
4
Azithromycin (Zithromax®)
Antibiotic/bacterial infection
1
Bedaquiline (Sirturo®)
Anti-infective/drug-resistant tuberculosis
2
Bepridil (Vascor®)
Anti-anginal/heart pain
1
Bortezomib (Velcade®, Bortecad®)
Proteasome inhibitor/multiple 
myeloma,lymphoma
2
Bosutinib (Bosulif®)
Tyrosine kinase inhibitor/leukemia
2
Chloral hydrate (Noctec®)
Sedative/sedation/insomnia
3
Chloroquine (Aralen®)
Anti-malarial/malaria infection
1
Chlorpromazine (Thorazine®)
Anti-psychotic/anti-
emetic/schizophrenia/nausea
1
Cilostazol (Pletal®)
Phosphodiesterase inhibitor/intermittent 
claudication
1
Ciprofloxacin (Cipro®)
Antibiotic/bacterial infection
3
Cisapride (Propulsid®)
GI stimulant/heartburn
1
Citalopram (Celexa®)
Anti-depressant/depression
1
Clarithromycin (Biaxin®)
Antibiotic/bacterial infection
1


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Generic Name (Brand Name)
Drug Class / Clinical Usage
Risk List
Clomipramine (Anafranil®)
Tricyclic Antidepressant/depression
3
Clozapine (Clozaril®)
Anti-psychotic/schizophrenia
2
Cocaine
Local anesthetic
1
Crizotinib (Xalkori®)
Kinase inhibitor/anti-cancer
2
Dabrafenib (Tafinlar®)
Anti-cancer/melanoma
2
Dasatinib (Sprycel®)
Tyrosine kinase inhibitor/leukemia
2
Desipramine (Pertofrane®)
Tricyclic antidepressant/depression
3
Dexmedetomidine (Precedex®, Dexdor®)
Sedative/sedation
2
Dexmethylphenidate (Focalin®)
CNS stimulant/ADHD
4
Dextroamphetamine (Dexedrine®)
CNS stimulant/ADHD
4
Dihydroartemis.+piperaquine (Eurartesim®)
Anti-malarial/malaria
2
Diphenhydramine (Benadryl®)
Antihistamine/allergic rhinitis, insomnia
3
Disopyramide (Norpace®)
Anti-arrhythmic/abnormal heart rhythm
1
Dobutamine (Dobutrex®)
Inotrope/Heart failure, shock
4
Dopamine (Intropine®)
Inotrope/Heart failure, shock
4
Dofetilide (Tikosyn®)
Anti-arrhythmic/abnormal heart rhythm
1
Dolasetron (Anzemet®)
Anti-nausea/nausea, vomiting
2
Domperidone (Motilium®)
Anti-nausea/nausea
1
Donepezil (Aricept®)
Cholinesterase inhibitor/Dementia
1
Doxepin (Sinequan®)
Tricyclic antidepressant/depression
3
Dronedarone (Multaq®)
Anti-arrhythmic/atrial fibrillation
1
Droperidol (Inapsine®)
Sedative;anti-nausea/anesthesia adjunct, nausea
1
Ephedrine (Rynatuss®, Broncholate®)
Bronchodilator, decongestant/Allergies, asthma
4
Epinphrine (Primatene®, Bronkaid®)
Vasoconstrictor/Anaphilaxis, allergic reactions
4
Eribulin (Halaven® )
Anti-cancer/metastatic breast neoplasias
2
Erythromycin (E.E.S.® )
Antibiotic;GI stimulant/bacterial infection; 
increase GI motility
1
Escitalopram (Cipralex®)
Anti-depressant/depression/ anxiety disorders
1
Famotidine (Pepcid®)
H2-receptor antagonist/peptic ulcer/GERD
2
Felbamate (Felbatrol®)
Anti-convulsant/seizure
2
Fenfluramine (Pondimin®, Ponderax®)
Appetite suppressant/Dieting, weight loss
4
Fingolimod (Gilenya®)
Immunosuppressant/multiple sclerosis
2
Flecainide (Tambocor®)
Anti-arrhythmic/abnormal heart rhythm
1
Fluconazole (Diflucan®)
Anti-fungal/fungal infection
3
Fluoxetine (Sarafem®)
Anti-depressant/depression
3
Formoterol (Foradil, Foralide)
Bronchodilator /Asthma
4
Foscarnet (Foscavir®)
Anti-viral/HIV infection
2
Fosphenytoin (Cerebyx®)
Anti-convulsant/seizure
2
Furosemide/Frusemide (Lasix®, Fusid®)
Diuretic/Increase urine & salt loss
3
Galantamine (Reminyl®)
Cholinesterase inhibitor/ dementia, Alzheimer's
3
Gatifloxacin (Tequin®)
Antibiotic/bacterial infection
2
Gemifloxacin (Factive®)
Antibiotic/bacterial infection
2
Granisetron (Kytril®)
Anti-nausea/nausea and vomiting
2
Halofantrine (Halfan®)
Anti-malarial/malaria infection
1
Haloperidol (Haldol®)
Anti-psychotic/schizophrenia, agitation
1
Hydrochlorothiazide (Apo-Hydro®)
Diuretic/increase urine & salt loss
3
Ibutilide (Corvert®)
Anti-arrhythmic/abnormal heart rhythm
1
Iloperidone (Fanapt®)
Antipsychotic, atypical/schizophrenia
2
Imipramine (Norfranil®)
Tricyclic antidepressant/depression
3
Indapamide (Lozol®)
Diuretic/stimulate urine & salt loss
3
Isoproterenol (Medihaler-Iso®, Isuprel®)
Bronchodilator/Allergic reaction
4
Isradipine (Dynacirc®)
Anti-hypertensive/high blood pressure
2
Itraconazole (Sporanox®)
Anti-fungal/fungal infection
3


CL_0254 4.0
Page 95 of 96
Protocol APL-B-021-13
Generic Name (Brand Name)
Drug Class / Clinical Usage
Risk List
Ivabradine (Procoralan®, Coralan®)
Anti-anginal/angina pectoris (heart pain)
3
Ketoconazole (Nizoral®)
Anti-fungal/fungal infection
3
Lapatinib (Tykerb®)
Anti-cancer/breast cancer, metastatic
2
Levalbuterol (Xopenex®, Levolin®)
Bronchodilator/Asthma
4
Levofloxacin (Levaquin®)
Antibiotic/bacterial infection
2
Levomethadyl (Orlaam®)
Opiate agonist/pain control, narcotic 
dependence
1
Lisdexamfetamine (Vyvanse®)
CNS stimulant/ADHD
4
Lithium (Lithobid®)
Anti-mania/bipolar disorder
2
Mesoridazine (Serentil®)
Anti-psychotic/schizophrenia
1
Metaproterenol (Metaprel®), Alupent®)
Bronchodilator/Asthma
4
Methadone (Methadose®)
Opiate agonist/pain control, narcotic 
dependence
1
Methamphetamine (Desoxyn®, Pervitin®)
CNS stimulant/Obesity, ADHD
4
Methylphenidate (Ritalin®, Concerta®)
CNS stimulant/ADHD
4
Metronidazole (Flagyl®)
Antibiotic/trichomoniasis, amebiasis, bacterial 
infection
3
Midodrine (ProAmatine®, Amatine®)
Vasoconstrictor/Low blood pressure, fainting
4
Mifepristone (Korlym®, Mifeprex®)
Progesterone antagonist/pregnancy termination
2
Mirabegron (Myrbetriq®)
Beta3 adrenergic antagonist/overactive bladder
2
Mirtazapine (Remeron®)
Anti-depressant/depression
2
Moexipril/HCTZ (Uniretic®)
Anti-hypertensive/high blood pressure
2
Moxifloxacin (Avelox®)
Antibiotic/bacterial infection
1
Nelfinavir (Viracept®)
Anti-viral/HIV/AIDS
3
Nicardipine (Cardene®)
Anti-hypertensive/high blood pressure
2
Nilotinib (Tasigna®)
Anti-cancer/leukemia
2
Norepinephrine (Levophed ®)
Vasoconstrictor/Shock, low blood pressure
4
Norfloxacin (Noroxin®, Ambigram®)
Antibiotic/bacterial infection
2
Nortriptyline (Pamelor®)
Tricyclic Antidepressant/depression
3
Ofloxacin (Floxin®)
Antibiotic/bacterial infection
2
Olanzapine (Zyprexa®)
Antipsychotic, atypical/schizophrenia, bipolar
2
Ondansetron (Zofran®)
Anti-emetic/nausea and vomiting
1
Oxytocin (Pitocin®)
Oxytocic/labor stimulation
2
Paliperidone (Invega®)
Antipsychotic, atypical/schizophrenia
2
Paroxetine (Paxil®)
Anti-depressant/depression
3
Pasireotide (Signifor®)
Somatostatin analog/Cushings Disease
2
Pazopanib (Votrient®)
Tyrosine kinase inhibitor/anti-cancer
2
Pentamidine (Pentam®)
Anti-infective/pneumocystis pneumonia
1
Perflutren lipid microspheres (Definity®)
Imaging contrast agent/echocardiography
2
Phentermine (Adipex P®, Adiphene®)
Appetite suppressant/Dieting, weight loss
4
Phenylephrine (Neosynephrine®)
Vasoconstrictor/Low blood pressure, allergies
4
Phenylpropanolamine (Acutrim,Dexatrim®)
Appetite suppressant/Obesity
4
Pimozide (Orap®)
Anti-psychotic/Tourette's tics
1
Pipamperone (Dipiperon®, Propitan®)
Antipsychotic/schizophrenia
2
Posaconazole (Noxafil®, Posamol®)
Anti-fungal/fungal infection
3
Probucol (Lorelco®)
Antilipemic/hypercholesterolemia
1
Procainamide (Procan®)
Anti-arrhythmic/abnormal heart rhythm
1
Promethazine (Phenergan®)
Anti-psychotic-anti-emetic/nausea
2
Protriptyline (Vivactil®)
Tricyclic antidepressant/depression
3
Pseudoephedrine (PediaCare®, Sudafed®)
Descongestant/Allergies, sinusitis, asthma
4
Quetiapine (Seroquel®)
Anti-psychotic/schizophrenia
2
Quinidine (Quinaglute®)
Anti-arrhythmic/abnormal heart rhythm
1
Quinine sulfate (Qualaquin®)
Anti-malarial/malaria or leg cramps
3
Ranolazine (Ranexa®)
Anti-anginal/chronic angina
2


CL_0254 4.0
Page 96 of 96
Protocol APL-B-021-13
Generic Name (Brand Name)
Drug Class / Clinical Usage
Risk List
Rilpivirine (Edurant®, Complera®)
Anti-viral/HIV/AIDS
2
Risperidone (Risperdal®)
Anti-psychotic/schizophrenia
2
Ritodrine (Yutopar®)
Muscle relaxant/Prevent premature labor
4
Ritonavir (Norvir®)
Protease inhibitor/HIV
3
Roxithromycin* (Rulide®)
Antibiotic/bacterial infection
2
Saquinavir (Invirase®)
Anti-viral/HIV/AIDS
2
Salmeterol (Serevent®, Advair®)
Bronchodilator/Asthma, COPD
4
Sertindole (Serdolect®)
Antipsychotic, atypical/anxiety, schizophrenia
2
Sertraline (Zoloft®)
Anti-depressant/depression
3
Sevoflurane (Ulane®)
Anesthetic, general/anesthesia
1
Sibutramine (Meridia®)
Appetite suppressant/Dieting, weight loss
4
Solifenacin (VESIcare®)
muscarinic recptr. anatagonist/overactive 
bladder
3
Sorafenib (Nexavar®)
Tyrosine kinase inhibitor/anti-cancer
2
Sotalol (Betapace®)
Anti-arrhythmic/abnormal heart rhythm
1
Sparfloxacin (Zagam®)
Antibiotic/bacterial infection
1
Sulpiride (Dogmatil®, Dolmatil®)
Anti-psychotic, atypical/schizophrenia
1
Sunitinib (Sutent®)
Anti-cancer/RCC, GIST
2
Tacrolimus (Prograf®)
Immunosuppressant/immune suppression
2
Tamoxifen (Nolvadex®)
Anti-cancer/breast cancer
2
Telaprevir (Incivek®, Incivo®)
Anti-viral/hepatitis C
3
Telavancin (Vibativ®)
Antibiotic/bacterial infection
2
Telithromycin (Ketek®)
Antibiotic/bacterial infection
2
Terbutaline (Brethine®, Bricanyl®)
Bronchodilator/Asthma, premature labor
4
Terfenadine (Seldane®)
Antihistamine/allergic rhinitis
1
Tetrabenazine (Nitoman®, Xenazine®)
Monoamine transptr inhibitor/chorea 
2
Thioridazine (Mellaril®)
Anti-psychotic/schizophrenia
1
Tizanidine (Zanaflex®)
Muscle relaxant/spasticity
2
Tolterodine (Detrol®, Detrusitol®)
Muscle relaxant/bladder spasm
2
Toremifene (Fareston®)
Estrogen agonist/antagonist/anti-cancer
2
Trazodone (Desyrel®)
Anti-depressant/depression, insomnia
3
Trimethoprim-Sulfa (Septra® or Bactrim®)
Antibiotic/bacterial infection
3
Trimipramine (Surmontil®)
Tricyclic antidepressant/depression
3
Vandetanib (Caprelsa®)
Anti-cancer/thyroid cancer
1
Vardenafil (Levitra®)
Phosphodiesterase inhibitor/vasodilator
2
Vemurafenib (Zelboraf®)
Kinase inhibitor/anti-cancer
2
Venlafaxine (Effexor®)
Anti-depressant/depression
2
Voriconazole (Vfend®)
Anti-fungal/fungal infection
3
Vorinostat (Zolinza®)
Anti-cancer/lymphoma
2
Ziprasidone (Geodon®)
Anti-psychotic/schizophrenia
2
A note about brand names: drugs are listed with up to two common brand names. 
There are many more brand names for some of the common drugs, such as 
pseudoephedrine and erythromycin.

SAP_001.pdf: 
 
 
 
 
 
 
 
 
 
 
 
APL-B-021-13 (NCT03070964) 
 
 
A Phase II Study of Plitidepsin in Patients with Relapsed or Refractory 
Angioimmunoblastic T-cell Lymphoma 
 
STATISTICAL ANALYSIS PLAN 
 
 
 
 
 
 
 
 
 
 
 
 
 
Version: 1.0 
Date: 13-October-2016


2 of 61 
TABLE OF CONTENTS  
 
1 
STUDY RATIONALE 
6 
2 
STUDY DESIGN 
7 
3 
OBJECTIVES AND ENDPOINTS 
8 
3.1 
Primary objective 
8 
3.2 
Secondary objectives 
8 
3.3 
Endpoints 
8 
4 
PATIENTS EVALUABILITY CRITERIA 
9 
4.1 
Analysis sets definitions 
9 
4.2 
Efficacy populations 
10 
4.3 
Safety population 
10 
5 
SAMPLE CONSIDERATIONS 
10 
6 
STATISTICAL METHODOLOGY FOR EFFICACY 
11 
6.1 
Planned analyses and definitions 
11 
6.1.1 
Primary endpoint analysis 
11 
6.1.2 
Secondary endpoints analyses 
11 
6.2 
Efficacy analysis methods 
12 
6.2.1 
Primary endpoint 
12 
6.2.2 
Secondary analyses 
12 
7 
STATISTICAL METHODOLOGY FOR SAFETY 
13 
7.1 
Toxicity and adverse events 
13 
7.2 
Clinical laboratory evaluation 
14 
7.3 
Vital signs, physical examination, left ventricular ejection fraction (LVEF) and 
electrocardiogram findings 
14 
7.4 
Deaths and other Serious Adverse Events 
14 
8 
OTHER ANALYSES 
14 
8.1 
Baseline and demographic data 
14 
8.2 
Treatment administration 
15 
8.3 
Subsequent therapy 
15 
8.4 
Protocol deviations 
15 
8.5 
Pharmacokinetic and biomarkers  analyses 
15 
8.6 
Imputation of incomplete dates 
16 
8.7 
Subgroup analyses 
16 
8.8 
Decimal places and methods for handling missing data 
17 
8.9 
Interim and group sequential analyses 
17 
8.10 
Identification of fixed or random effects models 
17 
9 
STATISTICAL SOFTWARE 
17 
APPENDIX I 
18 
10 Study Patients 
18 
10.1 
Patient disposition 
18 
10.2 
Reasons for treatment discontinuation 
19 
10.3 
Protocol deviations 
20 
11 Efficacy Evaluation 
21 
11.1 
Demographic and other baseline characteristics 
21 


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11.1.1 Patient characteristics at baseline 
21 
11.1.2 Local histopathological diagnosis 
21 
11.1.3 Disease at diagnosis, time from diagnosis and current disease 
22 
11.1.4 Prior anticancer therapy 
24 
11.1.5 Prior history 
25 
11.1.6 Physical examination, vital signs, electrocardiogram and other tests 
25 
11.1.7 Hematological values at baseline 
28 
11.1.8 Biochemical values at baseline 
29 
11.1.9 Other metabolic values at baseline 
29 
11.1.10 
Signs and symptoms at baseline 
30 
11.1.11 
Concomitant therapy and procedures at baseline 
30 
11.2 
Measurements of treatment compliance 
31 
11.3 
Efficacy analysis 
31 
11.3.1 Primary analysis 
31 
11.3.2 Secondary analyses 
32 
11.3.3 Follow-up 
38 
11.3.4 Multivariate analyses 
39 
11.3.5 Best reduction in sum of the product of the diameters lesions 
42 
11.3.6 Characteristics of responders 
42 
12 Safety Analysis 
43 
12.1 
Extent of exposure 
43 
12.1.1 Treatment administration 
43 
12.1.2 Cycle delays 
43 
12.1.3 Dose omissions 
44 
12.1.4 Dose reductions 
45 
12.1.5 Infusions temporarily interrupted 
46 
12.1.6 Prophylactic medication administration 
46 
12.2 
Adverse Events (AEs) 
47 
12.2.1 Display of adverse events 
47 
12.3 
Serious Adverse Events and deaths. 
49 
12.3.1 Serious Adverse Events 
49 
12.3.2 Deaths 
50 
12.4 
Clinical laboratory evaluation 
50 
12.4.1 Hematological abnormalities 
50 
12.4.2 Biochemical abnormalities 
52 
12.4.3 Other metabolic parameters 
53 
12.4.4 Laboratory values over time 
54 
12.5 
Vital signs, physical findings, LVEF, ECG and other tests related to safety 55 
12.5.1 Vital signs and physical findings 
55 
12.5.2 LVEF, ECG and other related tests 
55 
12.6 
Concomitant therapy / procedures according to the ATC classification. 
56 
12.7 
Safety analysis in special subgroups. 
57 
13 DB Listings 
59 
14 Section 16.2  ICH Listings 
60 
15 References 
61 
 


4 of 61 
ABBREVIATIONS AND GLOSSARY 
AE(s) 
Adverse Event(s) 
AITL 
Angioimmunoblastic T-cell Lymphoma 
ALT 
Alanine Aminotransferase 
ALP 
Alkaline Phosphatase 
ASCT 
Autologous Stem Cell Transplantation 
AST 
Aspartate Aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
BL 
Baseline 
BMI 
Body Mass Index 
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 
CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
DB 
Data Base 
DF 
Degrees of Freedom 
DoR 
Duration of Response 
ECG 
Electrocardiogram 
ECHO 
Echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EOT 
End of Treatment 
EPO 
Erythropoietin 
FDA 
Food and Drug Administration 
FU 
Follow-up 
G-CSF 
Granulocyte Colony Stimulating Factor 
IA 
Investigator Assessment 
IDMC 
Independent Data Monitorin Committe 
Ig 
Immunoglobulin 
IPI 
International Prognostic Index 
IR 
Independent Review 
IRC 
Independent Review Committee 
LDH 
Lactate Dehydrogenase 
LVEF 
Left Ventricular Ejection Fraction 
MedDRA 
Medical Dictionary for Regulatory Activities 
MUGA 
Multiple-gated Acquisition Scan 
NA 
Not Applicable 
NCI-CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
NE 
Not  Evaluable 
NHL 
Non-Hodgkin Lymphoma 
NOS 
Not Otherwise Specified 
ORR 
Overall Response Rate 
OS 
Overall Survival 
OS6 
Overall Survival at 6 months 
OS12 
Overall Survival at 12 months 
PCTL 
Peripheral T-cell Lymphoma 
PD 
Progressive Disease 
PFS 
Progression-free Survival 
PFS6 
Progression-free Survival at 6 months 
PFS12 
Progression-free Survival at 12 months 
PIAI 
Prognostic Index for AITL 
PIT 
Prognostic Index for Peripheral T-cell lymphoma 


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PK 
Pharmacokinetics 
PR 
Partial Remission 
PS 
Performance Status 
RBC 
Red Blood Cell 
R/R 
Relapsed/Refractory 
SAE(s) 
Serious Adverse Event(s) 
SD 
Stable Disease 
SOC 
System Organ Class 
SPD 
Sum of the Product of the Diameters 
StD 
Standard Deviation 
TTP 
Time to Tumor Progression 
ULN 
Upper Limit of Normal 
v 
Version 
WBC 
White Blood Cells 
WHO 
World Health Organization 
wk 
Week 
 


6 of 61 
1 STUDY RATIONALE 
Angioimmunoblastic T-cell lymphoma (AITL) is the second most common form of 
peripheral T-cell lymphoma (PTCL), accounting for approximately 20% of PTCLs and 2% 
of non-Hodgkin lymphomas (NHL). In the United States, the incidence is approximately 
0.05 cases per 100,000 person years. The disease is more common in Europe (29% of 
PTCL cases) than in the United States or Asia. 
The clinical course of AITL varies, with occasional spontaneous remissions. Nevertheless, 
the prognosis of the disease is dismal, with median survival < 3 years, and with 20–30% of 
long-term survivors. Different clinical risk factors as well as biological parameters have 
been described as prognostic factors. In a retrospective study of 157 cases of AITL, a 
multivariate analysis showed the following covariates as adversely associated with 
prognosis: male gender, anemia and the presence of mediastinal lymphadenopathy. 
Other systems such as the International Prognostic Index (IPI) or the prognostic index for 
peripheral T-cell lymphoma (PIT) were of limited value in this disease. Recently, a risk 
model for AITL (prognostic index for AITL, PIAI) was designed based on the following 
adverse covariates: age > 60 years, performance status ≥ 2, extranodal sites > 1, B-
symptoms, and platelet count < 150,000/mL. The simplified PIAI had a low-risk group 
(zero to one factors) with a 5-year survival of 44%, and a high-risk group (two to five 
factors) with a 5-year survival of 24%. 
In phase I studies conducted with plitidepsin, the schedule consisting of 1-hour i.v. infusion 
given weekly on D1, 8 and 15 q4wk was found to be the most convenient for patients with 
NHL. An exploratory phase II clinical trial (APL-B-013-02) was conducted to evaluate the 
efficacy, tolerability and pharmacokinetics of this weekly plitidepsin schedule at a starting 
dose of 3.2 mg/m2 in patients with relapsed/refractory (R/R) aggressive NHL. This phase II 
trial included two cohorts: patients with non-cutaneous PTCL and patients with other 
aggressive lymphomas. No remissions were found in the cohort of 33 patients with other 
aggressive lymphomas. However, interesting antitumor activity was observed in 29 
evaluable patients from the non-cutaneous PTCL cohort: ORR was 20.7% (95% CI, 8.0–
39.7%) and SD rate was 20.7%.  
Plitidepsin was well tolerated in this trial. The most common adverse events (AEs) in the 
non-cutaneous PTCL cohort were nausea, fatigue, vomiting, myalgia, muscle weakness and 
pyrexia. The most common grade 3/4 hematological abnormalities were lymphopenia, 
neutropenia, anemia and thrombocytopenia found in 28%, 12%, 10% and 10% of the cases, 
respectively. 
Nine patients with AITL were included in the cohort of 34 non-cutaneous PTCL patients. 
Of note, ORR in these nine patients was 33.3%, with CR in two patients (22.2%) and PR in 
one patient (11.1%). Furthermore, SD was reported in other two patients. The median 
number of previous lines was 2 and the DoR of the three responders was 121, 12 and 4 
weeks, respectively. It should be highlighted that the two patients with CR had bone 
marrow involvement at diagnosis and had previously failed high dose chemotherapy with 
stem cell transplantation (SCT) support. 
In summary, the interesting antitumor activity observed with plitidepsin in non-cutaneous 
PTCL was mainly found in patients with AITL. Bearing in mind the small number of 


7 of 61 
agents with meaningful activity in non-cutaneous PTCL and, in particular, the lack of 
specific agents with reliable and specific activity in AITL, and considering the important 
signs of activity of plitidepsin in this disease, this phase II clinical trial was designed to 
evaluate plitidepsin as single-agent treatment for patients with R/R AITL. 
The rationale of the exploratory biomarker objectives is related to recent studies exploring 
the genetic basis of the disease: a study by Odejide and colleagues showed high incidences 
of gene mutations of TET2, for example, in 85 AITL tissue samples, as well as in 
DNMT3A, and IDH2: common and frequent mutations that make AITL more comparable 
to myeloid disorders than other PTCLs and suggest the need to re-evaluate therapeutic 
strategies. 
Several studies have shown that plitidepsin induces apoptosis in a cell type- and dose-
dependent manner, and these effects are related to the induction of early oxidative stress, 
the activation of Rac1 GTPase and the inhibition of protein phosphatases, which in 
conjunction cause the sustained activation of JNK and p38 MAPK. The final consequence 
is the triggering of the mitochondrial apoptotic pathway with caspase 9 and caspase 3 
activation. Additional effects may be mediated by indirect effects on the cell 
microenvironment, mainly mediated by antiangiogenic properties and indirect effects on 
monocyte-derived cells, including follicular dendritic cells.  
 
2 STUDY DESIGN 
Prospective, multicenter, phase II clinical trial.  
The aim of this clinical trial is to determine the efficacy of plitidepsin in patients with 
relapsed/refractory AITL. A total of 60 patients will receive plitidepsin. The primary 
endpoint will be the ORR according to the Lugano classification response criteria per 
independent central review. 
An Independent Review Committee (IRC) consisting of medical specialists (radiologists 
and hematologists) who are directly involved in the care of patients with AITL but do not 
take part in this trial as investigators or sub-investigators, will review all efficacy data and 
will assign the date of objective response or progression/censoring according to their 
independent evaluation.  
Two futility analyses of the primary endpoint (ORR according to Lugano classification 
response criteria and per IRC) are planned around six months after approximately 25% and 
50% of eligible patients (i.e., 15 and 30 patients respectively with AITL confirmed by 
central pathological review) have been treated. Two or less responders out of 15 patients or 
seven or less responders out of 30 patients, according to boundaries and sample size 
assumptions, will mean that the alternative hypothesis could be rejected, and thus 
recruitment might be stopped at the time of the first or second futility analysis, respectively. 
Otherwise, accrual will continue to a total of 60 patients with AITL confirmed by central 
pathological review. This decision will be taken at the time by an Independent Data 
Monitoring Committee (IDMC). The IDMC, which will include specialists in PTCL 
supported by a medical statistician, will review data provided by the Investigators, the IRC 
efficacy assessments and safety information and will advise whether the study should 
continue. Recruitment can continue during the review period. 


8 of 61 
If there are 19 or more responders over the total of 60 patients, the efficacy of plitidepsin 
will be considered as clinically relevant in AITL patients. 
Operational details for the IRC and IDMC will be detailed in the corresponding charters.  
 
 
3 OBJECTIVES AND ENDPOINTS 
3.1 
Primary objective 
 To evaluate the efficacy of plitidepsin on the basis of overall response rate (ORR) in 
patients with relapsing/refractory angioimmunoblastic T-cell lymphoma (AITL). 
3.2 
Secondary objectives 
 To evaluate other efficacy endpoints (time-to-event parameters: duration of response 
[DoR], progression-free survival [PFS], PFS at 6/12 months [PFS6/PFS12], intrapatient 
PFS/TTP, overall survival [OS] and OS at 6/12 months [OS6/OS12]). 
 To evaluate the safety profile of plitidepsin in this patient population. 
 To characterize the pharmacokinetics (PK) of plitidepsin. 
 To identify biomarkers that may be predictive of plitidepsin activity. 
 
3.3 
Endpoints 
Primary endpoint:  
 
 Overall response rate (ORR), defined as the percentage of patients with remission, 
either complete (CR) or partial remission (PR), according to the Lugano 
classification response criteria  per independent central review. An external IRC 
will assign the objective response and a progression or censoring date for each 
patient. 
 
Secondary endpoints:  
 ORR per investigator. 
 CR rate, defined as the percentage of patients with complete remission according to  
the Lugano classification response criteria per independent central review and 
investigator assessment. 
 Duration of response (DoR), defined as the time from the date when the remission 
criteria (PR or CR, whichever is first achieved) are fulfilled to the first date when 
PD, recurrence or death (due to any cause) is documented. Response will be 
assessed according to the Lugano classification response criteria per independent 
central review and investigator assessment. 
 Progression-free survival (PFS), defined as the time from the date of first drug 
administration to the date of PD, death (of any cause), or last tumor evaluation; both 
independent central review and investigator assessment will be used for the 
determination of PFS. 


9 of 61 
 Progression-free survival at 6/12 months (PFS6/PFS12), defined as the Kaplan-
Meier estimate of the percentage of patients who are progression-free at six/twelve 
months after first drug administration; both independent central review and 
investigator assessment will be used for the determination of PFS. 
 Intrapatient PFS/TTP, defined as the ratio of PFS achieved with the experimental 
treatment versus the prior last TTP in the R/R setting. 
  Overall survival (OS), defined as the time from the date of first dose to the date of 
death (of any cause) or last patient contact. 
  Overall survival at 6/12 months (OS6/OS12), defined as the Kaplan-Meier estimate 
of the percentage of patients who are live at six/twelve months after first drug 
administration. 
  Treatment safety [AEs, serious adverse events (SAEs) and laboratory abnormalities] 
graded according to the NCI-CTCAE, v. 4. Dose reductions, skipped doses or dose 
delays required due to treatment-related AEs, and reasons for treatment 
discontinuations will be analyzed. 
 Pharmacokinetics (PK), samples for PK analysis will be obtained during Cycle 1 
exclusively.  
 Exploratory biomarker analysis, correlation of efficacy with molecular markers 
(targets/pathways) related to the mechanism of action of plitidepsin or to the 
disease.  
 
 
4 PATIENTS EVALUABILITY CRITERIA 
The study population will include patients who have relapsed or refractory AITL confirmed 
by local pathological assessment. To be included in this study, the patients must meet all 
inclusion criteria and no exclusion criteria.  
4.1 
Analysis sets definitions 
“All Included Patients” analysis set is defined as all patients who are included in the study 
(excluding patients who signed informed consent but are classified as screening failures), 
independent of whether they received the study drug. 
“All Treated Patients” analysis set is defined as all included patients who receive at least 
part of one dose or infusion of plitidepsin. 
“Per Protocol Patients” analysis set is defined as all eligible and treated patients with AITL 
diagnosis confirmed after central pathological review.  
“All Evaluable Patients” analysis set is define as all eligible patients with AITL diagnosis 
confirmed after central pathological review who receive at least two plitidepsin cycles in 
which at least two complete infusions have been administered and had at least one disease 
assessment as well as in patients who discontinue treatment without Cycle 3 tumor 
assessment after at least two plitidepsin infusions due to disease progression (PD) (or death 
due to PD) or toxicity (or death due to toxicity), defined as “early PD” and “treatment 
failures” respectively. 


10 of 61 
“All Responder Patients” analysis set is defined as all patients with CR or PR as overall 
best response. 
 
4.2 
Efficacy populations 
The “All Included Patients” analysis set will be used to show demographic and other 
baseline characteristics. 
The “Per Protocol Patients” analysis set will be used for the primary endpoint analysis of 
ORR by IRC and for the secondary analyses of ORR by investigator assessment, CR rate 
and PFS analyses, as well as for OS analyses. 
The “All Evaluable Patients” and “All Treated Patients” analysis sets will be used for the 
secondary endpoint analyses of ORR by IRC, ORR by investigator assessment, CR rate and 
PFS analyses, as well as for OS analyses. 
The “All Responder Patients” dataset will be used for the duration of response (DoR) 
calculation. 
 
4.3 
Safety population 
The safety analysis is based on the “All Treated Patients” analysis set. 
 
 
5 SAMPLE CONSIDERATIONS  
The primary endpoint for this study is ORR according to the Lugano classification response 
criteria per independent review in “Per Protocol Patients” population. 
A total of 60 patients with AITL confirmed by central pathological review will be treated, 
19 or more responders will be needed to get an overall estimate for response rate higher 
than 30% and its lower limit for the 95% confidence interval greater than 20% (31.7% 
CI95% 20.3%–45.0% following the binomial distribution).  
The type I error (alpha) associated with this one-sided test is 0.025 and the type II error 
(beta) is 0.1; hence, statistical power is 90%. The null hypothesis (H0) is set at ORR ≤ 20% 
(P0=0.208) versus the alternative hypothesis (H1) at ≥ 40% patients (Pa=0.41) having an 
objective response, the variance of the standardized test is under the null hypothesis.   
Two futility analyses of the primary endpoint (ORR according to Lugano classification and 
per IRC) are planned to reject the alternative hypothesis six months after 25% and 50% of 
eligible patients have been treated (15 and 30 patients, respectively). Pocock boundary and 
the actual number of patients confirmed by central pathological review will be used to 
control type II error for both analyses. For example, if there are two or less responders out 
of 15 patients or seven or less responders out of 30 patients, according to boundaries and 
sample size assumptions, the alternative hypothesis could be rejected, and thus recruitment 
might be stopped at the time of the first or second futility analysis, respectively. Otherwise, 


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accrual will continue to a total of 60 patients AITL confirmed by central pathological 
review. Active recruitment will not be halted while the analysis is being carried out. 
Therefore, if there are 19 or more responders of 60 patients, the null hypothesis can be 
rejected, allowing consideration of the observed activity plitidepsin as clinically relevant in 
the setting of patients with AITL. 
 
6 STATISTICAL METHODOLOGY FOR EFFICACY 
6.1 
Planned analyses and definitions 
6.1.1 Primary endpoint analysis 
Objective response is defined as having partial remission (PR) or better as best overall 
response based on the the Lugano classification response criteria per independent review. 
The objective response rate (ORR) is calculated as the number of objective responders 
divided by the number of patients in the “Per Protocol Patients” analysis set.  
6.1.2 Secondary endpoints analyses 
The overall response rate (ORR) is calculated as the number of objective responders based 
on the the Lugano classification response criteria per independent review divided by the 
number of patients in the “All Evaluable Patients” and “All Treated Patients” analysis sets.  
The overall response rate (ORR) is calculated as the number of objective responders based 
on the investigator criteria divided by the number of patients in the “Per Protocol Patients”, 
“All Evaluable Patients” and “All Treated Patients” analysis sets.  
The complete remission rate is calculated as the number of patients with complete 
remission based on the the Lugano classification response criteria per independent review 
or per investigator assessment divided by the number of patients in the “Per Protocol 
Patients”, “All Evaluable Patients” and “All Treated Patients” analysis sets.  
The duration of response (DoR) will be analyzed in the “All Responder Patient”. Duration 
of response will be calculated from the date of first documentation of response to the date 
of disease progression, recurrence or death with the same censoring rules as PFS. Response 
will be assessed according to the Lugano classification response criteria per independent 
central review and investigator assessment. 
Progression-free survival (PFS) is defined as the time from the date of first administration 
to the date of documented progressive disease (PD) or death (regardless of the cause of 
death). If the patient receives further antitumor therapy (including stem cell transplant) 
before, PFS will be censored on the date of the last disease assessment prior to the 
administration of this antitumor therapy. If the patient is lost to follow-up for the 
assessment of progression the PFS will be censored at the date of last valid tumor 
assessment. If the patient does not received any drug infusion, he/she will be censored at 
time zero. Both, independent central review and investigator assessments, will be used for 
the determination of PFS. 


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Progression-free survival at 6/12 months (PFS6/PFS12), defined as the Kaplan-Meier 
estimate of the percentage of patients who are progression-free at six/twelve months after 
first administration; both independent central review and investigator assessment will be 
used for the determination of PFS. 
Within-patient PFS/TTP, defined as the ratio of the PFS achieved with the experimental 
treatment versus prior last TTP. Intra-patient PFS/TTP ratio will be categorized and 
analyzed as a dichotomous variable. Clinical benefit will be defined if a >33% longer 
PFS/TTP with the experimental treatment vs. the TTP with the immediate prior 
chemotherapy (ratio >1.33) is achieved. 
Overall survival (OS), defined as the time from the date of first administration to the date 
of death (of any cause) or last patient contact. 
Overall survival at 6/12 months (OS6/OS12), defined as the Kaplan-Meier estimate of the 
percentage of patients who are alive at six/twelve months after first administration. 
Treatment safety [AEs, serious adverse events (SAEs) and laboratory abnormalities] 
graded according to the NCI-CTCAE, v. 4. Dose reductions, skipped doses or dose delays 
required due to treatment-related AEs, and reasons for treatment discontinuations will be 
analyzed. 
 
6.2 
Efficacy analysis methods 
6.2.1 Primary endpoint 
For the evaluation of the main primary endpoint, ORR, the ”Per Protocol Patients” 
population, the data from the Independent Review will be used. Binomial estimates with 
exact 95% CIs will be calculated for the analysis of response rate. A supportive analysis 
will be also done in the “All Evaluable Patients” and “All Treated Patients” populations and 
by investigator assessment as a secondary analysis.  
6.2.2 Secondary analyses 
Time to event endpoints will be used in an exploratory way. 
Binomial estimates with exact 95% CIs will be calculated for the analysis of complete 
remission rate in the “Per Protocol Patients”, “All Evaluable Patients” and “All Treated 
Patients”  analysis sets by independent review and investigator assessment.  
Duration of response will be analyzed according to the Kaplan-Meier method in “All 
Responder Patients” analysis set by independent review and investigator assessment.  
Time to response id defined as the time, in months, from the date of first drug 
administration to the first documentation of response method in “All Responder Patients” 
analysis set by independent review and investigator assessment.  
PFS analysis will be performed in “Per Protocol Patients”, “All Evaluable Patients” and 
“All Treated Patients” analysis sets analysis sets according to the Kaplan-Meier method by 
independent review and investigator assessment. The concordance between the IRC and 
investigator evaluation of response and PFS will be shown using counts and percentages. 


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OS analysis will be performed in “Per Protocol Patients”, “All Evaluable Patients” and “All 
Treated Patients” analysis sets analysis sets according to the Kaplan-Meier.  
Univariate evaluation of the influence of different prognostic factors on the main efficacy 
endpoints will be performed. If appropriate, univariate analyses will include prognostic 
factors/covariates widely reported and recognized by hematologist such as: sex, age at 
diagnosis, baseline ECOG, Body Surface Area, Ann arbor, extranodal disease, bone 
marrow involvement, B symptoms, baseline LDH xULN, bulky lesion, IPI, PIT, PIAI, 
Relapse or refractory, number of prior lines of treatment, previous SCT or time from last 
PD before inclusion. Further covariates could be included upon hematologist criteria. . …. 
Cox proportional hazard models for PFS and OS, and logistic regression models for ORR 
will include the prognostic factors specified for the univariate analysis. More relevant and 
explanatory covariates from the univariate analysis will be included in the multivariate 
analyses (p-value < 0.10). Prognostic factors with more than 10% missing values will be 
excluded in the multivariate analyses. 
 
7 STATISTICAL METHODOLOGY FOR SAFETY 
Patients are evaluable for general safety if they received any study treatment.  
7.1 
Toxicity and adverse events  
All the adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). 
The toxicity evaluation will be coded with the National Cancer Institute-Common 
Terminology Criteria for Adverse Events (NCI-CTCAE), version 4. 
As far as all the toxicities are concerned, the NCI-CTCAE grade will be used wherever an 
NCI-CTCAE grading exists. Otherwise, the severity will be noted. As a convention, the 
term «Grade» will always be used. Toxicities will be described according to the worst NCI-
CTCAE grade or, for toxicities which do not form the subject of NCI-CTCAE 
classification, according to the worst severity. For “Worst per cycle” calculation purpose, 
onset and end cycle of each event will be derived.  
Summary of overall adverse events will be done by body system and preferred term, by 
severity (worst toxicity grade) and by relationship to the study drug. Events with unknown 
relationship will be considered as related events for reporting purposes.  
A frequency table will be made for the AEs leading to cycle delay, dose reduction, skipped 
dose, or withdrawal of study medication. Adverse events with outcome of death will also be 
presented by relationship to the study drug. 
All events entered in Adverse Event form with the onset date before the first drug 
administration, will be reported as Signs and symptoms. Only those events with start date 
after/equal the first infusion date will be included in AE tables in Safety section (except 
those including evolution from baseline). 
 
 


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7.2 
Clinical laboratory evaluation 
Laboratory results will be classified according to the NCI-CTCAE version 4. All laboratory 
visits reported as “End of treatment” visit will be mapped to the last cycle visit. 
For hematology values: absolute neutrophil count, lymphocyte count, WBC count, platelet 
count and hemoglobin worst grade per patient and per cycle will be displayed.  
Time and duration of anemia, neutropenia and thrombocytopenia in cycles with grade 3-4 
abnormality will be tabulated. 
Overall cross tabulation will be presented for the worst grade during treatment versus the 
baseline toxicity grading of anemia, lymphopenia, leukopenia, neutropenia and 
thrombocytopenia. 
The worst grade per patient during treatment and per cycle will be also calculated for the 
biochemical tests: ALT, AST, Total bilirubin, AP, CPK, creatinine, calcium, potassium, 
sodium, glucose and albumin. 
Time and duration of AST, ALT and CPK increases in cycles with grade 3-4 abnormality 
will be tabulated. 
Overall cross tabulation will be presented for the worst grade during treatment versus the 
baseline toxicity grading of AST, ALT and CPK increase. 
7.3 
Vital signs, physical examination, left ventricular ejection fraction (LVEF) and 
electrocardiogram findings 
Tabulation will be made summarizing the performance status, body weight, LVEF and 
electrocardiogram abnormalities at baseline and during the treatment for each patient. 
7.4 
Deaths and other Serious Adverse Events 
Deaths and other Serious Adverse Events will be tabulated. 
 
8 OTHER ANALYSES 
Non-continuous variables will be described in frequency tables using counts and 
percentages. Continuous variables will be described by median, mean, standard deviation, 
minimum and maximum. 
8.1 
Baseline and demographic data 
Baseline data such as demographics, disease history, prior therapy, prior relevant history, 
signs and symptoms, electrocardiogram, LVEF, protein measurements, laboratory values 
and concomitant medication (ATC-WHO coded) will be described following standard 
tables detailed in Appendix I. When two or more assessments have been done for the same 
parameter, the last assessment before or on the first drug administration will be taken into 
account for the analysis. 


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8.2 
Treatment administration 
CRF cycles with a theoretical duration of 4 weeks will be used for this analysis. 
Total cumulative dose, time on treatment, dose intensity and relative dose intensity, cycle 
delay, dose omissions, and dose reductions will be described following standard tables 
detailed in Appendix I. 
Total cumulative dose, expressed in mg/m² is the sum of all the plitidepsin doses from the 
first cycle until last cycle including the dose received in last cycle. 
Patients will be considered to be on-treatment for the duration of their treatment and 30 
days following the last treatment dose. If the patient starts any new antitumor therapy 
outside this clinical trial or dies within 30 days of last treatment dose, the date of 
administration of this new therapy or the date of death will be considered the date of 
treatment discontinuation. 
However, as a convention, for dose intensity calculation purposes, the duration of the last 
cycle is considered to be 28 days. 
Intended dose intensity is the planned dose per cycle divided by the planned number of 
weeks by cycle (2.4mg/m2/wk for plitidepsin). 
Absolute dose intensity is the actual cumulative dose divided by the number of weeks of 
treatment. Relative dose intensity (%) is the ratio of absolute dose intensity divided by the 
intended dose intensity. 
The item «Infusion delayed: yes/no» in the case report form (CRF) will be used to calculate 
the delay (on day 1 infusion).  For cycles considered as delayed by the investigator, the 
delay will be calculated as: 
Delay:  Date of current drug administration – Date of previous drug administration – 28.  
The first infusion of the first cycle will be excluded from all cycle delay and cycle 
modification calculations. 
8.3 
Subsequent therapy 
A table summarizing the subsequent therapies received after treatment discontinuation will 
be shown. 
Time to first subsequent therapy or death will be analyzed as a measure of the time from 
first drug administration to treatment failure that leads to the need of a further treatment 
regimen. 
8.4 
Protocol deviations 
Analysis of inclusion/exclusion criteria deviations, retreatment restrictions, used 
concomitant medication and clinically relevant discontinuations will be done as described 
in Appendix I.   
8.5 
Pharmacokinetic and biomarkers  analyses 
These analyses will be detailed in separate documents. 


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8.6 
Imputation of incomplete dates 
The dates of certain historical or current clinical activities are key component for statistical 
analysis. Incomplete date appears when day, month or year is/are missing, and it could be 
imputed so that variables like time to and duration of certain event can be calculated. If 
none of day, month and year is available, then the date is missing, no imputation will be 
done. 
Before treatment start date 
If day of a date is unknown then the imputed day will be 15, if the month is also unknown 
then the imputed date will be July 1st. This assumption will be valid if the imputed date is 
earlier than the treatment start date; otherwise the imputed date will be the first day of the 
treatment start month. 
Between treatment start and end of treatment 
All date variables during treatment where information is needed and is not fully available, 
for example adverse events or concomitant medications, will be subject of imputation by 
means of SAS programming. If the day of a date is unknown then the imputed day will be 
1, if the month and/or year is also unknown then the imputed date will 1/January. This 
assumption will be valid if the imputed date is earlier than the treatment start date; 
otherwise, the imputed date will be the treatment start date. 
After end of treatment 
To ensure the most conservative approach for the main time-to-event variables (i.e. PFS 
and OS) that can be affected by missing values the following rules will be implemented by 
means of SAS programming: if the day of a date is unknown then the imputed day will be 
1; if the month is also unknown, then the imputed date will be 1/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 last drug administration date plus 1 day. 
8.7 
Subgroup analyses 
No specific subgroup analysis is planned for efficacy. However, the influence of prognostic 
factors on the efficacy endpoints will be studied in the multivariate analysis.  
No formal statistical allowance will be made for multiple subgroup investigations, but any 
apparent subgroup interactions will be interpreted appropriately in a cautious way. 
Analysis of safety profile by age, gender, race and body mass index (BMI) will be provided 
as specified in section 12.7. 
Handling of multicenter data 
Not applicable. 
Handling of multiple comparisons 
No formal statistical allowance will be made for multiple comparisons, therefore any 
apparent subgroup analysis will be interpreted appropriately in a cautious way. 
 


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8.8 
Decimal places and methods for handling missing data 
By default, all results will be rounded to one decimal, except in the case where variables are 
integer; in that case, they will be reported without decimals, for example, age in years, 
number of sites. For representing p-values four decimals will be selected as default but they 
could 
be 
rounded 
to 
fewer 
decimals 
if 
necessary. 
Missing values will not be included in the calculation of outputs. 
8.9 
Interim and group sequential analyses 
Two futility analyses of the primary endpoint (ORR according to the Lugano classification 
response criteria per independent review) are planned to reject the alternative hypothesis 
when ~25% and ~50% of the patients have been recruited (first 15 and 30 patients, 
respectively). Pocock boundary and the actual number of patients confirmed by central 
pathological review will be used to control type II error for both analyses. For example, if 
there are two or less responders out of 15 patients or seven or less responders out of 30 
patients, according to boundaries and sample size assumptions, the alternative hypothesis 
could be rejected, and thus recruitment might be stopped at the time of the first or second 
futility analysis, respectively.  
8.10 Identification of fixed or random effects models 
Not applicable 
 
 
9 STATISTICAL SOFTWARE 
Medidata Rave® EDC will be used for data entry and clinical data management. EAST 
v5.2 has been used to calculate sample size. SAS v9 (1) or superior will be used for all 
statistical analysis outputs. 
 
 


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APPENDIX I 
All tables will be created at the time of each analysis planned in the protocol if applicable, 
and at study end. 
10 Study Patients 
These analyses will be performed in “All Included patients” analysis set. 
10.1 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 Number of patients per population 
 
N 
% 
All Included Patients 
X 
X.X 
All Evaluable Patients 
 
 
All Treated Patients 
 
 
Per Protocol Patients 
 
 
Listing 10.1.2 Patients excluded from analysis populations 
Patient id. 
Population 
Exclusion reason 
 
 
 
 
Table 10.1.3 Patients accrual by institution 
 
Country 
Institution 
N 
% 
No. included 
Country 1 
Institution 1 
X 
X.X 
… 
 
 
Total 
 
 
… 
Institution 1 
 
 
… 
 
 
Total 
 
 
Total 
Institution 1 
 
 
… 
 
 
Total 
 
 
No. treated 
Country 1 
Institution 1 
 
 
… 
 
 
Total 
 
 
… 
Institution 1 
 
 
… 
 
 
Total 
 
 
Total 
Institution 1 
 
 
… 
 
 
Total 
 
 
Table 10.1.4 Study dates 
Date of first registration 
 
Date of first dose of the first patient 
 
Date of last registration 
 
Date of first dose of the last patient 
 
Date of last dose 
 
Date of last follow-up* 
 
(*) Last follow-up or exam or procedure before clinical cut-off or study closure 
 


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10.2 Reasons for treatment discontinuation 
Table 10.2.1 Treatment discontinuation 
 
N 
% 
Progressive disease 
X 
X.X 
Treatment related adverse event  
 
 
Non treatment related adverse event 
 
 
Patient refusal to treatment 
 
 
Investigator decision 
 
 
Death (due to toxicity)* 
 
 
Death (non-treatment-related)** 
 
 
Complete response 
 
 
PR or CR and eligible for consolidation with autologous or allogeneic SCT  
 
 
Other *** 
 
 
Total 
 
 
(*) Cause of death = study drug related (**) Cause of death = Malignant disease / non study drug related / Other (***) 
Specify (see listing 10.2.2). Patients included but not treated will not be shown in this table. 
 
 
When reason for discontinuation is toxicity or study treatment-related death, identify 
patients and describe them in depth here. 
Listing 10.2.2 Reasons for treatment discontinuation other than progressive disease. 
Patient id. 
Reason 
Last cycle 
Comments  
 
 
 
 
 
Listing 10.2.3 Treatment discontinuation due to AEs 
Patient id. Cycle 
Preferred  
term code 
Adverse event 
reported 
(verbatim) 
Grade  
Relationship  
Onset 
date 
Resolved 
date 
Significant 
consequences 
 
 
  
 
 
 
 
 
 
Table 10.2.4 Study discontinuation 
 
N 
% 
Study termination (clinical cut-off) 
X 
X.X 
Patient’s refusal 
 
 
Never treated* 
 
 
Death (due to toxicity)** 
 
 
Death (non-treatment-related)*** 
 
 
Investigator decision 
 
 
Patient’s follow-up completed 
 
 
Lost to follow-up 
 
 
Other **** 
 
 
Total 
 
 
(*) See Listing 10.2.6  (**) Cause of death = study drug related (***) Cause of death = Malignant disease / non study drug 
related / Other (****)See Listing 10.2.5  
Listing 10.2.5 Study discontinuation due to other reason 
Patient id. 
Specify 
 
 
Listing 10.2.6 Patients included but not treated 
Patient id. 
Off-study reason 
 
 


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Listing 10.2.7 Patients included without AITL diagnosis confirmed after central 
pathological review 
Patient id. 
Treated (Y/N) 
 
 
 
10.3 Protocol deviations  
 
Listing 10.3.1 Protocol deviations 
Patient id. 
Deviation type 
Description 
 
 
 
 
 
 


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11 Efficacy Evaluation 
11.1 Demographic and other baseline characteristics 
These analyses will be performed in “All Included patients” analysis set. 
11.1.1 Patient characteristics at baseline 
Table 11.1.1.1 Baseline characteristics: Gender 
 
N 
% 
Male 
X 
X.X 
Female  
 
 
Total 
 
 
Table 11.1.1.2 Baseline characteristics: Age at treatment registration 
N 
Median 
Mean 
StD 
Min 
Max 
 
 
 
 
 
 
Table 11.1.1.3 Baseline characteristics: Age grouped 
 
N 
% 
18-XX 
X 
X.X 
XX-YY 
 
 
≥65 
 
 
Total 
 
 
Table 11.1.1.4 Baseline characteristics: Race 
 
N 
% 
White 
X 
X.X 
…  
 
 
Total 
 
 
11.1.2 Local histopathological diagnosis 
Table 11.1.2.1 Histopathological diagnosis: Clinical features 
Systemic clinical manifestations 
N 
% 
Generalized lymphadenopathy 
X 
X.X 
Hepatosplenomegaly 
 
 
Skin rash/pruritus 
 
 
Polyclonal hypergammaglobulinemia 
 
 
Others 
 
 
Listing 11.1.2.2 Histopathological diagnosis: Clinical features, other clinical manifestations 
Patient id. 
Other systemic clinical manifestations 
 
 
 


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Table 11.1.2.3 Histopathological diagnosis: Pathologic and immunophenotypic features 
Common T-cell markers (Positive) 
N 
% 
  CD3 
X 
X.X 
  CD4 
 
 
  CD8 
 
 
  Other markers 
 
 
Expression of follicular TH (TFH) markers by the tumor cells 
(Positive) 
N 
% 
  PD1 
X 
X.X 
  BCL6 
 
 
  CXCL13 
 
 
  CD10 
 
 
  ICOS 
 
 
Hyperplasia of follicular dendritic cells (CD23+ and/or CD21+) 
N 
% 
  Hyperplasia of follicular dendritic cells (Present) 
X 
X.X 
  EBV in-situ hybridization (EBERs) (Positive) 
 
 
  Presence of CD30+ B-cell blast (Positive) 
 
 
  Other relevant features 
 
 
Listing 11.1.2.4 Histopathological diagnosis: Other common T-cell markers 
Patient id. 
Other common T-cell markers 
 
 
Listing 11.1.2.5 Histopathological diagnosis: Other relevant hyperplasia of follicular 
dentritic cell features  
Patient id. 
Other relevant features 
 
 
Listing 11.1.2.6 Patients without AITL diagnosis confirmed by local histopathological 
report  
Patient id. 
Reason 
 
 
 
11.1.3 Disease at diagnosis, time from diagnosis and current disease  
Table 11.1.3.1 Time from diagnosis to first infusion (months) 
N 
Median 
Mean 
StD 
Min 
Max 
X 
X.X 
X.X 
X.X 
X.X 
X.X 
Table 11.1.3.2 Time from last PD* to first infusion (weeks) 
N 
Median 
Mean 
StD 
Min 
Max 
X 
X.X 
X.X 
X.X 
X.X 
X.X 
(*)PD date will be taken from Lymphoma History form as date of relapsed or refractory disease. If the day or the month 
or the full date is missing, further information will be taken from Prior anticancer therapy form. After that, if the date is 
still incomplete, imputation rules described in section 8.6 will be used.      


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Table 11.1.3.3 Ann-Arbor Lymphoma stage at diagnosis. 
 
N 
% 
I-A 
X 
X.X 
I-B 
 
 
II-A 
 
 
... 
 
 
Total 
 
 
Table 11.1.3.4 Ann-Arbor Lymphoma stage at diagnosis I/II vs III/IV. 
 
N 
% 
I/II 
X 
X.X 
III/IV 
 
 
Total 
 
 
Table 11.1.3.5 Extranodal disease at diagnosis. 
 
N 
% 
Yes 
X 
X.X 
No 
 
 
Total 
 
 
Listing 11.1.2.6 Extranodal sites at diagnosis.  
Patient id. 
Extranodal sites 
 
 
Table 11.1.3.6 Bulky lesion at diagnosis 
 
N 
% 
Yes 
X 
XX.X 
No 
 
 
Total 
 
 
Table 11.1.3.7 International Prognostic Index at diagnosis 
 
N 
% 
Low risk (0-1 risk factors) 
X 
X.X 
Low-intermedite risk (2 risk factors) 
 
 
High-intermediate risk (3 risk factors) 
 
 
High risk (4-5 risk factors) 
 
 
Not available 
 
 
Total 
 
 
Table 11.1.3.8 Prognostic Index for Peripheral T-Cell Lymphoma (PIT) at diagnosis 
 
N 
% 
Group 1 
X 
X.X 
Group 2 
 
 
Group 3 
 
 
Group 4 
 
 
Not available 
 
 
Total 
 
 
 
Table 11.1.3.9 Prognostic Index for Angioimmunoblastic T-Cell Lymphoma (PIAI) at 
diagnosis 
 
N 
% 
Low risk group 
X 
X.X 
High risk group 
 
 
Not available 
 
 
Total 
 
 


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Table 11.1.3.10 Relapsed / Refractory at current disease 
 
N 
% 
Relapsed 
X 
X.X 
Refractory 
 
 
Total 
 
 
Table 11.1.3.11 International Prognostic Index at current disease 
 
N 
% 
Low risk (0-1 risk factors) 
X 
X.X 
Low-intermedite risk (2 risk factors) 
 
 
High-intermediate risk (3 risk factors) 
 
 
High risk (4-5 risk factors) 
 
 
Not available 
 
 
Total 
 
 
Table 11.1.3.12 Prognostic Index for Peripheral T-Cell Lymphoma (PIT) at current disease 
 
N 
% 
Group 1 
X 
X.X 
Group 2 
 
 
Group 3 
 
 
Group 4 
 
 
Not available 
 
 
Total 
 
 
 
Table 11.1.3.13 Prognostic Index for Angioimmunoblastic T-Cell Lymphoma (PIAI) at 
current disease 
 
N 
% 
Low risk group 
X 
X.X 
High risk group 
 
 
Not available 
 
 
Total 
 
 
Table 11.1.3.14 Baseline characteristics: protein measurements 
 
N 
Median 
Mean 
StD 
Min 
Max 
Ig G (g/dl) 
X 
X.X 
X.X 
X.X 
X.X 
X.X 
Ig A (g/dl) 
 
 
 
 
 
 
Ig M (g/dl) 
 
 
 
 
 
 
Listing 11.1.3.15 Baseline characteristics: protein measurements 
Patient id. 
Date 
Ig G (g/dl) 
Ig A (g/dl) 
Ig M (g/dl) 
Immunofixation 
serum 
 
 
 
 
 
 
 
11.1.4 Prior anticancer therapy 
Listing 11.1.4.1 Patients with prior radiotherapy 
Patient id. 
Intention 
Site (Anatomic) 
Total dose (Gy) 
First dose 
Last dose 
 
 
 
 
 
 
Listing 11.1.4.2 Patients with prior surgery 
Patient id. 
Site and procedures 
Date 
 
 
 


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Table 11.1.4.3 Number of lines of prior medical therapy 
 
N 
% 
1 
X 
X.X 
2 
 
 
... 
 
 
Total 
 
 
Median (Range) 
 
 
Table 11.1.4.4 Prior anticancer agents 
Antineoplastic and Immunomodulating agents (ATC-class.) 
 
 
N 
% 
Antineoplastic Agents (L01) 
X 
X.X 
…. 
 
 
…. 
 
 
Table 11.1.4.5 TTP to last prior anticancer therapy 
Time to progression. Last 
anticancer therapy (months) 
N 
Median 
Mean 
StD 
Min 
Max 
Total 
X 
X.X 
X.X 
X.X 
X.X 
X.X 
Table 11.1.4.6 Response to last therapy 
 
N 
% 
CR  
X 
X.X 
PR 
 
 
SD 
 
 
PD 
 
 
NE / NA / UNK 
 
 
Table 11.1.4.7 Prior stem cell transplantation 
 
N 
% 
0 
X 
X.X 
1 
 
 
≥2 
 
 
Type 
N 
% 
Autologous 
X 
X.X 
Allogeneic 
 
 
 
11.1.5 Prior history 
Listing 11.1.5.1 Prior history not resolved 
Patient id. 
Description 
Onset Date 
 
 
 
 
11.1.6 Physical examination, vital signs, electrocardiogram and other tests 
For the physical examination, vital signs, electrocardiogram and other tests, the last 
examination available before treatment will be described in the following tables. 
Table 11.1.6.1 Baseline characteristics: Physical exam 
 
N 
% 
Normal 
X 
X.X 
Abnormal* 
 
 
Total 
 
 
(*)See listing 11.1.6.2 


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Listing 11.1.6.2 Physical examination abnormalities 
Patient id. 
Body system examined 
Onset Date 
 
 
 
Table 11.1.6.3 Baseline characteristics: Physical exam and vital signs. 
Parameter 
N 
Median 
Mean 
StD 
Min 
Max 
Weight (kg.) 
X 
X.X 
X.X 
X.X 
X.X 
X.X 
Height (cm.) 
 
 
 
 
 
 
BSA (m2) 
 
 
 
 
 
 
Heart rate (beats/min) 
 
 
 
 
 
 
Systolic blood pressure (mmHg) 
 
 
 
 
 
 
Diastolic blood pressure (mmHg) 
 
 
 
 
 
 
Temperature (ºC) 
 
 
 
 
 
 
Table 11.1.6.4 Baseline characteristics: ECOG Performance Status 
 
N 
% 
0 
X 
X.X 
1 
 
 
2 
 
 
Total 
 
 
Table 11.1.6.5 Baseline characteristics: Electrocardiogram 
 
N 
% 
Normal 
X 
X.X 
Significant abnormalities* 
 
 
Non significant abnormalities 
 
 
Total 
 
 
(*)See tables of signs and symptoms or prior history for details and listing 11.1.6.6 
Listing 11.1.6.6 ECG abnormalities at baseline 
Patient 
id. 
Result 
Heart rate (bpm) 
QT interval 
(msec) 
Fridericia 
corrected QT 
(msec) 
Specify 
 
 
 
 
 
 
Table 11.1.6.7 Baseline characteristics: LVEF 
 
N 
% 
Normal 
X 
X.X 
Significant abnormalities* 
 
 
Non significant abnormalities* 
 
 
Total 
 
 
(*)See tables of signs and symptoms or prior history for details and listing 11.1.6.8 
Listing 11.1.6.8 Patients with Left Ventricular Ejection Fraction abnormalities at baseline 
Patient id. 
Date 
Result 
LVEF (%) 
Institutional normal range (%) 
Method 
 
 
 
 
 
 
Table 11.1.6.9 Baseline characteristics Median and range of LVEF 
 
N 
Median 
Mean 
StD 
Range 
MUGA 
X 
X.X 
X.X 
X.X 
X.X-X.X 
ECHO 
 
 
 
 
 
Both 
 
 
 
 
 
 


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Table 11.1.6.10 Baseline characteristics: Neurological examination 
 
N 
% 
Normal 
X 
X.X 
Abnormal* 
 
 
Total 
 
 
(*)See tables of signs and symptoms or prior history for details and listing 11.1.6.11 
Listing 11.1.6.11 Neurological examination abnormalities at baseline 
Patient id. 
Result 
Specify 
 
 
 
Table 11.1.6.12 Baseline characteristics: Urinary dipstick 
 
N 
% 
Normal 
X 
X.X 
Abnormal* 
 
 
Total 
 
 
(*)See table 11.1.6.13 for further details 
Listing 11.1.6.13 Patients with abnormal urinary dipstick at baseline 
Patient id. 
Date 
Result 
Proteinuria 
Leukocytes  
Red Blood 
Cells 
 
 
 
 
 
 
Table 11.1.6.14 Baseline characteristics: Coombs test result 
 
N 
% 
Positive 
X 
X.X 
Negative 
 
 
Total 
 
 
Table 11.1.6.15 Baseline characteristics: Viral serology results 
 
N 
% 
Hepatitis B 
 
 
   Positive 
X 
X.X 
   Negative 
 
 
   Not done 
 
 
   Total 
 
 
Hepatitis C 
 
 
   Positive 
X 
X.X 
   Negative 
 
 
   Not done 
 
 
   Total 
 
 
Cytomegalovirus 
 
 
   Positive 
X 
X.X 
   Negative 
 
 
   Not done 
 
 
   Total 
 
 
Listing 11.1.6.16 Patients with positive viral serology results at baseline 
Patient 
id. 
Date 
Hepatitis B (HBC) 
Hepatitis C 
Cytomegalovirus 
Surface 
antigen 
Surface 
antibody 
Core antibody 
HCV 
CMV pp65 Quantitative CMV 
DNA PCR 
 
 
 
 
 
 
 
 
 


28 of 61 
Table 11.1.6.17 Baseline characteristics: Adequate contraception 
 
N 
% 
Yes 
X 
X.X 
No 
 
 
NA* 
 
 
Total 
 
 
(*) Specify reasons 
Table 11.1.6.18  Baseline characteristics: Pregnancy test 
 
N 
% 
Yes 
X 
X.X 
No 
 
 
NA* 
 
 
Not done 
 
 
Total 
 
 
(*) Specify reasons 
 
11.1.7 Hematological values at baseline 
Table 11.1.7.1 Hematological abnormalities at baseline   
 
N 
Grade  
1 
… 
Grade  
4 
All* 
 
N 
N 
% 
… 
N 
% 
N 
% 
Leukopenia 
X 
X 
X.X 
 
X 
X.X 
X 
X.X 
Anemia 
 
 
 
 
 
 
 
 
Thrombocytopenia  
 
 
 
 
 
 
 
 
Neutropenia 
 
 
 
 
 
 
 
 
Lymphopenia  
 
 
 
 
 
 
 
 
(*)Any grade 
 
Table 11.1.7.2 Hematology values at baseline 
 
N 
Median 
Mean 
StD 
Range 
WBC (109/L) 
X 
X.X 
X.X 
X.X 
X.X-X.X 
Hemoglobin (g/dL) 
 
 
 
 
 
Hematocrit (%) 
 
 
 
 
 
Platelets (109/L) 
 
 
 
 
 
Neutrophils (109/L) 
 
 
 
 
 
Lymphocytes (109/L) 
 
 
 
 
 
Listing 11.1.7.3 Hematological tests not assessed at baseline 
Patient id. 
Lab. test 
 
 
Listing 11.1.7.4 Hematological abnormalities at baseline. Grade ≥ 2 
Patient id 
Parameter 
Value 
Grade 
 
 
X.X 
 
 


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11.1.8 Biochemical values at baseline 
 
Table 11.1.8.1 Biochemical abnormalities at baseline 
 
N 
Grade  
1 
… 
Grade  
4 
All* 
 
N 
N 
% 
… 
N 
% 
N 
% 
AST increase 
X 
X 
X.X 
 
X 
X.X 
X 
X.X 
ALT increase 
 
 
 
 
 
 
 
 
Total bilirubin increase 
 
 
 
 
 
 
 
 
ALP increase 
 
 
 
 
 
 
 
 
Creatinine increase 
 
 
 
 
 
 
 
 
CPK increase 
 
 
 
 
 
 
 
 
(*)Any grade 
 
Table 11.1.8.2 Biochemical values at baseline 
 
N 
Median 
Mean 
StD 
Range 
AST (IU/L) 
X 
X.X 
X.X 
X.X 
X.X-X.X 
ALT (IU/L) 
 
 
 
 
 
Total bilirubin (mg/dL) 
 
 
 
 
 
Direct bilirubin (mg/dL) 
 
 
 
 
 
ALP (IU/L) 
 
 
 
 
 
Creatinine (mg/dL) 
 
 
 
 
 
Creatinine Clearance (ml/min) 
 
 
 
 
 
CPK (IU/L) 
 
 
 
 
 
CPK MB (IU/L) 
 
 
 
 
 
Total proteins (g/dL) 
 
 
 
 
 
Albumin (g/dL) 
 
 
 
 
 
Uric acid (mg/dL) 
 
 
 
 
 
LDH (IU/L) 
 
 
 
 
 
CRP (mg/dL) 
 
 
 
 
 
Beta-2-microglobulin (mg/L) 
 
 
 
 
 
Listing 11.1.8.3 Biochemical tests not assessed at baseline 
Patient id. 
Lab. test 
… 
 
Listing 11.1.8.4 Biochemical abnormalities at baseline. Grade ≥ 2 
Patient id 
Parameter 
Value 
Grade 
 
 
X.X 
 
11.1.9 Other metabolic values at baseline 
Table 11.1.9.1 Other metabolic abnormalities at baseline 
 
N 
Grade  
1 
… 
Grade  
4 
All* 
 
N 
N 
% 
… 
N 
% 
N 
% 
Hyperglycemia  
X 
X 
X.X 
 
X 
X.X 
X 
X.X 
Hypoglycemia  
 
 
 
 
 
 
 
 
…. 
 
 
 
 
 
 
 
 
Hypoalbuminemia  
 
 
 
 
 
 
 
 
(*)Any grade 
 


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Table 11.1.9.2 Other metabolic values at baseline 
 
N 
Median 
Mean 
Std 
Range 
Sodium (mmol/L) 
X 
X.X 
X.X 
X.X 
X.X-X.X 
Potassium (mmol/L) 
 
 
 
 
 
Calcium (mmol/L) 
 
 
 
 
 
Magnesium (mmol/L) 
 
 
 
 
 
Glucose (mmol/L) 
 
 
 
 
 
Listing 11.1.9.3 Metabolic tests not assessed at baseline 
Patient id. 
Lab. test 
… 
 
Listing 11.1.9.4 Metabolic abnormalities at baseline. Grade ≥ 2 
Patient id 
Parameter 
Value 
Grade 
 
 
X,X 
 
 
11.1.10 Signs and symptoms at baseline 
Table 11.1.10.1 Patients with signs and symptoms at baseline 
 
N 
% 
No. signs and symptoms per patient 
 
 
0 
1 
2 
X 
X.X 
 3 
 
 
Median (Range) 
X.X (X-X) 
 
 
Table 11.1.10.2 Signs and symptoms at baseline  
 
 
N 
Grade  
1 
… 
Grade  
4 
All* 
SOC 
Preferred Term 
N 
N 
% 
… 
N 
% 
N 
% 
Gastrointestinal disorders 
 
X 
X 
X.X 
 
X 
X.X 
X 
X.X 
Diarrhea NOS 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
General disorders and 
administration site conditions 
Fatigue 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
(*)Any grade 
Listing 11.1.10.3 Signs and Symptoms at baseline 
Patient id. 
Sign/symptom 
Grade 
Onset date 
Relationship 
Treated 
 
 
 
 
 
 
 
11.1.11 Concomitant therapy and procedures at baseline 
Concomitant medication at baseline according to the ATC classification. 
Table 11.1.11.1 Agents of concomitant therapy started at baseline 
Medication Term 
(ATC level 1 ) 
Medication Term 
(ATC level 2) 
Medication Term 
(ATC level 4) 
Preferred Name 
N 
% 
 
 
 
 
X 
X.X 
 


31 of 61 
 Listing 11.1.11.2  Concomitant therapy at baseline 
Patient 
id. 
Type 
Drug name  ATC Code 
Route 
Total daily 
dose 
Start date 
Reason for use 
Indication for 
therapeutic 
reason 
 
 
 
 
 
 
 
 
 
Listing 11.1.11.3  Concomitant procedures at baseline 
Patient id. 
Procedure 
Date 
Indication 
AE/MH/Other 
Comments 
 
 
 
 
 
 
 
11.2 Measurements of treatment compliance 
Not applicable. 
11.3 Efficacy analysis 
11.3.1 Primary analysis 
 
Table 11.3.1.1 Response rate by the Lugano classification response criteria (Independent 
Review assessment and “Per Protocol Patients” population) 
Response 
 
N 
% 
CR  
X 
X.X 
PR 
 
 
SD 
 
 
PD 
 
 
NE 
 
 
 
Table 11.3.1.2 Response rate estimates by the Lugano classification response criteria 
(Independent Review assessment and “Per Protocol Patients” population) 
 
Proportion 
Lower 95% limit 
Upper 95% limit 
Response rate 
X.X 
X.X 
X.X 
Binomial exact estimator and 95% confidence interval 
 
Table 11.3.1.3 Response rate by the Lugano classification response criteria (Independent 
Review assessment and “Per Protocol Patients” population) in first futility analysis 
Response 
N 
% 
Pocock 
boundary 
CR  
X 
X.X 
 
PR 
 
 
 
SD 
 
 
 
PD 
 
 
 
NE 
 
 
 
 
Table 11.3.1.4 Response rate by the Lugano classification response criteria (Independent 
Review assessment and “Per Protocol Patients” population) in second futility analysis 
Response 
N 
% 
Pocock 
boundary 
CR  
X 
X.X 
 
PR 
 
 
 
SD 
 
 
 
PD 
 
 
 
NE 
 
 
 


32 of 61 
 
11.3.2 Secondary analyses 
 
Table 11.3.2.1 Response rate by the Lugano classification response criteria (Investigator 
assessment and “Per Protocol Patients” population) 
Response 
 
N 
% 
CR  
X 
X.X 
PR 
 
 
SD 
 
 
PD 
 
 
NE 
 
 
 
Table 11.3.2.2 Response rate estimates by the Lugano classification response criteria 
(Investigator assessment and “Per Protocol Patients” population) 
 
Proportion 
Lower 95% limit 
Upper 95% limit 
Response rate 
X.X 
X.X 
X.X 
Binomial exact estimator and 95% confidence interval 
 
Table 11.3.2.3 Response rate by the Lugano classification response criteria (Independent 
Review assessment and “All Evaluable Patients” population) 
Response 
 
N 
% 
CR  
X 
X.X 
PR 
 
 
SD 
 
 
PD 
 
 
NE 
 
 
 
Table 11.3.2.4 Response rate estimates by the Lugano classification response criteria 
(Independent Review assessment and “All Evaluable Patients” population) 
 
Proportion 
Lower 95% limit 
Upper 95% limit 
Response rate 
X.X 
X.X 
X.X 
Binomial exact estimator and 95% confidence interval 
 
Table 11.3.2.5 Response rate by the Lugano classification response criteria (Investigator 
assessment and “All Evaluable Patients” population) 
Response 
 
N 
% 
CR  
X 
X.X 
PR 
 
 
SD 
 
 
PD 
 
 
NE 
 
 
 


33 of 61 
Table 11.3.2.6 Response rate estimates by the Lugano classification response criteria 
(Investigator assessment and “All Evaluable Patients” population) 
 
Proportion 
Lower 95% limit 
Upper 95% limit 
Response rate 
X.X 
X.X 
X.X 
Binomial exact estimator and 95% confidence interval 
 
Table 11.3.2.7 Response rate by the Lugano classification response criteria (Independent 
Review assessment and “All Treated Patients” population) 
Response 
 
N 
% 
CR  
X 
X.X 
PR 
 
 
SD 
 
 
PD 
 
 
NE 
 
 
 
Table 11.3.2.8 Response rate estimates by the Lugano classification response criteria 
(Independent Review assessment and “All Treated Patients” population) 
 
Proportion 
Lower 95% limit 
Upper 95% limit 
Response rate 
X.X 
X.X 
X.X 
Binomial exact estimator and 95% confidence interval 
 
Table 11.3.2.9 Response rate by the Lugano classification response criteria (Investigator 
assessment and “All Treated Patients” population) 
Response 
 
N 
% 
CR  
X 
X.X 
PR 
 
 
SD 
 
 
PD 
 
 
NE 
 
 
 
Table 11.3.2.10 Response rate estimates by the Lugano classification response criteria 
(Investigator assessment and “All Treated Patients” population) 
 
Proportion 
Lower 95% limit 
Upper 95% limit 
Response rate 
X.X 
X.X 
X.X 
Binomial exact estimator and 95% confidence interval 
 
Table 11.3.2.11 ORR – Concordance between Independent Review assessment and 
Investigator assessment ( “Per Protocol Patients” population)  
 
Response by Investigator assessment 
Response by IRC 
CR 
PR 
SD 
PD 
NE 
CR 
 
 
 
 
 
PR 
 
 
 
 
 
SD 
 
 
 
 
 
PD 
 
 
 
 
 
NE 
 
 
 
 
 
 
Table 11.3.2.12 CR rate estimates by the Lugano classification response criteria 
(Independent Review assessment and “Per Protocol Patients” population) 
 
Proportion 
Lower 95% limit 
Upper 95% limit 
CR rate 
X.X 
X.X 
X.X 
Binomial exact estimator and 95% confidence interval 
 


34 of 61 
Table 11.3.2.13 CR rate estimates by the Lugano classification response criteria 
(Independent Review assessment and “All Evaluable Patients” population) 
 
Proportion 
Lower 95% limit 
Upper 95% limit 
CR rate 
X.X 
X.X 
X.X 
Binomial exact estimator and 95% confidence interval 
 
Table 11.3.2.14 CR rate estimates by the Lugano classification response criteria 
(Independent Review and “All Treated Patients” population) 
 
Proportion 
Lower 95% limit 
Upper 95% limit 
CR rate 
X.X 
X.X 
X.X 
Binomial exact estimator and 95% confidence interval 
 
Table 11.3.2.15 CR rate estimates by the Lugano classification response criteria 
(Investigator assessment and “Per Protocol Patients” population) 
 
Proportion 
Lower 95% limit 
Upper 95% limit 
CR rate 
X.X 
X.X 
X.X 
Binomial exact estimator and 95% confidence interval 
 
Table 11.3.2.16 CR rate estimates by the Lugano classification response criteria 
(Investigator assessment and “All Evaluable Patients” population) 
 
Proportion 
Lower 95% limit 
Upper 95% limit 
CR rate 
X.X 
X.X 
X.X 
Binomial exact estimator and 95% confidence interval 
 
Table 11.3.2.17 CR rate estimates by the Lugano classification response criteria 
(Investigator assessment and “All Treated Patients” population) 
 
Proportion 
Lower 95% limit 
Upper 95% limit 
CR rate 
X.X 
X.X 
X.X 
Binomial exact estimator and 95% confidence interval 
 
Table 11.3.2.18 Duration of response (Independent Review assessment and “All Responder 
Patients” population) 
N 
X 
Events 
X 
Censored 
X 
Median DoR 
X.X 
Kaplan-Meier plot will be also shown (Figure 11.3.2.18)  
 
Table 11.3.2.19 Duration of response (Investigator assessment and “All Responder 
Patients” population) 
N 
X 
Events 
X 
Censored 
X 
Median DoR 
X.X 
Kaplan-Meier plot will be also shown (Figure 11.3.2.19)  
 
Table 11.3.2.20 Time to response (Independent Review assessment and “All Responder 
Patients” population) 
N 
X 
Median 
X 
Minimum 
X 
Maximum 
X.X 
 


35 of 61 
Table 11.3.2.21 Time to response (Investigator assessment and “All Responder Patients” 
population) 
N 
X 
Median 
X 
Minimum 
X 
Maximum 
X.X 
Table 11.3.2.22 PFS (Independent Review assessment and “Per Protocol Patients” 
population) 
N 
X 
Events 
X 
Censored 
X 
Median PFS 
X.X 
PFS at 6 months 
X.X 
PFS at 12 months 
X.X 
Kaplan-Meier plot will be also shown (Figure 11.3.2.22)  
Table 11.3.2.23 PFS (Independent Review assessment and “All Evaluable Patients” 
population) 
N 
X 
Events 
X 
Censored 
X 
Median PFS 
X.X 
PFS at 6 months 
X.X 
PFS at 12 months 
X.X 
Kaplan-Meier plot will be also shown (Figure 11.3.2.23)  
Table 11.3.2.24 PFS (Independent Review assessment and “All Treated Patients” 
population) 
N 
X 
Events 
X 
Censored 
X 
Median PFS 
X.X 
PFS at 6 months 
X.X 
PFS at 12 months 
X.X 
Kaplan-Meier plot will be also shown (Figure 11.3.2.24)  
Table 11.3.2.25 PFS (Investigator assessment and “Per Protocol Patients” population) 
N 
X 
Events 
X 
Censored 
X 
Median PFS 
X.X 
PFS at 6 months 
X.X 
PFS at 12 months 
X.X 
Kaplan-Meier plot will be also shown (Figure 11.3.2.25)  
Table 11.3.2.26 PFS (Investigator assessment and “All Evaluable Patients” population) 
N 
X 
Events 
X 
Censored 
X 
Median PFS 
X.X 
PFS at 6 months 
X.X 
PFS at 12 months 
X.X 
Kaplan-Meier plot will be also shown (Figure 11.3.2.26)  


36 of 61 
Table 11.3.2.27 PFS (Investigator assessment and “All Treated Patients” population) 
N 
X 
Events 
X 
Censored 
X 
Median PFS 
X.X 
PFS at 6 months 
X.X 
PFS at 12 months 
X.X 
Kaplan-Meier plot will be also shown (Figure 11.3.2.27)  
 
Table 11.3.2.28 PFS – Concordance between Independent Review assessment and 
Investigator assessment ( “Per Protocol Patients” population)  
 
N 
% 
Event by investigator 
 
 
  Agreement on event 
 
 
      Same date 
 
 
      Later date 
 
 
      Earlier date 
 
 
Censored by investigator 
 
 
  Agreement on censoring 
 
 
      Same date 
 
 
      Different date 
 
 
Agreement on status 
 
 
Agreement on status and date 
 
 
 
 
Table 11.3.2.29 Intra-patient PFS/TTP ratio (Independent Review assessment and “Per 
Protocol Patients” population) 
Ratio 
 
N 
% 
≤1.33  
X 
X.X 
>1.33 
 
 
 
Table 11.3.2.30 Intra-patient PFS/TTP ratio (Independent Review assessment and “All 
Evaluable Patients” population) 
Ratio 
 
N 
% 
≤1.33  
X 
X.X 
>1.33 
 
 
 
Table 11.3.2.31 Intra-patient PFS/TTP ratio (Independent Review assessment and “All 
Treated Patients” population) 
Ratio 
 
N 
% 
≤1.33  
X 
X.X 
>1.33 
 
 
 
Table 11.3.2.32 Intra-patient PFS/TTP ratio estimates (Independent Review assessment and 
“Per Protocol Patients” population) 
 
Proportion 
Lower 95% limit 
Upper 95% limit 
Ratio 
X.X 
X.X 
X.X 
Binomial exact estimator and 95% confidence interval 
 


37 of 61 
Table 11.3.2.33 Intra-patient PFS/TTP ratio estimates (Independent Review assessment and 
“All Evaluable Patients” population) 
 
Proportion 
Lower 95% limit 
Upper 95% limit 
Ratio 
X.X 
X.X 
X.X 
Binomial exact estimator and 95% confidence interval 
 
Table 11.3.2.34 Intra-patient PFS/TTP ratio estimates (Independent Review assessment and 
“All Treated Patients” population) 
 
Proportion 
Lower 95% limit 
Upper 95% limit 
Ratio 
X.X 
X.X 
X.X 
Binomial exact estimator and 95% confidence interval 
 
Table 11.3.2.35 Intra-patient PFS/TTP ratio (Investigator assessment and “Per Protocol 
Patients” population) 
Ratio 
 
N 
% 
≤1.33  
X 
X.X 
>1.33 
 
 
 
Table 11.3.2.36 Intra-patient PFS/TTP ratio (Investigator assessment and “All Evaluable 
Patients” population) 
Ratio 
 
N 
% 
≤1.33  
X 
X.X 
>1.33 
 
 
 
Table 11.3.2.37 Intra-patient PFS/TTP ratio (Investigator assessment and “All Treated 
Patients” population) 
Ratio 
 
N 
% 
≤1.33  
X 
X.X 
>1.33 
 
 
 
Table 11.3.2.38 Intra-patient PFS/TTP ratio estimates (Investigator assessment and “Per 
Protocol Patients” population) 
 
Proportion 
Lower 95% limit 
Upper 95% limit 
Ratio 
X.X 
X.X 
X.X 
Binomial exact estimator and 95% confidence interval 
 
Table 11.3.2.39 Intra-patient PFS/TTP ratio estimates (Investigator assessment and “All 
Evaluable Patients” population) 
 
Proportion 
Lower 95% limit 
Upper 95% limit 
Ratio 
X.X 
X.X 
X.X 
Binomial exact estimator and 95% confidence interval 
 
Table 11.3.2.40 Intra-patient PFS/TTP ratio estimates (Investigator assessment and “All 
Treated Patients” population) 
 
Proportion 
Lower 95% limit 
Upper 95% limit 
Ratio 
X.X 
X.X 
X.X 
Binomial exact estimator and 95% confidence interval 
 


38 of 61 
Table 11.3.2.41 OS (“Per Protocol Patients” population) 
N 
X 
Events 
X 
Censored 
X 
Median OS 
X.X 
OS at 6 months 
X.X 
OS at 12 months 
X.X 
Kaplan-Meier plot will be also shown (Figure 11.3.2.41). 
 
Table 11.3.2.42 OS (“All Evaluable Patients” population) 
N 
X 
Events 
X 
Censored 
X 
Median OS 
X.X 
OS at 6 months 
X.X 
OS at 12 months 
X.X 
Kaplan-Meier plot will be also shown (Figure 11.3.2.42). 
 
Table 11.3.2.43 OS (“All Treated Patients” population) 
N 
X 
Events 
X 
Censored 
X 
Median OS 
X.X 
OS at 6 months 
X.X 
OS at 12 months 
X.X 
Kaplan-Meier plot will be also shown (Figure 11.3.2.43). 
 
11.3.3 Follow-up 
 
Median follow-up assessments will be calculated using the Kaplan-Meier method reversing 
the censoring values (2). In addition, descriptive median and range will be calculated. 
 
Table 11.3.3.1 Median FU for PFS 
 
Median 
95% CI  
Follow-up 
X.X 
X.X-X.X 
 
Table 11.3.3.2 Descriptive median FU for PFS 
 
Median 
Min 
Max 
Follow-up 
X.X 
X.X 
X.X 
 
Table 11.3.3.3 Median FU for OS 
 
Median 
95% CI  
Follow-up 
X.X 
X.X-X.X 
 
Table 11.3.3.4 Descriptive median FU for OS 
 
Median 
Min 
Max 
Follow-up 
X.X 
X.X 
X.X 
 
 
 


39 of 61 
11.3.4 Multivariate analyses 
 
Table 11.3.4.1 Multivariate analysis of PFS (Independent Review assessment and “Per 
Protocol Patients” population) 
Analysis of Maximum Likelihood Estimates 
Variable Label 
Variable 
values 
DF 
Parameter 
Estimate 
Standard 
Error 
Chi-
Square 
Pr > ChiSq 
Hazard 
Ratio 
95% Hazard 
Ratio 
Confidence 
Limits 
 
 
 
X.X 
X.X 
X.X 
X.XXXX 
X.X 
X.X-X.X 
List of covariates in section 6.2.2 
 
Table 11.3.4.2 Multivariate analysis of PFS (Investigator assessment and “Per Protocol 
Patients” population) 
Analysis of Maximum Likelihood Estimates 
Variable Label 
Variable 
values 
DF 
Parameter 
Estimate 
Standard 
Error 
Chi-
Square 
Pr > ChiSq 
Hazard 
Ratio 
95% Hazard 
Ratio 
Confidence 
Limits 
 
 
 
X.X 
X.X 
X.X 
X.XXXX 
X.X 
X.X-X.X 
List of covariates in section 6.2.2 
 
Table 11.3.4.3 Multivariate analysis of PFS (Independent Review assessment and “All 
Evaluable Patients” population) 
Analysis of Maximum Likelihood Estimates 
Variable Label 
Variable 
values 
DF 
Parameter 
Estimate 
Standard 
Error 
Chi-
Square 
Pr > ChiSq 
Hazard 
Ratio 
95% Hazard 
Ratio 
Confidence 
Limits 
 
 
 
X.X 
X.X 
X.X 
X.XXXX 
X.X 
X.X-X.X 
List of covariates in section 6.2.2 
 
Table 11.3.4.4 Multivariate analysis of PFS (Investigator assessment and “All 
EvaluablePatients” population) 
Analysis of Maximum Likelihood Estimates 
Variable Label 
Variable 
values 
DF 
Parameter 
Estimate 
Standard 
Error 
Chi-
Square 
Pr > ChiSq 
Hazard 
Ratio 
95% Hazard 
Ratio 
Confidence 
Limits 
 
 
 
X.X 
X.X 
X.X 
X.XXXX 
X.X 
X.X-X.X 
List of covariates in section 6.2.2 
 


40 of 61 
Table 11.3.4.5 Multivariate analysis of PFS (Independent Review assessment and “All 
Treated Patients” population) 
Analysis of Maximum Likelihood Estimates 
Variable Label 
Variable 
values 
DF 
Parameter 
Estimate 
Standard 
Error 
Chi-
Square 
Pr > ChiSq 
Hazard 
Ratio 
95% Hazard 
Ratio 
Confidence 
Limits 
 
 
 
X.X 
X.X 
X.X 
X.XXXX 
X.X 
X.X-X.X 
List of covariates in section 6.2.2 
 
Table 11.3.4.6 Multivariate analysis of PFS (Investigator assessment and “All Treated 
Patients” population) 
Analysis of Maximum Likelihood Estimates 
Variable Label 
Variable 
values 
DF 
Parameter 
Estimate 
Standard 
Error 
Chi-
Square 
Pr > ChiSq 
Hazard 
Ratio 
95% Hazard 
Ratio 
Confidence 
Limits 
 
 
 
X.X 
X.X 
X.X 
X.XXXX 
X.X 
X.X-X.X 
List of covariates in section 6.2.2 
 
Table 11.3.4.7 Multivariate analysis of ORR (Independent Review assessment and “Per 
Protocol Patients” population) 
Analysis of Maximum Likelihood Estimates 
Variable Label 
Variable 
values 
DF 
Parameter 
Estimate 
Standard 
Error 
Chi-
Square 
Pr > ChiSq 
Odds 
Ratio 
95% Odds 
Ratio 
Confidence 
Limits 
 
 
 
X.X 
X.X 
X.X 
X.XXXX 
X.X 
X.X-X.X 
List of covariates in section 6.2.2 
 
Table 11.3.4.8 Multivariate analysis of ORR (Investigator assessment and “Per Protocol 
Patients” population) 
Analysis of Maximum Likelihood Estimates 
Variable Label 
Variable 
values 
DF 
Parameter 
Estimate 
Standard 
Error 
Chi-
Square 
Pr > ChiSq 
Odds 
Ratio 
95% Odds 
Ratio 
Confidence 
Limits 
 
 
 
X.X 
X.X 
X.X 
X.XXXX 
X.X 
X.X-X.X 
List of covariates in section 6.2.2


41 of 61 
Table 11.3.4.9 Multivariate analysis of ORR (Independent Review assessment and “All 
Evaluable Patients” population) 
Analysis of Maximum Likelihood Estimates 
Variable Label 
Variable 
values 
DF 
Parameter 
Estimate 
Standard 
Error 
Chi-
Square 
Pr > ChiSq 
Odds 
Ratio 
95% Odds 
Ratio 
Confidence 
Limits 
 
 
 
X.X 
X.X 
X.X 
X.XXXX 
X.X 
X.X-X.X 
List of covariates in section 6.2.2 
 
Table 11.3.4.10 Multivariate analysis of ORR (Investigator assessment and “All Evaluable 
Patients” population) 
Analysis of Maximum Likelihood Estimates 
Variable Label 
Variable 
values 
DF 
Parameter 
Estimate 
Standard 
Error 
Chi-
Square 
Pr > ChiSq 
Odds 
Ratio 
95% Odds 
Ratio 
Confidence 
Limits 
 
 
 
X.X 
X.X 
X.X 
X.XXXX 
X.X 
X.X-X.X 
List of covariates in section 6.2.2 
 
Table 11.3.4.11 Multivariate analysis of ORR (Independent Review assessment and “All 
Treated Patients” population) 
Analysis of Maximum Likelihood Estimates 
Variable Label 
Variable 
values 
DF 
Parameter 
Estimate 
Standard 
Error 
Chi-
Square 
Pr > ChiSq 
Odds 
Ratio 
95% Odds 
Ratio 
Confidence 
Limits 
 
 
 
X.X 
X.X 
X.X 
X.XXXX 
X.X 
X.X-X.X 
List of covariates in section 6.2.2 
 
Table 11.3.4.12 Multivariate analysis of ORR (Investigator assessment and “All Treated 
Patients” population) 
Analysis of Maximum Likelihood Estimates 
Variable Label 
Variable 
values 
DF 
Parameter 
Estimate 
Standard 
Error 
Chi-
Square 
Pr > ChiSq 
Odds 
Ratio 
95% Odds 
Ratio 
Confidence 
Limits 
 
 
 
X.X 
X.X 
X.X 
X.XXXX 
X.X 
X.X-X.X 
List of covariates in section 6.2.2 
 
Table 11.3.4.13 Multivariate analysis of OS (“Per Protocol Patients” population) 
Analysis of Maximum Likelihood Estimates 
Variable Label 
Variable 
values 
DF 
Parameter 
Estimate 
Standard 
Error 
Chi-
Square 
Pr > ChiSq 
Hazard 
Ratio 
95% Hazard 
Ratio 
Confidence 
Limits 
 
 
 
X.X 
X.X 
X.X 
X.XXXX 
X.X 
X.X-X.X 
List of covariates in section 6.2.2 
 


42 of 61 
Table 11.3.4.14 Multivariate analysis of OS (“All Evaluable Patients” population) 
Analysis of Maximum Likelihood Estimates 
Variable Label 
Variable 
values 
DF 
Parameter 
Estimate 
Standard 
Error 
Chi-
Square 
Pr > ChiSq 
Hazard 
Ratio 
95% Hazard 
Ratio 
Confidence 
Limits 
 
 
 
X.X 
X.X 
X.X 
X.XXXX 
X.X 
X.X-X.X 
List of covariates in section 6.2.2 
 
Table 11.3.4.15 Multivariate analysis of OS (“All Treated Patients” population) 
Analysis of Maximum Likelihood Estimates 
Variable Label 
Variable 
values 
DF 
Parameter 
Estimate 
Standard 
Error 
Chi-
Square 
Pr > ChiSq 
Hazard 
Ratio 
95% Hazard 
Ratio 
Confidence 
Limits 
 
 
 
X.X 
X.X 
X.X 
X.XXXX 
X.X 
X.X-X.X 
List of covariates in section 6.2.2 
 
11.3.5 Best reduction in sum of the product of the diameters lesions 
 
Table 11.3.5.1 Best reduction in sum of product of diameters from baseline 
SPD 
N 
Median 
Mean 
StD 
Min 
Max 
 
X 
X.X 
X.X 
X.X 
X.X 
X.X 
Waterfall plot (Figure 11.3.5.1) will be also shown for all patients with at one disease assessment after treatment.  
 
11.3.6 Characteristics of responders  
A summary of the main characteristics of patients showing clinical benefit, defined as 
patients with PR or better as best response or SD longer than 6 months assessed by 
Independent Review or by Investigators will be shown. 
 
Listing 11.3.6.1 Characteristics of patients with clinical benefit.  
Patient 
id. 
Gender 
PS 
Age 
Ann-
Arbor 
stage 
Bulky 
Lesion 
Relapsed / 
Refractory 
IPI 
PAI 
PIAI 
No. 
of 
prior 
lines 
Cycles 
received 
Best 
response 
Lugano 
(IA) 
Best 
response 
Lugano 
(IR) 
Best 
PET 
SUV 
reduction 
(%) 
PFS 
(IA) 
DR 
(IA) 
PFS 
(IR) 
DR 
(IR) 
OS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IR- Independent review IA- Investigator assessment 
 
 


43 of 61 
12 Safety Analysis 
Safety analysis will be carried out on the “All Treated Patients” population.  
12.1 Extent of exposure 
12.1.1 Treatment administration 
 
Table 12.1.1.1  Number of cycles administered and dose intensity 
No. of cycles administered per patient 
N 
% 
1 
X 
X.X 
2 
 
 
3 
 
 
… 
 
 
Median (range) 
X.X (X-X) 
 Time on treatment (weeks) 
Median  
Range 
 
X.X 
X.X-X.X 
Plitidepsin cumulative dose (mg/m²) 
 
X.X 
X.X-X.X 
Median 
Range 
Plitidepsin dose intensity (mg/m²/wk) 
 
X.X 
X.X-X.X 
Median 
Range 
Plitidepsin relative dose intensity (%)  
 
X.X 
X.X-X.X 
Median 
Range 
 
12.1.2 Cycle delays  
12.1.2.1 Number of patients and cycles with dosing delay, any relationship 
Listing 12.1.2.1.1 Delays 
Patient 
id. 
Cycle 
Day 
Previous 
cycle 
Previous 
cycle start 
date 
Delayed 
cycle 
Delayed 
cycle start 
date 
Dose Delay 
calculated. 
(days) 
Reason 
for dose 
delay 
Dose 
Delay 
Spec. 
 
 
 
 
 
 
 
X 
 
 
 
Table 12.1.2.1.2 Number of patients and cycles with dosing delay, any relationship 
 
N 
% 
No. of patients treated 
X 
X.X 
No. of patients susceptible to have a dosing delay* 
 
 
No. of patients with any dose delay** 
 
 
No. of cycles administered 
 
 
No. of cycles susceptible to be delayed*** 
 
 
No. of cycles with dosing delay**** 
 
 
No. of patients with  
 
 
No cycles delayed 
 
 
1 cycle delayed  
 
 
2 cycles delayed 
 
 
 3 cycles delayed 
 
 
(*) All patients with more than one cycle. (**) Denominator = Number of patients susceptible to have a dosing delay 
(***) All cycles excluding first cycle. (****) Denominator= Number of cycles susceptible to be delayed  
 


44 of 61 
Table 12.1.2.1.3 Number of patients and cycles with dosing delay according to the 
relationship 
 
Treatment-related 
Non-treatment-related 
N 
% 
N 
% 
No. of patients with * 
X 
X.X 
 
 
1 cycle delayed  
 
 
 
 
2 cycles delayed 
 
 
 
 
 3 cycles delayed 
 
 
 
 
No. of cycles with 
dosing delay** 
 
 
 
 
(*) Denominator = Number of patients susceptible to have a dosing delay (**) Denominator= Number of cycles 
susceptible to be delayed.  
 
Table 12.1.2.1.4 Length of dosing delay. 
 
Treatment-related 
Non-treatment-related 
Total 
Length of delay  
Median (range) 
 
 
 
Length of delay 
N 
% 
N 
% 
N 
% 
<= 7 days 
X 
X.X 
 
 
 
 
>7 days and <=14 days 
 
 
 
 
 
 
> 14 days 
 
 
 
 
 
 
(*) Denominator= Number of cycles susceptible to be delayed.  
 
Listing 12.1.2.1.5 Cycle delays due to AEs 
Patient 
id. 
Cycle 
Delay 
reason 
according 
to Exposure 
form 
Preferred  
term code 
Adverse 
event 
reported 
(verbatim) 
Grade 
Relationship 
Onset 
date 
Resolved date 
Significant 
consequences 
 
 
 
  
 
 
 
 
 
AEs with action = ‘Dose delayed’ or ‘Reduced and delayed’. 
 
12.1.3 Dose omissions 
Listing 12.1.3.1 Dose omissions 
Patient id. 
Cycle 
Day 
Cycle start date 
Reason for dose 
omission 
Dose omission 
Spec. 
 
 
 
 
 
 
Table 12.1.3.2 Number of patients and cycles with dose omitted, any relationship 
 
N 
% 
No. of patients treated 
X 
X.X 
No. of patients susceptible to have a dose omission *  
 
 
No. of patients with any dose omitted ** 
 
 
No. of patients with **: 
 
 
No plitidepsin omissions 
 
 
1 cycle with plitidepsin dose omitted  
 
 
2 cycles with plitidepsin dose omitted 
 
 
 3 cycles with plitidepsin dose omitted 
 
 
No. of cycles administered 
 
 
No. of cycles susceptible to have any dose omitted*** 
 
 
No. of cycles with plitidepsin dosing omitted**** 
 
 
No. of cycles with plitidepsin dosing omitted (treatment-related) 
 
 
(*) All patients with more than one infusion. (**) Denominator = Number of patients susceptible to have a dose omission 
(***) All cycles excluding first cycle. (****) Denominator= Number of cycles susceptible to have a dose omission  
NA: Not applicable 


45 of 61 
Table 12.1.3.3 Number of cycles with treatment-related dose omission by patient 
 
N 
% 
No. of patients with: 
X 
X.X 
No omission 
 
 
1 cycle with treatment-related plitidepsin dose omitted 
 
 
2 cycles with treatment-related plitidepsin dose omitted 
 
 
 3 cycles with treatment-related plitidepsin dose omitted 
 
 
Denominator= Number of patients that were on treatment on day 8 of cycle 1. 
NA: Not applicable 
Table 12.1.3.4 Reasons for dose omissions 
Reasons for omissions 
 
N 
% 
Treatment-related 
X 
X.X 
Non–treatment-related 
 
 
NA: Not applicable 
 
Listing  12.1.3.5 Dose omissions due to AEs 
Patient id. Cycle 
Preferred  
term code 
Adverse event 
reported 
(verbatim) 
Grade 
Relationship 
Onset 
date 
Resolved 
date  
Significant 
consequences 
 
 
  
 
 
 
 
 
AEs with action = ‘Dose skipped” on day 8 or 15. 
 
12.1.4 Dose reductions 
All dose reductions should be considered and described, specifying the reason for 
reduction (drug related, non-drug related or other causes).  
Listing 12.1.4.1 Dose reductions 
Patient id. 
Cycle 
Day 
Cycle start date Previous dose Reduced dose 
Reason for 
dose 
reduction 
Dose 
reduction 
Spec. 
 
 
 
 
 
 
 
 
 
Table 12.1.4.2 Number of patients and cycles with dose reduction, any relationship 
 
N 
% 
No. of patients treated 
X 
X.X 
No. of patients susceptible to have a dose reduced* 
 
 
No. of patients with any dose reduced** 
 
 
No. of patients with**: 
 
 
No plitidepsin reduction 
 
 
1 cycle with plitidepsin dose reduced  
 
 
2 cycles with plitidepsin dose reduced 
 
 
No. of cycles administered 
 
 
No. of cycles susceptible to have any dose reduced***  
 
 
No. of cycles with plitidepsin dose reduced **** 
 
 
No. of cycles with plitidepsin dose reduced (Treatment-related) 
 
 
(*) All patients with more than one infusion. (**) Denominator = Number of patients susceptible to have a dose reduced 
(***) All cycles excluding first cycle of those patients who have only received the first infusion. (****) Denominator= 
Number of cycles susceptible to have a dose omission  
NA: Not applicable 
 


46 of 61 
Table 12.1.4.3 Number of patients and cycles with dose reduction according to the 
relationship 
Reasons for reductions 
 
N 
% 
No. of cycles with dose reductions* 
 
Treatment-related 
X 
X.X 
Non-treatment-related 
 
 
 (*) Denominator= Number of cycles susceptible to have a dose omission 
NA: Not applicable 
 
Listing  12.1.4.4 Dose reductions due to AEs 
Patient id. Cycle 
Preferred  
term code 
Adverse event 
reported 
(verbatim) 
Grade 
Relationship 
Onset 
date 
Resolved 
date  
Significant 
consequences 
 
 
  
 
 
 
 
 
AEs with action = ‘Dose reduced/adjusted’ or ‘Reduced and delayed’. 
 
12.1.5 Infusions temporarily interrupted  
A listing of the patients who had infusions temporarily interrupted with the corresponding 
reasons will be provided. 
Listing  12.1.5.1 Interrupted Infusions listing. 
Patient id. 
Cycle 
Infusion 
Interrupted 
Reason 
 
 
 
Yes 
 
 
12.1.6 Prophylactic medication administration  
A listing of the patients who have not received Ondansetron, Diphenhydramine and 
Ranitidine or equivalents with the corresponding reasons will be reported. 
Listing  12.1.6.1 Patients and cycles without prophylactic medication administration 
Patient id. 
Cycle 
Infusion 
Prophylactic medication 
not taken* 
Reason 
… 
 
 
 
 
(*) Ondansetron, diphenhydramine or ranitidine. 


47 of 61 
12.2 Adverse Events (AEs) 
12.2.1 Display of adverse events 
 
Table 12.2.1.1 Summary of adverse events. 
 
N (%) 
Patients with at least one AE regardless relationship 
X (X.X) 
Any treatment-related AE 
 
Any grade 3/4 AE 
 
Any grade 3/4 treatment-related AE 
 
Any SAE in DB 
 
Any treatment-related SAE  
 
Any grade 3/4 SAE  
 
Any grade 3/4 treatment-related SAE  
 
AEs leading to death 
 
AEs treatment-related leading to death 
 
AEs leading to dose delay 
 
AEs leading to dose reduction 
 
AEs leading to treatment discontinuation 
 
AEs treatment-related leading to treatment discontinuation 
 
Table 12.2.1.2 Evolution of lymphoma-related AEs at baseline 
 
 
Worst grade per patient 
Total 
0 
1 
… 
N 
% 
N 
% 
N 
% 
N 
% 
Baseline 
Fatigue  
Grade 0 
X 
X.X 
X 
X.X 
X 
X.X 
X 
X.X 
Grade 1 
 
 
 
 
 
 
 
 
…… 
 
 
 
 
 
 
 
 
Bone Pain 
Grade 0 
 
 
 
 
 
 
 
 
Grade 1 
 
 
 
 
 
 
 
 
…… 
 
 
 
 
 
 
 
 
Myopathy 
Grade 0 
 
 
 
 
 
 
 
 
Grade 1 
 
 
 
 
 
 
 
 
…… 
 
 
 
 
 
 
 
 
……………………. 
 
Table 12.2.1.3 Treatment-related* adverse events. Worst grade by patient 
 
 
Grade  
1 
… 
Grade  
4 
All** 
SOC 
Preferred Term 
N 
% 
… 
N 
% 
N 
% 
Blood and lymphatic 
system disorders 
Anemia NOS 
X 
X.X 
 
X 
X.X 
X 
X.X 
… 
 
 
 
 
 
 
 
Cardiac disorders 
Arrhythmia NOS 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
(*) or Uknown relationship (**) Any grade  
 


48 of 61 
Table 12.2.1.4 Treatment-related* adverse events. Worst grade by cycle 
 
 
Grade  
1 
… 
Grade  
4 
All** 
SOC 
Preferred Term 
N 
% 
… 
N 
% 
N 
% 
Blood and lymphatic 
system disorders 
Anemia NOS 
X 
X.X 
 
X 
X.X 
X 
X.X 
… 
 
 
 
 
 
 
 
Cardiac disorders 
Arrhythmia NOS 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
(*) or Uknown relationship (**) Any grade  
 
Table 12.2.1.5 Adverse Events regardless of relationship. Worst grade by patient 
 
 
Grade  
1 
… 
Grade  
4 
All* 
SOC 
Preferred Term 
N 
% 
… 
N 
% 
N 
% 
Blood and lymphatic 
system disorders 
Anemia NOS 
X 
X.X 
 
X 
X.X 
X 
X.X 
… 
 
 
 
 
 
 
 
Cardiac disorders 
Arrhythmia NOS 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
(*) Any grade 
 
Table 12.2.1.6 Adverse Events regardless of relationship. Worst grade by cycle 
 
 
Grade  
1 
… 
Grade  
4 
All* 
SOC 
Preferred Term 
N 
% 
… 
N 
% 
N 
% 
Blood and lymphatic 
system disorders 
Anemia NOS 
X 
X.X 
 
X 
X.X 
X 
X.X 
… 
 
 
 
 
 
 
 
Cardiac disorders 
Arrhythmia NOS 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
(*) Any grade 
 
Listing 12.2.1.7 Treatment-related* grade 3-4 adverse events. Worst grade by patient 
Patient id. 
SOC Name 
Preferred term 
Grade 
 
 
 
 
(*) or Uknown relationship  
 
Listing 12.2.1.8 Treatment-related* grade 3-4 adverse events. Worst grade by cycle 
Patient id. 
Cycle 
SOC Name 
Preferred term 
Grade 
 
 
 
 
 
(*) or Uknown relationship  
 
Listing 12.2.1.9 Adverse Events grade 3-4 regardless of relationship. Worst grade by 
patient 
Patient id. 
SOC Name 
Preferred term 
Grade 
 
 
 
 
 
Listing 12.2.1.10 Adverse Events grade 3-4 regardless of relationship. Worst grade by cycle 
Patient id. 
Cycle 
SOC Name 
Preferred term 
Grade 
 
 
 
 
 
 
At the time of the analysis, if appropriate, grouping of similar or clinically related items 
will be made. 


49 of 61 
12.3 Serious Adverse Events and deaths.  
12.3.1 Serious Adverse Events 
Table 12.3.1.1 Treatment-related* SAEs. Worst grade by patient 
 
 
Grade  
1 
… 
Grade  
4 
All** 
SOC 
Preferred Term 
N 
% 
… 
N 
% 
N 
% 
Blood and lymphatic 
system disorders 
Anemia NOS 
X 
X.X 
 
X 
X.X 
X 
X.X 
… 
 
 
 
 
 
 
 
Cardiac disorders 
Arrhythmia NOS 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
(*) or Uknown relationship (**) Any grade  
 
Table 12.3.1.2 Treatment-related* SAEs. Worst grade by cycle 
 
 
Grade  
1 
… 
Grade  
4 
All** 
SOC 
Preferred Term 
N 
% 
… 
N 
% 
N 
% 
Blood and lymphatic 
system disorders 
Anemia NOS 
X 
X.X 
 
X 
X.X 
X 
X.X 
… 
 
 
 
 
 
 
 
Cardiac disorders 
Arrhythmia NOS 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
(*) or Uknown relationship (**) Any grade  
 
Table 12.3.1.3 SAEs regardless of relationship. Worst grade by patient 
 
 
Grade  
1 
… 
Grade  
4 
All* 
SOC 
Preferred Term 
N 
% 
… 
N 
% 
N 
% 
Blood and lymphatic 
system disorders 
Anemia NOS 
X 
X.X 
 
X 
X.X 
X 
X.X 
… 
 
 
 
 
 
 
 
Cardiac disorders 
Arrhythmia NOS 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
(*) Any grade 
 
Table 12.3.1.4 SAEs regardless of relationship. Worst grade by cycle 
 
 
Grade  
1 
… 
Grade  
4 
All* 
SOC 
Preferred Term 
N 
% 
… 
N 
% 
N 
% 
Blood and lymphatic 
system disorders 
Anemia NOS 
X 
X.X 
 
X 
X.X 
X 
X.X 
… 
 
 
 
 
 
 
 
Cardiac disorders 
Arrhythmia NOS 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
(*) Any grade 
 
Listing 12.3.1.5 SAEs 
Patient 
id. 
Cycle Preferred  
term code 
Adverse 
event 
reported 
(verbatim) 
Status Grade 
Relationship 
Onset 
date 
Resolved 
date 
Action Serious Criteria 
 
 
  
 
 
 
 
 
 
 
 
SAEs narratives will be provided by the pharmacovigilance department. 


50 of 61 
12.3.2 Deaths 
 
Table 12.3.2.1 Cause of death 
Reason* 
N 
% 
Malignant disease 
X 
X.X 
Treatment-related adverse event  
 
 
Other  
 
 
Total 
 
 
(*) Denominator=Number of patients who died 
 
Listing 12.3.2.2 Deaths 
Patient 
id. 
Death 
date 
Cause Comments 
Autopsy 
Autopsy report 
available 
Number of 
cycles 
administered  
Last 
infusion 
date  
Time on 
treatment* 
Time from 
Last dose** 
 
 
 
 
 
 
 
 
 
 
(*)Time on treatment: defined as last infusion date plus 30 days, or date of death or subsequent therapy (whichever comes 
first) minus first infusion date.  (**)Time from last dose defined as death date minus last infusion date.  
 
Listing 12.3.2.3 Deaths due to AEs 
Patient id. Cycle Preferred  term 
code 
Adverse event 
reported 
(verbatim) 
Grade 
Relationship 
Onset 
date  
Resolved date 
Action 
 
 
  
 
 
 
 
 
 
12.4 Clinical laboratory evaluation 
12.4.1 Hematological abnormalities 
Hematological toxicities classified according to the NCI-CTCAE will be calculated for all 
cycles. The worst grade reached by each patient during treatment will be also calculated. 
If serious toxicities happen, special follow-up, with descriptives and graphs (boxplots, line 
plots) will be made to find out the pattern of thrombocytopenia and neutropenia within and 
between the different cycles. 
Table 12.4.1.1 Hematological abnormalities during treatment, worst grade per patient 
 
N 
Grade  
1 
… 
Grade  
4 
All* 
 
N 
N 
% 
… 
N 
% 
N 
% 
Leukopenia 
X 
X 
X.X 
 
X 
X.X 
X 
X.X 
Anemia 
 
 
 
 
 
 
 
 
Thrombocytopenia 
 
 
 
 
 
 
 
 
Neutropenia 
 
 
 
 
 
 
 
 
Lymphopenia 
 
 
 
 
 
 
 
 
(*) Any grade 
 


51 of 61 
Table 12.4.1.2 Hematological abnormalities during treatment, worst grade per cycle 
 
N 
Grade  
1 
… 
Grade  
4 
All* 
 
N 
N 
% 
… 
N 
% 
N 
% 
Leukopenia 
X 
X 
X.X 
 
X 
X.X 
X 
X.X 
Anemia 
 
 
 
 
 
 
 
 
Thrombocytopenia 
 
 
 
 
 
 
 
 
Neutropenia 
 
 
 
 
 
 
 
 
Lymphopenia 
 
 
 
 
 
 
 
 
(*) Any grade 
 
Listing 12.4.1.3 Grade 3-4 hematological abnormalities during treatment. Worst grade per 
patient 
Patient id. 
Test 
Grade 
 
 
 
 
Listing 12.4.1.4 Grade 3-4 hematological abnormalities during treatment. Worst grade per 
cycle 
Patient id. 
Test 
Grade 
 
 
 
Listing 12.4.1.5 Hematological tests not assessed at any treatment visit per patient 
Patient id. 
Lab. test 
 
 
Listing 12.4.1.6 Hematological tests not assessed by patient and cycle 
Patient id. 
Cycle 
Lab. test 
 
 
 
Table 12.4.1.7 Platelets and RBC transfusions during the study 
 
Platelets (Units) 
Red Blood Cells (Units) 
 
 
 
 
 
 
N 
(%) 
N 
(%) 
Platelets (Units) 
0 transfusions 
X 
X.X 
X 
X.X 
1 transfusion 
 
 
 
 
… 
 
 
 
 
Median (range) 
 
 
 
 
Red Blood Cells (Units) 
 
0 transfusions 
 
 
 
 
1 transfusion 
 
 
 
 
… 
 
 
 
 
Median (range) 
 
 
 
 
 
These tables will be complemented with plots for the median nadir of neutrophils (Figure 
12.4.1.8), platelets count (Figure 12.4.1.9) and hemoglobin values (Figure 12.4.1.10) by 
cycle along the treatment. Furthermore, if appropriate, graphs of the intercycle time course 
of neutropenia and thrombocytopenia will be provided. Eventually, graphs comparing the 
time course during the first and second cycle will be created.  
 


52 of 61 
12.4.2 Biochemical abnormalities 
Grades of liver toxicity and intercycle pattern of creatinine, CPK, bilirubin, transaminases 
increase and alkaline phosphatase increase during a cycle will be calculated, as it is 
explained in the corresponding section for hematological toxicities. 
 
Table 12.4.2.1 Biochemical abnormalities during treatment, worst grade per patient 
 
N 
Grade  
1 
… 
Grade  
4 
All* 
 
N 
N 
% 
… 
N 
% 
N 
% 
AST increase 
X 
X 
X.X 
 
X 
X.X 
X 
X.X 
ALT increase 
 
 
 
 
 
 
 
 
Total bilirubin increase 
 
 
 
 
 
 
 
 
ALP increase 
 
 
 
 
 
 
 
 
Creatinine increase 
 
 
 
 
 
 
 
 
CPK increase 
 
 
 
 
 
 
 
 
(*) Any grade 
 
Table 12.4.2.2 Biochemical abnormalities during treatment, worst grade per cycle 
 
N 
Grade  
1 
… 
Grade  
4 
All* 
 
N 
N 
% 
… 
N 
% 
N 
% 
AST increase 
X 
X 
X.X 
 
X 
X.X 
X 
X.X 
ALT increase 
 
 
 
 
 
 
 
 
Total bilirubin increase 
 
 
 
 
 
 
 
 
ALP increase 
 
 
 
 
 
 
 
 
Creatinine increase 
 
 
 
 
 
 
 
 
CPK increase 
 
 
 
 
 
 
 
 
(*) Any grade 
 
Listing 12.4.2.3 Grade 3-4 biochemical abnormalities during treatment. Worst grade per 
patient 
Patient id. 
Test 
Grade 
 
 
 
 
Listing 12.4.2.4 Grade 3-4 biochemical abnormalities during treatment. Worst grade per 
cycle 
Patient id. 
Cycle 
Test 
Grade 
 
 
 
 
Listing 12.4.2.5 Biochemical tests not assessed at any treatment visit by patient 
Patient id. 
Lab. test 
 
 
Listing 12.4.2.6 Biochemical tests not assessed by patient and cycle 
Patient id. 
Cycle 
Lab. test 
 
 
 
 
These tables will be complemented with plots for the median peak of ALT (Figure 12.4.2.7
), AST (Figure 12.4.2.8) and CPK values (Figure 12.4.2.9) by cycle along the treatment. If 
appropriate, graphs of the intercycle time course of ALT, AST and CPK will be provided.  
 


53 of 61 
12.4.3 Other metabolic parameters 
 
Table 12.4.3.1 Metabolic abnormalities during treatment, worst grade per patient 
 
N 
Grade  
1 
… 
Grade  
4 
All* 
 
N 
N 
% 
… 
N 
% 
N 
% 
Hyperglycemia 
X 
X 
X.X 
 
X 
X.X 
X 
X.X 
Hypoglycemia 
 
 
 
 
 
 
 
 
Hypoalbuminemia 
 
 
 
 
 
 
 
 
…. 
 
 
 
 
 
 
 
 
(*) Any grade 
 
Table 12.4.3.2 Metabolic abnormalities during treatment, worst grade per cycle 
 
N 
Grade  
1 
… 
Grade  
4 
All* 
 
N 
N 
% 
… 
N 
% 
N 
% 
Hyperglycemia 
X 
X 
X.X 
 
X 
X.X 
X 
X.X 
Hypoglycemia 
 
 
 
 
 
 
 
 
Hypoalbuminemia 
 
 
 
 
 
 
 
 
…. 
 
 
 
 
 
 
 
 
(*) Any grade 
 
Listing 12.4.3.3 Grade 3-4 metabolic abnormalities during treatment. Worst grade by 
patient 
Patient id. 
Test 
Grade 
 
 
 
 
Listing 12.4.3.4 Grade 3-4 metabolic abnormalities during treatment. Worst grade by cycle 
Patient id. 
Cycle 
Test 
Grade 
 
 
 
 
Listing 12.4.3.5 Metabolic tests not assessed at any treatment visit by patient 
Patient id. 
Lab. test 
 
 
Listing 12.4.3.6 Metabolic tests not assessed by patient and cycle 
Patient id. 
Cycle 
Lab. test 
 
 
 
 


54 of 61 
12.4.4 Laboratory values over time 
In this section, grades 3-4 hematological and liver enzyme abnormalities will be displayed 
according to the cycle in which they occurred. 
Table 12.4.4.1 Evolution of hematological abnormalities from baseline, worst case per 
patient. 
 
 
Worst grade per patient 
Total 
0 
1 
… 
 
 
 
 
 
 
 
 
Baseline 
Neutropenia  
Grade 0 
 
 
 
 
 
 
 
 
Grade 1 
 
 
 
 
 
 
 
 
…… 
 
 
 
 
 
 
 
 
Thrombocytopenia 
Grade 0 
 
 
 
 
 
 
 
 
Grade 1 
 
 
 
 
 
 
 
 
…… 
 
 
 
 
 
 
 
 
…. 
Grade 0 
 
 
 
 
 
 
 
 
Grade 1 
 
 
 
 
 
 
 
 
…… 
 
 
 
 
 
 
 
 
Table 12.4.4.2 Evolution of transaminases abnormalities from BL, worst case per patient. 
 
 
Worst grade per patient 
Total 
0 
1 
… 
N 
% 
N 
% 
N 
% 
N 
% 
Baseline 
AST increase 
X 
X.X 
X 
X.X 
 
 
X 
X.X 
 
Grade 1 
 
 
 
 
 
 
 
 
…… 
 
 
 
 
 
 
 
 
ALT increase 
Grade 0 
 
 
 
 
 
 
 
 
Grade 1 
 
 
 
 
 
 
 
 
…… 
 
 
 
 
 
 
 
 
…. 
Grade 0 
 
 
 
 
 
 
 
 
Grade 1 
 
 
 
 
 
 
 
 
…… 
 
 
 
 
 
 
 
 
 
Table 12.4.4.3 Grade 3-4 laboratory abnormalities in the first cycle and in all other cycles 
Laboratory  
abnormalities 
 
Cycle 1 
Cycle>1 
No. of cycles 
evaluated 
No. of cycles 
grade 3-4 
% 
No. of cycles 
evaluated 
No. of 
cycles 
grade 3-4 
% 
Thrombocytopenia  
X 
X 
X.X 
X 
X 
X.X 
Neutropenia  
 
 
 
 
 
 
ALP  
 
 
 
 
 
 
Total bilirubin  
 
 
 
 
 
 
AST  
 
 
 
 
 
 
ALT  
 
 
 
 
 
 
CPK 
 
 
 
 
 
 
 


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Table 12.4.4.4 Hemtological time-course pattern 
Laboratory abnormalities 
Onset 
day  
grade 3-
4 
Days in 
grade 3-
4 
Day of recovery to grade 2 
Days to recovery 
<=28 
29-35 
>35 
<=28 
29-35 
>35 
Anemia 
X (X-X) X (X-X) X (X.X%) 
X (X.X%) X (X.X%) X (X.X%) X (X.X%) X (X.X%) 
Neutropenia 
 
 
 
 
 
 
 
 
Thrombocytopenia 
 
 
 
 
 
 
 
 
 
 
Table 12.4.4.5 ALT/AST/CPK time-course pattern 
Laboratory abnormalities 
Onset 
day  
grade 3-
4 
Days in 
grade 3-
4 
Day of recovery to 2.5 x ULN 
Days to recovery 
<=28 
29-35 
>35 
<=28 
29-35 
>35 
ALT 
X (X-X) X (X-X) X (X.X%) 
X (X.X%) X (X.X%) X (X.X%) X (X.X%) X (X.X%) 
AST 
 
 
 
 
 
 
 
 
CPK 
 
 
 
 
 
 
 
 
 
12.5 Vital signs, physical findings, LVEF, ECG and other tests related to safety 
12.5.1 Vital signs and physical findings 
 
Table 12.5.1.1 ECOG performance status during the study 
(*) Worst ECOG PS of the cycle determinations. 
 
Table 12.5.1.2 Weight by patient per cycle 
(*) % of changes respect to baseline 
 
12.5.2 LVEF, ECG and other related tests 
Listing 12.5.2.1 Electrocardiogram results. Evolution during the study. 
Patient id. 
Cycle 
ECG result 
 
 
 
  
Cycle/PS* 
  
0 
1 
2 
3 
.. 
.. 
.. 
Patient id. 
  
… 
 
 
 
 
. 
. 
. 
… 
 
 
 
 
. 
. 
. 
  
Cycle/Weight 
  
0 
(kg) 
1* 
(%) 
2* 
(%) 
3* 
(%) 
.. 
.. 
.. 
Patient id. 
  
… 
X.X 
X.X 
X.X 
X.X 
. 
. 
. 
 
 
 
 
 
 
 
 


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Listing 12.5.2.2 LVEF evolution during the study. 
Patient id. 
LVEF(%) 
Baseline* 
Minimun*  
End of treatment* 
 
X.X 
X.X 
X.X 
Median(Range) 
X.X (X.X-X.X) 
X.X (X.X-X.X) 
X.X (X.X-X.X) 
(*) LVEF (%) value and method 
Listing 12.5.2.3 Median change in LVEF. 
Cycles 
LVEF 
Baseline 
X.X (X.X-X.X) 
Minimun 
X.X (X.X-X.X) 
End of treatment 
X.X (X.X-X.X) 
 
12.6 Concomitant therapy / procedures according to the ATC classification. 
Table 12.6.1 Concomitant medication during treatment (ATC levels) 
Medication Term 
(ATC level 1 ) 
Medication Term 
(ATC level 2) 
Medication Term 
(ATC level 4) 
Preferred Name 
 
N 
% 
 
 
 
 
X 
X.X 
 
Listing  12.6.2 Patients with EPO or G-CSF. 
Patient id. 
Type 
Route 
Dose 
Unit 
Start date 
Stop 
date 
Reason 
Indication 
 
 
 
 
 
 
 
 
 
Listing  12.6.3 Patients with any transfusion during treatment 
Patient 
Cycle 
Date 
Blodd product 
Specify 
Total units 
Irradiated 
 
 
 
 
 
 
 
Taken from concomitant therapy dataset. 
Table 12.6.4 G-CSF, transfusions or EPO during treatment 
 
N 
% 
G-CSF 
X 
X.X 
Platelets transfusions 
 
 
Packed red cells transfusions 
 
 
Plasma transfusions 
 
 
Cryoprecipitates 
 
 
Clotting factors 
 
 
EPO 
 
 
Table 12.6.5 Subsequent therapy 
 
N 
% 
Type 
X 
X.X 
  Chemotherapy 
 
 
   … 
 
 
Subsequent chemotherapy agents (ATC) 
 
 
  … 
 
 
   … 
 
 
 


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Table 12.6.6 Time to subsequent therapy or death 
  
Arm A 
Arm B  
Parameter 
p-value 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Time to subsequent therapy or 
death 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
Kaplan-Meier plot will be also shown (Figure 12.6.7)  
 
12.7 Safety analysis in special subgroups. 
Table 12.7.1 Worst grade 3-4 by patient in special subgroups (Gender) 
 
Male 
Female 
N 
Grade 3-4 
% 
N 
Grade 3-4 
% 
Thrombocytopenia  
X 
X 
X.X 
X 
X 
X.X 
Neutropenia  
 
 
 
 
 
 
ALP  
 
 
 
 
 
 
Total bilirubin  
 
 
 
 
 
 
AST  
 
 
 
 
 
 
ALT  
 
 
 
 
 
 
CPK 
 
 
 
 
 
 
Nausea 
 
 
 
 
 
 
Vomiting 
 
 
 
 
 
 
Fatigue 
 
 
 
 
 
 
Other* 
 
 
 
 
 
 
(*)Any treatment-related toxicity present in >=5% of patients in any group 
 
Table 12.7.2 Worst grade 3-4 by patient in special subgroups (Race) 
 
White 
Other 
N 
Grade 3-4 
% 
N 
Grade 3-4 
% 
Thrombocytopenia  
X 
X 
X.X 
X 
X 
X.X 
Neutropenia  
 
 
 
 
 
 
ALP  
 
 
 
 
 
 
Total bilirubin  
 
 
 
 
 
 
AST  
 
 
 
 
 
 
ALT  
 
 
 
 
 
 
CPK 
 
 
 
 
 
 
Nausea 
 
 
 
 
 
 
Vomiting 
 
 
 
 
 
 
Fatigue 
 
 
 
 
 
 
Other* 
 
 
 
 
 
 
(*)Any treatment-related toxicity present in >=5% of patients in any group 
 


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Table 12.7.3 Worst grade 3-4 by patient in special subgroups (Age) 
 
<65 years old 
≥65 years old 
N 
Grade 3-4 
% 
N 
Grade 3-4 
% 
Thrombocytopenia  
X 
X 
X.X 
X 
X 
X.X 
Neutropenia  
 
 
 
 
 
 
ALP  
 
 
 
 
 
 
Total bilirubin  
 
 
 
 
 
 
AST  
 
 
 
 
 
 
ALT  
 
 
 
 
 
 
CPK 
 
 
 
 
 
 
Nausea 
 
 
 
 
 
 
Vomiting 
 
 
 
 
 
 
Fatigue 
 
 
 
 
 
 
Other* 
 
 
 
 
 
 
(*)Any treatment-related toxicity present in >=5% of patients in any group 
 
Table 12.7.4 Worst grade 3-4 by patient in special subgroups (BMI) 
 
<30 
≥30 
N 
Grade 3-4 
% 
N 
Grade 3-4 
% 
Thrombocytopenia  
X 
X 
X.X 
X 
X 
X.X 
Neutropenia  
 
 
 
 
 
 
ALP 
 
 
 
 
 
 
Total bilirubin  
 
 
 
 
 
 
AST  
 
 
 
 
 
 
ALT  
 
 
 
 
 
 
CPK 
 
 
 
 
 
 
Nausea 
 
 
 
 
 
 
Vomiting 
 
 
 
 
 
 
Fatigue 
 
 
 
 
 
 
Other* 
 
 
 
 
 
 
(*)Any treatment-related toxicity present in >=5% of patients in any group 
 


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APPENDIX II 
13 DB Listings 
 
CRF Listings. 
 
-Listing 13.1.1: Screening 
-Listing 13.1.2: Demography 
-Listing 13.1.3: Contraception and pregnancy test 
-Listing 13.1.4: Medical history 
-Listing 13.1.5: Lymphoma history 
-Listing 13.1.6: Prior radiotherapy 
-Listing 13.1.7: Prior surgery 
-Listing 13.1.8: Prior anticancer therapy 
-Listing 13.1.9: Prophylactic medication 
-Listing 13.1.10: Drug administration 
-Listing 13.1.11: Hematology laboratory values 
-Listing 13.1.12: Coagulation laboratory values 
-Listing 13.1.13: Biochemical laboratory values 
-Listing 13.1.14: Other metabolic laboratory values 
-Listing 13.1.15: Urinary dipstick 
-Listing 13.1.16: Viral serology 
-Listing 13.1.17: Coombs Test 
-Listing 13.1.18: Protein measurements 
-Listing 13.1.19: Physical examination 
-Listing 13.1.20: Performance status 
-Listing 13.1.21: Neurological examination 
-Listing 13.1.22: Vital signs 
-Listing 13.1.23: Electrocardiogram 
-Listing 13.1.24: LVEF 
-Listing 13.1.25: Bone marrow assessment 
-Listing 13.1.26: Blood product use 
-Listing 13.1.27: Adverse events (including signs and symptoms) 
-Listing 13.1.28: Concomitant medications 
-Listing 13.1.29: Concomitant procedures 
-Listing 13.1.30: Other tests/procedures 
-Listing 13.1.31: Tumor evaluation 
-Listing 13.1.32: Overall response assessment by cycle 
-Listing 13.1.33: Best overall response 
-Listing 13.1.34: End of treatment 
-Listing 13.1.35: Follow up 
-Listing 13.1.36: Medical treatment (after end of treatment) 
-Listing 13.1.37: Surgery procedures (after end of treatment) 
-Listing 13.1.38: Radiotherapy (after end of treatment) 
-Listing 13.1.39: Death report form 
-Listing 13.1.40: Off study 


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APPENDIX II 
14 Section 16.2  ICH Listings 
 
-ICH Listing 16.2.1: Discontinued patients 
-ICH Listing 16.2.2: Protocol deviations 
-ICH Listing 16.2.3: Patients excluded from the efficacy analysis 
-ICH Listing 16.2.4: Demographic data 
-ICH Listing 16.2.5: Compliance and-or Drug Concentration Data 
-ICH Listing 16.2.6: Individual Efficacy Response data 
-ICH Listing 16.2.7: Adverse Events 
-ICH Listing 16.2.8: Individual laboratory measurements 
 


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15 References 
 
1. SAS OnlineDoc, V9.  
2. Parmar M. Machin D. Survival analysis. A practical approach. Wiley, Chichester, 
1995.