A Phase 1/2 Study to Investigate the Safety, Pharmacokinetics and Efficacy of EDO-S101, a First-in-Class Alkylating Histone Deacetylase Inhibition (HDACi) Fusion Molecule, in Patients With Advanced Solid Tumors. Sub-study to Characterize the Effects of Tinostamustine at a Dose of 60mg/m2 Administered During a 60 Minutes Infusion on Cardiac Repolarization, in Patients With Advanced Solid Tumors. Sub-study to Characterize the Effects of Tinostamustine at a Dose of 80mg/m2 Administered During a 80 Minutes Infusion on Cardiac Repolarization, in Patients With Advanced Solid Tumors.
Phase: PHASE1
Conditions: Small Cell Lung Cancer, Soft Tissue Sarcoma, Triple-negative Breast Cancer, Ovarian Cancer, Endometrial Cancer
Sponsor: Mundipharma Research Limited

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Protocol Number: EDO-S101-1002 sub study v6.7 
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A Phase 1/2 Study to Investigate the Safety, Pharmacokinetics and Efficacy of Tinostamustine, a 
First-in-Class Alkylating Histone Deacetylase Inhibition (HDACi) Fusion Molecule, in Patients 
with Advanced Solid Tumors  
 
Sub-study to Characterize the Effects of Tinostamustine at a Dose of 80 mg/m2 Administered 
during a 80-minute Infusion on Cardiac Repolarization in Patients with Advanced Solid  
Tumors 
 
NCT number 
NCT03345485 
 
 
 
 
 
CONFIDENTIALITY STATEMENT 
The information contained herein is the proprietary property of Mundipharma Research Limited and any 
unauthorized disclosure of such information without prior written authorization by Mundipharma 
Research Limited is expressly prohibited. 
 
 

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PROTOCOL SIGNATURE PAGE  
A Phase 1/2 Study to Investigate the Safety, Pharmacokinetics and Efficacy of Tinostamustine, a 
First-in-Class Alkylating Histone Deacetylase Inhibition (HDACi) Fusion Molecule, in Patients 
with Advanced Solid Tumors  
 
Sub-study to Characterize the Effects of Tinostamustine at a Dose of 80mg/m2 Administered 
during a 80-minute Infusion on Cardiac Repolarization in Patients with Advanced Solid  
Tumors 
 
 
By signing below, the Investigator agrees to adhere to the protocol as written and agrees that any 
changes to the protocol will be agreed to and approved by Mundipharma Research Limited. Prior to 
instituting those changes, the Investigator will obtain approval from the Institutional Review Board (IRB) 
or Independent Ethics Committee (IEC). 
This trial will be conducted in accordance with the current International Council for Harmonization (ICH) 
guidance, the Good Clinical Practice (GCP) guidance, the Declaration of Helsinki, the United States (US) 
Food and Drug Administration (FDA) regulations and local IRB and legal requirements. 
Investigator Signature 
________________________________ 
Date: _____________ 
 
Name of Investigator (print) ________________________________ 
  
 

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TABLE OF CONTENTS 
TABLE OF CONTENTS......................................................................................................................... 3 
TABLE OF TABLES .............................................................................................................................. 6 
ABBREVIATIONS AND DEFINITIONS OF TERMS ............................................................................. 7 
1 
PROTOCOL SYNOPSIS ........................................................................................................... 11 
2 
SCHEDULE OF ASSESSMENTS ............................................................................................. 18 
3 
INTRODUCTION ........................................................................................................................ 22 
3.1 
Background ........................................................................................................................ 23 
3.2 
Clinical Data ....................................................................................................................... 23 
3.3 
Sub-study Rationale .......................................................................................................... 25 
4 
SUB-STUDY OBJECTIVES ...................................................................................................... 26 
4.1 
Primary Objectives............................................................................................................. 26 
4.2 
Secondary Objectives ........................................................................................................ 26 
4.3 
Exploratory Objective ........................................................................................................ 26 
5 
TRIAL DESIGN .......................................................................................................................... 27 
5.1 
Overall Sub-Study Design ................................................................................................. 27 
6 
SELECTION AND WITHDRAWAL OF PATIENTS .................................................................. 29 
6.1 
Inclusion Criteria for sub-study .......................................................................................... 29 
6.2 
Exclusion Criteria for sub-study ......................................................................................... 30 
6.3 
Trial Termination ................................................................................................................ 31 
6.3.1 
Withdrawal of Patient from Trial Treatment ..................................................... 31 
7 
TRIAL ASSESSMENTS............................................................................................................. 32 
7.1 
Screening ........................................................................................................................... 32 
7.2 
Informed Consent .............................................................................................................. 32 
7.3 
Inclusion/Exclusion Criteria ............................................................................................... 32 
7.4 
Demographics and Medical History ................................................................................... 32 
7.5 
Physical Examination ........................................................................................................ 32 
7.6 
Vital Signs, Height and Weight .......................................................................................... 33 
7.7 
ECOG Performance Status ............................................................................................... 33 
7.8 
12-Lead ECG (Safety and Holter) ..................................................................................... 33 
7.9 
Pharmacodynamics (Gene Expression) ............................................................................ 34 
7.10 
Clinical Laboratory Tests (Hematology, Chemistry and Urinalysis) .................................. 34 
7.11 
Pregnancy Testing and Contraception .............................................................................. 35 
7.12 
Adverse Events (AEs) ....................................................................................................... 36 
7.13 
Infusion Site and Allergic Reaction Assessment ............................................................... 36 

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7.14 
Prohibited Concomitant Medications and Procedures ...................................................... 36 
7.14.1 
Steroids ........................................................................................................... 36 
7.14.2 
Valproic Acid.................................................................................................... 36 
7.14.3 
Allopurinol ........................................................................................................ 36 
7.14.4 
Serotonin 5-HT3 receptor antagonists ............................................................ 37 
7.14.5 
NK1 receptor antagonists ................................................................................ 37 
7.14.6 
Investigational agents ...................................................................................... 37 
7.15 
Efficacy Evaluations .......................................................................................................... 37 
7.15.1 
Baseline Disease Assessment ........................................................................ 37 
7.15.2 
Disease Response Assessments .................................................................... 37 
7.15.3 
Follow-up Assessments .................................................................................. 37 
7.16 
PK Assessments................................................................................................................ 38 
7.17 
Missed Visits ...................................................................................................................... 38 
8 
TRIAL TREATMENT .................................................................................................................. 39 
8.1 
Investigational Drug Description ........................................................................................ 39 
8.2 
Storage and Dispensing .................................................................................................... 39 
8.3 
Supply, Packaging and Labeling ....................................................................................... 39 
8.4 
Treatment Allocation .......................................................................................................... 39 
8.5 
Investigational Product Administration .............................................................................. 40 
8.6 
Treatment Criteria Beyond Cycle 1, Day 1 ........................................................................ 40 
8.7 
Dose Modification Guidelines and Stopping Rules for Patients who Experience 
Clinically Significant QTcF Prolongations .......................................................................... 40 
8.8 
Investigational Product Accountability ............................................................................... 41 
8.9 
Supportive Care ................................................................................................................. 42 
8.10 
Drug Interactions/Precautions ........................................................................................... 42 
8.11 
Overdose ........................................................................................................................... 43 
9 
AES AND SAES ........................................................................................................................ 44 
9.1 
Definition of an Adverse Event (AE) .................................................................................. 44 
9.2 
Recording Adverse Events ................................................................................................ 45 
9.3 
Serious Adverse Events .................................................................................................... 47 
9.4 
Events of Special Interest .................................................................................................. 48 
9.5 
Suspected Unexpected Serious Adverse Reactions (SUSARs) ....................................... 48 
9.6 
Reporting of AEs, SAEs, Serious and Unexpected Adverse Experiences ....................... 49 
9.6.1 
Reporting AEs and SAEs to the Sponsor ........................................................ 49 
9.6.2 
Reporting Suspected Unexpected Serious Adverse Reactions ...................... 49 
9.6.3 
Reporting of Grade 4 and Grade 5 AEs .......................................................... 49 
9.6.4 
Reporting Pregnancy ....................................................................................... 50 

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9.6.5 
Reporting to the IRB/IEC ................................................................................. 50 
9.6.6 
Annual Safety and Progress Reports (DSUR) ................................................ 50 
10 
TRIAL ADMINISTRATION ........................................................................................................ 51 
10.1 
Case Report Forms and Source Documentation .............................................................. 51 
10.2 
Good Clinical Practice Statement ...................................................................................... 51 
10.3 
Investigator Documentation ............................................................................................... 51 
10.4 
Record Retention ............................................................................................................... 51 
10.5 
Protocol Deviations and Amendment ................................................................................ 52 
10.6 
Institutional Review Board and Independent Ethics Committee ....................................... 52 
10.7 
Sponsor Monitoring and Auditing ...................................................................................... 52 
10.8 
General Informed Consent and Sub-study Informed Consent for Genetic 
Samples ............................................................................................................................. 53 
10.9 
Confidentiality .................................................................................................................... 54 
10.10 Financial Disclosure .......................................................................................................... 54 
10.11 Reporting and Publication Policy ....................................................................................... 54 
10.12 Insurance ........................................................................................................................... 55 
11 
REFERENCES ........................................................................................................................... 56 
12 
APPENDICES ............................................................................................................................ 57 
12.1 
Appendix A: Eastern Cooperative Oncology Group (ECOG) Performance Status 
Scale10 ............................................................................................................................... 57 
12.2 
Appendix B: NYHA Functional Classification .................................................................... 58 
12.3 
Appendix C: New response evaluation criteria in solid tumors: Revised RECIST 
guideline (version 1.1) ....................................................................................................... 59 
12.4 
Appendix D: ASCO and CAP Guidelines on HER2 Testing in Breast Cancer .................. 65 
 

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TABLE OF TABLES 
Table 1 
Schedule of Assessments ........................................................................... 18 
 

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ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Explanation 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
ASCO 
American Society of Clinical Oncology 
AST 
Aspartate aminotransferase 
AUC 
Area under the curve 
BSA 
Body surface area 
BUN 
Blood urea nitrogen 
CA 
Competent Authority 
CAP 
College of American Pathologists 
CFR 
Code of Federal Regulations 
Cmax 
Maximum plasma concentration 
CNS 
Central nervous system 
CR 
Complete response 
CRP 
C-reactive protein 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLT 
Dose-limiting toxicity 
DME 
Dose-modifying event 
DNA 
Deoxyribonucleic acid 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
ELISA 
Enzyme-linked immunoassay 
FA 
Full analysis 
FDA 
Food and Drug Administration 
FFPE 
Formalin fixed paraffin embedded 
GCP 
Good Clinical Practice 

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Abbreviation 
Explanation 
GGT 
Gamma-glutamyl transaminase 
GIST 
Gastrointestinal stromal tumors 
HDACi 
Histone deacetylase inhibitor 
HER2 
Human epidermal growth factor receptor 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human immunodeficiency virus 
HPβCD 
Hydroxyl-propyl-β-cyclodextrin 
i.v. 
Intravenous; Intravenously 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IHC 
Immunohistochemistry 
IME 
Important medical event 
IMP 
Investigational Medicinal Product 
INN 
International Nonproprietary Name 
IRB 
Institutional Review Board 
ISH 
In situ hybridization 
LDH 
Lactate dehydrogenase 
LLN 
Lower Limit of Normal 
MAD 
Maximum administered dose 
MedDRA 
Medical Dictionary for Regulatory Activities 
miRNA 
Micro ribonucleic acid 
MM 
Multiple myeloma 
MRI 
Magnetic resonance imaging 
mRNA 
Messenger ribonucleic acid 
MTD 
Maximum tolerated dose 
NCI 
National Cancer Institute 
NYHA 
New York Heart Association 
ORR 
Objective response rate 
OS 
Overall survival 

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Abbreviation 
Explanation 
PARP 
Poly (ADP-ribose) polymerase 
PFS 
Progression free survival 
Ph. Eur. 
Pharmacopoeia Europaea  
PI 
Principal Investigator 
PK 
Pharmacokinetic 
PMN 
Polymorphonuclear 
PO QD 
orally, once daily 
QT 
A measure of the time between the start of the Q wave and the end of 
the T wave in the heart's electrical cycle. The QT interval represents 
electrical depolarization and repolarization of the ventricles. 
QTc 
Corrected QT interval 
QTcF 
QT corrected by Fredericia 
RBC 
Red blood cell count 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RNA 
Ribonucleic acid 
RP2D 
Recommended Phase 2 dose 
SADR 
Serious Adverse Drug Reactions 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SCLC 
Small cell lung cancer 
SD 
Stable disease 
SJS 
Stevens-Johnson syndrome 
SmPC 
Summary of Product Characteristics 
SRC 
Safety Review Committee 
STS 
Soft tissue sarcoma 
SUSAR 
Suspected unexpected serious adverse reaction 
TdP 
Torsades de pointes 
TEAE 
Treatment-emergent adverse event 
TEN 
Toxic epidermal necrosis 
TLS 
Tumor lysis syndrome 
Tmax 
Time to maximum concentration 

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Abbreviation 
Explanation 
TNBC 
Triple negative breast cancer 
ULN 
Upper limit of normal 
US, USA 
United States, United States of America 
USP 
United States Pharmacopeia 
WBC 
White blood cell count 
 

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1 
PROTOCOL SYNOPSIS  
Title 
Sub-study to Characterize the Effects of Tinostamustine at a Dose of 80 
mg/m2 Administered during a 80-minute Infusion on Cardiac Repolariza-
tion in Patients with Advanced Solid Tumors. 
Protocol Number 
EDO-S101-1002 
Trial Sponsor 
Mundipharma Research Limited 
Objectives 
Primary objective  
• 
To characterize the effect of tinostamustine at a dose of 80 mg/m2 on 
cardiac repolarization (QTcF) and other ECG parameters in 6-12 pa-
tients with solid tumors who have progressed after at least one line of 
therapy and for whom no other standard therapy with proven clinical 
benefit is available. Tinostamustine will be administered intravenously 
(i.v.) on Day 1 and 15 of each 4-week treatment cycle. 
Secondary objective:  
• To evaluate safety and tolerability of tinostamustine. 
• To determine the plasma concentrations of tinostamustine and 
metabolites (M2 and M8) following tinostamustine administration of 80 
mg/m2 over 80 minutes on Day 1 and 15 of a 4-week treatment cycle.  
• To determine overall response (ORR), the clinical benefit rate (CBR) 
and stable disease at 4 months and duration of response (DR). 
• To determine the progression free survival (PFS).  
• To determine the overall survival time (OS).  
• To determine duration of response. 
Exploratory objective: 
• 
Not applicable for the sub study. 
Clinical Phase 
Phase 1 sub-study to Phase 1/2 clinical trial EDO-S101-1002 
Investigational 
Medicinal Product 
Tinostamustine (EDO-S101) 
No. of Patients 
Maximum 12 patients.  Six patients will be recruited initially; recruitment may be 
extended  to 12 (see sub study stopping rules) 
Number of Centers 
Up to three centers 

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Trial Design 
This sub-study is designed to better characterize the effect of tinostamustine on 
cardiac repolarization (QTc) and other ECG parameters, for the treatment of 
solid tumors as investigated in EDO-S101-1002 trial.  
A subgroup of 6 to 12 patients treated with a dose of 80 mg/m2 tinostamustine 
administered over 80 minutes will be studied with intense ECG measurements, 
including 30 hr Holter monitoring, and PK sampling. The PK sampling will occur 
on Day 1 and Day 15  in cycle 1,only.  
The relationship between Cmax, and AUC will be examined relative to any pro-
longation of the QTcF seen on central ECG reading and simple descriptive sta-
tistics will be applied as appropriate.  
Following enrollment of 6-12 patients the sub study will be stopped.  
Sub-Study 
Stopping Rules 
Patient level Stopping Rules for sub-study for administering 
Tinostamustine  
 
QTc stopping rules 
Stopping rules in this sub-study apply for patients who experience QTc 
prolongations >500 ms or change from baseline >60 ms (Grade 3) that are not 
transient or occur in more than 1 treatment cycle. Baseline QTc is defined as 
the average of the triplicate QTcF interval collected prior to D1 dosing for each 
cycle.  
If the QTcF value on the electrocardiogram (ECG) machine printout is >500 ms 
or represents an increase > 60 ms from baseline, 2 additional ECGs are to be 
performed approximately 1 minute apart. If the average QTcF of the 3 ECGs is 
>500 ms or increased > 60 ms from baseline, the tinostamustine infusion must 
be stopped. The patient should stay in the unit until the QTcF has decreased 
to ≤450 ms. In addition, the patient is to be continuously observed for syncope 
or other clinically relevant cardiac events. 
A thorough evaluation of ECGs, including expedited central review of Grade 3 
QTc prolongations by an independent assessor, will be performed. The 
decision will then be made by the Sponsor in consultation with the Medical 
Monitor, whether tinostamustine treatment is to continue or be postponed. 
Non-QTc stopping rules 
Patients will be discontinued from further treatment if they experience a Grade 
4 non-hematologic toxicity that has been deemed as related to tinostamustine 
treatment. 
 
Trial level Stopping Rules  
Six patients will be recruited to the sub study.  If ≥ 2 or more patients have 
centrally confirmed QTc prolongation >500 ms or change from baseline >60 
ms (Grade 3), or 1 patient has a QTc prolongation clinical related event (e.g., a 
4-beat run of ventricular tachycardia or repeating couplets on the 24-hour 

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Holter monitor), then up to 6 additional patients will be recruited. 
If ≥2 patients have a centrally confirmed QTc prolongation clinical related event 
(e.g. a 4-beat run of ventricular tachycardia or repeating couplets on the 24-
hour Holter monitor) or ≥4 patients have centrally confirmed QTcF prolongation 
>500 ms, or change from baseline >60 ms (Grade 3), then further patient re-
cruitment will be stopped and the sub study will be assessed by the Sponsor 
and regulatory agency.  
 
If ≥2 patients enrolled in the sub-study experience a Grade 4 QTc prolonga-
tion, that is confirmed by central reading and no underlying cause for the event 
is identified, this will result in the sub-study stoppage.  
Any treatment related death reported on the sub-study will result in the stop-
page of the sub-study. 
Sub-study 
Population 
Inclusion Criteria for sub-study: 
• 
Signed informed consent. 
• 
Patients age ≥18 years at signing of the informed consent. 
• 
Histologically confirmed diagnosis of advanced or metastatic solid tu-
mors, disease should have progressed following at least 1 line of therapy 
and no other standard therapy with proven clinical benefit is available or 
recommended based on the investigator’s individual risk-benefit assess-
ment for the patient. Women with triple negative breast cancer must 
have had at least 3 prior lines of therapy and there remains no other 
standard therapy with proven clinical benefit. 
• 
Patients with secondary metastasis to the central nervous system (CNS) 
are eligible if they have had brain metastases resected or have received 
radiation therapy ending at least 4 weeks prior to trial day 1 and they 
meet all the following criteria:  
(1) Residual neurological symptoms ≤ Grade 1 
(2) No glucocorticoid requirements or patients may be receiving low 
doses of glucocorticoids providing the dose has been stable for at 
least 2 weeks prior to starting the trial medication 
(3) Follow-up imaging does not show progression of treated lesions and 
no new lesions  
• 
Evaluable disease; either measurable on imaging or with informative 
tumor marker as assessed by RECIST version 1.1.  
• 
Eastern Cooperative Oncology Group (ECOG) performance status ≤2 
(Section 12.1). 
• 
Absolute neutrophil count (ANC) (polymorphonuclear [PMN] cells plus 
bands) >1,000 µL. 

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• 
Platelets ≥100,000 µL. Platelet transfusions within the 14 days before 
Day 1 of Cycle 1 is prohibited. 
• 
Aspartate aminotransferase/alanine aminotransferase (AST/ALT) ≤3× 
upper limit of normal (ULN). In cases with liver involvement ALT/ AST 
≤5× ULN. 
• 
Total bilirubin ≤1.5 x upper limit of normal (ULN), or patients diagnosed 
with Gilbert's syndrome, that have been reviewed and approved by the 
medical monitor  
• 
Renal function: estimated creatinine clearance by Cockcroft-Gault 
formula ≥ 45 mL/min  
• 
Serum potassium and magnesium at least at the lowest limit 
of normal (LLN) range, before every IMP administration. If it is 
below LLN, supplementation is permissible. 
• 
Women of child-bearing potential, and their partners, must be willing to 
use at least 2 effective forms of birth control during the trial drug 
administration and after the administration of IMP to be eligible to 
participate. Female study participants of child-bearing potential must 
continue using contraception for at least six months after 
the last administration of the IMP. Female study participants should be 
willing to have a pregnancy test performed at screening, ≤ 1 day prior 
to day 1 of each IMP administration and at 
study treatment discontinuation. Male study participants who are 
sexually active with a woman of child-bearing potential should also use 
a condom during treatment and for at least ninety (90) days after the 
last administration of IMP. Vasectomized partners and patients must be 
willing to use a secondary method of effective birth control. 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 trial treatment. 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 patient. 
Exclusion Criteria for sub-study: 
• 
Patients with primary central nervous system (CNS) cancer.  
• 
Patients with QTc interval (Fridericia’s formula) >450 ms.  
• 
Patients who are on treatment with drugs known to prolong the QT/QTc 
interval. Refer to CredibleMeds list of drugs with known risk of Torsade 
des 
pointes 
(TdP): 
https://crediblemeds.org/index.php/drugsearch Patients who are being 

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treated with Valproic Acid for any indication (epilepsy, mood disorder) 
must be excluded. 
• 
Any serious medical condition that interferes with adherence to trial 
procedures.  
• 
Prior history of another solid tumor malignancy diagnosed within the last 
3 years of trial enrollment excluding adequately treated basal cell 
carcinoma of the skin, squamous cell carcinoma of the skin, or in situ 
cervical cancer, in situ breast cancer, in situ prostate cancer (patients 
must have shown no evidence of active disease for 2 years prior to 
enrollment)  
• 
Pregnant or breast-feeding women. 
• 
New York Heart Association (NYHA) stage III/IV congestive heart fail-
ure (Section 12.2). The following arrhythmias: atrial fibrillation/flutter 
with poor rate control, documented sustained ventricular tachycardia 
(defined as >30 seconds or requiring cardioversion before 30 seconds 
have elapsed) or TdP, ventricular preexcitation (Wolff Parkinson White 
syndrome) Brugada Syndrome, Complete LBBB, QRS > 120 ms. Myo-
cardial infarction or acute coronary syndrome within previous 6 months; 
or severe COPD or severe uncontrollable hypertension. 
• 
Implanted pacemaker or implantable cardiac defibrillator (ICD)  
• 
Significant co-morbidities (e.g., active infection requiring systemic 
therapy, history of human immunodeficiency virus [HIV] infection, or 
active Hepatitis B or Hepatitis C). 
• 
Use of other investigational agents or previous anticancer therapies 
within 28 days prior to the first dose of tinostamustine, provided the 
patient has recovered from any related toxicities ≥Grade 1 (except 
alopecia).  
• 
Steroid treatment within 7 days prior to trial treatment. Patients that 
require intermittent use of bronchodilators, topical steroids, or local 
steroid injections will not be excluded from the trial. Patients who have 
been stabilized to 10 mg prednisolone orally (PO) once daily (QD) (or 
equivalent), daily (or less) at least 7 days prior to Investigational 
Medicinal Product administration are allowed.  
Dose and Schedule The dose of 80 mg/m2 tinostamustine will be administered over 80 minutes. 
Administration is on Day 1 and Day 15 in a 28-day cycle.  There will be a 
maximum of 6 cycles of treatment according to the Sub study protocol.  At the 
Investigators’ discretion and Sponsor approval, treatment can be continued 

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beyond 6 cycles in responding patients or patients who have experienced 
clinical benefit up to a maximum of 12 cycles. 
Duration of sub-
study / Patient 
Participation 
The number of patients participating in this sub-study is 6 initially but may be 
expanded to 12. An estimated four months for patient enrollment and 12 months 
for follow-up. 
Safety Evaluations 
Safety assessments include physical examinations, ECOG performance status 
determinations, electrocardiograms (ECGs), pregnancy testing for women of 
childbearing potential, documentation of treatment-emergent adverse events 
(TEAEs), clinical laboratory evaluations including hematology, blood chemistry 
and urinalysis, vital signs, and documentation of concomitant medication usage.  
Toxicities are assessed for severity using the National Cancer Institute (NCI) 
Common Terminology Criteria for Adverse Events (CTCAE) version 4.03, June 
2010, with the exception that assessment of QTc prolongations constituting AEs 
of special interest are based on CTCAE version 5.0.  
Efficacy 
Evaluations  
Efficacy evaluations in this sub-study will include ORR (i.e., patients with a CR 
plus patients with a PR of any duration), rate of patients with SD of at least 4 
months duration, duration of response, PFS, and OS. 
Radiologic response assessment by computed tomography (CT) or magnetic 
resonance imaging (MRI) will be performed at baseline and every 2 cycles 
during treatment and every 2 months after stop of treatment. Tumor response 
will be evaluated according to RECIST version 1.1 (Section 12.3). 
Pharmacokinetic 
Assessments 
Plasma samples will be collected to determine the concentrations of 
tinostamustine, and its 2 metabolites M2 and M8, by a method fully validated 
according to the relevant guidelines. PK samples are to be collected from the 
arm opposite of that used for tinostamustine administration. 
Blood sampling will occur in Cycle 1 only at each drug administration and should 
be collected following the 10-minute supine resting periods described for the 
continuous Holter recordings. The schedule is provided in Section 7.16 of this 
protocol.  
Pharmacodynamic 
Assessments 
 Not applicable for sub study. 

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Sample Size 
Determination, 
Analyses 
No formal sample size determination  

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Classification: FOR INTERNAL DISTRIBUTION ONLY 
2 
SCHEDULE OF ASSESSMENTS 
Table 1 
Schedule of Assessments 
Procedure 
Screening 
28 days from Base-
line (First Day IMP 
Administration); 
Scans 28 days from 
Baseline15 
Cycle 1 and Subsequent Cycles1 
IMP 
Discontinuation 
(at any time or Day 
28 of last cycle)14 
Follow-up,12,13 
Day 
114 
Day 
214 
Day 
1514 
Day 
1614 
Day 
2214 
Informed Consent 
X 
 
 
 
 
 
 
 
Eligibility Criteria 
X 
 
 
 
 
 
 
 
Demographics and Medical History 
(including prior cancer therapies) 
X 
 
 
 
 
 
 
 
Complete Physical Examination 
X 
X 
 
 
 
 
X 
 
Abbreviated Physical Examina-
tion15 
 
 
 
X 
 
X 
 
 
Weight and Height2  
X 
X 
 
 
 
 
 
 
Vital Signs3 
X 
X 
 
X 
 
X 
X 
 
ECOG Performance Status 
X 
X 
 
X 
 
X 
X 
 
12-lead ECG Assessments (Safety 
and Holter)4 
X 
X 
 
X 
 
 
 
 
PK Assessments5 
 
X5 
X1 
X5 
X1 
 
 
 
Gene Expression Profiling6 
n/a 
 
 
 
 
 
 
 

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Procedure 
Screening 
28 days from Base-
line (First Day IMP 
Administration); 
Scans 28 days from 
Baseline15 
Cycle 1 and Subsequent Cycles1 
IMP 
Discontinuation 
(at any time or Day 
28 of last cycle)14 
Follow-up,12,13 
Day 
114 
Day 
214 
Day 
1514 
Day 
1614 
Day 
2214 
Hematology7 
X 
X 
 
X 
 
X 
X 
 
Serum Chemistry8 
X 
X 
 
X 
 
 
X 
 
Urinalysis 
X 
 
 
 
 
 
X 
 
Pregnancy Test (urine or serum)9 
X 
X 
 
 
 
 
X 
 
Baseline and Response Assess-
ments10, 12 
X 
 
 
 
 
 
X 
 
Record AEs 
 
X 
X 
X 
X 
X 
X 
 
Assessment of Infusion Site and 
potential allergic reactions11 
 
X 
 
X 
 
 
 
 
Record Concomitant Therapies 
and Procedures 
X 
X 
 
X 
 
X 
X 
 
Trial Drug Administration 
 
X 
 
X 
 
 
 
 
Obtain PFS Information12 
 
 
 
 
 
 
 
X 
Survival Follow-up 
 
 
 
 
 
 
 
X13 
1 Visits on Day 2 and 16 in Cycle 1 only: 30h from the start of infusion the day before. 
2 Height will be measured at screening or baseline only. The weight will be measured at screening and on Day 1 of each cycle. The documentation of weight will be used for 
trial drug calculations of BSA. BSA will be calculated using the DuBois formula for each patient at the site.  
3 Resting supine blood pressure, pulse, respiratory rate, and temperature will be measured at Screening, Day 1, 15, and 22, and at IMP discontinuation. On each treatment 
day blood pressure, pulse, and respiratory rate will be recorded pre-dose, 3 (±10 minutes), and 6 (±10 minutes) hours from the start of the tinostamustine infusion. Temperature 

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will be recorded at pre-dose on each treatment day. After Cycle 1 the vitals for the 3- and 6-hour time points are considered optional assessments and should be done at the 
Investigator’s discretion. If the 3- and 6-hour time points are not done, the Investigator must provide adequate instruction to the patient regarding potential allergic reactions, 
and this should be clearly documented in the patient chart.  
 4 All ECGs will be obtained digitally using a Global Instrumentation (Manlius, NY, USA) M12R ECG and are to be performed after the patient is supine for 10 minutes. A 
triplicate ECG will be performed during Screening (at least 1-2 minutes between each measurement) and will be read centrally to determine patient eligibility for the trial. A 
triplicate ECG is to be performed before tinostamustine administration on D1 (i.e., day of tinostamustine dosing) in each cycle. Furthermore, patients are to have single ECGs 
performed at 30 and triplicate at 80 minutes from the start of tinostamustine administration on D1 and D15 each treatment cycle. Additional single ECGs will be conducted at 
IMP discontinuation and as clinically indicated. 
Holter monitoring will commence 60 minutes prior to the start of the infusion on C1D1 and will continue through 30 hours from the start of infusion. Replicate 10 second, 12-
lead ECGs will be extracted from the continuous recording at each of the following time points on C1D1 and C1D15: 
• 
C1D1: -45, -30, -15 minutes predose, and 5, 10, 20, 30, 45, 60, 80, 95, 110, 150 minutes, 3h30, 5h, 7h, 10h, 24h, 30 hours from the start of infusion. 
• 
C1D15: prior to the start of infusion, and 5, 10, 20, 30, 45, 60, 80, 95, 110, 150 minutes, 3h30, 5h, 7h, 10h, 24h, 30 hours from the start of infusion. 
5 The blood sampling schedule for the PK assessment is conducted on Day 1 and 15 of Cycle 1, only. Multiple samples are taken as follows: up to 0.5 hours prior to dose 
administration and at 5, 10, 20, 30, 45, 60, 80, 95, 110, 150 minutes, 3h30, 5h, 7h, 10h, 24h, and 30 hours from the start of the tinostamustine infusion. See section 7.16 for 
sampling windows. 
6 not applicable for sub study 
7 Hematology will include white blood cell count (WBC) and differential, RBC, hemoglobin, hematocrit, platelets and absolute neutrophil count (ANC). Blood samples will be 
collected at Screening, Days 1, 15 and 22 of each cycle, from cycle 1 to cycle 6, and at the time of trial drug discontinuation (at any time or Day 28 of the last treatment cycle). 
Patients continuing on trial until PD or intolerable toxicity, will have blood samples collected on days of drug administrations and at the time of trial drug discontinuation (at 
any time or Day 28 of the last treatment cycle). Windows for haematology are Days 1 (- 2 days), 15 (-2 days) and 22 (+/- 2 days) 
8 Serum chemistry will include albumin, total protein, creatinine clearance by Cockcroft-Gault formula, uric acid, blood urea nitrogen (BUN), sodium, potassium, magnesium, 
calcium, glucose, total bilirubin, alkaline phosphatase, AST, ALT, gamma-glutamyl transferase (GGT), lactate dehydrogenase (LDH) and C-reactive protein (CRP). Windows 
for biochemistry are Days 1 (- 2 days), 15 (-2 days) and 22 (+/- 2 days) 
9 Women of childbearing potential. 
10 Patients will have a baseline tumor assessment done within the 28 days (with a 7-day window) prior to Cycle 1, Day 1. Response assessment by imaging after Cycle 2, 4 
and 6. In addition, the response assessment may be performed at any time according to symptoms and clinical judgment of the treating physician. 
11 Assessment of infusion site reactions must be performed on each treatment day at pre-dose, 80 mins (±15 min). The patient will be observed at 80 mins (±15 min post 
dose) for potential allergic reactions (See Section 8.10 for possible infusion reactions). The Investigator must provide adequate instruction to the patient regarding potential 
allergic reactions, and this should be clearly documented in the patient chart. 
12 For patients who discontinue trial treatment for reasons other than PD, tumor assessments per RECIST will be performed every 8 weeks (± 2 weeks) until documentation 
of disease progression or the initiation of a subsequent anti-cancer therapy, whichever comes first. 
13 Patients will be contacted every 3 to 4 months for the subsequent use of anti-cancer therapy as well as survival for a maximum of 12 months after the end of their last cycle 
of treatment. 
14 Scans should be done within 28 days of baseline (with a 7-day window). The window for visits on Day 15 and 22 in cycle 1 is +/-1 day; the window for visits in cycle 2 
onwards is +/-2 days, unless the tinostamustine dose is delayed due to toxicity (see Section 8.6). 

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15 Abbreviated physical examination is directed by disease site and symptoms. 

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3 
INTRODUCTION 
Initially regarded as “epigenetic modifiers” acting predominantly through chromatin remodeling by 
maintaining histone acetylation, histone deacetylase (HDAC) inhibitors (HDACi) are recognized to 
exert multiple cytotoxic actions in cancer cells, often through acetylation of non-histone proteins. 
Some well-recognized mechanisms of HDACi lethality include, in addition to relaxation of DNA and 
de-repression of gene transcription, interference with chaperone protein function, free radical gener-
ation, induction of deoxyribonucleic acid (DNA) damage, up-regulation of endogenous inhibitors of 
cell cycle progression, e.g., p21, and promotion of apoptosis. This class of agents is relatively selec-
tive for transformed cells, at least in nonclinical trials. In recent years, additional mechanisms of action 
of these agents have been uncovered. For example, HDACi compounds interfere with multiple DNA 
repair processes, as well as disrupt cell cycle checkpoints, critical to the maintenance of genomic 
integrity in the face of diverse genotoxic insults. Despite their nonclinical potential, the clinical use of 
HDAC inhibitors remains restricted to certain subsets of T-cell lymphoma. Currently, it appears likely 
that the ultimate role of these agents will lie in rational combinations, only a few of which have been 
pursued in the clinic to date.3 
Multiple lines of recent data have begun to suggest that there is biologically important synergy that 
exists between alkylating agents and HDAC inhibitors. For example, in one trial the combination of 
bendamustine, an alkylating agent, and entinostat, a HDAC inhibitor, synergistically inhibits prolifer-
ation of multiple myeloma (MM) cells via induction of apoptosis and DNA damage response. In this 
trial, cell growth assays showed that bendamustine or entinostat inhibited proliferation in a dose-
dependent manner, and their combinations synergistically induced growth inhibition in all MM cells 
tested. An apoptotic enzyme-linked immunoassay (ELISA) and western blot assays on poly (ADP-
ribose) polymerase (PARP) cleavage and caspase-8 and caspase-3 revealed that bendamustine in 
combination with entinostat exhibited a much more potent activity than either agent alone to promote 
the MM cells undergoing apoptosis in a dose-dependent manner. Flow cytometric analysis found that 
entinostat exhibited distinct effects on cell cycle progression in different lines and bendamustine 
mainly arrested the cells at S phase, whereas their combinations dramatically blocked the S cells 
entering G2/M phase. Furthermore, trials on DNA damage response indicated that phosphohistone 
H2A.X (P-H2A.X), a hallmark of DNA double strand break, along with phosphorylated CHK2 (P-
CHK2) was significantly enhanced by the combinations of bendamustine and entinostat as compared 
to either agent alone. These molecular changes were correlated with the increases in mitotic catas-
trophe.4 
Tinostamustine is a first in class alkylating HDAC inhibitor that is being developed for the treatment 
of relapsed/refractory hematologic malignancies and solid tumors. The compound underwent broad 
evaluation in nonclinical models for human cancer. In in vitro and in vivo trials demonstrate efficacy 
in models of Hodgkin lymphoma, aggressive non-Hodgkin lymphoma, multiple myeloma, T-cell lym-
phoma and acute myeloid leukemia. In solid tumors activity was seen in models of sarcoma, small 
cell lung cancer (SCLC), non-small cell lung cancer, breast cancer, ovarian cancer and glioblastoma. 
The efficacy was independent from p53 status and cell lines resistant to other chemotherapy agents 
still responded to tinostamustine, including cell lines particularly resistant to bendamustine. Mecha-
nistically, tinostamustine induces a strong DNA damage response, evidenced by a rise of ɣ-pH2AX 

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and p53, while DNA damage response was suppressed. Consequently, in vitro experiments showed 
synergy with DNA repair influencing agents such as PARP inhibitors. 
 
3.1 
Background 
3.2 
Clinical Data 
Please refer to the Investigators Brochure for full details of supporting clinical data. 
Tinostamustine has been investigated in 4 industry sponsored clinical trials in patients, with 
haematologic malignancies or solid tumours as follows: 
• 
Study EDO-S101-1001, a phase 1 study to investigate the safety, pharmacokinetic (PK) 
profiles and efficacy of tinostamustine in patients with relapsed/refractory haematologic 
malignancies. Stage 1 determined the safety, tolerability, MTD and recommended phase 2 
doses (RP2D). Stage 2 is ongoing and is the cohort expansion phase utilising RP2D from 
Stage 1. 
• 
Study EDO-S101-1002, a phase 1/2 study to investigate the safety, PK and efficacy of 
tinostamustine in patients with advanced solid tumours.  Phase 1 was the dose escalation 
phase to determine the safety, tolerability, MTD, and RP2D.  Phase 2 is ongoing and is the 
cohort expansion phase using the RP2D from phase 1. In addition, Study EDO S101-1002 
sub-study (n=6) (protocol version 6.2) was completed using a dose of 60 mg/m2 infused over 
60 minutes in the United states (US). The sub study was completed and 6 patients were 
recruited.  
• 
Study EDO-S101-1003, a phase 1 clinical study of tinostamustine in Japanese patients with 
relapsed/refractory haematologic malignancies.  This study is complete. 
• 
Study EDO-S101-1004, a phase 1/2, international, multi-centre, open-label study of salvage 
treatment with tinostamustine conditioning followed by autologous stem cell transplant (ASCT) 
in patients with relapsed/refractory MM (N=6). This study was terminated in March 2019. 
The main toxicities associated with tinostamustine are haematologic abnormalities, primarily 
thrombocytopenia, anaemia, neutropenia, leukopenia, and lymphopenia. Haematologic abnormalities 
are the most common Grade 3/4 toxicities. Gastrointestinal symptoms, namely nausea, with or 
without vomiting, and fatigue are also common. 
One of the clinical trials, EDO-S101-1004, was put on hold on 5 March 2019 due to the occurrence 
of clinically significant Frederica corrected QT interval (QTcF) prolongations detected in 3 out of 
6 patients. Although the QTc prolongations were transient and asymptomatic, the sponsor terminated 
the trial on 13 March 2019 and decided not to pursue further development of this high-dose indication. 

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The sponsor also put recruitment for all other studies on hold to allow an in-depth analysis of clini-
cally relevant ECG findings and a consequential benefit risk assessment. Occurrence of QTc obser-
vations within 6 hours of the start of infusion was used to infer a potential causal relationship with 
tinostamustine. Data from this analysis were included in the Benefit and Risk Assessment Report 
(BRAv2.0, 2019).   
The benefit risk assessment (112 patients) concluded that benefit in terms of response rates out-
weighs the risks of a QTc prolonging effect of tinostamustine, which has been shown to be transient 
in nature, does not increase with re-exposure and has not been associated with high-risk clinical 
symptoms. Therefore, the trials continued after implementation of risk mitigation measures.  
Nineteen patients were enrolled after the re-start of the studies till the DLP of the Investigator’s Bro-
chure (IB) version 6.0. Patients were treated with tinostamustine doses of 60 to 100 mg/m2 adminis-
tered over a 60-minute infusion. Digital 12-lead ECG recorders were used to monitor cardiac safety 
during each tinostamustine administration in 16 of these patients enrolled to EDO-S101-1001 and 
the sub-study of EDO-S101-1002. Three patients enrolled to EDO-S101-1003 trial had ECGs per-
formed on local ECG machines.   
None of these patients developed G3 or higher QTc prolongations confirmed by central reading. 
Enrolment to studies EDO-S101-1001 and EDO-S101-1002 continues; enrolment to study 
EDO-S101-1003 is complete.   
Evidence of anti-tumour activity has been seen in patients with haematologic malignancies and solid 
tumours. Among patients treated thus far at various dose levels, disease response assessments are 
available for 79 patients. Among patients with haematological malignancies (HM) (N=52) (from EDO-
S101-1001 and EDO-S101-1003 studies), 3 experienced complete response (CR), 11 experienced 
partial response (PR), 1 experienced minor response (MR), and 14 experienced stable disease (SD). 
In addition, 3 patients experienced PR and 3 patients experienced SD in the expansion phase of 
EDO-S101-1001 (9 patients were still ongoing as of DLP). In patients with solid tumours (N=22) 
1 patient experienced PR and 10 patients experienced SD (in EDO-S101-1002). In addition, 1 patient 
experienced PR and 8 patients experienced SD in the expansion phase (phase 2) (N=23 ongoing as 
of DLP).  
From the prematurely terminated trial (EDO-S101-1004), 1 PR, 1 very good partial response (VGPR) 
and 2 cases of SD were recorded (N=6). 
A summary of findings to date in tinostamustine clinical trials is presented in Section Error! R
eference source not found. of the IB. 
The benefit risk assessment concluded that benefit in terms of response rates outweighs the risks of 
a QTc prolonging effect of tinostamustine, which has been shown to be transient in nature, does not 
increase with re-exposure and has not been associated with high risk clinical symptoms.  
Therefore, the trials continued at planned doses of up to 100 mg/m2 with implementation of adequate 
risk mitigation measures.   
The benefit risk assessment proposed risk mitigation measures which were introduced via substantial 
protocol amendments before recruitment to the trials on hold was resumed. 
 

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3.3 
Sub-study Rationale 
A sub study designed to characterize the effect of Tinostamustine 60 mg/m2 infused over 60 minutes 
on cardiac repolarization (QTc) and other ECG parameters was completed in Dec 2020.  None of the 
patients who were dosed exhibited G3 or higher QTc prolongations.  Therefore, this study supported 
continued investigation of tinostamustine and a further sub study utilizing a higher dose infused over 
a longer infusion time is now proposed.   
This new sub-study will utilize the methodology used in the previous Sub study (EDO-S101-1002 
version 6.2) to characterize the effect of Tinostamustine 80 mg/m2 infused over 80 minutes on cardiac 
repolarization (QTc) and other ECG parameters.  As the dose has been increased from the recently 
completed sub study it was decided to prolong the infusion duration accordingly.  

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4 
SUB-STUDY OBJECTIVES 
4.1 
Primary Objectives 
• 
To characterize the effect of tinostamustine at a dose of 80 mg/m2 on cardiac repolarization 
(QTcF) and other ECG parameters in patients with solid tumors who have progressed after at 
least one line of therapy and for whom no other standard therapy with proven clinical benefit 
is available. Tinostamustine will be administered intravenously (i.v.) on Day 1 and 15 
of each 4-week treatment cycle. 
4.2 
Secondary Objectives 
• To evaluate safety and tolerability of tinostamustine. 
• To determine the plasma concentrations of tinostamustine and metabolites (M2 and M8) 
following tinostamustine administration of 80 mg/m2 over 80 minutes on Day 1 and 15 of a 4-
week treatment cycle.  
• To determine overall response (ORR), the clinical benefit rate (CBR) and stable disease at 4 
months and duration of response (DR). 
• To determine the progression free survival (PFS).  
• To determine the overall survival time (OS).  
• To determine duration of response. 
4.3 
Exploratory Objective 
• 
not applicable for the sub study. 

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5 
TRIAL DESIGN 
5.1 
Overall Sub-Study Design 
This sub-study is designed to characterize the effect of tinostamustine on cardiac repolarization (QTc) 
and other ECG parameters, for the treatment of solid tumors as investigated in the Phase 1 portion 
of the EDO-S101-1002 trial.  
A subgroup of 6-12 patients treated with a dose of 80 mg/m2 tinostamustine administered over 80 
minutes will be studied with intense ECG monitoring, including 30-h Holter monitoring, and PK sam-
pling at cycle 1 Day 1 and Day 15  (Day 1 and Day 15). 
The relationship between Cmax, and AUC will be examined relative to any prolongation of the QTcF 
seen on central ECG reading and simple descriptive statistics will be applied as appropriate. 
Patients will then be treated in accordance with the main trial protocol and treatment will continue as 
foreseen up to trial completion. 
Following enrollment of 6-12 patients, the sub study will be stopped. Additional patients beyond the 
initial 6-12 patients at the 80 mg/m2 dose or new cohorts evaluating higher doses can only be enrolled 
following review of the data. 
Patient level Stopping Rules for sub-study for administering Tinostamustine  
QTc stopping rules 
Stopping rules in this sub-study apply for patients who experience QTc prolongations >500 ms or 
change from baseline >60 ms (Grade 3) that are not transient or occur in more than 1 treatment 
cycle. Baseline QTcF is defined as the average of the triplicate QTcF interval collected prior to D1 
dosing for each cycle. If the QTcF value on the electrocardiogram (ECG) machine printout is >500 
ms or represents an increase > 60 ms from baseline, 2 additional ECGs are to be performed 
approximately 1 minute apart. If the average QTcF of the 3 ECGs is >500 ms or increased > 60 ms 
from baseline, the tinostamustine infusion must be stopped. The patient should stay in the unit until 
the QTcF has decreased to ≤450 ms. In addition, the patient is to be continuously observed for 
syncope or other clinically relevant cardiac events. 
A thorough evaluation of ECGs, including expedited central review of Grade 3 QTc prolongations by 
an independent assessor, will be performed. The decision will then be made by the Sponsor in 
consultation with the Medical Monitor, whether tinostamustine treatment is to continue or be 
postponed. 
Non-QTc stopping rules 
Patients will be discontinued from further treatment if they experience a Grade 4 non-hematologic 
toxicity that has been deemed as related to tinostamustine treatment. 
Trial Level Stopping Rules  
Six patients will be recruited to the sub study.  If ≥ 2 or more patients have centrally confirmed QTc 
prolongation >500 ms, or change from baseline >60 ms (Grade 3), or 1 patient has a QTc 
prolongation clinical related event (e.g., a 4-beat run of ventricular tachycardia or repeating couplets 
on the 24-hour Holter monitor), then up to 6 additional patients will be recruited. 

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If ≥2 patients have centrally confirmed QTc prolongation clinical related event (e.g. a 4-beat run of 
ventricular tachycardia or repeating couplets on the 24-hour Holter monitor) or ≥4 patients have cen-
trally confirmed QTc prolongation >500 ms, or change from baseline >60 ms (Grade 3) then further 
patient recruitment will be stopped, and the sub study will be assessed by the Sponsor and regulatory 
agency.  
If ≥2 patients enrolled in the sub-study experience a Grade 4 QTc prolongation, that is confirmed by 
central reading and no underlying cause for the event is identified, this will result in the sub-study 
stoppage.  
 Any treatment related death reported on the sub-study will result in the stoppage of the sub-study. 
 
(Refer to Section 8.7, Dose modification guidelines and stopping rules, for the management of 
patients who experience clinically significant QTcF prolongations). 

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6 
SELECTION AND WITHDRAWAL OF PATIENTS 
6.1 
Inclusion Criteria for sub-study  
• 
Signed informed consent. 
• 
Patients age ≥18 years at signing of the informed consent. 
• 
Histologically confirmed diagnosis of advanced or metastatic solid tumors, disease should 
have progressed following at least 1 line of therapy and no other standard therapy with proven 
clinical benefit is available or recommended based on the investigator’s individual risk-benefit 
assessment for the patient. Women with triple negative breast cancer must have had at least 
3 prior lines of therapy and there remains no other standard therapy with proven clinical 
benefit. 
• 
Patients with secondary metastasis to the central nervous system (CNS) are eligible if they 
have had brain metastases resected or have received radiation therapy ending at least 
4 weeks prior to trial day 1 and they meet all the following criteria:  
(1) Residual neurological symptoms ≤Grade 1. 
(2) No glucocorticoid requirements or patients may be receiving low doses of glucocorticoids 
providing the dose has been stable for at least 2 weeks prior to starting the trial medication. 
(3) Follow-up imaging does not show progression of treated lesions and no new lesions  
• 
Evaluable disease; either measurable on imaging or with informative tumor marker as 
assessed by RECIST version 1.1. 
• 
Eastern Cooperative Oncology Group (ECOG) performance status ≤2 (Section 12.1). 
• 
Absolute neutrophil count (ANC) (polymorphonuclear [PMN] cells plus bands) >1,000 µL. 
• 
Platelets ≥100,000 µL.  Platelet transfusions within the 14 days before Day 1 of Cycle 1 is 
prohibited 
• 
Aspartate aminotransferase/alanine aminotransferase (AST/ALT) ≤3× ULN. In cases with liver 
involvement ALT/ AST ≤5× ULN. 
• 
Total bilirubin ≤1.5 x upper limit of normal (ULN), or patients diagnosed with Gilbert's syn-
drome, that have been reviewed and approved by the medical monitor.  
• 
Renal function: Estimated creatinine clearance by Cockcroft-Gault formula ≥ 45 mL/min. 
• 
Serum potassium and magnesium at least at the lowest limit of normal (LLN) range, before 
every IMP administration. If it is below LLN, supplementation is permissible.  
• 
Women of child-bearing potential, and their partners, must be willing to use at least 2 effective 
forms of birth control during the trial drug administration and after the administration of IMP to 
be eligible to participate. Female study participants of child-bearing potential must continue 
using contraception for at least six months after the last administration of the IMP. Female 
study participants should be willing to have a pregnancy test performed at screening, ≤ 1 day 
prior to day 1 of each IMP administration and at study treatment discontinuation. Male study 

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participants who are sexually active with a woman of child-bearing potential should also use 
a condom during treatment and for at least ninety (90) days after the last administration of 
IMP. Vasectomized partners and patients must be willing to use a secondary method of 
effective birth control. 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 trial treatment. 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 patient. 
6.2 
Exclusion Criteria for sub-study  
To be eligible to participate in the trial, a patient cannot meet any of the following exclusion criteria: 
• 
Patients with primary CNS cancer.  
• 
Patients with QTc interval (Fridericia’s formula) >450 ms. 
• 
Patients who are on treatment with drugs known to prolong the QT/QTc interval. Refer to 
CredibleMeds list 
of drugs with known risk of Torsade des pointes (TdP): 
https://crediblemeds.org/index.php/drugsearch. 
• 
Patients who are being treated with valproic acid for any of its indication (epilepsy, mood 
disorder) must be excluded. Any serious medical condition that interferes with adherence to 
trial procedures.  
• 
Prior history of another solid tumor malignancy diagnosed within the last 3 years of trial 
enrollment excluding adequately treated basal cell carcinoma of the skin, squamous cell 
carcinoma of the skin, or in situ cervical cancer, in situ breast cancer, in situ prostate cancer 
(patients must have shown no evidence of active disease for 2 years prior to enrollment). 
• 
Pregnant or breast-feeding women. 
• 
New York Heart Association (NYHA) stage III/IV congestive heart failure (Section 12.2). The 
following arrhythmias: atrial fibrillation/flutter with poor rate control, documented sustained 
ventricular tachycardia (defined as >30 seconds or requiring cardioversion before 30 sec-
onds have elapsed) or TdP, ventricular preexcitation (Wolff Parkinson White syndrome) Bru-
gada Syndrome, Complete LBBB, QRS > 120 ms.  Myocardial infarction or acute coronary 
syndrome within previous 6 months, or severe COPD or severe uncontrollable hypertension.  
• 
Implanted pacemaker or implantable cardiac defibrillator (ICD)  
• 
Significant co-morbidities (e.g., active infection requiring systemic therapy, history of human 
immunodeficiency virus [HIV] infection, or active Hepatitis B or Hepatitis C). 
• 
Use of other investigational agents or previous anticancer therapies within 28 days prior to 
the first dose of tinostamustine, provided the patient has recovered from any related toxicities 
≥Grade 1 (except alopecia). 
• 
Steroid treatment within 7 days prior to trial treatment. Patients that require intermittent use of 
bronchodilators, topical steroids, or local steroid injections will not be excluded from the trial. 
Patients who have been stabilized to 10 mg prednisolone orally (PO) once daily (QD) (or 
equivalent), daily (or less) at least 7 days prior to trial drug administration are allowed. 

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6.3 
Trial Termination 
6.3.1 Withdrawal of Patient from Trial Treatment 
Patients can withdraw from the trial at any time for any reason if they wish to do so without any 
consequences for their further medical treatment. The investigator can decide to withdraw a patient 
from the trial for urgent medical reasons. Furthermore, patients will need to be discontinued from 
further trial treatment in the event of any of the following: 
• 
Unmanageable toxicity. 
• 
Pregnancy. 
• 
Physician decision if continuation is not in the patient’s best interest. 
• 
Termination of the trial by the Sponsor. 
• 
Other reasons (e.g. major protocol violation, non-compliance). 
• 
Progressive disease. 
If a patient is withdrawn from the trial, the primary reason must be recorded in the electronic case 
report form (eCRF) and the Investigator should make every effort to perform the assessments listed 
in the Schedule of Assessments (Table 1) under the Investigational product Discontinuation column 
(at any time or Day 28 of the last treatment cycle). 

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7 
TRIAL ASSESSMENTS 
A tabular schedule of evaluations and procedures is provided in Table 1 (Schedule of Assessments).  
7.1 
Screening 
The Investigator at each trial site is responsible for maintaining a record of all patients screened, 
including both those who enter the trial and those who are excluded. Screening procedures will be 
performed no more than 28 days prior to baseline, with the exception for scans that will be performed 
no more than 28 days prior to baseline (with 7-day window). The baseline is defined as the first day 
on which investigational product is administered. Screening procedures are listed in Table 1 
(Schedule of Assessments). 
7.2 
Informed Consent 
Each potential patient must sign a written ICF prior to performing any trial specific procedures. A copy 
of the signed informed consent form will be provided to the patient.. 
7.3 
Inclusion/Exclusion Criteria 
Inclusion and exclusion criteria will be reviewed for each potential patient during Screening. All eligible 
patients will be treated with tinostamustine employing sequential enrollment (i.e. as they qualify for 
participation). 
7.4 
Demographics and Medical History 
Each patient’s medical history will be documented at Screening, including demographic information, 
relevant medical history, current primary cancer diagnosis, and prior cancer treatments 
(chemotherapies and immunotherapies, radiation therapy, surgeries, etc.). 
7.5 
Physical Examination 
A complete physical examination will be performed at Screening, at Day 1 (-2 days) of each cycle 
and at the time of investigational product discontinuation (at any time or Day 28 of the last treatment 
cycle). On Day 15 and Day 22, abbreviated physical examination directed by disease site and 
symptoms will be performed. The abbreviated physical examination includes vitals and ECOG 
performance status. 
The findings of each examination will be recorded on the source documents and in the eCRF. The 
complete physical examination will include: 
• 
General appearance 
• 
Head, eyes, ears, nose, and throat 
• 
Respiratory 
• 
Cardiovascular 
• 
Musculoskeletal 
• 
Abdomen 

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• 
Neurologic 
• 
Extremities 
• 
Dermatologic 
• 
Lymphatics 
Interim or symptom-directed physical examinations will be performed at other times, if necessary, at 
the discretion of the Investigator to evaluate potential adverse events or clinical laboratory 
abnormalities. 
7.6 
Vital Signs, Height and Weight 
Vital signs will include resting supine blood pressure, pulse, respiratory rate, and temperature. Vital 
sign determinations will be performed at Screening, Days 1, 15 and 22. On each treatment day blood 
pressure, pulse, and respiratory rate will be recorded pre-dose, 3 hours (±10 minutes), and 6 hours 
(±10 minutes) from the start of the tinostamustine infusion, and at the time of investigational product 
discontinuation (at any time or Day 28 of the last treatment cycle). Due to the burden on the patients, 
after Cycle 1 the vitals for the 3- and 6-hour time points are considered optional assessments and 
should be done at the Investigator’s discretion. If the 3- and 6-hour time points are not done, the 
Investigator must provide adequate instruction to the patient regarding potential allergic reactions, 
and this should be clearly documented in the patient chart. 
Temperature will be recorded at pre-dose on each treatment day. Height will be measured at 
Screening or baseline only. Weight will be measured at Screening and in conjunction with vital sign 
determinations at Day 1 of each treatment cycle. The weight measured on Day 1 of each cycle will 
be used for investigational product calculations of body surface area (BSA). BSA will be calculated 
using the same formula for each patient at the site. The DuBois formula will be used to calculate the 
BSA. 
7.7 
ECOG Performance Status 
ECOG performance status of each patient will be assessed at Screening and at every visit when a 
physical exam is performed including the time of investigational product discontinuation (at any time 
or Day 28 of the last treatment cycle) using the criteria provided in Section 12.1. 
7.8 
12-Lead ECG (Safety and Holter) 
All ECGs will be obtained digitally using a Global Instrumentation (Manlius, NY, USA) M12R ECG 
and are to be performed after the patient is supine for 10 minutes. 
A triplicate ECG will be performed during Screening (at least 1-2 minutes between each 
measurement) to determine patient eligibility for the trial and will be reviewed centrally.  
During tinostamustine treatment, 2 types of ECGs are to be performed: Holter and safety ECGs. 
Holter ECGs are stored continuously on a digital medium and will not be available for review until the 
data is received by ERT and analyzed (Section 7.8.1.1). Holter ECG readings will be used for the 
final data analysis from selected predetermined time points as detailed below and will be read 
centrally using a high-resolution manual on-screen caliper semiautomatic method with annotations. 

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Safety ECGs (standard digital 12-lead) will be immediately available to site staff for assessment 
(Section 7.8.1.2). 
7.8.1.1 Holter ECGs 
Holter monitoring will commence 60 minutes prior to the start of the tinostamustine infusion on C1D1 
and up to 15 minutes prior to the start of tinostamustine infusion in C1D15 and will continue through 
30 hours from the start of infusion.  
Replicate 10 second, 12-lead ECGs will be extracted from the continuous recording at each of the 
following time points on C1D1 and C1D15: 
• 
C1D1: -45, -30, -15 minutes predose, and 5, 10, 20, 30, 45, 60, 80, 95, 110, 150 min, 3h30, 
5h, 7h, 10h, 24h, and 30h from the start of tinostamustine infusion. 
• 
C1D15: prior to the start of infusion, and 0 (predose, up to 0.5h prior to the start of the infusion), 
5, 10, 20, 30, 45, 60, 80, 95, 110, 150 min, 3h30, 5h, 7h, 10h, 24h, and 30h from the start of 
tinostamustine infusion.  
The central reader interpretation of ECGs extracted from Holter monitoring will be used to determine 
all ECG data for trial endpoints including baseline QTcF interval for cardiac safety analyses.  
7.8.1.2 Safety ECGs 
A triplicate ECG is to be performed before tinostamustine administration on D1 (i.e., day of 
tinostamustine dosing) in each cycle. Furthermore, patients are to have single ECGs performed at 30 
minutes (+/- 5 minutes) and triplicate ECGs at 80 minutes (+/- 5 minutes) from the start of 
tinostamustine administration on D1 and D15 of each treatment cycle.  
In addition, additional ECGs may be conducted as clinically indicated during the tinostamustine 
infusion.  
Expedited central reading of safety ECGs will be requested in all cases of Grade 3 or higher QTcF 
prolongations that occur within 6 hours from start of infusion. The results of the expedited central 
review will be made available to the site within 6 hours.  
The Investigator’s interpretation of ECGs will be used for patient safety management during the trial. 
For SAE reporting: initial assessment and reporting will be based on the local reading of the safety 
ECG and may be corrected if not confirmed by central reading. 
7.9 
Pharmacodynamics (Gene Expression) 
Not applicable for the sub study. 
7.10 
Clinical Laboratory Tests (Hematology, Chemistry and Urinalysis) 
Certified local laboratories will perform all clinical laboratory tests and results will be provided to the 
Investigator. Blood samples for hematology determinations will be collected at Screening, Days 1 (- 
2 days), 15 (-2 days) and 22 (+/- 2 days) of treatment cycles 1 to the last treatment cycle, and at the 
time of investigational product discontinuation (at any time or Day 28 of the last treatment cycle). On 
tinostamustine administration days, blood samples for laboratory tests are to be collected and re-
viewed by the investigator before the start of tinostamustine infusion. Serum potassium and 

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magnesium should be at least at the LLN before the start of tinostamustine infusion. If it is below LLN, 
they would need to be corrected and rechecked before the infusion proceeds.  
Hematology tests will include white blood cell count (WBC) plus differential, red blood cell count 
(RBC), hemoglobin, hematocrit, platelets and an ANC determination. 
Blood samples for serum chemistry determinations will be collected at Screening, Day 1 (- 2 days) 
and 15 (-2 days) of each treatment cycle, and at the time of investigational product discontinuation 
(at any time or Day 28 of the last treatment cycle).  
On days of drug administrations, blood samples for hematology and serum chemistry determinations 
will be collected prior to administration of the investigational product. Additional samples can be col-
lected, and determinations performed if clinically indicated.  
Blood chemistry tests will include albumin, total protein, creatinine clearance by Cockcroft-Gault for-
mula, uric acid, blood urea nitrogen, sodium, potassium, magnesium, calcium, glucose, total bilirubin, 
alkaline phosphatase, AST, ALT, gamma-glutamyl transferase (GGT), lactate dehydrogenase (LDH), 
and C-reactive protein (CRP). In addition, an evaluation of potassium and magnesium levels at 
screening and before every tinostamustine infusion will be performed and if lower than normal this 
would need to be corrected before the infusion proceeds. 
Urine for routine urinalysis will be collected at Screening and at the time of investigational medicinal 
product discontinuation (at any time or Day 28 of the last treatment cycle). Urine microscopic exami-
nation will be performed if there are any positive findings upon dipstick assessment. Urinalysis pa-
rameters will be pH, Specific gravity, blood, total protein, ketones, leukocytes, nitrites and glucose. 
In the event of a clinically significant laboratory toxicity that is greater than or equal to Grade 2, more 
frequent laboratory tests should be performed until resolution or stabilization to less than or equal to 
Grade 1. 
7.11 
Pregnancy Testing and Contraception 
A serum or urine pregnancy test will be performed for female patients of childbearing potential at 
Screening, on D1, of each treatment cycle (prior to tinostamustine administration), and at the time of 
discontinuation of tinostamustine. The test results at Screening and D1 must be negative for the 
patient to be enrolled in the trial. A positive urine pregnancy test result observed following enrollment 
should be confirmed with a repeat serum pregnancy test and if confirmed positive, the patient must 
be withdrawn from treatment immediately. See Section 9.6.4 for details regarding the pregnancy 
reporting procedure.  A woman of child-bearing potential is defined as a female who does not meet 
the criteria for “Women Not of Childbearing Potential”: women ≥55 years of age and 12 
consecutive months without menstrual bleeding or <55 years of age after surgical sterilization.  
Female study participants must be willing to use at least TWO highly effective forms of contraception. 
This should start from the time of study enrollment and continue throughout tinostamustine 
administration and for at least six months after the last administration of IMP  
Male subjects who intend to be sexually active with a woman of childbearing potential must use TWO 
highly effective forms of contraception including a condom during treatment and for at least 90 days 
after the last administration of IMP. Vasectomized partners and patients must be willing to use a 
secondary method of effective birth control. Sexual abstinence is considered a highly effective method 

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only if defined as refraining from heterosexual intercourse during the entire period of risk associated 
with the trial 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 patient.  
7.12 
Adverse Events (AEs) 
Monitoring and recording of AEs will be conducted from the time of ICF signature through to point of 
discontinuation of tinostamustine (D28 of last treatment cycle). Only AEs ongoing at Tinostamustine 
Discontinuation Visit are required to be followed to resolution or stabilization. In the event of a clinically 
significant laboratory toxicity that is ≥Grade 2, more frequent laboratory tests should be performed 
until resolution to Grade 1 or stabilization (i.e., the CTCAE grade remains the same for at least 14 
days). The final resolution/stabilization date is recorded in the AE eCRF. During Follow-up, any new 
SAE commencing within 30 days of Tinostamustine Discontinuation should be recorded and followed 
to resolution. 
7.13 
Infusion Site and Allergic Reaction Assessment 
All injection site reactions will be considered TEAEs. However, the nature and severity of each 
injection site reaction will be determined using the CTCAE criteria, version 4.03 (June 2010) in Phase 
2.  
A 2 mg/mL tinostamustine infusion solution after reconstitution will be utilized. Assessment of injection 
site reactions must be performed on each treatment day at pre-dose and end of infusion.  Additional 
evaluation must be performed in patients who present signs and symptoms of injection site reactions 
at the end of infusion. (See Section 8.10 for possible infusion reactions). The Investigator must 
provide adequate instruction to the patient regarding potential allergic reactions, and this should be 
clearly documented in the patient chart. 
7.14 
Prohibited Concomitant Medications and Procedures 
7.14.1 Steroids 
Use of bronchodilators, topical steroids, or local steroid injections will only be allowed for patients who 
require intermittent therapy. Treatment with steroids will be allowed for patients who have been 
stabilized to oral daily administration of prednisone 10 mg PO QD (or equivalent) or less, 7 days prior 
to tinostamustine administration (except for patients with secondary metastasis to CNS disease as 
permitted in the inclusion criteria Section 6.1 and patients with rash and/or allergic reactions as 
permitted in Section 8.9). 
7.14.2 Valproic Acid 
Patients receiving valproic acid for any indication (epilepsy, mood disorder) must be excluded from 
the trialas valproic acid is the same class of drug as tinostamustine . 
7.14.3 Allopurinol 
Pre-treatment with allopurinol is contraindicated. There may be increased risk of severe skin toxicity 
when tinostamustine and allopurinol are administered concomitantly. As prevention in patients with 
high risk for developing tumor lysis syndrome (TLS) or for the treatment of established TLS, patients 
should receive rasburicase. 

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7.14.4 Serotonin 5-HT3 receptor antagonists 
Palonosetron (Aloxi®) is the only serotonin 5-HT3 receptor antagonist that does not cause significant 
QTc changes; therefore, if required, it could be used for antiemetic prevention.  
Ondansetron (Zofran®) is associated with QTc prolongation and cardiac arrhythmias, with a dose 
related effect. Consequently, it is contraindicated from 24 hrs before tinostamustine infusion until 24 
hrs after the end of the tinostamustine infusion. Given the short half-life of tinostamustine, 
ondansetron can be used, if needed, for the prophylaxis of delayed nausea and vomiting.. This is 
related to the half-life of 4-6 hours of ondansetron. This interval should be extended to 48 hours in 
patients with mild biological hepatic impairment but who are still eligible (see inclusion and exclusion 
criteria). In this category of patients, a significant prolongation of ondansetron’s half-life has been 
reported. 
7.14.5 NK1 receptor antagonists 
Aprepitant (Emend®) is not allowed, since interactions with alkylating agents have been 
demonstrated. Aprepitant has additional interactions that could lead to an increase of side effects or 
decrease in efficacy of tinostamustine. 
7.14.6 Investigational agents 
Use of other anti-cancer investigational agents within 28 days prior to the first dose of tinostamustine 
provided the patient has recovered from any related toxicities ≥Grade 1.  
Use of any other investigational medicinal product or non-approved experimental therapy is not 
allowed. 
7.15 
Efficacy Evaluations 
7.15.1 Baseline Disease Assessment 
Baseline (Screening Visit) tumor assessments will be performed using CT scan. Patients will have a 
baseline tumor assessment done within the 28 days (+7-day window) prior to Cycle 1, Day 1. 
7.15.2 Disease Response Assessments 
Radiologic response assessment by computed tomography (CT) or magnetic resonance imaging 
(MRI) will be performed at baseline and every 2 cycles. Tumor response will be evaluated according 
to RECIST version 1.1 (Section 12.3). 
7.15.3 Follow-up Assessments 
PFS Response Follow-up 
Patients who have discontinued trial treatment for reasons other than PD will be assessed per 
RECIST 1.1 every 8 weeks (± 2 weeks) until documentation of PD or the initiation of a subsequent 
anti-cancer therapy, whichever comes first. 
Survival Follow-up 
Patients will be contacted every 3 to 4 months for the subsequent use of anti-cancer therapy as well 
as survival for a maximum of 12 months after the end of their last cycle of treatment.  

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7.16 
PK Assessments 
Plasma samples will be collected for determination of tinostamustine concentrations as well as its 2 
metabolites, M2 and M8, using a method fully validated according to the relevant guidelines. The PK 
profile of tinostamustine, and the 2 metabolites, M2 and M8 in plasma will be  characterized at Cycle 
1, Day 1 and Day 15. The blood sampling schedule for the PK assessment is conducted at Cycle 1, 
Day 1 and 15.  
Samples are taken as follows:  0 (predose, up to 0.5h prior to the start of the infusion), 5, 10, 20, 30, 
45, 60, 80, 95, 110, 150 min, 3h30 m, 5h, 7h, 10h, 24h, and 30h from the start of the tinostamustine 
infusion. 
 
The following time windows are permissible for all PK blood draws: 
Sampling Time 
Time from Scheduled Sampling Allowed 
Pre dose 
 
5 minute to 80 minute samples 
 
95 minute to 10 hr samples  
≤ 30 min before infusion start 
± 2 minutes 
± 5 minutes 
24h and 30 h samples 
± 15 minutes 
 
The PK assessments together with the ECG Holter results will be used to perform a concentration 
QTc-analysis following a separate statistical analysis plan (SAP). 
7.17 
Missed Visits 
If a patient misses a scheduled visit to the trial site, the patient will continue on protocol and attend 
the next scheduled visit. In this case, the treating medical team should at least contact the patient by 
phone to establish patient status. If a patient misses 2 scheduled visits, his or her continued trial 
participation will be re-evaluated for possible non-compliance. 

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8 
TRIAL TREATMENT 
8.1 
Investigational Drug Description 
Other Names: Tinostamustine is the International Nonproprietary Name (INN) of the Investigational 
Medicinal Product (IMP). Tinostamustine is a first in class alkylating HDACi fusion molecule that is 
being investigated for the treatment of relapsed/refractory hematologic malignancies and advanced 
solid tumours. The active pharmaceutical ingredient is insoluble in water and having its optimal 
solubility in an acidic medium. The drug substance is sensitive to degradation at pH values below 4.5 
and precipitates in blood at pH 7. In addition, it rapidly hydrolyses in water and is sensitive to ambient 
temperature. The chemical structure of tinostamustine is comprised of 3 chemical moieties that 
include 
a 
DNA 
alkylation 
moiety, 
a 
purine- 
like 
benzimidazole 
ring 
and 
a 
histone- deacetylase inhibiting moiety. 
8.2 
Storage and Dispensing 
Tinostamustine should be stored at 2 to 8°C in a secure area with access limited to the Investigator 
and authorized site staff. Before administration each vial tinostamustine needs to be reconstituted 
with 20 mL of 0.9% saline and the solution must be further diluted with 0.9% saline to a total volume 
of 50mL. The diluted solution is stored in an infusion container (bottle or bag) for a maximum of 10 
hours, of which a maximum of 4 hours may be at room temperature, with the remaining storage period 
at 2-8°C.  The storage period at room temperature must include equilibration at room temperature 
and the infusion duration. Tinostamustine is compatible with infusion materials indicated in the 
Pharmacy Manual.  
Only patients enrolled in the trial may receive investigational product. At Day 1 and Day 15 of each 
28-day treatment cycle, the single dose of tinostamustine is to be dispensed only by the Principal 
Investigator (PI), sub-Investigators, or authorized personnel at the institution(s) specified on the US 
Food and Drug Administration (FDA) Form 1572 (if applicable) and listed on the delegation of 
authority log.  
Under no circumstances is the investigational drug to be used other than as directed within this trial 
protocol. 
8.3 
Supply, Packaging and Labeling 
Tinostamustine is provided as a lyophilized powder in single dose, sealed glass vials. Each 50 mL 
vial will contain 100 mg tinostamustine. Hydroxyl-propyl-β-cyclodextrin (HPβCD) is present as the 
main functional excipient to keep the drug in solution at physiological pH after reconstitution. The vials 
are of clear glass Type I and stopper (V10 F597 W4432/50 WESTAR RS, Westar Pharmaceuticals 
Services) as well as Aluminium flip-off cap (20 mm, Westar Pharmaceuticals Services) to ensure 
container closure. All materials are in conformance with United States Pharmacopeia (USP) and 
Pharmacopoea Europaea (Ph. Eur.). 
8.4 
Treatment Allocation 
Trial number allocation for eligible patients will be completed according to a process defined by the 
Sponsor. 

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8.5 
Investigational Product Administration 
Following Screening, all patients who are eligible to participate in the sub study protocol will receive 
a single dose of tinostamustine 80 mg/m2 on Day 1 and Day 15 of each treatment cycle. The 
investigational product (reconstituted and diluted solution as described in Section Error! Reference s
ource not found.) will be administered by i.v. infusion through a peripheral vein or port over a precise 
80-minute (+/- 2 minute) infusion time. 
Instructions for preparation and administration of the IMP infusion are provided in the Pharmacy 
Manual. The PI or qualified site personnel will administer tinostamustine by i.v. infusion using a 
calibrated infusion pump. A full record of the infusion process will be kept using the source data 
document included in the Pharmacy manual. 
Preparation and dispensing of the investigational product will be handled by the investigational site 
pharmacy. Instructions for safe handling of the investigational product are provided in the Pharmacy 
Manual. The requirements for maintaining drug accountability are provided in Section 8.8 of this 
protocol. 
8.6 
Treatment Criteria Beyond Cycle 1, Day 1 
For a patient to receive the next dose of therapy, the following criteria must be met:  
• 
No active infection 
• 
ANC ≥1,000/mm3 
• 
platelets ≥ 100,000/ µL or >65% of platelet baseline level (whichever is higher). Baseline for 
D15 is the level of platelets before tinostamustine administration on D1 of the same cy-
cle.   Baseline for D1 administration is the level of platelets on D1 of the previous treatment 
cycle. 
• 
non-hematologic treatment related toxicities have improved to ≤Grade 1 or to the patient’s 
baseline values (except alopecia). 
In the event of toxicity leading to dose delay, tinostamustine dose will be reduced to 60 mg/m2.  If 
toxicity issues are resolved, the original dose can be administered at the next cycle, at investigator’s 
discretion.    
If a patient does not meet these criteria, next dosing will be delayed, by up to 14 days and the patient 
should be evaluated within 48-72 hours. If the next administration is delayed by more than 14 days, 
the investigator will determine if there is clinical benefit for patient to continue treatment when the 
patient’s toxicity returns to Grade 1 or the patient’s pre-event baseline. The medical monitor must be 
informed of any treatment delay (email: EDOS101-medical-monitor@mundipharma-rd.eu).  
8.7 
Dose Modification Guidelines and Stopping Rules for Patients who Experience 
Clinically Significant QTcF Prolongations 
If the QTcF value on the ECG machine printout is >500 ms or represents an increase >60 ms from 
baseline, 2 additional ECGs are to be performed approximately 1 minute apart. If the average QTcF 
of the 3 ECGs is >500 ms or increased >60 ms from baseline, the tinostamustine infusion must be 

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stopped. The patient should stay in the unit until the QTcF has decreased to ≤450ms. In addition, the 
patient is to be continuously observed for syncope or other clinically relevant cardiac events. 
A thorough evaluation of ECGs, including the expedited central reading of Grade 3 QTc 
prolongations, needs to be performed. The decision will then be made by the investigator in 
accordance with the Sponsor, whether treatment can continue, and administration of tinostamustine 
is to be postponed. Please also refer to the sub-study specific patient level stopping criteria as detailed 
in Section 5.1 Overall Sub-Study Design. 
As a general rule:  
• 
Administration of ≥50% of the planned dose will be considered as a full dose. 
• 
If a dose of up to 50% of the planned dose was administered, the remainder to a full 
planned dose can be administered the following day(s).  
- If the centrally reviewed QTcF value confirms the local finding and is >500 ms or in-
creased >60 ms from baseline, the dose of the subsequent cycles should be reduced.  
- If a centrally confirmed QTc prolongation (>500 ms or increased >60 ms from baseline) 
occurs again with the reduced dose, the patient will be taken off trial treatment.  
- If the QTc prolongation is not confirmed by a central assessor, meaning a central read 
of ≤500 ms or increased ≤60 ms from baseline, the patient can continue the treatment 
with the initially planned dose within the judgement of the investigator. 
Summary Guidance: 
If centrally reviewed QTcF value confirms local 
measurement of >500ms or increase >60 ms 
from baseline (Grade 3)  
1st occurrence: 
Reduce dose to 60 mg/m2 in subsequent cycles  
If centrally reviewed QTcF value confirms local 
measurement of >500ms or increase >60 ms 
from baseline  
2nd occurrence: 
Investigational treatment should be discontin-
ued 
If centrally reviewed QTcF does not confirm lo-
cal measurement of > 500 ms or increased 
>60 ms from baseline 
Investigational treatment can continue as 
planned according investigator's judgement 
 
8.8 
Investigational Product Accountability 
Investigational drug accountability records will be maintained throughout the course of the trial. The 
Investigator or designee will document the amount of tinostamustine received, the amount dispensed 
to trial patients and the amount destroyed locally. 
Unused tinostamustine remaining at the completion of the trial will be destroyed at the site per 
institutional standard operating procedures, provided that destruction is documented. Destruction of 
drug supplies will take place only when drug accountability has been completed and the 
Sponsor/Contract Research Organization (CRO) has given written approval for destruction. 

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8.9 
Supportive Care 
Unless otherwise prohibited (see Section 7.14), supportive therapy for optimal medical care may be 
administered per institutional standard of care at the trial centers. Such supportive therapies may 
include but are not limited to: 
1. For neutropenia: Growth factor support is allowed per institutional standards..  
2. For diarrhea: Appropriate treatment is allowed, e.g. loperamide, atropine-diphenoxylate, or 
octreotide. 
3. For nausea and/or vomiting, see guidelines in Section 7.14.4.  
4. For rash and/or allergic reactions: Steroids like hydrocortisone, dexamethasone, and 
antihistamines.  
8.10 
Drug Interactions/Precautions 
There are no known drug interactions with tinostamustine 
As a precaution, patients who are on treatment with drugs known to prolong QT/QTc interval and 
those who have QTc interval longer than 450 ms are excluded. The most current list of drugs with 
known risk of TdP issued by Credible Meds: https://crediblemeds.org/new-drug-list should be re-
viewed by the Investigator (or delegated site staff) prior to dosing a patient . Precautions of use of the 
5HT3 receptor antagonists are discussed in Section 7.14.4. 
• 
Tinostamustine is a molecule composed of an alkylating moiety similar to bendamustine and 
a histone- deacetylase inhibiting moiety similar to vorinostat. Based on the clinical experience 
with these 2 agents, potential toxicities that may be seen with tinostamustine include some of 
the more common toxicities outlined below in addition to other, rare but serious toxicities such 
as TLS seen with bendamustine and thromboembolism observed with vorinostat. 
• 
TLS was reported in patients with a large tumor burden. Onset typically occurs within the first 
treatment cycle with chemotherapeutic agent and, without intervention may lead to acute renal 
failure and death. Preventive measures include vigorous hydration and close monitoring of 
blood chemistry. Pretreatment with allopurinol as co-administration with alkylating agents is 
contraindicated as it increases the likelihood of mild to severe skin toxicity. Skin reactions 
including rash, toxic skin reactions and bullous exanthema. Cases of Stevens-Johnson 
syndrome (SJS) and toxic epidermal necrosis (TEN), some fatal, have been reported when 
chemo therapeutic agents were administered concomitantly with allopurinol and other 
medications known to cause these syndromes. Patients with skin reactions must be closely 
monitored. If skin reactions are severe or progressive treatment must be discontinued. 
Rasburicase is recommended instead of allopurinol. 
• 
Patients treated with many alkylating agents are at risk for reactivation of infections including 
(but not limited to) hepatitis B, cytomegalovirus, Mycobacterium tuberculosis, and herpes 
zoster. Patients should undergo appropriate measures (including clinical and laboratory 
monitoring, prophylaxis, and treatment) for infection and infection reactivation prior to 
administration.  

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• 
The most common serious drug-related adverse reactions associated with HDAC inhibitors 
were pulmonary embolism and anemia. Physicians should be alerted to the signs and 
symptoms of these events, particularly in patients with a prior history of thromboembolic 
events. 
• 
Hyperglycemia has been observed in association with HDAC inhibitors’ treatment; therefore, 
serum glucose should be monitored, especially in diabetic or potentially diabetic patients. 
Adjustment of diet and/or therapy for increased glucose may be necessary. 
• 
Infusion 
reactions 
(hypersensitivity) 
to 
alkylating agents may 
be 
immediate 
/or delayed.  Symptoms include fever, chills, pruritus, and rash. In rare instances severe 
anaphylactic and anaphylactoid reactions have occurred.  
Assessment of infusion site reactions must be performed on each treatment day at pre-dose, 
80 minutes (±15 minutes). The patient will be observed at 80 minutes (± 15 minutes post-
dose) for potential allergic reactions (See Section 8.10 for possible infusion reactions).  
The Investigator must provide adequate instruction to the patient regarding potential allergic 
reactions, and this should be clearly documented in the patient chart. 
Allergic reactions during or shortly after the infusion may cause skin itching, rash, reddening 
of the skin, swelling of the face, hands, feet, shortness of breath or anaphylactic reactions. 
These reactions are generally transient and disappear after symptomatic treatment is applied. 
Patients should be carefully monitored for all reactions after the infusions and take appropriate 
prophylactic measures with corticosteroids and/or antihistamines to prevent such or more 
severe reactions in subsequent treatment cycles. 
8.11 
Overdose 
Investigational product will be administered by the Investigator or qualified site personnel. Therefore, 
it is highly unlikely that an overdose will occur. However, in the event of an investigational product 
overdose due to pharmacy error, the PI and Sponsor/Sponsor’s designee should be immediately 
notified and, if signs or symptoms are present, the overdose recorded as a TEAE. The patient should 
be carefully monitored for potential adverse reactions and symptomatic treatment instituted as per 
institutional standards of care.  

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9 
AES AND SAES 
9.1 
Definition of an Adverse Event (AE) 
An AE is any untoward medical occurrence associated with the use of a drug in humans, whether or 
not considered drug related and is any event arising during participation in the clinical trial from the 
point of signature on the ICF. An AE can therefore be any unfavorable and unintended sign, symptom, 
or disease temporally associated with the use of a drug, without any judgment about causality. An AE 
can arise from any use of the drug from any route of administration, formulation, or dose, including 
an overdose. 
AEs also include: 
• 
A new disease or exacerbation of a pre-existing disease e.g., increase in frequency or worsen-
ing in nature. 
• 
Any deterioration in measurements of laboratory values or other clinical tests (e.g., ECG, vital 
signs or X-ray) that results in symptoms, a change in treatment, or discontinuation from ti-
nostamustine. 
• 
Other medical events regardless of their relationship to tinostamustine, such as accidents, falls 
and any injuries resulting from them. 
AEs do not include: 
• 
Medical or surgical procedures (e.g., surgery, endoscopy, tooth extraction, transfusion); the 
condition that leads to the procedure is an AE. 
• 
Pre-existing diseases or conditions present or detected at the start of the trial that do not 
worsen in severity or frequency. 
• 
Situations where an untoward medical occurrence has not occurred (e.g. hospitalization for 
elective surgery, social and/or convenience admissions). 
• 
Overdose of either Investigational or concomitant medication without any signs or 
symptoms. Note: Overdose should be recorded in special situation dedicated forms and 
reported to sponsor or designated vendor within 24 hours. 
A clinically significant laboratory assessment (as determined by the Investigator) is considered an AE 
and must be recorded in patients’ source documents and the eCRF.  
Disease progression is a worsening of a patient’s condition attributable to the disease for which the 
trial medication is being given. This may be an increase in severity of the disease or an increase in 
the symptoms of the disease. Disease progression itself and death from disease progression should 
not be recorded as an AE. 
However, new or increasing symptoms not related to disease progression should be reported as AEs. 

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9.2 
Recording Adverse Events 
All AEs must be reported from the time of ICF signature through the point of tinostamustine 
discontinuation. Only AEs ongoing at time of Tinostamustine Discontinuation Visit are required to be 
followed to resolution or stabilization of event and then final resolution date is recorded in the AE 
eCRF. During Follow-up, any new SAE commencing within 30 days of Tinostamustine 
Discontinuation should be recorded and followed to resolution. 
Whenever possible, a diagnosis should be given when signs and symptoms are due to common 
etiology (e.g., cough, runny nose, sneezing, sore throat, and head congestion should be reported as 
‘upper respiratory infection’). AE reporting and severity grading will be assessed using the NCI 
CTCAE, version 4.03 (June 2010), with the exception that in Phase 2, QTc prolongations will be 
assessed for severity using CTCAE version 5.0. For those events without assigned CTCAE grades, 
the recommendation on page 1 of the CTCAE that converts mild, moderate, and severe into CTCAE 
grades 
should 
be 
used. 
A 
copy 
of 
the 
NCI 
CTCAE 
is 
available 
online 
at: 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.  
· 
Seriousness 
For definition of seriousness criteria refer to Section 9.3. All seriousness criteria that apply have to be 
recorded.  
· 
Action Taken with tinostamustine 
The action taken with tinostamustine as a result of the AE has to be documented. In the situation that 
the AE leads to permanent discontinuation of tinostamustine, this meets the definition of an AE 
leading to Subject’s withdrawal from the study.  
· 
Treatment for the AE 
Any treatment for an AE, whether pharmacological or other (e.g., surgical) treatment, has to be rec-
orded in the eCRF. 
· 
Outcome 
The outcome recorded should be reflective of the outcome at the time of reporting the AE. The follow-
ing categories should be used: 
Not recovered/Not Resolved 
- 
Indicates that the event is ongoing and there has been no recovery. 
Recovering/Resolving 
- 
Indicates that the event is in the process of recovery but has not yet fully resolved. 
Recovered/Resolved 
- 
Indicates that the event has fully resolved. 
Recovered/Resolved with sequelae 
- 
Indicates that there is a residual, possibly permanent consequence of the event (e.g., resid-
ual hemiparesis subsequent to stroke). 
Fatal 

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- 
Indicates that the Subject died due to the event. The outcome “fatal” applies only to the 
event(s) that were the cause(s) of death. For other adverse events that were ongoing at the time of 
death, the outcome must be recorded as “not recovered” and not “fatal”. 
Unknown 
Indicates that the outcome of the AE cannot be determined despite the best efforts of the Investigator.  
This may be due to the Subject being ‘Lost to Follow-up’ and therefore the Safety Follow-Up visit 
could not be performed. 
· 
Causal Relationship of AE 
The causal relationship of all AEs to tinostamustine treatment will be determined by the Investigator 
according to best medical judgment, as follows: 
• 
Definitely related: This category applies when, after careful medical consideration, there is 
almost no consideration of other causation. 
• 
Probably related: There is a clinically plausible time sequence between onset of the AE 
and trial treatment administration. The AE is unlikely to be caused by a concurrent and/or un-derlying 
illness, other drugs, or procedures. If applicable, the AE follows a clinically consistent resolution 
pattern upon withdrawal of tinostamustine. 
• 
Possibly related: There is a clinically plausible time sequence between onset of the AE and 
trial treatment administration, but the AE could also have been caused by the concur-rent/underlying 
illness, other drugs, or procedures. Information regarding tinostamustine withdrawal may be lacking 
or unclear. “Possible” should be used when trial treatment ad-ministration is one of several biologically 
plausible causes of the AE. 
• 
Unlikely related: The AE is most likely due to a non-trial-treatment-related cause. However, 
association with the trial treatment cannot be completely ruled out. 
• 
Unrelated: Another cause of the AE is most plausible, and a clinically plausible temporal 
sequence is inconsistent with the onset of the AE and trial treatment administration and/or a causal 
relationship is considered biologically implausible. 
For the causality assessment of QTc prolongations, see Section 9.4. 
For the purpose of regulatory reporting requirements, causal relationship criteria given as definite, 
probable, and possible will be considered treatment-related, while unlikely and unrelated will be 
considered not treatment-related. 
· 
Follow up of AE 
Adverse events should be followed up to determine the outcome.  The cut off for information collec-
tion in the eCRF for AEs and SAEs including any follow up lab information is according to Section 
9.2.  Any AE that is still ongoing at this visit will have an outcome of ‘Recovering/Resolving’ or ‘Not 
Recov-ered/Not Resolved’ in the eCRF. After that all information still needs to be collected in the 
source and for SAEs the information needs to be forwarded to the Sponsor. 
• 
All efforts to collect follow-up information must be documented in the Subject’s source data 
as soon as it is received. 

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• 
All AEs must be followed up by the Investigator until: 
- 
the AE is resolved or resolved with sequelae and all other queries related to the AE have been 
clarified, or  
- 
the end of the period of observation (= last study visit), or 
- 
the Investigator considers it medically justifiable to stop further follow-up 
 
• 
If the Subject had an AE with fatal outcome, an autopsy report should be provided if possible.  
• 
If SAEs are ongoing at the time of the Subject’s last study visit, an additional safety follow-up 
visit should be scheduled for those Subjects.  This visit will be documented in the source notes 
and not in the eCRF. 
The Investigator should set the interval to the additional safety follow-up visit according to his/ her 
medical judgement. If the EDC system is closed, information from this visit should be forwarded to 
the Sponsor using the paper SAE form. 
The Investigator should respond to any queries raised by the Sponsor in relation to adverse events, 
including provision of supporting documentation within the requested timeline.  
In case of fatal or life-threatening SAEs the Sponsor may request urgent clarification within one 
business day. 
Subjects who were treated with IMP but did not complete the study as per protocol, should receive 
all the examinations and investigations scheduled for the last study visit. The Investigator should 
make all efforts to contact Subjects lost to follow-up and document the attempts in the Subject’s 
source data. 
 
9.3 
Serious Adverse Events 
A SAE is any AE that is considered ‘serious’ if, in the view of either the Investigator or Sponsor, it 
results in any of the following: 
• 
Is fatal; 
• 
Is life-threatening (defined as an immediate risk of death from the event as it occurred); 
• 
Requires in-patient hospitalization or prolongation of existing hospitalization (Exception: 
Hospitalization for elective treatment of a pre-existing condition that did not worsen during 
the trial and is not considered an adverse event. Note: Complications that occur during 
hospitalization are adverse events and if a complication prolongs hospitalization, then the 
event is serious); 
• 
Results in persistent or significant disability/incapacity, or substantial disruption of the abil-
ity to conduct normal life functions; 
• 
Is a congenital anomaly/birth defect; 
• 
Important medical events may be considered serious when, based upon appropriate 

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medical judgment, they may jeopardize the patient and may require medical or surgical in-
tervention to prevent one of the outcomes listed in this definition. 
Examples of important medical events which may meet the definition of a SAE include: intensive 
treatment in the emergency room or at home for allergic bronchospasm, certain abnormalities 
(e.g., blood dyscrasias), convulsions that do not result in hospitalization, or the development of drug 
dependency or drug abuse. 
Events exempt from immediate reporting as SAEs.  
Hospitalization for pre-existing conditions e.g. elective procedures planned prior to study entry, which 
has not worsened do not require SAE reporting. All events related to disease progression, including 
events resulting in death, are not considered SAEs. They need to be nevertheless clearly documented 
as events due to disease progression in the eCRF.  
9.4 
Events of Special Interest 
Based on data obtained across the development program of tinostamustine, the Sponsor has 
identified QTc prolongations as events of special interest for which the following reporting 
requirements apply based on local ECGs: 
1) All QTc prolongations Grade 2 need to be reported as AEs by entering them in the AE section 
of the eCRF 
2) All QTc prolongations Grade 3 (per the most recent CTCAE 5.0 criteria) are to be considered 
clinically significant and need to be reported as SAEs if they fulfill the following criteria: 
QTcF >500 ms or QTcF increase from baseline >60 ms  
Note that either 1 or >1 occurrence within 1 treatment cycle of 28 days will be regarded as 1 single 
event. Occurrences in more than 1 treatment cycle will be regarded as separate events in 1 patient. 
For events meeting criterion 2, an SAE report form needs to be submitted as for all other SAEs. 
Based on available PK data, a causal relationship with tinostamustine has to be assumed, if the QTc 
prolongation occurs within 6 hours from the start of tinostamustine infusion. Therefore, all SAEs 
identified as per point 2 above will be considered Serious Adverse Drug Reactions (SADR). 
9.5 
Suspected Unexpected Serious Adverse Reactions (SUSARs) 
Adverse reactions are all untoward and unintended responses to an investigational product related 
to any dose administered.  
Unexpected adverse reactions qualify as SUSARs if the following 3 conditions are met: 
1. the event must be serious; 
2. there must be a certain degree of probability that the event is a harmful and an undesirable reac-
tion to the medicinal product under investigation, regardless of the administered dose; 
3. the adverse reaction must be unexpected, that is to say, the nature and severity of the adverse 
reaction are not in agreement with the product information as recorded in: 
- Investigator’s Brochure for an unauthorized medicinal product: 
- For this trial,  the most current IB version contains the Reference Safety Information for the 

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expectedness assessment 
 
9.6 
Reporting of AEs, SAEs, Serious and Unexpected Adverse Experiences 
9.6.1 
Reporting AEs and SAEs to the Sponsor 
All AEs must be reported in the eCRF from the time of ICF signature to the point  of tinostamustine 
discontinuation. Only AEs ongoing at time of Tinostamustine Discontinuation Visit are required to be 
followed to resolution or stabilization of event and then final resolution date is recorded in the AE 
eCRF. During Follow-up, any new SAE commencing within 30 days of tinostamustine discontinuation 
should be recorded and followed to resolution. If the Investigator becomes aware of safety information 
that appears to be drug related, involving a patient who participated in the trial, even after an individual 
patient has completed the trial, this should also be reported to the Sponsor or the designated vendor. 
In addition, all treatment related SAEs should be followed until resolution or stabilization. 
All SAEs, regardless of relationship to tinostamustine, must be additionally reported to the Sponsor 
or the designated vendor within 24 hours of the Investigator becoming aware of the event using the 
SAE form. Follow-up SAE reports must be submitted by the Investigator as new information becomes 
available or as requested by the Sponsor or designated vendor. Supportive source documents have 
also to be provided together with the SAE form.  
• 
All SAEs have to be reported via e-mail or fax by using the Mundipharma SAE Report 
Form and a cover page which are available in the Investigator site file. The SAE reporting con-
tact of the Sponsor is Mundipharma Drug Safety & PV: 
   
Mundipharma Drug Safety 
and PV  
Tel: +44 (0) 1223 424444 (Not 24-hour coverage; for 
24-hour details please see the Investigator Site file)  
Fax: +44 (0)1223 426002  
E-Mail: drugsafetycentral@mundipharma-rd.eu  
 
 
9.6.2 
Reporting Suspected Unexpected Serious Adverse Reactions 
The responsibility for expedited reporting of SUSARs within 7 days (life-threatening and death cases) 
or 15 days (all other SUSARs) is with the Sponsor or its delegated vendor. 
The Sponsor or the designated vendor (their agent) will report to the regulatory authorities, 
institutional review boards (IRBs) and investigators (as applicable) as per national regulations of the 
countries where the ongoing tinostamustine trials are conducted,  
9.6.3 
Reporting of Grade 4 and Grade 5 AEs 
All grade 4 AEs (per definition "life-threatening") and grade 5 ("death"), as per CTCAE, version 5.0, 
that occur during the trial are to be reported as SAEs, with the exception of Grade 4 laboratory 
abnormalities, which are to be reported as SAEs only if, in the Investigator’s judgement, they are 
considered immediately life-threatening. 
 

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9.6.4 
Reporting Pregnancy 
If a female patient or the female partner of a male patient becomes pregnant during the course of the 
trial and within 6 months from the last dose of IMP administration, the Investigator must report the 
pregnancy to the Sponsor or its designated vendor, using the Pregnancy Reporting Form within 24 
hours of becoming aware of the event. The Investigator must obtain consent to collect pregnancy 
information (including the status of the newborn, if applicable). If possible, pregnancy needs to be 
followed up until its termination (birth, abortion, miscarriage)  
If some of the information required for completion of the Pregnancy Reporting Form is unavailable at 
the time of the initial report, follow-up reports will be completed and submitted within 24 hours of 
becoming aware of the new information. The Investigator is required to follow the pregnancy through 
delivery. The outcome of the pregnancy and the status of the newborn (if applicable) will be reported 
on the Pregnancy Reporting Form within 24 hours of becoming aware. 
9.6.5 
Reporting to the IRB/IEC 
SAEs will be reported to their IRB/IEC by the Investigator according to the IRB/IEC’s policy and 
procedures. 
9.6.6 
Annual Safety and Progress Reports (DSUR) 
In addition to the expedited reporting of SUSARs, the Sponsor will submit, once a year throughout 
the clinical trial, a safety and progress report in DSUR format to applicable competent authorities. 
The DSUR or an Executive Summary of the DSUR will be submitted to the IRBs/IECs as applicable 
per local requirements. 

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10 
TRIAL ADMINISTRATION 
10.1 
Case Report Forms and Source Documentation 
In order to provide the Sponsor/CRO with accurate, complete, and legible data, the following criteria 
are to be maintained: 
• 
Source documents will be completed according to a source document agreement outlining all 
the data that is to be collected in the source documents throughout the trial. 
• 
Investigator/institution should maintain adequate and accurate source documents that in-
clude all pertinent observations on the trial patients. Source data should be attributable, legi-
ble, contemporaneous, original, accurate and complete. Changes to the source data should 
be traceable, should not obscure the original entry and should be explained if necessary. 
Electronic data capture (EDC)/eCRF entries should be made as close to the visit of the subject as 
possible. Data reported on the eCRF should be completed accurately and in a timely manner 
according to the eCRF guidelines and ICH E6 R2 4.9.2 and 4.9.3 
10.2 
Good Clinical Practice Statement 
This trial is to be performed in full compliance with the protocol, the Declaration of Helsinki, ICH, and 
all applicable local Good Clinical Practices (GCP) and regulations. All required trial documentation 
will be archived as required by competent authorities.  
10.3 
Investigator Documentation 
The Investigator will provide the Sponsor with a fully executed FDA form 1572 (or applicable 
alternative Investigator statements) including the Investigator’s curriculum vitae.  
10.4 
Record Retention 
The circumstances of completion or termination of the trial notwithstanding, the Investigator has the 
responsibility to retain all trial documents, including but not limited to the protocol, copies of 
eCRFs/EDC, Investigator's Brochure/Summary of Product Characteristics (SmPC), regulatory 
agency registration documents, ICFs, and IEC correspondence. 
The site should plan on retaining trial documents for approximately 15 years after completion of the 
trial. This will include copies of the eCRF/EDC. 
It is requested that at the completion of the required retention period, or should the Investigator retire 
or relocate, the Investigator contact the Sponsor, allowing the Sponsor the option of permanently 
retaining the trial records. Records retained will be stored independently of the Sponsor, and the 
Sponsor will not be permitted direct access to this data. The measures implemented for the archiving 
in a separate location from the sponsor (i.e. an archiving depot) and the access of the site to these 
records, will be provided to the site if necessary. 

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10.5 
Protocol Deviations and Amendment 
The Investigator is not permitted to alter or deviate from the protocol. All deviations should be reported 
by the Investigator to their IRB/IEC. An immediate and unapproved deviation is permitted if immediate 
health care concerns mandate it. 
All protocol revisions (Amendments) must originate with and be documented by the Sponsor. In the 
US, the Investigator must submit all amendments to his/her IRB/IEC for review and approval prior to 
implementation; documentation of approval signed by the chairperson or designee must be sent to 
the Sponsor.  
 
10.6 
Institutional Review Board and Independent Ethics Committee 
Federal regulations and ICH require that approval be obtained from an IRB/IEC prior to participation 
of patients in research trials. Approval by the Competent Authority, if applicable, or as required by 
local laws and regulations, is also required in Europe. Prior to the trial onset, the protocol, any protocol 
amendments, ICFs/assent forms, advertisements to be used for patient recruitment, and any other 
written information regarding this trial to be provided to a patient or patient’s legal guardian, must be 
approved by the IRB/IEC. 
All IRB/IEC approvals must be dated and signed by the IRB/IEC Chairperson or designee and must 
identify the IRB/IEC by name and address, the clinical protocol by title and/or protocol number, and 
the date approval or favorable opinion was granted for the clinical research. 
No drug will be released to the site to dose a patient until written IRB/IEC authorization has been 
received by the Sponsor or designee. 
The Investigator is responsible for obtaining continuing review of the clinical research at least annually 
or more often if specified by the IRB/IEC. The Investigator must supply the Sponsor or designee with 
written documentation of the approval of the continued clinical research. 
The Investigator, sponsor, or its designee as applicable, will make all attempts to ensure that the 
IRB/IEC is constituted and operates in accordance with Federal and ICH GCP and any local 
regulations. 
In the case of early termination/temporary halt of the trial, the Investigator should notify the IRB/IEC 
and Competent Authority (CA) within 15 days and a detailed written explanation of the reasons for 
the termination/halt should be given. If the IEC decides to suspend or terminate the trial, the 
Investigator will immediately send the notice of trial suspension or termination by the IRB/IEC to the 
CRO. 
At the end of the trial, the Sponsor should notify the IRB/IEC and CA within 90 days. The end of the 
trial will be the date of the last scheduled trial visit for the last Subject in the trial. The Sponsor will 
always also provide the IRB/IEC/CA with a summary of the trial’s outcome. 
10.7 
Sponsor Monitoring and Auditing 
After satisfactory receipt of the Clinical Trial Agreement and all other necessary regulatory paperwork, 
the Sponsor’s monitor will arrange that all trial material be delivered to the trial site at a mutually 
convenient time. An initiation visit by the Sponsor representative and its monitoring personnel will be 

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made. At this meeting, all personnel expected to be involved in the conduct of the trial will undergo 
an orientation to include review of trial protocol, instruction for eCRF completion and overall 
responsibilities, including those for drug accountability and trial file maintenance. 
Throughout the course of the trial, the Sponsor’s representative monitor will make frequent contact 
with the Investigator. This will include telephone and/or on-site visits. During these visits, eCRFs will 
be reviewed for completeness and adherence to the protocol. As part of the data verification process, 
it is expected that source documents (e.g., hospital records, office records) will be made available for 
review by the monitor. The monitor also will perform drug accountability checks and may periodically 
request review of the Investigator’s trial file to ensure completeness of documentation in all respects 
of trial conduct. 
Upon trial completion, the monitor will arrange for a final review of the site trial files, after which the 
file should be secured by storage for the appropriate period as specified in Section 10.4.  
Audits will be conducted on a frequency which is based on risk and proportionate to the complexity 
of the trial. Additional audits may be performed if there is cause for concern or when requested by 
Sponsor, CRO, or competent authority. Regular audits will usually be performed with advance notice. 
Audits may be performed without notice. Authority inspections may occur at any time as deemed 
appropriate by the responsible authority in the country. 
Audits and authority inspections may be performed without notice, especially where the Sponsor or 
competent authority deems necessary to investigate patient safety, welfare, scientific integrity, 
compliance and/or fraud (a for-cause audit). The Investigator is required to support audit or authority 
inspections, to be available to the auditors/inspectors upon request and to permit the auditor/inspector 
direct access to source data/documents. 
10.8 
General Informed Consent and Sub-study Informed Consent for Genetic Samples  
The Investigator will explain the nature of the trial as described in the general ICF and will inform the 
patient that participation is voluntary and that they can withdraw at any time and that withdrawal 
consent will not affect his/her subsequent medical treatment or relationship with the treating 
physician.  
Information on the purpose of genetic research in the gene-expression sub-trial is provided, either in 
the main ICF or a separate ICF to allow the patient to decide whether he or she want to participate in 
this part of the trial. Participation in this genetic research is voluntary.  
The applicable ICFs must be approved by the IRB/IEC before use in the clinical trial.  
The subject will be asked to sign and date the ICF prior to any trial-specific procedures being 
performed. The subject should understand the ICF before signing and dating the ICF. The Investigator 
or person obtaining consent must also sign and date the form. Each subject will be given a copy of 
the signed informed consent and written information. No subject can enter the trial before his/her 
informed written consent, and in the USA the Health Insurance Portability and Accountability Act 
(HIPAA) authorization] has been obtained. Each patient’s signed ICF, including additional ICFs 
signed (e.g. for re-consent, and the pharmacogenomic sub-set) must be kept on file by the 
Investigator for possible inspection by regulatory authorities and/or the Sponsor personnel.  

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Each patient’s signed informed consent form must be kept on file by the Investigator for possible 
inspection by regulatory authorities and/or the Sponsor personnel.  
 
10.9 
Confidentiality 
The Investigator and his staff shall maintain the confidentiality of all patient records. Patient data will 
be made available to CRAs and auditors commissioned by the Sponsor, and to FDA and other 
competent authorities during inspections. 
Data that is transmitted by the Investigator to the Sponsor, competent authority, or IRB/IEC will not 
be directly traceable to the patient. In the event that a publication of this research incorporates a 
patient’s medical data, that data will not identify the patient. The subject’s name will not appear on 
documents transmitted to the Sponsor in order to maintain confidentiality. Additional 
anonymization/pseudonymization laws as applicable by country will also be adhered to. 
Processing of data and/or samples will be carried out in accordance with federal and local regulations. 
This applies to all trial data in whatever format it is collected and recorded. 
10.10 Financial Disclosure 
The Investigator and sub-investigators, as noted on the Form FDA 1572 (or applicable alternative 
Investigator statement), shall provide the Sponsor with accurate financial disclosure information as 
required under 21 Code of Federal Regulations (CFR) 54. The Investigator shall promptly update this 
information if any relevant changes occur during the trial and for 1 year following the completion of 
the trial. 
10.11 Reporting and Publication Policy 
The Sponsor will determine the identity of the Co-ordinating Investigator for the trial who will review 
and sign off the Clinical Trial Report. This decision will be based on involvement in the trial including, 
but not limited to, trial design, Subject recruitment and interpretation of trial data. 
Clinical trials will be registered in public databases and summary results released / disseminated via 
publically available clinical trials databases according to the Sponsor’s standard operating procedures 
(SOPs) and local requirements. As a general rule, both Phase 1 Healthy Volunteer studies and trials 
using a medicinal product in the normal course of medical practice (for example Non Interventional 
trials and Post Marketing Surveillance trials), are excluded from the above public registration and 
reporting requirements. If such trials and trials do require public registration and/or reporting, this will 
be undertaken according to local requirements.  
The Sponsor registers clinical trials and posts the summary results as required by local and federal 
regulations. 
Following the end of the clinical trial, the summary results should be made publicly available according 
to accepted timelines and requirements, usually within 12 months of trial completion. Special note 
should be taken to ensure timelines for the release of pediatric trial results are met, which may be 6 
months from trial completion. 
For multi-site trials, it is mandatory that the first publication be based on data obtained from all 
analyzed Subjects; therefore, Investigators participating in multi-site trials must not present data 

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gathered individually or by a subgroup of sites prior to the full, initial publication, unless this has been 
agreed to by all other Investigators and the Sponsor. Publication of clinical trial results may include 
the presentation of such work at national and international congresses, symposia, professional 
meetings, peer-reviewed journals, and via other appropriate channels. Named authors and 
contributors to such publications shall be determined by the Sponsor in accordance with both the 
Company Publication Policy (which can be found at: http://www.mundipharma-rd.eu/research-
areas/publications.html) and the generally accepted criteria for authorship as outlined by the ICMJE 
authorship guidelines. The data associated with any publication will be and shall remain the sole 
property of the Sponsor; the copyright of the document may be transferred to the scientific peer-
reviewed journal prior to and as part of the publication process, as appropriate. 
Subject to the paragraph above, the site may publish or present the results of the clinical trial subject 
to the protection of the Sponsor or its nominee(s) intellectual property rights, know- how, and its 
proprietary information. The Sponsor must be furnished with a copy of any proposed publication or 
presentation at least 60 days prior to submission for review and comment. Upon notice by the 
Sponsor, however, that the Sponsor intends to secure its intellectual property rights (for example, file 
a patent application relating to the trial) or that Sponsor requires for its know-how or proprietary 
information to be removed prior to such publication, such publication may be delayed for a further 6 
months or until its intellectual property rights have been secured, whichever is the later. The site 
further agrees that Sponsor’s reasonable comments in relation to the proposed publication will be 
incorporated into the publication. 
10.12 Insurance 
The Sponsor shall have clinical trial insurance in accordance with applicable national regulations. 
This insurance provides cover for damage to research participants through injury or death caused by 
trial participation and is independent of investigational drug causality. 

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11 
REFERENCES 
1. Storer B.E. Design and Analysis of Phase I Clinical Trials Biometrics. 45, no. 3 (1989): 925-
937.  
2. Bose P, Da Y, Grant S. Histone deacetylase inhibitor (HDACI) mechanisms of action: Emerg-
ing insights. Pharmacology & Therapeutics Volume 143, Issue 3, September 2014, Pages 
323–336. 
3. Cai B, Lyu H, Huang J, Wang S, Lee CK, Gao C, Liu B. Combination of bendamustine and 
entinostat synergistically inhibits proliferation of multiple myeloma cells via induction of apop-
tosis and DNA damage response. Cancer Lett. 2013 Jul 28;335(2):343-50.  
4. Schoeffski P, et al. “Weekly administration of bendamustine: a phase I study in patients with 
advanced progressive solid tumors.” Ann Oncol 2000; 11:729–734.  
5. Schoeffski P, et al. “Repeated administration of short infusions of bendamustine: a phase I 
study in patients with advanced progressive solid tumors.” J Cancer Res Clin Oncol 2000; 
126:41–47.  
6. Rasschert M, et al. “A Phase 1 study of Bendamustine hydrochloride administred on Day 1 
and 2 every 3 weeks in patients with solid tumors.” Br J Cancer 2007;96 1692-1698. 
7. Rasschert M, et al. “A phase I study of bendamustine hydrochloride administered once every 
3 weeks in patients with solid tumors.” Anti-Cancer Drugs 2007, 18:587–595. 
8. Data on file at Mundipharma Research Limited. 
9. Jagannath S, Richardson PG, Barlogie B, Berenson JR, Singhal S, Irwin D, Srkalovic G, 
Schenkein DP, Esseltine DL, Anderson KC; SUMMIT/CREST Investigators. “Bortezomib in 
combination with dexamethasone for the treatment of patients with relapsed and/or refractory 
multiple myeloma with less than optimal response to bortezomib alone.” Haematologica. 2006 
Jul;91(7):929-34. 
10. Oken MM, Creech RH, Tormey DC, et al. “Toxicity and response criteria of the Eastern Co-
operative Oncology Group.” Am J Clin Oncol. 1982; 5:649-655. 
11. Viet Hong Phan, Cindy Tan, Anneliese Rittau, Hongmei Xu, Andrew J McLachlan, Stephen J 
Clarke. "An Update on Ethnic Differences in Drug Metabolism and Toxicity from Anti-Cancer 
Drugs." Expert Opinion on Drug Metabolism & Toxicology 7, no. 11 (2011): 1395-1410. 
12. Dolan, Peter H. O’Donnell and M. Eileen. "Cancer Pharmacoethnicity: Ethnic Differences in 
Susceptibility to the Effects of Chemotherapy." Clin Cancer Res. 15, no. 15 (2009): 4806–
4814. 
13. Simon R (1989). “Optimal Two-Stage Designs for Phase II Clinical Trials.” Controlled Clinical 
Trials 10: 1-10. 
 

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12 
APPENDICES 
12.1 
Appendix A: 
Eastern Cooperative Oncology Group (ECOG) Performance 
Status Scale10 
ECOG Performance Status 
Grade 
Description 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work activi-
ties. Up and about more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair 
5 
Dead 
 

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12.2 
Appendix B:NYHA Functional Classification 
NYHA Class 
Symptoms 
I 
Cardiac disease, but no symptoms and no limitation in ordinary physical ac-
tivity, e.g. no shortness of breath when walking, climbing stairs, etc. 
II 
Mild symptoms (mild shortness of breath and/or angina) and slight limitation 
during ordinary activity. 
III 
Marked limitation in activity due to symptoms, even during less-than-ordi-
nary activity, e.g. walking short distances (20 to 100 meters). Comfortable 
only at rest. 
IV 
Severe limitations. Experiences symptoms even while at rest. Mostly 
bedbound patients. 
 

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12.3 
Appendix C:New response evaluation criteria in solid tumors: Revised RECIST guide-
line (version 1.1) 
QUICK REFERENCE 
Eligibility 
Only patients with measurable disease at baseline should be included in protocols where objective 
tumor response is the primary endpoint.  
— Measurable disease - the presence of at least one measurable lesion. If the measurable disease 
is restricted to a solitary lesion, its neoplastic nature should be confirmed by cytology/histology.  
— Measurable lesions - lesions that can be accurately measured in at least one dimension (longest 
diameter in the plane of measurement is to be recorded) with a minimum size of: 
o 10 mm by CT scan (CT scan slice thickness no greater than 5 mm) 
o 10 mm caliper measurement by clinical exam (lesions which cannot be accurately measured 
with calipers should be recorded as non-measurable) 
o 20 mm by chest X-ray. 
Malignant lymph nodes: to be considered pathologically enlarged and measureable, a lymph node must 
be ≥15 mm in short axis when assessed by CT scan (CT scan slice thickness recommended to be no 
greater than 5 mm). At Baseline and follow-up, only the short axis will be measured and followed. 
— Non-measurable lesions - all other lesions, including small lesions (longest diameter <10 mm or 
pathological lymph nodes with ≥10 to <15 mm short axis) as well as truly non-measurable lesions. 
Lesions considered truly non-measurable include: leptomeningeal disease, ascites, pleural/pericar-
dial effusion, inflammatory breast disease, lymphangitis cutis/pulmonis, abdominal masses/ab-
dominal organomegaly identified by physical exam that is not measurable by reproducible imaging 
techniques. 
o For special considerations regarding lesion measurability for bone lesions, cystic lesions and 
lesions with prior local treatment, consult the RECIST 1.1 guidelines in the Study Reference 
Manual. 
o All measurements should be taken and recorded in metric notation using a ruler or calipers. All 
baseline evaluations should be performed as closely as possible to the beginning of treatment 
and never more than 4 weeks before beginning of treatment.  
o The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up.  
o Clinical lesions will only be considered measurable when they are superficial (e.g., skin nodules 
and palpable lymph nodes). For the case of skin lesions, either a CT scan or documentation by 
color photography, including a ruler to estimate the size of the lesion, is to be done. 
Methods of Measurement  
• 
CT and MRI are the best currently available and reproducible methods to measure target lesions 
selected for response assessment. Conventional CT and MRI should be performed with cuts of 
10 mm or less in slice thickness contiguously. Spiral CT should be performed using a 5 mm 

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contiguous reconstruction algorithm. This applies to tumors of the chest, abdomen, and pelvis. 
Head and neck tumors and those of extremities usually require specific protocols. 
• 
Lesions on chest X-ray are acceptable as measurable lesions when they are clearly defined and 
surrounded by aerated lung. However, CT is preferable.  
• 
When the primary endpoint of the trial is objective response evaluation, ultrasound (US) should 
not be used to measure tumor lesions. It is, however, a possible alternative to clinical measure-
ments of superficial palpable lymph nodes, subcutaneous lesions and thyroid nodules. US might 
also be useful to confirm the complete disappearance of superficial lesions usually assessed by 
clinical examination. 
• 
The utilization of endoscopy and laparoscopy for objective tumor evaluation has not yet been fully 
and widely validated. Their uses in this specific context require sophisticated equipment and a 
high level of expertise that may only be available in some centers. Therefore, the utilization of 
such techniques for objective tumor response should be restricted to validation purposes in spe-
cialized centers. However, such techniques can be useful in confirming complete pathological 
response when biopsies are obtained. 
• 
Tumor markers alone cannot be used to assess response. If markers are initially above the upper 
normal limit, they must normalize for a patient to be considered in complete clinical response 
when all lesions have disappeared. 
• 
Cytology and histology can be used to differentiate between PR and CR in rare cases (e.g., after 
treatment to differentiate between residual benign lesions and residual malignant lesions in tumor 
types such as germ cell tumors). 
Baseline documentation of “Target” and “Non-Target” lesions 
— Target Lesions - all measurable lesions up to a maximum of 2 lesions per organ and 5 lesions 
in total, representative of all involved organs should be identified as target lesions and recorded 
and measured at baseline.  
o Target lesions should be selected on the basis of their size (lesions with the longest diameter) 
and their suitability for accurate repeated measurements (either by imaging techniques or 
clinically).  
o A sum of the longest diameter (LD) for all target lesions will be calculated and reported as the 
baseline sum LD. The baseline sum LD will be used as reference by which to characterize the 
objective tumor. 
— Non-target lesions - all other lesions (or sites of disease) should be identified as non-target 
lesions and should also be recorded at baseline. Measurements of these lesions are not required, 
but the presence or absence of each should be noted throughout follow-up. 

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Response Criteria: 
Evaluation of target lesions 
Complete Response (CR): 
Disappearance of all target lesions. Any pathological lymph 
nodes (whether target or non-target) must have reduction in 
short axis to <10 mm). 
Partial Response (PR): 
At least a 30% decrease in the sum of the LD of target lesions, 
taking as reference the baseline sum LD 
Progressive Disease (PD): 
At least a 20% increase in the sum of the LD of target lesions 
from the smallest sum of the LD recorded since the treatment 
started; the sum must also demonstrate an absolute increase 
of at least 5 mm. The appearance of ≥1 new lesion is also con-
sidered progression. 
Stable Disease (SD): 
Neither sufficient shrinkage to qualify for PR nor sufficient in-
crease to qualify for PD, taking as reference the smallest sum 
LD since the treatment started 
 
Evaluation of non-target lesions 
Complete Response (CR): 
Disappearance of all non-target lesions and normalization of 
tumor marker level. All lymph nodes must be non-pathological 
in size (<10 mm short axis) 
Incomplete Response/ 
Stable Disease (SD):  
Persistence of one or more non-target lesion(s) or/and mainte-
nance of tumor marker level above the normal limits 
Progressive Disease (PD): 
Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions* 
* Although a clear progression of “non target” lesions only is exceptional, in such circumstances, the opinion 
of the treating physician should prevail and the progression status should be confirmed later on by the review 
panel (or trial chair). 
Evaluation of best objective response 
o The best objective response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for PD the smallest measurements 

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recorded since the treatment started). In general, the patient's best response assignment will 
depend on the achievement of both measurement and confirmation criteria  
Target Lesions 
Non-Target Lesions 
New Lesions 
Objective Response 
CR 
CR 
No 
CR 
CR 
Incomplete response/SD 
No 
PR 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
o Patients with a global deterioration of health status requiring discontinuation of treatment with-
out objective evidence of disease progression at that time should be classified as having 
“symptomatic deterioration”. Every effort should be made to document the objective progres-
sion even after discontinuation of treatment.  
o In some circumstances it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of complete response depends on this determination, it is recommended 
that the residual lesion be investigated (fine needle aspirate/biopsy) to confirm the complete 
response status.  
Confirmation 
o The main goal of confirmation of objective response is to avoid overestimating the response 
rate observed. In cases where confirmation of response is not feasible, it should be made 
clear when reporting the outcome of such trials that the responses are not confirmed.  
o To be assigned a status of PR or CR, changes in tumor measurements must be confirmed by 
repeat assessments that should be performed no less than 4 weeks after the criteria for re-
sponse are first met. Longer intervals as determined by the trial protocol may also be appro-
priate.  
o In the case of SD, follow-up measurements must have met the SD criteria at least once after 
trial entry at a minimum interval (in general, not less than 6-8 weeks) that is defined in the trial 
protocol  
Duration of objective response 

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o The duration of objective response is measured from the time measurement criteria are met 
for CR or PR (whichever status is recorded first) until the first date that recurrence or PD is 
objectively documented, taking as reference for PD the smallest measurements recorded 
since the treatment started. 
Duration of stable disease 
o SD is measured from the start of the treatment until the criteria for disease progression are 
met, taking as reference the smallest measurements recorded since the treatment started. 
o The clinical relevance of the duration of SD varies for different tumor types and grades. There-
fore, it is highly recommended that the protocol specifies the minimal time interval required 
between 2 measurements for determination of SD. This time interval should take into account 
the expected clinical benefit that such a status may bring to the population under study. 
Definition of CT tumor response by RECIST 1.1 criteria: 
The following table outlines the response categories by RECIST 1.1 criteria. 
Target Lesions 
Non-Target Lesions 
New Le-
sions 
Overall Response 
Complete Response  
(sum of diameters=0 mm) 
Complete response 
No 
Complete Response 
Complete Response 
Non-complete res-
ponse, non-progres-
sive disease 
No 
Partial Response 
Complete Response 
Not evaluated 
No 
Partial Response 
(decrease in sum of target 
lesions by ≥30%) 
Non-progressive dis-
ease OR 
Not evaluated 
No 
Stable Disease 
Non-progressive dis-
ease OR 
Not evaluated 
No 
Stable Disease 
Not all evaluated 
Non-progressive dis-
ease 
No 
Not Evaluable 

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Progressive Disease 
(increase in sum of target 
lesions by ≥20% with an ab-
solute increase in summed 
diameters by 5mm) 
Any 
Yes or No 
Progressive Disease 
Any 
Progressive Disease 
Yes or No 
Any 
Any 
Yes 
E.A. Eisenhauer, et al. New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1) European 
Journal of Cancer 45 (2009) 228–247 doi:10.1016/j.ejca.2008.10.026. 

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12.4 
Appendix D:ASCO and CAP Guidelines on HER2 Testing in Breast Cancer 
To determine HER2-negativity, IHC or in situ hybridization can be used. Below are the CAP 
guidelines as a reference: 
HER2 Testing by Immunohistochemistry (IHC): 
Negative (Score 0): No staining observed or Incomplete, faint/barely perceptible membrane 
staining in ≤10% of invasive tumor cells 
Negative (Score 1+): Incomplete, faint/barely perceptible membrane staining in >10% of 
invasive tumor cells 
HER2 Testing by In Situ Hybridization: 
Reporting Results of HER2 Testing by In Situ Hybridization (single-probe assay): 
Negative (not amplified): Average HER2 copy number <4.0 signals/cell 
Reporting Results of HER2 Testing by In Situ Hybridization (dual-probe assay): 
Negative (not amplified): HER2/CEP17 ratio <2.0 AND average HER2 copy number 
<4.0 signals/cell