Conditions: Small Cell Lung Cancer Soft Tissue Sarcoma Triple-negative Breast Cancer Ovarian Cancer Endometrial Cancer
Keywords: Phase 1 (P1) Solid Tumor Small Cell Lung Cancer (SCLC) Breast Cancer Ovarian Cancer (OC) Soft Tissue Sarcoma (STS) Relapsed/Refractory Triple Negative Gastrointestinal stromal tumors (GIST) Epithelial cancer Peritoneal cancer Fallopian tube cancer Metastatic Advanced Endometrial Cancer (EC) Phase 2 (P2) Corrected QT interval (QTc) System Organ Class (SOC) Preferred Term (PT) Day 1 (D1) Day 15 (D15) Treatment-Emergent Adverse Events (TEAEs) Investigational Medicinal Product (IMP) Polymorphonuclear cell (PMN) Progressive Response (PR) Stable disease (SD) Maximum administered dose (MAD) Dose-limiting toxicity (DLT)
Allocation: NON_RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 71
Healthy volunteers: no

Brief summary:
Tinostamustine (EDO-S101) is a first-in-class alkylating deacetylase inhibitor designed to improve drug access to deoxyribonucleic acid (DNA) strands, induce DNA damage and counteract its repair in cancer cells. The main purpose of this study is to assess the safety, tolerability and efficacy of Tinostamustine in subjects with advanced solid tumours. Subjects will be given Tinostamustine via intravenous infusion on Days 1 and 15 of a 4-week cycle, the dose and infusion time will vary depending on the phase of the study.

Detailed description:
The study consists of 2 phases and 2 sub-studies:

This study is a multi-centre, open-label phase 1/2 study of single agent EDO-S101 in subjects with advanced solid tumours.

Phase 1 part of the study is designed to determine the safety, tolerability, maximum tolerated dose (MTD), recommended phase 2 dose (RP2D) and the Pharmacokinetic (PK) of EDO-S101 as a single agent in patients with solid tumours who have progressed after at least one (1) line of therapy and for whom no other standard therapy with proven clinical benefit is available.

Phase 2 part of the study is designed to evaluate the overall response rate (ORR) of the RP2D, plus the rate of patients with stable disease (SD) at 4 or 6 months, depending on the type of solid tumour. The RP2D was determined after phase 1 to be 80 mg/m2 of EDO-S101 administered over 1 hour on Day 1 and Day 15 of each 4-week treatment cycle.

In addition, two sub-studies are designed to better characterize the effect of EDO-S101: one at a dose of 60 mg/m2 administered over 60 minutes and the second at a dose of 80 mg/m2 administered over 80 minutes on cardiac repolarization (QTc) and other ECG parameters in the subjects with solid tumours.

Subjects were eligible for these studies if they had a histologically confirmed solid tumour, signed informed consent and met the inclusion/exclusion criteria. After providing informed consent, subjects were screened, and all procedures were performed as per protocol.

Arms:
arm 1: None arm 2: None arm 3: None arm 4: None arm 5: None arm 6: None arm 7: None arm 8: None arm 9: None arm 10: None arm 11: None arm 12: None arm 13: None

Interventions: intervention 1: Tinostamustine 60mg/m2 over 30min intervention 2: Tinostamustine 80mg/m2 over 30min intervention 3: Tinostamustine 100mg/m2 over 30min intervention 4: Tinostamustine 60mg/m2 over 60min intervention 5: Tinostamustine 80mg/m2 over 60min intervention 6: Tinostamustine 100mg/m2 over 60min intervention 7: Tinostamustine 80mg/m2 over 80min
Intervention descriptions: intervention 1: Tinostamustine as a single agent was administered at doses of 60mg/m2 by intravenous infusion over 30 minutes on Days (D) 1 and 15 of each 28-day cycle. intervention 2: Tinostamustine as a single agent was administered at doses of 80mg/m2 by intravenous infusion over 30 minutes on Days (D) 1 and 15 of each 28-day cycle. intervention 3: Tinostamustine as a single agent was administered at doses of 100mg/m2 by intravenous infusion over 30 minutes on Days (D) 1 and 15 of each 28-day cycle. intervention 4: Tinostamustine as a single agent was administered at doses of 60mg/m2 by intravenous infusion over 60 minutes on Days (D) 1 and 15 of each 28-day cycle. intervention 5: Tinostamustine as a single agent was administered at doses of 80mg/m2 by intravenous infusion over 60 minutes on Days (D) 1 and 15 of each 28-day cycle. intervention 6: Tinostamustine as a single agent was administered at doses of 100mg/m2 by intravenous infusion over 60 minutes on Days (D) 1 and 15 of each 28-day cycle. intervention 7: Tinostamustine as a single agent was administered at doses of 80mg/m2 by intravenous infusion over 80 minutes on Days (D) 1 and 15 of each 28-day cycle.

Protocol document:
SAP_004.pdf: 











































































































Prot_002.pdf: 
Mundipharma Research Limited 
Protocol Number: EDO-S101-1002 v6.2 
Confidential and Proprietary 
08 April 2020 
Page 1 of 61 
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 60 mg/m2 Administered 
during a 60-minute Infusion on Cardiac Repolarization in 6 Patients with Advanced Solid Tu-
mors 
 
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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TABLE OF CONTENTS 
TABLE OF CONTENTS......................................................................................................................... 2 
TABLE OF TABLES .............................................................................................................................. 5 
ABBREVIATIONS AND DEFINITIONS OF TERMS ............................................................................. 6 
1 
PROTOCOL SYNOPSIS ........................................................................................................... 10 
2 
SCHEDULE OF ASSESSMENTS ............................................................................................. 17 
3 
INTRODUCTION ........................................................................................................................ 21 
3.1 
Background ........................................................................................................................ 22 
3.2 
Preclinical Pharmacology and Toxicology ......................................................................... 22 
3.3 
Preclinical Cardiac Safety .................................................................................................. 23 
3.4 
Clinical Data ....................................................................................................................... 23 
3.4.1 
Clinical Cardiac Safety .................................................................................... 23 
3.5 
Sub-study Rationale .......................................................................................................... 24 
4 
SUB-STUDY OBJECTIVES ...................................................................................................... 25 
4.1 
Primary Objectives............................................................................................................. 25 
4.2 
Secondary Objectives ........................................................................................................ 25 
4.3 
Exploratory Objective ........................................................................................................ 25 
5 
TRIAL DESIGN .......................................................................................................................... 26 
5.1 
Overall Sub-Study Design ................................................................................................. 26 
6 
SELECTION AND WITHDRAWAL OF PATIENTS .................................................................. 28 
6.1 
Inclusion Criteria for sub-study .......................................................................................... 28 
6.2 
Exclusion Criteria for sub-study ......................................................................................... 29 
6.3 
Trial Termination ................................................................................................................ 29 
6.3.1 
Withdrawal of Patient from Trial Treatment ..................................................... 29 
7 
TRIAL ASSESSMENTS............................................................................................................. 31 
7.1 
Screening ........................................................................................................................... 31 
7.2 
Informed Consent .............................................................................................................. 31 
7.3 
Inclusion/Exclusion Criteria ............................................................................................... 31 
7.4 
Demographics and Medical History ................................................................................... 31 
7.5 
Physical Examination ........................................................................................................ 31 
7.6 
Vital Signs, Height and Weight .......................................................................................... 32 
7.7 
ECOG Performance Status ............................................................................................... 32 
7.8 
12-Lead ECG (Safety and Holter) ..................................................................................... 32 
7.9 
Pharmacodynamics (Gene Expression) ............................................................................ 33 
7.10 
Clinical Laboratory Tests (Hematology, Chemistry and Urinalysis) .................................. 34 


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7.11 
Pregnancy Testing ............................................................................................................. 35 
7.12 
Treatment-Emergent Adverse Events (TEAEs) ................................................................ 35 
7.13 
Infusion Site and Allergic Reaction Assessment ............................................................... 35 
7.14 
Prohibited Concomitant Medications and Procedures ...................................................... 35 
7.14.1 
Steroids ........................................................................................................... 35 
7.14.2 
Valproic Acid.................................................................................................... 36 
7.14.3 
Allopurinol ........................................................................................................ 36 
7.14.4 
Serotonin 5-HT3 receptor antagonists ............................................................ 36 
7.14.5 
NK1 receptor antagonists ................................................................................ 36 
7.14.6 
Investigational agents ...................................................................................... 36 
7.15 
Efficacy Evaluations .......................................................................................................... 36 
7.15.1 
Baseline Disease Assessment ........................................................................ 36 
7.15.2 
Disease Response Assessments .................................................................... 36 
7.15.3 
Follow-up Assessments .................................................................................. 36 
7.16 
PK Assessments................................................................................................................ 37 
7.17 
Missed Visits ...................................................................................................................... 37 
8 
TRIAL TREATMENT .................................................................................................................. 38 
8.1 
Investigational Drug Description ........................................................................................ 38 
8.2 
Storage and Dispensing .................................................................................................... 38 
8.3 
Supply, Packaging and Labeling ....................................................................................... 38 
8.4 
Treatment Allocation .......................................................................................................... 38 
8.5 
Investigational Product Administration .............................................................................. 39 
8.6 
Treatment Criteria Beyond Cycle 1, Day 1 ........................................................................ 39 
8.7 
Dose Modification Guidelines and Stopping Rules for Patients who Experience 
Clinically Significant QTcF Prolongations .......................................................................... 39 
8.8 
Investigational Product Accountability ............................................................................... 40 
8.9 
Supportive Care ................................................................................................................. 40 
8.10 
Drug Interactions/Precautions ........................................................................................... 41 
8.11 
Overdose ........................................................................................................................... 42 
9 
TEAES AND SAES .................................................................................................................... 43 
9.1 
Definition of a Treatment Emergent Adverse Event (TEAE) ............................................. 43 
9.2 
Recording Adverse Events ................................................................................................ 43 
9.3 
Serious Adverse Events .................................................................................................... 44 
9.4 
Events of Special Interest .................................................................................................. 45 
9.5 
Suspected Unexpected Serious Adverse Reactions (SUSARs) ....................................... 45 
9.6 
Reporting of TEAEs, SAEs, Serious and Unexpected Adverse Experiences ................... 46 
9.6.1 
Reporting TEAEs and SAEs to the Sponsor ................................................... 46 


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9.6.2 
Reporting Suspected Unexpected Serious Adverse Reactions ...................... 46 
9.6.3 
Reporting of Grade 4 and Grade 5 TEAEs ..................................................... 46 
9.6.4 
Reporting of Important Medical Events of Special Interest ............................. 46 
9.6.5 
Reporting Pregnancy ....................................................................................... 46 
9.6.6 
Reporting to the IRB/IEC ................................................................................. 47 
9.6.7 
Annual Safety and Progress Reports (DSUR) ................................................ 47 
10 
TRIAL ADMINISTRATION ........................................................................................................ 48 
10.1 
Case Report Forms and Source Documentation .............................................................. 48 
10.2 
Good Clinical Practice Statement ...................................................................................... 48 
10.3 
Investigator Documentation ............................................................................................... 48 
10.4 
Record Retention ............................................................................................................... 48 
10.5 
Protocol Deviations and Amendment ................................................................................ 48 
10.6 
Institutional Review Board and Independent Ethics Committee ....................................... 49 
10.7 
Sponsor Monitoring and Auditing ...................................................................................... 49 
10.8 
General Informed Consent and Sub-study Informed Consent for Genetic 
Samples ............................................................................................................................. 50 
10.9 
Confidentiality .................................................................................................................... 50 
10.10 Financial Disclosure .......................................................................................................... 51 
10.11 Reporting and Publication Policy ....................................................................................... 51 
10.12 Insurance ........................................................................................................................... 52 
11 
REFERENCES ........................................................................................................................... 53 
12 
APPENDICES ............................................................................................................................ 54 
12.1 
Appendix A: Eastern Cooperative Oncology Group (ECOG) Performance Status 
Scale10 ............................................................................................................................... 54 
12.2 
Appendix B: NYHA Functional Classification .................................................................... 55 
12.3 
Appendix C: New response evaluation criteria in solid tumors: Revised RECIST 
guideline (version 1.1) ....................................................................................................... 56 
12.4 
Appendix D: ASCO and CAP Guidelines on HER2 Testing in Breast Cancer .................. 61 
 


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TABLE OF TABLES 
Table 1 
Schedule of Assessments ........................................................................... 17 
 


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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 
INN 
International Nonproprietary Name 
IRB 
Institutional Review Board 
ISH 
In situ hybridization 
LDH 
Lactate dehydrogenase 
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 
PARP 
Poly (ADP-ribose) polymerase 
PFS 
Progression free survival 


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Abbreviation 
Explanation 
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 
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 
TNBC 
Triple negative breast cancer 
ULN 
Upper limit of normal 
US, USA 
United States, United States of America 


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Abbreviation 
Explanation 
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 60 
mg/m2 Administered during a 60-minute Infusion on Cardiac Repolariza-
tion in 6 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 60 mg/m2 on 
cardiac repolarization (QTcF) and other ECG parameters in 6 patients 
with solid tumors who have progressed after at least one line of ther-
apy 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 establish the pharmacokinetic (PK) profile of tinostamustine 60 
mg/m2 administered over 1 hour on Day 1 and 15 of each 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: 
• 
To correlate the extent of gene expression changes in tumor samples 
with anti-tumor activity. 
Clinical Phase 
Phase 1 sub-study to Phase 1/2 clinical trial EDO-S101-1002 
Trial Drug 
Tinostamustine (EDO-S101) 
No. of Patients 
Maximum 6 patients  
Number of Centers 
Up to three centers; 6 patients will be enrolled in the United States.   


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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 the Phase 1 portion of the EDO-S101-1002 trial.  
An additional subgroup of six (6) patients treated with a dose of 60 mg/m2 ti-
nostamustine administered over 60 minutes will be studied with intense ECG 
measurements, including 24-h Holter monitoring, and PK sampling. The PK 
sampling will occur at the first 2 treatment infusions in cycle 1 assuming no 
Grade 3 or higher (CTCAE v.5) QTcF prolongation in any 2 subjects or any fatal 
cardiac event occur in 1 or more subjects.  
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. In particular, the distribution of the Cmax 
levels and the variability of the QTcF in this population will be described as well 
as the apparent relationship between Cmax and QTcF changes for the assess-
ment of further dose escalation to ensure subject safety. 
These 6 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 patients the study will be stopped. Additionally, if any 
two or more patients have grade 3 or greater centrally confirmed QTc prolonga-
tion or QTcF increased >60 ms from baseline or ≥1 patient has a fatal cardiac 
event related to tinostamustine, the trial will be stopped. 
Additional patients beyond the initial 6 patients at the 60 mg/m2 dose or new 
cohorts evaluating higher doses can only be enrolled following review of the data 
with regulatory authorities. 
Sub-Study 
Stopping Rules 
Stopping Rules for sub-study for administering Tinostamustine  
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.  
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 baseline. 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 


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will then be made by the Sponsor in consultation with the Medical Monitor, 
whether tinostamustine treatment is to continue or be postponed. 
If any two or more patients have grade 3 or greater centrally confirmed QTc 
prolongation or QTcF increased >60 ms from baseline or ≥1 patient has a fatal 
cardiac event related to tinostamustine , the trial will be stopped.  
 (Refer to Section 8.7, Dose modification guidelines and stopping rules, for the 
management of patients who experience clinically significant QTcF 
prolongations). 
General stopping rules for sub-study: 
If 2 patients from the cohort of 6 experience the following AEs at Grade 3 judged 
to be causally related to study drug or application procedure, the sub-study will 
be stopped for enrollment and the patients already recruited stopped for further 
treatment.   
• 
G3 deep venous thrombosis  
• 
G3 serum creatinine 
• 
G3 nervous system disorders excluding headache  
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 


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(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.  
• 
Discontinuation of previous cancer therapies at least 3 weeks or 5 half-
lives, whichever is shorter, as long as the patient has recovered to 
eligibility levels prior to treatment in this trial. 
• 
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. 
• 
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 mg/dL unless elevated due to known Gilbert’s 
syndrome. 
• 
Creatinine ≤1.5 ULN. 
• 
Serum potassium and magnesium within normal range, at baseline 
(supplementation is permissible). 
• 
Men and 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 for at least 90 days after the administration of the trial 
drug to be eligible to participate. 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): http://crediblemeds.org/new-drug-list. 


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• 
Patients who are being treated with Valproic Acid for any indication 
(epilepsy, mood disorder) must be excluded or must stop using the 
medication and have a wash out period of 3.5 days prior to first dose of 
tinostamustine in this trial. 
• 
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,  
• 
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 within 30 days or 5 half-lives prior to 
the first dose of tinostamustine, provided the patient has recovered from 
any related toxicities ≥Grade 1.  
• 
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.  
Dose and Schedule The dose of 60 mg/m2 tinostamustine administered over 60 minutes. 
Administration D1 and D15 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 beyond 6 cycles 
in responding patients or patients who have experienced clinical benefit up to a 
maximum of 12 cycles. 


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Duration of sub-
study / Patient 
Participation 
The number of patients participating in this sub-study is 6 at maximum. An 
estimated three 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 in both stages of the trial 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 
Patient participation in the gene expression analysis is not mandatory for 
enrollment into the trial. If the patient agrees to participate in the gene expression 
analysis, a fresh or archival tissue sample will be collected during screening. 
Formalin fixed paraffin embedded (FFPE) biopsy samples will be used. The 
Affymetrix chip technology for analyzing total ribonucleic acid (RNA) will be 
used. For formalin fixed paraffin embedded samples, RecoverAll method from 
Ambion® for isolating total RNA will be used. The isolated RNA is total RNA and 
will contain both messenger RNA (mRNA) and micro RNA (miRNA). The 


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expression profile will be analyzed for correlation with response or resistance to 
therapy. Details of sample preparation and shipping are described in the 
Laboratory Manual. 
Sample Size 
Determination, 
Analyses 
No formal sample size determination  


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2 
SCHEDULE OF ASSESSMENTS 
Table 1 
Schedule of Assessments 
Procedure 
Screening 
28 days from Base-
line (First Day Trial 
Drug Administra-
tion); Scans 28 days 
from Baseline15 
Cycle 1 and Subsequent Cycles1 
Trial Drug 
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 
X 
 
 
 
 
 
 
 


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Procedure 
Screening 
28 days from Base-
line (First Day Trial 
Drug Administra-
tion); Scans 28 days 
from Baseline15 
Cycle 1 and Subsequent Cycles1 
Trial Drug 
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 TEAEs 
 
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: 24h (±2 hr) 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 trial 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 60 minutes from the start of tinostamustine administration on D1 and D15 each treatment cycle. Additional single ECGs will be conducted at 
90, 120 and 180 min and at study drug discontinuation. Additional ECGs may be conducted as clinically indicated. 
Holter monitoring will commence 60 minutes prior to the start of the infusion on C1D1 and will continue through 24 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 15, 30, 45, 60, 75, 90, 120, 180, 360 minutes and 24 hours from the start of infusion. 
• 
C1D15: prior to the start of infusion, and 15, 30, 45, 60, 75, 90, 120, 180, 360 minutes and 24 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 15, 30 and 45 minutes, 1 hour, 75 and 90 minutes, and 2, 3, 6, and 24 hours from the start of the tinostamustine infusion, from the start of drug 
administration. Samples will be taken at the same time and as close to the exact time point as possible, with sample draw windows: 15, 30, 45, 60, 75, and 90 minutes (±5 
minutes); 2, 3 and 6 hr (±10 minutes), and 24 hr (±2 hr). In Phase 1, the PK profiles of tinostamustine in plasma were assessed in each patient during the escalation phase 
and in Phase 2, at centers participating a maximum of 55 patients consecutively enrolled will participate in the PK analysis. The remaining patients will have only one PK 
assessment at the end of infusion. 
6 Best efforts will be undertaken to obtain specimens of tumor from patients. Information on the purpose of genetic research in the gene-expression sub-trial is provided, either 
in the main ICF or a separate ICF, based on applicable regulatory requirements, 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. See Section 7.9 and the Laboratory Manual for tumor sample requirements. 
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).  
8 Serum chemistry will include albumin, total protein, creatinine, uric acid, blood urea nitrogen (BUN), sodium, potassium, calcium, glucose, total bilirubin, alkaline phosphatase, 
AST, ALT, gamma-glutamyl transferase (GGT), lactate dehydrogenase (LDH) and C-reactive protein (CRP). 
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, 1 hr (±15 min). The patient will be observed at 1 hr (±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 until 1 year after the last patient’s first treatment (C1D1). 


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


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3 
INTRODUCTION 
Tinostamustine (formerly EDO-S101) is a first-in-class alkylating deacetylase inhibiting molecule 
(DACi), a fusion of an alkylator, bendamustine, and a histone-deacetylase inhibitor (HDACi), vori-
nostat. 
The compound was designed to be a fully bi-functional molecule with the hypothesis that HDAC inhi-
bition would relax chromatin by increased acetylation of histones and make it more accessible to 
deoxyribonucleic acid (DNA) damaging moiety. Additionally, the assumption was that a molecule that 
would not be cleaved in the mammalian organism might be the optimal approach to exploit the syn-
ergies of both modes of action. This way, differences caused by the route of administration and phar-
macokinetic (PK) profile of two independent drugs would be irrelevant and maximum activity and a 
clear safety profile would be expected to be seen. 
Tinostamustine has been investigated for the treatment of patients with hematologic malignancies 
(EDO-S101-1001) and solid tumors (EDO-S101-1002) at doses ranging from 20 mg/m2 to 120 mg/m2 
once every 3 or 2 weeks, respectively.  The most common toxicities observed have been hematologic 
in nature, including Grade 3/4 neutropenia, thrombocytopenia, and febrile neutropenia, including 
dose-limiting cases.  Based on the experience with bendamustine, which has a kaliuretic effect and 
might lead to hypokalemia, potassium levels were evaluated before every tinostamustine infusion, 
with potassium supplementation considered if levels were <3.5 mmol/L. Mild (Grade 1) hypokalemia 
was observed in 2 patients in the initial clinical study.  Clinically significant QTc prolongation was not 
observed in either trial. 
Based on these findings, the utility of tinostamustine as a conditioning agent prior to autologous stem 
cell transplantation (ASCT) was considered plausible. Study EDO-S101-1004 (TITANIUM) was there-
fore designed to explore the potential efficacy and safety of tinostamustine used as conditioning agent 
for ASCT in patients with relapsed/refractory multiple myeloma who had undergone a prior ASCT, a 
population of patients for whom ASCT was indicated.  The initial dose of tinostamustine in the Phase 
1 portion of the study was 180 mg/m2, with escalation to 220, 260, and then 300 mg/m2 (or higher) 
planned, using a standard 3+3 design.   
In study EDO-S101-1004, 3 subjects have been dosed with tinostamustine 180 mg/m2 and 3 subjects 
with 220 mg/m2 as a 1-hour infusion. In the 180 mg/m2 cohort, one subject had a >60 ms QTcF 
increase, and a second had a 30-60 ms QTcF increase. In the 220 mg/m2 cohort, one subject had a 
nearly 60 ms increase in QTcF, and one subject had a > 90 ms increase in QTcF to a peak QTcF of 
509 ms, 60 minutes after dosing. In all cases, the peak increase in QTc occurred 45-90 minutes after 
dosing, with QTc returning to baseline within 90-180 minutes. Three of the four subjects with large 
QTcF increases (nearly 60ms increase over baseline or higher) had tinostamustine plasma concen-
trations > 3000 ng/mL.   
Based in the QTc effects observed in the first two cohorts in TITANIUM, the trial has been cancelled, 
and the sponsor plans to amend the two ongoing trials, EDO-S101-1001 and EDO-S101-1002, to 
include more intense ECG and PK collection in order to allow a precise characterization of the effects 
of tinostamustine, at the dosages being investigated for the treatment of hematologic and solid tu-
mors, on cardiac repolarization (QTc) and other ECG parameters. 
 


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3.1 
Background 
3.2 
Preclinical Pharmacology and Toxicology 
Tinostamustine is a small molecule with molecular weight 415 Dalton, and is an alkylating histone-
deacetylase inhibitor (HDACi) fusion molecule with full bi-functional properties. The compound is 
made of bendamustine as alkylator and vorinostat as HDACi, covalently linked together in one mole-
cule.   
Tinostamustine has been administered as a 1-hour IV infusion to beagle dogs at doses up to 15 
mg/kg.  The half-life of tinostamustine is short, approximately 5-10 min. The plasma concentration 
declines rapidly after the infusion is stopped. In dogs administered 15 mg/kg, tinostamustine was not 
detectable by 0.5 hours post infusion.   
An in vitro metabolic study was performed with human, rat and dog hepatocytes in which ti-
nostamustine at the concentrations of 1 and 10 μM was incubated with cryopreserved hepatocytes. 
Tinostamustine is primarily metabolized by i) oxidation of the hydroxy amide moiety to carboxylic acid; 
ii) hydrolysis of 1 of 2 chlorine atoms; iii) oxidative shortening of the aliphatic side-chain; iv) loss of 
one chloroethyl group; and v) combinations of these biotransformations. For all but 2 metabolites 
found in the samples, the elemental composition could be proposed. Tinostamustine was stable in 
negative control sample. After 90 minutes incubation in the medium alone at the concentration of 10 
μM, tinostamustine accounted for 94% of total drug-related material. The functional moieties of ti-
nostamustine were the most sensitive to metabolic degradation. Accordingly, all metabolites would 
be considered less- active than the parent compound. 
The main metabolite in the human 90-minute sample was M2 (hydrolysis of 2 Cl atoms at the alkyl-
ating site), accounting for 15% of the total metabolites. All relevant metabolites found in human were 
qualitatively present in other species, while in different distributions. M2 metabolite was present only 
in a limited amount (2%) after 90 minutes incubation with both, rat and dog hepatocytes. Hence, 
within the non-clinical toxicology program, in these species the contribution of M2 to the overall toxi-
cology of tinostamustine was limited. 
The excretion profile of tinostamustine was evaluated in a radiolabeled study following IV administra-
tion of [14C]-tinostamustine as bolus and as 1-hour infusion in male rats. Two doses were investigated, 
15 and 30 mg/kg. Main blood and plasma PK parameters were also calculated. No relevant differ-
ences in excretion profile were observed between the 2 modes of administration. After a single IV 
administration 35.6-39.8% radioactivity was eliminated in faeces, 8.0-13.3% with urine, and 25% with 
expired air as [14C]-CO2. At the end of the excreta collection period, the radioactive dose recovered 
from the carcasses of the animals after IV dosing ranged between 9.4- 12.3%.  The total cumulative 
amount of radioactivity recovered within 72 hours after dosing was between 60.6-67.2% of the ad-
ministered dose. 
The non-clinical toxicology study program for tinostamustine was performed according to the Inter-
national Council for Harmonisation S9 Guidance “Nonclinical Evaluation for Anticancer Pharmaceu-
ticals.” in the standard rodent species rat (Sprague Dawley) and in the standard non- rodent species 
dog (Beagle). Single dose toxicology/toxicokinetic studies were conducted in both species and a re-
peat-dose study in rats. 


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Overall, the non-clinical toxicology single dose studies showed that tinostamustine has a toxicity pro-
file similar to alkylators; bone marrow toxicity and depletion of white blood cells with nadir at Day 7 
and recovery by Day 21 were demonstrated in both species. Other observed toxicities included em-
esis and liquid feces in dogs and inappetence in rats. No organ toxicity was observed within the single 
dose studies apart of reversible reduced cellularity of the bone marrow and other lymphatic tissues 
(lymph nodes, thymus and spleen). 
Toxicity reported in the repeat dose study was similar to the toxicity observed in single dose studies. 
However, minimal to moderate secondary treatment-related findings linked to immunosuppression 
were present in the lumbar lymph nodes, lungs, heart (minimal to slight inflammatory cell infiltrates in 
the myocardium), and at injection sites. Following a 28-day treatment-free period, there was complete 
recovery in the thymus, lungs and liver, while partial recovery was observed in the spleen, lymph 
nodes, Peyer’s patches, bone marrow, heart, and injection sites. 
3.3 
Preclinical Cardiac Safety 
A GLP in vitro hERG safety assay determined IC50 for the inhibitory effect of tinostamustine on hERG 
potassium current at 0.38 µM, a concentration lower than needed for preclinical efficacy.  The ti-
nostamustine effect on cardiac activity was also evaluated in dogs in an exploratory toxicology MTD 
(maximum tolerated dose) study and in the subsequent telemetric study in which tinostamustine was 
administered by 1-hour IV infusion. Both studies showed that tinostamustine had no effect on the 
ECG parameters, including the QTc interval. Only a moderate decrease of systolic and diastolic pres-
sure was observed in the telemetric study, resulting in overall decreases in mean arterial and pulse 
pressure. 
3.4 
Clinical Data 
Tinostamustine has been evaluated in 3 clinical studies to date, Study EDO-S101-1001 in 55 patients 
(46 patients in the escalation part and 9 patients in the expansion part) with hematologic malignancies 
and Study EDO-S101-1002 in 45 patients with solid tumors (22 patients in phase I and 23 patients in 
phase II), and as a conditioning agent prior to autologous stem cell transplantation to 6 patients in 
EDO-S101-1004. A total of 106 patients have been treated to date in the 3 clinical studies. 
3.4.1 Clinical Cardiac Safety 
3.4.1.1 EDO-S101-1001 
EDO-S101-1001 is a Phase 1 study designed to evaluate the safety, pharmacokinetics (PK), and 
efficacy of tinostamustine in patients with relapsed/refractory hematologic malignancies. Ti-
nostamustine was administered at doses ranging from 20 -120 mg/m2 on D1 of 21-day cycles with 
infusion durations ranging from 30-60 minutes.  The MTD was identified as 100 mg/m2 administered 
over 1 hour.  12-lead ECGs were collected at screening and in triplicate one hour prior to dosing on 
Day 1 of Cycle 1. Additional ECGs were performed at 15, 30, 45, 60, +/-5min; 90 and 120 minutes 
+/-15min and at 3, 4, and 24 hours +/-30min from the start of EDO-S101 infusion, in Cycle 1 only and 
study discontinuation, and were not centrally measured.  However, all ECGs which were reported to 
have prolonged QTc based on the ECG machine generated measurements were reviewed by an 
independent cardiac safety expert.  Although the ECG machine generated measurements indicated 
that several subjects had marked QTc prolongation, an independent review of these ECGs revealed 
that no subjects had QTcF > 500 ms, only 2 subjects had QTcF > 480 ms, and only 2 subjects had 


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QTcF increases of > 60 ms.  The most extreme example of an ECG machine QTc over-measurement 
occurred for a subject in EDO-S101-1001, who had ECG machine reported QTcB and QTcF meas-
urements of 677 ms and 644 ms, respectively, at the discontinuation visit (a 208 ms increase from 
the baseline QTcF, 434 ms).  The manually measured QTcF was 463 ms (a 46 ms increase from the 
baseline QTcF of 417 ms). 
3.4.1.2 EDO-S101-1002 
EDO-S101-1002 is a Phase 1/2 study designed to evaluate the safety, pharmacokinetics (PK), and 
efficacy of tinostamustine in patients with advanced solid tumors.  Tinostamustine was administered 
at doses of 60 -100 mg/m2 with infusion durations of 30 or 60 minutes.  ECGs were collected in 
triplicate at screening, C1D1, C1D15, and study discontinuation while single ECGs were collected 
during subsequent cycles.  ECG measurements were not centralized.  However, all ECGs which were 
reported to have prolonged QTc based on the ECG machine generated measurements were re-
viewed by an independent cardiac safety expert.  Although the ECG machine generated measure-
ments indicated that several subjects had marked QTc prolongation, an independent review of these 
ECGs revealed that 1 subject had QTcF > 500 ms, and only 1 subject had QTcF 480-500 ms. 
3.4.1.3 EDO-S101-1004 
• 
EDO-S101-1004 was designed as a 2-part, international, multi-center, open-label study of sal-
vage treatment with tinostamustine conditioning followed by autologous stem cell transplant 
(ASCT) in patients with relapsed/ refractory multiple myeloma (MM).  The total dose of ti-
nostamustine is administered on Day -1, with ASCT on Day 1.  The initial tinostamustine dose 
was 180 mg/m2, and the second cohort received 220 mg/m2.  Continuous 12 lead holter ECGs 
which allowed collection of both safety ECGs, for standard ECG measurements and holter, were 
collected on Day -1, the day of tinostamustine administration, for 24 hours. Replicate ECGs were 
extracted from the continuous 12 lead ECG recordings and were analyzed by ERT using the high 
precision QT method.  Baseline time points were obtained on Day -1 directly prior to dosing 0 
minutes [before start of infusion].  Post-dose time points occurred at the following times after start 
of the infusion: 15, 30, 45, 60 and 75 minutes and 3, 6, and 24 hours following the start of the 
infusion. 
• 
Prior to study termination, 3 subjects were dosed with 180 mg/m2, and 3 subjects with 220 mg/m2.   
• 
In the 180 mg/m2 cohort, one subject had a >60 ms QTcF increase, and a second had a 30-60 
ms QTcF increase.   
• 
In the 220 mg/m2 cohort, one subject had a nearly 60 ms increase in QTcF, and one subject had 
a > 90 ms increase in QTcF to a peak QTcF of 509 ms, 60 minutes after dosing.  In all cases, 
the peak increase in QTc occurred 45-90 minutes after dosing, with QTc returning to baseline 
within 90-180 minutes.  Three of the four subjects with large QTcF increases (nearly 60 ms in-
crease over baseline or higher) had tinostamustine Cmax > 3000 ng/mL. 
3.5 
Sub-study Rationale 
This sub-study is designed to better characterize the effect of Tinostamustine on cardiac repolariza-
tion (QTc) and other ECG parameters, at the dosages investigated for the treatment of solid tumors 
in the phase 1 portion of EDO-S101-1002 trial.  


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4 
SUB-STUDY OBJECTIVES 
4.1 
Primary Objectives 
• 
To characterize the effect of tinostamustine at a dose of 60 mg/m2 on cardiac repolarization 
(QTcF) and other ECG parameters in 6 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 establish the pharmacokinetic (PK) profile of tinostamustine 60 mg/m2 administered over 
1 hour on Day 1 and 15 of each 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 
• 
To correlate the extent of gene expression changes in tumor samples with anti-tumor activity. 


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5 
TRIAL DESIGN 
5.1 
Overall Sub-Study 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 the Phase 1 
portion of the EDO-S101-1002 trial.  
An additional subgroup of six (6) patients treated with a dose of 60 mg/m2 tinostamustine administered 
over 60 minutes will be studied with intense ECG measurements, including 24-h Holter monitoring, 
and PK sampling. The PK sampling will occur at the first 2 treatment infusions in cycle 1 assuming 
no Grade 3 or higher (CTCAE v.5) QTcF prolongation occurs in any two or more patients or QTcF 
increased >60 ms from baseline or ≥1 patient has a fatal cardiac event related to tinostamustine, the 
trial will be stopped 
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. In par-
ticular, the distribution of the Cmax levels and the variability of the QTcF in this population will be 
described as well as the apparent relationship between Cmax and QTcF changes for the assess-
ment of further dose escalation to ensure subject safety. 
These 6 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 patients the study will be stopped. Additionally, if any two or more patients 
have grade 3 or greater centrally confirmed QTc prolongation or QTcF increased >60 ms from base-
line or ≥1 patient has a fatal cardiac event related to tinostamustine, the trial will be stopped. 
Additional patients beyond the initial 6 patients at the 60 mg/m2 dose or new cohorts evaluating 
higher doses can only be enrolled following review of the data with regulatory authorities. 
Stopping Rules for sub-study for administering Tinostamustine  
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.  
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 baseline. 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. 


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If any two or more patients have grade 3 or greater centrally confirmed QTc prolongation or QTcF 
increased >60 ms from baseline or ≥1 patient has a fatal cardiac event related to tinostamustine, the 
trial will be stopped.  
(Refer to Section 8.7, Dose modification guidelines and stopping rules, for the management of 
patients who experience clinically significant QTcF prolongations). 
General stopping rules for sub-study: 
If 2 patients from the cohort of 6 experience the following AEs at Grade 3 judged to be causally related 
to study drug or application procedure, the sub-study will be stopped for enrollment and the patients 
already recruited stopped for further treatment.   
• 
G3 deep venous thrombosis  
• 
G3 serum creatinine 
• 
G3 nervous system disorders excluding headache  


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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. 
• 
Discontinuation of previous cancer therapies at least 3 weeks or 5 half-lives, whichever is 
shorter, as long as the patient has recovered to eligibility levels prior to treatment in this trial. 
• 
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. 
• 
Aspartate aminotransferase/alanine aminotransferase (AST/ALT) ≤3× ULN. In cases with liver 
involvement ALT/ AST ≤5× ULN. 
• 
Total bilirubin ≤1.5 mg/dL unless elevated due to known Gilbert’s syndrome. 
• 
Creatinine ≤1.5 ULN. 
• 
Serum potassium and magnesium within normal range, at baseline (supplementation is 
permissible).  
• 
Men and 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 for at least 90 days 
after the administration of the trial drug to be eligible to participate. 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. 


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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): 
http://crediblemeds.org/new-drug-list. 
• 
Patients who are being treated with valproic acid for any of its indication (epilepsy, mood 
disorder) must be excluded or must stop using the medication and have a wash out period of 
3.5 days prior to first dose of tinostamustine in this trial.  
• 
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,  
• 
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 within 30 days or 5 half-lives prior to the first dose of 
tinostamustine, provided the patient has recovered from any related toxicities ≥Grade 1. 
• 
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. 
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 


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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. Separate consent must be 
provided for collection of samples for determination of gene expression. 
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 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 
• 
Neurologic 


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• 
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. 
Safety ECGs (standard digital 12-lead) will be immediately available to site staff for assessment 
(Section 7.8.1.2). 


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7.8.1.1 Holter ECGs 
Holter monitoring will commence 60 minutes prior to the start of the infusion on C1D1 and 15 minutes 
prior to the start of infusion in C1D15 and will continue through 24 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 15, 30, 45, 60, 75, 90, 120, 180, 360 minutes and 
24 hours from the start of infusion. 
• 
C1D15: prior to the start of infusion, and 15, 30, 45, 60, 75, 90, 120, 180, 360 minutes and 24 
hours from the start of 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 
and triplicate ECGs at 60 minutes from the start of tinostamustine administration on D1 and D15 of 
each treatment cycle. Additional single ECGs will be conducted at 90, 120 and 180 min and at study 
drug discontinuation. 
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) 
Patient participation in the gene expression analysis is not mandatory for enrollment into the trial. 
Information on the purpose of genetic research in the gene-expression sub-trial is provided, either in 
the main ICF or a separate ICF, based on applicable regulatory requirements, 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. 
If the patient agrees to participate in the gene expression analysis, a fresh or archival tissue sample 
will be collected during Screening. Formalin fixed paraffin embedded (FFPE) biopsy samples will be 
used. The Affymetrix chip technology for analyzing total ribonucleic acid (RNA) will be used. For for-
malin fixed paraffin embedded samples, RecoverAll method from Ambion® for isolating total RNA will 
be used. The isolated RNA is total RNA and will contain both messenger RNA (mRNA) and micro 
RNA (miRNA). The expression profile will be analyzed for correlation with response or resistance to 
therapy. Details of sample preparation and shipping are described in the Laboratory Manual. 


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Samples will be stored in accordance with the IRB/IEC approved ICF and applicable laws. Several 
steps will be taken to keep the patients identity and the genetic test result confidential throughout the 
trial (e.g., double coding of the samples; restricted access to the samples and testing results). 
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, 15 
and 22 of treatment cycles 1 to 6, 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 before the start of tinostamustine infusion. Patients continuing on 
trial beyond Cycle 6 will have blood samples collected on days of investigational product administra-
tions and at the time of investigational product discontinuation (at any time or Day 28 of the last 
treatment cycle).  
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 and 15 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, uric acid, blood urea nitrogen, 
sodium, potassium, calcium, glucose, total bilirubin, alkaline phosphatase, AST, ALT, gamma-glu-
tamyl transferase (GGT), lactate dehydrogenase (LDH), and C-reactive protein (CRP). In addition, an 
evaluation of potassium levels 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 product 
discontinuation (at any time or Day 28 of the last treatment cycle). Urine microscopic examination will 
be performed if there are any positive findings upon dipstick assessment. 
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. 


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7.11 
Pregnancy Testing 
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 9.6.5 for details regarding the pregnancy 
reporting procedure. 
Males and female patients of child-bearing potential and their partners, must be willing to use at least 
2 effective forms of birth control during tinostamustine administration and for at least ninety (90) days 
after the administration.  
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 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 
Treatment-Emergent Adverse Events (TEAEs) 
Monitoring and recording of TEAEs will be conducted from the time of start of first dose administration 
to discontinuation of tinostamustine (D28 of last treatment cycle). TEAEs, including serious adverse 
events (SAEs), will be captured in the eCRFs from the first day of tinostamustine dosing through 
discontinuation of tinostamustine. 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.  
In Phase 2, a 2 mg/mL tinostamustine infusion solution after reconstitution will be utilized as outlined 
in the IB V5.0. Assessment of injection site reactions must be performed on each treatment day at 
pre-dose and 1-hour (± 15 minutes) post dose.  
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. 


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7.14.2 Valproic Acid 
Patients receiving valproic acid for any indication (epilepsy, mood disorder) must be excluded from 
the trial or must stop using the medication and have a wash out period of 3.5 days. 
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. 
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 during the administration of tinostamustine. Given 
the short half-life of tinostamustine, ondansetron can be used, if needed, for the prophylaxis of 
delayed nausea and vomiting. A minimal interval of 24 hours should be respected between the last 
intake of ondansetron and the next tinostamustine infusion. 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 30 days or 5 half-lives 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 


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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 until 1 year after the last patient’s first treatment (C1D1). 
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, M2 and M8 in plasma will be assessed by analyzing parameters such as 
Cmax, AUC, and time to maximum concentration (Tmax), and elimination half-life at each drug admin-
istration of Cycle 1 in each patient. The blood sampling schedule for the PK assessment is conducted 
in Cycle 1 only on Day 1 and 15 during tinostamustine administration. Samples are taken as follows: 
up to 0.5 hours prior to dose administration and at 15, 30 and 45 minutes, 1 hour, 75 and 90 minutes, 
and 2, 3, 6, and 24 hours 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 
From > 0 up to ≤ 90 minutes post dose 
± 5 minutes 
From > 2 hours to 6 hours post dose 
± 10 minutes 
At 24 hours post dose 
± 2 hours 
 
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: The International Nonproprietary Name (INN) for tinostamustine is Tinostamustine. 
Tinostamustine is a first in class alkylating HDACi fusion molecule that is being investigated for the 
treatment of relapsed/refractory hematologic malignancies. 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 vorinostat group. 
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 reconstituted and diluted solution should be stored for not more than 8 hours at 2 - 8ºC. 
Intravenous administration should take place after subsequent equilibration at room temperature 
(25°C) within 2 hours including infusion duration. Tinostamustine is compatible with infusion materials 
indicated in the Pharmacy Manual.  
Only patients enrolled in the trial may receive investigational product. At the beginning of each 21-
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 (relevant for USA) 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 60 mg/m2 on Day 1 and Day 15 of each treatment cycle. The 
investigational product (reconstituted and diluted solution as described in Section 8.2) will be 
administered by i.v. infusion through a peripheral vein or port over a 60-minute infusion time. 
Instructions for preparation of each dose of investigational product during each phase of the trial are 
provided in the Pharmacy Manual. The PI or qualified site personnel will administer tinostamustine 
by i.v. infusion. 
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:  
• 
ANC ≥1,000/mm3 
• 
platelets ≥75,000/mm3 
• 
non-hematologic treatment related toxicities have improved to ≤Grade 1 or to the patient’s 
baseline values (except alopecia) 
If a patient does not meet these criteria, dosing will be delayed, and the patient should be evaluated 
within 48-72 hours. If the next cycle is delayed by more than 3 weeks, the patient should not receive 
further treatment with tinostamustine. In these situations, if the patient is experiencing clinical benefit 
and has a favorable benefit/risk profile, trial participation may continue with a reduced dose of ti-
nostamustine (50 mg/m2) or resume at the patient’s current dose, if agreed upon by the Sponsor and 
the Investigator. Additionally, after Cycle 1 the Investigator and Sponsor may decide to reduce a 
patient’s dose in case of safety concerns. The reduced dose will be maintained as such, based on 
the Sponsor's and Investigator’s determination of any ongoing safety concerns. 
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 
stopped. The patient should stay in the unit until the QTcF has decreased to baseline. 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.  


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If any two or more patients have grade 3 or greater centrally confirmed QTc prolongation or QTcF 
increased >60 ms from baseline or ≥1 patient has a fatal cardiac event related to tinostamustine, the 
trial will be stopped.  
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 50 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. 
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: 
1. For neutropenia: Growth factor support is allowed in Cycle 1 only beyond Day 7. There are 
no restrictions for subsequent cycles.  


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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. An updated list of drugs with known 
risk of TdP issued by Credible Meds: https://crediblemeds.org/new-drug-list will be provided to all 
participating centers every time a new list is issued. Precautions of use of the 5HT3 receptor antag-
onists are discussed in Section 7.14.4. 
• 
Tinostamustine is a fusion molecule composed of an alkylating agent with a backbone similar 
to bendamustine and a histone deacetylase inhibitor 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 bendamustine 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 is contraindicated. Rasburicase is recommended 
instead of allopurinol. There may be increased risk of severe skin toxicity when bendamustine 
and allopurinol are administered concomitantly. 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 bendamustine was 
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. 
• 
Patients treated with bendamustine 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.  
• 
The most common serious drug-related adverse reactions associated with vorinostat 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 vorinostat; 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. 


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• 
Infusion reactions to bendamustine have occurred commonly in clinical trials. Symptoms 
include fever, chills, pruritus, and rash. In rare instances severe anaphylactic and 
anaphylactoid reactions have occurred, particularly in the second and subsequent cycles of 
therapy.  
Assessment of infusion site reactions must be performed on each treatment day at pre-dose, 
1 hr (±15 minutes). The patient will be observed at 1 hr (± 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 
TEAES AND SAES 
9.1 
Definition of a Treatment Emergent Adverse Event (TEAE) 
A TEAE is any untoward medical occurrence associated with the use of a drug in humans, whether 
or not considered drug related. A TEAE can therefore be any unfavorable and unintended sign, 
symptom, or disease temporally associated with the use of a drug, without any judgment about 
causality. A TEAE can arise from any use of the drug from any route of administration, formulation, 
or dose, including an overdose. 
TEAEs also include: 
• 
An exacerbation of a pre-existing illness. 
• 
An increase in frequency or intensity of a pre-existing episodic event or condition. 
• 
A condition detected or diagnosed after tinostamustine administration even though it may 
have been present prior to the start of the trial. 
TEAEs do not include: 
• 
Medical or surgical procedures (e.g., surgery, endoscopy, tooth extraction, transfusion); the 
condition that leads to the procedure is a TEAE. 
• 
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. 
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. As the CTCAE are used for 
laboratory parameters, as a general rule all ≥Grade 3 events are to be considered TEAEs. 
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.  
New or increasing symptoms related to disease progression should be reported as TEAEs, however, 
disease progression itself and death from disease progression should not be recorded as a TEAE. 
9.2 
Recording Adverse Events 
All TEAEs must be reported from the start of dosing of the first dose of tinostamustine through the 
time 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’). TEAE reporting and severity grading will be assessed using the NCI 


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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.  
The causal relationship of all TEAEs to investigational 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 
underlying illness, other drugs, or procedures. If applicable, the AE follows a clinically con-
sistent 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. 
9.3 
Serious Adverse Events 
A SAE is any TEAE that is considered ‘serious’ if, in the view of either the Investigator or Sponsor, it 
results in any of the following outcomes: 
• 
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; 


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• 
Is a congenital anomaly/birth defect; 
• 
Though not included in the above definitions, may be considered serious when, based upon 
appropriate medical judgment, they may jeopardize the patient and may require medical or 
surgical intervention 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. 
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: 


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- For this trial, Section 7. 4 (Table 7.2) of the most current IB version contains the Reference 
Safety Information for the expectedness assessment 
9.6 
Reporting of TEAEs, SAEs, Serious and Unexpected Adverse Experiences 
9.6.1 
Reporting TEAEs and SAEs to the Sponsor 
All TEAEs must be reported in the eCRF from the start of administration of the first dose of 
tinostamustine through the time 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.  
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 will report to the regulatory authorities as per national regulations of the countries where 
the ongoing tinostamustine trials are conducted and will provide the case documentation to the CROs 
for reporting to the applicable IRBs/IECs. 
Investigators will be informed as per national requirements. 
9.6.3 
Reporting of Grade 4 and Grade 5 TEAEs 
All grade 4 AEs (per definition "life-threatening") and grade 5 ("death"), as per CTCAE, version 4.03, 
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. 
9.6.4 
Reporting of Important Medical Events of Special Interest 
Important medical events (IME) of a clinically significant severity grade (≥Grade 3) may also qualify 
as SAEs. To establish consistency across trials with tinostamustine, the IME list published by the 
European Medicines Agency and regularly updated (current version April 2019) serves as a 
reference. 
9.6.5 
Reporting Pregnancy 
If a female patient or the female partner of a male patient becomes pregnant during the course of the 
trial, 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 


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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. 
9.6.6 
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. 
9.6.7 
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. 
Electronic data capture (EDC)/eCRF entries should be made as close to the visit of the subject as 
possible.  
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. 
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.  
 


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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 
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. 


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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.  
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. 


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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 
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 


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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. 
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). 


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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 rec-
orded 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 


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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 
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 


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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 
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 

Prot_001.pdf: 
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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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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 

Prot_000.pdf: 
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CLINICAL TRIAL PROTOCOL 
TITLE:  
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  
PROTOCOL NUMBER:  
EDO-S101-1002 
VERSION:  
8.1 
ISSUE DATE:  
10 May 2021 
 
22 March 2021 (version 7.2) 
27 September 2020 (version 7.1) 
05 September 2020 (version 7.0) 
28 January 2020 (version 6.0) 
04 February 2019 (Version 5.0) 
31 October 2018 (Version 4.0) 
06 April 2018 (Version 3.0) 
30 August 2017 (Version 2.0) 
28 June 2017 (Version 1.1) 
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 
Protocol Title:  
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 Ad-
vanced 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 .............................................................................................................................. 7 
ABBREVIATIONS AND DEFINITIONS OF TERMS ............................................................................. 8 
1 
PROTOCOL SYNOPSIS ........................................................................................................... 12 
2 
SCHEDULE OF ASSESSMENTS ............................................................................................. 25 
3 
INTRODUCTION ........................................................................................................................ 29 
3.1 
Background ........................................................................................................................ 29 
3.2 
Rationale for Dose and Schedule ...................................................................................... 30 
3.3 
Trial Rationale .................................................................................................................... 30 
4 
TRIAL OBJECTIVES ................................................................................................................. 32 
4.1 
Primary Objectives............................................................................................................. 32 
4.2 
Secondary Objectives ........................................................................................................ 32 
4.3 
Exploratory Objective ........................................................................................................ 32 
5 
TRIAL DESIGN .......................................................................................................................... 33 
5.1 
Overall Trial Design ........................................................................................................... 33 
5.2 
Dose Escalation and Schedules ........................................................................................ 35 
5.3 
Definition of DLT ................................................................................................................ 36 
5.4 
Stopping Rules for Phase 2 ............................................................................................... 37 
6 
SELECTION AND WITHDRAWAL OF PATIENTS .................................................................. 38 
6.1 
General Inclusion Criteria for Phase 1 and Phase 2 Portions of Trial ............................... 38 
6.2 
Exclusion Criteria for Phase 1 and Phase 2 Portions of the Trial ..................................... 39 
6.3 
Phase 2 Evaluation of Toxicity and Response Rate in Selected Solid Tumours; 
Specific Eligibility Criteria .................................................................................................. 39 
6.3.1 
Cohort 1 Patient Population: Relapsed/Refractory Small-cell Lung 
Cancer (SCLC) ................................................................................................ 40 
6.3.2 
Cohort 2 Patient Population: Relapsed/Refractory Soft Tissue 
Sarcoma .......................................................................................................... 40 
6.3.3 
Cohort 3 Patient Population: Relapsed/Refractory Triple Negative 
Breast Cancer ................................................................................................. 40 
6.3.4 
Cohort 4 Patient Population: Relapsed/Refractory Ovarian Cancer ............... 41 
6.3.5 
Cohort 5 Patient Population: Relapsed/Refractory Endometrial 
Cancer ............................................................................................................. 41 
6.3.6 
Withdrawal of Patient from Trial Treatment ..................................................... 41 
6.3.7 
Early Trial Termination .................................................................................... 42 


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7 
TRIAL ASSESSMENTS............................................................................................................. 43 
7.1 
Screening ........................................................................................................................... 43 
7.2 
Informed Consent .............................................................................................................. 43 
7.3 
Inclusion/Exclusion Criteria and Patient Treatment Assignment ....................................... 43 
7.4 
Demographics and Medical History ................................................................................... 43 
7.5 
Physical Examination ........................................................................................................ 43 
7.6 
Vital Signs, Height and Weight .......................................................................................... 44 
7.7 
ECOG Performance Status ............................................................................................... 44 
7.8 
12-Lead ECG (Safety and Holter) ..................................................................................... 44 
7.9 
Pharmacodynamics (Gene Expression) ............................................................................ 45 
7.10 
Clinical Laboratory Tests (Hematology, Chemistry and Urinalysis) .................................. 46 
7.11 
Pregnancy Testing and Contraception .............................................................................. 46 
7.12 
Adverse Events (AEs) ....................................................................................................... 47 
7.13 
Infusion Site and Allergic Reaction Assessment ............................................................... 47 
7.14 
Prohibited Concomitant Medications and Procedures ...................................................... 48 
7.14.1 
Steroids ........................................................................................................... 48 
7.14.2 
Valproic Acid.................................................................................................... 48 
7.14.3 
Allopurinol ........................................................................................................ 48 
7.14.4 
Serotonin 5-HT3 receptor antagonists ............................................................ 48 
7.14.5 
NK1 receptor antagonists ................................................................................ 48 
7.14.6 
Investigational agents ...................................................................................... 48 
7.15 
Efficacy Evaluations .......................................................................................................... 49 
7.15.1 
Baseline Disease Assessment ........................................................................ 49 
7.15.2 
Disease Response Assessments .................................................................... 49 
7.15.3 
Follow-up Assessments .................................................................................. 49 
7.16 
PK Assessments................................................................................................................ 49 
7.17 
Missed Visits ...................................................................................................................... 50 
8 
TRIAL TREATMENT .................................................................................................................. 51 
8.1 
Investigational Medicinal Product Description ................................................................... 51 
8.2 
Storage and Dispensing .................................................................................................... 51 
8.3 
Supply, Packaging and Labeling ....................................................................................... 51 
8.4 
Treatment Allocation .......................................................................................................... 51 
8.5 
Investigational Medicinal Product Administration .............................................................. 52 
8.6 
Treatment Criteria Beyond Cycle 1, Day 1 ........................................................................ 52 
8.7 
Dose Modification Guidelines and Stopping Rules for Patients Who Experience 
Clinically Significant QTcF Prolongations .......................................................................... 53 
8.8 
Investigational Medicinal Product Accountability ............................................................... 54 


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8.9 
Supportive Care ................................................................................................................. 54 
8.10 
Drug Interactions/Precautions ........................................................................................... 54 
8.11 
Overdose ........................................................................................................................... 55 
9 
AES AND SAES ........................................................................................................................ 56 
9.1 
Definition of Adverse Event (AE) ....................................................................................... 56 
9.2 
Recording Adverse Events ................................................................................................ 56 
9.3 
Serious Adverse Events .................................................................................................... 59 
9.4 
Events of Special Interest .................................................................................................. 60 
9.5 
Suspected Unexpected Serious Adverse Reactions (SUSARs) ....................................... 60 
9.6 
Reporting of AEs, SAEs, Serious and Unexpected Adverse Experiences ....................... 60 
9.6.1 
Reporting AEs and SAEs to the Sponsor ........................................................ 60 
9.6.2 
Reporting Suspected Unexpected Serious Adverse Reactions ...................... 61 
9.6.3 
Reporting of Grade 4 and Grade 5 AEs .......................................................... 61 
9.6.4 
Reporting of Important Medical Events of Special Interest ............................. 61 
9.6.5 
Reporting Pregnancy ....................................................................................... 61 
9.6.6 
Reporting to the IRB/IEC ................................................................................. 62 
9.6.7 
Annual Safety and Progress Reports (DSUR) ................................................ 62 
10 
STATISTICAL ANALYSES ....................................................................................................... 63 
10.1 
Trial Populations ................................................................................................................ 63 
10.1.1 
Full Analysis Population .................................................................................. 63 
10.1.2 
Safety Population ............................................................................................ 63 
10.1.3 
Pharmacokinetic Population ............................................................................ 63 
10.2 
Unit of Analysis .................................................................................................................. 63 
10.2.1 
Sample Size and Power Considerations ......................................................... 63 
10.3 
Data Analysis ..................................................................................................................... 64 
10.3.1 
Demographics and Baseline Characteristics .................................................. 64 
10.3.2 
Safety Analysis ................................................................................................ 64 
10.3.3 
Efficacy Analyses ............................................................................................ 64 
10.3.4 
Pharmacokinetic Analysis ............................................................................... 65 
10.3.5 
Deviations from the Statistical Plan ................................................................. 65 
11 
TRIAL ADMINISTRATION ........................................................................................................ 66 
11.1 
Case Report Forms and Source Documentation .............................................................. 66 
11.2 
Good Clinical Practice Statement ...................................................................................... 66 
11.3 
Investigator Documentation ............................................................................................... 66 
11.4 
Record Retention ............................................................................................................... 66 
11.5 
Protocol Deviations and Amendment ................................................................................ 67 
11.6 
Institutional Review Board and Independent Ethics Committee ....................................... 67 


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11.7 
Sponsor Monitoring and Auditing ...................................................................................... 67 
11.8 
General Informed Consent and Sub-trial Informed Consent for Genetic Samples ........... 68 
11.9 
Confidentiality .................................................................................................................... 69 
11.10 Financial Disclosure .......................................................................................................... 69 
11.11 Reporting and Publication Policy ....................................................................................... 69 
11.12 Insurance ........................................................................................................................... 70 
12 
REFERENCES ........................................................................................................................... 71 
13 
APPENDICES ............................................................................................................................ 72 
13.1 
Appendix A: Eastern Cooperative Oncology Group (ECOG) Performance Status 
Scale10 ............................................................................................................................... 72 
13.2 
Appendix B: NYHA Functional Classification .................................................................... 73 
13.3 
Appendix C: New response evaluation criteria in solid tumours: Revised RECIST 
guideline (version 1.1) ....................................................................................................... 74 
13.4 
Appendix D: ASCO and CAP Guidelines on HER2 Testing in Breast Cancer .................. 79 
 


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TABLE OF TABLES 
Table 1 
Schedule of Assessments ........................................................................... 25 
Table 2 
Dose Level, Infusion Time, and Dosing Frequency ...................................... 35 
 


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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 
IV 
Intravenous; Intravenously 
ICF 
Informed consent form 
ICH 
International Council for Harmonization 
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 
MMMT 
Malignant Mixed Mullerian Tumor 
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 


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Abbreviation 
Explanation 
OS 
Overall survival 
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 
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 
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  
Protocol Number 
EDO-S101-1002 
Trial Sponsor 
Mundipharma Research Limited 
Objectives 
Phase 1: Dose Escalation until Maximum Administered Dose (MAD): 
Primary objective: 
To determine the safety, tolerability, maximum tolerated dose (MTD), and 
recommended phase 2 dose (RP2D) of tinostamustine as a single agent in 
patients with solid tumors who have progressed after at least 1 line of therapy 
and for whom no other standard therapy with proven clinical benefit is 
available. The MTD was to be determined for intravenous (IV) administration 
on Day 1 and 15 of a 4-week treatment cycle. 
In October 2018, the Safety Review Committee recommended 80 mg/m2 
administered over 1 hour on Day 1 and 15 of each 4-week treatment cycle as 
the dose for Phase 2. 
Secondary objective: 
• To establish the pharmacokinetic (PK) profile of tinostamustine. 
Phase 2: Evaluation of Response Rate in Selected Solid Tumor Cohorts: 
Primary objective: 
• 
To determine the objective response rate (ORR) [complete response 
(CR) plus partial response (PR)] of any duration, plus the rate of 
patients with stable disease (SD) of at least 4 months duration at a dose 
of 80 mg/m2 administered over 1 hour on Day 1 and 15 of each 4-week 
treatment cycle. 
Secondary objectives: 
• To evaluate safety and tolerability of 80 mg/m2 of tinostamustine 
administered over 1 hour on Day 1 and 15 of each 4-week treatment 
cycle.  


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• To determine the progression free survival (PFS) time for patients who 
received 80 mg/m2 of tinostamustine administered over 1 hour on 
Day 1 and 15 of each 4-week treatment cycle. 
• To determine the overall survival time (OS) for patients who received 
80 mg/m2 of tinostamustine administered over 1 hour on Day 1 and 15 
of each 4-week treatment cycle. 
• To determine duration of response. 
• To establish the whole PK profiles of tinostamustine. 
Exploratory objective: 
• To correlate the extent of gene expression changes in tumor samples 
with anti-tumor activity. 
Clinical Phase 
Phase 1/2 
Investigational 
Medicinal Product 
Tinostamustine (EDO-S101) 
No. of Patients 
Phase 1: Dose Escalation until MAD: Total number of patients in the dose 
escalation scheme was expected to be 42 at the maximum (3 per cohort, at MTD 
6 per cohort for 2 schedules and 6 dose levels). In October 2018, enrollment to 
Phase 1 closed with 22 patients treated with tinostamustine. 
Phase 2: Evaluation of Toxicity and Response Rate in Selected Solid 
Tumor Cohorts: Five (5) cohorts with 10 evaluable patients in each cohort 
expanding to a possible 29 in each cohort under a Simon 2-stage design13, 
resulting in a sample size ranging from 56 to 160. 
Number of Centers 
Multicenter trial; 10-13 centers (Phase 1: 2 centers; Phase 2: 10-15 centers) in 
the United States, Canada and Europe will participate.  
Trial Design 
The trial is designed as an open label, Phase 1/2 trial of single agent 
tinostamustine. The Phase 1 portion of the trial was designed to define the MTD 
by evaluating toxicities during dose escalation until MAD. The Phase 2 portion 
of the trial is designed to evaluate ORR of the RP2D (80 mg/m2 of tinostamustine 
administered over 1 hour on Day 1 and 15 of each 4-week treatment cycle) at 4 
or 6 months, depending on the type of solid tumor. Secondary objectives are 
evaluation of safety and tolerability of the RP2D in selected solid tumors. 
Patients will be eligible for this trial if they have a histologically confirmed solid 
tumor, sign informed consent and meet the inclusion/exclusion criteria. After 


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enrollment, patients will be screened, and all procedures will be performed as 
per protocol.  
In Phase 1, tinostamustine doses were escalated following the standard 3+3 
cohort design.1 The decision to escalate to the next dose level occurred after all 
patients in a cohort had completed 1 cycle of therapy and were considered 
evaluable for safety and toxicity. A Safety Review Committee (SRC) that 
included the Investigators and Sponsor/sponsor’s representatives reviewed 
available data including toxicity and activity data to reach consensus on dose 
levels and determination of the MTD and RP2D. The dose levels and schedules 
are defined in Section 3.2 and shown in Table 2.  
In the 3+3 design, if one of the 3 patients had a dose-limiting toxicity (DLT) (as 
defined below), the cohort was to be expanded to a maximum of 6 patients. If 
only one of the 6 patients had a DLT, dose escalation was to continue. If 2 
patients have a DLT, dose escalation was to stop, regardless of the number of 
patients that had been treated in this cohort. If 2 or more DLTs occurred in a 6-
patient cohort, this dose was declared the MAD. A decision was to be taken by 
the Sponsor and SRC to open intermediary dose levels below the MAD to better 
define the MTD. The MTD was confirmed when 6 patients were treated at a dose 
level with less than 2 DLTs. In case a patient experienced a DLT at dose level 
one (60 mg/m2) at any administration schedule, the Investigational Medicinal 
Product was to be reduced one dose level to 40 mg/m2. 
In October 2018, the SRC recommended 80 mg/m2 administered over 1 hour on 
Day 1 and 15 of each 4-week treatment cycle as the RP2D. 
During Phase 1, the PK characteristics of tinostamustine, and its 2 metabolites 
M2 and M8, were to be determined at all dose levels. Blood samples for PK 
determinations were obtained in Cycle 1 at each time of Investigational 
Medicinal Product (IMP) administration, from each patient.  
The second phase of the trial (Phase 2) is designed to evaluate ORR of the 
RP2D (80 mg/m2 of tinostamustine administered over 1 hour on Day 1 and 15 
of each 4-week treatment cycle) at 4 or 6 months in cohorts of patients with 
defined solid tumors. Five cohorts will be opened to recruit patients with: 
(1) relapsed/refractory small cell lung cancer (SCLC) 
(2) relapsed/refractory soft tissue sarcoma (STS) 
(3) relapsed/refractory triple-negative breast cancer (TNBC)* 
(4) relapsed/refractory ovarian cancer  
(5) relapsed/refractory endometrial cancer* 
*On 05 March 2021, following an evaluation of the development of EDO-S101 
(Tinostamustine) across multiple studies, the Sponsor has taken the decision to halt 
recruitment into the Cohorts for relapsed/refractory triple-negative breast cancer (TNBC) 


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and relapsed/refractory endometrial cancer on this study. This decision was made to 
enable focusing of resources into a defined and select set of patient cohorts. 
 
Each cohort will recruit 10 patients who will be treated at 80 mg/m2 administered 
over 1 hour on Day 1 and 15 of each 4-week treatment cycle and monitored for 
safety and efficacy. Each cohort may treat an additional 19 patients (29 in total) 
if there is evidence of 2 successes in that cohort. Success is defined as either a 
CR or a PR of any duration, or SD of at least 4 months duration. The Sponsor 
may suspend or discontinue enrollment to an expansion cohort at any time due 
to slow patient accrual rates or other reasonable cause. 
In Phase 2, the PK profile of tinostamustine and its 2 metabolites, M2 and M8, 
will be assessed in Cycle 1 in a minimum of 50 patients.  
Treatment may continue until progression or intolerable toxicity, up to a 
maximum of 12 cycles.  Investigator and the Sponsor may decide to reduce a 
patient’s dose to 60 mg/m2 in case of safety concerns.  If toxicity issues are 
resolved, the original dose can be administered at the next cycle. If the patient 
cannot tolerate the reduced dose, then the patient will be withdrawn from the 
study. 
Patient assessments, except for imaging studies, will be performed at the end 
of each treatment cycle and at the time of Investigational Medicinal Product 
discontinuation (at any time or Day 28 of the last treatment cycle). Tumor 
response assessment by imaging will be performed at baseline and every 2 
cycles during treatment and every 2 months after stopping treatment according 
to the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1 
(Section 13.3). 
Stopping Rules 
Stopping Rules (Phase 1): 
To ensure patients’ safety, stopping rules were applied in Phase 1. If 66% or 
more patients treated at any given time of the dose escalation part of the trial 
experienced the following Grade 2 toxicities, the trial was to be stopped for 
enrollment and the risk assessed and addressed by the Sponsor. 
• 
Grade 2 venous thrombosis  
• 
Grade 2 increase of serum creatinine (>1.5 - 3.0 x upper limit of normal 
[ULN]) 
• 
Grade 2 nervous system disorders excluding headache  
Stopping Rules for Phase 2 
Stopping rules in Phase 2 apply for patients who experience QTc 
prolongations >500 ms or change from baseline >60 ms (Grade 3) that are not 


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transient or occur in more than 1 treatment 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 baseline. 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 Investigator in consultation with the Medical Monitor, 
whether tinostamustine treatment is to continue, be postponed or be stopped. 
(Refer to Section 8.7, Dose modification guidelines and stopping rules, for the 
management of patients who experience clinically significant QTcF 
prolongations). 
• 
Trial Popula-
tion Phase 1 
and 2 
General Inclusion Criteria for Phase 1 and Phase 2 portions of Trial: 
• 
Patient willing and able to sign the informed consent. 
• 
Patients age ≥18 years at signing of the informed consent. 
• 
Life expectancy > 3 months. 
• 
Histologically confirmed diagnosis of advanced or metastatic solid 
tumors, disease should have progressed during or following at least 1 
previous 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. 
• 
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 of the following criteria:  
(1) Residual neurological symptoms ≤ Grade 1 
(2) No glucocorticoids requirement 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 (Section 7.14.1) 
(3) Follow-up imaging studies show no progression of treated lesions 
and no new lesions  
• 
Evaluable disease; measurable on imaging as assessed by RECIST 
version 1.1.  


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• 
Eastern Cooperative Oncology Group (ECOG) performance status ≤2 
(Section 13.1). 
• 
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× 
upper limit of normal (ULN). In cases with liver involvement ALT/ AST 
≤5× ULN. 
• 
Total bilirubin ≤1.5 mg/dL unless elevated due to known Gilbert’s 
syndrome. 
• 
Creatinine ≤1.5 ULN. 
• 
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. 
• 
 Female study participants of child-bearing potential and their partners, 
and male study participants who intend to be sexually active with a 
woman of child-bearing potential, 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 IMP administration.  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 males 
are considered fertile; therefore, 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 Phase 1 and Phase 2 portions of Trial: 
• 
Patients with primary central nervous system (CNS) cancer.  
• 
Patients with QTc interval (Fridericia’s formula) >450 ms.  


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• 
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): http://crediblemeds.org/new-drug-list. 
• 
Patients who are being treated with Valproic Acid for any indication 
(epilepsy, mood disorder).  
• 
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 breastfeeding women. 
• 
New York Heart Association (NYHA) stage III/IV congestive heart failure 
(Section 13.2). 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. 
• 
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.  
• 
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.  
Trial Population 
(Phase 2) 
Specific Eligibility Criteria for Each Patient Cohort in Phase 2 portion of 
the Trial 
Phase 2 patients must meet the cohort-specific inclusion/exclusion criteria in 
addition to the general inclusion/exclusion criteria previously noted. 
Confirmation of the availability of a tumor sample from the primary or recurrent 
cancer must be provided (archival samples are acceptable). 


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Cohort 1: Relapsed/Refractory Small Cell Lung Cancer 
1. Histologically or cytologically confirmed limited or extensive disease 
stage of SCLC.  
2. Must have received at least 1 line of prior combination chemotherapy or 
biological 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.  
3. At least 28 days should have elapsed since prior treatment as long as 
the patient has recovered from any related toxicities to ≤ Grade 1 (or ≤ 
Grade 2 for any symptomatic neuropathy or endocrinopathies). 
4. Prior radiotherapy is acceptable provided the patient has recovered from 
any radiotherapy related acute toxicities. 
5. The disease should be progressing during or relapsing after the previous 
treatment. 
6. Presence of measurable disease as defined by RECIST version 1.1. 
Tumor lesions situated in a previously irradiated area, or in an area 
subjected to other loco-regional therapy, are usually not considered 
measurable unless there has been demonstrated progression in the 
lesion. 
Cohort 2: Relapsed/Refractory Soft Tissue Sarcoma 
1. Histologically confirmed diagnosis of advanced, unresectable, or 
metastatic STS not amenable to curative treatment with surgery or 
radiotherapy 
excluding: 
neuroblastoma, 
GIST, 
embryonal 
rhabdomyosarcoma, Kaposi sarcoma, chondrosarcoma, osteosarcoma 
or Ewing’s sarcoma. 
2. Must have received at least 1 prior line chemotherapy or biological 
therapy regimen 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. At least 28 days  
should have elapsed since prior chemotherapy as long as the patient 
recovered from any related toxicities to ≤ Grade 1 (or ≤Grade 2 for any 
symptomatic neuropathy or endocrinopathies). 
3. The disease should be progressing during or relapsing after the previous 
treatment. 
4. Presence of measurable disease as defined by RECIST version 1.1. 
Tumor lesions situated in a previously irradiated area, or in an area 
subjected to other loco-regional therapy, are usually not considered 


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measurable unless there has been demonstrated progression in the 
lesion. 
Cohort 3: Relapsed/Refractory Triple Negative Breast Cancer  
RECRUITMENT INTO THIS COHORT HAS NOW BEEN HALTED 
Cohort 4: Relapsed/Refractory Ovarian Cancer 
1. Histologically or cytologically confirmed advanced ovarian cancer 
epithelial ovarian cancer including primary peritoneal cancer or fallopian 
tube cancer (excluding borderline ovarian cancer, malignant mixed 
Mullerian tumor (MMMT)) of high grade serous histology, or high grade 
endometrioid cancer, that is resistant or refractory to platinum 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.  Clear cell carcinomas are excluded. 
Patients with primary platinum refractory disease (failure to respond 
to initial platinum treatment or relapse within 4 weeks) and patients 
with primary platinum resistant disease (progression within 6 months 
of completing first line platinum-based therapy) are excluded from 
the study. 
2. At least 28 days should have elapsed since prior chemotherapy, as long 
as the patient recovered from acute toxicity of previous therapies to ≤ 
Grade 1 (or ≤ Grade 2 for any symptomatic neuropathy or 
endocrinopathies). 
3. The disease should be progressing during or relapsing after the previous 
treatment. 
4. Presence of measurable disease as defined by RECIST version 1.1. 
Tumor lesions situated in a previously irradiated area, or in an area 
subjected to other loco-regional therapy, are usually not considered 
measurable unless there has been demonstrated progression in the 
lesion. 
Cohort 5: Relapsed/Refractory Endometrial Cancer  
RECRUITMENT INTO THIS COHORT HAS NOW BEEN HALTED  
Dose and Schedule The starting dose in Phase 1 was 60 mg/m2 and the escalation schedule was 
selected based on the experience from the ongoing First-in-human Phase 1 trial 
in patients with relapsed/refractory hematologic malignances. 
The dose selected for Phase 2, based on Phase 1 data, is 80 mg/m.2 
administered over a 60-minute infusion, on D1 and D15 of a 4-week cycle. 


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Phase 1  
Dose Escalation 
Plan 
Dose escalation for each patient was conducted according to the following 
schemes: 
Dose Level 
Tino-
stamustine 
Dose 
Administration 
Schedule 
-1* 
40 mg/m2  
30 min infusion 
D1 and D15  
every 28 days 
1 – Starting 
Dose 
60 mg/m2  
30 min infusion 
D1 and D15  
every 28 days 
2 
80 mg/m2  
30 min infusion 
D1 and D15  
every 28 days 
3 
100 mg/m2  
30 min infusion 
D1 and D15  
every 28 days 
4** 
60 mg/m2 
60 min infusion 
D1 and D15  
every 28 days 
5 
80 mg/m2  
60 min infusion 
D1 and D15  
every 28 days 
6*** 
100 mg/m2  
60 min infusion 
D1 and D15  
every 28 days 
*If a patient experienced a DLT at dose level one (60 mg/m2), tinostamustine was to 
be reduced one dose level to 40 mg/m2. 
** If a patient experienced a DLT at the 60 mg/m2, 60-minute infusion dose-level, 
tinostamustine was to be reduced one dose level to 40 mg/m2, 60 minutes infusion 
time. 
***Additional dose escalations were to be considered until the MAD was reached.  
Phase 2  
Evaluation of 
Toxicity and 
Response Rate in 
Selected Solid 
Tumor Cohorts 
The Phase 2 portion of the trial will follow a Simon 2-stage design. The RP2D 
(80 mg/m2 administered over 1 hour (± 5 minutes) on Day 1 and 15 of each 4-
week treatment cycle) will be further investigated in patients with specific types 
of solid tumors. There will be 5 cohorts, each with 10 patients and potentially 
increased up to 29 patients, and each with the following tumor type: 
• 
Cohort 1: Relapsed/refractory SCLC 
• 
Cohort 2: Relapsed/refractory STS 
• 
Cohort 3: Relapsed/refractory TNBC*  
• 
Cohort 4: Relapsed/refractory ovarian cancer 


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• 
Cohort 5: Relapsed/refractory endometrial cancer* 
*On 05 March 2021, following an evaluation of the development of EDO-S101 
(Tinostamustine) across multiple studies, the Sponsor has taken the decision to halt 
recruitment into the Cohorts for relapsed/refractory triple-negative breast cancer (TNBC) 
and relapsed/refractory endometrial cancer on this study. This decision was made to 
enable focusing of resources into a defined and select set of patient cohorts. 
 
In stage 1, 10 patients will be treated in each cohort, potential efficacy and the 
decision to expand into stage 2 or not may be taken prior to the 10th patient 
completing the study. During the assessment of stage 1, enrollment into the 
expanded cohort (stage 2) will continue. If there are no successes or only 1 
success in the first 10 patients enrolled into each specific stage 1 cohort, 
recruitment to that cohort will be stopped. If there are 2 or more successes in 
the first 10 patients enrolled in a given cohort, up to an additional 19 patients 
may be treated in stage 2 to a total of 29. If it becomes clear that there will be 5 
or fewer successes in a cohort of 29 patients, then the cohort will be stopped for 
lack of efficacy.  
In each cohort, a success is defined as: 
CR or PR of any duration, or SD that persists for at least 4 months 
The Sponsor may suspend or discontinue enrollment to an expansion cohort at 
any time due to slow patient accrual rates or other reasonable cause. 
Duration of Trial/ 
Patient 
Participation 
In October 2018 enrollment to Phase 1 closed with 22 patients treated with 
tinostamustine. 
The total number of patients who will participate in the Phase 2 portion of the 
trial is expected to be between 56 and 160. The total number of participants is 
expected in both Phases 1 and 2 to be 182 at maximum. The duration of Phase 
2 of the trial is expected to be approximately 24 months for patient enrollment 
and treatment with 12 months of follow up for a total duration of 36 months. 
Safety Evaluations 
Safety assessments include physical examinations, ECOG performance status 
determinations, electrocardiograms (ECGs), pregnancy testing for women of 
child-bearing potential, documentation of adverse events (AEs), clinical 
laboratory evaluations including hematology, blood chemistry and urinalysis, 
vital signs, and documentation of concomitant medication usage.  
Toxicities in both stages of the trial 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 in Phase 2, 
assessment of QTc prolongations constituting AEs of special interest are 


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based on CTCAE version 5.0.  
Efficacy 
Evaluations  
Efficacy evaluations in Phase 2 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 13.3). 
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.  
In Phase 1, the PK profiles of tinostamustine in plasma were assessed in each 
patient during the escalation phase, and in Phase 2, a minimum of 50 patients 
will be assessed. Blood sampling will occur in Cycle 1 only at each drug 
administration. The schedule is provided in Section 7.16 of this protocol.  
Pharmacodynamic 
Evaluations 
Patient participation in the gene expression analysis is not mandatory for 
enrollment into the trial. If the patient agrees to participate in the gene expression 
analysis, a fresh or archival tissue sample will be collected during screening. 
Formalin fixed paraffin embedded (FFPE) biopsy samples will be used. The 
Affymetrix chip technology for analyzing total ribonucleic acid (RNA) will be 
used. For formalin fixed paraffin embedded samples, RecoverAll method from 
Ambion® for isolating total RNA will be used. The isolated RNA is total RNA and 
will contain both messenger RNA (mRNA) and micro RNA (miRNA). The 
expression profile will be analyzed for correlation with response or resistance to 
therapy. Details of sample preparation and shipping are described in the 
Laboratory Manual. 
Sample Size 
Determination, 
Analyses 
For Phase 1 a formal sample size determination and power calculation were not 
performed. Based on experience from previously published similar trials, a total 
number of 42 patients at maximum in the dose escalation stage of the trial was 
considered to be sufficient for meeting the objectives of this trial. In Phase 2, 56 
to 160 patients (10 or 29 evaluable patients in each of the disease cohorts) are 
considered to be sufficient for meeting the objectives of this trial, following 
Simon's optimal 2-stage design methodology.13 Assuming the proportion of 
treatment successes that do not warrant further investigation (π0) is 0.10, the 
proportion of treatment successes that warrant further investigation (π1) is 0.30, 
an 80% power and a 5% Type I error rate.  


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 In stage 1, 10 patients will be treated in each cohort; potential efficacy and the 
decision to expand into stage 2 or not may be taken prior to the 10th patient 
completing the study. During the assessment of stage 1, enrollment into the 
expanded cohort (stage 2) will continue. However, it is anticipated that new 
patients will enroll infrequently due to the expected low recruitment rate. From 
stage 1, if there are no successes or only 1 success in the 10 stage 1 patients, 
the complete cohort will be stopped for lack of efficacy. If there are 2 or more 
successes in stage 1 an additional 19 patients may be treated for a total of 29 
in a cohort. If it becomes clear that there will be 5 or fewer successes in a cohort 
of 29 patients, then the cohort will be stopped for lack of efficacy. 


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2 
SCHEDULE OF ASSESSMENTS 
Table 1 
Schedule of Assessments 
Procedure 
Screening 
28 days from Base-
line (First Day Inves-
tigational Medicinal 
Product Administra-
tion); Scans 28 days 
from Baseline15 
Cycle 1 and Subsequent Cycles1 
Investigational Me-
dicinal Product 
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 
 
 
X 
 
PK Assessments5 
 
X5 
X1 
X5 
X1 
 
 
 
Gene Expression Profiling6 
X 
 
 
 
 
 
 
 


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Procedure 
Screening 
28 days from Base-
line (First Day Inves-
tigational Medicinal 
Product Administra-
tion); Scans 28 days 
from Baseline15 
Cycle 1 and Subsequent Cycles1 
Investigational Me-
dicinal Product 
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 
 
Investigational Medicinal Product 
Administration 
 
X 
 
X 
 
 
 
 
Obtain PFS Information12 
 
 
 
 
 
 
 
X 
Survival Follow-up 
 
 
 
 
 
 
 
X13 
1 Visits on Day 2 and 16 in Cycle 1 only: 24h (±2 h) 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 
Investigational Medicinal Product calculations of BSA. BSA will be calculated using the DuBois formula for each patient at the site.  


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3 Resting supine blood pressure, pulse, respiratory rate, and temperature will be measured at Screening, Day 1, 15, and 22, and at trial 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 
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) 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 minutes and triplicate at 60 minutes from the start of tinostamustine administration on D1 and D15 each treatment cycle and a single ECG on D28 (±2 days) of last 
treatment cycle. Additional ECGs may be conducted as clinically indicated. 
Holter monitoring will commence 60 minutes prior to the start of  tinostamustine infusion on C1D1 and 15 min prior to the start of tinostamustine infusion on C1D15 and will 
continue through 24 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 15, 30, 45, 60, 75, 90, 120, 180, 360 minutes and 24 hours from the start of tinostamustine infusion. 
• 
C1D15: prior to the start of infusion, and 15, 30, 45, 60, 75, 90, 120, 180, 360 minutes and 24 hours from the start of tinostamustine infusion. 
5 The blood sampling schedule for the PK assessment is conducted on Day 1 and 15 of Cycle 1 only. Samples are taken as follows: up to 0.5 hours prior to dose administration 
and at 15, 30 and 45 minutes, 1 hour, 75 and 90 minutes, and 2, 3, 6, and 24 hours from the start of the tinostamustine infusion. Samples will be taken at the same time and 
as close to the exact time point as possible, with sample draw windows: 15, 30, 45 (±5 minutes) 60 (-5 minutes as close to the calculated end of the IMP infusion as possible 
and before the end of IMP infusion), 75, and 90 minutes (±5 minutes); 2, 3 and 6 hr (±10 minutes), and 24 hr (±2 hr). In Phase 1, the PK profiles of tinostamustine in plasma 
were assessed in each patient during the escalation phase and in Phase 2, a minimum of 50 patients will participate in the PK analysis.  
6 Patients will be requested to participate to gene expression research. Information on the purpose of genetic research in the gene-expression sub-trial is provided, either in 
the main ICF or a separate ICF, based on applicable regulatory requirements, 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. See Section 7.9 and the Laboratory Manual for tumor sample requirements. 
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 (- 2 days), 15 (- 2 days) and 22 (+/- 2 days) of each cycle, from cycle 1 to the last cycle of treatment, prior to IMP administration on Days 1 & 
15, and at the time of IMP discontinuation (at any time or Day 28 of the last treatment cycle).  Results should be reviewed prior to IMP administration. 
8 Serum chemistry will include albumin, total protein, creatinine, 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). Blood samples will be collected at Screening, Days 
1 (- 2 days), 15 (- 2 days) and 22 (+/- 2 days) of each cycle, from cycle 1 to the last cycle of treatment, prior to IMP administration on Days 1 & 15, and at the time of IMP 
discontinuation (at any time or Day 28 of the last treatment cycle).  Results should be reviewed prior to IMP administration. If potassium and/or magnesium levels before 
tinostamustine infusion are lower than normal they would need to be corrected and rechecked before the infusion proceeds. 
9 Women of childbearing 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. 
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, (8, 10 and 12 if applicable). In addition, the response assessment may be performed at any time according to symptoms and clinical judgment of the treating physician. 


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11 Assessment of infusion site reactions must be performed on each treatment day at pre-dose, 1 hr (±15 min). The patient will be observed at 1 hr (±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 until 1 year after the last patient’s first treatment (C1D1). 
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). 
15 Abbreviated physical examination is directed by disease site and symptoms. 


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3 
INTRODUCTION 
3.1 
Background 
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 
generation, 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 
selective 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 
proliferation 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 catastrophe.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 
lymphoma 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. 
Mechanistically, tinostamustine induces a strong DNA damage response, evidenced by a rise of ɣ-


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pH2AX and p53, while DNA damage response was suppressed. Consequently, in vitro experiments 
showed synergy with DNA repair influencing agents such as PARP inhibitors.  
3.2 
Rationale for Dose and Schedule  
A weekly administration achieving exposure at or over 1 µM of tinostamustine was more effective in 
solid tumor models than dosing once every 3 weeks. The starting dose in Phase 1 of 60 mg/m2 was 
set following the experience that doses of 20, 40, 60, and 80mg/m2 and 100mg/m2 given once every 
3 weeks have been administered safely to humans in an ongoing First-in-human Phase 1 trial in 
relapsed/refractory hematological malignancies. Tinostamustine will be given intravenously (i.v.) on 
Day 1 and 15 in a 4-week cycle. 
  
The overall risk associated with tinostamustine treatment is expected to be similar to other alkylators, 
like bendamustine. The profile of toxicity seen in the nonclinical studies was similar to the toxicity 
seen in patients treated with bendamustine. In a series of phase I trials performed with bendamustine 
in patients with solid tumors various doses and schedules were evaluated as shown in the table 
below. DLTs occurred at various doses between 90 mg/m2 and 280 mg/m2 depending on the 
frequency of dosing. 
Author  
Bendamustine Schedule 
MTD 
RP2D 
DLT 
Organ  
Toxicity 
Schoffski4 
weekly for 8 consecutive 
weeks  
80 mg/m2 
60 mg/m2 
fatigue, mouth dryness NA 
Schoffski5 
D1 and D8 every 4 weeks 
160 mg/m2 140 mg/m2 fatigue, mouth dryness mild cardiac 
arrhythmia  
Rasschert6  
D1 every 3 weeks  
280 mg/m2 260 mg/m2 fatigue, cardiac toxicity cardiac 
Rasschert7 
D1 and D2 every 3 weeks 
180 mg/m2 160 mg/m2 febrile neutropenia, 
thrombocytopenia 
NA 
3.3 
Trial Rationale 
The ability to fuse discrete small molecules with different types of pharmacologic activity has created 
remarkable opportunities in drug discovery and development. Bendamustine itself is a fusion 
molecule of the nitrogen mustard mechlorethamine and a purine analog based on fludarabine that 
exhibits unique activity where cancer cells have become resistant to conventional alkylating agents. 
In fact, randomized clinical trials have established that the combination of rituximab and 
bendamustine exhibits less toxicity and greater efficacy compared to a conventional R-CHOP based 
regimen. This concept opens the prospect that other rational fusion molecules could exhibit activity 
even greater than that seen in the parent molecule.  
Tinostamustine is a unique new chemical entity. In the current and ongoing first-in-human dose 
escalation trial, some patients with relapsed or refractory hematological malignancies, for which there 


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are no available approved therapies, benefited from treatment. The benefit risk assessment is in 
favour of further development of this molecule in humans.  
This clinical trial represents the first in human experience in patients with solid tumors with this novel 
first in class drug. 


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4 
TRIAL OBJECTIVES 
4.1 
Primary Objectives 
Phase 1: Dose Escalation until Maximum Administered Dose (MAD) (Complete): 
• 
To determine the safety, tolerability, maximum tolerated dose (MTD), and recommended 
phase 2 dose (RP2D) of tinostamustine as a single agent in patients with solid tumors who 
have progressed after at least 1 line of therapy and for whom no other standard therapy with 
proven clinical benefit is available. The MTD was to be determined for i.v. administration on 
Day 1 and 15 of a 4-week treatment cycle.  
In October 2018, the Safety Review Committee recommended 80 mg/m2 administered over 1 
hour on Day 1 and 15 of each 4-week treatment cycle as the dose for Phase 2. 
Phase 2: Evaluation of Response Rate in Selected Solid Tumor Cohorts 
• 
To determine the objective response rate (ORR) [complete response (CR) plus partial 
response (PR)] of any duration, plus the rate of patients with stable disease (SD) of at least 4 
months duration at a dose of 80 mg/m2 administered over 1 hour on Day 1 and 15 of each 4-
week treatment cycle. 
4.2 
Secondary Objectives 
Phase 1: Dose Escalation until MAD (Complete): 
• 
To establish the pharmacokinetic (PK) profile of tinostamustine. 
Phase 2: To evaluate safety and tolerability of 80 mg/m2 of tinostamustine administered over 1 hour 
on Day 1 and 15 of each 4-week treatment cycle. 
• 
To determine the progression-free survival (PFS) time for patients who received 80 mg/m2 of 
tinostamustine administered over 1 hour on Day 1 and 15 of each 4-week treatment cycle. 
• 
To determine the overall survival (OS) for patients who received 80 mg/m2 of tinostamustine 
administered over 1 hour on Day 1 and 15 of each 4-week treatment cycle. 
• 
To determine duration of response. 
• 
To establish the whole PK profiles of tinostamustine. 
4.3 
Exploratory Objective 
• 
To correlate the extent of gene expression changes in tumor samples with anti-tumor activity. 


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5 
TRIAL DESIGN 
5.1 
Overall Trial Design 
The trial is designed as an open label, Phase 1/2 trial of single agent tinostamustine. The Phase 1 
portion of the trial aimed to define the MTD, the PK of tinostamustine and its 2 metabolites, M2 and 
M8 and to identify the RP2D. The Phase 2 portion of the trial is designed to evaluate the ORR plus 
the rate of patients with SD of at least 4 months duration of the RP2D (80 mg/m2 of tinostamustine 
administered over 1 hour (± 5minutes) on Day 1 and 15 of each 4-week treatment cycle). Secondary 
objectives are evaluation of the safety and tolerability of the RP2D in selected solid tumor indications.  
Phase 1: Dose Escalation until MAD (Complete): 
In the Phase 1 portion of the trial, tinostamustine was escalated following the standard 3+3 design. 
The decision to escalate to the next dose level occurred after all patients in a given cohort completed 
Cycle 1 of treatment and were evaluated for safety and toxicity. A Safety Review Committee (SRC) 
that includes the Investigators and Sponsor/sponsor’s representatives reviewed available data 
including toxicity and activity data to reach consensus on dose levels and determination of the MTD 
and RP2D. The dose escalation levels are defined in Section 3.2 and Table 2. 
In the 3+3 design, if one of the 3 patients had a dose-limiting toxicity (DLT) (as defined below), the 
cohort was to be expanded to a maximum of 6 patients. If only 1 of the 6 patients had a DLT, dose 
escalation was to continue. If 2 patients had a DLT, dose escalation was to stop, regardless of the 
number of patients that had been treated in this cohort (e.g., if patients 1 and 4 had DLTs then patients 
5 and 6 would not be treated). If 2 or more DLTs occurred in a 6-patient cohort, this dose was to be 
declared the MAD, and the prior dose level or an intermediate dose level was to be declared the MTD. 
The MTD was confirmed when 6 patients were treated at a dose level with less than 2 DLTs.  
In Phase 1, the PK profiles of tinostamustine in plasma were assessed in each patient during the 
escalation phase, and in Phase 2, a minimum of 50 patients will participate in the PK analysis. Blood 
sampling will occur in Cycle 1 only at each drug administration. 
The RP2D was defined by the Sponsor after all information on safety, toxicity and pharmacokinetics 
of the various dose levels and in respect of the underlying diseases was reviewed. The following data 
were considered for the selection of the respective RP2D to go forward to the Phase 2 portion of the 
protocol: 
• 
DLTs and also all investigational product-related Grade 2 toxicities in all escalation cohorts;  
• 
Dose-modifying events (DMEs): DMEs that were similar to DLTs but occur subsequent to 
Cycle 1; 
• 
Maximum dose delivered per administration in a schedule and the related plasma Cmax during 
infusion consistently delivering >1 µM of tinostamustine (parent compound); and  
• 
Quality of response and duration of response in all escalation cohorts. 
In October 2018, the SRC recommended 80 mg/m2 administered over 1 hour on Day 1 and 15 of 
each 4-week treatment cycle as the dose for Phase 2. 
Phase 2: Evaluation of Response Rate in Selected Solid Tumor Cohorts  


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The Phase 2 portion of the trial is designed to determine the ORR plus the rate of patients with SD of 
at least 4 months duration of the RP2D (80 mg/m2 of tinostamustine administered over 1 hour on 
Day 1 and 15 of each 4-week treatment cycle). 
The following cohorts will be opened to recruit patients.  
• 
Cohort 1: Relapsed/refractory SCLC  
• 
Cohort 2: Relapsed/refractory STS 
• 
Cohort 3: Relapsed/refractory TNBC* 
• 
Cohort 4: Relapsed/refractory ovarian cancer 
• 
Cohort 5: Relapsed/refractory endometrial cancer* 
*On 05 March 2021, following an evaluation of the development of EDO-S101 (Tinostamustine) across multiple 
studies, the Sponsor has taken the decision to halt recruitment into the Cohorts for relapsed/refractory triple-
negative breast cancer (TNBC) and relapsed/refractory endometrial cancer on this study. This decision was 
made to enable focusing of resources into a defined and select set of patient cohorts. 
Each cohort will recruit 10 patients (stage 1) expanding to a possible 29 (stage 2) under a Simon 2-
stage design13, resulting in a total number of patients treated at 80 mg/m2 administered over 1 hour 
(± 5 minutes) on Day 1 and 15 of each 4-week treatment cycle between 56 to 160 who will be 
monitored for safety and efficacy. In Phase 2 the PK profile of tinostamustine will be assessed in a 
minimum of 50 patients.  
If there are no successes or only 1 success in the first 10 patients enrolled into each specific Phase 
2 cohort, recruitment to that cohort will be stopped. Recruitment to stage 2 may continue while stage 
1 is being evaluated, however, this is expected to be relatively few patients. If there are 2 or more 
successes in the first 10 patients enrolled in a given phase 2 cohort, an additional 19 patients will be 
treated for a total of 29. If it becomes clear that there will be 5 or fewer successes in a cohort of 29 
patients, then the cohort will be stopped for lack of efficacy. 
In each cohort, a success is defined as: CR or PR of any duration, or SD that persists for at least 
4 months. 
The Sponsor may suspend or discontinue enrollment to an expansion cohort at any time due to slow 
patient accrual rates or other reasonable cause. 
Stopping Rules (Phase 1): 
To ensure patients’ safety, stopping rules were applied in the dose escalation phase. If 66% or more 
patients treated at any given time of the dose escalation part of the trial experienced the following 
Grade 2 toxicities, the trial was to be stopped for enrollment and the risk was to be assessed and 
addressed by the Sponsor. 
• 
Grade 2 venous thrombosis  
• 
Grade 2 increase of serum creatinine (>1.5 - 3.0 x upper limit of normal [ULN]) 
• 
Grade 2 nervous system disorders excluding headache  
 Treatment may continue until progression or intolerable toxicity up to a maximum of 12 cycles.  
Investigator and the Sponsor may decide to reduce a patient’s dose in case of safety concerns. If 


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toxicity issues are resolved, the original dose can be administered at the next cycle. If the patient 
cannot tolerate the reduced dose, then the patient will be withdrawn from the study. 
Radiologic response assessment by computed tomography scans will be performed at baseline and 
every 2 cycles. Tumor response will be evaluated according to the Response Evaluation Criteria in 
Solid Tumors (RECIST) version 1.1 (Section 13.3). 
The duration of the Phase 2 portion of the trial is expected to be approximately 24 months for patient 
enrollment and treatment with 12 months of follow up for a total duration of 36 months. 
5.2 
Dose Escalation and Schedules 
The dose levels, infusion time, and dosing frequency for each cohort of patients during dose 
escalation is summarized in Table 2.  
Table 2 
Dose Level, Infusion Time, and Dosing Frequency 
Dose Level 
Tinostamustine Dose 
Administration 
Schedule 
-1* 
40 mg/m2  
30 min infusion 
D1 and D15  
every 28 days 
1 – Starting 
Dose 
60 mg/m2  
30 min infusion 
D1 and D15  
every 28 days 
2 
80 mg/m2  
30 min infusion 
D1 and D15  
every 28 days 
3 
100 mg/m2  
30 min infusion 
D1 and D15  
every 28 days 
4** 
60 mg/m2 
60 min infusion 
D1 and D15  
every 28 days 
5 
80 mg/m2  
60 min infusion 
D1 and D15  
every 28 days 
6*** 
100 mg/m2  
60 min infusion 
D1 and D15  
every 28 days 
* If a patient experiences a DLT at dose level one (60 mg/m2), tinostamustine will be reduced one dose level to 40 mg/m2. 
** If a patient experiences a DLT at the 60 mg/m2, 60-minute infusion dose-level, tinostamustine will be reduced one dose 
level to 40 mg/m2, 60 minutes infusion time. 
*** Additional dose escalations will be considered until the MAD is reached. 
The SRC and the Sponsor in agreement may increase the number of patients treated at a given pre-
specified or intermediary dose level and dosing schedule to better define the safety profile of ti-
nostamustine and enhance the clinical experience at each participating site. Dose levels may be 
expanded to include additional patients if such patients can be enrolled ≤ 14 days after the third (or 
sixth) patient was first dosed with tinostamustine in a given cohort.  


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During the trial, the SRC and Sponsor may have decided if additional or intermediary dose groups 
were to be opened at dose levels below the MAD to better define the MTD. 
5.3 
Definition of DLT 
Toxicities will be assessed regarding type and severity using the National Cancer Institute (NCI) 
Common Terminology Criteria for Adverse Events (CTCAE) version 4.03, June 2010, with the 
exception that in Phase 2, assessment of QTc prolongations constituting AEs of special interest will 
be based on CTCAE version 5.0. Toxicity data will be collected for all patients throughout their time 
on trial.  
DLTs were defined as:  
• 
Hematologic DLTs 
- Grade 4 neutropenia lasting for 5 days or more; 
- Grade 3 or 4 neutropenia with fever ≥38.5C  
- Grade 3 thrombocytopenia with bleeding which requires platelets transfusion  
- Grade 4 thrombocytopenia  
• 
Non-Hematologic DLTs  
- ≥Grade 3 nausea, vomiting that persists beyond 2 days despite administration of optimal 
supportive treatment.  
- ≥Grade 3 diarrhea that persists ≥2 days despite use of optimal anti-diarrheal treatments 
- Serum creatinine ≥3 x ULN 
- Bilirubin ≥3 x ULN 
- ≥Grade 3 ALT and AST in patients without liver metastases 
- ≥Grade 4 ALT and AST in patients with liver metastases 
- Other non-hematologic toxicities of ≥Grade 3, except for the following: 
▪ 
Adverse events related to the underlying disease  
▪ 
CTCAE Grade 3 fatigue 
▪ 
Alopecia 
▪ 
Isolated, asymptomatic elevations in biochemistry laboratory values lasting 
≤7 days. This includes electrolyte abnormalities that respond to medical intervention 
• 
Any toxicity resulting in a delay of the next dose (Cycle 2 Day 1) ≥14 days 
If at any time during Phase 1 dose escalation a patient experienced a DLT, the trial treatment was to 
be stopped and the toxicity(ies) in question followed until resolution to CTCAE ≤Grade 1 or baseline. 
If the treating physician decided to re-initiate treatment, tinostamustine was to be reduced one dose 
level. Once a dose level reduction occurred, patients were required to remain at this reduced dose.  
For dose escalation and determination of the MTD, only DLTs that occurred during the first cycle of 
treatment were to be considered in decisions regarding dose escalation. DLTs or other clinically 


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significant toxicities that occur after cycle 1 (dose modifying events) were taken into consideration 
when determining the RP2D. 
Patients who experienced a non-laboratory, tinostamustine-related DLT were to be evaluated weekly 
until resolution to ≤Grade 1 or return to baseline and then monthly until return to baseline or 
stabilization of the event, whichever came first. For abnormal laboratory values that qualified as DLTs, 
patients were to be followed twice weekly until values return to ≤Grade 1 or baseline, whichever came 
first. 
For the Phase 2 dose cohort expansion, a patient must meet the treatment criteria described in Sec-
tion 8.6 to receive the next dose of therapy. The Investigator in consultation with the Sponsor may 
decide to reduce a patient’s dose to 60 mg/m2 in case of safety concerns. If toxicity issues are re-
solved, the original dose can be administered at the next cycle. If the patient cannot tolerate the 
reduced dose, then the patient will be withdrawn from the study. 
5.4 
Stopping Rules for Phase 2 
Stopping rules in Phase 2 apply for patients who experience QTc prolongations >500 ms or change 
from baseline >60ms (Grade 3) that are not transient or occur in more than 1 treatment 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 
baseline. 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 Investigator in 
consultation with the Medical Monitor, whether tinostamustine treatment is to continue be postponed 
or stopped. (Refer to Section 8.7, Dose Modification Guidelines and Stopping Rules for Patients Who 
Experience Clinically Significant QTcF Prolongations). 


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6 
SELECTION AND WITHDRAWAL OF PATIENTS 
6.1 
General Inclusion Criteria for Phase 1 and Phase 2 Portions of Trial 
To be eligible for participation in the trial, patients must meet all of the following inclusion criteria: 
• 
Patient willing and able to sign the informed consent. 
• 
Patients age ≥18 years at signing of the informed consent. 
• 
Life expectancy > 3 months. 
• 
Histologically confirmed diagnosis of advanced or metastatic solid tumors, disease should 
have progressed during or following at least 1 previous 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. 
• 
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 of the following criteria:  
(1) Residual neurological symptoms ≤Grade 1. 
(2) No glucocorticoids requirement 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 
(cf Section 7.14.1). 
(3) Follow-up imaging studies show no progression of treated lesions and no new lesions  
• 
Evaluable disease; measurable on imaging as assessed by RECIST version 1.1. 
• 
Eastern Cooperative Oncology Group (ECOG) performance status ≤2 (Section 13.1). 
• 
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 mg/dL unless elevated due to known Gilbert’s syndrome. 
• 
Creatinine ≤1.5 ULN. 
• 
Serum potassium and magnesium at least at the lowest limit of normal (LLN), before every 
IMP administration. If it is below the LLN, supplementation is permissible.  
• 
Female study participants of child-bearing potential and their partners, and male study 
participants who intend to be sexually active with a woman of child-bearing potential, 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 IMP administration. For female study 
participants of child-bearing potential this 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 


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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 
males are considered fertile; therefore, 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 Phase 1 and Phase 2 Portions of the Trial 
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): 
http://crediblemeds.org/new-drug-list. 
• 
Patients who are being treated with valproic acid for any indication (epilepsy, mood disorder).  
• 
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 breastfeeding women. 
• 
New York Heart Association (NYHA) stage III/IV congestive heart failure (Section 13.2). 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. 
• 
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. 
• 
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 IMP administration are allowed. 
6.3 
Phase 2 Evaluation of Toxicity and Response Rate in Selected Solid Tumours; 


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Specific Eligibility Criteria 
Phase 2 patients must meet the cohort-specific inclusion/exclusion criteria in addition to the general 
inclusion/exclusion criteria for Phase 1 and Phase 2 trial listed above.  
Confirmation of the availability of a tumor sample from the primary or recurrent cancer must be pro-
vided (archival samples are acceptable). 
6.3.1 Cohort 1 Patient Population: Relapsed/Refractory Small-cell Lung Cancer (SCLC) 
1. Histologically or cytologically confirmed limited or extensive disease stage of SCLC.  
2. Must have received at least 1 line of prior combination chemotherapy or biological 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.  
3. At least 28 days should have elapsed since prior treatment as long as the patient has 
recovered from any related toxicities to ≤ Grade 1 (or ≤ Grade 2 for any symptomatic 
neuropathy or endocrinopathies). 
4. Prior radiotherapy is acceptable provided the patient has recovered from any radiotherapy 
related acute toxicities. 
5. The disease should be progressing during or relapsing after the previous treatment. 
6. Presence of measurable disease as defined by RECIST version 1.1. Tumor lesions situ-
ated in a previously irradiated area, or in an area subjected to other loco-regional ther-
apy, are usually not considered measurable unless there has been demonstrated pro-
gression in the lesion. 
6.3.2 Cohort 2 Patient Population: Relapsed/Refractory Soft Tissue Sarcoma 
1. Histologically confirmed diagnosis of advanced, unresectable, or metastatic STS not 
amenable to curative treatment with surgery or radiotherapy excluding: neuroblastoma, GIST, 
embryonal rhabdomyosarcoma, Kaposi sarcoma, chondrosarcoma, osteosarcoma or Ewing’s 
sarcoma.  
2. Must have received at least 1 prior line chemotherapy or biological therapy regimen 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. At least 28 days should have 
elapsed since prior chemotherapy, as long as the patient recovered from any related toxicities 
to ≤ Grade 1 (or ≤Grade 2 for any symptomatic neuropathy or endocrinopathies). 
3. The disease should be progressing during or relapsing after the previous treatment. 
4. Presence of measurable disease as defined by RECIST version 1.1. Tumor lesions situated 
in a previously irradiated area, or in an area subjected to other loco-regional therapy, are 
usually not considered measurable unless there has been demonstrated progression in the 
lesion. 
6.3.3 Cohort 3 Patient Population: Relapsed/Refractory Triple Negative Breast Cancer 
RECRUITMENT INTO THIS COHORT HAS NOW BEEN HALTED 
 


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6.3.4 Cohort 4 Patient Population: Relapsed/Refractory Ovarian Cancer 
1. Histologically or cytologically confirmed advanced ovarian cancer:  epithelial ovarian can-
cer, including primary peritoneal cancer or fallopian tube cancer (excluding borderline 
ovarian cancer, MMMT) of high grade serous histology, or high grade endometrioid can-
cer, that is resistant or refractory to platinum 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. Clear cell carcinomas are excluded. 
Patients with primary platinum refractory disease (failure to respond to initial platinum 
treatment or relapse within 4 weeks) and patients with primary platinum resistant disease 
(progression within 6 months of completing first line platinum-based therapy) are ex-
cluded from the study.  
2. At least 28 days should have elapsed since prior chemotherapy as long as the patient 
recovered from acute toxicity of previous therapies to ≤ Grade 1 (or ≤ Grade 2 for any 
symptomatic neuropathy or endocrinopathies). 
3. The disease should be progressing during or relapsing after the previous treatment. 
4. Presence of measurable disease as defined by RECIST version 1.1. Tumor lesions 
situated in a previously irradiated area, or in an area subjected to other loco-regional 
therapy, are usually not considered measurable unless there has been demonstrated 
progression in the lesion. 
6.3.5 Cohort 5 Patient Population: Relapsed/Refractory Endometrial Cancer 
RECRUITMENT INTO THIS COHORT HAS NOW BEEN HALTED. 
 
6.3.6 Withdrawal of Patient from Trial Treatment 
Patients can withdraw from the trial at any time without giving 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). 
Patients who are withdrawn prior to receiving  


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6.3.7 Early Trial Termination 
The Sponsor has the right to close a trial site, the trial or an expansion cohort at any time. Whenever 
possible, mutual consultation between the Sponsor and the Investigators should occur before a final 
decision. Events that may trigger early trial termination include, but are not limited to: 
• 
Initial dose level exceeds the MTD or other toxicity finding (Stage 1 only). 
• 
Change in development plans for the investigational product. 
• 
Slow recruitment. 
If based on continuous safety monitoring across the development program, the benefit-risk ratio for 
the use of the investigational product would become negative, the Sponsor will decide about 
discontinuation of the development program in parts or in its entirety. 
The Sponsor will notify the accredited Institutional Review Board (IRB)/Independent Ethics 
Committee (IEC) as well as the applicable competent authorities without undue delay of a temporary 
halt and early termination including the reason for such an action. The investigator will ensure that all 
patients are kept informed. 


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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 i.e., scans performed no more than 35 
days prior to baseline will be accepted). 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. Separate consent must be 
provided for collection of samples for determination of gene expression. 
7.3 
Inclusion/Exclusion Criteria and Patient Treatment Assignment 
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). In the first phase of the trial (Phase 1), the dose received for each eligible patient was 
dependent on the requirements of the dose escalation scheme at the time the patient was enrolled. 
In the second phase of the trial (Phase 2), all patients will be treated with the tinostamustine at 80 
mg/m2 administered over 1 hour on Day 1 and 15 of each 4-week treatment cycle. 
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 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 


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• 
Musculoskeletal 
• 
Abdomen 
• 
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 medicinal product discontinuation (at 
any time or Day 28 of the last treatment cycle) using the criteria provided in Section 13.1. 
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 


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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. 
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 tinostamustine infusion on C1D1 and 
15 minutes prior to the start of tinostamustine infusion in C1D15 and will continue through 24 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 pre-dose, and 15, 30, 45, 60, 75, 90, 120, 180, 360 minutes and 
24 hours from the start of tinostamustine infusion. 
• 
C1D15: prior to the start of infusion, and 15, 30, 45, 60, 75, 90, 120, 180, 360 minutes and 24 
hours from the start of 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 (+/- 5min) and triplicate ECGs at 60 minutes (+/- 5 min) from the start of tinostamustine 
administration on D1 and D15 of each treatment cycle and a single ECG on D28 (±2 days) of last 
treatment cycle, at the end of study visit. 
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) 
Patient participation in the gene expression analysis is not mandatory for enrollment into the trial. 
Information on the purpose of genetic research in the gene-expression sub-trial is provided, either in 
the main ICF or a separate ICF, based on applicable regulatory requirements, 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. 
If the patient agrees to participate in the gene expression analysis, a fresh or archival tissue sample 
will be collected during Screening. Formalin fixed paraffin embedded (FFPE) biopsy samples will be 
used. The Affymetrix chip technology for analyzing total ribonucleic acid (RNA) will be used. For for-
malin fixed paraffin embedded samples, RecoverAll method from Ambion® for isolating total RNA will 
be used. The isolated RNA is total RNA and will contain both messenger RNA (mRNA) and micro 


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RNA (miRNA). The expression profile will be analyzed for correlation with response or resistance to 
therapy. Details of sample preparation and shipping are described in the Laboratory Manual. 
Samples will be stored in accordance with the IRB/IEC approved ICF and applicable laws. Several 
steps will be taken to keep the patient’s identity and the genetic test result confidential throughout the 
trial (e.g., double coding of the samples; restricted access to the samples and testing results). 
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 cycle 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 magne-
sium 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 in-
clude white blood cell count (WBC) plus differential, red blood cell count (RBC), hemoglobin, hema-
tocrit, platelets and an ANC determination. 
Blood samples for serum chemistry determinations will be collected at Screening, Day 1 and 15 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, 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 ti-
nostamustine 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 product 
discontinuation (at any time or Day 28 of the last treatment cycle). Urine microscopic examination will 
be performed if there are any positive findings upon dipstick assessment. 
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 child-bearing potential at 
Screening on day -1 of each treatment cycle (prior to tinostamustine administration), and at the time 
of discontinuation of tinostamustine administration. 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 9.6.5 for details 


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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 of child-bearing potential and their partners, and male study 
participants who intend to be sexually active with a woman of child-bearing potential, must be willing 
to use at least TWO highly effective forms of contraception from the time of study enrollment and 
continue throughout tinostamustine administration. For female study participants of child-bearing 
potential this must continue using contraception for at least six months after the last administration of 
the IMP. 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 males are considered fertile; therefore, 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 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 to point of 
discontinuation of tinostamustine (D28 of last treatment cycle). AEs, including serious adverse events 
(SAEs), will be captured in the eCRFs from the time of ICF signature through to point of 
discontinuation of tinostamustine. 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 Visit should be recorded and followed 
to resolution. 
7.13 Infusion Site and Allergic Reaction Assessment 
All injection site reactions will be considered AEs. 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.  
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 at 
the end of infusion.  Additional evaluation must be performed at 1-hour (± 15 minutes) post dose 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. 
 


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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 trial. 
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. 
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 during the administration of tinostamustine. Given 
the short half-life of tinostamustine, ondansetron can be used, if needed, for the prophylaxis of 
delayed nausea and vomiting. A minimal interval of 24 hours should be respected between the last 
intake of ondansetron and the next tinostamustine infusion. 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. 


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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 13.3). 
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 until 1 year after the last patient’s first treatment (C1D1). 
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, M2 and M8 in plasma will be assessed by analyzing parameters such as 
Cmax, AUC, and time to maximum concentration (Tmax), and elimination half-life at each drug admin-
istration of Cycle 1 in each patient during the dose escalation and in Phase 2 a minimum of 50 patients 
will participate in the PK analysis. The blood sampling schedule for the PK assessment is conducted 
in Cycle 1 only on Day 1 and 15 during tinostamustine administration. Samples are taken as follows: 
up to 0.5 hours prior to dose administration and at 15, 30 and 45 minutes, 1 hour, 75 and 90 minutes, 
and 2, 3, 6, and 24 hours 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 
From > 0 up to ≤ 90minutes from the 
start of tinostamustine infusion 
except for 60min. 
  
± 5 minutes 
At 60 minutes from the start of ti-
nostamustine infusion 
 
From > 2 hours to 6 hours from the start 
of tinostamustine infusion  
- 5 minutes but as close to the calculated 
end of the IMP infusion as possible and be-
fore the end of IMP infusion 
 
± 10 minutes 


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At 24 hours from the start of ti-
nostamustine infusion  
± 2 hours 
 
Timings may need to be adjusted to allow for the infusion technique (priming of the line). Any change 
must be documented (following discussion with the Sponsor) for each patient by the site. 
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 Medicinal Product Description 
Other Names: tinostamustine is the International Nonproprietary Name (INN) of the Investigational 
Medicinal Product.  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 
tumors. 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 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 the infusion duration of 1 hour  
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 
4-week 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 (relevant for USA) 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 Aluminum 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 and dosing cohort assignment for eligible patients will be completed according 
to a process defined by the Sponsor. 


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8.5 
Investigational Medicinal Product Administration 
Following Screening, all patients who were eligible to participate in the first phase of the trial (Phase 
1) were assigned to a dosing cohort and receive a single dose of tinostamustine at the beginning of 
each treatment cycle. The investigational product (reconstituted and diluted solution as described in 
Section 8.2) was administered by i.v. infusion through a peripheral vein or port over a 30-minute 
infusion time for the first 3 dose levels (See Table 2). Starting at the fourth dosing cohort (See Table 
2), the investigational product was administered by i.v. infusion through a peripheral vein or port over 
a 60-minute infusion time. For Phase 2, the dose is 80 mg/m2 administered over 1 hour (± 5 
minutes) on Day 1 and 15 of each 4-week treatment cycle. 
The timing of the IMP infusion is affected by whether the iv line is pre-filled with saline or IMP: 
• 
If the iv line is pre-filled with saline, the start of actual IMP administration will be delayed until 
the saline is flushed through, and the end of the IMP infusion will be delayed by the same 
period of time as the last of the IMP is flushed through.  
• 
If the line is pre-filled with IMP, then the start of the IMP administration will occur at the start 
of the infusion, and the IMP infusion will finish after 60 minutes when the IMP is flushed from 
the line.  
Instructions for preparation of each dose of investigational product during each phase of the trial are 
provided in the Pharmacy Manual. The PI or qualified site personnel will administer tinostamustine 
by i.v. infusion. 
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 tinostamustine, the following criteria must be met:  
• 
No active infection  
• 
ANC ≥1,000/ µL  
• 
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 cycle.   
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, 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 


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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 
stopped. Remove the infusion bag to ensure that the infusion is stopped. The patient should stay in 
the unit until the QTcF has decreased to baseline. 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 administration of tinostamustine can continue or whether 
administration of tinostamustine is to be postponed.  
As a general rule:  
• 
Administration of ≥50% of the planned dose will be considered as a full dose. 
• 
If less than 50% of the planned dose was administered, the remainder to a full planned 
dose can be administered on the following day.  
- If the centrally reviewed QTcF value confirms the local finding and is >500 ms or in-
creased >60 ms from baseline, subsequent doses 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 for subsequent 
doses  
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 
 


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8.8 
Investigational Medicinal 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. 
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 was allowed in Cycle 1 only beyond Day 7 in Phase 1 
only. There were no restrictions for subsequent cycles. In Phase 2 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 
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 
chemotherapeutic agents were administered concomitantly with allopurinol and other 
medications known to cause these syndromes. Patients with skin reactions must be closely 


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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.  
• 
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.occurred. Assessment of infusion site reactions must be performed 
on each treatment day at pre-dose, 1 hr (±15 minutes). The patient will be observed at 1 hr (± 
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 an AE. 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 Adverse Event (AE) 
An AE is any untoward medical occurrence associated with the use of a drugs in humans, whether 
or not considered drug related. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding, for example), 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 
worsening 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 tinostamustine. 
• 
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.AE. 
9.2 
Recording Adverse Events 
All AEs must be reported from the time of ICF signature through the point of tinostamustine discon-
tinuation. Only AEs ongoing at time of Tinostamustine Discontinuation Visit are required to be fol-
lowed to resolution or stabilization of event and then final resolution date is recorded in the AE eCRF. 


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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/pro-
tocolDevelopment/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 lead-
ing 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 fol-
lowing 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. re-
sidual hemiparesis subsequent to stroke). 
 
Fatal 
- 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 


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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 
underlying illness, other drugs, or procedures. If applicable, the AE follows a clinically con-
sistent 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 collection 
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. 
· 
All AEs must be followed up by the Investigator until: 
o 
the AE is resolved or resolved with sequelae and all other queries related to the AE 
have been clarified, or  
o 
the end of the period of observation (= last study visit), or 
o 
the Investigator considers it medically justifiable to stop further follow-up 


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· 
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. 
o 
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.  
o 
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 medi-
cal judgment, they may jeopardize the patient and may require medical or surgical interven-
tion to prevent one of the SAE criteria 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 


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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 
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 


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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 contact 
of the Sponsor is Mundipharma Drug Safety & PV.  
Mundipharma Drug Safety 
and PV 
Tel: +44 (0) 1223 424444 (Not 24-hour cov-
erage; for 24-hour details please see the In-
vestigator 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 designated vendor will report to the regulatory authorities as per national regulations 
of the countries where the ongoing tinostamustine trials are conducted and will provide the case 
documentation to the CROs for reporting to the applicable IRBs/IECs. 
Investigators will be informed as per national requirements. 
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 4.03, 
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. 
9.6.4 
Reporting of Important Medical Events of Special Interest 
Important medical events (IME) of a clinically significant severity grade (≥Grade 3) may also qualify 
as SAEs. To establish consistency across trials with tinostamustine, the IME list published by the 
European Medicines Agency and regularly updated (current version April 2019) serves as a 
reference. 
9.6.5 
Reporting Pregnancy 
If a female patient or the female partner of a male patient becomes pregnant during the course of the 
trial and within 90 days from the last dose 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 


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(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. 
9.6.6 
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. 
9.6.7 
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 STATISTICAL ANALYSES 
10.1 Trial Populations 
10.1.1 Full Analysis Population 
All patients who received at least 1 dose of trial treatment and had at least 1 post-baseline response 
evaluation will be included in the Full Analysis (FA) Population. Efficacy analyses will be performed 
on data from all patients in the FA Population. 
10.1.2 Safety Population 
All patients who received at least 1 dose of trial treatment will be included in the Safety Population. 
Safety analyses will be performed on data from all patients in the Safety Population. 
10.1.3 Pharmacokinetic Population 
All enrolled patients in the Safety Population with at least 1 quantifiable pre-dose and 1 quantifiable 
post-dose PK plasma concentration in Cycle 1 will be included in the PK Population. PK analyses will 
be performed using the PK population. 
10.2 Unit of Analysis 
Not applicable. 
10.2.1 Sample Size and Power Considerations 
A formal sample size determination and power calculation were not performed. Based on experience 
from previously published similar trials, a total number of 21 (minimum) to 42 (maximum) patients in 
the dose escalation stage of the trial and 56 to 160 patients (10 or 29 evaluable patients in each of 
the 5 disease cohorts) in the expansion stage of the trial are considered to be sufficient for meeting 
the objectives of this trial, following Simon's optimal 2-stage design methodology13. Assuming the 
proportion of treatment successes that do not warrant further investigation (π0) is 0.10, the proportion 
of treatment successes that warrant further investigation (π1) is 0.30, an 80% power and a 5% Type 
I error rate. The one-sided hypotheses to be tested are: 
H0: π ≤π0 
H1: π ≥π1 
where π is the actual probability of success. 
In stage 1, 10 patients will be treated in each cohort; potential efficacy and the decision to expand 
into stage 2 or not may be taken prior to the 10th patient completing the study. During the assessment 
of stage 1, enrollment into the expanded cohort (stage 2) will continue. However, it is anticipated that 
new patients will enroll infrequently due to the expected low recruitment rate. From stage 1, if there 
are no successes or only 1 success in the 10 stage 1 patients, the complete cohort will be stopped 
for lack of efficacy. If there are 2 or more successes in stage 1 an additional 19 patients may be 
treated for a total of 29 in a cohort. If it becomes clear that there will be 5 or fewer successes in a 
cohort of 29 patients, then the cohort will be stopped for lack of efficacy. 
The Sponsor may suspend or discontinue enrollment to an expansion cohort at any time due to slow 
patient accrual rates or other reasonable cause. 


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10.3 Data Analysis 
A detailed SAP will be finalized prior to any statistical report and database lock. 
In general, summaries for continuous and ordinal variables will include the number of observations 
(n), arithmetic mean, standard deviation, median, minimum, and maximum. Summaries for discrete 
variables will include frequency counts and percentages. All statistical tests, if any, will be 2-sided 
with a significance level of 0.10 unless otherwise specified. Additionally, 90% confidence intervals will 
be reported. 
10.3.1 Demographics and Baseline Characteristics 
Demographic information will include age, gender, ethnicity and race11,12 Demographics and baseline 
characteristics will be summarized descriptively. Height and weight, which will be recorded in 
conjunction with vital sign determinations performed at the Screening visit, will be reported with the 
demographic information listed above. Patient demographics: gender, ethnicity, race, and age 
category will be presented using discrete summary statistics. Age, height, and weight will be 
presented using continuous summary statistics.  
10.3.2 Safety Analysis 
For Phase 1, patient safety data were summarized under the dose cohort in which they were enrolled.  
For Phase 2, patient safety data will be summarized by disease cohort as well as overall disease 
cohorts. (i.e., relapsed/refractory SCLC, relapsed/refractory STS, relapsed/refractory TNBC, 
relapsed/refractory ovarian cancer, relapsed/refractory endometrial cancer).  
Additionally, as appropriate, Phase 1 and Phase 2 safety measures will be summarized combining 
Phase 1 measures obtained under RP2D and schedule with Phase 2, accounting for disease cohort.  
The safety analysis will summarize AEs for all treated patients using discrete summaries at the 
patient- and event-level by system organ class and preferred term. An AE will be defined as occurring 
on or after the day that treatment is initiated. AEs, AEs leading to death, SAEs, and AEs resulting in 
trial discontinuation will be summarized similarly. AEs will also be summarized by NCI-CTCAE Grade. 
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA®) for purposes of 
summarization. All AEs occurring during the trial will be included in by-patient data listings and 
tabulated. 
Safety analyses are described in detail in the SAP. 
10.3.3 Efficacy Analyses 
Efficacy variables of Phase 2 patients will include ORR (i.e. CR or PR of any duration), plus SD of at 
least 4 months, duration of response, PFS, and OS. CR, PR, SD are defined by RECIST criteria 
(Section 13.3).  
Response rates will be summarized using discrete statistics by disease cohort as well as all disease 
cohorts combined. Post-treatment RECIST assessments are used to determine best overall re-
sponse. PFS is defined as the number of days between the date of the first dose of treatment and the 
first date of disease progression or death. Overall survival is defined as the number days between 
the date of the first dose of treatment and the date of death. PFS and OS will be estimated using 
Kaplan-Meier method. The estimated survival probabilities will be presented via Kaplan-Meier curves 


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and median survival will be reported. The survival analysis will be performed by disease cohort as 
well as all disease cohorts combined. Handling of censoring will be discussed in full in the SAP. 
10.3.4 Pharmacokinetic Analysis 
PK analysis will be performed using the PK population. PK parameters at all doses will include Cmax, 
Tmax, half-life, AUC0-12, AUC0-t, clearance, volume of distribution, and elimination rate constant. Other 
PK parameters may be calculated, as appropriate. The initial calculation of PK parameters will be 
performed using non-compartmental analysis. Model-based parameter estimation may be performed 
following examination of the data. Plasma concentrations and PK parameters will be summarized 
using continuous statistics by dose and infusion time. Figures will be created to display mean and 
individual patient tinostamustine and its 2 metabolites concentration-time curves in plasma on a linear 
scale as well as on a semi-log scale. Plasma concentrations will be processed throughout the PK 
software for PK data generation. The PK parameters were calculated by non-compartmental analysis 
(NCA), using Phoenix® WinNonlin® (Version 8.1 – Certara – Princeton – USA). Handling of 
concentrations below limit of quantitation (BLOQ) will be detailed in a separate analysis plan.  
For Phase 1, patient data will be summarized under the dose level and schedule they received for 
the Cycle being summarized.  
For Phase 2, patient data will be summarized by disease cohort (if sample size permits) as well as 
overall disease cohorts. 
Additionally, as appropriate, Phase 1 and Phase 2 measures will be summarized combining Phase 1 
measures obtained under RP2D and schedule with Phase 2.  
Additional details regarding PK analyses are provided in a separate PK SAP. 
10.3.5 Deviations from the Statistical Plan 
Any deviation(s) from the final SAP in the final analysis will be described and justification given in the 
final report. 


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11 TRIAL ADMINISTRATION 
11.1 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 include 
all pertinent observations on the trial patients. Source data should be attributable, legible, 
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 add ICH E6 R2 4.9.2 and 4.9.3. 
11.2 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.  
11.3 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.  
11.4 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, Investigator's 
Brochure/Summary of Product Characteristics (SmPC), regulatory agency registration documents, 
ICFs, and IEC correspondence, according to ICH E6 (R2) requirements. 
The site should plan on retaining trial documents for approximately 15 years after completion of the 
trial. This will include copies of the completed eCRF/EDC. The investigator should have control of 
and continuous access to the eCRF data. 
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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11.5 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.  
 
11.6 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. 
11.7 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 
made. At this meeting, all personnel expected to be involved in the conduct of the trial will undergo 


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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 11.4.  
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. 
11.8 General Informed Consent and Sub-trial 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.  
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.  
 


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11.9 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. 
11.10 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. 
11.11 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 
publicly 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. 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 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 


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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. 
11.12 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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12 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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13 APPENDICES 
13.1 
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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13.2 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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13.3 Appendix C: New response evaluation criteria in solid tumours: Revised RECIST 
guideline (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 measurable, a lymph node must 
be ≥15 mm in short axis when assessed by CT scan (CT scan slice thickness recommended to be no 
greater than 5 mm). At Baseline and 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. 
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). 


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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 rec-
orded 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 


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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 
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 


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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 
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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13.4 
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